REGULUS THERAPEUTICS INC. The interim unaudited condensed financial statements and this Management's Discussion and Analysis of Financial Condition and Results of Operations should be read in conjunction with the financial statements and notes thereto for the year endedDecember 31, 2020 and the related Management's Discussion and Analysis of Financial Condition and Results of Operations, both of which are contained in our Annual Report on Form 10-K for the year endedDecember 31, 2020 , or Annual Report, filed with theSecurities and Exchange Commission onMarch 9, 2021 . Past operating results are not necessarily indicative of results that may occur in future periods. FORWARD-LOOKING STATEMENTS This quarterly report on Form 10-Q contains "forward-looking statements" within the meaning of the federal securities laws made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Our actual results could differ materially from those anticipated in these forward-looking statements as a result of various factors, including those set forth below under Part II, Item 1A, "Risk Factors" in this quarterly report on Form 10-Q. Except as required by law, we assume no obligation to update these forward-looking statements, whether as a result of new information, future events or otherwise. These statements, which represent our current expectations or beliefs concerning various future events, may contain words such as "may," "will," "expect," "anticipate," "intend," "plan," "believe," "estimate" or other words indicating future results, though not all forward-looking statements necessarily contain these identifying words. Such statements may include, but are not limited to, statements concerning the following: •the initiation, cost, timing, progress and results of, and our expected ability to undertake certain activities and accomplish certain goals with respect to our research and development activities, preclinical studies and clinical trials; •our ability to obtain and maintain regulatory approval of our product candidates, and any related restrictions, limitations, and/or warnings in the label of an approved product candidate; •our ability to obtain funding for our operations; •our plans to research, develop and commercialize our product candidates; •the potential election of any strategic collaboration partner to pursue development and commercialization of any programs or product candidates that are subject to a collaboration with such partner; •our ability to attract collaborators with relevant development, regulatory and commercialization expertise; •future activities to be undertaken by our strategic collaboration partners, collaborators and other third parties; •our ability to obtain and maintain intellectual property protection for our product candidates; •the size and growth potential of the markets for our product candidates, and our ability to serve those markets; •our ability to successfully commercialize, and our expectations regarding future therapeutic and commercial potential with respect to our product candidates; •the rate and degree of market acceptance of our product candidates; 21 -------------------------------------------------------------------------------- •our ability to develop sales and marketing capabilities, whether alone or with potential future collaborators; •regulatory developments inthe United States and foreign countries; •the performance of our third-party suppliers and manufacturers; •the success of competing therapies that are or may become available; •the loss of key scientific or management personnel; •our ability to successfully secure and deploy capital; •our ability to satisfy our debt obligations; •the accuracy of our estimates regarding future expenses, future revenues, capital requirements and need for additional financing; •the potential impact of the COVID-19 pandemic on our business; and •the risks and other forward-looking statements described under the caption "Risk Factors" under Part II, Item 1A of this quarterly report on Form 10-Q. In addition, statements that "we believe" and similar statements reflect our beliefs and opinions on the relevant subject. These statements are based upon information available to us as of the date of this report, and while we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted an exhaustive inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain and investors are cautioned not to unduly rely upon these statements. OVERVIEW We are a clinical-stage biopharmaceutical company focused on discovering and developing first-in-class drugs targeting microRNAs to treat diseases with significant unmet medical need. We were formed in 2007 when Alnylam Pharmaceuticals, Inc. ("Alnylam") and Ionis Pharmaceuticals, Inc. ("Ionis") contributed significant intellectual property, know-how and financial and human capital to pursue the development of drugs targeting microRNAs pursuant to a license and collaboration agreement. Our lead product candidates are RG-012 and RGLS8429. RG-012 is an anti-miR targeting miR-21 for the treatment of Alport syndrome, a life-threatening kidney disease with no approved therapy available. InNovember 2018 , we and Sanofi agreed to transition further development activities of our miR-21 programs, including our RG-012 program, to Sanofi. As a result, Sanofi became responsible for all costs incurred in the development of RG-012 and any other miR-21 programs. The transition activities were completed in the second quarter of 2019. RGLS8429, an anti-miR targeting miR-17, is our next-generation compound for the treatment of autosomal dominant polycystic kidney disease ("ADPKD"), which is currently in initial new drug application ("IND")-enabling studies. In addition to these programs, we continue to develop a pipeline of preclinical drug product candidates. microRNAs are naturally occurring ribonucleic acid ("RNA") molecules that play a critical role in regulating key biological pathways. Scientific research has shown that an imbalance, or dysregulation, of microRNAs is directly linked to many diseases. Furthermore, many different infectious pathogens interact and bind to host microRNA to survive. To date, over 500 microRNAs have been identified in humans, each of which can bind to multiple messenger RNAs that control key aspects of cell biology. Since many diseases are multi-factorial, involving multiple targets and pathways, the ability to modulate multiple pathways by targeting a single microRNA provides a new therapeutic approach for treating complex diseases. RNA plays an essential role in the process used by cells to encode and translate genetic information from deoxyribonucleic acid ("DNA") to proteins. RNA is comprised of subunits called nucleotides and is synthesized from a DNA template by a process known as transcription. Transcription generates different types of RNA, including messenger RNAs that carry the information for proteins in the sequence of their nucleotides. In contrast, microRNAs are RNAs that do not code for proteins but rather are responsible for regulating gene expression by modulating the translation and decay of target messenger RNAs. By interacting with many messenger RNAs, a single microRNA can regulate the expression of multiple genes involved in the normal function of a biological pathway. Many pathogens, including viruses, bacteria and parasites, also use host microRNAs to regulate the cellular environment for survival. In some instances, the host microRNAs are essential for the replication and/or survival of the pathogen. For example, miR-122 is a microRNA expressed in human hepatocytes and is a key factor for the replication of the hepatitis C virus ("HCV"). We believe that microRNA therapeutics have the potential to become a new and major class of drugs with broad therapeutic application for the following reasons: 22 -------------------------------------------------------------------------------- •microRNAs play a critical role in regulating biological pathways by controlling the translation of many target genes; •microRNA therapeutics regulate disease pathways which may result in more effective treatment of complex multi-factorial diseases; •many human pathogens, including viruses, bacteria and parasites, use microRNAs (host and pathogen encoded) to enable their replication and suppression of host immune responses; and •microRNA therapeutics may be synergistic with other therapies because of their different mechanism of action. We have assembled significant expertise in the microRNA field, including expertise in microRNA biology and oligonucleotide chemistry, a broad intellectual property estate, relationships with key opinion leaders and a disciplined drug discovery and development process. We are using our microRNA expertise to develop chemically modified, single-stranded oligonucleotides that we call anti-miRs to modulate microRNAs and address underlying disease. We believe microRNAs may play a critical role in complex disease and that targeting them with anti-miRs may become a source of a new and major class of drugs with broad therapeutic application, much like small molecules, biologics and monoclonal antibodies. We believe that microRNA biomarkers may be used to select optimal patient segments in clinical trials and to monitor disease progression or relapse. We believe these microRNA biomarkers can be applied toward drugs that we develop and drugs developed by other companies with which we partner or collaborate. Since our inception throughSeptember 30, 2021 , we have received$384.0 million from the sale of our equity and convertible debt securities,$101.8 million from our strategic collaborations, principally from upfront payments, research funding and preclinical and clinical milestones, and$19.8 million in net proceeds from our Term Loan. As ofSeptember 30, 2021 , we had cash and cash equivalents of$35.8 million . Lead Product Candidates
We currently have two lead product candidates.
RG-012: InMay 2017 , we completed a Phase 1 multiple-ascending dose ("MAD") clinical trial in 24 healthy volunteers (six-week repeat dosing) to determine safety, tolerability and pharmacokinetics ("PK") of RG-012 prior to chronic dosing in patients. In Phase 1 clinical trials to date, RG-012 was well-tolerated, and there were no serious adverse events ("SAEs") reported. In the third quarter of 2017, we initiated HERA, a Phase 2 randomized (1:1), double-blinded, placebo-controlled clinical trial evaluating the safety and efficacy of RG-012 in 40 Alport syndrome patients. In parallel, a renal biopsy study was also initiated in the third quarter of 2017 to evaluate RG-012 renal tissue PK, target engagement and downstream effects on genomic disease biomarkers. Kidney tissue concentrations were achieved in biopsy patients that would be predictive of therapeutic benefit based on animal disease models. In addition, modulation of the target, miR-21, was observed. InDecember 2017 , we concluded our global ATHENA natural history of disease study. RG-012 has received orphan designation in boththe United States andEurope . InNovember 2018 , we and Sanofi agreed to transition further development activities of our miR-21 programs, including our RG-012 program to Sanofi. As a result, Sanofi became responsible for all costs incurred in the development of these miR-21 programs. The transition activities, including the transfer of the IND, were completed in the second quarter of 2019. Sanofi is currently enrolling patients into a Phase 2 clinical trial, with sites inthe United States ,Europe ,Australia andChina . RGLS8429: RGLS8429, an anti-miR targeting miR-17, is our next-generation compound for the treatment of ADPKD. InOctober 2021 , we announced that we would discontinue further development of our first generation compound for the treatment of ADPKD, RGLS4326, based on discussions with the FDA and data from the second cohort of patients in the Phase 1b trial of RGLS4326. RGLS8429 has completed an extensive 14-week non-GLP toxicity study in mice at significantly higher doses than RGLS4326. Additionally, with the completion of the dosing phase of the IND-enabling GLP toxicity studies, we believe RGLS8429 has demonstrated a superior pharmacological profile.Administration of RGLS8429 has not shown any of the off-target CNS effects that were seen with RGLS4326 at the top doses tested in chronic preclinical toxicology studies, and has equal potency to RGLS4326 for its molecular target (miR-17) in both in-vitro and in-vivo efficacy studies. We expect to have a pre-IND meeting with the FDA for RGLS8429 in late 2021. We plan to submit an IND, and, subject to FDA clearance of the IND, initiate a Phase 1 clinical study for RGLS8429 in the second quarter of 2022. Our Phase 1 plans include a single dose escalation study in healthy volunteers to enable a multi-dose study in ADPKD patients around the dose levels where robust clinical biomarker effects were demonstrated with RGLS4326. We anticipate reporting top-line biomarker data in the first cohort of RGLS8429 treated patients in early 2023.
Preclinical Pipeline
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A major focus of our preclinical research has historically targeted dysregulated
microRNAs implicated in diseases of high unmet medical need where we know we can
effectively deliver to the target tissue or organ, such as the liver and kidney.
We also have early discovery programs investigating additional microRNA targets
for immunology, nephrology, oncology and indications for which there is microRNA
dysregulation or in disease settings where the host microRNAs are essential for
the replication and/or survival of the pathogen. We have multiple programs in
various stages of preclinical development. While we are not currently advancing
these programs to IND, we are working to explore the potential of microRNAs in
these therapeutic areas.
FINANCIAL OPERATIONS OVERVIEW
Revenue
Our revenues generally consist of upfront payments for licenses or options to
obtain licenses in the future, milestone payments and payments for other
research services under collaboration agreements.
In the future, we may generate revenue from a combination of license fees and
other upfront payments, payments for research and development services,
milestone payments, product sales and royalties in connection with strategic
collaborations. We expect that any revenue we generate will fluctuate from
quarter-to-quarter as a result of the timing of our achievement of preclinical,
clinical, regulatory and commercialization milestones, if at all, the timing and
amount of payments relating to such milestones and the extent to which any of
our products are approved and successfully commercialized by us or our strategic
collaboration partners. If our current or future collaboration partners do not
elect or otherwise agree to fund our development costs pursuant to our current
or future strategic collaboration agreements, or we or our strategic
collaboration partner fails to develop product candidates in a timely manner or
obtain regulatory approval for them, our ability to generate future revenues,
and our results of operations and financial position would be adversely
affected.
Research and development expenses
Research and development expenses consist of costs associated with our research
activities, including our drug discovery efforts and the development of our
therapeutic programs. Our research and development expenses include:
•employee-related expenses, including salaries, benefits, travel and stock-based
compensation expense;
•external research and development expenses incurred under arrangements with
third parties, such as contract research organizations, or CROs, contract
manufacturing organizations, or CMOs, other clinical trial related vendors,
consultants and our scientific advisors;
•license fees; and
•facilities, depreciation and other allocated expenses, which include direct and
allocated expenses for rent and maintenance of facilities, amortization of
leasehold improvements and equipment, and laboratory and other supplies.
We expense research and development costs as incurred. We account for
nonrefundable advance payments for goods and services that will be used in
future research and development activities as expenses when the service has been
performed or when the goods have been received. Certain of the raw materials
used in the process of manufacturing drug product are capitalized upon their
acquisition and expensed upon usage, as we have determined these materials have
alternative future use.
To date, we have conducted research on many different microRNAs with the goal of
understanding how they function and identifying those that might be targets for
therapeutic modulation. At any given time we are working on multiple targets,
primarily within our therapeutic areas of focus. Our organization is structured
to allow the rapid deployment and shifting of resources to focus on the most
promising targets based on our ongoing research. As a result, in the early phase
of our development programs, our research and development costs are not tied to
any specific target. However, we are currently spending the vast majority of our
research and development resources on our lead development programs.
Since our inception, we have incurred a total of approximately $386.8 million in
research and development expenses through September 30, 2021 .
The process of conducting clinical trials and preclinical studies necessary to
obtain regulatory approval is costly and time consuming. We, or our strategic
collaboration partners, may never succeed in achieving marketing approval for
any of our product candidates. The probability of success for each product
candidate may be affected by numerous factors, including preclinical data,
clinical data, competition, manufacturing capability and commercial viability.
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Successful development of future product candidates is highly uncertain and may
not result in approved products. Completion dates and completion costs can vary
significantly for each future product candidate and are difficult to predict. We
anticipate we will make determinations as to which programs to pursue and how
much funding to direct to each program on an ongoing basis in response to our
ability to maintain or enter into new collaborations with respect to each
program or potential product candidate, the scientific and clinical success of
each future product candidate, as well as ongoing assessments as to each future
product candidate's commercial potential. We will need to raise additional
capital and may seek additional collaborations in the future in order to advance
our various programs.
General and administrative expenses
General and administrative expenses consist primarily of salaries and related
benefits, including stock-based compensation, related to our executive, finance,
legal, business development and support functions. Other general and
administrative expenses include allocated facility-related costs not otherwise
included in research and development expenses and professional fees for
auditing, tax and legal services, some of which are incurred as a result of
being a publicly-traded company.
Other income (expense), net
Other income (expense) consists primarily of interest income and expense and
various income or expense items of a non-recurring nature. We earn interest
income from interest-bearing accounts and money market funds for cash and cash
equivalents and marketable securities, such as interest-bearing bonds, for our
short-term investments. Interest expense is primarily attributable to interest
charges associated with borrowings under our secured Term Loan.
CRITICAL ACCOUNTING POLICIES AND ESTIMATES
There have been no significant changes to our critical accounting policies since
December 31, 2020 . For a description of critical accounting policies that affect
our significant judgments and estimates used in the preparation of our financial
statements, refer to Item 7 in Management's Discussion and Analysis of Financial
Condition and Results of Operations and Note 1 to our financial statements
contained in our Annual Report and Note 1 to our condensed financial statements
contained in this quarterly report on Form 10-Q.
RESULTS OF OPERATIONS
Comparison of the three and nine months ended September 30, 2021 and 2020
The following table summarizes our results of operations for the three and nine
months ended September 30, 2021 and 2020 (in thousands):
Three months ended Nine months ended
September 30, September 30,
2021 2020 2021 2020
Revenue under collaborations $ - $ 5,000 $ - $ 5,006
Research and development expenses 5,915 4,036 13,385 11,396
General and administrative expenses 2,504 2,059 7,471 6,736
Interest and other (expenses) income, net (209) (428) 182 (1,289)
Revenue under collaborations
Our revenues are generated from ongoing collaborations, and generally consist of upfront payments for licenses or options to obtain licenses in the future, milestone payments and payments for other research services. Revenue was zero for the three and nine months endedSeptember 30, 2021 , compared to$5.0 million for the three and nine months endedSeptember 30, 2020 . Revenue during the three and nine months endedSeptember 30, 2020 primarily consisted of$5.0 million of revenue recognized during the third quarter of 2020 upon the completion of transfer and verification of certain materials sold to Sanofi. Research and development expenses The following tables summarize the components of our research and development expenses for the periods indicated, together with year-over-year changes (dollars in thousands): 25 --------------------------------------------------------------------------------
Increase (decrease)
Three months Three months
ended September ended September
30, 2021 % of total 30, 2020 % of total $ %
Research and development
Personnel and internal expenses $ 1,456 24 % $ 1,736 43 % $ (280) (16) %
Third-party and outsourced
expenses 4,148 70 % 1,935 48 % 2,213 114 %
Non-cash stock-based compensation 277 5 % 255 6 % 22 9 %
Depreciation 34 1 % 110 3 % (76) (69) %
Total research and development
expenses $ 5,915 100 % $ 4,036 100 % $ 1,879 47 %
Increase (decrease)
Nine months Nine months
ended September ended September
30, 2021 % of total 30, 2020 % of total $ %
Research and development
Personnel and internal expenses $ 4,511 34 % $ 4,384 38 % $ 127 3 %
Third-party and outsourced
expenses 7,782 58 % 6,094 54 % 1,688 28 %
Non-cash stock-based compensation 687 5 % 571 5 % 116 20 %
Depreciation 405 3 % 347 3 % 58 17 %
Total research and development
expenses $ 13,385 100 % $ 11,396 100 % $ 1,989 17 %
Research and development expenses were $5.9 million and $13.4 million for the
three and nine months ended September 30, 2021 , compared to $4.0 million and
$11.4 million for the three and nine months ended September 30, 2020 . These
amounts reflect the internal and external costs associated with advancing our
clinical and preclinical pipeline. The aggregate increases for the three and
nine months ended September 30, 2021 , as compared to the three and nine months
ended September 30, 2020 , were attributable to increases in external research
and development expenses, which were primarily driven by an increase in spend on
third-party drug manufacturing for our RG8429 product candidate.
General and administrative expenses
General and administrative expenses were $2.5 million and $7.5 million for the
three and nine months ended September 30, 2021 , compared to $2.1 million and
$6.7 million for the three and nine months ended September 30, 2020 . These
amounts reflect personnel-related and ongoing general business operating costs.
Interest and other income (expenses), net
Net interest and other expenses were $0.2 million for the three months ended
September 30, 2021 , compared to net interest and other expenses of $0.4 million
for the three months ended September 30, 2020 . These amounts were primarily
related to interest charges associated with our outstanding Term Loan. Net
interest and other income was $0.2 million for the nine months ended
September 30, 2021 , compared to net interest and other expenses of $1.3 million
for the nine months ended September 30, 2020 . Net interest and other income for
the nine months ended September 30, 2021 included a $0.7 million gain on
forgiveness of our PPP loan during the second quarter of 2021, partially offset
by interest charges associated with our outstanding Term Loan. Net interest and
other expenses for the nine months ended September 30, 2020 were primarily
related to interest charges associated with our outstanding Term Loan.
LIQUIDITY AND CAPITAL RESOURCES
Since our inception through September 30, 2021 , we have received $384.0 million
from the sale of our equity and convertible debt securities, $101.8 million from
our collaborations, principally from upfront payments, research funding and
preclinical and clinical milestones, and $19.8 million in net proceeds from our
Term Loan. As of September 30, 2021 , we had cash and cash equivalents of $35.8
million .
The accompanying financial statements have been prepared on a basis which
assumes we are a going concern, and does not include any adjustments to reflect
the possible future effects on the recoverability and classification of assets
or the amounts and classifications of liabilities that may result from any
uncertainty related to our ability to continue as a going concern.
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If we are unable to maintain sufficient financial resources, our business,
financial condition and results of operations will be materially and adversely
affected. There can be no assurance that we will be able to obtain the needed
financing on acceptable terms or at all. Additionally, equity or debt financings
may have a dilutive effect on the holdings of our existing stockholders. These
factors raise substantial doubt about our ability to continue as a going
concern.
Our future capital requirements are difficult to forecast and will depend on
many factors, including:
•whether and when we achieve any milestones under our collaboration and license
agreement with Sanofi;
•the terms and timing of any other strategic collaboration, licensing and other
arrangements that we may establish;
•the initiation, progress, timing and completion of preclinical studies and
clinical trials for our development programs and product candidates, and
associated costs;
•the number and characteristics of product candidates that we pursue;
•the outcome, timing and cost of regulatory approvals;
•delays that may be caused by changing regulatory requirements;
•the cost and timing of hiring new employees to support our continued growth;
•the costs involved in filing and prosecuting patent applications and enforcing
and defending patent claims;
•the costs and timing of procuring clinical and commercial supplies of our
product candidates;
•the costs and timing of establishing sales, marketing and distribution
capabilities, and the pricing and reimbursement for any products for which we
may receive regulatory approval;
•the extent to which we acquire or invest in businesses, products or
technologies; and
•payments under our Term Loan.
The following table shows a summary of our cash flows for the nine months ended
Nine months ended
September 30,
2021 2020
(unaudited)
Net cash (used in) provided by:
Operating activities $ (16,297) $ (15,725)
Investing activities (210) (11)
Financing activities 21,330 (542)
Total $ 4,823 $ (16,278)
Operating activities
Net cash used in operating activities was $16.3 million for the nine months
ended September 30, 2021 , compared to $15.7 million for the nine months ended
September 30, 2020 .
Investing activities
Net cash used in investing activities was $0.2 million for the nine months ended
September 30, 2021 , compared to less than $0.1 million for the nine months ended
September 30, 2020 .
Financing activities
Net cash provided by financing activities was $21.3 million for the nine months
ended September 30, 2021 , compared to net cash used in financing activities of
$0.5 million for the nine months ended September 30, 2020 . Net cash provided by
financing activities for the nine months ended September 30, 2021 was primarily
attributable to proceeds from the issuance of our common stock in our ATM
Offering.
CONTRACTUAL OBLIGATIONS AND COMMITMENTS
As of September 30, 2021 , there have been no material changes, outside of the
ordinary course of business, in our outstanding contractual obligations from
those disclosed in Note 8 Commitments and Contingencies, Note 9 Debt, and Note
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Leases to our financial statements contained in our Annual Report, with the exception of the Campus Point Lease, Assignment Agreement and Consent with Campus Point Landlord concerning our new corporate headquarters and the assignment of our previous corporate headquarters (refer to Note 8 to our condensed financial statements contained in this quarterly report on Form 10-Q), and full forgiveness of our$0.7 million PPP Loan (refer to Note 5 to our condensed financial statements contained in this quarterly report on Form 10-Q). OFF-BALANCE SHEET ARRANGEMENTS As ofSeptember 30, 2021 , we did not have any off-balance sheet arrangements.
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