TALPHERA, INC. The following discussion and analysis should be read in conjunction with the unaudited financial statements and notes thereto included in Part I, Item 1 of this Quarterly Report on Form 10-Q, or Form 10-Q, and with the audited Consolidated Financial Statements and related notes thereto included as part of our Annual Report on Form 10-K for the year endedDecember 31, 2020 , or Annual Report.
About
We are a specialty pharmaceutical company focused on the development and commercialization of innovative therapies for use in medically supervised settings.
Our Portfolio The following table summarizes our portfolio of products and product candidates. Product/Product Candidate Description Target Use Status DSUVIA® Sufentanil Moderate-to-severe Received
sublingual tablet, acute pain in a Administration, or FDA, approval
30 mcg medically in November 2018; commercial
supervised launch began first quarter of
setting, 2019.
administered by a
healthcare
professional
DZUVEO® Sufentanil Moderate-to-severe Granted European Commission, or
sublingual tablet, acute pain in a EC, marketing approval in June
30 mcg medically 2018. Sunset date extended to
monitored setting, December 31, 2022 by EC. To be
administered by a commercialized in Europe by
healthcare Laboratoire Aguettant.
professional
Zalviso® Sufentanil Moderate-to-severe In the U.S., positive results
sublingual tablet acute pain in the from Phase 3 trial, IAP312,
system, 15 mcg hospital setting, announced in August 2017.
administered by Currently evaluating the timing
the patient as of the resubmission of the New
needed Drug Application, or NDA, which
is in part dependent on the
finalization of the FDA's new
opioid approval guidelines and
process.
Approved in the European Union,
where it was marketed
commercially by Grünenthal
through May 12, 2021. We intend
to find a replacement license
agreement for Zalviso in Europe.
Ephedrine Ephedrine pre-filled Clinically Product candidate licensed from
syringe, containing important Laboratoire Aguettant, or
10 ml of a solution hypotension Aguettant, pending submission
of 3 mg/ml ephedrine occurring in the for approval to FDA under New
hydrochloride for setting of Drug Application, or NDA.
injection anesthesia Approved in the European Union,
marketed by Aguettant.
Phenylephrine Phenylephrine Clinically Product candidate licensed from
prefilled syringe important Aguettant, pending submission
containing 10 ml of hypotension for approval to FDA under New
a solution of 50 resulting Drug Application, or NDA.
mcg/ml phenylephrine primarily from Approved in
the
hydrochloride for vasodilation in marketed by Aguettant.
injection the setting of
anesthesia.
ARX-02 Higher Strength Cancer Phase 2clinical trial and End
Sufentanil breakthrough pain of Phase 2 meeting completed.
Sublingual Tablet in opioid-tolerant
Investigational New Drug, or
patients IND, application was
inactivated.
Future development contingent
upon identification of corporate
partnership resources.
ARX-03 Combination Mild sedation and Phase 2 clinical trial and End
Sufentanil/Triazolam pain relief during of Phase 2 meeting completed.
Sublingual Tablet painful procedures IND application was inactivated.
in a physician's Future development contingent
office upon identification of corporate
partnership resources.
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Out-License Agreement (DZUVEO)
OnJuly 14, 2021 , we entered into a License and Commercialization Agreement, or the DZUVEO Agreement, with Aguettant pursuant to which Aguettant obtained the exclusive right to develop and commercialize DZUVEO in theEuropean Union ,Norway ,Iceland ,Liechtenstein ,Andorra ,Vatican City ,Monaco ,Switzerland and theUnited Kingdom , or the DZUVEO Territory, for the management of acute moderate to severe pain in adults in medically monitored settings. We will supply Aguettant with primary packaged product and Aguettant will then complete secondary packaging of the finished product. We are entitled to receive up to €47.0 million in a combination of up-front and sales-based milestone payments. Refer to Note 12 "Subsequent Events" in the accompanying notes to the Condensed Consolidated Financial Statements for additional information. In-License Agreement OnJuly 14, 2021 , we entered into a License and Commercialization Agreement, or the PFS Agreement, with Aguettant pursuant to which we obtained the exclusive right to develop and, subject to FDA approval, commercialize inthe United States (i) an ephedrine pre-filled syringe containing 10 ml of a solution of 3 mg/ml ephedrine hydrochloride for injection, and (ii) a phenylephrine prefilled syringe containing 10 ml of a solution of 50 mcg/ml phenylephrine hydrochloride for injection. Aguettant will supply the Company with the products for use in commercialization, if they are approved in theU.S. Aguettant is entitled to receive up to$24 million in sales-based milestone payments. Refer to Note 12 "Subsequent Events" in the accompanying notes to the Condensed Consolidated Financial Statements for additional information. General Trends and Outlook COVID-19-related Government-mandated orders and related safety policies on account of the COVID-19 pandemic continue to prevent us from operating our business in the normal course. Beginning in early 2020, state and local officials issued orders in response to the pandemic which included, among other things, requirements for residents to shelter in place and for non-essential businesses to cease activities at facilities within certain cities, counties, and states. State and local officials have taken different approaches to these orders, and some have not issued any such orders. Once issued, the orders have been relaxed and then tightened, depending on the rate of COVID-19 cases. As a result of these orders, we implemented a work from home policy for ourCalifornia -based employees and we continue to adhere to the various and diverse orders issued by government officials in the jurisdictions in which we operate. In addition, some hospitals, ambulatory surgery centers and other healthcare facilities have barred visitors that are not caregivers or mission-critical and otherwise restricted access to such facilities. As a result, the educational and promotional efforts of our commercial and medical affairs personnel have been substantially reduced, and in some cases, stopped. Cancellation or delays of formulary committee meetings and delays of elective surgeries have also affected the pace of formulary approvals and, consequently, the rate of adoption and use of DSUVIA. We expect our near-term sales volumes to continue to be adversely impacted as long as access to healthcare facilities by our commercial and medical affairs personnel continues to be limited, especially in light of the rise in COVID-19 cases associated with the Delta variant. We will continue to evaluate the impact on our revenues and related metrics and operating expenses during this period and assess the need to adjust our expenses and expectations. 22 -------------------------------------------------------------------------------- As a result of international travel restrictions, the timing for testing and acceptance of our DSUVIA fully automated packaging line, and subsequent FDA approval, has been delayed. Based on our best estimate, now that the line has been installed, we expect FDA approval in 2022. We will continue to engage with various elements of our supply chain and distribution channel, including our customers, contract manufacturers, and logistics and transportation providers, to meet demand for products and to remain informed of any challenges within our supply chain. We continue to monitor demand and intend to adapt our plans as needed to continue to drive our business and meet our obligations during the evolving COVID-19 pandemic. However, if the COVID-19 pandemic continues and persists for an extended period of time, we may face disruptions to our supply chain and operations, and associated delays in the manufacturing and supply of our products. Such supply disruptions may adversely impact our ability to generate sales of and revenues from our products and our business, financial condition, results of operations and growth prospects could be adversely affected. As the global pandemic of COVID-19 continues to rapidly evolve, it could result in a significant long-term disruption of global financial markets, reducing our ability to access capital, which could in the future negatively affect our liquidity. The extent to which the COVID-19 pandemic impacts our business, our ability to generate sales of and revenues from our approved products, and our future clinical development and regulatory efforts will depend on future developments that are highly uncertain and cannot be predicted with confidence, such as the ultimate geographic spread of the disease, the duration of the outbreak, travel restrictions, quarantines and social distancing requirements inthe United States and other countries, business closures or business disruptions and the effectiveness of actions taken inthe United States and other countries to contain and treat the virus. Financial Overview We have incurred net losses and generated negative cash flows from operations since inception and expect to incur losses in the future as we continue commercialization activities to support theU.S. launch of DSUVIA, support European sales of DZUVEO by Aguettant, and of Zalviso by any replacement partner, and fund any future research and development activities needed to support the FDA regulatory review of our product candidates. As a result, we expect to continue to incur operating losses and negative cash flows until such time as DSUVIA has gained market acceptance and generated significant revenues. We will incur capital expenditures related to our fully automated packaging line for DSUVIA, which has now been installed, and for which we expect FDA approval in 2022. We anticipate that the fully automated line for DSUVIA will contribute to a significant decrease in costs of goods sold in 2022 and beyond. Our net loss for the three and six months endedJune 30, 2021 was$9.9 million and$18.8 million , respectively, compared to net losses of$6.6 million and$22.5 million for the three and six months endedJune 30, 2020 , respectively. As ofJune 30, 2021 , we had an accumulated deficit of$457.3 million . As ofJune 30, 2021 , we had cash, cash equivalents and short-term investments totaling$55.3 million compared to$42.9 million as ofDecember 31, 2020 . Critical Accounting Estimates The accompanying discussion and analysis of our financial condition and results of operations are based upon our unaudited Condensed Consolidated Financial Statements and the related disclosures, which have been prepared in accordance with accounting principles generally accepted inthe United States . The preparation of these financial statements requires us to make estimates, assumptions and judgments that affect the reported amounts in our financial statements and accompanying notes. We base our estimates on historical experience and on various other assumptions that we believe to be reasonable under the circumstances, the results of which form the basis for making judgments about the carrying values of assets and liabilities that are not readily apparent from other sources. Actual results may differ from these estimates under different assumptions or conditions. To the extent that there are material differences between these estimates and actual results, our future financial statement presentation, financial condition, results of operations and cash flows will be affected. Our critical accounting policies and estimates are detailed in our Annual Report. There have been no significant changes to our critical accounting policies or significant judgements and estimates for the three and six months endedJune 30, 2021 , from those previously disclosed in our Annual Report, except to reflect that we apply the graded-vesting attribution method to awards with market conditions that include graded-vesting features. Additionally, we use the Monte Carlo Simulation model to evaluate the derived service period and fair value of awards with market conditions, including assumptions of historical volatility and risk-free interest rate commensurate with the vesting term. 23 --------------------------------------------------------------------------------
Results of Operations Our results of operations have fluctuated from period to period and may continue to fluctuate in the future, based upon the progress of our commercial launch of DSUVIA, our research and development efforts, variations in the level of expenditures related to commercial launch, development efforts and debt service obligations during any given period, and the uncertainty as to the extent and magnitude of the impact from the COVID-19 pandemic. Results of operations for any period may be unrelated to results of operations for any other period. In addition, historical results should not be viewed as indicative of future operating results. In particular, to the extent our commercial and medical affairs personnel continue to be subject to varying levels of restriction on accessing hospitals and ambulatory surgical centers due to COVID-19, and to the extent government authorities and certain healthcare providers are continuing to limit elective surgeries, we expect our sales volume to be adversely affected.
Three and Six Months Ended
Revenue Product Sales Revenue
Product sales revenue consists of sales of DSUVIA in the
Product sales revenue by product for the three and six months ended
Three Months Ended June 30, Six Months Ended June 30,
$ Change % Change $ Change % Change
2021 vs. 2021 vs. 2021 vs. 2021 vs.
2021 2020 2020 2020 2021 2020 2020 2020
(In thousands, except percentages)
DSUVIA $ 392 $ 2 $ 390 19,500 % $ 573 $ 157 $ 416 265 %
Zalviso - 301 (301 ) (100 )% 270 420 (150 ) (36 )%
Total product sales
revenue $ 392 $ 303 $ 89 29 % $ 843 $ 577 $ 266 46 %
The increase in product sales revenue for the three and six months ended June
30, 2021 , as compared to the three and six months ended June 30, 2020 , was
primarily the result of increased sales of DSUVIA. Zalviso was sold by
Grünenthal GmbH , or Grünenthal, under the Collaboration and License Agreement
and the Manufacture and Supply Agreement, or the Grünenthal Agreements in the
European Union through May 12, 2021 .
Contract and Other Collaboration Revenue
Contract and other collaboration revenue included revenue under the Grünenthal Agreements related to research and development services, non-cash royalty revenue related to the sale of the majority of our royalty rights and certain commercial sales milestones under the Grünenthal Agreements toSWK Funding, LLC , or SWK, (assignee of PDL BioPharma, Inc., or PDL), in a transaction referred to as the Royalty Monetization, and royalty revenue for sales of Zalviso inEurope .
Contract and other collaboration revenue for the three and six months ended
Three Months Ended June 30, Six Months Ended June 30,
$ Change % Change $ Change % Change
2021 vs. 2021 vs. 2021 vs. 2021 vs.
2021 2020 2020 2020 2021 2020 2020 2020
(In thousands, except percentages)
Non-cash royalty
revenue related to
Royalty
Monetization (See
Note 7) $ 38 $ 37 $ 1 3 % $ 83 $ 121 $ (38 ) (31 )%
Royalty revenue 13 12 1 8 % 28 40 (12 ) (30 )%
Other revenue - 2,572 (2,572 ) (100 )% - 2,572 (2,572 ) (100 )%
Total contract and
other collaboration
revenue $ 51 $ 2,621 $ (2,570 ) (98 )% $ 111 $ 2,733 $ (2,622 ) (96 )%
We estimate and recognize royalty revenue and non-cash royalty revenue on a
quarterly basis. Adjustments to estimated revenue are recognized in the
subsequent quarter based on actual revenue earned per the royalty reports
received from Grünenthal. As mentioned above, Grünenthal has terminated the
Grünenthal Agreements, accordingly the rights to market and sell Zalviso in
Europe reverted back to us on May 12, 2021 . In May 2020 , upon notification of
early termination by Grünenthal, we recognized approximately $2.6 million of
deferred revenue for the discount on Zalviso manufacturing services which were
no longer a performance obligation.
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--------------------------------------------------------------------------------Cost of Goods Sold
We commenced commercial sales of DSUVIA in the first quarter of 2019.
Total cost of goods sold for the three and six months ended
Three Months Ended June 30, Six Months Ended June 30,
$ Change % Change $ Change % Change
2021 vs. 2021 vs. 2021 vs. 2021 vs.
2021 2020 2020 2020 2021 2020 2020 2020
(In thousands, except percentages)
Direct costs $ 124 $ 379 $ (255 ) (67 )% $ 435 $ 625 $ (190 ) (30 )%
Indirect costs 916 991 (75 ) (8 )% 1,645 2,256 (611 ) (27 )%
Total costs of
goods sold $ 1,040 $ 1,370 $ (330 ) (24 )% $ 2,080 $ 2,881 $ (801 ) (28 )%
Direct costs from contract manufacturers for DSUVIA and Zalviso totaled $0.1
million and $0.4 million , respectively, in the three and six months ended June
30, 2021 , and included inventory impairment charges of $0 and $0.1 million ,
respectively, primarily related to Zalviso component parts inventory. Direct
costs from contract manufacturers for DSUVIA and Zalviso in the three and six
months ended June 30, 2020 totaled $0.4 million and $0.6 million , respectively,
and included inventory impairment charges of $0.3 million , and $0.4 million ,
respectively. In the six months ended June 30, 2020 , $0.3 million of these
charges related to the termination of the Grünenthal Agreements, while $0.1
million related to DSUVIA inventory that may expire before being sold. Direct
cost of goods sold for DSUVIA and Zalviso includes the inventory costs of the
active pharmaceutical ingredient, or API, third-party contract manufacturing
costs, estimated warranty costs, packaging and distribution costs, shipping,
handling and storage costs.
The indirect costs to manufacture DSUVIA and Zalviso totaled $0.9 million and
$1.6 million in the three and six months ended June 30, 2021 , respectively,
while the indirect costs to manufacture DSUVIA and Zalviso totaled $1.0 million
and $2.3 million in the three and six months ended June 30, 2020 , respectively.
Indirect costs include internal personnel and related costs for purchasing,
supply chain, quality assurance, depreciation and related expenses.
Research and Development Expenses
The majority of our operating expenses to date have been for research and development activities related to Zalviso and DSUVIA. Research and development expenses included the following:
• expenses incurred under agreements with contract research organizations and
clinical trial sites;
• employee-related expenses, which include salaries, benefits and stock-based
compensation;
• payments to third party pharmaceutical and engineering development
contractors;
• payments to third party manufacturers;
• depreciation and other allocated expenses, which include direct and allocated
expenses for rent and maintenance of facilities and equipment, and equipment
and laboratory and other supply costs; and
• costs for equipment and laboratory and other supplies.
We expect to incur future research and development expenditures to support the
FDA regulatory review of our product candidates. The timing of the resubmission
of the Zalviso NDA is in part dependent on the finalization of the FDA's new
opioid approval guidelines and process.
We track external development expenses on a program-by-program basis. Our
development resources are shared among all our programs. Compensation and
benefits, facilities, depreciation, stock-based compensation, and development
support services are not allocated specifically to projects and are considered
research and development overhead.
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Below is a summary of our research and development expenses for the three and
six months ended
Three Months Ended June 30, Six Months Ended June 30,
$ Change % Change $ Change % Change
Drug 2021 vs. 2021 vs. 2021 vs. 2021 vs.
Indication/Description 2021 2020 2020 2020 2021 2020 2020 2020
(In thousands, except percentages)
DSUVIA $ 182 $ 187 $ (5 ) (3 )% $ 344 $ 479 $ (135 ) (28 )%
Zalviso 6 3 3 100 % 12 32 (20 ) (63 )%
Overhead 536 623 (87 ) (14 )% 1,337 1,714 (377 ) (22 )%
Total research and
development expenses $ 724 $ 813 $ (89 ) (11 )% $ 1,693 $ 2,225 $ (532 ) (24 )%
Research and development expenses for the three and six months ended
Selling, General and Administrative Expenses
Selling, general and administrative expenses consisted primarily of salaries, benefits and stock-based compensation for personnel engaged in commercialization, administration, finance and business development activities. Other significant expenses included allocated facility costs and professional fees for general legal, audit and consulting services.
Total selling, general and administrative expenses for the three and six months
ended
Three Months Ended June 30, Six Months Ended June 30,
$ Change % Change $ Change % Change
2021 vs. 2021 vs. 2021 vs. 2021 vs.
2021 2020 2020 2020 2021 2020 2020 2020
(In thousands, except percentages)
Selling, general
and administrative
expenses $ 8,694 $ 7,575 $ 1,119 15 % $ 16,338 $ 20,886 $ (4,548 ) (22 )% Selling, general and administrative expenses increased by$1.1 million and decreased by$4.5 million during the three and six months endedJune 30, 2021 , as compared to the three and six months endedJune 30, 2020 , respectively. The increase for the three months endedJune 30, 2021 , as compared to the three months endedJune 30, 2020 is primarily due to a$0.5 million increase in business development expenses and a$0.5 million increase in facilities-related expenses primarily due to the loss on lease termination of ourRedwood City lease. The decrease for the six months endedJune 30, 2021 , as compared to the six months endedJune 30, 2020 , is primarily due to net decreases in selling, general and administrative expenses including a$2.0 million reduction in personnel-related costs, a decrease in business development expenses of$1.3 million (primarily due to the termination fee of approximately$1.8 million received inJune 2020 from Tetraphase Pharmaceuticals, Inc. related to the termination of our merger agreement), a$0.8 million reduction in DSUVIA commercialization-related expenses, such as travel, and net decreases in other selling, general and administrative expenses of$0.4 million .
In
26
--------------------------------------------------------------------------------Other Income (Expense)
Total other income (expense) for the three and six months ended
Three Months Ended June 30, Six Months Ended June 30,
$ Change % Change $ Change % Change
2021 vs. 2021 vs. 2021 vs. 2021 vs.
2021 2020 2020 2020 2021 2020 2020 2020
(In thousands, except percentages)
Interest expense $ (614 ) $ (872 ) $ 258 (30 )% $ (1,286 ) $ (1,727 ) $ 441 (26 )%
Interest income and
other income
(expense), net (16 ) 270 (286 ) (106 )% 60 205 (145 ) (71 )%
Non-cash interest
income (expense) on
liability related
to sale of future
royalties 799 834 (35 ) (4 )% 1,581 1,677 (96 ) (6 )%
Total other income
(expense) $ 169 $ 232 $ (63 ) (27 )% $ 355 $ 155 $ 200 129 %
Interest expense consisted primarily of interest accrued or paid on our debt
obligation agreements and amortization of debt discounts. Interest expense
decreased for the three and six months ended June 30, 2021 , as compared to the
three and six months ended June 30, 2020 , primarily as a result of a lower
outstanding loan balance. As of June 30, 2021 , the accrued balance due under the
Loan Agreement with Oxford was $17.2 million . Refer to Note 5 "Long-Term Debt"
in the accompanying notes to the Condensed Consolidated Financial Statements for
additional information.
Interest income and other income (expense), net, for the three and six months
ended June 30, 2021 and 2020, primarily consisted of interest earned on our
investments and the change in the fair value of our contingent put option.
Interest income decreased in the three and six months ended June 30, 2021 as
compared to the three and six months ended June 30, 2020 , primarily due to lower
yields on our investments.
The non-cash interest income on the liability related to the sale of future
royalties is attributable to the Royalty Monetization that we completed in
September 2015 . As described in Note 7 "Liability Related to Sale of Future
Royalties", the Royalty Monetization has been recorded as debt under the
applicable accounting guidance. We periodically assess the expected royalty and
milestone payments using a combination of historical results, internal
projections and forecasts from external sources. To the extent such payments are
greater or less than our initial estimates or the timing of such payments is
materially different than our original estimates, we will prospectively adjust
the amortization of the liability and the interest rate.
The effective interest income rate for each of the three and six months ended
Liquidity and Capital Resources
Liquidity We have incurred losses and generated negative cash flows from operations since inception. We expect to continue to incur significant losses in 2021 and may incur significant losses and negative cash flows from operations in the future. We have funded our operations primarily through issuance of equity securities, borrowings, payments from Grünenthal, the monetization of certain future royalties and commercial sales milestones from the European sales of Zalviso by Grünenthal, funding of approximately$22.6 million from theDoD , and more recently with revenues from sales of DSUVIA since the commercial launch in the first quarter of 2019. As ofJune 30, 2021 , we had cash, cash equivalents and investments totaling$55.3 million compared to$42.9 million as ofDecember 31, 2020 . The increase was primarily due to net proceeds received from the issuance of common stock in connection with equity offerings in the first quarter of 2021, partially offset by cash required to fund our continuing operations, including debt service, as we continued our commercialization activities for DSUVIA, including installation of our fully automated packaging line for DSUVIA, and business development activities. We anticipate that our existing capital resources will permit us to meet our capital and operational requirements for at least the next twelve months; however, our expectations may change depending on a number of factors including the extent and magnitude of the impact from the COVID-19 pandemic, in particular the negative impact on sales volumes as our sales force is limited in its access to potential customers, our expenditures related tothe United States commercial launch of DSUVIA and the timing of business development activities. Our existing capital resources will not be sufficient to fund our operations until such time as we may be able to generate sufficient revenues to sustain our operations. 27
-------------------------------------------------------------------------------- OnJanuary 22, 2021 , we completed an underwritten public offering in which we issued and sold 14,500,000 shares of our common stock to the underwriter at a price of$1.7625 per share. OnJanuary 27, 2021 , the underwriters exercised their option in full and purchased an additional 2,175,000 shares at a price of$1.7625 per share. The total net proceeds from this offering of an aggregate 16,675,000 shares were approximately$28.9 million . We entered into a Controlled Equity OfferingSM Sales Agreement, or the ATM Agreement, withCantor Fitzgerald & Co. , or Cantor, as agent, pursuant to which we may offer and sell, from time to time through Cantor, shares of our common stock. As ofJune 30, 2021 , we had issued and sold an aggregate of approximately 14.2 million shares of common stock pursuant to the ATM Agreement, for which we had received net proceeds of approximately$42.6 million , after deducting commissions, fees and expenses of approximately$1.2 million . As ofJune 30, 2021 , we have the ability to sell approximately$36.1 million of our common stock under the ATM Agreement. OnMay 30, 2019 , we entered into the Loan Agreement with Oxford. Under the Loan Agreement, we borrowed an aggregate principal amount of$25.0 million under a term loan. After deducting all loan initiation costs and outstanding interest on the prior loan agreement with Hercules, we received$15.9 million in net proceeds. As ofJune 30, 2021 , the accrued balance under the Loan Agreement was$17.2 million . For more information, see Note 5 "Long-Term Debt" in the accompanying notes to the Condensed Consolidated Financial Statements. Our cash and investment balances are held in a variety of interest-bearing instruments, including obligations of commercial paper, corporate debt securities,U.S. government sponsored enterprise debt securities and money market funds. Cash in excess of immediate requirements is invested with a view toward capital preservation and liquidity. We do not expect COVID-19 to have a material impact on our high quality, short-dated investments. Cash Flows
The following is a summary of our cash flows for the periods indicated and has been derived from our Condensed Consolidated Financial Statements which are included elsewhere in this Form 10-Q (in thousands):
Six Months Ended June 30,
2021 2020
Net cash used in operating activities $ (18,055 ) $ (24,054 )
Net cash (used in) provided by investing activities (15,032 ) 29,578
Net cash provided by financing activities 32,140 1,581
Cash Flows from Operating Activities
The primary use of cash for our operating activities during these periods was to fund commercial activities for our approved product, DSUVIA. Our cash used in operating activities also reflected changes in our working capital, net of adjustments for non-cash charges, such as depreciation and amortization of our fixed assets, stock-based compensation, non-cash interest income (expense) related to the sale of future royalties and interest expense related to our debt financings. Cash used in operating activities of$18.1 million during the six months endedJune 30, 2021 , reflected a net loss of$18.8 million , partially offset by aggregate non-cash charges of$2.0 million and included an approximate$1.3 million net change in our operating assets and liabilities. Non-cash charges included$2.3 million for stock-based compensation expense,$1.6 million in non-cash interest income on the liability related to the Royalty Monetization, and$1.0 million in depreciation and amortization expense. The net change in our operating assets and liabilities included a$1.0 million decrease in accrued liabilities. Cash used in operating activities of$24.1 million during the six months endedJune 30, 2020 , reflected a net loss of$22.5 million , partially offset by aggregate non-cash charges of$2.3 million and included an approximate$3.8 million net change in our operating assets and liabilities. Non-cash charges included$2.2 million for stock-based compensation expense,$1.7 million in non-cash interest income on the liability related to the royalty monetization and$1.0 million in depreciation expense. The net change in our operating assets and liabilities included a$1.8 million decrease in accrued liabilities, a$2.9 million decrease in deferred revenue and a$0.7 million increase in accounts payable.
Cash Flows from Investing Activities
Our investing activities have consisted primarily of our capital expenditures and purchases and sales and maturities of our available-for-sale investments.
28
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During the six months ended June 30, 2021 , cash used in investing activities of
$15.0 million was primarily the net result of $38.2 million for purchases of
investments and $1.6 million for purchases of property and equipment, partially
offset by $24.8 million in proceeds from maturity of investments. During the six
months ended June 30, 2020 , cash provided by investing activities of $29.6
million was the net result of $58.6 million in proceeds from maturity of
investments, offset by $28.8 million for purchases of investments and purchases
of property and equipment of $0.2 million .
Cash Flows from Financing Activities
Cash flows from financing activities primarily reflect proceeds from the sale of our securities and payments made on debt financings.
During the six months endedJune 30, 2021 , cash provided by financing activities of$32.1 million was primarily due to$36.4 million in net proceeds received in connection with equity financings, partially offset by$4.2 million used for payment of long-term debt. During the six months endedJune 30, 2020 , cash provided by financing activities was primarily due to$1.4 million in net proceeds received under the ATM Agreement and$0.2 million in proceeds as a result of stock purchases made under our Amended 2011 ESPP, partially offset by$0.1 million used for payment of employee tax obligations relating to the vesting of restricted stock units.
Operating Capital and Capital Expenditure Requirements
Our current operating plan includes expenditures related to the continued launch of DSUVIA inthe United States . This plan includes an assumption that COVID-19 related restrictions will not increase considerably, and includes anticipated activities required to resubmit the Zalviso NDA. These assumptions may change as a result of many factors. We will continue to evaluate the work necessary to successfully launch DSUVIA and gain approval of our product candidates inthe United States and intend to update our cash forecasts accordingly. Our forecast that our existing capital resources will permit us to meet our capital and operational requirements through at least the next twelve months is a forward-looking statement that involves risks and uncertainties, and actual results could vary materially.
Our future capital requirements may vary materially from our expectations based on numerous factors, including, but not limited to, the following:
• the impact and timing of COVID-19 on our operations, our sales
representatives' access to hospitals or other healthcare facilities, and our
level of sales;
• expenditures related to the launch of DSUVIA and potential commercialization
of our product candidates, if approved;
• future manufacturing, selling and marketing costs related to DSUVIA and our
product candidates, if approved, including our contractual obligations to
Aguettant under the DZUVEO Agreement;
• costs associated with business development activities and licensing
transactions;
• the outcome, timing and cost of the regulatory submissions for our product
candidates and any approvals for our product candidates;
• the initiation, progress, timing and completion of any post-approval clinical
trials for DSUVIA, or our product candidates, if approved;
• changes in the focus and direction of our business strategy and/or research
and development programs;
• milestone and royalty revenue we receive under our collaborative development
and commercialization arrangements, including the DZUVEO Agreement;
• delays that may be caused by changing regulatory requirements;
• the costs involved in filing and prosecuting patent applications and enforcing
and defending patent claims;
• the timing and terms of future in-licensing and out-licensing transactions;
• the cost and timing of establishing sales, marketing, manufacturing and
distribution capabilities;
• the cost of procuring clinical and commercial supplies of DSUVIA and our
product candidates, if approved;
• the extent to which we acquire or invest in businesses, products and product
candidates or technologies; and
• the expenses associated with litigation.
In the long-term, our existing capital resources will not be sufficient to fund
our operations until such time as we may be able to generate sufficient revenues
to sustain our operations. We will have to raise additional funds through the
sale of our equity securities, monetization of current and future assets,
issuance of debt or debt-like securities or from development and licensing
arrangements to sustain our operations and continue our development programs.
29--------------------------------------------------------------------------------
Please see "Part II., Item 1A. Risk Factors-Risks Related to Our Financial
Condition and Need for
Off-Balance Sheet Arrangements
Through
Item 3. Quantitative and Qualitative Disclosures About Market Risk
We are a smaller reporting company as defined by Rule 12b-2 of the Securities Exchange Act of 1934, as amended, or the Exchange Act, and are not required to provide the information specified under this item.
Item 4. Controls and Procedures
We maintain disclosure controls and procedures (as defined in Exchange Act Rule 13a-15(e) and 15d-15(e)) that are designed to ensure that information required to be disclosed in our reports under the Securities Exchange Act of 1934, as amended, or the Exchange Act, and the rules and regulations thereunder, is recorded, processed, summarized and reported within the time periods specified in theSEC's rules and forms and that such information is accumulated and communicated to our management, including our Chief Executive Officer and Chief Financial Officer, to allow for timely decisions regarding required disclosure. In designing and evaluating the disclosure controls and procedures, management recognizes that any controls and procedures, no matter how well designed and operated, can provide only reasonable assurance of achieving the desired control objectives, and management is required to apply its judgment in evaluating the cost-benefit relationship of possible controls and procedures. Evaluation of disclosure controls and procedures. As required by Rule 13a-15(b) under the Exchange Act, we carried out an evaluation, under the supervision and with the participation of our management, including our Chief Executive Officer and Chief Financial Officer, of the effectiveness of the design and operation of our disclosure controls and procedures as of the end of the period covered by this Quarterly Report on Form 10-Q. Based on the foregoing, our Chief Executive Officer and Chief Financial Officer concluded that our disclosure controls and procedures were effective at the reasonable assurance level. Changes in internal control over financial reporting. There have been no changes in our internal control over financial reporting during our most recent fiscal quarter that have materially affected, or are reasonably likely to materially affect, our internal control over financial reporting. PART II. OTHER INFORMATION Item 1. Legal Proceedings From time to time we may be involved in legal proceedings relating to intellectual property, commercial, employment and other matters arising in the ordinary course of business. Such matters are subject to uncertainty and there can be no assurance that such legal proceedings will not have a material adverse effect on our business, results of operations, financial position or cash flows. Other than the following, we believe there are no legal proceedings pending that could, individually or in the aggregate, have a material adverse effect on our results of operations or financial condition: OnJune 8, 2021 , a securities class action complaint was filed in theU.S. District Court for the Northern District of California against us and two of our officers. The plaintiff is a purported stockholder of the Company. The complaint alleges that defendants violated Sections 10(b) and 20(a) of the Exchange Act and SEC Rule 10b-5 by making false and misleading statements and omissions of material fact about our disclosure controls and procedures with respect to our marketing of DSUVIA. The complaint seeks unspecified damages, interest, attorneys' fees, and other costs. Motions for appointment of lead plaintiff under the Private Securities Litigation Reform Act were filed onAugust 9, 2021 and a hearing on the motions has been noticed forDecember 16, 2021 . Please see "Item 1A. Risk Factors-Risks of a General Nature -- Our involvement in securities-related class action litigation could divert our resources and management's attention and harm our business." OnJuly 6, 2021 , a purported shareholder derivative complaint was filed in theU.S. District Court for the Northern District of California . The complaint names ten of our officers and directors and asserts state and federal claims based on the same alleged misstatements as the shareholder class action complaint. The complaint seeks unspecified damages, attorneys' fees, and other costs. Please see "Item 1A. Risk Factors-Risks of a General Nature-Litigation may substantially increase our costs and harm our business." We believe that these lawsuits are without merit, and we intend to vigorously defend against them. Given the uncertainty of litigation, the preliminary stage of the cases, and the legal standards that must be met for, among other things, class certification and success on the merits, we cannot estimate the reasonably possible loss or range of loss that may result from these actions. 30 --------------------------------------------------------------------------------
Item 1A. Risk Factors This Quarterly Report on Form 10-Q contains forward-looking information based on our current expectations. Because our actual results may differ materially from any forward-looking statements made by or on behalf of us, this section includes a discussion of important factors that could affect our actual future results, including, but not limited to, our revenues, expenses, net loss and loss per share. You should carefully consider these risk factors, together with all of the other information included in this Quarterly Report on Form 10-Q as well as our other publicly available filings with theU.S. Securities and Exchange Commission , orSEC . Summary Risk Factors Our business is subject to numerous risks, as more fully described in this section below this summary. You should read these risks before you invest in our common stock. We may be unable, for many reasons, including those that are beyond our control, to implement our business strategy. In particular, our risks include: ? Our business is being adversely impacted by the COVID-19 pandemic.
? We have incurred significant losses since our inception, anticipate that we
will continue to incur significant losses in 2021 and may continue to incur
losses in the future.
? We have not yet generated significant product revenue and may never be
profitable.
? We will require additional capital and may be unable to raise capital, which
would force us to delay, reduce or eliminate our commercialization efforts and
product development programs and could cause us to cease operations.
? Positive clinical results obtained to date for Zalviso may be disputed in FDA
review, do not guarantee regulatory approval and may not be obtained from
future clinical trials.
? Existing and future legislation may increase the difficulty and cost for us to
commercialize our products and affect the prices we may obtain.
? Guidelines and recommendations published by government agencies, as well as
non-governmental organizations, and existing laws and regulations can reduce
the use of DSUVIA, and Zalviso, if approved in
? Zalviso may cause adverse effects or have other properties that could delay or
prevent regulatory approval or limit the scope of any approved label or market
acceptance. DSUVIA may cause adverse effects or have other properties that
could limit market acceptance.
? Although we have obtained regulatory approval for DSUVIA, and even if we
obtain regulatory approval for Zalviso in
collaborators face extensive regulatory requirements and our products may face
future development and regulatory difficulties.
? The commercial success of DSUVIA and Zalviso, if approved, in the United
States, as well as DZUVEO and Zalviso in
acceptance of these products by the medical community, including physicians,
nurses, patients, and pharmacy and therapeutics committees.
? If we are unable to maintain or grow our sales and marketing capabilities or
enter into agreements with third parties to market and sell our products, we
may be unable to generate sufficient product revenue.
? A key part of our business strategy is to establish collaborative
relationships to commercialize and fund development and approval of our
products, particularly outside of
establishing and maintaining collaborative relationships, which may
significantly limit our ability to develop and commercialize our products
successfully, if at all.
? If we cannot defend our issued patents from third party claims or if our
pending patent applications fail to issue, our business could be adversely
affected.
? The market price of our common stock may be highly volatile.
? Litigation may substantially increase our costs and harm our business.
? Our involvement in securities-related class action litigation could divert our
resources and management's attention and harm our business.
We have marked with an asterisk (*) those risks described below that reflect
substantive changes from, or additions to, the risks described in our Annual
Report on Form 10-K for the year ended December 31, 2020 .
Risks Related to COVID-19 Pandemic
Our business is being adversely impacted by the COVID-19 pandemic.*
Our business has been adversely affected by the COVID-19 outbreak. Federal, state, local and foreign government orders on account of the COVID-19 pandemic are preventing us from conducting certain activities. Following local and state government orders inCalifornia , where our corporate office is located and many of our employees live, we implemented work from home policies, which are limiting certain of our operations. If the COVID-19 outbreak continues, we may need to limit operations further and implement additional limitations, such as extending our work from home policies. 31 -------------------------------------------------------------------------------- In response to the COVID-19 pandemic, some hospitals, ambulatory surgery centers and other healthcare facilities have barred visitors that are not caregivers or mission-critical and we have no visibility as to when these restrictions on access will be lifted for all of our customers. As a result, our commercial and medical affairs teams' educational and promotional efforts have been reduced, and in some cases, stopped. Furthermore, some governments, hospitals and doctors, as a measure to combat the further spread of COVID-19, reduced the number of procedures in which DSUVIA is administered as part of the pain treatment program, and temporarily halted performing elective surgeries, which adversely impacted the level of our sales relating to such procedures. We expect our near-term sales volumes to be adversely impacted for as long as access to healthcare facilities by our commercial and medical affairs personnel and the number of procedures in which DSUVIA is administered continues to be limited. The ultimate impact of the COVID-19 outbreak remains highly uncertain and subject to change. We do not yet know the full extent of potential delays or impacts on our business, healthcare systems or the global economy as a whole. However, these effects could have a material impact on our operations, and we will continue to monitor the COVID-19 situation closely.
Risks Related to Commercialization
Our success is highly dependent on our ability to successfully commercialize DSUVIA.*
We invested a significant portion of our efforts and financial resources to develop and gain regulatory approval for DSUVIA and expect to continue making significant investments to commercialize DSUVIA. We believe our success is highly dependent on, and a significant portion of the value of our company relates to, our ability to successfully commercialize DSUVIA inthe United States . The commercial success of DSUVIA depends heavily on numerous factors, including: • our ability to market, sell, and distribute DSUVIA;
• our ability to establish and maintain commercial manufacturing with third
parties;
• acceptance by the medical community, including physicians, nurses, patients
and pharmacy and therapeutics committees;
• acceptance of pricing and placement on payers' formularies;
• our ability to effectively compete with other medications for the treatment of
moderate-to-severe acute pain in medically supervised settings, including
IV-opioids and any subsequently approved products;
• effective management of, and compliance with, the DSUVIA Risk Evaluation and
Mitigation Strategy, or REMS, program;
• continued demonstration of an acceptable safety profile of DSUVIA; and
• our ability to obtain, maintain, enforce, and defend our intellectual property
rights and claims.
If we are unable to successfully commercialize DSUVIA, our business, financial condition, and results of operations will be materially harmed.
The commercial success of DSUVIA and, if approved, Zalviso and our other product candidates inthe United States , as well as DZUVEO and Zalviso inEurope , will depend upon the acceptance of these products by the medical community, including physicians, nurses, patients, and pharmacy and therapeutics committees.*
The degree of market acceptance of DSUVIA and, if approved, Zalviso and our
other product candidates in
• demonstration of clinical safety and efficacy compared to other products;
• the relative convenience, ease of administration and acceptance by physicians,
patients and health care payers;
• the use of our approved products by a healthcare professional for patient
types that were not specifically studied in clinical trials;
• the prevalence and severity of any adverse events, or AEs, or serious adverse
events, or SAEs;
• overcoming any perceptions of sufentanil as a potentially unsafe drug due to
its high potency opioid status;
• limitations or warnings contained in the
FDA, -approved label for DSUVIA and, if approved, our other product
candidates, or the
DZUVEO or Zalviso;
• restrictions or limitations placed on DSUVIA due to the REMS program or, if
approved, on our product candidates;
• availability of alternative treatments;
• existing capital investment by hospitals in IV PCA technology;
• pricing and cost-effectiveness;
32--------------------------------------------------------------------------------
• the effectiveness of our current or any future collaborators' sales and
marketing strategies;
• our ability to obtain formulary approvals; and
• our ability to obtain and maintain sufficient third-party coverage and
reimbursement.
If our approved products do not achieve an adequate level of acceptance by the
medical community, including physicians, nurses, patients and pharmacy and
therapeutics committees, we may not generate sufficient revenue and become or
remain profitable.
If we are unable to maintain or grow our sales and marketing capabilities or
enter into agreements with third parties to market and sell our products, we may
be unable to generate sufficient product revenue.*
In order to commercialize DSUVIA and our product candidates, if approved, in the
United States , we must maintain or grow internal sales, marketing, distribution,
managerial and other capabilities or make arrangements with third parties to
perform these services. We have entered into agreements with third parties for
the distribution of DSUVIA and may enter into such agreements for our product
candidates, if approved, in the United States , including the product candidates
we in-licensed from Laboratoire Aguettant , or Aguettant, in July 2021 pursuant
to a License and Commercialization Agreement, or the PFS Agreement; however, if
these third parties do not perform as expected or there are delays in
establishing such relationships, our ability to effectively distribute products
would suffer.
We have entered into strategic partnerships with third parties to commercialize
our products outside of the United States . For example, in 2013 we entered into
a collaboration with Grünenthal GmbH , or Grünenthal, for the commercialization
of Zalviso in Europe and Australia , and in July 2021 , we entered a License and
Commercialization Agreement, or the DZUVEO Agreement, with Aguettant for the
commercialization of DZUVEO in the European Union , Norway , Iceland ,
Liechtenstein , Andorra , Vatican City , Monaco , Switzerland and the United
Kingdom , or the DZUVEO Territory. Grünenthal ceased commercializing Zalviso on
May 12, 2021 and the rights to market and sell Zalviso reverted back to us. We
intend to enter into additional strategic partnerships with third parties to
commercialize our products outside of the United States , including a replacement
license agreement for Zalviso in Europe . Per the terms of the royalty
monetization arrangement with SWK Funding, LLC , or SWK (assignee of PDL
BioPharma, Inc., or PDL), or the Royalty Monetization, we are obligated to use
commercially reasonable efforts to negotiate a replacement license agreement, or
New Arrangement. Accordingly, even if we are able to enter into a New
Arrangement, and that licensee is successful in commercializing Zalviso in
Europe , we will receive only a portion of any royalties until the capped amount
owing to SWK is reached.
We face significant competition in seeking appropriate strategic partners, and
these strategic partnerships can be intricate and time consuming to negotiate
and document. We may not be able to negotiate future strategic partnerships on
acceptable terms, or at all. We are unable to predict when, if ever, we will
enter into any new strategic partnerships because of the numerous risks and
uncertainties associated with establishing strategic partnerships. Our current
or future collaboration partners, if any, may not dedicate sufficient resources
to the commercialization of our products and product candidates, if approved, or
may otherwise fail in their commercialization due to factors beyond our control.
If we are unable to establish effective collaborations to enable the sale of our
products to healthcare professionals and in geographical regions that will not
be covered by our own marketing and sales force, or if our potential future
collaboration partners do not successfully commercialize our products, our
ability to generate revenues from product sales will be adversely affected.
If we are unable to maintain or grow adequate sales, marketing and distribution
capabilities, whether independently or with third parties, we may not be able to
generate sufficient product revenue and become profitable. We compete with many
companies that currently have extensive and well-funded marketing and sales
operations. Without an internal team or the support of a third party to perform
marketing and sales functions, we may be unable to compete successfully against
these more established companies.
A key part of our business strategy is to establish collaborative relationships
to commercialize and fund development and approval of our products, particularly
outside of the United States . We may not succeed in establishing and maintaining
collaborative relationships, which may significantly limit our ability to
develop and commercialize our products successfully, if at all.*
We will need to establish and maintain successful collaborative relationships to
obtain international sales, marketing and distribution capabilities for our
products. The process of establishing and maintaining collaborative
relationships is difficult, time-consuming and involves significant uncertainty.
For example:
• our partners may seek to renegotiate or terminate their relationships with us
due to unsatisfactory clinical or regulatory results, manufacturing issues, a
change in business strategy, a change of control or other reasons;
• our contracts for collaborative arrangements are or may be terminable at will
on written notice and may otherwise expire or terminate, and we may not have
alternatives available to achieve the potential for our products in those
territories or markets;
• our partners may choose to pursue alternative technologies, including those of
our competitors;
33--------------------------------------------------------------------------------
• we may have disputes with a partner that could lead to litigation or
arbitration, including in connection with any contractual force majeure
notices tied to the COVID-19 pandemic;
• we have limited control over the decisions of our partners, and they may
change the priority of our programs in a manner that would result in
termination of the agreement or add significant delays to the partnered
program;
• our ability to generate future payments and royalties from our partners
depends upon the abilities of our partners to establish the safety and
efficacy of our drugs, maintain regulatory approvals and our ability to
successfully manufacture and achieve market acceptance of our products;
• we or our partners may fail to properly initiate, maintain or defend our
intellectual property rights, where applicable, or a party may use our
proprietary information in such a way as to invite litigation that could
jeopardize or potentially invalidate our proprietary information or expose us
to potential liability;
• our partners may not devote sufficient capital or resources towards our
products; and
• our partners may not comply with applicable government regulatory requirements
necessary to successfully market and sell our products.
If any collaborator fails to fulfill its responsibilities in a timely manner, or
at all, any research, clinical development, manufacturing or commercialization
efforts pursuant to that collaboration could be delayed or terminated, or it may
be necessary for us to assume responsibility for expenses or activities that
would otherwise have been the responsibility of our collaborator. For example,
Grünenthal has terminated the collaboration agreement for the commercialization
of Zalviso in Europe . The rights to market and sell Zalviso in Europe reverted
back to us on May 12, 2021 . We have a continuing obligation, through the term of
the Royalty Monetization with SWK, to use commercially reasonable efforts to
negotiate a New Arrangement. If we are unable to establish and maintain
collaborative relationships on acceptable terms we may have to undertake
development and commercialization activities at our own expense.
In March 2020 , we reduced the size of our commercial team and, given our reduced
workforce, we may experience difficulties in retaining our existing employees
and managing our operations, including our continued commercialization of
DSUVIA.
In
We will need to retain and maintain our existing sales, managerial, operational, finance and other personnel and resources in order to continue the commercialization of DSUVIA and manage our operations. Our current infrastructure may be inadequate to support our strategy and our workforce reduction may be disruptive to our operations, may negatively affect our productivity, and constrain our commercialization activities. For example, our workforce reduction could yield unanticipated consequences, such as attrition beyond planned staff reductions, negative impact on employee morale and our corporate culture, or increase difficulties in our day-to-day operations and prevent us from successfully commercializing DSUVIA as rapidly as planned. If we encounter such unanticipated consequences, we may have difficulty retaining and attracting personnel. In addition, the implementation of any additional workforce or expense reduction programs may divert the efforts of our management team and other key employees, which could adversely affect our business. Furthermore, we may not realize, in full or in part, the anticipated benefits, savings and improvements in our cost structure from our cost reduction plan, due to unforeseen difficulties, delays or unexpected costs. If we are unable to realize the expected operational efficiencies and cost savings from the cost reduction plan, our operating results and financial condition would be adversely affected.
Guidelines and recommendations published by government agencies, as well as
non-governmental organizations, and existing laws and regulations can reduce the
use of DSUVIA, and Zalviso, if approved in
Government agencies and non-governmental organizations promulgate regulations and guidelines applicable to certain drug classes that may include DSUVIA and Zalviso, if approved inthe United States . Recommendations of government agencies or non-governmental organizations may relate to such matters as maximum quantities dispensed to patients, dosage, route of administration, and use of concomitant therapies. Government agencies and non-governmental organizations have offered commentary and guidelines on the use of opioid-containing products. We are uncertain how these activities and guidelines may impact DSUVIA and our ability to gain marketing approval of Zalviso inthe United States . Regulations or guidelines suggesting the reduced use of certain drug classes that may include DSUVIA or Zalviso, or the use of competitive or alternative products as the standard-of-care to be followed by patients and healthcare providers, could result in decreased use of DSUVIA or Zalviso, if approved, or negatively impact our ability to gain market acceptance and market share. TheU.S. government and state legislatures have prioritized combatting the growing misuse and addiction to opioids and opioid overdose deaths and have enacted legislation and regulations as well as other measures intended to fight the opioid epidemic. Addressing opioid drug abuse is a priority for the currentU.S. administration and the FDA and is part of a broader initiative led by theU.S. Department of Health and Human Services , or HHS. Overall, there is greater scrutiny of entities involved in the manufacture, sale and distribution of opioids. These initiatives, existing laws and regulations, and any negative publicity related to opioids may have a material impact on our business and our ability to manufacture opioid products. 34
-------------------------------------------------------------------------------- Governmental investigations, inquiries, and regulatory actions and lawsuits brought against us by government agencies and private parties with respect to our commercialization of opioids could adversely affect our business, financial condition, results of operations and cash flows. As a result of greater public awareness of the public health issue of opioid abuse, there has been increased scrutiny of, and investigation into, the commercial practices of opioid manufacturers by state and federal agencies. As a result of our manufacturing and commercial sale of DSUVIA inthe United States and Zalviso inEurope , we could become the subject of federal, state and foreign government investigations and enforcement actions, focused on the misuse and abuse of opioid medications. In addition, a significant number of lawsuits have been filed against opioid manufacturers, distributors, and others in the supply chain by cities, counties, state Attorney's General and private persons seeking to hold them accountable for opioid misuse and abuse. The lawsuits assert a variety of claims, including, but not limited to, public nuisance, negligence, civil conspiracy, fraud, violations of the Racketeer Influenced and Corrupt Organizations Act, or RICO, or similar state laws, violations of state Controlled Substance Acts or state False Claims Acts, product liability, consumer fraud, unfair or deceptive trade practices, false advertising, insurance fraud, unjust enrichment and other common law and statutory claims arising from defendants' manufacturing, distribution, marketing and promotion of opioids and seek restitution, damages, injunctive and other relief and attorneys' fees and costs. The claims generally are based on alleged misrepresentations and/or omissions in connection with the sale and marketing of prescription opioid medications and/or an alleged failure to take adequate steps to prevent abuse and diversion. While DSUVIA is designed for use solely in certified medically supervised healthcare settings and administered only by a healthcare professional in these settings, and is not distributed or available at retail pharmacies to patients by prescription, we can provide no assurance that parties will not file lawsuits of this type against us in the future. In addition, current public perceptions of the public health issue of opioid abuse may present challenges to favorable resolution of any potential claims. Accordingly, we cannot predict whether we may become subject to these kinds of investigations and lawsuits in the future, and if we were to be named as a defendant in such actions, we cannot predict the ultimate outcome. Any allegations against us may negatively affect our business in various ways, including through harm to our reputation. If we were required to defend ourselves in these matters, we would likely incur significant legal costs and could in the future be required to pay significant amounts as a result of fines, penalties, settlements or judgments. It is unlikely that our current product liability insurance would fully cover these potential liabilities, if at all. Moreover, we may be unable to maintain insurance in the future on acceptable terms or with adequate coverage against potential liabilities or other losses. For more information about our product liability insurance and exclusions therefrom, please see the risk factor entitled "We face potential product liability claims, and, if such claims are successful, we may incur substantial liability" elsewhere in this section. The resolution of one or more of these matters could have a material adverse effect on our business, financial condition, results of operations and cash flows. Furthermore, in the current climate, stories regarding prescription drug abuse and the diversion of opioids and other controlled substances are frequently in the media or advocated by public interest groups. Unfavorable publicity regarding the use or misuse of opioid drugs, the limitations of abuse-deterrent formulations, the ability of drug abusers to discover previously unknown ways to abuse opioid products, public inquiries and investigations into prescription drug abuse, litigation, or regulatory activity regarding sales, marketing, distribution or storage of opioids could have a material adverse effect on our reputation and impact on the results of litigation. Finally, various government entities, includingCongress , state legislatures or other policy-making bodies, or public interest groups have in the past and may in the future hold hearings, conduct investigations and/or issue reports calling attention to the opioid crisis, and may mention or criticize the perceived role of manufacturers, including us, in the opioid crisis. Similarly, press organizations have and likely will continue to report on these issues, and such reporting may result in adverse publicity for us, resulting in reputational harm.
Approval of Zalviso and DZUVEO in
Our collaborations with international partners, including Grünenthal and Aguettant, have required, and will require, us to supply product to support the commercialization of our products inEurope and it is likely that any New Arrangement would also include such a requirement. Entering into international business relationships subjects us to additional risks including:
• multiple, conflicting, and changing laws and regulations such as privacy and
data regulations, transparency regulations, tax laws, export and import
restrictions, employment laws, regulatory requirements, including for drug
approvals, and other governmental approvals, permits, and licenses;
• EMA "sunset clause" requirements, which apply to DZUVEO, providing that the
marketing authorization of a medicine will cease to be valid if it is not
placed on the market within three years of the authorization being granted or
if it is removed from the market for three consecutive years; however, the
35
--------------------------------------------------------------------------------• reduced protection for intellectual property rights;
• unexpected changes in tariffs, trade barriers and regulatory requirements;
• different payer reimbursement regimes, governmental payers, patient self-pay
systems and price controls;
• economic weakness, including inflation, or political instability in particular
foreign economies and markets;
• production shortages resulting from any events affecting raw material supply
or manufacturing capabilities abroad; and
• business interruptions resulting from pandemics, geopolitical actions,
including war and terrorism, or natural disasters including earthquakes,
typhoons, floods and fires.
Any of these factors could have a material adverse effect on our business.
If we, or current and potential partners, are unable to compete effectively, our products may not reach their commercial potential.
TheU.S. biotechnology and pharmaceutical industries are characterized by intense competition and cost pressure. DSUVIA competes, and our product candidates, if approved in theU.S. , will compete, with a number of existing and future pharmaceuticals and drug delivery devices developed, manufactured and marketed by others. In particular, DSUVIA may compete with a wide variety of products and product candidates including (i) injectable opioid products, such as morphine, fentanyl, hydromorphone and meperidine; (ii) oral opioids such as oxycodone and hydrocodone; (iii) generic injectable local anesthetics, such as bupivacaine or branded formulations thereof; (iv) non-steroidal anti-inflammatory drugs, or NSAIDS, including ketorolac in intranasal or generic IV form, and IV meloxicam; and (v) transmucosal fentanyl products. Zalviso, if approved in theU.S. , may compete with a number of opioid-based treatment options, includingIV PCA pumps, oral PCA devices, and transdermal opioid PCAs. The PFS product candidates, if approved in theU.S. , may compete with other ready-to-use formulations of ephedrine and phenylephrine. Key competitive factors affecting the commercial success of our approved products are likely to be efficacy, safety profile, reliability, convenience of dosing, price and reimbursement. Many of our competitors and potential competitors have substantially greater financial, technical and human resources than we do and significantly greater experience in the discovery and development of drug candidates, obtaining FDA and other regulatory approval of products, and the commercialization of those products. Accordingly, our competitors may be more successful than we are in obtaining FDA approval for drugs and achieving widespread market acceptance. Our competitors' drugs or drug delivery systems may be more effective, have fewer adverse effects, be less expensive to develop and manufacture, or be more effectively marketed and sold than any product we may seek to commercialize. This may render our products obsolete or non-competitive. We anticipate that we will face intense and increasing competition as new drugs enter the market, additional technologies become available, and competitors establish collaborative or licensing relationships, which may adversely affect our competitive position. These and other competitive risks may materially adversely affect our ability to attain or sustain profitable operations. Hospital or other health care facility formulary approvals for DSUVIA or our product candidates, if approved, inthe United States may not be achieved, or could be subject to certain restrictions, which could make it difficult for us to sell our products. Obtaining hospital or other health care facility formulary approvals can be an expensive and time-consuming process. We cannot be certain if and when we will obtain formulary approvals to allow us to sell our products into our target markets. In particular, the restrictions on our commercial and medical affairs teams' access to hospitals and other health care facilities has adversely impacted the number of formulary approvals we anticipated achieving in 2020, and for as long as these restrictions remain in place, or new restrictions are implemented, we may have limited visibility or difficulties in obtaining these formulary approvals in the future. Failure to obtain timely formulary approval will limit our commercial success. If we are successful in obtaining formulary approvals, we may need to complete evaluation programs whereby DSUVIA, or our product candidates, if approved, is used on a limited basis for certain patient types. The evaluation period may last several months and there can be no assurance that use during the evaluation period will lead to formulary approvals of DSUVIA, or our product candidates, if approved. Further, even successful formulary approvals may be subject to certain restrictions based on patient type or hospital protocol. Failure to obtain timely formulary approvals for DSUVIA, or our product candidates, if approved, would materially adversely affect our ability to attain or sustain profitable operations.
Coverage and adequate reimbursement may not be available for DSUVIA or our
product candidates, if approved, in
Our ability to commercialize DSUVIA or our product candidates, if approved, inthe United States , and any collaboration partner's ability to commercialize DZUVEO or Zalviso inEurope successfully will depend, in part, on the extent to which coverage and adequate reimbursement will be available from government payer programs at the federal and state levels, authorities, including Medicare and Medicaid, private health insurers, managed care plans and other third-party payers. 36
-------------------------------------------------------------------------------- No uniform policy requirement for coverage and reimbursement for drug products exists among third-party payers inthe United States orEurope . Therefore, coverage and reimbursement can differ significantly from payer to payer. As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our products to each payer separately, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance. Our inability to promptly obtain and sufficiently maintain coverage and adequate reimbursement rates from third party payers could significantly harm our operating results, our ability to raise capital needed to commercialize our approved drugs and our overall financial condition. A primary trend in theU.S. healthcare industry and elsewhere is cost containment. Government authorities and other third-party payers have attempted to control costs by limiting coverage and the amount of reimbursement for particular medical products. There have been a number of legislative and regulatory proposals to change the healthcare system inthe United States and in some foreign jurisdictions that could affect our ability to sell our products profitably. These legislative and/or regulatory changes may negatively impact the reimbursement for our products, following approval. The availability of numerous generic pain medications may also substantially reduce the likelihood of reimbursement for DSUVIA or Zalviso, if approved, inthe United States , and DSUVIA/DZUVEO and Zalviso inEurope and elsewhere. The application of user fees to generic drug products may expedite the approval of additional pain medication generic drugs. We expect to experience pricing pressures in connection with our sales of DSUVIA and Zalviso, if approved, inthe United States , and future product sales of Zalviso and DZUVEO inEurope , due to the trend toward managed healthcare, the increasing influence of health maintenance organizations and additional legislative changes. If we fail to successfully secure and maintain reimbursement coverage for our products or are significantly delayed in doing so, we will have difficulty achieving market acceptance of our products and our business will be harmed. Furthermore, market acceptance and sales of our products will depend on reimbursement policies and may be affected by future healthcare reform measures. Government authorities and third-party payers, such as private health insurers, hospitals and health maintenance organizations, decide which drugs they will pay for and establish reimbursement levels. We cannot be sure that reimbursement will be available for DSUVIA or our product candidates, if approved, inthe United States , or DZUVEO or Zalviso inEurope . Also, reimbursement amounts may reduce the demand for, or the price of, our products. For example, we anticipate we may need comparator studies of DZUVEO inEurope to ensure premium reimbursement in certain countries. If reimbursement is not available, or is available only to limited levels, we may not be able to successfully commercialize DSUVIA or our product candidates, if approved, inthe United States , or DZUVEO or Zalviso inEurope . Additionally, the regulations that govern marketing approvals, pricing, coverage and reimbursement for new drugs vary widely from country to country. Current and future legislation may significantly change the approval requirements in ways that could involve additional costs and cause delays in obtaining approvals. Some countries require approval of the sale price of a product before it can be marketed. In many countries, the pricing review period begins after marketing or product licensing approval is granted. In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted. As a result, we might obtain marketing approval for a product in a particular country, but then be subject to price regulations that delay commercial launch of the product, possibly for lengthy time periods, and negatively impact the revenues able to be generated from the sale of the product in that country. For example, separate pricing and reimbursement approvals may impact any future collaboration partners' ability to market and successfully commercialize our products in the 27 member states of theEuropean Union . Adverse pricing limitations may hinder our ability to recoup our investment in DSUVIA inthe United States , or Zalviso, even after obtaining FDA marketing approval.
The FDA and other regulatory agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses.
If we are found to have improperly promoted off-label uses of our products, including DSUVIA or our product candidates, if approved, inthe United States , we may become subject to significant liability. Such enforcement has become more common in the industry. The FDA and other regulatory agencies strictly regulate the promotional claims that may be made about prescription drug products. In particular, a product may not be promoted for uses that are not approved by the FDA or such other regulatory agencies as reflected in the product's approved labeling. While we have received marketing approval for DSUVIA for our proposed indication, physicians may nevertheless use our products for their patients in a manner that is inconsistent with the approved label, if the physicians personally believe in their professional medical judgment it could be used in such manner. However, if the FDA determines that our promotional materials or training constitutes promotion of an off-label use, it could request that we modify our training or promotional materials or subject us to regulatory or enforcement actions, including the issuance of an untitled letter, a warning letter, injunction, seizure, civil fine or criminal penalties and a requirement for corrective advertising, includingDear Doctor letters. It is also possible that other federal, state or foreign enforcement authorities might take action if they consider our promotional or training materials to constitute promotion of an off-label use, which could result in significant civil, criminal and/or administrative penalties, damages, fines, disgorgement, individual imprisonment, exclusion from government-funded healthcare programs, such as Medicare and Medicaid, contractual damages, reputational harm, increased losses and diminished profits and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our financial results. The FDA or other enforcement authorities could also request that we enter into a consent decree or a corporate integrity agreement or seek a permanent injunction against us under which specified promotional conduct is monitored, changed or curtailed. If we cannot successfully manage the promotion of DSUVIA or our product candidates, if approved, inthe United States , we could become subject to significant liability, which would materially adversely affect our business and financial condition. 37 --------------------------------------------------------------------------------
If we are unable to establish and maintain relationships with group purchasing organizations any future revenues or future profitability could be jeopardized.
Many end-users of pharmaceutical products have relationships with group purchasing organizations, or GPOs, whereby such GPOs provide such end-users access to a broad range of pharmaceutical products from multiple suppliers at competitive prices and, in certain cases, exercise considerable influence over the drug purchasing decisions of such end-users. Hospitals and other end-users contract with the GPO of their choice for their purchasing needs. We expect to derive revenue from end-user customers that are members of GPOs for DSUVIA and our product candidates, if approved. Establishing and maintaining strong relationships with these GPOs will require us to be a reliable supplier, remain price competitive and comply with FDA regulations. The GPOs with whom we have relationships may have relationships with manufacturers that sell competing products, and such GPOs may earn higher margins from these products or combinations of competing products or may prefer products other than ours for other reasons. If we are unable to establish or maintain our GPO relationships, sales of DSUVIA and our product candidates, if approved, and related revenues could be negatively impacted.
We intend to rely on a limited number of distributors and pharmaceutical
wholesalers to distribute DSUVIA and our product candidates, if approved, in
We intend to rely primarily upon distributors and pharmaceutical wholesalers in connection with the distribution of DSUVIA and our product candidates, if approved, inthe United States . As part of the DSUVIA REMS program, we monitor distribution and audit wholesalers' data and will monitor such data from other distributors. If our distributors and wholesalers do not comply with the DSUVIA REMS requirements, or if we are unable to establish or maintain our business relationships with these distributors and pharmaceutical wholesalers on commercially acceptable terms, or if our distributors and wholesalers are unable to distribute our drugs for regulatory, compliance or any other reason, it could have a material adverse effect on our sales and may prevent us from achieving profitability.
Risks Related to Clinical Development and Regulatory Approval
Existing and future legislation may increase the difficulty and cost for us to commercialize our products and affect the prices we may obtain.*
Inthe United States and some foreign jurisdictions, the legislative landscape continues to evolve, including changes to the regulation of opioid-containing products. There have been a number of legislative and regulatory changes and proposed changes regarding healthcare systems that could prevent or delay marketing approval of Zalviso outside ofEurope . These changes will restrict or regulate post-approval activities for DSUVIA, DZUVEO and Zalviso, and affect our ability to profitably sell any products for which we obtain marketing approval. For example, inFebruary 2016 , the FDA announced a comprehensive action plan to take concrete steps towards reducing the impact of opioid abuse on American families and communities. As part of this plan, the FDA announced that it intended to review product and labeling decisions and re-examine the risk-benefit paradigm for opioids. InJune 2019 , the FDA issued draft guidance related to a new benefit/risk framework for new opioid analgesic products, which proposes that the new product candidate show some benefit over an existing product. InSeptember 2019 , the FDA held a public hearing to receive stakeholder input on the approval process for new opioids. InJanuary 2020 ,FDA's Anesthetic and Analgesic Drug Products Advisory Committee recommended against the approval of a new opioid analgesic, oxycodegol, the NDA for which was subsequently withdrawn by its sponsor. The timing of the resubmission of the Zalviso NDA is dependent upon the finalization of theFDA's new opioid approval guidelines and process. In theEuropean Union , or EU, the pricing of prescription drugs is subject to government control.The EU also provides options for its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use. In addition, the EMA has a "sunset clause" which provides that the marketing authorization of a medicine will cease to be valid if it is not placed on the market within three years of the authorization being granted or if it is removed from the market for three consecutive years; however, theEuropean Commission has extended this date toDecember 31, 2022 for DZUVEO. 38
-------------------------------------------------------------------------------- Inthe United States , the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively, the Affordable Care Act was enacted in an effort to, among other things, broaden access to health insurance, reduce or constrain the growth of healthcare spending, enhance remedies against fraud and abuse, impose new taxes and fees on the health industry and impose additional health policy reforms. Aspects of the Affordable Care Act that may impact our business include:
• extension of manufacturers' Medicaid rebate liability to covered drugs
dispensed to individuals who are enrolled in Medicaid managed care
organizations;
• expansion of the entities eligible for discounts under the Public Health
Service pharmaceutical pricing program;
• expansion of eligibility criteria for Medicaid programs, thereby potentially
increasing manufacturers' Medicaid rebate liability;
• expansion of healthcare fraud and abuse laws, including the federal False
Claims Act and the federal Anti-Kickback Statute, new government investigative
powers and enhanced penalties for non-compliance; and
• a
in, and conduct comparative clinical effectiveness research, along with
funding for such research.
The Affordable Care Act continues to substantially change health care financing
and delivery by both governmental and private insurers, which may increase our
regulatory burdens and operating costs.
There have been executive, judicial and Congressional challenges to certain
aspects of the Affordable Care Act. While Congress has not passed comprehensive
repeal legislation, several bills affecting the implementation of certain taxes
under the Affordable Care Act have been signed into law. The Tax Cuts and Jobs
Act of 2017 includes a provision that repealed, effective January 1, 2019 , the
tax-based shared responsibility payment imposed by the Affordable Care Act on
certain individuals who fail to maintain qualifying health coverage for all or
part of a year that is commonly referred to as the "individual mandate". On June
17, 2021 , the U.S. Supreme Court dismissed a challenge on procedural grounds
that argued the Affordable Care Act is unconstitutional in its entirety because
the "individual mandate" was repealed by Congress . Thus, the Affordable Care Act
will remain in effect in its current form. Moreover, prior to the U.S. Supreme
Court ruling, on January 28, 2021 , President Biden issued an executive order
that initiated a special enrollment period for purposes of obtaining health
insurance coverage through the Affordable Care Act marketplace, which began on
February 15, 2021 and will remain open through August 15, 2021 . The executive
order instructed certain governmental agencies to review and reconsider their
existing policies and rules that limit access to healthcare, including among
others, reexamining Medicaid demonstration projects and waiver programs that
include work requirements, and policies that create unnecessary barriers to
obtaining access to health insurance coverage through Medicaid or the Affordable
Care Act. . It is possible that the Affordable Care Act will be subject to
judicial or Congressional challenges in the future. It is also unclear how any
such challenges and the healthcare reform measures of the Biden administration
will impact the Affordable Care Act. We expect that the Affordable Care Act and
other healthcare reform measures that may be adopted in the future, could have a
material adverse effect on our industry generally and on our ability to
successfully commercialize our products. We cannot predict the likelihood,
nature or extent of government regulation that may arise from future legislation
or administrative action, either in the United States or abroad. If we or our
collaborators are slow or unable to adapt to changes in existing requirements or
the adoption of new requirements or policies, or if we or our collaborators are
not able to maintain regulatory compliance, our products may lose regulatory
approval and we may not achieve or sustain profitability, which would adversely
affect our business.
In addition, other legislative changes have been proposed and adopted in the
United States since the Affordable Care Act was enacted. Aggregate reductions of
Medicare payments to providers of 2% per fiscal year went into effect on April
1, 2013 and due to subsequent legislative amendments to the statute will stay in
effect through 2030, with the exception of a temporary suspension from May 1,
2020 through December 31, 2021 due to the COVID-19 pandemic, unless
Congressional action is taken. The American Taxpayer Relief Act further reduced
Medicare payments to several providers, including hospitals.
Moreover, the Drug Supply Chain Security Act of 2013 imposes additional
obligations on manufacturers of pharmaceutical products, among others, related
to product tracking and tracing. Among the requirements of this legislation,
manufacturers are required to provide certain information regarding the drug
product to individuals and entities to which product ownership is transferred,
label drug product with a product identifier, and keep certain records regarding
the drug product.
39-------------------------------------------------------------------------------- Inthe United States , there has been increasing legislative and enforcement interest with respect to specialty drug pricing practices. Specifically, there have been several recentU.S. Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing and reform government program reimbursement methodologies for drugs. At the federal level, the Trump administration used several means to propose or implement drug pricing reform, including through federal budget proposals, executive orders and policy initiatives. For example, onJuly 24, 2020 andSeptember 13, 2020 ,President Trump announced several executive orders related to prescription drug pricing that attempt to implement several of the administration's proposals. The FDA also released a final rule, effectiveNovember 30, 2020 , implementing a portion of the importation executive order providing guidance for states to build and submit importation plans for drugs fromCanada . Further, onNovember 20, 2020 , HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law. The implementation of the rule has been delayed by the Biden administration fromJanuary 1, 2022 toJanuary 1, 2023 in response to ongoing litigation. The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which has also been delayed untilJanuary 1, 2023 . Further, onNovember 20, 2020 , CMS issued an interim final rule implementingPresident Trump's Most Favored Nation, or MFN, executive order, which would tie Medicare Part B payments for certain physician-administered drugs to the lowest price paid in other economically advanced countries, effectiveJanuary 1, 2021 . OnDecember 28, 2020 , theU.S. District Court for the Northern District of California issued a nationwide preliminary injunction against implementation of the interim final rule. OnJanuary 13, 2021 , in a separate lawsuit brought by industry groups in theU.S. District Court of Maryland , the government defendants entered a joint motion to stay litigation on the condition that the government would not appeal the preliminary injunction granted in theU.S. District Court for the Northern District of California and that performance for any final regulation stemming from the MFN model interim final rule shall not commence earlier than sixty (60) days after publication of that regulation in theFederal Register . Additionally, based on a recent executive order, the Biden administration expressed its intent to pursue certain policy initiatives to reduce drug prices. At the state level, legislatures are increasingly passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, measures designed to encourage importation from other countries and bulk purchasing. Furthermore, even after initial price and reimbursement approvals, reductions in prices and changes in reimbursement levels can be triggered by multiple factors, including reference pricing systems and publication of discounts by third party payers or authorities in other countries. InEurope , prices can be reduced further by parallel distribution and parallel trade, i.e., arbitrage between low-priced and high-priced countries. If any of these events occur, revenue from sales of Zalviso and DZUVEO inEurope would be negatively affected. Legislative and regulatory proposals have been made to expand post-approval requirements and further restrict sales and promotional activities for pharmaceutical products. We are not sure whether additional legislative changes will be enacted, or whether the FDA regulations, guidance or interpretations will be changed, or what the impact of such changes on the marketing approvals of our products, if any, may be. We expect that additional healthcare reform measures will be adopted within and outsidethe United States in the future, any of which could negatively impact our business. For instance, it is possible that additional governmental action is taken in response to the COVID-19 pandemic. The continuing efforts of the government, insurance companies, managed care organizations and other payers of healthcare services to contain or reduce costs of healthcare may adversely affect the demand for any drug products for which we have obtained or may obtain regulatory approval, our ability to set a price that we believe is fair for our products, our ability to obtain coverage and reimbursement approval for a product, our ability to generate revenues and achieve or maintain profitability, and the level of taxes that we are required to pay. We may experience market resistance, delays or rejections based upon additional government regulation from future legislation or administrative action, or changes in regulatory agency policy regarding opioids generally, and sufentanil specifically. InFebruary 2016 , the FDA announced a comprehensive action plan to take concrete steps towards reducing the impact of opioid abuse on American families and communities. As part of this plan, the FDA announced that it intended to review product and labeling decisions and re-examine the risk-benefit paradigm for opioids. InJune 2019 , the FDA issued draft guidance related to a new benefit/risk framework for new opioid analgesic products, which proposes that the new product candidate show some benefit over an existing product. InSeptember 2019 , the FDA held a public hearing to receive stakeholder input on the approval process for new opioids. The timing of the resubmission of the Zalviso NDA is dependent upon the finalization of theFDA's new opioid approval guidelines and process. InMay 2017 , anOpioid Policy Steering Committee was established to address and advise regulators on opioid use. The Committee was charged with three initial questions: (i) should the FDA require mandatory education for healthcare professionals, or HCPs, who prescribe opioids; (ii) should the FDA take steps to ensure the number of prescribed opioid doses is more closely tailored to the medical indication; and (iii) is the FDA properly considering the risk of abuse and misuse of opioids during its drug review process. Zalviso has not been designed with an abuse-deterrent formulation and is not tamper-resistant. As a result, Zalviso has not undergone testing for tamper-resistance or abuse deterrence.
The FDA can delay, limit or deny marketing approval for many reasons, including:
• a product candidate may not be considered safe or effective;
• the manufacturing processes or facilities we have selected may not meet the
applicable requirements; and
• changes in their approval policies or adoption of new regulations may require
additional work on our part.
Part of the regulatory approval process includes compliance inspections of
manufacturing facilities to ensure adherence to applicable regulations and
guidelines. The regulatory agency may delay, limit or deny marketing approval of
our product candidate, Zalviso, as a result of such inspections. We, our
contract manufacturers, and their vendors, are all subject to preapproval and
post-approval inspections at any time. The results of these inspections could
impact our ability to obtain FDA approval for Zalviso and, if approved, our
ability to launch and successfully commercialize Zalviso in the United States .
In addition, results of FDA inspections could impact our ability to maintain FDA
approval of DSUVIA, and our ability to expand and sustain commercial sales of
DSUVIA in the United States .
40-------------------------------------------------------------------------------- Any delay in, or failure to receive or maintain, approval for Zalviso inthe United States could prevent us from generating meaningful revenues or achieving profitability. Zalviso may not be approved even if we believe it has achieved its endpoints in clinical trials. Regulatory agencies, including the FDA, or their advisors, may disagree with our trial design and our interpretations of data from preclinical studies and clinical trials. Regulatory agencies may change requirements for approval even after a clinical trial design has been approved. The FDA exercises significant discretion over the regulation of combination products, including the discretion to require separate marketing applications for the drug and device components in a combination product. Zalviso is being regulated as a drug product under the NDA process administered by the FDA. The FDA could in the future require additional regulation of Zalviso, or DSUVIA, under the medical device provisions of the Federal Food, Drug and Cosmetic Act, or FDCA. We must comply with the Quality Systems Regulation, or QSR, which sets forth theFDA's current good manufacturing practice, or cGMP, requirements for medical devices, and other applicable government regulations and corresponding foreign standards for drug cGMPs. If we fail to comply with these regulations, it could have a material adverse effect on our business and financial condition. Regulatory agencies also may approve a product candidate for fewer or more limited indications than requested or may grant approval subject to the performance of post-marketing trials. For example, DSUVIA is subject to a deferred post-marketing requirement for study in the pediatric population ages 6-17 years. As required in the DSUVIA FDA approval letter, a final protocol for this trial was submitted to the FDA inAugust 2020 , in conjunction with a request to defer initiation of pediatric studies until additional post-market safety data is obtained in adult patients using DSUVIA. In addition, regulatory agencies may not approve the labeling claims that are necessary or desirable for the successful commercialization of our product candidates. For example, we intend to seek approval of Zalviso for the management of moderate-to-severe acute pain in adult patients in the hospital setting; however, our clinical trial data was generated exclusively from the post-operative segment of this population, and the FDA may restrict any approval to post-operative patients only, which would reduce the size of the commercial opportunity.
The success of Zalviso relies, in part, on obtaining regulatory approval in
The success of Zalviso relies, in part, upon our ability to develop and receive regulatory approval of this product candidate inthe United States for the management of moderate-to-severe acute pain in adult patients in the hospital setting. Our Phase 3 program for Zalviso initially consisted of three Phase 3 clinical trials. We reported positive top-line data from each of these trials and submitted an NDA for Zalviso to the FDA inSeptember 2013 , which the FDA then accepted for filing inDecember 2013 . InJuly 2014 , the FDA issued a Complete Response Letter, or CRL, for our NDA for Zalviso, or the Zalviso CRL. The Zalviso CRL contained requests for additional information on the Zalviso System to ensure proper use of the device. The requests include submission of data demonstrating a reduction in the incidence of device errors, changes to address inadvertent dosing, among other items, and submission of additional data to support the shelf life of the product. Furthermore, inMarch 2015 , we received correspondence from the FDA stating that in addition to the bench testing and two Human Factors studies we had performed in response to the issues identified in the Zalviso CRL, a clinical trial was needed to assess the risk of inadvertent dispensing and overall risk of dispensing failures. Based on the results of our Type C meeting with the FDA inSeptember 2015 , we completed the protocol review with the FDA and initiated this study, IAP312, inSeptember 2016 . IAP312 was a Phase 3 study in post-operative patients designed to evaluate the effectiveness of changes made to the functionality and usability of the Zalviso device and to take into account comments from the FDA on the study protocol. The IAP312 study was designed to rule out a 5% device failure rate. The study design required a minimum of 315 patients. In the IAP312 study, sites proactively looked for tablets that were dispensed by the patient but failed to be placed under the tongue, known as dropped tablets. The FDA refers to dropped tablets as inadvertent dispensing. Correspondence from the FDA suggests that they may include the rate of inadvertent dispensing along with the device failures to calculate a total error rate. The IAP312 study evaluated all incidents of misplaced tablets; however, per the protocol, the error rate calculation does not include the rate of inadvertent dispensing. If the FDA includes the rate of inadvertent dispensing along with the device failures to calculate a total error rate, the resulting error rate may be unacceptable to the FDA. Further, the correspondence from the FDA suggests that we may need to modify the REMS program for Zalviso to address dropped tablets. The IAP312 results will supplement the three Phase 3 trials already completed in the Zalviso NDA resubmission. The timing of the resubmission of the Zalviso NDA is dependent upon the finalization of theFDA's new opioid approval guidelines and process. There is no guarantee that the additional work we performed related to Zalviso, including the IAP312 trial, will result in our successfully obtaining FDA approval of Zalviso in a timely fashion, if at all. Although we believe the IAP312 study met safety, satisfaction and device usability expectations, there is no guarantee the IAP312 trial results will address the issues raised by the FDA. For example, the FDA may include the rate of inadvertent dispensing along with the device failures to calculate a total error rate and the resulting error rate may be unacceptable to the FDA, or the FDA may still have concerns regarding the performance of the device, inadvertent dosing (dropped tablets), or other issues. At any future point in time, the FDA could require us to complete further clinical, Human Factors, pharmaceutical, reprocessing or other studies, which could delay or preclude any NDA resubmission or approval of the NDA and could require us to obtain significant additional funding. We may not be able to identify appropriate remediations to issues that the FDA may raise, and we may not have sufficient time or financial resources to conduct future activities to remediate issues raised by the FDA. We intend to seek a label indication for Zalviso for the management of moderate-to-severe acute pain in adult patients in the hospital setting. However, our clinical trial data was generated exclusively from the post-operative segment of this population, and the FDA may restrict any approval to post-operative patients only, which would reduce our commercial opportunity. 41 -------------------------------------------------------------------------------- Upon resubmission of the Zalviso NDA, the FDA may hold an advisory committee meeting to obtain committee input on the safety and efficacy of Zalviso. Typically, advisory committees will provide responses to specific questions asked by the FDA, including the committee's view on the approvability of the drug under review. Advisory committee decisions are not binding, but an adverse decision at the advisory committee may have a negative impact on the regulatory review of Zalviso. Additionally, we may choose to engage in the dispute resolution process with the FDA. Our proposed trade name of Zalviso has been approved by the EMA and is currently being used inEurope . It has also been conditionally approved by the FDA, which must approve all drug trade names to avoid medication errors and misbranding. However, the FDA may withdraw this approval in which case any brand recognition or goodwill that we establish with the name Zalviso prior to commercialization may be worthless. Any delay in approval by the FDA of the Zalviso NDA, once it is resubmitted, may negatively impact our stock price and harm our business operations. Any delay in obtaining, or inability to obtain, regulatory approval would prevent us from commercializing Zalviso inthe United States , generating revenues and potentially achieving profitability. If any of these events occur, we may be forced to delay or abandon our development efforts for Zalviso, which would have a material adverse effect on our business. Positive clinical results obtained to date for Zalviso may be disputed in FDA review, do not guarantee regulatory approval and may not be obtained from future clinical trials. We have reported positive top-line data from each of our four Zalviso Phase 3 clinical trials completed to date, as well as our Phase 2 clinical trials for Zalviso. However, even if we believe that the data obtained from clinical trials is positive, the FDA has, and in the future could, determine that the data from our trials was negative or inconclusive or could reach a different conclusion than we did on that same data. Negative or inconclusive results of a clinical trial or difference of opinion could cause the FDA to require us to repeat the trial or conduct additional clinical trials prior to obtaining approval for commercialization, and there is no guarantee that additional trials would achieve positive results or that the FDA will agree with our interpretation of the results. If the FDA were to require any additional clinical trials for Zalviso, our development efforts would be further delayed, which would have a material adverse effect on our business. Any such determination by the FDA would delay the timing of our commercialization plan for Zalviso and adversely affect our business operations. Delays in clinical trials are common and have many causes, and any delay could result in increased costs to us and jeopardize or delay our ability to obtain regulatory approval and commence product sales. We have experienced and may in the future experience delays in clinical trials of our product candidates. While we have completed four Phase 3 clinical trials and several Phase 2 clinical trials for Zalviso, future clinical trials may not begin on time, have an effective design, enroll a sufficient number of patients or be completed on schedule, if at all. For example, we postponed the start of IAP312, originally planned for the first quarter of 2016, toSeptember 2016 . The postponement was due to a delay in the receipt and testing of final clinical supplies for this trial. As a result, the development timeline for Zalviso was further extended.
Our post-approval clinical trials for DSUVIA, or any future FDA-required clinical trials for Zalviso, could be delayed for a variety of reasons, including:
• inability to raise funding necessary to initiate or continue a trial; • delays in obtaining regulatory approval to commence a trial; • delays in reaching agreement with the FDA on final trial design;
• imposition of a clinical hold by the FDA,
or other regulatory authorities;
• delays in reaching agreement on acceptable terms with prospective contract
research organizations, or CROs, and clinical trial sites;
• delays in obtaining required IRB approval at each site;
• delays in recruiting suitable patients to participate in a trial;
• delays in the testing, validation, manufacture and delivery of the tablets and
device components of DSUVIA or Zalviso;
• delays in having patients complete participation in a trial or return for
post-treatment follow-up;
42--------------------------------------------------------------------------------
• clinical sites dropping out of a trial to the detriment of enrollment or being
delayed in entering data to allow for clinical trial database closure;
• time required to add new clinical sites; or
• delays by our contract manufacturers to produce and deliver sufficient supply
of clinical trial materials.
If any future FDA-required clinical trials are delayed for any reason, our
development costs may increase, our approval process for Zalviso could be
delayed, our ability to commercialize and commence sales of Zalviso could be
materially harmed, and our ability to maintain FDA approval of DSUVIA could be
jeopardized, which could have a material adverse effect on our business.
Zalviso may cause adverse effects or have other properties that could delay or
prevent regulatory approval or limit the scope of any approved label or market
acceptance. DSUVIA may cause adverse effects or have other properties that could
limit market acceptance.
Adverse events, or AEs, caused by Zalviso could cause us, other reviewing
entities, clinical trial sites or regulatory authorities to interrupt, delay or
halt any future FDA-required clinical trials and could result in the denial of
regulatory approval. Phase 2 clinical trials we conducted with Zalviso did
generate some AEs, but no significant adverse events, or SAEs, related to the
trial drug. In our Phase 3 active-comparator clinical trial (IAP309), 8% of
Zalviso-treated patients dropped out of the trial prematurely due to an AE (11%
in the IV patient-controlled morphine group), and we observed three serious
adverse events, or SAEs, that were assessed as possibly or probably related to
study drug (one- respiratory depression in the Zalviso group and two- abdominal
distension and ileus in the IV patient-controlled morphine group). In our Phase
3, double-blind, placebo-controlled, abdominal surgery trial (IAP310), 6% of
Zalviso-treated patients dropped out of the trial prematurely due to an AE (9%
in placebo group). There were no SAEs determined to be related to study drug. In
our Phase 3, double-blind, placebo-controlled, orthopedic surgery trial
(IAP311), 7% of Zalviso-treated patients dropped out of the trial prematurely
due to an AE (7% in placebo group). Four patients (three in the Zalviso group
and one in the placebo group) experienced an SAE considered possibly or probably
related to the trial drug by the investigator. The SAEs possibly or probably
attributed to Zalviso were severe oxygen saturation decrease, sinus tachycardia
and confusional state. In our Phase 3 multicenter, open-label study of Zalviso
(IAP312), 3% of patients dropped out prematurely due to an AE. Five patients
experienced SAEs in the IAP312 study and none of these were considered possibly
or probably related to the study drug by the investigator.
In our Phase 2 DSUVIA placebo-controlled bunionectomy study (SAP202), two
patients in the DSUVIA 30 mcg group (5%) discontinued treatment due to an AE,
one unrelated to study drug and the other probably related to study drug. There
were no SAEs deemed related to study drug. In our Phase 3 placebo-controlled
abdominal surgery study (SAP301), one DSUVIA-treated patient (1%) dropped out of
the trial prematurely due to an AE (4% in placebo group). There were two SAEs
determined to be related to study drug in the placebo-treated group and no
related SAEs in the DSUVIA group. In our Phase 3 open-label, single-arm
emergency room study (SAP302), no DSUVIA-treated patients dropped out of the
trial prematurely due to an AE. One patient had an SAE - angina pectoris -
possibly related to study drug. In our post-operative study in patients aged 40
years or older (SAP303), 3% of DSUVIA-treated patients dropped out of the trial
prematurely due to an AE. There were no SAEs deemed related to study drug.
If DSUVIA or, if approved, Zalviso cause serious or unexpected side effects after receiving marketing approval, a number of potentially significant negative consequences could result, including:
• regulatory authorities may withdraw their approval of the product or impose
restrictions on its distribution in the form of a modified REMS program;
• regulatory authorities may require the addition of labeling statements, such
as warnings or contraindications;
• we may be required to change the way the product is administered or conduct
additional clinical trials;
• we could be sued and held liable for harm caused to patients; or
• our reputation may suffer.
Any of these events could prevent us from achieving or maintaining market acceptance of DSUVIA or, if approved, Zalviso, and could substantially increase the costs of commercializing our products.
Additional time may be required to obtain
DSUVIA and Zalviso are combination products with both drug and device
components. The FDA requires both the drug and device components of combination
product candidates to be reviewed as part of an NDA submission. There are very
few examples of the FDA approval process for drug/device combination products
such as DSUVIA and Zalviso. As a result, we experienced delays in the
development and commercialization of DSUVIA, and may experience future delays in
the development and commercialization of Zalviso, due to regulatory
uncertainties in the product development and approval process, in particular as
it relates to a drug/device combination product approval under an NDA.
43
--------------------------------------------------------------------------------The process for obtaining approval of an NDA is time consuming, subject to unanticipated delays and costs, and requires the commitment of substantial resources.
If the FDA determines that any of the clinical work submitted, including the clinical trials, Human Factors studies and bench testing submitted for a product candidate in support of an NDA were not conducted in full compliance with the applicable protocols for these trials, studies and testing as well as with applicable regulations and standards, or if the FDA does not agree with our interpretation of the results of such trials, studies and testing, the FDA may reject the data and results. The FDA may audit some or all of our clinical trial sites to determine the integrity of our clinical data. The FDA may audit some or all of our Human Factors study sites to determine the integrity of our data and may audit the data and results of bench testing. Any rejection of any of our data would negatively impact our ability to obtain marketing authorization for our product candidate, Zalviso, and would have a material adverse effect on our business and financial condition. In addition, an NDA may not be approved, or approval may be delayed, as a result of changes in FDA policies for drug approval during the review period. For example, although many products have been approved by the FDA in recent years under Section 505(b)(2) of the FDCA, objections have been raised to theFDA's interpretation of Section 505(b)(2). If challenges to theFDA's interpretation of Section 505(b) (2) are successful, the FDA may be required to change its interpretation, which could delay or prevent the approval of such an NDA. More generally, theFDA's comprehensive action plan to take concrete steps towards reducing the impact of opioid abuse on American families and communities may result in delays and challenges in obtaining NDA approval. Any significant delay in the acceptance, review or approval of an NDA that we have submitted would have a material adverse effect on our business and financial condition and would require us to obtain significant additional funding. Although we have obtained regulatory approval for DSUVIA, and even if we obtain regulatory approval for Zalviso inthe United States , we and our collaborators face extensive regulatory requirements, and our products may face future development and regulatory difficulties.* Although we have obtained regulatory approval for DSUVIA, and even if we obtain regulatory approval for Zalviso inthe United States , the FDA may impose significant restrictions on the indicated uses or marketing of our products or impose ongoing requirements for potentially costly post-approval trials or post-market surveillance. For example, DSUVIA is subject to a deferred post-marketing requirement for study in the pediatric population ages 6-17 years. A final protocol for this trial was submitted to the FDA inAugust 2020 , in conjunction with a request to defer initiation of pediatric studies until additional post-market safety data is obtained in adult patients using DSUVIA. Additionally, the labeling approved for DSUVIA includes restrictions on use due to the opioid nature of sufentanil. If approved, the labeling for Zalviso will likely include similar restrictions on use. DSUVIA inthe United States is also subject to ongoing FDA requirements governing the labeling, packaging, storage, distribution, safety surveillance, advertising, promotion, record-keeping and reporting of safety and other post-market information. The holder of an approved NDA is obligated to monitor and report AEs and any failure of a product to meet the specifications in the NDA. The holder of an approved NDA must also submit new or supplemental applications and obtain FDA approval for certain changes to the approved product, product labeling or manufacturing process. Advertising and promotional materials must comply with FDA rules concerning the advertising and promotion of DSUVIA and are subject to FDA review, in addition to other potentially applicable federal and state laws. Failure to comply with these regulations can result in the receipt of warning letters and further liability if off-label promotion is involved. For example, onFebruary 11, 2021 , we received a warning letter from theOffice of Prescription Drug Promotion , or OPDP, of the FDA relating to a banner advertisement we submitted to the OPDP onDecember 6, 2019 , and a tabletop display we submitted onFebruary 28, 2020 , and resubmitted to the OPDP at its request onSeptember 23, 2020 . We submitted the materials to the OPDP pursuant to the FDA requirement that sponsors submit all promotional materials to the FDA at the time of their initial dissemination or publication. TheFDA's concerns identified in the letter include its view that the promotional material makes misleading claims and representations about the risks and efficacy of DSUVIA because the material does not reveal facts that are material in light of the representations made. As a result, we conducted a review of our marketing materials to identify any potential revisions in light of the letter. We responded to the FDA within the timeframe requested in the letter and, onMarch 23, 2021 , held a teleconference with OPDP to seek guidance and clarification on the concerns raised in the letter. Following our meeting with OPDP, we conducted a further review of our marketing materials to identify any potential revisions in light of the letter and OPDP's guidance. We submitted a second response to FDA onApril 7, 2021 and onJune 17, 2021 , we announced that the FDA agreed with our proposed plan to update certain promotional materials, including providing a letter to healthcare professionals, or the DHCP letter, explaining the corrections to the discontinued promotional materials. We will also include this DHCP letter on the DSUVIA.com website for a period of eight months. Although we believe we have updated all promotional materials currently in use by our commercial team to address theFDA's concerns and we expect to receive a close-out letter from the FDA after the DHCP letters have been sent to the identified healthcare professionals and the letter has been posted on the website for eight months, we cannot give any assurances that we will receive such close-out letter or that we will not receive additional FDA warning letters in the future. If approved, Zalviso will be subject to these same requirements. 44
-------------------------------------------------------------------------------- We must also register and obtain various state prescription drug distribution licenses and controlled substance permits, and any delay or failure to obtain or maintain these licenses or permits may limit our market and materially impact our business. In certain states we cannot apply for a license until a drug is approved by the FDA. The state licensing process may take several months which would delay commercialization in those states. In addition, manufacturers of drug products and their facilities are subject to payment of user fees and continual review and periodic inspections by the FDA and other regulatory authorities for compliance with cGMPs and adherence to commitments made in the NDA. If we, or a regulatory agency, discover previously unknown problems with a product, such as AEs of unanticipated severity or frequency, or problems with the facilities where the product is manufactured, a regulatory agency may impose restrictions relative to that product or the manufacturing facilities, including requiring recall or withdrawal of the product from the market or suspension of manufacturing.
If we fail to comply with applicable regulatory requirements following approval of our products, a regulatory agency may:
• issue a warning letter asserting that we are in violation of the law;
• seek an injunction or impose civil or criminal penalties or monetary fines;
• suspend or withdraw regulatory approval; • suspend any ongoing clinical trials;
• refuse to approve a pending NDA or supplements to an NDA submitted by us;
• seize product; or
• refuse to allow us to enter into supply contracts, including government
contracts.
Any government investigation of alleged violations of law could require us to
expend significant time and resources in response and could generate negative
publicity. The occurrence of any event or penalty described above may inhibit
our ability to commercialize DSUVIA, or, if approved, Zalviso, and generate
revenues.
Except for Zalviso and DZUVEO, which are both approved in Europe , we may never
obtain additional regulatory approvals for our products and product candidates
outside of the United States , which would limit our ability to realize their
full market potential.*
In order to market any products outside of the United States , we or our
commercial partners, must establish and comply with numerous and varying
regulatory requirements of other countries regarding safety and efficacy. On
September 22, 2015 , we announced that the EC had granted marketing approval for
Grünenthal's MAA for Zalviso for the management of acute moderate-to-severe
post-operative pain in adult patients. In April 2016 , Grünenthal completed the
first commercial sale of Zalviso. Grünenthal terminated the collaboration,
effective November 13, 2020 . The terms of the Grünenthal Agreements were
extended to May 12, 2021 to enable Grünenthal to sell down its Zalviso
inventory, a right it had under the Grünenthal Agreements. Grünenthal's rights
to market and sell Zalviso reverted back to us on May 12, 2021 . We have not yet
negotiated a New Arrangement and there can be no assurance that we will
successfully enter into a New Arrangement. In June 2018 , we announced that the
EC had granted marketing approval of DZUVEO for the treatment of patients with
moderate-to-severe acute pain in medically monitored settings. In July 2021 , we
entered into the DZUVEO Agreement with Aguettant.
Part of the foreign regulatory approval process includes compliance inspections
of manufacturing facilities to ensure adherence to applicable regulations and
guidelines. The foreign regulatory agency may delay, limit or deny marketing
approval as a result of such inspections. We, our contract manufacturers, and
their vendors, are all subject to preapproval and post-approval inspections at
any time. The results of these inspections could impact our ability to obtain
regulatory approval of DSUVIA and Zalviso in countries outside of the United
States and Europe , or our ability to launch and successfully commercialize these
products, once approved. In addition, results of EMA inspections could impact
our ability to maintain EC approval of Zalviso and DZUVEO, and any future
collaboration partner's ability to expand and sustain commercial sales of
Zalviso or DZUVEO in Europe .
Outside of Europe , clinical trials conducted in one country may not be accepted
by regulatory authorities in other countries, and regulatory approval in one
country does not mean that regulatory approval will be obtained in any other
country. Approval processes vary among countries and can involve additional
product testing and validation and additional administrative review periods.
Seeking foreign regulatory approval could result in difficulties and costs for
us and require additional non-clinical trials or clinical trials, which could be
costly and time consuming. Regulatory requirements can vary widely from
country-to-country and could delay or prevent the introduction of our products
in those countries. Our current clinical trial data may not be sufficient to
support marketing approval or premium reimbursement in all territories. For
example, we anticipate we may need comparator studies for DZUVEO in Europe to
ensure premium reimbursement in certain countries. While we have obtained
approval of DZUVEO in Europe , we will be substantially dependent on Aguettant to
comply with regulatory requirements. If we, or our commercial partners, fail to
comply with regulatory requirements in international markets or to obtain and
maintain required approvals, or if regulatory approvals in international markets
are delayed, our target market will be reduced and our ability to realize the
full market potential of our products will be harmed.
45
--------------------------------------------------------------------------------DSUVIA requires, and, if approved, Zalviso will require, a REMS program.
DSUVIA was approved inthe United States with a REMS program. If Zalviso is approved inthe United States , it will also require a REMS program. The DSUVIA REMS program includes restrictions on product distribution and use only in certified medically supervised settings. Before DSUVIA is distributed, an authorized representative from each medically supervised setting must sign an attestation that they have the ability to manage acute opioid overdose and will train all relevant staff on administration of DSUVIA, including the importance of only dispensing the product in a medically supervised setting. Therefore, REMS-certification is a key gating item to generating product revenues for DSUVIA. In addition, the REMS program for DSUVIA may significantly increase our costs to commercialize this product. While we have received pre-clearance from the FDA regarding certain aspects of the proposed required REMS program for Zalviso, we cannot predict the final REMS program to be required as part of any FDA approval of Zalviso. Depending on the extent of the REMS requirements, anyU.S. launch may be delayed, the costs to commercialize Zalviso may increase substantially and the potential commercial market could be restricted. Furthermore, risks of sufentanil that are not adequately addressed through the proposed REMS program for Zalviso may also prevent or delay its approval for commercialization.
Risks Related to Our Financial Condition and Need for
We have incurred significant losses since our inception, anticipate that we will continue to incur significant losses in 2021 and may continue to incur losses in the future.
We have incurred significant net losses in each year since our inception in
We have devoted most of our financial resources to research and development, including our non-clinical development activities and clinical trials. To date, we have financed our operations primarily through the issuance of equity securities, borrowings, payments from Grünenthal, the monetization of certain future royalties and commercial sales milestones from the European sales of Zalviso by Grünenthal, funding from theDepartment of Defense , orDoD , and more recently with revenues from sales of DSUVIA since the commercial launch in the first quarter of 2019. The size of our future net losses will depend, in part, on the rate of future expenditures and our ability to generate revenues. We expect to continue to incur substantial expenses as we support commercialization activities for DSUVIA, manufacturing and supply activities for DZUVEO, and research and development activities for Zalviso and the PFS Products, including the FDA regulatory review of the Zalviso NDA, once resubmitted. If DSUVIA is not successfully commercialized in theU.S. , if our product candidates are not successfully developed or commercialized in theU.S. , or if revenues are insufficient following marketing approval, we will not achieve profitability and our business may fail. Our success is also dependent on current and future collaborations to market our products outside ofthe United States , which may not materialize or prove to be successful.
We have not yet generated significant product revenue and may never be profitable.
Our ability to generate revenue from commercial sales and achieve profitability depends on our ability, alone and with collaborators, to successfully complete the development of, obtain the necessary regulatory approvals for, and commercialize our products. Although we received FDA approval of DSUVIA and began the commercial launch of DSUVIA inthe United States , we may never generate enough revenues from sales of DSUVIA, or our product candidates, if approved, inthe United States to become profitable. Although the EC granted marketing approval of DZUVEO inJune 2018 , we only recently entered into the DZUVEO Agreement with Aguettant to commercialize DZUVEO inEurope and there can be no assurance that Aguettant will successfully commercialize DZUVEO. While we had a collaboration agreement with Grünenthal for commercialization of Zalviso inEurope andAustralia it has been terminated, and Grünenthal was unable to achieve a level of commercial sales of Zalviso for which we were able to receive sales milestone payments. Grünenthal's rights to market and sell Zalviso reverted back to us onMay 12, 2021 . InSeptember 2015 , we consummated a monetization transaction with PDL pursuant to which we sold to PDL for$65.0 million 75% of the European royalties from sales of Zalviso and 80% of the first four commercial milestones under the Amended License Agreement, subject to a capped amount. OnAugust 31, 2020 , PDL announced it sold its royalty interest for Zalviso to SWK. As mentioned above, Grünenthal has terminated the Grünenthal Agreements and the rights reverted back to us onMay 12, 2021 . Per the terms of the Royalty Monetization, we are obligated to use commercially reasonable efforts to negotiate a New Arrangement. Accordingly, even if we are able to enter into a New Arrangement, and that licensee is successful in commercializing Zalviso inEurope , we will receive only a portion of any royalties until the capped amount owing under the Royalty Monetization is reached. We do not anticipate generating significant near-term revenues from DSUVIA or our product candidates, if approved, inthe United States . Our ability to generate future revenues from product sales depends heavily on our success in:
• maintaining regulatory approval for DSUVIA and obtaining and maintaining
regulatory approval for our product candidates in
• launching and commercializing DSUVIA and our product candidates, if approved,
in
institutionally focused sales force, and launching and commercializing DZUVEO
and Zalviso internationally through collaborations, which may require
additional funding.
Because of the numerous risks and uncertainties associated with launching a
commercial pharmaceutical product, pharmaceutical product development and the
regulatory environment, we are unable to predict the timing or amount of
increased expenses, or when, or if, we will be able to achieve or maintain
profitability. Our expenses could increase beyond expectations if we are delayed
in receiving regulatory approval for our product candidates in the United
States , or if we are required by the FDA to complete activities in addition to
those we currently anticipate or have already completed.
46
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We anticipate continuing to incur significant costs associated with
commercializing DSUVIA in the United States . Even if we are able to generate
revenues from the sale of DSUVIA or our product candidates, if approved, in the
United States , we may not become profitable and may need to obtain additional
funding to continue operations.
Future sales of DSUVIA to the DoD are not predictable, may occur on an irregular
basis and may not meet our expectations due to various U.S. government-related
factors that are beyond our control and into which we have little to no
visibility, including the timing and extent of future U.S. military deployments.
If DoD spending on DSUVIA does not meet our expectations, it could adversely
affect our expected results of operations, financial condition and liquidity.
In April 2020 , DSUVIA achieved Milestone C approval by the DoD , a decision that
clears the path for the DoD to begin placing orders for DSUVIA. In September
2020 , we announced that DSUVIA was added to the DoD Joint Deployment Formulary,
a core list of pharmaceutical products that are designated for deploying
military units across all service branches. Future sales of DSUVIA to the DoD
are not predictable, may occur on an irregular basis, and may not meet our
expectations due to various U.S. government-related factors that are beyond our
control and into which we have little to no visibility, including the timing and
extent of future U.S. military deployments. Even if we do generate revenue from
such sales, we may never generate revenue that is significant or predictable,
which could impair our value and our ability to raise capital, expand our
business or continue our operations. The placement of new orders by the DoD is,
among other things, contingent upon overall U.S. government policies, budget and
appropriation decisions and processes which are driven by numerous factors,
including geo-political events, deployment of military units, macroeconomic
conditions, and the ability of the U.S. government to enact relevant
legislation, such as appropriations bills and accords on the debt ceiling. Our
expectations about the timing and size of initial stocking orders for U.S. Army
sets, kits and outfits, or SKOs, and other orders by the DoD are based on our
understanding of troop deployment schedules. If DoD spending on DSUVIA does not
meet our expectations, it could have a material adverse effect on our expected
results of operations, financial condition and liquidity.
We have been substantially dependent on Grünenthal to successfully commercialize
Zalviso in Europe and they have terminated their collaboration agreement with
us.
Under our agreements with Grünenthal, we granted Grünenthal rights to
commercialize Zalviso in Europe for human use in pain treatment within, or
dispensed by, hospitals, hospices, nursing homes and other medically supervised
settings. In September 2015 , the EC granted marketing approval for Grünenthal's
MAA for Zalviso for the management of acute moderate-to-severe post-operative
pain in adult patients, and Grünenthal began its European launch of Zalviso with
the first commercial sale occurring in April 2016 . Grünenthal terminated the
collaboration, effective November 13, 2020 . The terms of the Grünenthal
Agreements were extended to May 12, 2021 to enable Grünenthal to sell down its
Zalviso inventory, a right it had under the Grünenthal Agreements. Grünenthal's
rights to market and sell Zalviso reverted back to us on May 12, 2021 .
During the pilot and launch phases in the various European countries, Grünenthal
reported certain issues from HCPs with the initial set up of the Zalviso
controllers before being given to patients for use. To address the issues, we
have assisted Grünenthal with implementing additional training for HCPs and we
have revised the controller software. Controllers with the revised software,
which were delivered in December 2016 , have undergone extensive bench testing
and we believe we have successfully addressed the issues as presented.
Additional devices were delivered beginning in early 2017. Controllers with the
U.S. version of the revised software were also used in the IAP312 clinical study
that was initiated in September 2016 . There can be no assurance that the issues
identified in the initial pilot and launch phases by Grünenthal will not have a
material adverse impact on future sales of Zalviso in Europe . Further, if new
issues occur, there may be a material adverse impact on the future sales of
Zalviso in Europe which may have a negative impact on future revenues received
and recognized by us.
We have not realized the expected benefits from our collaboration with Grünenthal, and may not realize the expected benefits from any New Arrangement, due to a number of important factors, including:
• The timing and amount of any payments we may receive under our agreements will
depend on, among other things, the efforts, allocation of resources, and
successful commercialization of Zalviso by any future collaboration partner in
Europe ;
• Grünenthal changed the focus of its commercialization efforts to pursue
higher-priority programs and any future collaboration partner may do the same;
• Grünenthal stopped its commercialization efforts in countries where it had the
sole right to commercialize Zalviso, requiring us to find another
collaboration partner for Zalviso in Europe ; and
• Grünenthal has terminated its agreements with us, and any future collaboration
partner may also terminate any future agreement with us, adversely affecting
our potential revenue from Zalviso;
47-------------------------------------------------------------------------------- Any failures in commercialization of Zalviso outsidethe United States could have a material adverse impact on our business, including an adverse impact on the commercialization of DSUVIA or the development of Zalviso inthe United States , if related to issues underlying the sufentanil sublingual tablet technology, safety or efficacy. Additionally, we agreed to certain representations and covenants relating to the Grünenthal Agreements under our agreements with PDL, and, if we breach those representations or covenants, we may become subject to indemnification claims by SWK (assignee of PDL) and liable to SWK for its indemnifiable losses relating to such breaches. The amount of such losses could be material and could have a material adverse impact on our business.
We will be substantially dependent on Aguettant to successfully commercialize
DZUVEO in
InJune 2018 , the EC granted marketing approval for DZUVEO and inJuly 2021 we entered into the DZUVEO Agreement with Aguettant to commercialize DZUVEO inEurope . We will be substantially dependent on Aguettant to successfully commercialize DZUVEO inEurope . Any failures in the commercialization of DZUVEO inEurope could have a significant adverse impact on our revenues and operating results. The DZUVEO Agreement requires us to support the manufacturing and supply of DZUVEO for Aguettant. In addition, we anticipate we may need comparator studies inEurope to ensure premium reimbursement in certain countries. Our inability to profitably manufacture and supply DZUVEO to Aguettant, or to successfully complete these additional comparator studies and obtain premium reimbursement in certain countries, may prevent, limit or delay commercialization and any associated future revenues from DZUVEO inEurope .
We have limited experience commercializing DSUVIA, which may make it difficult to predict our future performance or evaluate our business and prospects.
Since inception, our operations have been primarily focused on developing our technology and undertaking pharmaceutical development and clinical trials for DSUVIA and Zalviso, understanding the market potential for DSUVIA and Zalviso, and preparing for the commercialization of DSUVIA and the potential commercialization of Zalviso inthe United States . We launched commercialization efforts for DSUVIA inFebruary 2019 . As a result of our limited commercialization experience, any predictions that are made about our future performance, or viability, or evaluation of our business and prospects, may not be accurate. We will require additional capital and may be unable to raise capital, which would force us to delay, reduce or eliminate our commercialization efforts and product development programs and could cause us to cease operations. Launch of a commercial pharmaceutical product and pharmaceutical development activities can be time consuming and costly. We expect to incur significant expenditures in connection with supporting our ongoing commercialization activities for DSUVIA, manufacturing and supply activities for DZUVEO, and research and development activities for Zalviso and the PFS Products, including the FDA regulatory review of the Zalviso NDA, once resubmitted. While we believe we have sufficient capital resources to continue planned operations for at least the next twelve months, we will need additional capital to pursue full commercialization of DSUVIA and our product candidates, if approved. Clinical trials, regulatory reviews, and the launch of commercial product are expensive activities. In addition, commercialization costs for DSUVIA and our product candidates, if approved, inthe United States may be significantly higher than estimated as a result of technical difficulties or otherwise. Revenues may be lower than expected and costs to produce such revenues may exceed those revenues. We will need to seek additional capital to continue operations. Such capital demands could be substantial. In the future, we may seek to sell additional equity securities, including under the Sales Agreement with Cantor, and debt securities, monetize or securitize certain assets including future royalty streams and milestones, refinance our loan agreement, obtain a revolving credit facility, enter into product development, license or distribution agreements with third parties, or divest DSUVIA, DZUVEO or Zalviso. Such arrangements may not be available on favorable terms, if at all. Future events and circumstances, including those beyond our control, may cause us to consume capital more rapidly than we currently anticipate. Furthermore, any product development, licensing, distribution or sale agreements that we enter into may require us to relinquish valuable rights. We may not be able to obtain sufficient additional funding or enter into a strategic transaction in a timely manner. If adequate funds are not available, we would be required to reduce our workforce, reduce the scope of, or cease, the commercial launch of DSUVIA, or the development of our product candidates in advance of the date on which we exhaust our cash resources to ensure that we have sufficient capital to meet our obligations and continue on a path designed to preserve stockholder value. Securing additional financing may divert our management from our day-to-day activities, which may adversely affect our ability to commercialize DSUVIA or develop our product candidates. In addition, we cannot guarantee that future financing will be available in sufficient amounts or on terms acceptable to us, if at all. If we are unable to raise additional capital when required or on acceptable terms, we may be required to:
• significantly scale back or discontinue the commercialization of DSUVIA, or
the development of our product candidates;
• seek additional corporate partners for Zalviso on terms that might be less
favorable than might otherwise be available;
48--------------------------------------------------------------------------------
• seek corporate partners for DSUVIA/DZUVEO on terms that might be less
favorable than might otherwise be available; or
• relinquish, or license on unfavorable terms, our rights to technologies or
products that we otherwise would seek to develop or commercialize ourselves.
To fund our operations, we may sell additional equity securities, which may result in dilution to our stockholders, or debt securities, which may impose restrictions on our business.
We expect that significant additional capital will be needed in the future to continue our planned operations. In order to raise additional funds to support our operations, we may sell additional equity securities, including under the Controlled Equity OfferingSM Sales Agreement, or the ATM Agreement, withCantor Fitzgerald & Co. , or Cantor, as agent. We may sell common stock, convertible securities, or other equity securities in one or more transactions at prices and in a manner we determine from time to time. Selling additional equity securities may result in dilution to our existing stockholders and new investors may be materially diluted by subsequent sales. Incurring additional indebtedness, including through the sale of debt securities, would result in increased fixed payment obligations and could also result in additional restrictive covenants, such as limitations on our ability to incur additional debt, limitations on our ability to acquire, sell or license intellectual property rights and other operating restrictions, such as minimum cash balances, that could adversely impact our ability to conduct our business. Sales of equity or debt securities may also provide new investors with rights superior to our existing stockholders. If we are unable to expand our operations or otherwise capitalize on our business opportunities, our business, financial condition and results of operations could be materially adversely affected, and we may not be able to meet our debt service obligations. In addition, worsening economic conditions and other adverse effects or developments relating to the ongoing COVID-19 pandemic may negatively affect the market price of our stock, regardless of our actual operating performance. The market price for our common stock is likely to continue to be volatile, particularly due to the ongoing COVID-19 pandemic, and subject to significant price and volume fluctuations in response to market, industry and other factors. If additional funding is not available on favorable terms, if at all, due to these factors, we may not be able to obtain sufficient additional funding to support our operations. The terms of our loan agreement with Oxford may restrict our current and future operations, particularly our ability to respond to changes in business or to take certain actions, including to pay dividends to our stockholders. OnMay 30, 2019 , we entered into the Loan Agreement withOxford Finance LLC , or Oxford, aDelaware limited liability company, as the Lender. The Loan Agreement contains, and any future indebtedness we incur will likely contain, a number of restrictive covenants that impose operating restrictions, including restrictions on our ability to engage in acts that may be in our best long-term interests. The Loan Agreement includes covenants that, among other things, restrict our ability to (i) declare dividends or redeem or repurchase equity interests; (ii) incur additional liens; (iii) make loans and investments; (iv) incur additional indebtedness; (v) engage in mergers, acquisitions, and asset sales; (vi) transact with affiliates; (vii) undergo a change in control; (viii) add or change business locations; and (ix) engage in businesses that are not related to our existing business. The Loan Agreement also requires that we at all times maintain unrestricted cash of not less than$5.0 million . A breach of any of these covenants could result in an event of default under the Loan Agreement. Upon the occurrence of such an event of default, a default interest rate of an additional 5% may be applied to the outstanding loan balances and all outstanding obligations under the Loan Agreement can be declared to be immediately due and payable If our indebtedness is accelerated, we cannot assure you that we will have sufficient assets to repay the indebtedness. The restrictions and covenants in the Loan Agreement and any future financing agreements may adversely affect our ability to finance future operations or capital needs or to engage in other business activities.
We might be unable to service our existing debt due to a lack of cash flow and might be subject to default.
As ofJune 30, 2021 , we had approximately$17.2 million of accrued debt under the Loan Agreement. The Loan Agreement has a scheduled maturity date ofJune 1, 2023 and is secured by a first priority security interest in substantially all of our assets, with the exception of our intellectual property and those assets sold under the Royalty Monetization, where the security interest is limited to proceeds of intellectual property if it is licensed or sold. If we do not make the required payments when due, either at maturity, or at applicable installment payment dates, or if we breach the agreement or become insolvent, the Lender could elect to declare all amounts outstanding, together with accrued and unpaid interest, and other payments, to be immediately due and payable. Additional capital may not be available on terms acceptable to us, or at all. Even if we were able to repay the full amount in cash, any such repayment could leave us with little or no working capital for our business. If we are unable to repay those amounts, the Lender will have a first claim on our assets pledged under the Loan Agreement. If the lender should attempt to foreclose on the collateral, it is unlikely that there would be any assets remaining after repayment in full of such secured indebtedness. Any default under the Loan Agreement and resulting foreclosure would have a material adverse effect on our financial condition and our ability to continue our operations. 49
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Risks Related to Our Reliance on Third Parties
We rely on third party manufacturers to produce commercial supplies of DSUVIA inthe United States , commercial supplies of Zalviso inEurope , and clinical supplies of Zalviso inthe United States , and will rely on third party manufacturers to produce DZUVEO for Aguettant and on Aguettant to produce commercial supplies of the PFS Products, if approved, inthe United States . The failure of third-party manufacturers to provide us with adequate commercial and clinical supplies could result in a material adverse effect on our business.*
Third party manufacturers produce commercial and clinical supplies of our products and product candidates. Reliance on third party manufacturers entails many risks including:
• the inability to meet our product specifications and quality requirements
consistently;
• a delay or inability to procure or expand sufficient manufacturing capacity;
• manufacturing and product quality issues related to scale-up of manufacturing;
• costs and validation of new equipment and facilities required for scale-up;
• a failure to maintain in good order our production and manufacturing equipment
for our products;
• a failure to comply with cGMP and similar foreign standards;
• the inability to negotiate manufacturing or supply agreements with third
parties under commercially reasonable terms;
• termination or nonrenewal of manufacturing or supply agreements with third
parties in a manner or at a time that is costly or damaging to us;
• the reliance on a limited number of sources, and in some cases, single sources
for product components, such that if we are unable to secure a sufficient
supply of these product components, we will be unable to manufacture and sell
our products in a timely fashion, in sufficient quantities or under acceptable
terms;
• the lack of qualified backup suppliers for those components that are currently
purchased from a sole or single source supplier;
• operations of our third-party manufacturers or suppliers could be disrupted by
conditions unrelated to our business or operations, including the bankruptcy
of the manufacturer or supplier, or government orders related to the COVID-19
pandemic;
• carrier disruptions or increased costs that are beyond our control; and
• the failure to deliver our products under specified storage conditions and in
a timely manner.
Any of these events could lead to stock outs, inability to successfully commercialize our products, clinical trial delays, or failure to obtain regulatory approval. Some of these events could be the basis for FDA action, including injunction, recall, seizure, or total or partial suspension of production.
In addition, the DZUVEO Agreement requires us to manufacture and supply DZUVEO to Aguettant. As mentioned above, we were obligated to manufacture and supply Zalviso under the Grünenthal Agreements for use inEurope and their other licensed territories and will likely be required to do so under any New Arrangement. If we are unable to establish a reliable commercial supply of DZUVEO for Aguettant, and, if a New Arrangement is entered into, Zalviso forEurope , we may be unable to satisfy our obligations under the DZUVEO Agreement or any New Arrangement in a timely manner or at all, and we may, as a result, be in breach of such agreements. If any such breach, or other breach, were to be material and remain uncured, it could result in termination of the agreement, which in turn could, in the case of a New Arrangement, result in us being responsible for indemnification of losses suffered by SWK (assignee of PDL) under the Royalty Monetization. If any of these events were to occur, our business would be materially adversely affected.
We rely on limited sources of supply for the active pharmaceutical ingredient, or API, of DSUVIA and Zalviso and any disruption in the chain of supply may cause a delay in supplying DSUVIA and Zalviso.
Currently we only have one supplier qualified as a vendor for the manufacture of DSUVIA, known as DZUVEO inEurope , and Zalviso with the FDA and EMA, respectively. If supply from the approved vendor is interrupted, there could be a significant disruption in commercial supply. For example, our API provider for DSUVIA is changing its process for manufacturing our drug, which could impact our commercial supply of API for DSUVIA. This change in process requires a regulatory submission to the FDA.The European Health Authority has approved the change in process for both DZUVEO and Zalviso in the EU. In theU.S. , a regulatory submission has been submitted to support the use of the API made with the new manufacturing process, but there is no guarantee that the FDA will approve the submission. For example, inJuly 2019 , we received notice from the FDA that a deficiency in the API manufacturer's drug master file, or DMF, will need to be addressed before the submission can be approved. The API manufacturer responded to theFDA's DMF deficiency notice for the new manufacturing process, and we resubmitted the Supplemental NDA seeking approval of use of the new manufacturing process API. Any alternate vendor would need to be qualified through an NDA supplement and/or an MAA variation which could result in delays. The FDA or other regulatory agencies outside ofthe United States may also require additional trials if a new sufentanil supplier is relied upon for commercial production. 50
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Manufacture of sufentanil sublingual tablets requires specialized equipment and expertise.
Ethanol, which is used in the manufacturing process for our sufentanil sublingual tablets, is flammable, and sufentanil is a highly potent, Schedule II controlled substance. These factors necessitate the use of specialized equipment and facilities for manufacture of sufentanil sublingual tablets. There are a limited number of facilities that can accommodate our manufacturing process and we need to use dedicated equipment throughout development and commercial manufacturing to avoid the possibility of cross-contamination. If our equipment breaks down or needs to be repaired or replaced, it may cause significant disruption in clinical or commercial supply, which could result in delay in the process of obtaining approval for or sale of our products. Furthermore, we are using one manufacturer to produce our sufentanil sublingual tablets. Any problems with our existing facility or equipment, including ongoing expansion, may impair our ability to successfully commercialize DSUVIA or Zalviso, if approved, complete our clinical trials and increase our cost.
Manufacturing issues may arise that could delay or increase costs related to commercialization, product development and regulatory approval.*
We have relied, and will continue to rely, on contract manufacturers, component fabricators and third-party service providers to produce the necessary DSUVIA single-dose applicator, or SDA, and Zalviso devices for the commercial marketplace. We currently outsource manufacturing and packaging of the DSUVIA SDA and the controller, dispenser and cartridge components of the Zalviso device to third parties and intend to continue to do so. Some of these component purchases were made and will continue to be made utilizing short-term purchase agreements and we may not be able to enter into long-term agreements for commercial supply of DSUVIA, DZUVEO or Zalviso devices with each of the third-party manufacturers or may be unable to do so on acceptable terms. In addition, we have encountered and may continue to encounter production issues with our current or future contract manufacturers and other third party service providers, including the reliability of the production equipment, quality of the components produced, their inability to meet demand or other unanticipated delays including scale-up and automating processes, which could adversely impact our ability to supply our customers with DSUVIA, Zalviso and DZUVEO inEurope , and, if approved, Zalviso in theU.S. and any other foreign territories. As we scale up manufacturing of DSUVIA and Zalviso, if approved, and conduct required stability testing, product, packaging, equipment and process-related issues may require refinement or resolution. For example, as we scale up, we may identify significant issues which could result in failure to maintain regulatory approval of DSUVIA, increased scrutiny by regulatory agencies, delays in clinical program and regulatory approval, increases in our operating expenses, or failure to obtain approval for our product candidates inthe United States . We have built out a suite within our CMO's production facility inCincinnati, Ohio that serves as a manufacturing facility for clinical and commercial supplies of sufentanil sublingual tablets. Late-stage development and manufacture of registration stability lots, which were utilized in clinical trials, were manufactured at this location. While we produced a number of commercial lots to support Grünenthal's launch inEurope , our experience is limited, which impacted our ability to deliver commercial supplies to Grünenthal on a timely basis, and may in the future impact our ability to deliver commercial supplies under any New Arrangement, if required, on a timely basis. InJanuary 2013 , we entered into an agreement with a CMO to manufacture, supply, and provide certain validation and stability services with respect to Zalviso for potential sales inthe United States ,Canada ,Mexico and other countries, subject to agreement by the parties to any additional fees for such other countries. OnAugust 22, 2017 , we entered into an amendment to this agreement to manufacture, supply, and provide certain validation and stability services with respect to DSUVIA for sales inthe United States , and potential sales inCanada andMexico , and other countries. There is no guarantee that our CMO's services will be satisfactory or that they will continue to meet the strict regulatory guidelines of the FDA or other foreign regulatory agencies. If our CMO cannot provide us with an adequate supply of sufentanil sublingual tablets, we may be required to pursue alternative sources of manufacturing capacity. Switching or adding commercial manufacturing capability can involve substantial cost and require extensive management time and focus, as well as additional regulatory filings which may result in significant delays. In addition, there is a natural transition period when a new manufacturing facility commences work. As a result, delays may occur, which can materially impact our ability to meet our desired commercial timelines, thereby increasing our costs and reducing our ability to generate revenue. 51
-------------------------------------------------------------------------------- The facilities of any of our future manufacturers of sufentanil-containing sublingual tablets must be approved by the FDA or the relevant foreign regulatory agency, such as the EMA, before commercial distribution from such manufacturers occurs. We do not fully control the manufacturing process of sufentanil sublingual tablets and are completely dependent on these third-party manufacturing partners for compliance with the FDA or other foreign regulatory agency's requirements for manufacture. In addition, although our third-party manufacturers are well-established commercial manufacturers, we are dependent on their continued adherence to cGMP manufacturing and acceptable changes to their process. If our manufacturers do not meet the FDA or other foreign regulatory agency's strict regulatory requirements, they will not be able to secure FDA or other foreign regulatory agency approval for their manufacturing facilities. Although European inspectors have approved our tablet manufacturing site, our third-party manufacturing partner is responsible for maintaining compliance with the relevant foreign regulatory agency's requirements. If the FDA or the relevant foreign regulatory agency does not approve these facilities for the commercial manufacture of sufentanil sublingual tablets, we will need to find alternative suppliers, which would result in significant delays in obtaining FDA approval for Zalviso, and other foreign regulatory agency approval of DSUVIA/DZUVEO and Zalviso outsideEurope . These challenges may have a material adverse impact on our business, results of operations, financial condition and prospects. We may not be able to establish additional sources of supply for sufentanil-containing sublingual tablets or device manufacture. Such suppliers are subject to FDA and other foreign regulatory agency's regulations requiring that materials be produced under cGMPs or Quality System Regulations, or QSR, or in ISO 13485 accredited manufacturers, and subject to ongoing inspections by regulatory agencies. Failure by any of our suppliers to comply with applicable regulations may result in delays and interruptions to our product supply while we seek to secure another supplier that meets all regulatory requirements. In addition, if we are unable to establish a reliable commercial supply of Zalviso forEurope , we may be unable to satisfy our obligations under any New Arrangement, if required, in a timely manner or at all, and we may, as a result, be in breach of any New Arrangement. For DSUVIA, we currently package the finished goods under a manual process and would package DZUVEO in the same manner. The capacity and cost to package the goods under this manual process are not optimal to support successful future sales of DSUVIA and DZUVEO. We have purchased and installed an automated filling and packaging line to support increased capacity packaging for DSUVIA and DZUVEO. Despite the delays due to the impact of COVID-19, we have now completed the acquisition and installation of this line; however, there can be no assurance that we will be able to obtain the necessary regulatory approvals to manufacture product on this line. We rely on third parties to conduct, supervise and monitor our clinical trials, and if those third parties perform in an unsatisfactory manner, it may harm our business. We utilized contract research organizations, or CROs, for the conduct of the Phase 2 and 3 clinical trials of DSUVIA, as well as our Phase 3 clinical program for Zalviso. We rely on CROs, as well as clinical trial sites, to ensure the proper and timely conduct of our clinical trials and document preparation. While we have agreements governing their activities, we have limited influence over their actual performance. We have relied and plan to continue to rely upon CROs to monitor and manage data for our post-approval clinical programs for DSUVIA and any FDA-required clinical programs for Zalviso, as well as the execution of nonclinical and clinical trials. We control only certain aspects of our CROs' activities. Nevertheless, we are responsible for ensuring that each of our trials is conducted in accordance with the applicable protocol, legal, regulatory and scientific standards and our reliance on the CROs does not relieve us of our regulatory responsibilities. We, and our CROs, are required to comply with theFDA's current good clinical practices, or cGCPs, which are regulations and guidelines enforced by the FDA for all product candidates in clinical development. The FDA enforces these cGCPs through periodic inspections of trial sponsors, principal investigators and clinical trial sites. If we or our CROs fail to comply with applicable cGCPs, the clinical data generated in our clinical trials may be deemed unreliable and the FDA may require us to perform additional clinical trials before approving our marketing applications. Upon inspection, the FDA may determine that our clinical trials do not comply with cGCPs. Accordingly, if our CROs or clinical trial sites fail to comply with these regulations, we may be required to repeat clinical trials, which would delay the regulatory process. Our CROs are not our employees, and we cannot control whether or not they devote sufficient time and resources to our ongoing clinical and nonclinical programs. These CROs may also have relationships with other commercial entities, including our competitors, for whom they may also be conducting clinical trials, or other drug development activities which could harm our competitive position. We face the risk of potential unauthorized disclosure or misappropriation of our intellectual property by CROs, which may allow our potential competitors to access our proprietary technology. If our CROs do not successfully carry out their contractual duties or obligations, fail to meet expected deadlines, or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to our clinical protocols or regulatory requirements, or for any other reasons, our clinical trials may be extended, delayed or terminated, and we may not be able to obtain regulatory approval for, or successfully commercialize Zalviso. As a result, our financial results and the commercial prospects for Zalviso, if approved, would be harmed, our costs could increase, and our ability to generate revenues could be delayed. 52 --------------------------------------------------------------------------------
Risks Related to Our Business Operations and Industry
Failure to receive required quotas of controlled substances or comply with the
Our sufentanil-based products are subject to extensive regulation by theDEA , due to their status as scheduled drugs. Sufentanil is classified as a Schedule II controlled substance, considered to present a high risk of abuse. The manufacture, shipment, storage, sale and use of controlled substances are subject to a high degree of regulation, including security, record-keeping and reporting obligations enforced by theDEA and also by comparable state agencies. In addition, our contract manufacturers are required to maintain relevant licenses and registrations. This high degree of regulation can result in significant compliance costs, which may have an adverse effect on the commercialization of DSUVIA and the development and commercialization of Zalviso, if approved. TheDEA limits the availability and production of all Schedule II controlled substances, including sufentanil, through a quota system. TheDEA requires substantial evidence and documentation of expected legitimate medical and scientific needs before assigning quotas to manufacturers. Our contract manufacturers apply for quotas on our behalf. We will need significantly greater amounts of sufentanil to successfully commercialize DSUVIA, to support European commercialization of DZUVEO and Zalviso, and to commercialize Zalviso, if approved inthe United States . Any delay by theDEA in establishing the procurement quota, reduction in our quota for sufentanil, failure to increase our quota over time to meet anticipated increases in demand, or refusal by theDEA to establish the procurement quota could delay or stop the commercial sale of our approved products or the clinical development of Zalviso inthe United States . This, in turn, could have a material adverse effect on our business, results of operations, financial condition and prospects.
Our relationships with clinical investigators, health care professionals, consultants, commercial partners, third-party payers, hospitals, and other customers are subject to applicable anti-kickback, fraud and abuse and other healthcare laws, which could expose us to significant penalties.
Healthcare providers, including physicians, and others play a primary role in the recommendation and prescribing of any products for which we may obtain marketing approval. Our business operations and arrangements with investigators, healthcare professionals, consultants, commercial partners, hospitals, third-party payers and customers may expose us to broadly applicable fraud and abuse and other healthcare laws. These laws may constrain the business or financial arrangements and relationships through which we research, market, sell and distribute the products for which we obtain marketing approval. Applicable federal and state healthcare laws include, but are not limited to, the following:
• the federal healthcare Anti-Kickback Statute, which prohibits, among other
things, persons or entities from knowingly and willfully soliciting, offering,
receiving or paying any remuneration (including any kickback, bribe, or
rebate), directly or indirectly, overtly or covertly, in cash or in kind, to
induce or reward either the referral of an individual for, or the purchase,
lease, order or recommendation of, any good, facility, item or service, for
which payment may be made, in whole or in part, under federal healthcare
programs such as Medicare and Medicaid;
• the federal civil and criminal false claims laws, which prohibit, among other
things, individuals or entities from knowingly presenting, or causing to be
presented, to the federal government, claims for payment or approval that are
false or fraudulent or from knowingly making a false statement to improperly
avoid, decrease or conceal an obligation to pay money to the federal
government;
• the federal Health Insurance Portability and Accountability Act of 1996, or
HIPAA, which, among other things, imposes criminal liability for knowingly and
willfully executing, or attempting to execute, a scheme to defraud any
healthcare benefit program or to obtain, by means of false or fraudulent
pretenses, representations, or promises, any of the money or property owned
by, or under the custody or control of, any healthcare benefit program,
regardless of the payer (e.g., public or private) and knowingly or willfully
falsifying, concealing, or covering up by any trick or device a material fact
or making any materially false statement in connection with the delivery of,
or payment for, healthcare benefits, items or services relating to healthcare
matters;
• HIPAA, as amended by the Health Information Technology for Economic and
Clinical Health Act, or HITECH, and their implementing regulations, which
impose certain obligations, including mandatory contractual terms, on covered
healthcare providers, health plans and clearinghouses, and their respective
business associates that perform services for them that involve the use, or
disclosure of, individually identifiable health information, as well as their
covered subcontractors with respect to safeguarding the privacy, security and
transmission of individually identifiable health information;
• foreign laws, regulations, standards and regulatory guidance which govern the
collection, use, disclosure, retention, security and transfer of personal
data, including the
which introduces strict requirements for processing personal data of
individuals within the European Union ;
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• the federal transparency law, enacted as part of the Affordable Care Act, and
its implementing regulations, which requires certain manufacturers of drugs,
devices, biologicals and medical supplies to report annually to the CMS
information related to payments and other transfers of value provided to
physicians, (defined to include, doctors, dentists, optometrists, podiatrists
and chiropractors) and teaching hospitals, as well as ownership and investment
interests held by physicians and their immediate family members. Beginning in
2022, applicable manufacturers also will be required to report such
information regarding payments and other transfers of value made to physician
assistants, nurse practitioners, clinical nurse specialists, anesthesiologist
assistants, certified registered nurse anesthetists and certified nurse
midwives during the previous year;
• analogous state laws that may apply to our business practices, including but
not limited to, state laws that require pharmaceutical companies to implement
compliance programs and/or comply with the pharmaceutical industry's voluntary
compliance guidelines; state laws that impose restrictions on pharmaceutical
companies' marketing practices and require manufacturers to track and file
reports relating to pricing and marketing information, which requires tracking
and reporting gifts, compensation and other remuneration and items of value
provided to healthcare professionals and entities, state and local laws that
require the registration of pharmaceutical sales representatives, and state
laws governing the privacy and security of health information in certain
circumstances, many of which differ from each other in significant ways, with
differing effects; and
• the federal Foreign Corrupt Practices Act of 1977, United Kingdom Bribery Act
2010 and other similar anti-bribery laws in other jurisdictions which
generally prohibit companies and their intermediaries from providing money or
anything of value to officials of foreign governments, foreign political
parties, or international organizations with the intent to obtain or retain
business or seek a business advantage.
Recently, there has been a substantial increase in anti-bribery law enforcement
activity by U.S. regulators, with more frequent and aggressive investigations
and enforcement proceedings by both the Department of Justice and the SEC . A
determination that our operations or activities are not, or were not, in
compliance with United States or foreign laws or regulations could result in the
imposition of substantial fines, interruptions of business, loss of supplier,
vendor or other third-party relationships, termination of necessary licenses and
permits, and other legal or equitable sanctions. Other internal or government
investigations or legal or regulatory proceedings, including lawsuits brought by
private litigants, may also follow as a consequence.
Efforts to ensure that our business arrangements with third parties will comply
with applicable healthcare laws involve substantial costs. It is possible that
governmental authorities will conclude that our business practices may not
comply with current or future statutes, regulations, agency guidance or case law
involving applicable fraud and abuse or other healthcare laws. If our operations
are found to be in violation of any of these or any other healthcare regulatory
laws or any other governmental regulations that may apply to us, we may be
subject to significant civil, criminal and administrative penalties, damages,
fines, disgorgement, imprisonment, exclusion from government funded healthcare
programs, such as Medicare and Medicaid, contractual damages, reputational harm,
increased losses and diminished profits, additional oversight and reporting
obligations if we become subject to a corporate integrity agreement or other
agreement to resolve allegations of non-compliance with these laws, and the
curtailment or restructuring of our operations any of which could adversely
affect our ability to operate our business and our financial results. Any action
against us for violation of these laws, even if we successfully defend against
it, could cause us to incur significant legal expenses or divert our
management's attention from the operation of our business.
In order to supply the Zalviso device to any future collaborator for commercial
sales in Europe , we must maintain conformity of our quality system to applicable
ISO standards and must comply with applicable European laws and directives.
We underwent a Conformité Européenne approval process for the Zalviso device,
more commonly known as a CE Mark approval process. We received CE Mark approval
in December 2014 , which permits the commercial sale of the Zalviso device in
Europe . In connection with the CE Mark approval, we were also granted
International Standards Organization , or ISO, 13485:2003 certification of our
quality management system in November 2014 . This is an internationally
recognized quality standard for medical devices. The CE Mark was originally
issued by the British Standards Institution , or BSI, a Notified Body, or NB,
located in the United Kingdom , or U.K. , or BSI-U.K. The CE Mark file and
certification has been transferred to the Netherlands NB of BSI, or BSI-NL , to
mitigate the uncertainty with regards to Brexit. The ISO certification issued
through BSI-U.K. was recently upgraded to the latest version of the standard,
ISO 13485:2016 through BSI-U.K. and remains in effect. BSI ISO 13485:2016
certification recognizes that consistent quality policies and procedures are in
place for the development, design and manufacturing of medical devices. The
certification indicates that we have successfully implemented a quality system
that conforms to ISO 13485 standards for medical devices. Certification to this
standard is one of the key regulatory requirements for a CE Mark in the EU and
European Economic Area (which includes the 27 EU member states as well as
Norway , Iceland and Liechtenstein ), or EEA, as well as to meet equivalent
requirements in other international markets. The certification applies to the
Redwood City, California location which designs, manufactures and distributes
finished medical devices, and includes critical suppliers. If we fail to remain
in compliance with applicable European laws and directives, we would be unable
to continue to affix the CE Mark to our Zalviso device, which would prevent any
future collaboration partner from selling these devices within the EU and EEA.
54-------------------------------------------------------------------------------- Significant disruptions of our information technology systems or data security incidents could result in significant financial, legal, regulatory, business and reputational harm to us. We are increasingly dependent on information technology systems and infrastructure, including mobile technologies, to operate our business. In the ordinary course of our business, we collect, store, process and transmit large amounts of sensitive information, including intellectual property, proprietary business information, personal information and other confidential information. It is critical that we do so in a secure manner to maintain the confidentiality, integrity and availability of such sensitive information. We have also outsourced elements of our operations (including elements of our information technology infrastructure) to third parties, and as a result, we manage a number of third-party vendors who may or could have access to our computer networks or our confidential information. In addition, many of those third parties in turn subcontract or outsource some of their responsibilities to third parties. While all information technology operations are inherently vulnerable to inadvertent or intentional security breaches, incidents, attacks and exposures, the accessibility and distributed nature of our information technology systems, and the sensitive information stored on those systems, make such systems potentially vulnerable to unintentional or malicious internal and external attacks on our technology environment. Potential vulnerabilities can be exploited from inadvertent or intentional actions of our employees, third-party vendors, business partners, or by malicious third parties. Attacks of this nature are increasing in their frequency, levels of persistence, sophistication and intensity, and are being conducted by sophisticated and organized groups and individuals with a wide range of motives (including, but not limited to, industrial espionage) and expertise, including organized criminal groups, "hacktivists," nation states and others. In addition to the extraction of sensitive information, such attacks could include the deployment of harmful malware, ransomware, denial-of-service attacks, social engineering and other means to affect service reliability and threaten the confidentiality, integrity and availability of information. In addition, the prevalent use of mobile devices increases the risk of data security incidents. Significant disruptions of our third-party vendors' and/or business partners' information technology systems or other similar data security incidents could adversely affect our business operations and result in the loss, misappropriation, and/or unauthorized access, use or disclosure of, or the prevention of access to, sensitive information, which could result in financial, legal, regulatory, business and reputational harm to us. In addition, information technology system disruptions, whether from attacks on our technology environment or from computer viruses, natural disasters, terrorism, war and telecommunication and electrical failures, could result in a material disruption of our development programs and our business operations. For example, the loss of clinical trial data from completed or future clinical trials could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data. There is no way of knowing with certainty whether we have experienced any data security incidents that have not been discovered. While we have no reason to believe this to be the case, attackers have become very sophisticated in the way they conceal access to systems, and many companies that have been attacked are not aware that they have been attacked. Any event that leads to unauthorized access, use or disclosure of personal information, including but not limited to personal information regarding our patients or employees, could disrupt our business, harm our reputation, compel us to comply with applicable federal and state breach notification laws and foreign law equivalents, subject us to time consuming, distracting and expensive litigation, regulatory investigation and oversight, mandatory corrective action, require us to verify the correctness of database contents, or otherwise subject us to liability under laws, regulations and contractual obligations, including those that protect the privacy and security of personal information. This could result in increased costs to us, and result in significant legal and financial exposure and/or reputational harm. In addition, any failure or perceived failure by us or our vendors or business partners to comply with our privacy, confidentiality or data security-related legal or other obligations to third parties, or any further security incidents or other inappropriate access events that result in the unauthorized access, release or transfer of sensitive information, which could include personally identifiable information, may result in governmental investigations, enforcement actions, regulatory fines, litigation, or public statements against us by advocacy groups or others, and could cause third parties, including clinical sites, regulators or current and potential partners, to lose trust in us or we could be subject to claims by third parties that we have breached our privacy- or confidentiality-related obligations, which could materially and adversely affect our business and prospects. Moreover, data security incidents and other inappropriate access can be difficult to detect, and any delay in identifying them may lead to increased harm of the type described above. While we have implemented security measures intended to protect our information technology systems and infrastructure, there can be no assurance that such measures will successfully prevent service interruptions or security incidents.
Business interruptions could delay our operations and sales efforts.
Our headquarters is located in theSan Francisco Bay Area , near known earthquake fault zones and is vulnerable to significant damage from earthquakes. Our contract manufacturers, suppliers, clinical trial sites and local and national transportation vendors are all subject to business interruptions due to weather, outbreaks of pandemic diseases, natural disasters, or man-made incidents. We are also vulnerable to other types of natural disasters and other events that could disrupt our operations. If any of these events occurred and prevented us or third parties on which we rely from using all or a significant portion of our or their facilities, it may be difficult or, in certain cases, impossible for us to continue our business and operations for a substantial period of time. We do not carry insurance for earthquakes or other natural disasters, and we may not carry sufficient business interruption insurance to compensate us for losses that may occur. Any losses or damages we incur could have a material adverse effect on our business operations. 55 --------------------------------------------------------------------------------
Our future success depends on our ability to retain key executives and to attract, retain and motivate qualified personnel.
We are highly dependent on principal members of our executive team, the loss of whose services may adversely impact the achievement of our objectives. While we have entered into offer letters with each of our executive officers, any of them could leave our employment at any time, as all of our employees are "at will" employees. Recruiting and retaining qualified scientific, manufacturing, and commercial personnel will also be critical to our success. We may not be able to attract and retain these personnel on acceptable terms given the competition among numerous pharmaceutical and biotechnology companies for similar personnel. We also experience competition for the hiring of scientific and clinical personnel from universities and research institutions. There is currently a shortage of skilled executives in our industry, which is likely to continue. As a result, competition for skilled personnel is intense and the turnover rate can be high. In addition, failure to succeed in clinical trials, or delays in the regulatory approval process, may make it more challenging to recruit and retain qualified personnel. The inability to recruit or loss of the services of any executive or key employee might impede the progress of our research, development and commercialization objectives.
We may acquire companies, product candidates or products or engage in strategic transactions, which could divert our management's attention and cause us to incur various costs and expenses.
We may acquire or invest in companies, product candidates or products that we believe could complement or expand our business or otherwise offer growth opportunities. The pursuit of potential acquisitions or investments may divert the attention of management and has caused, and in the future may cause, us to incur various costs and expenses in identifying, investigating, and pursuing them, whether or not they are consummated. We may not be able to identify desirable acquisitions or investments or be successful in completing or realizing anticipated benefits from such transactions. In addition, the acquisition of product candidates and products is a highly competitive area, and many other companies are pursuing the same or similar product candidates to those that we may consider attractive. Larger companies with more well-established and diverse revenue streams may have a competitive advantage over us due to their size, financial resources and more extensive clinical development and commercialization capabilities.
In addition, we may receive inquiries relating to potential strategic transactions, including collaborations, licenses, and acquisitions. Such potential transactions may divert the attention of management and may cause us to incur various costs and expenses in investigating and evaluating such transactions, whether or not they are consummated.
We face potential product liability claims, and, if such claims are successful, we may incur substantial liability.
Commercial sales of DSUVIA and Zalviso expose us to the risk of product liability claims. Product liability claims might be brought against us by patients, health care providers, pharmaceutical companies or others selling or otherwise coming into contact with our products. If we cannot successfully defend against product liability claims, we could incur substantial liability and costs. In addition, regardless of merit or eventual outcome, product liability claims may result in: • impairment of our business reputation; • costs due to related litigation; • distraction of management's attention from our primary business; • substantial monetary awards to patients or other claimants; • the inability to commercialize our products; and • decreased demand for our products. Our current product liability insurance coverage may not be sufficient to reimburse us for any expenses or losses we may suffer. In addition, our current product liability insurance contains an exclusion related to any claims related to our products from a governmental body, or payer, or those claims arising from a multi-plaintiff action for bodily injury or property damage. Multi-plaintiff claims caused by product defects are covered. This exclusion does not apply to any bodily injury claim related to our products made by an individual. On occasion, large judgments have been awarded in class action lawsuits based on drugs that had unanticipated adverse effects. A successful product liability claim, or series of claims, brought against us could cause our stock price to decline and, if judgments are excluded from our insurance coverage or exceed our insurance coverage, could adversely affect our results of operations and business. Moreover, insurance coverage is becoming increasingly expensive, and, in the future, we may not be able to maintain insurance coverage at a reasonable cost or in sufficient amounts to protect us against losses due to liability. Our insurance coverage included the sale of Zalviso to our former commercial partner, Grünenthal, and will likely include the sale of Zalviso by any future commercial partner. We intend to commercialize and promote DZUVEO inEurope with a strategic partner which may result in further expansion of our insurance coverage to include sales of DZUVEO inEurope . There can be no assurance that such coverage will be adequate to protect us against any future losses due to liability. 56
-------------------------------------------------------------------------------- Our employees, independent contractors, principal investigators, consultants, commercial partners and vendors may engage in misconduct or other improper activities, including non-compliance with regulatory standards and requirements and insider trading. We are exposed to the risk that our employees, independent contractors, investigators, consultants, commercial partners and vendors may engage in fraudulent conduct or other illegal activity. Misconduct by these parties could include intentional, reckless and/or negligent conduct that violates (1) regulations implemented by the FDA and similar foreign regulatory bodies; (2) laws requiring the reporting of true, complete and accurate information to such regulatory bodies; (3) healthcare fraud and abuse laws ofthe United States and similar foreign fraudulent misconduct laws; and (4) laws requiring the reporting of financial information or data accurately. The promotion, sales and marketing of healthcare items and services, as well as certain business arrangements in the healthcare industry are subject to extensive laws designed to prevent misconduct, including fraud, kickbacks, self-dealing and other abusive practices. These laws may restrict or prohibit a wide range of pricing, discounting, marketing, structuring and commission(s), certain customer incentive programs and other business arrangements generally. Activities subject to these laws also involve the improper use of information obtained in the course of patient recruitment for clinical trials. It is not always possible to identify and deter employee and other third-party misconduct. The precautions we take to detect and prevent inappropriate conduct may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to comply with these laws. If any such actions are instituted against us, and we are not successful in defending ourselves, those actions could have a significant impact on our business, including the imposition of significant civil, criminal and administrative penalties, damages, monetary fines, disgorgement, imprisonment, additional oversight and reporting obligations if we become subject to a corporate integrity agreement or similar agreements to resolve allegations of non-compliance with these laws, possible exclusion from participation in Medicare, Medicaid and other federal healthcare programs, contractual damages, reputational harm, diminished profits and future earnings, and curtailment of our operations, any of which could adversely affect our ability to operate our business and our results of operations.
Risks Related to Our Intellectual Property
If we cannot defend our issued patents from third party claims or if our pending patent applications fail to issue, our business could be adversely affected.
To protect our proprietary technology, we rely on patents as well as other intellectual property protections including trade secrets, nondisclosure agreements, and confidentiality provisions. As ofJune 30, 2021 , we are the owner of record of 89 issued patents worldwide. These issued patents cover AcelRx's sufentanil sublingual tablet, medication delivery devices and other platform technology. These issued patents include patents we have listed in theFDA's Orange Book for DSUVIA, and patents expected to provide coverage until 2031. These issued patents also include a European patent covering the DZUVEO device that is expected to provide coverage until at least 2036. Because sufentanil is not a new chemical entity, its regulatory exclusivity period inthe United States is limited to three years under the Hatch-Waxman Act. While the FDA may not approve a 505(b)(2) NDA or abbreviated new drug application, or ANDA, using DSUVIA as its reference listed drug prior toNovember 2, 2021 , we may be subject to certification based on the patents we have listed in theFDA's Orange Book for DSUVIA and engage in litigation against such a 505(b)(2) or ANDA applicant at any time. In addition, we are pursuing a number ofU.S. non-provisional patent applications and foreign national applications directed to DSUVIA and Zalviso. The patent applications that we have filed and have not yet been granted may fail to result in issued patents inthe United States or in foreign countries. Even if the patents do successfully issue, third parties may challenge the patents. Our commercial success will depend in part on successfully defending our current patents against third party challenges and expanding our existing patent portfolio to provide additional layers of patent protection, as well as extending patent protection. There can be no assurance that we will be successful in defending our existing and future patents against third party challenges, or that our pending patent applications will result in additional issued patents.
The patent positions of pharmaceutical companies, including ours, can be highly
uncertain and involve complex and evolving legal and factual questions. No
consistent policy regarding the breadth of claims allowed in pharmaceutical
patents has emerged to date in
There is also no assurance that any patents issued to us will not become the
subject of adversarial proceedings such as opposition, inter partes review,
post-grant review, reissue, supplemental examination, re-examination or other
post-issuance proceedings. In addition, there is no assurance that the
respective court or agency in such adversarial proceedings would not make
unfavorable decisions, such as reducing the scope of a patent of ours or
determining that a patent of ours is invalid or unenforceable. There is also no
assurance that any patents issued to us will provide us with competitive
advantages, will not be challenged by any third parties, or that the patents of
others will not prevent the commercialization of products incorporating our
technology. Furthermore, there can be no guarantee that others will not
independently develop similar products, duplicate any of our products, or design
around our patents.
57-------------------------------------------------------------------------------- Litigation involving patents, patent applications and other proprietary rights is expensive and time consuming. If we are involved in such litigation, it could cause delays in bringing our products to market and interfere with our business. Our commercial success depends in part on not infringing patents and proprietary rights of third parties. Although we are not currently aware of litigation or other proceedings or third-party claims of intellectual property infringement related to DSUVIA or Zalviso, the pharmaceutical industry is characterized by extensive litigation regarding patents and other intellectual property rights. As we enter our target markets, it is possible that competitors or other third parties will claim that our products and/or processes infringe on their intellectual property rights. These third parties may have obtained and may in the future obtain patents covering products or processes that are similar to, or may include compositions or methods that encompass our technology, allowing them to claim that the use of our technologies infringes on these patents. In a patent infringement claim against us, we may assert, as a defense, that we do not infringe the relevant patent claims, that the patent is invalid or both. The strength of our defenses will depend on the patents asserted, the interpretation of these patents, and our ability to invalidate the asserted patents. However, we could be unsuccessful in advancing non-infringement and invalidity arguments in our defense. Inthe United States , issued patents enjoy a presumption of validity, and the party challenging the validity of a patent claim must present clear and convincing evidence of invalidity, which is a high burden of proof. Conversely, the patent owner need only prove infringement by a preponderance of the evidence, which is a lower burden of proof. If we were found by a court to have infringed a valid patent claim, we could be prevented from using the patented technology and be required to pay the owner of the patent for damages for past sales and for the right to license the patented technology for future sales. If we decide to pursue a license to one or more of these patents, we may not be able to obtain a license on commercially reasonable terms, if at all, or the license we obtain may require us to pay substantial royalties or grant cross licenses to our patent rights. For example, if the relevant patent is owned by a competitor, that competitor may choose not to license patent rights to us. If we decide to develop alternative technology, we may not be able to do so in a timely or cost-effective manner, if at all. In addition, because patent applications can take years to issue and are often afforded confidentiality for some period of time there may currently be pending applications, unknown to us, that later result in issued patents that could cover one or more of our products. It is possible that we may in the future receive communications from competitors and other companies alleging that we may be infringing their patents, trade secrets or other intellectual property rights, offering licenses to such intellectual property or threatening litigation. In addition to patent infringement claims, third parties may assert copyright, trademark or other proprietary rights against us. We may need to expend considerable resources to counter such claims and may not be successful in our defense. Our business may suffer if a finding of infringement is established.
It is difficult and costly to protect our proprietary rights, and we may not be able to ensure their protection.
The patent positions of pharmaceutical companies can be highly uncertain and involve complex legal and factual questions for which important legal principles remain unresolved. No consistent policy regarding the breadth of claims allowed in pharmaceutical patents has emerged to date inthe United States . The pharmaceutical patent situation outsidethe United States is even more uncertain. Changes in either the patent laws or in interpretations of patent laws inthe United States and other countries may diminish the value of our intellectual property. We cannot predict the breadth of claims that may be allowed or enforced in the patents that may be issued from the applications we currently, or may in the future, own or license from third parties. Claims could be brought regarding the validity of our patents by third parties and regulatory agencies. Further, if any patent license we obtain is deemed invalid and/or unenforceable, it could impact our ability to commercialize or partner our technology. Competitors or third parties may infringe our patents. We may decide it is necessary to file patent infringement claims, which can be expensive and time-consuming. In addition, in an infringement proceeding, a court may decide that a patent of ours is not valid or is unenforceable, or that the third party's technology does not in fact infringe upon our patents. An adverse determination of any litigation or defense proceedings could put one or more of our patents at risk of being invalidated or interpreted narrowly and could put our related pending patent applications at risk of not issuing. Litigation may fail and, even if successful, may result in substantial costs and be a distraction to our management. We may not be able to prevent misappropriation of our proprietary rights, particularly in countries outsidethe United States where patent rights may be more difficult to enforce. Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential or sensitive information could be compromised by disclosure in the event of litigation. In addition, during the course of litigation there could be public announcements of the results of hearings, motions or other interim proceedings or developments. If securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock. 58 --------------------------------------------------------------------------------
The degree of future protection for our proprietary rights is uncertain, and we cannot ensure that:
• we were the first to make the inventions covered by each of our pending patent
applications or issued patents;
• our patent applications were filed before the inventions covered by each
patent or patent application was published by a third party;
• we were the first to file patent applications for these inventions;
• others will not independently develop similar or alternative technologies or
duplicate any of our technologies;
• any patents issued to us or our collaborators will provide a basis for
commercially viable products, will provide us with any competitive advantages
or will not be challenged by third parties; or
• the patents of others will not have an adverse effect on our business.
If we do not adequately protect our proprietary rights, competitors may be able to use our technologies and erode or negate any competitive advantage we may have, which could materially harm our business, negatively affect our position in the marketplace, limit our ability to commercialize DSUVIA and Zalviso, if approved, and delay or render impossible our achievement of profitability.
We may be unable to adequately prevent disclosure of trade secrets and other proprietary information.
We rely on trade secrets to protect our proprietary know-how and technological advances, especially where we do not believe patent protection is appropriate or obtainable. However, trade secrets are difficult to protect. We rely in part on confidentiality agreements with our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors to protect our trade secrets and other proprietary information. These agreements may not effectively prevent disclosure of confidential information and may not provide an adequate remedy in the event of unauthorized disclosure of confidential information. In addition, others may independently discover our trade secrets and proprietary information. Costly and time-consuming litigation could be necessary to enforce and determine the scope of our proprietary rights. Failure to obtain or maintain trade secret protection could enable competitors to use our proprietary information to develop products that compete with our products or cause additional, material adverse effects upon our competitive business position.
Periodic maintenance fees, renewal fees, annuity fees and various other governmental fees on patents and applications will be due to be paid to the United States Patent and Trademark Office and various foreign governmental patent agencies in several stages over the lifetime of the patents and/or applications.
We have systems in place, including use of third-party vendors, to manage payment of periodic maintenance fees, renewal fees, annuity fees and various other patent and application fees. The United States Patent and Trademark Office, or the USPTO, and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent application process. There are situations in which noncompliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction. If this occurs, our competitors might be able to enter the market, which would have a material adverse effect on our business.
We may not be able to enforce our intellectual property rights throughout the world.
The laws of some foreign countries do not protect intellectual property rights to the same extent as the laws ofthe United States . Many companies have encountered significant problems in protecting and defending intellectual property rights in certain foreign jurisdictions. The legal systems of some countries, particularly developing countries, do not favor the enforcement of patents and other intellectual property protection, especially those relating to life sciences. This could make it difficult for us to stop the infringement of our patents or the misappropriation of our other intellectual property rights. For example, many foreign countries have compulsory licensing laws under which a patent owner must grant licenses to third parties. In addition, many countries limit the enforceability of patents against third parties, including government agencies or government contractors. In these countries, patents may provide limited or no benefit. Proceedings to enforce our patent rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business. Accordingly, our efforts to protect our intellectual property rights in such countries may be inadequate. Additionally, claims may be brought regarding the validity of our patents by third parties and regulatory agencies inthe United States and foreign countries. In addition, changes in the law and legal decisions by courts inthe United States and foreign countries may affect our ability to obtain adequate protection for our technology and the enforcement of intellectual property. 59
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We have not yet registered our trademarks in all our potential markets, and failure to secure those registrations could adversely affect our business.
We have registered our ACELRX mark inthe United States ,Canada , the EU andIndia . In early 2014, the FDA accepted the Zalviso mark and, inNovember 2018 , the FDA accepted the DSUVIA mark. Although we are not currently aware of any oppositions to or cancellations of our registered trademarks or pending applications, it is possible that one or more of the applications could be subject to opposition or cancellation after the marks are registered. The registrations will be subject to use and maintenance requirements. It is also possible that we have not yet registered all of our trademarks in all of our potential markets, such as securing the registration of DSUVIA inCanada , and that there are names or symbols other than "ACELRX" that may be protectable marks for which we have not sought registration, and failure to secure those registrations could adversely affect our business. Opposition or cancellation proceedings may be filed against our trademarks and our trademarks may not survive such proceedings.
Risks Related to Ownership of Our Common Stock
The market price of our common stock may be highly volatile.*
The trading price of our common stock has experienced significant volatility and is likely to be volatile in the future. For example, the closing price of our common stock ranged between$1.03 and$2.77 during the first six months of 2021, and between$0.76 and$2.07 during the year endedDecember 31, 2020 . Our stock price could be subject to wide fluctuations in response to a variety of factors, including the following:
• failure to successfully commercialize DSUVIA in
successfully develop and commercialize our product candidates in the United
States;
• inability to obtain additional funding needed to conduct our planned business
operations;
• inability to satisfactorily comply with FDA regulations concerning the
advertising and promotion of DSUVIA, including receiving a close out letter
resolving the concerns raised by FDA in the warning letter delivered to us on
February 11, 2021 ;
• the integration and performance of any assets or businesses we acquire;
• our inability to develop and commercialize products and product candidates
that we in-license;
• uncertainties regarding the magnitude and duration of impacts we are
experiencing due to COVID-19;
• the perception of limited market sizes or pricing for our products;
• further delays in resubmitting the NDA for Zalviso, and any additional adverse
developments or perceived adverse developments with respect to the
review of the Zalviso NDA, upon resubmission;
• inability to enter into, or unfavorable terms associated with, a New
Arrangement for the commercialization of Zalviso in Europe ;
• safety issues;
• adverse results or delays in future clinical trials;
• changes in laws or regulations applicable to our products;
• inability to obtain adequate product supply for our products, or the inability
to do so at acceptable prices;
• adverse regulatory decisions;
• changes in the structure of the healthcare payment systems;
• inability to maintain regulatory approvals for DZUVEO and Zalviso in the
Zalviso;
• introduction of new products, services or technologies by our competitors;
• failure to meet or exceed financial projections we provide to the public;
• failure to meet or exceed the estimates and projections of the investment
community;
• decisions by our collaboration partners regarding market access, pricing, and
commercialization efforts in countries where they have the right to
commercialize our products;
• failure to maintain our existing collaborations or enter into new
collaborations;
• the perception of the pharmaceutical industry generally, and of opioid
manufacturers more specifically, by the public, legislatures, regulators and
the investment community;
60--------------------------------------------------------------------------------
• announcements of significant acquisitions, strategic partnerships, joint
ventures, or other significant transactions, including disposition
transactions, or capital commitments by us or our competitors;
• disputes or other developments relating to employment matters, business
development efforts, proprietary rights, including patents, litigation matters
and our ability to obtain patent protection for our technologies;
• additions or departures of key management or scientific personnel;
• costs associated with potential governmental investigations, inquiries,
regulatory actions or lawsuits that may be brought against us as a result of
us being an opioid manufacturer;
• other types of significant lawsuits, including patent, stockholder, securities
class action and derivative litigation;
• changes in the market valuations of similar companies;
• sales of our common stock by us or our stockholders in the future; and
• trading volume of our common stock. In addition, the stock market in general, and The Nasdaq Global Market, or Nasdaq, in particular, have experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of these companies. Broad market and industry factors may negatively affect the market price of our common stock, regardless of our actual operating performance.
Sales of a substantial number of shares of our common stock in the public market by our stockholders could cause our stock price to fall.
Because we will continue to need additional capital in the future to continue to expand our business and our research and development activities, among other things, we may conduct additional equity offerings. For example, under the universal shelf registration statement filed by us inJune 2020 and declared effective by theSEC inJuly 2020 , we may offer and sell any combination of common stock, preferred stock, debt securities and warrants in one or more offerings, up to a cumulative value of$150 million . To date, we have approximately$54.5 million remaining under such universal shelf registration statement. Sales of a substantial number of shares of our common stock in the public market or the perception that these sales might occur, could depress the market price of our common stock and could impair our ability to raise capital through the sale of additional equity securities. Our management is authorized to grant stock options and other equity-based awards to our employees, directors and consultants under our equity incentive plans. Grants under our equity incentive plans may also cause our stockholders to experience additional dilution, which could cause our stock price to fall. We may also issue shares of our common stock as consideration in mergers, acquisitions and other business development transactions. We are unable to predict the effect that sales may have on the prevailing market price of our common stock. All of our shares of common stock outstanding are eligible for sale in the public market, subject in some cases to the volume limitations and manner of sale requirements of Rule 144 under the Securities Act. Sales of stock by our stockholders could have a material adverse effect on the trading price of our common stock.
We do not intend to pay dividends on our common stock so any returns will be limited to the value of our stock.
We have never declared or paid any cash dividends on our capital stock, and we are prohibited from doing so under the terms of the Loan Agreement. Regardless of the restrictions in the Loan Agreement or the terms of any potential future indebtedness, we anticipate that we will retain all available funds and any future earnings to support our operations and finance the growth and development of our business and, therefore, we do not expect to pay cash dividends in the foreseeable future. Any future determination related to our dividend policy will be made at the discretion of our Board of Directors and will depend on then-existing conditions, including our financial condition, operating results, contractual restrictions, capital requirements, business prospects and other factors our Board of Directors may deem relevant. Provisions in our amended and restated certificate of incorporation and bylaws, as well as provisions ofDelaware law, could make it more difficult for a third party to acquire us or increase the cost of acquiring us, even if doing so would benefit our stockholders or remove our current management. Some provisions of our charter documents andDelaware law may have anti-takeover effects that could discourage an acquisition of us by others, even if an acquisition would be beneficial to our stockholders and may prevent attempts by our stockholders to replace or remove our current management. These provisions include:
• authorizing the issuance of "blank check" preferred stock, the terms of which
may be established and shares of which may be issued without stockholder
approval;
• limiting the removal of directors by the stockholders;
• a staggered Board of Directors;
• prohibiting stockholder action by written consent, thereby requiring all
stockholder actions to be taken at a meeting of our stockholders;
61--------------------------------------------------------------------------------
• eliminating the ability of stockholders to call a special meeting of
stockholders; and
• establishing advance notice requirements for nominations for election to our
Board of Directors or for proposing matters that can be acted upon at
stockholder meetings.
These provisions may frustrate or prevent any attempts by our stockholders to
replace or remove our current management by making it more difficult for
stockholders to replace members of our Board of Directors, which is responsible
for appointing the members of our management. In addition, we are subject to
Section 203 of the Delaware General Corporation Law, which generally prohibits a
Delaware corporation from engaging in any of a broad range of business
combinations with an interested stockholder for a period of three years
following the date on which the stockholder became an interested stockholder,
unless such transactions are approved by our Board of Directors. This provision
could have the effect of delaying or preventing a change of control, whether or
not it is desired by or beneficial to our stockholders. Further, other
provisions of Delaware law may also discourage, delay or prevent someone from
acquiring us or merging with us.
Risks of a General Nature
Litigation may substantially increase our costs and harm our business.*
We have been, are, and may in the future become, party to lawsuits including, without limitation, actions and proceedings in the ordinary course of business relating to our directors, officers, stockholders, intellectual property rights, employment matters and the safety or efficacy of our products, which will cause us to incur legal fees and other costs related thereto, including potential expenses for the reimbursement of legal fees of officers and directors under indemnification obligations. The expense of defending against such litigation may be significant and there can be no assurance that we will be successful in any defense. Further, the amount of time that may be required to resolve such lawsuits is unpredictable, and these actions may divert management's attention from the day-to-day operations of our business, which could adversely affect our business, results of operations, and cash flows. Our insurance carriers may deny coverage, may be inadequately capitalized to pay on valid claims, or our policy limits may be inadequate to fully satisfy any damage awards or settlements. If this were to happen, the payment of any such awards could have a material adverse effect on our consolidated operations, cash flows and financial position. Additionally, any such claims, whether or not successful, could damage our reputation and business. Litigation is subject to inherent uncertainties, and an adverse result in such matters that may arise from time to time could have a material adverse effect on our business, results of operations, and financial condition. Please see "Part II. Other Information-Item 1. Legal Proceedings" for additional information about pending legal proceedings.
Our involvement in securities-related class action litigation could divert our resources and management's attention and harm our business.*
The stock markets have from time-to-time experienced significant price and volume fluctuations that have affected the market prices for the common stock of pharmaceutical companies. These broad market fluctuations may cause the market price of our common stock to decline. In addition, the market price of our common stock may vary significantly based on AcelRx-specific events, such as receipt of complete response letters, warnings letters, such as the warning letter we received from the FDA onFebruary 11, 2021 , negative clinical results, a negative vote or decision by an FDA advisory committee, or other negative feedback from the FDA, EMA, or other regulatory agencies. In the past, securities-related class action litigation has often been brought against a company following a decline in the market price of its securities. This risk is especially relevant for us because biotechnology and biopharmaceutical companies often experience significant stock price volatility in connection with their investigational drug candidate development programs and theFDA's review of their NDAs. Following receipt of theFDA's warning letter, a securities class action complaint was filed against us and two of our officers onJune 8, 2021 in theUnited States District Court for the Northern District of California . Please see "Part II. Other Information-Item 1. Legal Proceedings" for additional information about this pending legal proceeding. Securities-related class action litigation often is expensive and diverts management's attention and our financial resources, which could harm our business. If AcelRx experiences a decline in its stock price, we could face additional securities class action lawsuits.
Our ability to use our net operating loss carryforwards and certain other tax attributes may be limited.
As of
62
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Our ability to use our federal and state net operating losses to offset
potential future taxable income and related income taxes that would otherwise be
due is dependent upon our generation of future taxable income before the
expiration dates of the net operating losses, and we cannot predict with
certainty when, or whether, we will generate sufficient taxable income to use
all of our net operating losses. Federal net operating losses generated prior to
2018 will continue to be governed by the net operating loss tax rules as they
existed prior to the adoption of the Tax Cuts and Jobs Act of 2017, or Tax Act,
which means that generally they will expire 20 years after they were generated
if not used prior thereto. Many states have similar laws. Accordingly, our
federal and state net operating losses could expire unused and be unavailable to
offset future income tax liabilities. Under the newly enacted Tax Act as
modified by CARES Act, federal net operating losses incurred in tax years
beginning after December 31, 2017 and before January 1, 2021 may be carried back
to each of the five tax years preceding such loss, and federal net operating
losses arising in tax years beginning after December 31, 2020 may not be carried
back. Moreover, federal net operating losses generated in tax years ending after
December 31, 2017 may be carried forward indefinitely, but the deductibility of
such federal net operating losses is limited to 80% of current year taxable
income for tax years beginning after December 31, 2020 .
In addition, under Section 382 of the Internal Revenue Code of 1986, as amended,
if a corporation undergoes an "ownership change," generally defined as a greater
than 50% change (by value) in its equity ownership over a three-year period, the
corporation's ability to use its pre-change net operating loss carryforwards and
other pre-change tax attributes (such as research tax credits) to offset its
post-change income may be limited. The completion of the July 2013 public equity
offering, together with our public equity offering in December 2012, our initial
public offering, private placements and other transactions that have occurred,
have triggered such an ownership change. In addition, since we will need to
raise substantial additional funding to finance our operations, we may undergo
further ownership changes in the future. In the future, if we earn net taxable
income, our ability to use our pre-change net operating loss carryforwards to
offset United States federal taxable income may be subject to limitations, which
could potentially result in increased future tax liability to us.
Our effective tax rate may fluctuate, and we may incur obligations in tax jurisdictions in excess of accrued amounts.
We are subject to taxation in numerousU.S. states and territories. As a result, our effective tax rate is derived from a combination of applicable tax rates in the various places that we operate. In preparing our financial statements, we estimate the amount of tax that will become payable in each of such places. Nevertheless, our effective tax rate may be different than experienced in the past due to numerous factors, including passage of the newly enacted federal income tax law, changes in the mix of our profitability from state to state, the results of examinations and audits of our tax filings, our inability to secure or sustain acceptable agreements with tax authorities, changes in accounting for income taxes and changes in tax laws. Any of these factors could cause us to experience an effective tax rate significantly different from previous periods or our current expectations and may result in tax obligations in excess of amounts accrued in our financial statements.
Item 2. Unregistered Sales of Equity Securities and Use of Proceeds
None.
Item 3. Defaults Upon Senior Securities
None.
Item 4. Mine Safety Disclosures
Not applicable.
Item 5. Other Information
None.
63--------------------------------------------------------------------------------
Item 6. Exhibits
Incorporation By Reference
Exhibit SEC
Number Exhibit Description Form File No. Exhibit Filing Date
3.1 Amended and Restated Certificate of 8-K 001-35068 3.1 02/18/2011
Incorporation of the Registrant.
3.2 Certificate of Amendment of Amended and 8-K 001-35068 3.1 6/25/2019
Restated Certificate of Incorporation of the
Registrant.
3.3 Amended and Restated Bylaws of the S-1 333-170594 3.4 01/07/2011
Registrant.
10.1§# Commercial Supply Agreement, effective
March 31, 2021 by and between Catalent
Pharma Solutions, LLC and the Registrant.
10.2+ Amended and Restated 2020 Equity Incentive 8-K 001-35068
10.1 6/17/2021
Plan
31.1 Certification of Principal Executive
Officer pursuant to Rules 13a-14(a) and
15d-14(a) promulgated under the Securities
Exchange Act of 1934, as amended.
31.2 Certification of Principal Financial and
Accounting Officer pursuant to Rules
13a-14(a) and 15d-14(a) promulgated under
the Securities Exchange Act of 1934, as
amended.
32.1 Certifications of Chief Executive Officer
and Chief Financial Officer pursuant to 18
U.S.C. Section 1350, as adopted pursuant to
Section 906 of the Sarbanes-Oxley Act of
2002.*
101.INS Inline XBRL Instance Document- the instance
document does not appear in the Interactive
Data File because its XBRL tags are embedded
within the Inline XBRL document.
101.SCH Inline XBRL Taxonomy Schema Document.
101.CAL Inline XBRL Taxonomy Calculation Linkbase
Document.
101.DEF Inline XBRL Taxonomy Definition Linkbase
Document.
101.LAB Inline XBRL Taxonomy Label Linkbase
Document.
101.PRE Inline XBRL Taxonomy Presentation Linkbase
Document.
104 Cover Page Interactive Data File (formatted
as inline XBRL with applicable taxonomy
extension information contained in Exhibits
101.INS, 101.SCH, 101.CAL, 101.DEF, 101.LAB,
and 101.PRE).
--------------------------------------------------------------------------------
§ Schedules omitted pursuant to Item 601(a)(5) of Regulation S-K. The
Registrant agrees to furnish supplementally a copy of any omitted schedule upon
request by the
+ Indicates management contract or compensatory plan.
# Material in the exhibit marked with an "[***]" has been omitted because it
is confidential, not material, and would be competitively harmful if publicly
disclosed.
* The certifications attached as Exhibit 32.1 accompany this Quarterly
Report on Form 10-Q pursuant to 18 U.S.C. Section 1350, as adopted pursuant to
Section 906 of the Sarbanes-Oxley Act of 2002, and shall not be deemed "filed"
by the Registrant for purposes of Section 18 of the Securities Exchange Act of
1934, as amended.
64--------------------------------------------------------------------------------
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