INTELLIA THERAPEUTICS, INC. Forward-looking Information
This Quarterly Report on Form 10-Q contains forward-looking statements which are made pursuant to the safe harbor provisions of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended (the "Exchange Act"). These statements may be identified by such forward-looking terminology as "may," "should," "expects," "intends," "plans," "anticipates," "believes," "estimates," "predicts," "potential," "continue" or the negative of these terms or other comparable terminology. Our forward-looking statements are based on a series of expectations, assumptions, estimates and projections about our company, are not guarantees of future results or performance and involve substantial risks and uncertainty. We may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements. Our business and our forward-looking statements involve substantial known and unknown risks and uncertainties, including the risks and uncertainties inherent in our statements regarding:
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our ability to execute our clinical study strategy for NTLA-2001, our program
for the treatment of transthyretin ("ATTR") amyloidosis, including the ability
to successfully complete our Phase 1 study and determine a recommended dose in
our ongoing Phase 1 study that can be advanced into later-stage studies, or the
success of such program;
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our ability to execute our clinical study strategy for NTLA-2002, our program
for the treatment of hereditary angioedema ("HAE"), including the ability to
successfully complete our Phase 1/2 study and determine a recommended dose that
can be advanced into later-stage studies, or the success of such program;
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the anticipated timing of our Investigational New Drug ("IND") or IND-equivalent filing for NTLA-3001, our program for the treatment of alpha-1 antitrypsin deficiency ("AATD")-associated lung disease, or the success of such program;
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our ability to successfully execute our development plans for our preclinical programs, including NTLA-2003 and NTLA-6001;
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our ability to use a modular platform capability or other strategies to efficiently discover and develop product candidates, including by applying learnings from one program to other programs;
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our ability to research, develop or maintain a pipeline of product candidates, including in vivo and allogeneic ex vivo product candidates;
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our ability to manufacture or obtain materials for our preclinical and clinical studies, and our product candidates;
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our ability to advance any product candidates into, and successfully complete, clinical studies, including clinical studies necessary for regulatory approval and commercialization, and to demonstrate to the regulators that the product candidates are safe, effective, pure and potent and that their benefits outweigh known and potential risks for the intended patient population;
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our ability to advance our genome editing and therapeutic delivery capabilities;
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the scope of protection we are able to develop, establish and maintain for intellectual property rights, including patents and license rights, covering our product candidates and technology;
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our ability to operate, including commercializing products, without infringing or breaching the proprietary or contractual rights of others;
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the issuance or enforcement of, and compliance with, regulatory requirements and guidance regarding preclinical and clinical studies relevant to genome editing and our product candidates;
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the market acceptance, pricing and reimbursement of our product candidates, if approved;
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estimates of our expenses, future revenues, capital requirements and our needs for additional financing;
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the potential benefits of strategic agreements, such as collaborations, co-development and co-commercialization, acquisitions, dispositions, mergers, joint ventures, and investment agreements, and our ability to establish and maintain strategic arrangements under favorable terms;
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our ability to acquire and maintain relevant intellectual property licenses and rights, and the scope and terms of such rights;
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developments relating to our licensors, licensees, third parties and ventures from which we derive or license rights, as well as collaborators, competitors and our industry;
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the effect of the ongoing COVID-19 pandemic, including mitigation efforts and economic effects, on any of the foregoing or other aspects of our business operations; and
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other risks and uncertainties, including those listed under the caption "Risk Factors."
All of our express or implied forward-looking statements are as of the date of this Quarterly Report on Form 10-Q only. In each case, actual results may differ materially from such forward-looking information. We can give no assurance that such expectations or forward-looking statements will prove to be correct. An occurrence of or any material adverse change in one or more of the risk factors or risks and uncertainties referred to in this Quarterly Report on Form 10-Q or included in our other public disclosures or our other periodic reports or other documents or filings filed with or furnished to theSecurities and Exchange Commission (the "SEC") could materially and adversely affect our business, prospects, financial condition and results of operations. Except as required by law, we do not undertake or plan to update or revise any such forward-looking statements to reflect actual results, changes in plans, assumptions, estimates or projections or other circumstances affecting such forward-looking statements occurring after the date of this Quarterly Report on Form 10-Q, even if such results, changes or circumstances make it clear that any forward-looking information will not be realized. Any public statements or disclosures by us following this Quarterly Report on Form 10-Q that modify or impact any of the forward-looking statements contained in this Quarterly Report on Form 10-Q will be deemed to modify or supersede such statements in this Quarterly Report on Form 10-Q. Management OverviewIntellia Therapeutics, Inc. ("we," "us," "our," "Intellia," or the "Company") is a leading clinical-stage genome editing company, focused on developing novel, potentially curative therapeutics leveraging CRISPR/Cas9-based technologies. CRISPR/Cas9, an acronym for Clustered, Regularly Interspaced Short Palindromic Repeats ("CRISPR")/CRISPR associated 9 ("Cas9"), is a technology for genome editing, the process of altering selected sequences of genomic deoxyribonucleic acid ("DNA"). To fully realize the transformative potential of CRISPR/Cas9-based technologies, we are building a full-spectrum genome editing company, by leveraging our modular platform, to advance in vivo and ex vivo therapies for diseases with high unmet need by pursuing two primary approaches. Our in vivo programs use intravenously administered CRISPR as the therapy, in which proprietary delivery technology enables highly precise editing of disease-causing genes directly within specific target tissues. Our ex vivo programs use CRISPR to create the therapy by using engineered human cells. Our deep scientific, technical and clinical development experience, along with our robust intellectual property ("IP") portfolio, have enabled us to take a leadership role in harnessing the full potential of genome editing to create new classes of genetic medicine. Our management's discussion and analysis of our financial condition and results of operations are based upon our unaudited condensed consolidated financial statements included in this Quarterly Report on Form 10-Q, which have been prepared by us in accordance with accounting principles generally accepted inthe United States of America ("U.S. GAAP") for interim periods and with Regulation S-X, promulgated under the Securities Exchange Act of 1934, as amended. This discussion and analysis should be read in conjunction with the unaudited condensed consolidated financial statements and the notes thereto included elsewhere in this Quarterly Report on Form 10-Q as well as in conjunction with the audited financial statements and notes thereto included in our Annual Report on Form 10-K ("Annual Report") for the year endedDecember 31, 2021 . Treating-and potentially curing-a broad range of severe diseases will require multiple gene editing approaches. With proprietary CRISPR/Cas9-based technology at the core of our platform, we continue to add new capabilities to expand our current solutions for addressing a multitude of life-threatening diseases. These additions include our proprietary base editor, as well as novel CRISPR enzymes, which provide us with the capabilities to achieve multiple editing strategies.
We continue to advance our platform's modular solutions and research efforts on genome editing technologies as well as delivery and cell engineering capabilities to generate additional development candidates.
Our mission is to transform the lives of people with severe diseases by developing curative genome editing treatments. We believe we can deliver on our mission and provide long-term benefits for all of our stakeholders by focusing on four key elements:
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Develop curative CRISPR/Cas9-based medicines;
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--------------------------------------------------------------------------------• Advance our science; •
Be the best place to make therapies; and
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Focus on long-term sustainability.
Our strategy is to build a full-spectrum genome editing company, by leveraging our modular platform, to advance in vivo and ex vivo therapies for diseases with high unmet need. For in vivo applications to address genetic diseases, we deploy CRISPR/Cas9 as the therapy that targets cells within the body. In parallel, we are developing ex vivo applications to address immuno-oncology and autoimmune diseases, where CRISPR/Cas9 is the tool that creates the engineered cell therapy. All of our revenue to date has been collaboration revenue. Since our inception and throughJune 30, 2022 , we have raised an aggregate of approximately$1,861.1 million to fund our operations through our initial public offering ("IPO") and concurrent private placements, follow-on public offerings, at-the-market offerings, and the sale of convertible preferred stock, as well as through our collaboration agreements. Our lead in vivo candidate, NTLA-2001 for the treatment of transthyretin ("ATTR") amyloidosis, is the first CRISPR/Cas9-based therapy candidate to be administered systemically, via intravenous infusion, for precision editing of a gene in a target tissue in humans. In parallel, we are developing ex vivo applications to address immuno-oncology and autoimmune diseases, where CRISPR/Cas9 is the tool that creates the engineered cell therapy. For NTLA-5001, a wholly-owned, autologous T cell receptor ("TCR")-T cell candidate for the treatment of acute myeloid leukemia ("AML"), we are pivoting towards an allogeneic version of this program currently in preclinical development. In addition,Novartis Institutes for BioMedical Research, Inc. ("Novartis") is advancing a clinical program using our ex vivo technology to engineer hematopoietic stem cells ("HSCs") for the treatment of sickle cell disease.
Our Pipeline
In Vivo Programs
Our selection criteria include identifying diseases that originate in the liver;
have well-defined mutations that can be addressed by a knockout or insertion
approach; have readily measurable therapeutic endpoints with observable clinical
responses; and for which effective treatments are absent, limited or unduly
burdensome. Our initial in vivo indications target genetic liver diseases,
including our ATTR amyloidosis, hereditary angioedema ("HAE") and alpha-1
antitrypsin deficiency ("AATD") development programs. Our current efforts on in
vivo delivery focus on the use of lipid nanoparticles ("LNPs") for delivery of
the CRISPR/Cas9 complex to the liver.
Transthyretin ("ATTR") Amyloidosis Program
NTLA-2001 is the first investigational CRISPR-based therapy to be systemically
delivered to edit genes inside the human body and has the potential to be the
first single-dose treatment for ATTR amyloidosis. Delivered with our in vivo LNP
technology, NTLA-2001 offers the possibility of halting and reversing the
disease by driving a deep, potentially lifelong reduction in transthyretin
("TTR") protein after a single dose. NTLA-2001 is being evaluated in a Phase 1,
two-part, open-label study in adults with hereditary transthyretin amyloidosis
with polyneuropathy ("ATTRv-PN") or transthyretin amyloidosis with
cardiomyopathy ("ATTR-CM"). To date, over 30 patients have been treated across
the polyneuropathy and cardiomyopathy arms. The growing body of data,
particularly at the two highest doses tested, demonstrated treatment with
NTLA-2001 resulted in rapid, deep and highly consistent reductions of serum TTR.
In the ATTR-CM arm, in August 2022 , we announced the completion of the
dose-escalation portion of the study. We are finalizing selection of a fixed
dose, at or near the fixed-dose equivalent of the 0.7 mg/kg dose, for evaluation
in the dose-expansion portion of the study, subject to regulatory approval. The
selection is based on clinical data from patients with ATTR-CM dosed at the 0.7
mg/kg and 1.0 mg/kg doses which yielded similar TTR reductions. Additionally,
both doses were generally well-tolerated. We remain on track to present interim
data from the cardiomyopathy arm later this year.
In the ATTRv-PN arm, in August 2022 , subject to regulatory approval, we
announced plans to add a second cohort to the dose-expansion portion of the
polyneuropathy arm, which will evaluate the same fixed dose selected for the
dose-expansion portion of the cardiomyopathy arm cohort. The decision to study a
second dose is based on the following: (1) the emerging data from the
dose-escalation portion of the cardiomyopathy arm showed similar serum TTR
reduction at both the 0.7 mg/kg and 1.0 mg/kg doses, (2) the comparability of
performance at the 0.7 mg/kg and 1.0 mg/kg dose in the dose-escalation portion
of the polyneuropathy arm, which led to an 86% and 93% mean and 97% and 98%
maximum TTR reduction at day 28, respectively,
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and (3) a significant elevation in liver enzymes, which normalized without
medical intervention, observed at day 28 in a patient treated in the
dose-expansion portion of the polyneuropathy arm at the 80 mg dose (the fixed
dose corresponding to 1.0 mg/kg). While the adverse event is considered possibly
related to study drug, this patient was asymptomatic, had no increase in
bilirubin and the event was deemed nonserious by the investigator. We plan to
submit a protocol amendment to evaluate a fixed dose corresponding to 0.7 mg/kg
in the dose-expansion portion, with enrollment across both arms expected to be
completed by the end of 2022, subject to regulatory feedback.
In June 2022 , we presented at the European Association for the Study of the
Liver ("EASL") International Liver Congress 2022 updated interim data from our
ongoing Phase 1 study of NTLA-2001 in patients with ATTRv-PN. Extended follow-up
data from 15 ATTRv-PN patients, treated across all four single-ascending dose
cohorts, showed deep, dose-dependent reductions in serum TTR observed with prior
readouts were sustained through the last measured timepoint of follow-up,
reaching 12 months in the 0.1 mg/kg and 0.3 mg/kg cohorts and six months in the
0.7 mg/kg and 1.0 mg/kg cohorts. Both 0.7 mg/kg and 1.0 mg/kg doses led to
greater than 85% mean TTR reduction at day 28. The durability and persistence of
effect continue to support NTLA-2001 as a potential one-time treatment to
permanently inactivate the TTR gene and reduce the disease-causing protein.
NTLA-2001 is the subject of a co-development and co-promotion ("Co/Co")
agreement directed to our first collaboration target with Regeneron
Pharmaceuticals, Inc. ("Regeneron"), ATTR (the "ATTR Co/Co"), for which we are
the clinical and commercial lead party and Regeneron is the participating party.
Regeneron shares in approximately 25% of worldwide development costs and
commercial profits for the ATTR program. For more information regarding our
collaboration with Regeneron, see the section below entitled "Collaborations and
Other Arrangements - Regeneron".
Hereditary Angioedema ("HAE") Program
NTLA-2002 is our wholly-owned candidate for the treatment of HAE. We are progressing the single-ascending dose portion of our first-in-human study. We anticipate presenting interim data in the second half of 2022, including safety, kallikrein reduction and HAE attack rate data. These initial results are expected to characterize the emerging safety and activity profile of NTLA-2002, and potentially demonstrate the modularity of our proprietary, CRISPR-based, LNP platform.
Alpha-1 Antitrypsin Deficiency ("AATD") Program
NTLA-3001 for associated lung disease:
NTLA-3001 is our wholly-owned, first-in-class CRISPR-mediated in vivo targeted
gene insertion development candidate for the treatment of AATD-associated lung
disease. It is designed to precisely insert a functional copy of the SERPINA1
gene, which encodes the alpha-1 antitrypsin ("A1AT") protein, with the potential
to restore permanent expression of functional A1AT protein to therapeutic levels
after a single dose. This approach seeks to improve patient outcomes, including
eliminating the need for weekly IV infusions of A1AT augmentation therapy or
lung transplant in severe cases. We are conducting investigational new drug
("IND")-enabling activities for NTLA-3001, with plans to file an IND or
IND-equivalent in 2023.
NTLA-2003 for associated liver disease:
NTLA-2003 is our wholly-owned in vivo knockout development candidate for the
treatment of AATD-associated liver disease. It is designed to inactivate the
SERPINA1 gene responsible for the production of abnormal A1AT protein in the
liver. This approach aims to halt the progression of liver disease and eliminate
the need for liver transplant in severe cases. We are conducting IND-enabling
activities for NTLA-2003.
In Vivo Research Programs
We continue to work on various liver-focused programs, such as hemophilia A and
hemophilia B, which we are co-developing with Regeneron, primary hyperoxaluria
type 1, as well as other liver targets, which are worked on both independently
and in partnership with Regeneron, which leverage our capabilities to knockout,
insert and make consecutive edits to the genome.
In the third quarter of 2021, we and Regeneron, the lead party for this program,
nominated a Factor 9 ("F9") gene insertion development candidate for our
Hemophilia B ("Hem B") program, leveraging our jointly developed targeted
transgene insertion capabilities to insert F9. F9 is a gene that encodes for
Factor IX ("FIX"), a blood-clotting protein that is missing or defective in Hem
B patients. In preclinical studies, we and Regeneron demonstrated the first
CRISPR/Cas9-mediated targeted transgene insertion in the liver of non-human
primates ("NHPs"), which resulted in circulating FIX levels at or above those
found in normal human plasma. At the 2019 American Society of Gene and Cell
Therapy Annual Meeting, we presented data demonstrating the
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first CRISPR/Cas9-mediated, targeted transgene insertion in the liver of NHPs,
using F9 as a model gene. Following a single dose to NHPs of the hybrid
LNP-adeno-associated virus ("AAV") delivery system containing an F9 DNA
template, we demonstrated that the circulating human FIX protein levels achieved
in NHPs were at or above normal levels. Additionally, the NHP data expands on
the durability of clinically relevant human FIX protein levels achieved in mice
for over 12 months.
In September 2020 , we presented data that showed the persistence of in vivo
CRISPR/Cas9 edits in regenerated liver tissue, both knockout and insertion, and
corresponding durability of effect following a partial hepatectomy ("PHx") and
liver regrowth in a murine model. Unlike traditional gene therapy, for which a
significant loss (over 80%) in transgene expression was observed in the
insertion PHx model, our targeted gene insertion approach yielded durable edits,
with no significant loss in expression.
We are further investigating delivery strategies that target tissues outside of
the liver. For example, at the Keystone eSymposium: Precision Engineering of the
Genome, Epigenome and Transcriptome in March 2021 , we presented preclinical data
establishing proof-of-concept for non-viral genome editing of bone marrow and
HSCs in mice. This represented our first demonstration of systemic in vivo
genome editing in bone marrow using our proprietary non-viral delivery platform.
We believe these results extend our modular in vivo capabilities to treat
inherited blood disorders such as sickle cell disease. In addition, we announced
a collaboration with SparingVision SAS ("SparingVision") to develop novel
genomic medicines utilizing CRISPR/Cas9 technology for the treatment of ocular
diseases.
With the continued progression of our in vivo research programs, we plan to advance at least one new in vivo development candidate by the end of 2022.
Ex Vivo Programs
We are independently researching and developing proprietary engineered cell
therapies to treat various oncological and other disease indications, for
example TCR-engineered T cells and chimeric antigen receptor T ("CAR-T") cells
for immuno-oncology applications and engineered regulatory T cells for
autoimmune disorders. Our diverse product strategy includes multiple elements.
In particular:
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We are developing TCR-engineered T cells as immuno-oncological therapies. For example, in our existing collaboration with Ospedale San Raffaele,Milan , a leading European research-university hospital, we have identified optimized TCRs that recognize a tumor target,Wilms' Tumor 1 ("WT1"), that could be used to treat a variety of blood cancers and solid tumors; and
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We are developing allogeneic cellular therapies, which are those derived from
unrelated donors and modified outside of the human body to allow them to be
administered to an unrelated patient. These allogeneic cellular therapies could
be used to treat both oncological and immunological diseases. Our proprietary
technologies, including our LNP-based cell engineering platform and novel
allogeneic solution, offer significant advantages over both autologous cell
therapies and allogeneic approaches being investigated by others. Preclinical
data presented on our differentiated allogeneic engineering platform showed
allogeneic T cells were shielded from immune rejection, both host T and natural
killer ("NK") cell attack.
In addition, we strategically partner with others who possess complementary
capabilities or technologies to bring forth innovative engineered cell therapies
outside of our core areas of focus. This includes collaborations with AvenCell
and Kyverna, who will be leveraging our ex vivo genome editing platform to
develop novel cell therapies for a variety of therapeutic indications, as well
as ONK Therapeutics, Ltd. ("ONK") to advance CRISPR-edited NK cell therapies.
Further, our partner Novartis is developing therapies directed to selected
targets using CAR-T cells for oncology indications, as well as HSC and ocular
stem cell ("OSC")-based therapies.
Acute Myeloid Leukemia ("AML") Program
NTLA-5001 is our investigational autologous TCR-T cell therapy engineered to
target the WT1 antigen for the treatment of all genetic subtypes of AML. In
InAugust 2022 we announced our decision to concentrate our ex vivo development efforts exclusively on allogeneic cell therapies manufactured from healthy donors. Our proprietary technologies, including our LNP-based cell engineering platform and novel allogeneic solution, offer significant advantages over both autologous and current investigational allogeneic approaches. As 27 --------------------------------------------------------------------------------
described below under CD30+ Lymphomas, preclinical data presented on our differentiated allogeneic engineering platform showed allogeneic T cells were shielded from immune rejection, both host T and NK cell attack.
In addition, we announced plans to discontinue our first-in-human study of NTLA-5001 and are pivoting to an allogeneic version of this program currently in preclinical development. This decision is not due to any safety or efficacy data emerging from the trial. It is instead based on the potential of our allogeneic platform to consistently deliver a high-quality, readily available and persistent cell product for treatment of aggressive cancers. Preclinical data supporting the development of a WT1-directed allogeneic TCR-T cell candidate will be presented at a future scientific conference in 2022.
CD30+ Lymphomas
NTLA-6001 is our wholly-owned, allogeneic CAR-T development candidate targeting CD30 for the treatment of CD30-expressing hematologic cancers, including relapsed or refractory classical Hodgkin lymphoma ("cHL"). NTLA-6001 is the first candidate developed using our proprietary allogeneic cell engineering platform. We are conducting IND-enabling activities for NTLA-6001.
At the Keystone Symposium onMay 1, 2022 we presented preclinical data leading to the development of NTLA-6001. The data demonstrated that our proprietary allogeneic solution created T cells that not only avoid immune recognition by host CD4 and CD8 T cells, but also were protected from NK cell-mediated killing in in vitro and in vivo mouse models. Furthermore, allogeneic T cells engineered specifically with LNPs retained their viability, cell expansion, memory phenotype, cytotoxic and cytokine secretion characteristics.
Ex Vivo Research Programs
We are developing engineered cell therapies to treat a range of hematological and solid tumors. We are pursuing modalities, such as TCR, with broad potential in multiple indications. We are advancing efforts for allogeneic therapies to move from liquid to solid tumors. Our researchers are developing and improving cell-engineering manufacturing and delivery processes that, we believe, may allow us to deliver T cell therapies with high levels of editing, robust levels of cell expansion, desirable memory phenotypes, improved function and no translocations above background levels. Our proprietary T cell engineering process using LNPs to engineer cell therapies enables multiple, sequential gene edits. We have shared preclinical data demonstrating that our LNP-based engineering technology is a significant improvement over electroporation, the standard engineering process used to introduce proteins and nucleic acids into cells. The resulting T cells engineered with LNPs had improved cell properties and performance both in vitro and in vivo as compared to electroporation. The data support the ability of our platform to be used for a variety of targeting modalities, including CAR and TCRs, and to support both autologous and allogeneic T cell candidates. The LNP-based approach has been used in our NTLA-5001 program and multiple ex vivo candidates in development by us and our collaborators.
In
Novartis-Led Sickle Cell Disease and Other Research Programs
InDecember 2019 , the research term under our collaboration agreement with Novartis entered into in 2014 (the "2014 Novartis Agreement") ended, although the 2014 Novartis Agreement remains in effect. Under the 2014 Novartis Agreement, Novartis has selected particular CAR-T cell, HSC and OSC targets for continued development. Novartis has initiated clinical studies for OTQ923 and HIX763, two therapeutic candidates, based on CRISPR/Cas9 editing of HSCs that resulted from our research collaboration with Novartis. Novartis is currently recruiting patients for its Phase 1/2 study of these investigational candidates for treatment of sickle cell diseases. Novartis is developing several other product candidates arising from the 2014 Novartis Agreement. For more information regarding our collaboration with Novartis, see the section below entitled "Collaborations and Other Arrangements - Novartis". 28 --------------------------------------------------------------------------------
Collaborations and Other Arrangements
To accelerate the development and commercialization of CRISPR/Cas9-based products in multiple therapeutic areas, we have formed, and intend to seek other opportunities to form, strategic alliances with collaborators who can augment our leadership in CRISPR/Cas9 therapeutic development.
Regeneron
InApril 2016 , we entered into a license and collaboration agreement with Regeneron (the "2016 Regeneron Agreement"). The 2016 Regeneron Agreement has two principal components: (i) a product development component under which the parties will research, develop and commercialize CRISPR/Cas-based therapeutic products primarily focused on genome editing in the liver; and (ii) a technology collaboration component, pursuant to which the parties will engage in research and development activities aimed at discovering and developing novel technologies and improvements to CRISPR/Cas technology to enhance our genome editing platform. We may also access the Regeneron Genetics Center and proprietary mouse models to be provided by Regeneron for a limited number of our liver programs. At the inception of the 2016 Regeneron Agreement, Regeneron selected the first of its 10 targets, ATTR, which is subject to the ATTR Co/Co. OnMay 30, 2020 , we entered into (i) amendment no. 1 (the "2020 Regeneron Amendment") to the 2016 Regeneron Agreement, (ii) co-development and co-funding agreements for the treatment of hemophilia A and hemophilia B (the "Hemophilia Co/Co") agreements and (iii) a stock purchase agreement. The collaboration expansion builds upon the jointly developed targeted transgene insertion capabilities designed to durably restore missing therapeutic protein, and to overcome the limitations of traditional gene therapy. The collaboration was extended untilApril 2024 , at which point Regeneron has an option to renew for an additional two years. The 2020 Regeneron Amendment also grants Regeneron exclusive rights to develop products for five additional in vivo CRISPR/Cas-based therapeutic liver targets and non-exclusive rights to independently develop and commercialize up to 10 ex vivo gene edited products made using certain defined cell types. Refer to Note 7 to our condensed consolidated financial statements of this Quarterly Report on Form 10-Q for additional information related to the terms of the agreement between us and Regeneron.
OnJuly 30, 2021 , we finalized a transaction in which we,Cellex Cell Professionals GmbH ("Cellex") and funds managed byBlackstone Life Sciences Advisors L.L.C. ("BXLS") established a new universal CAR-T cell therapy company, AvenCell, and entered into two agreements with AvenCell: (i) a license and collaboration agreement (the "LCA"), under which we will collaborate to develop allogeneic universal CAR-T cell therapies and granted AvenCell a license to develop and commercialize genome edited universal CAR-T cell therapies (limited to its use with their switchable, universal CAR-T cellUniCAR and RevCAR platforms); and (ii) a co-development and co-funding agreement (the "AvenCell Co/Co") under which we will co-develop and co-commercialize allogeneic universal CAR-T cell products for an immuno-oncology indication. In addition to the license, we will collaborate with AvenCell on at least seven universal CAR-T cell products that combine our allogeneic T cell technology with AvenCell's switchable, universal CAR-T cell technology, referred to as the ("Allo Collaboration"). Additionally, AvenCell will pay us to provide supply and manufacturing services for them, including supplying good manufacturing practice ("GMP") CRISPR reagents to support the research and development of all CRISPR Products (as defined in the LCA) under the Allo Collaboration until the completion of the first Pivotal Trial (as defined in the LCA) of the first such CRISPR Product. We will also have one additional option to enter into a second co-development and co-funding agreement from selected allogeneic universal CAR-T cell therapy products that the parties intend to develop under the Allo Collaboration for a payment of$30.0 million to AvenCell.
In exchange for the license, we received a 33.33% equity interest in AvenCell at the time of the initial closing. Refer to Notes 7 and 8 to our condensed consolidated financial statements of this Quarterly Report on Form 10-Q for additional information related to the terms of the agreement between us and AvenCell.
SparingVision SAS ("SparingVision")
InOctober 2021 , we and SparingVision, a genomic medicine company developing vision saving treatments for ocular diseases, entered into a license and collaboration agreement (the "SparingVision LCA"), to develop novel genomic medicines utilizing CRISPR/Cas9 technology for the treatment of ocular diseases. We will grant SparingVision exclusive rights to our proprietary in vivo CRISPR/Cas9-based genome editing technology for up to three ocular targets addressing diseases with significant unmet medical need. In addition, the parties will research and develop novel self-inactivating AAV vectors and LNP-based approaches 29 --------------------------------------------------------------------------------
to address delivery of CRISPR/Cas9 genome editing reagents to the retina. SparingVision will lead and fund the preclinical and clinical development for the genome editing product candidates pursued under the collaboration.
In exchange for the license, we received an 11% equity ownership in SparingVision as of the closing date as well as three warrants attached to each share received for the right to purchase additional shares at designated prices that are subject to certain vesting conditions. We will also be eligible to receive certain research, development and commercial milestone cash payments (up to approximately$200 million per product) as well as royalties on potential future sales of products arising from the collaboration. We will have an option to obtain exclusiveU.S. commercialization rights for product candidates arising from two of three collaboration targets. For product candidates we choose to option, we will pay an opt-in fee between$10.0 million and$20.0 million depending on the stage of development of the target, reimburse certain costs, share in 50% of development costs and pay royalties to SparingVision onU.S. sales. Refer to Notes 7 and 8 to our condensed consolidated financial statements of this Quarterly Report on Form 10-Q for additional information related to the terms of the agreement between us and SparingVision.
InDecember 2021 , we entered into a licensing and collaboration agreement with Kyverna, a cell therapy company engineering a new class of therapies for autoimmune and inflammatory diseases, for the development of an allogeneic CD19 CAR-T cell therapy for the treatment of a variety of B cell-mediated autoimmune diseases. We granted Kyverna rights to our proprietary ex vivo CRISPR/Cas9-based allogeneic platform for the development of KYV-201, an allogeneic CD19 CAR-T cell investigational candidate for the treatment of select autoimmune diseases. This is a novel approach aimed at targeting CD19 for inflammatory diseases as compared to traditional oncology indications. Kyverna will lead and fund preclinical and clinical development for KYV-201 and we will be eligible to receive certain development and commercial milestone payments, as well as low-to-mid-single-digit royalties on potential future sales. We may also exercise an option to leadU.S. commercialization for KYV-201 under a co-development and co-commercialization agreement. If we choose to co-develop and co-commercialize KYV-201, we will pay an opt-in fee of$5.0 million and share in 50% of development costs and future net profit and/or loss arising from commercializing KYV-201 in theU.S. Kyverna retains all rights outside of theU.S. , and we will receive low-to-mid-single-digit royalties on net sales generated outside of theU.S. In exchange for the license, we received an equity ownership of preferred stock in Kyverna. We separately made an additional investment in Kyverna, purchasing incremental shares of Kyverna's preferred stock in exchange for$3.0 million in cash, bringing our investment to approximately 7% ownership in Kyverna at the time of closing. Refer to Notes 7 and 8 to our condensed consolidated financial statements of this Quarterly Report on Form 10-Q for additional information related to the terms of the agreement between us and Kyverna.
InFebruary 2022 , we announced a license, collaboration and option agreement with ONK for the development of engineered NK cell therapies for the treatment of cancer. The agreement grants ONK a non-exclusive license to our proprietary ex vivo CRISPR/Cas9-based genome editing platform and our LNP-based delivery technologies for development of up to five allogeneic NK cell therapies. ONK will be responsible for preclinical and clinical development for the engineered NK cell therapies enabled by the agreement. We will be eligible to receive up to$184 million per product in development and commercial milestone payments, as well as up to mid-single-digit royalties on potential future sales. In addition, the agreement grants us options to co-develop and co-commercialize up to two products worldwide with rights to lead commercialization in theU.S. Refer to Note 7 to our condensed consolidated financial statements of this Quarterly Report on Form 10-Q for additional information related to the terms of the agreement between us and ONK.
Novartis
InDecember 2014 , we entered into the 2014 Novartis Agreement, primarily focused on the research of new ex vivo CRISPR/Cas9-edited therapies using CAR-T cells and HSCs. The agreement was amended inDecember 2018 to also include research on OSCs. InDecember 2019 , per the terms of the 2014 Novartis Agreement, the research term ended, although the 2014 Novartis Agreement remains in effect, for which we will be eligible to receive milestone and royalty payments in the future. InJune 2021 , we entered into Amendment No. 3 (the "Amendment") to the 2014 Novartis Agreement. The Amendment amends Novartis' rights with respect to all of the CAR-T Therapeutic Targets (as defined in the 2014 Novartis Agreement) that Novartis selected under the 2014 Novartis Agreement, including (a) making Novartis' license non-exclusive for such CAR-T Therapeutic Targets, (b) removing Novartis' diligence and related reporting obligations for such CAR-T Therapeutic Targets, and (c) refining the scope of Novartis' sublicense rights for such CAR-T Therapeutic Targets. We made a one-time payment to Novartis of$10.0 30 -------------------------------------------------------------------------------- million within 30 days after the effective date of the Amendment, which was recorded as research and development expense in the consolidated statement of operations and comprehensive loss for the year endedDecember 31, 2021 . SinceDecember 31, 2021 , there have been no other material changes to the key terms of the 2014 Novartis Agreement and the Novartis Amendment. Refer to Note 7 to our condensed consolidated financial statements of this Quarterly Report on Form 10-Q for additional information related to the terms of the agreement between us and Novartis. Financial Overview Collaboration Revenue Our revenue consists of collaboration revenue, including amounts recognized related to upfront technology access payments for licenses, technology access fees, research funding and milestone payments earned under our collaboration and license agreements. Research and Development Research and development expenses consist of expenses incurred in performing research and development activities, such as compensation and benefits, which includes equity-based compensation, for full-time research and development employees, allocated facility-related expenses, overhead expenses, license and milestone fees, contract research, development and manufacturing services, clinical trial costs and other related costs.
General and Administrative
General and administrative expenses consist primarily of compensation and benefits, including equity-based compensation, for our executive, finance, legal, human resources, business development and support functions. Also included in general and administrative expenses are allocated facility-related costs not otherwise included in research and development expenses, travel expenses and professional fees for auditing, tax and legal services, including IP-related legal services, and other consulting fees and expenses.
Other (Expense) Income, Net
Other (expense) income consists of interest income earned on our cash, cash equivalents, restricted cash equivalents and marketable securities, loss from equity method investment and change in fair value of contingent consideration.
Results of Operations
The following discussion of the financial condition and results of operations should be read in conjunction with the accompanying condensed consolidated financial statements and the related footnotes thereto.
Comparison of Three Months Ended
The following table summarizes our results of operations for the three months
ended
Three Months Ended June 30, Period-to-
2022 2021 Period Change
(In thousands)
Collaboration revenue $ 14,030 $ 6,550 $ 7,480
Operating expenses:
Research and development 90,199 58,884 31,315
General and administrative 22,132 16,683 5,449
Total operating expenses 112,331 75,567 36,764
Operating loss (98,301 ) (69,017 ) (29,284 )
Other (expense) income, net:
Interest income 703 211 492
Loss from equity method investment (3,252 ) - (3,252 )
Change in fair value of contingent
consideration 172 - 172
Total other (expense) income, net (2,377 ) 211 (2,588 )
Net loss $ (100,678 ) $ (68,806 ) $ (31,872 )
31--------------------------------------------------------------------------------
Collaboration Revenue
Collaboration revenue increased by approximately$7.5 million to$14.0 million during the three months endedJune 30, 2022 , as compared to$6.6 million during the three months endedJune 30, 2021 . The increase in collaboration revenue during the three months endedJune 30, 2022 is primarily due to our joint venture with AvenCell and revenue from the Kyverna LCA. Refer to Note 7 to our condensed consolidated financial statements appearing elsewhere in this Quarterly Report on Form 10-Q for further details.
Research and Development
Research and development expenses increased by approximately$31.3 million to$90.2 million during the three months endedJune 30, 2022 , as compared to$58.9 million during the three months endedJune 30, 2021 . The following table summarizes our research and development expenses for the three months endedJune 30, 2022 and 2021, together with the changes in those items in dollars and the respective percentages of change: Three Months Ended June 30, Period-to- Percent 2022 2021 Period Change Change (In thousands) External development expenses by program: NTLA-2001$ 9,017 $ 4,280 $ 4,737 111 % NTLA-2002 3,357 1,561 1,796 115 % NTLA-5001 4,757 4,724 33 1 % Unallocated research and development expenses: Employee-related expenses 28,824 15,635 13,189 84 % Research materials and contracted services 21,122 18,679 2,443 13 % Facility-related expenses 8,174 6,778 1,396 21 % Stock-based compensation 14,079 6,135 7,944 129 % Other 869 1,092 (223 ) -20 % Total research and development expenses$ 90,199 $ 58,884 $ 31,315 53 % The increase in research and development expenses for the three months endedJune 30, 2022 compared to the three months endedJune 30, 2021 was primarily attributable to:
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a
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a
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a$2.4 million increase in research materials and contracted services primarily driven by an increase in drug component expenses to support our pipeline, partially offset by a$10.0 million one-time payment related to the amendment of the 2014 Novartis Agreement inJune 2021 ;
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a
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a
General and Administrative
General and administrative expenses increased by$5.4 million to$22.1 million during the three months endedJune 30, 2022 , compared to$16.7 million during the three months endedJune 30, 2021 . This increase was primarily related to employee-related expenses, including an increase in stock-based compensation of$4.5 million , driven by our larger workforce.
Other (Expense) Income, Net
The increase in other (expense) income of$2.6 million is primarily related to our share of three months of AvenCell's losses generated in the first quarter of 2022 of$3.3 million , offset in part by a$0.5 million increase in interest income and a reduction in the fair value of our contingent consideration liability of$0.2 million .
Comparison of Six Months Ended
The following table summarizes our results of operations for the six months
ended
Six Months Ended June 30, Period-to-
2022 2021 Period Change
(In thousands)
Collaboration revenue $ 25,282 $ 12,995 $ 12,287
Operating expenses:
Research and development 223,294 98,160 125,134
General and administrative 44,535 30,277 14,258
Total operating expenses 267,829 128,437 139,392
Operating loss (242,547 ) (115,442 ) (127,105 )
Other (expense) income, net:
Interest income 1,243 431 812
Loss from equity method investment (5,997 ) - (5,997 )
Change in fair value of contingent
consideration (249 ) - (249 )
Total other (expense) income, net (5,003 ) 431 (5,434 )
Net loss $ (247,550 ) $ (115,011 ) $ (132,539 )
Collaboration Revenue
Collaboration revenue increased by approximately $12.3 million to $25.3 million
during the six months ended June 30, 2022 , as compared to $13.0 million during
the six months ended June 30, 2021 . The increase in collaboration revenue during
the six months ended June 30, 2022 is primarily due to our joint venture with
AvenCell and revenue from the Kyverna LCA. Refer to Note 7 to our condensed
consolidated financial statements appearing elsewhere in this Quarterly Report
on Form 10-Q for further details.
Research and Development
Research and development expenses increased by$125.1 million to$223.3 million during the six months endedJune 30, 2022 , as compared to$98.2 million during the six months endedJune 30, 2021 . 33 -------------------------------------------------------------------------------- The following table summarizes our research and development expenses for the six months endedJune 30, 2022 and 2021, together with the changes in those items in dollars (in thousands) and the respective percentages of change: Six Months Ended June 30, Period-to- Percent 2022 2021 Period Change Change (In thousands) External development expenses by program: NTLA-2001$ 17,589 $ 6,602 $ 10,987 166 % NTLA-2002 5,057 3,716 1,341 36 % NTLA-5001 9,879 9,252 627 7 % Unallocated research and development expenses: Employee-related expenses 53,536 29,302 24,234 83 % Research materials and contracted services 38,751 25,656 13,095 51 % In-process research and development 55,990 - 55,990 0 % Facility-related expenses 16,699 11,960 4,739 40 % Stock-based compensation 24,353 9,626 14,727 153 % Other 1,440 2,046 (606 ) -30 % Total research and development expenses$ 223,294 $ 98,160 $ 125,134 127 %
The increase in research and development expenses for the six months ended
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an
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a
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a
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a$13.1 million increase in research materials and contracted services primarily driven by an increase in drug component expenses to support our pipeline, partially offset by a$10.0 million one-time payment related to the amendment of the 2014 Novartis Agreement inJune 2021 ;
•
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a
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a
General and Administrative
General and administrative expenses increased by approximately$14.3 million to$44.5 million during the six months endedJune 30, 2022 , compared to$30.3 million during the six months endedJune 30, 2021 . This increase was primarily related to an increase in employee related expenses, including stock-based compensation of$9.8 million . Other (Expense) Income, Net 34
-------------------------------------------------------------------------------- The increase in other (expense) income of$5.4 million is primarily related to our share of six months of AvenCell's losses generated in the fourth quarter of 2021 and the first quarter of 2022 totaling$6.0 million and an increase in the fair value of our contingent consideration liability of$0.2 million , offset in part by a$0.8 million increase in interest income.
Liquidity and Capital Resources
Since our inception throughJune 30, 2022 , we have raised an aggregate of approximately$1,861.1 million to fund our operations through our collaboration agreements, our initial public offering and concurrent private placements, follow-on public offerings, at-the-market offerings and the sale of convertible preferred stock.
As of
We are eligible to earn a significant amount of milestone payments and royalties, in each case, on a per-product basis under our collaborations with Novartis, SparingVision and ONK, on a per-target basis under our collaboration with Regeneron and upon achievement of certain events under our collaboration with Kyverna. Our ability to earn these milestone payments and the timing of achieving these milestones is dependent upon the outcome of our research and development activities and is uncertain at this time. Our rights to payments under our collaboration agreements are our only committed external source of funds. Follow-on Offerings InJuly 2021 , we closed an underwritten public offering of 4,758,620 shares of common stock, including the exercise in full of the underwriters' option to purchase an additional 620,689 shares of common stock, at the public offering price of$145.00 per share, for aggregate net proceeds of$648.3 million , after deducting approximately$41.7 million in underwriting discounts and offering costs.
At-the-Market Offering Programs
InAugust 2019 , we entered into an Open Market Sale Agreement (the "2019 Sale Agreement") withJefferies LLC ("Jefferies"), under which Jefferies is able to offer and sell, from time to time in "at-the-market" offerings, shares of our common stock having aggregate gross proceeds of up to$150.0 million . We agreed to pay to Jefferies cash commissions of 3.0% of the gross proceeds of sales of common stock under the 2019 Sale Agreement. During 2021, we issued 641,709 shares of our common stock in a series of sales at an average price of$72.79 per share in accordance with the 2019 Sale Agreement, for aggregate net proceeds of$45.3 million after payment of cash commissions to Jefferies and approximately$0.1 million related to legal, accounting and other fees in connection with the sales. During the first half of 2022, we issued 579,788 shares of our common stock in a series of sales at an average price of$69.43 per share in accordance with the 2019 Sale Agreement, for aggregate net proceeds of$38.9 million after payment of cash commissions to Jefferies and approximately$0.2 million related to legal, accounting and other fees in connection with the sales.
As of
InMarch 2022 , we entered into an Open Market Sale Agreement (the "2022 Sale Agreement") with Jefferies, under which Jefferies is able to offer and sell, from time to time in "at-the-market" offerings, shares of our common stock having aggregate gross proceeds of up to$400.0 million . We agreed to pay to Jefferies cash commissions of 3.0% of the gross proceeds of sales of common stock under the 2022 Sale Agreement. No shares have been issued under the 2022 Sale Agreement throughJune 30, 2022 . 35 --------------------------------------------------------------------------------
Funding Requirements
Our primary uses of capital are, and we expect will continue to be, research and
development contracted services, clinical trial costs, compensation and related
expenses, laboratory and office facilities, research supplies, legal and
regulatory expenses, patent prosecution filing and maintenance costs for our
licensed IP, milestone and royalty payments and general overhead costs. During
the second half of 2022, we expect our expenses to increase compared to prior
periods in connection with our ongoing activities as we continue to grow our
research and development team, development of our clinical programs and advance
additional programs into clinical development.
Because our lead programs are still in the early clinical stage and the outcome
of these efforts is uncertain, we cannot estimate the actual amounts necessary
to successfully complete the development and commercialization of any future
product candidates or whether, or when, we may achieve profitability. Until such
time as we can generate substantial product revenues, if ever, we expect to
finance our ongoing cash needs through equity financings and collaboration
arrangements. We receive cost reimbursements from Regeneron for the
transthyretin ("ATTR") amyloidosis and hemophilia programs. Additionally, we are
eligible to earn milestone payments and royalties, in each case, on a
per-product basis under our collaborations with Novartis, SparingVision and ONK,
on a per-target basis under our collaboration with Regeneron, and upon
achievement of certain events with Kyverna, subject to the provisions of our
agreements with each of them. Except for these sources of funding, we will not
have any committed external source of liquidity. To the extent that we raise
additional capital through the future sale of equity, the ownership interest of
our stockholders will be diluted, and the terms of these securities may include
liquidation or other preferences that adversely affect the rights of our
existing stockholders. If we raise additional funds through collaboration
arrangements in the future, we may have to relinquish valuable rights to our
technologies, future revenue streams or product candidates or grant licenses on
terms that may not be favorable to us. If we are unable to raise additional
funds through equity financings when needed, we may be required to delay, limit,
reduce or terminate our product development or future commercialization efforts
or grant rights to develop and market product candidates that we would otherwise
prefer to develop and market ourselves.
Outlook
Based on our research and development plans and our expectations related to the progress of our programs, we expect that our cash, cash equivalents and marketable securities as ofJune 30, 2022 , as well as research and cost reimbursement funding from Regeneron, AvenCell and SparingVision, will enable us to fund our ongoing operating expenses and capital expenditure requirements beyond the next 24 months, excluding any potential milestone payments or extension fees that could be earned and distributed under our collaboration agreements or any strategic use of capital not currently in the base case planning assumptions. We have based this estimate on current assumptions that may prove to be wrong, and we could use our capital resources sooner than we expect. Our ability to generate revenue and achieve profitability depends significantly on our success in many areas, including: developing our delivery technologies and our CRISPR/Cas9 technology platform; selecting appropriate product candidates to develop; completing research and preclinical and clinical development of selected product candidates; obtaining regulatory approvals and marketing authorizations for product candidates for which we complete clinical trials; developing a sustainable and scalable manufacturing process for product candidates; launching and commercializing product candidates for which we obtain regulatory approvals and marketing authorizations, either directly or with a collaborator or distributor; obtaining market acceptance of our product candidates; addressing any competing technological and market developments; negotiating favorable terms in any collaboration, licensing, or other arrangements into which we may enter; maintaining good relationships with our collaborators and licensors; maintaining, protecting, and expanding our portfolio of IP rights, including patents, trade secrets, and know-how; and attracting, hiring, and retaining qualified personnel.
Cash Flows
The following is a summary of cash flows for the six months endedJune 30, 2022 and 2021: Six Months EndedJune 30, 2022 2021 (In millions)
Net cash used in operating activities
142.8 7.7
Net cash provided by financing activities 53.2 65.7
36--------------------------------------------------------------------------------
Net cash used in operating activities
Net cash used in operating activities of$164.9 million during the six months endedJune 30, 2022 primarily reflects the increased spend in our research and development activities, offset in part by the receipt of$3.8 million in payments from our collaboration partners during that period. Net cash used in operating activities of$105.4 million during the six months endedJune 30, 2021 primarily reflects the increased spend in our research and development activities, offset in part by the receipt of$3.2 million in payments from our collaboration partners during that period.
Net cash provided by investing activities
During the six months endedJune 30, 2022 and 2021, our investing activities provided cash of$142.8 million and$7.7 million , respectively. The increase in the six months endedJune 30, 2022 is primarily due to$224.6 million in marketable securities maturing, offset in part by$44.8 million in net cash for the acquisition of Rewrite,$31.5 million of marketable securities purchased and$5.4 million in cash for the purchase of property and equipment. The increase in the six months endedJune 30, 2021 is primarily due to an increase in marketable securities activity during the period, as$185.4 million in marketable securities were purchased and$198.5 million in marketable securities matured, offset in part by$5.4 million for the purchase of property and equipment during the period.
Net cash provided by financing activities
Net cash provided by financing activities of$53.2 million during the six months endedJune 30, 2022 includes$38.9 million in net proceeds from at-the-market offerings,$13.3 million in cash received from the exercise of stock options and$1.1 million in cash received from the issuance of shares through our employee stock purchase plan. Net cash provided by financing activities of$65.7 million during the six months endedJune 30, 2021 includes$45.3 million in net proceeds from at-the-market offerings,$19.5 million in cash received from the exercise of stock options and$1.0 million in cash received from the issuance of shares through our employee stock purchase plan.
Critical Accounting Policies
Our critical accounting policies require the most significant judgments and estimates in the preparation of our condensed consolidated financial statements. Management has determined that our most critical accounting policies are those relating to revenue recognition and equity-based compensation. There have been no changes to our critical accounting policies from those which were discussed in our Annual Report for the year endedDecember 31, 2021 .
Recent Accounting Pronouncements
Please read Note 2, "Summary of Significant Accounting Policies", to our condensed consolidated financial statements included in Part I, Item 1, "Notes to Condensed Consolidated Financial Statements," of this Quarterly Report on Form 10-Q for a description of recent accounting pronouncements applicable to our business. Contractual Obligations There were no material changes to our contractual obligations during the three months endedJune 30, 2022 . For a complete discussion of our contractual obligations, please refer to our Management's Discussion and Analysis of Financial Condition and Results of Operations in our Annual Report for the year endedDecember 31, 2021 .
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