We have based these forward-looking statements largely on our current expectations and projections about our business, the industry in which we operate and financial trends that we believe may affect our business, financial condition, results of operations and prospects, and these forward-looking statements are not actually achieveguarantees of future performance or development. These forward-looking statements speak only as of the plans, intentionsdate of this Annual Report on Form 10-K and are subject to a number of risks, uncertainties and assumptions described in the section titled “Risk Factors” and elsewhere in this Annual Report on Form 10-K. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or expectations disclosedquantified, you should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in our forward-looking statements may not be achieved or occur and you should not place undue reliance on ouractual results could differ materially from those projected in the forward-looking statements. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events or otherwise.

In addition, statements thatsuch as “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 Annual Report on Form 10-K, 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. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-lookingThese statements we

make. We have included important factors in the cautionary statements included in this Annual Report on Form 10-K, particularly in the "Risk Factors" section, that we believe could cause actual results or events to differ materially from the forward-looking statements that we make.  

You should read this Annual Report on Form 10-K and the documents that we have filed as exhibits to Annual Report on Form 10-K completely and with the understanding that our actual future results may be materially different from what we expect. The forward-looking statements contained in this Annual Report on Form 10-K are made as of the date of this Annual Report on Form 10-K, and we do not assume any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by applicable law.

This Annual Report on Form 10-K includes statistical and other industry and market data that we obtained from industry publications and research, surveys and studies conducted by third parties as well as our own estimates of potential market opportunities. All of the market data used in this Annual Report on Form 10-K involves a number of assumptions and limitations,inherently uncertain and you are cautioned not to give undue weightunduly rely upon these statements.

PART I

Except where the context otherwise requires or where otherwise indicated, the terms “Enliven,” “we,” “us,” “our,” “our company,” “the company,” and “our business” refer to such data. Industry publicationsEnliven Therapeutics, Inc. and third-party research, surveysits wholly-owned subsidiaries. In addition, the word “Imara” refers to the company, and studies generally indicate that their information has been obtained from sources believedthe words “Former Enliven” refer to be reliable, although they do not guaranteeEnliven Inc. (formerly, Enliven Therapeutics, Inc.), prior to the accuracy or completeness of such information. Our estimatescompletion of the potential market opportunities for our product candidates include several key assumptions basedmerger with Imara Inc. on our industry knowledge, industry publications, third-party research and other surveys, which may be based on a small sample size and may fail to accurately reflect market opportunities. While we believe that our internal assumptions are reasonable, no independent source has verified such assumptions.February 23, 2023 (the “Merger”).

RISK FACTOR SUMMARY

Our business is subject to a number of risks that if realized could materially affect our business, financial condition, results of operations, cash flows and access to liquidity. These risks are discussed more fully in Part I, Item 1A. “Risk Factors” of this Annual Report on Form 10-K. Our principal risks include the following:

PART I

Item 1. Business.

Overview

We are a clinical-stage biopharmaceutical company dedicated to developing and commercializing novel therapeutics to treat patients suffering from rare inherited genetic disorders of hemoglobin, known as hemoglobinopathies, and other serious diseases. Our pipeline is builtfocused on the discovery and development of small molecule inhibitors to help patients with cancer not only live longer, but live better. We aim to address existing and emerging unmet needs with a precision oncology approach that improves survival and enhances overall patient well-being. Our discovery process combines deep insights in clinically validated biological targets and differentiated therapeutic potentialchemistry with the goal of ourdesigning therapies for unmet needs. By combining clinically validated targets and specific target product profiles with disciplined clinical trial design and regulatory strategy, we aim to develop drugs with an increased probability of clinical and commercial success. “Clinically validated targets” refers to biological targets that have demonstrated statistical significance on efficacy endpoints in published third-party clinical trials. We have assembled a team of seasoned drug hunters with significant expertise in discovery and development of small molecule kinase inhibitors. Our team includes leading chemists who have been the primary or co-inventor of over 20 product candidates that have been advanced to clinical trials, including four FDA approved products: Koselugo (selumetinib), Mektovi (binimetinib), Tukysa (tucatinib), and Retevmo (selpercatinib). We are currently advancing two parallel lead product candidates, ELVN-001 and ELVN-002, as well as pursuing several additional research stage opportunities that align with our development approach.

The following table summarizes our parallel lead product candidates:

Our first product candidate, tovinontrine (IMR-687)ELVN-001, is a potent, highly selective, small molecule kinase inhibitor designed to specifically target the breakpoint cluster region – Abelson (“BCR-ABL”) gene fusion, the oncogenic driver for patients with chronic myeloid leukemia (“CML”). Although the approval of BCR-ABL tyrosine kinase inhibitors (“TKIs”) has significantly improved the life expectancy of patients with CML, tolerability, safety, resistance and patient convenience concerns have become more prominent as patients can now expect to live on therapy for decades. Achieving this survival benefit requires continuous daily therapy, and all available active-site TKIs have off-target activity resulting in treatment-related adverse events and drug discontinuation due to intolerance or resistance. These issues can result in the loss of molecular response and disease progression for many patients and drive approximately 20% of patients to switch therapy within the first year of therapy and approximately 40% to switch in the first 5 years of therapy. These factors, prolonged treatment course, off-target toxicities, and acquired resistance, explain why the global market for CML supports multiple blockbuster products, exceeding $6.0 billion of sales in 2022, and why there remains significant unmet need for an effective and more tolerable treatment. In our preclinical studies, ELVN-001 has demonstrated improved kinome selectivity, tolerability and robust tumor growth inhibition when compared to certain leading and investigational therapies. In addition, ELVN-001 was highly active against the T315I mutation, which confers resistance to nearly all approved TKIs. As a selective active site inhibitor, ELVN-001's mechanism of action potentially represents a complementary option to allosteric BCR-ABL inhibitors (e.g., Scemblix), which ismay play an oral, highly selective, potent small molecule inhibitorincreasingly important role in the standard of phosphodiesterase-9,care for CML. Specifically, ELVN-001 was also designed to have activity against mutations known to confer resistance to Scemblix. ELVN-001 was designed to be a more attractive option for patients with comorbidities, on concomitant medications or PDE9.  Tovinontrinedesiring more freedom from stringent administration requirements. ELVN-001 is currently being evaluated in a Phase 2b1 clinical development for the treatment of sickle cell disease, or SCD, and β-thalassemiatrial in adults with CML, and we expectplan to begin clinical development of tovinontrine in heart failure with preserved ejection fraction, or HFpEF,present Phase 1a safety and efficacy data in the second quarter of 2022.2024.

Our second product candidate, ELVN-002, is a potent, highly selective, central nervous system ("CNS") penetrant and irreversible human epidermal growth factor receptor 2 (“HER2”) inhibitor with activity against wild type HER2 and various HER2 mutations. The majority of the TKIs targeting this population are dual epidermal growth factor receptor (“EGFR”) and HER2 inhibitors and are dose limited by EGFR-related toxicities. ELVN-002 is designed to inhibit wild type HER2 and key mutations of HER2, while sparing wild-type EGFR and avoiding EGFR-related toxicities. We believe that if ELVN-002 achieves this profile, it will be able to achieve an improved therapeutic index compared to current approved and investigational TKIs as well as provide a meaningful therapeutic option to patients with brain metastases, a key mechanism of resistance to current therapies in patients with non-small cell lung cancer (“NSCLC”), breast cancer (“BRC”), and other HER2 driven diseases. ELVN-002 was specifically designed to enable rational combination therapies, which, we believe, will be important for the treatment of patients with metastatic HER2 overexpressing and amplified cancers. In particular, we believe there is an attractive opportunity to address HER2+ colorectal cancer ("CRC"), BRC and NSCLC, in combination with standard of care. Additionally, due to the success of Enhertu, an antibody drug conjugate that targets HER2 expressing cancers, the HER2 treatment paradigm is changing rapidly. With Enhertu moving up in the treatment paradigm to earlier lines of therapy across HER2-altered cancers, a new unmet need is emerging for patients who cannot tolerate or progress on this new treatment option. We believe there will be an increasing need for therapies for these patients. ELVN-002 has demonstrated robust activity in preclinical models against wild type HER2 and various HER2 mutations, including an intracranial model, at well-tolerated doses. Our focus for this program is in NSCLC, BRC, and CRC as a single agent and/or in combination with standard of care. We have nearly completed our monotherapy Phase 1a dose escalation for ELVN-002 in HER2 altered tumors. This patient population includes patients with any HER2 mutant and HER2 amplified or overexpressed tumors, including patients who have received prior therapies, such as TKIs and antibody-drug conjugates ("ADCs"). We expect to share initial safety and efficacy data from the Phase 1a trial in 2024. Additionally, we filed an investigational new drug application ("IND") and received FDA clearance in the first quarter of 2024 for an additional Phase 1 trial evaluating the combination of ELVN-002 with trastuzumab in HER2+ solid tumors, and ELVN-002 with trastuzumab and chemotherapy in patients with HER2+ CRC and BRC. We expect to begin enrolling patients in this trial by mid-2024.

Over the last several years, it has become increasingly clear that cancers developing in various sites throughout the body often share the same genomic alterations. More specifically, research and clinical data suggest that some tumors are primarily or exclusively dependent on aberrantly activated enzymes, including kinases for their proliferation and survival. Kinases are cellular enzymes that regulate the biological activity of proteins through a process known as phosphorylation and represent one of the largest classes of oncogenic drivers when aberrantly mutated or expressed in the cell. Kinase inhibition is a proven approach to fighting cancer and for nearly two decades has effectively addressed an increasing number of oncology indications. However, despite the advancement of precision medicine in oncology, a significant unmet need remains for the majority of cancer patients for whom no targeted therapies exist or whose cancer has developed resistance to currently available targeted treatments.

We believe that the fundamental change in the development of targeted kinase inhibitor therapies together with our development approach, which is rooted in validated biology and differentiated chemistry, represents a unique opportunity to provide cancer patients with medicines offering improved therapeutic profiles. To capitalize on this opportunity, we continue to advance our research pipeline. We have completed IND enabling studies for our third program, have an additional program in lead optimization and have multiple efforts ongoing in target validation and lead identification. In the near-term, we plan to remain focused on progressing ELVN-001 and ELVN-002 and will prioritize taking full advantage of the development opportunities related to these programs before initiating a potential clinical trial for a third program.

Our Strategy

Our mission is to help patients with cancer not only live longer, but live better. The key elements of our strategy are:

While we have made progress towards our mission, we are still in the early stages of development and have not completed any clinical trials.

Our Team

We have assembled a team with significant expertise in drug discovery, development and commercialization with particular strengths in the discovery of small molecule kinase inhibitors. Our team includes:

Former Enliven was co-founded in 2019 by Sam Kintz, M.B.A., Joseph P. Lyssikatos, Ph.D. and Anish Patel, Pharm.D. Dr. Lyssikatos, our Chief Scientific Officer, is a renowned medicinal chemist, who helped build and scale Array BioPharma’s medicinal chemistry efforts and has held leadership positions at Genentech and Biogen. Dr. Lyssikatos is a co-inventor or co-author on over 220 issued patents and peer-reviewed publications and has led and been a key scientific contributor to over 30 programs. Mr. Kintz, our President and Chief Executive Officer, most recently held research and strategy leadership roles at AbbVie-Stemcentrx. Previously, Mr. Kintz worked at Roche Venture Fund and prior to that, at Genentech, as a medicinal chemist in the small-molecule discovery organization. Dr. Patel, our Chief Operating Officer, brings development, medical affairs, and commercial experience. He has held leadership roles at Pharmacyclics, MedImmune/AstraZeneca, and Berlex/Bayer. Our management team also consists of Helen Collins, M.D., Benjamin Hohl and Galya Blachman, Ph.D., Esq. Dr. Collins, our Chief Medical Officer, most recently served as Chief Medical Officer at Five Prime Therapeutics, until its acquisition by Amgen, where she led the development of bemarituzumab, an investigational targeted antibody, which was granted Breakthrough Therapy Designation by the FDA. Previously, Dr. Collins held leadership positions in clinical development and medical affairs at Amgen and Gilead Sciences. Mr. Hohl, our Chief Financial Officer and Head of Corporate Development, worked at Goldman Sachs Healthcare Investment Banking for nearly a decade advising on and executing biopharmaceutical and life sciences financings and strategic transactions. Dr. Blachman, our Chief Legal Officer and Head of Business Development, most recently served as the General Counsel and Chief Compliance officer of 5AM Ventures and the Chief Operating Officer of the 4:59 Initiative, 5AM Venture’s incubation arm. Prior to that, Dr. Blachman worked at AbbVie Stemcentrx and two corporate law firms.

In addition to our strong leadership team, the expertise and experience of our scientific advisors position us well to realize our mission of helping patients live longer, better lives. Our scientific advisors advise on matters associated with small molecule research and development, including preclinical and clinical development and regulatory and commercial positioning. The precision oncology experts on our scientific advisory board include the following members:

Our Development Approach

As a chemistry-led, precision oncology company, our primary focus lies in opportunities emerging from validated biology, where we believe we can improve on the standard of care. Specifically, we are focused on developing kinase inhibitors that:

At Enliven, we have assembled a team of seasoned drug hunters and are building a focused pipeline of programs. Using our expertise and the foundational principles driving our approach, we believe we are in a unique position to develop therapies to help patients not only live longer, but live better through our precision oncology solutions. Our development approach is rooted in the following principles:

Through our company’s focus on defining and establishing TPPs that address emerging unmet needs and potentially overlooked market opportunities, and our team’s experience in designing and developing therapeutics for unmet needs, we aim to build a pipeline of high-quality product candidates rather than simply a large number of programs.

Our parallel lead programs are focused on targeting known oncogenic drivers of cancer. Our BCR-ABL program aims to deliver enhanced target inhibition through better selectivity, resulting in better activity and improved long-term tolerability than approved or Nrf2.  

Disease Areas

Hemoglobinopathies

Hemoglobinopathies are a diverse range of rare inherited genetic disorders incurrent investigational active-site agents. Our product candidate, ELVN-001, was also designed to address resistance via the T315I gatekeeper mutation, for which there are limited treatment options. Our HER2 program is abnormal a potent, highly selective, CNS penetrant and irreversible HER2 inhibitor against wild type HER2 and various HER2 mutations. Our focus for this program is in NSCLC, BRC, and CRC as a single agent and/or decreased productionin combination with standard of hemoglobin,care. ELVN-002 is designed to inhibit HER2 and key mutations of HER2, while sparing wild-type EGFR and avoiding EGFR-related toxicities. We believe that if ELVN-002 achieves this profile, it will be able to achieve an improved therapeutic index compared to current approved and investigational TKIs as well as provide a meaningful therapeutic option to patients with brain metastases, a key mechanism of resistance to current therapies in patients with NSCLC, BRC, and other HER2 driven diseases.

Our Pipeline

We are focused on the iron-containing proteindiscovery and development of precision oncology therapies. We aim to do this by addressing issues such as tolerability and combinability, resistance, and disease escape through brain metastases. We are currently advancing two parallel lead product candidates, ELVN-001 and ELVN-002.

BCR-ABL Program: ELVN-001

ELVN-001 is a small molecule kinase inhibitor for the treatment of CML. ELVN-001 specifically targets the BCR-ABL fusion gene product, the oncogenic driver for patients with CML. ELVN-001 is a potent, highly selective, adenosine triphosphate, or ATP-competitive inhibitor of ABL1. ELVN-001 was also designed to have activity against T315I, the most common BCR-ABL mutation. T315I confers resistance to all the approved TKI therapies except asciminib and ponatinib. ELVN-001 was also designed to have activity against mutations known to confer resistance against asciminib. We believe that, given its marked kinome selectivity, attractive drug-like properties, and activity against T315I, ELVN-001 has the potential to represent an improved option for patients with CML across all lines of therapy in red blood cells, or RBCs, responsiblethe future.

CML Disease and Market Background

CML accounts for transporting oxygenapproximately 15% to 20% of leukemias in adults. This disease is divided into three stages of progressively advanced disease termed chronic phase ("CP"), accelerated phase, and blast crisis. Nearly 95% of patients with CML are diagnosed in the CP. In the last decade, the annual incidence of CML has remained steady at approximately two cases per 100,000 adults and was estimated to be 9,000 people in the United States in 2020. In 2018, there were approximately 62,000 patients living with CML in the United States. This population continues to grow, largely driven by improved survival rates attributable to the availability of BCR-ABL targeted therapies. The number of patients living with CML has more than doubled since the introduction of BCR-ABL TKIs. More than 75% of CML patients achieve normal survival outcomes when compared to the appropriate age-matched general population. However, roughly 70% of these patients require continuous TKI therapy in order to achieve this outcome and an additional 10% achieve near normal survival when compared to the appropriate age-matched general population with continuous TKI therapy.

The evolution of the CML treatment paradigm has been driven by improved efficacy as primarily demonstrated through improvements in major molecular response ("MMR"), a specific measure of BCR-ABL transcript levels in the blood. Hemoglobinopathies can be broadly categorized intoImatinib, a

first-generation small molecule BCR-ABL TKI, was approved for treatment of CML in 2001. Since imatinib’s approval, and with the introduction of several additional BCR-ABL TKIs, the 10-year survival rate improved from less than 20% to more than 80%. Because second generation TKIs (dasatinib, nilotinib, and bosutinib) elicit quicker molecular responses and higher rates of MMR and MR4.5, updates to the NCCN guidelines include recommendations to achieve deeper responses for some patients in the 1L setting. As a result, physicians now report that up to 50% of treatment-naïve patients start 1L therapy on a second generation TKI. Over the past 20 years, the treatment and market dynamics in CML have evolved considerably. Due to the success and availability of multiple TKIs, patients diagnosed with CML today have a significantly prolonged life expectancy. For many patients, however, this will require many years, if not decades, of therapy. The CML treatment dynamics and market insights lend an increased focus on better early efficacy and long-term tolerability. In fact, for third line patients, the top two groups.treatment goals for physicians and patients are to maintain or improve quality of life and to manage side effects.

Despite many significant advances in the treatment of CML, drug intolerance and resistance result in the loss of molecular response and disease progression for many patients. The availability of multiple treatment options has also likely driven an increase in switching rates. Approximately 20% of patients switch therapy within the first group, which includes SCD, results from structural abnormalitiesyear of treatment and up to 40% switch in hemoglobin that cause RBCsthe first five years of treatment. The majority of treatment switches occur early in the patient’s treatment course due to become inflexible and elongated (sickle-shaped), ultimately blocking blood flow to organs, which can lead to vaso-occlusive crises,intolerance or VOCs. SCD is characterized by debilitating pain, progressive multi-organ damage and early death. The global prevalencelack and/or loss of SCDmolecular response. As a result, it is estimated that approximately 50% of patients with CML in the United States (approximately 30,000 patients) have discontinued at least one TKI. In the 2L setting, switching occurs even more rapidly. Approximately 50% of 2L patients switch after two to three years as treatment durability wanes and TKI tolerability issues persist.

Asciminib, a fourth-generation agent, has demonstrated potential advantages over first-, second- and third-generation BCR-ABL TKIs in clinical trials. Currently marketed by Novartis, it is an allosteric inhibitor of BCR-ABL that specifically targets the ABL myristoyl pocket. Unlike the first-, second- and third-generation TKIs, which are active site inhibitors, asciminib represents an unfamiliar mechanism of action for physicians and its long-term tolerability, safety and resistance profile is not yet fully defined. As noted in the product labeling, drug-drug interactions and fasting requirements, two hours before and one hour after each dose, may present additional challenges in the context of a chronic disease. Furthermore, in clinical trials with a median treatment duration of less than 15 months, multiple resistance mutations to asciminib were observed, including M244V, E355G, F359V and T315I in the ATP binding site, and A337T and P465S in the myristoyl binding pocket. Lastly, in its 3L+ pivotal study, approximately 30% of patients discontinued due to lack of efficacy by 48 weeks and approximately 50% of patients discontinued asciminib by 96 weeks, but only 1.2% due to progressive disease or death. Hence, the majority of patients switch off asciminib due to lack of efficacy or adverse events and likely seek other TKI treatment options. We believe asciminib’s development progress to date, including Novartis’ move directly from a pivotal 3L+ trial, in which it demonstrated a superior rate of MMR at 6 months compared to bosutinib, to a 1L pivotal trial prior to its first FDA approval, highlights the heightened need for better agents in all lines of therapy for CML. This demand for better agents has been demonstrated by Novartis’ strong 3L+ launch of asciminib. In the fourth quarter of 2023, Scemblix achieved approximately $125 million in sales. This implies that asciminib is currently operating at an approximately $500 million annual sales run rate with 3L+ approval alone. Additionally, Novartis recently announced that Scemblix showed superior MMR rates vs standard of care in their 1L trial, which demonstrates that a selective BCR-ABL TKI has the potential to offer a better solution for CML patients across lines of therapy.

ELVN-001 Opportunity

In contrast to the ATP-competitive TKIs approved for the treatment of CML, ELVN-001 is highly selective within the kinome. Importantly, our preclinical studies showed that ELVN-001 did not meaningfully interfere with the activity of particular kinases known to limit the efficacy and tolerability of approved TKIs that suffer from a number of dose-limiting toxicities. We believe that the enhanced selectivity profile of ELVN-001 coupled with its predicted human PK may provide a wide therapeutic index. This in turn may enable greater and more prolonged target engagement as well as improved tolerability for long-term treatment. As demonstrated by the approved active site TKIs, there is a clear correlation between target coverage (as measured by fold above Phosphorylated CRKL IC50 at Cave) and 1L MMR at 12 months; better target coverage leads to higher 1L MMRs at 12 months. Additionally, the target coverage that the approved active site TKIs achieve in humans is approximately the same as the target coverage achieved in non-human primates ("NHPs"). In contrast, at well-tolerated doses, ELVN-001 achieved target coverage in NHPs that is well in excess of our target in humans. Therefore, we believe ELVN-001 could potentially have a wider therapeutic index compared to the currently approved active-site TKIs. If ELVN-001 achieves a wider therapeutic index in patients with CML, we believe it will confer faster and deeper molecular responses than those observed with the approved active site agents. Deep molecular responses have been shown to significantly predict overall survival and represent a highly sensitive marker to detect treatment differences, especially in early lines of therapy. Importantly for patients, this wide therapeutic index may not only drive deeper responses, but may also offer better tolerability, which is a top treatment goal in CML, particularly for patients who have had two prior TKIs. Additionally, we have designed ELVN-001 to be a more attractive option for patients who desire more freedom from

stringent administration requirements (e.g., fasting and drug-drug interactions), have co-morbidities, or are on concomitant medications. We believe tolerability and flexible use are important in a chronic disease setting where patients often require daily therapy for decades.

ELVN-001 has been designed to address the T315I mutation form of BCR-ABL while preserving high potency against the native BCR-ABL isoform. In preclinical models, ELVN-001 exhibited robust tumor growth inhibition in both native BCR-ABL and the T315I mutation. Based upon these data and given its enhanced kinome selectivity, we believe that ELVN-001 has the potential to be an improved option for patients with CML harboring the T315I mutation.

At the end of 2021, Novartis received 3L+ approval for its allosteric BCR-ABL inhibitor, asciminib. Early in its launch, asciminib has already achieved approximately 4.4$500 million of annualized sales, based on the results of the fourth quarter of 2023. Novartis is currently projecting asciminib to have greater than $2 billion of annual peak sales. We believe ELVN-001 is well-positioned to follow asciminib given its complementary mechanism of action (ATP-site/active form vs. allosteric/inactive form) to asciminib. In particular, ELVN-001 demonstrated in vitro activity against all of the asciminib-emergent mutations associated with lack of efficacy and treatment discontinuation in the ASCEMBL trial (Scemblix’s Phase 3 trial in 3L+ CML). In ASCEMBL, over 40% of patients including approximately 100,000discontinued asciminib by 96 weeks, but only 1.2% due to progressive disease or death. We believe this demonstrates a large opportunity for ELVN-001 in patients who ultimately switch off asciminib. Additionally, there is potentially a rationale for ELVN-001 to compete directly with asciminib across lines of therapy based on differentiated efficacy, tolerability or administration requirements for patients.

Clinical Development Plan

We anticipate initiating our Phase 1b dose escalation for ELVN-001 in adult patients with CML by mid-2024. Our Phase 1 clinical trial is designed to characterize the safety, tolerability, PK properties, and preliminary efficacy in a population of patients with CML with and without the T315I mutation. Assuming the results of the Phase 1 clinical trial are supportive and subject to feedback from regulatory authorities, subsequent trials would include a randomized pivotal trial(s) in patients with CML. Should efficacy and safety data also support potential benefit in patients with T315I, we would discuss with the FDA the optimal path forward for this patient population with limited options.

The objective of the trial is to (1) assess the safety and tolerability of ELVN-001 when administered to patients with CML, (2) understand the relationship between dose and schedule of drug with PK and anti-tumor activity, and (3) determine recommended doses for expansion in patients with CML with and without T315I. Our key efficacy measure will be the reduction of BCR-ABL transcripts in peripheral blood. We plan to present preliminary Phase 1a safety and efficacy data in the second quarter of 2024. By the time of this preliminary data release, we expect to have enrolled more than 20 patients in an efficacious dose range at the time of first data disclosure and expect that 10-20 patients will have been treated for over 3 months.

If our Phase 1 clinical data demonstrates an acceptable safety and tolerability profile and a strong positive efficacy signal, we would then engage with the FDA and other regulatory agencies to plan one or more registration-enabling trials in earlier lines of therapy in the United States and 134,000other geographies. Where possible, we plan to explore applicable regulatory strategies pursued by other targeted therapy companies, for example Orphan Drug Designation, Breakthrough Therapy and Fast Track designation, Priority Review and/or Accelerated Approval. However, because our product candidates are in early development, there can be no assurance that the FDA will permit us to utilize an expedited approval process for any of our product candidates. The FDA's accelerated approval pathways do not guarantee an accelerated review by the FDA. Even if our product candidates are granted a designation or qualify for expedited development, it may not actually lead to faster development or expedited regulatory review and approval or increase the likelihood that they will receive FDA approval.

HER2 Program: ELVN-002

ELVN-002 is a potent, highly selective, CNS penetrant and irreversible HER2 inhibitor with activity against wild type HER2 and various HER2 mutations. ELVN-002 is designed to inhibit wild type HER2 and key mutations of HER2, while sparing wild-type EGFR and avoiding EGFR-related toxicities. We believe that if ELVN-002 achieves this profile, it will be able to achieve an improved therapeutic index compared to current approved TKIs as well as provide a meaningful therapeutic option to patients with brain metastases, a key mechanism of resistance to current therapies in patients with NSCLC, BRC, and other HER2 driven cancers. Additionally, ELVN-002 was specifically designed to enable rational combination therapies, which, we believe, will be important for the treatment of patients with metastatic HER2 overexpressing and amplified cancers. Our focus for this program is in NSCLC, BRC, and CRC as a single agent and/or in combination with standard of care.

HER2 Altered Tumors and Market Background

The overexpression, amplification or mutation of HER2 is highly associated with aggressive forms of solid cancers, including BRC, NSCLC, CRC, and several others. In the United States alone, the incidence of HER2-altered cancer is over 150,000 patients annually, including approximately 63,000 with BRC, approximately 47,000 with NSCLC and approximately 9,000 with colon cancer. While up to 3% of patients with NSCLC harbor HER2 mutations, there are no FDA-approved TKIs for the treatment of HER2 mutant NSCLC. Most TKIs targeting this HER2 population are dual EGFR and HER2 inhibitors which have been dose-limited in the European Union.

The second group of hemoglobinopathies, which includes β-thalassemia, results from decreased production of hemoglobin or ineffective erythropoiesis (RBC production),clinic by EGFR-related toxicities, such as GI and skin toxicities. These toxicities necessitate restrictive dosing regimens, leading to fewer, smaller, paler RBCssuboptimal HER2 engagement and chronic anemia. β-thalassemia is often grouped into two subsets:attenuated therapeutic benefit. Moreover, while marketed TKIs provide a therapeutic benefit for patients with non-transfusion dependent thalassemia,cancers driven by HER2 overexpression, they may have limited efficacy in patients harboring specific genetic alterations.

Despite advances in treatments for HER2 altered tumors, the median overall survival is less than 12 months in the advanced stage, late line therapy setting. HER2 overexpressing and amplified tumors represent a large opportunity. While HER2 amplification or NTDT,overexpression is associated with many tumor types, including NSCLC, gastric cancer, CRC, and endometrial cancer, BRC currently represents the vast majority of HER2 related drug sales, as there are no TKIs that have received full FDA approval for the treatment of metastatic CRC or overexpressed/amplified NSCLC. The standard of care for HER2 metastatic BRC is chemotherapy in combination with one or more anti-HER2 monoclonal antibodies, such as trastuzumab or pertuzumab. Fam-trastuzumab deruxtecan (Enhertu) and ado-trastuzumab emtansine (Kadcyla) are both approved HER2 ADCs; however, they carry two and three black box warnings, respectively. Approved TKIs for metastatic BRC include dual EGFR and HER2 inhibitors, such as neratinib and lapatinib, in combination with capecitabine. Tucatinib is the only HER2-selective TKI and is approved in combination with trastuzumab and capecitabine. Despite demonstrating improved overall survival, the combination results in 80% all grade diarrhea (13% > Grade 3) and affords a median progression free survival of only 7.8 months. Of note, single agent tucatinib had an objective response rate ("ORR") of only 11% in late line metastatic BRC. This is perhaps not surprising given that tucatinib only achieved concentrations above its IC90 for HER2 in approximately 40% of patients all day (over 24 hours) at its FDA approved dose. Despite its limitations, Tukysa (tucatinib) is currently generating over $400 million in annualized revenue with a 2L+ HER2+ metastatic BRC label in combination with trastuzumab and chemotherapy (capecitabine) and 2L+ RAS wild type, HER2+ metastatic CRC in combination with trastuzumab. Additionally, recent tucatinib and Kadcyla combination data in HER2+ metastatic BRC supports a larger opportunity for ELVN-002 in metastatic BRC and demonstrates the rationale for TKI and ADC combinations more broadly. Notwithstanding tremendous advances in therapeutic options for HER2 metastatic BRC, there are still no curative treatments. Approximately 25% of patients experience primary or acquired resistance and up to 50% of patients develop brain metastases.

Due to the recent approvals and success of Enhertu, the HER2-altered cancer treatment paradigm is shifting. In 2022, annual Enhertu sales were approximately $1.6 billion and it is estimated that they will be more than $10 billion by 2028. However, Enhertu does not provide sustained disease control for all patients as approximately 25% of patients receiving Enhertu in 2L+ metastatic BRC progress within 12 months of treatment. Due to this dynamic and the fact that a standard of care regimen has not been established post-Enhertu, we believe there is a significant patient need and market opportunity in the post-Enhertu setting. Based on the precedent established by tucatinib in HER2+ BRC and CRC, we believe dual HER2-targeting may represent an important treatment option for patients with transfusion dependent thalassemia,HER2+ cancers, especially for those who progress or TDT. If left untreated, β-thalassemia causes severe anemia, splenomegaly, skeletal abnormalities, leg ulcers, iron overload,are intolerant to Enhertu.

ELVN-002 Opportunity

ELVN-002 is a potent, highly selective, CNS penetrant and organ failure, often leadingirreversible HER2 inhibitor with activity against wild type HER2 and various HER2 mutations. ELVN-002 was designed to early death. The global prevalence of β-thalassemia is estimatedachieve an improved therapeutic index compared to be approximately 288,000current approved and investigational TKIs in the broad HER2 population, including HER2 mutant, amplified and overexpressed tumors. Due to significant structural homology between EGFR and HER2, most investigational agents targeting HER2 mutations are dual EGFR and HER2 inhibitors and are dose-limited by EGFR-related toxicities. This has contributed to limited efficacy for patients with HER2 mutations, particularly in NSCLC. In contrast, ELVN-002 was greater than 100 times more selective for HER2 over EGFR in preclinical studies. Tucatinib, a reversible small molecule inhibitor, represents the total combined prevalenceonly approved selective HER2 orally active drug. However, it only achieves IC90 coverage in approximately 40% of patients and lacks potency against key mutations in NSCLC and BRC. ELVN-002 has demonstrated higher potency compared to tucatinib against wild type HER2 and HER2 mutations in our preclinical studies. Moreover, ELVN-002 elicited more robust tumor growth inhibition, including regressions, compared to tucatinib in HER2-amplified subcutaneous and intracranial models. ELVN-002 also demonstrated an improved safety margin in NHPs compared to tucatinib. Due to its larger safety margin, irreversible inhibition and improved PK profile, we believe ELVN-002 has the potential to achieve better target inhibition and improved efficacy compared to tucatinib. Taking all of this into consideration, we believe ELVN-002 may offer an improved treatment option compared to dual EGFR/HER2 TKIs as well as tucatinib for HER2-altered cancers, including for patients with CNS metastases.

Clinical Development Plan

We have nearly completed our Phase 1a dose escalation for ELVN-002 as a single agent in patients with solid tumors with HER2 alterations. This Phase 1 clinical trial is designed to characterize the safety, tolerability, PK properties, and preliminary efficacy in a population of patients with HER2 mutant and HER2 amplified or overexpressed solid tumors.

The objective of the trial is to (1) assess the safety and tolerability of ELVN-002, (2) understand the relationship between dose and schedule of drug with PK and anti-tumor activity, and (3) determine recommended doses for expansion as a single agent in HER2 mutant lung cancer. We plan to present Phase 1a safety and efficacy data in 2024.

Based on data from the single agent Phase 1 clinical trial, we filed another IND for ELVN-002 and received clearance of the IND from the FDA in the first quarter of 2024 to evaluate the combination of ELVN-002 with trastuzumab in HER2+ solid tumors, and ELVN-002 with trastuzumab and chemotherapy in patients with HER2+ colorectal and breast cancer. This Phase 1 clinical trial is designed to characterize the safety, tolerability, PK properties, and preliminary efficacy in patients with HER2+ solid tumors. Should the emerging clinical data be supportive, we will also evaluate safety, tolerability, and PK of ELVN-002 with trastuzumab and chemotherapy in patients with HER2+ CRC and BRC, and its preliminary efficacy in CRC.

After our Phase 1 clinical trials, and dependent on our data and alignment with the FDA, we believe there are multiple opportunities for a HER2 TKI including in lung cancer, BRC, and CRC as a single agent and/or in combination with standard of care.

Based on the totality of the Phase 1 clinical data and predicated upon an acceptable safety and tolerability profile and a strong positive efficacy signal, we then expect to engage with the FDA and other regulatory agencies to plan one or more registration-enabling trials in the United States and other geographies. Where possible, we plan to explore applicable regulatory strategies pursued by other targeted therapy companies, for example Orphan Drug Designation, Breakthrough Therapy and Fast Track designation, Priority Review and/or Accelerated Approval. However, because our product candidates are in early development, there can be no assurance that the European Union estimatedFDA will permit us to be approximately 19,000 patients.utilize an expedited approval process for any of our product candidates. The FDA’s accelerated approval pathways do not guarantee an accelerated review by the FDA. Even if our product candidates are granted a designation or qualify for expedited development, it may not actually lead to faster development or expedited regulatory review and approval or increase the likelihood that they will receive FDA approval.

SCD and β-thalassemia are both designated as rare diseases in the United States and the European Union.

Heart Failure with Preserved Ejection FractionAdditional Programs

Heart failure with preserved ejection fraction, or HFpEF, also known as diastolic heart failure, is typically caused by abnormalities of cardiac filling, which leads to symptoms such as shortness of breath, exercise intolerance and fluid retention. Characteristics of HFpEF are heterogeneous, but commonly include ventricular hypertrophy, diastolic dysfunction, endothelial dysfunction, insulin resistance, and inflammation. Comorbidities, such as hypertension, anemia, chronic kidney disease, diabetes, and obesity, are also common in HFpEF and are thought to contribute to its development.  HFpEF accounts for approximately half of all cases of heart failure and has become the predominant form of heart failure over time.   Prevalence in the United States is estimated to be approximately 3-4 million patients.  In contrast to heart failure with reduced ejection fraction, or HFrEF, there are relatively few treatment options to improve symptoms and outcomes for patients and there are currently only two FDA-approved products (Entresto and Jardiance) for the treatment of HFpEF.

Product Candidates

Tovinontrine (IMR-687)

Our lead candidate, tovinontrine, is a highly selective and potent small molecule inhibitor of PDE9. PDE9 selectively degrades cyclic guanosine monophosphate, or cGMP, an active signaling molecule that plays an important role in vascular biology. Lower levels of cGMP are found in patients with SCD and β-thalassemia and are associated with reduced blood flow, increased inflammation, greater cell adhesion and reduced nitric oxide mediated vasodilation. Blocking PDE9 acts to increase cGMP levels, which is associated with several benefits including the potential reactivation of fetal hemoglobin, or HbF, a natural hemoglobin produced during fetal development, lower white blood cell, or WBC, activation and reduced adhesion across various cell types. Increased levels of HbF in RBCs have been demonstrated to improve symptomology and substantially lower disease burden in both patients with SCD and patients with β-thalassemia and, along with reduced WBC adhesion and platelet aggregation, may result in fewer VOCs for SCD patients.

In addition levels of cGMPto our two lead programs, we are often reduced in patientscurrently pursuing several additional research stage opportunities that align with heart failure. Augmenting cGMP through the natriuretic peptide-cGMP pathway has been shown to mediate cardioprotective effects that lead to reduced heart failure disease progression and fewer cardiac events.

We believe tovinontrine may have advantages over other therapies, including having a multimodalour development approach, and being an oral dosing regimen. In addition, tovinontrine tabletsfor which we have been shown to be stable at high temperatures and in humid conditions, potentially enabling worldwide access, including in areas where SCD and ß-thalassemia are endemic.

SCD Program

We are currently conducting the Ardent Phase 2b clinical trial of tovinontrine, a randomized, double-blind, placebo-controlled trial in approximately 115 adult patients with SCD.established TPPs. We have completed enrollmentIND enabling studies for our third program, have an additional program in lead optimization and have multiple efforts ongoing in target validation and lead identification. In the Ardentnear-term, we plan to remain focused on progressing ELVN-001 and ELVN-002 and will prioritize taking full advantage of the development opportunities related to these programs before initiating a potential clinical trial and expect to report interim data from this trial in the first week of April 2022 and final data in the second half of 2022.  In November 2021, we made the decision to change the primary endpoint of the Ardent trial to annualized rate of VOCs followingfor a written recommendation from the FDA.  HbF response, which was previously the primary endpoint, will continue to be evaluated as a key secondary endpoint.third program.

 The Ardent trial follows completion of our Phase 2a clinical trial of tovinontrine in SCD, which demonstrated a well-tolerated safety profile for tovinontrine and potential benefits from tovinontrine with respect to VOCs.  Changes in SCD-related biomarkers were variable.  

We are also conducting a long-term open label extension, or OLE, clinical trial of tovinontrine, which is comprised of patients who completed our Phase 2a clinical trial of tovinontrine.  Data from the OLE trial presented at the American Society of Hematology (ASH) Annual Meeting in December 2021 demonstrated a well-tolerated safety profile for tovinontrine, potential benefits from tovinontrine with respect to VOCs and improvements in certain SCD-related biomarkers, including HbF and F-cells, through 12 months of treatment on the OLE trial.  Competition

In the second quarter of 2022, we expect to initiate a new, long-term OLE trial of tovinontrine for patients who complete the Ardent Phase 2b clinical trial in SCD.  In addition to patients from the Ardent trial, we expect patients from the ongoing Phase 2a OLE trial to roll over into this new OLE trial, resulting in one OLE trial with patients from both the Phase 2a clinical trial and the Ardent Phase 2b clinical trial.

ß-thalassemia Program

We are also conducting the Forte Phase 2b clinical trial of tovinontrine, a randomized, double-blind, placebo-controlled trial in approximately 120 TDT and NTDT patients with ß-thalassemia.  In November 2021, we presented data from a pre-specified interim analysis from the Forte trial in TDT patients.  The interim analysis data demonstrated a well-tolerated safety profile for tovinontrine and a trend for reduced transfusion burden in the higher dose cohort.  We expect to report additional interim data for TDT and NTDT patients from the Forte trial in the first week of April 2022 and data from the final analysis of the Forte clinical trial in the second half of 2022.

HFpEF Program

In the second quarter of 2022, we expect to dose the first patient in the SP₉IN Phase 2 clinical trial of tovinontrine in HFpEF.  The SP₉IN trial will be a randomized, placebo-controlled trial of approximately 170 patients 45 years of age or older with enriched PDE9 expression and persistent symptoms of HFpEF.  The primary endpoint of the trial will be the change in N-terminal pro b-type natriuretic peptide, or NT-proBNP, levels.

IMR-261

We have commenced research activities for IMR-261 (formerly CXA-10), an oral, clinical-ready activator of Nrf2.  In pre-clinical models of SCD, IMR-261 was observed to activate expression of HbF and reduce VOCs. Furthermore, in a preclinical model of ß-thalassemia, IMR-261 was observed to increase hemoglobin and enhance RBC maturation.  We have initiated work on drug product manufacturing for IMR-261 as we explore potential clinical development paths in hemoglobinopathies, iron disorders and potentially other areas.

Prior to its acquisition by us, IMR-261 was evaluated by Complexa, Inc. in Phase 2 clinical trials in focal segmental glomerulosclerosis, or FSGS, and pulmonary arterial hypertension, or PAH, and independent medical literature suggests potential in a broad array of RBC diseases, including disorders of hemoglobin, and iron overload diseases. 

Our Pipeline

We are advancing a pipeline of therapeutic programs to address diseases with significant unmet medical need. The following chart summarizes key information about our programs:

Our Strategy

Our goal is to become a leading biopharmaceutical company focused on the development and commercialization of novel therapies. To achieve this, we are focused on the following key strategies:

Sickle Cell Disease Overview

SCD is the most common type of inherited hemoglobinopathy. SCD is characterized by debilitating pain, progressive multi-organ damage and early death. Beginning early in life, patients suffer from blocked blood flow to tissues, known as vaso-occlusion, destruction of RBCs, known as hemolysis, and inadequate oxygen delivery, or hypoxia. The most common complication of SCD is pain, often a consequence of VOCs. A VOC occurs when circulation is obstructed by sickled RBCs, causing tissue damage to the organ and resultant pain. The outcomes of these events begin presenting early in childhood and quickly lead to heart and lung complications, renal disfunction, prolonged refractory penile erection (known as priapism), spleen enlargement and failure, stroke, retinopathy and mental and physical disabilities. Given the constellation of these comorbidities, patients with SCD have a diminished quality of life and on average have a significantly shorter lifespan than normal healthy adults, sometimes up to 20 to 30 years shorter.

SCD is caused by a single mutation in the gene that expresses the beta globin subunit of hemoglobin. Hemoglobin in RBCs consists of two beta globin and two alpha globin subunits. Hemoglobin’s primary function is to transport oxygen from the lungs to tissues throughout the body and return carbon dioxide back to the lungs. In oxygen rich environments, like the lungs, hemoglobin has a high affinity for oxygen and binds to it rapidly. In lower oxygen surroundings, like peripheral tissues, hemoglobin has a low affinity for oxygen and releases it quickly. The beta globin subunit mutation in SCD leads to the production of abnormal hemoglobin known as sickle hemoglobin, or HbS. HbS is comprised of two mutant beta globin and two normal alpha globin subunits. In reduced oxygen settings, HbS permits hydrophobic associations between the mutated beta globin subunits and the normal alpha subunits. This causes the oxygen deficient hemoglobin units to assemble into long chains in an event known as polymerization. These long, fixed chains of hemoglobin distort the flexible disc-like RBC into an inflexible crescent or “sickled” shape. Although the sickled RBC may convert back into a regular RBC in oxygen rich environments, it will return to its sickled form in lower oxygen environments and ultimately may be permanently sickled and/or be destroyed.

Although patients with SCD often present a spectrum of symptoms that can vary over time, patients are often grouped by their predominant symptomology: those that present with hemolytic anemia, which is largely driven by sickled RBCs, and those that present with painful VOCs, where RBCs, WBCs and other cell types play a role.

The Role of Fetal Hemoglobin on RBC Pathophysiology and SCD

One way to prevent the polymerization of HbS that results in sickled RBCs is to enhance the overall affinity of hemoglobin for oxygen, which reduces sickling in low oxygen environments and ameliorates pathophysiology of the disease. A promising approach to enhance hemoglobin-oxygen affinity is to reactivate production of inactive HbF, which we refer to as HbF induction. HbF is a natural hemoglobin that is activated during fetal development and is designed to give the growing fetus better access to oxygen from the maternal bloodstream. HbF has higher affinity for oxygen and ceases production approximately six months after birth, at which time it is replaced by adult hemoglobin that has lower oxygen affinity. Accordingly, newborns with SCD do not experience RBC sickling or resulting symptomology in the first four to five months of life. As HbF production declines and mutated HbS is produced in its place, SCD clinical manifestations begin to rapidly emerge. Some children with SCD mature into adulthood with persistence of HbF, otherwise known as hereditary persistence of HbF, and this reduces the long-term clinical manifestations of SCD. In some cases, these patients are essentially asymptomatic. A systematic literature review and series of quantitative meta-analyses revealed statistically significant associations between increases in HbF and clinical outcomes in SCD including mortality, stroke, acute chest syndrome, pain, blood transfusion, retinopathy and splenomegaly.

The Role of Other Cell Types in SCD

While HbF induction focuses primarily on the RBC aspect of SCD pathophysiology, non-RBC factors also play an important role in SCD. Several other cell types contribute to SCD, including WBCs, endothelial cells and platelets. Dysfunction of these cells, their inter-relationship and resulting downstream inflammatory processes contribute to numerous acute symptoms in SCD patients, such as painful VOCs and multi-organ damage. Third-party clinical data suggest that elevated WBCs are a predictor of increased risk of early death in patients with SCD. Furthermore, in patients with SCD, WBCs are activated and express higher levels of cell surface markers associated with adhesion, such as CD11a, CD11b and CD18. WBCs also interact with sickled RBCs and endothelial cells causing both cell aggregation and adhesion within the blood vessel. As a result, endothelial cells are damaged and secrete inflammatory signals that can ultimately lead to organ

damage. Platelets exacerbate this inflammatory cascade by releasing cell signaling molecules known as cytokines and further contribute to the cellular blockage in blood vessels that causes VOCs.

The Role of Adhesion Mediators in SCD

In addition to specific cell types playing a role in SCD, adhesion mediators cause RBCs, WBCs, endothelial cells and platelets to stick to one another. These adhesion mediators, known as cell adhesion molecules include selectins and vascular factors that form a multi-cellular lattice that contributes to blood vessel blockage. Inhibition of different types of adhesion mediators has recently become an approach to ameliorate SCD pathophysiology, which is distinct from approaches that solely target the underlying sickled RBC. Adhesion mediators can also be easily measured and therefore serve as reproducible biomarkers across RBCs, WBCs, endothelial cells and platelets.

Addressable Patient Population

The global incidence of SCD is estimated to be approximately 300,000 births annually, and by 2050, incidence is expected to rise to approximately 400,000 births annually. In the United States, where newborn screening for SCD is mandatory, the estimated prevalence is approximately 100,000 individuals. In the European Union, the estimated prevalence is approximately 134,000 individuals. The global prevalence of SCD is estimated to be approximately 4.4 million patients. SCD is most common among people of African, Middle Eastern and South Asian descent.

Approved and Emerging Modalities and Their Limitations

Approved Treatments

Managing SCD and its various clinical manifestations is complex, and patients have historically had limited options for treatment. In November 2019, the FDA granted accelerated approval for Oxbryta (voxelotor) for the treatment of SCD in patients 12 years of age and older and its label has subsequently been expanded to include patients four years of age and older. In February 2022, the European Commission approved Oxbryta for the treatment of hemolytic anemia in patients with SCD 12 years of age and older. Oxbryta is an oral therapy taken once daily and is the first approved treatment that directly inhibits sickle hemoglobin polymerization. In November 2019, the FDA also approved Adakveo (crizanlizumab), which has been demonstrated to reduce the frequency of VOCs in adult and pediatric patients aged 16 years and older with SCD. Adakveo received conditional approval in the European Union in October 2020 for the prevention of recurrent VOCs in SCD patients aged 16 years and older.  Adakveo is administered intravenously and binds to P-selectin, which is a cell adhesion protein that plays a central role in the multicellular interactions that can lead to VOCs.

While these approvals are important milestones for patients with SCD, we believe that there remains a significant unmet need for SCD therapies. Oxbryta was approved by the FDA on an accelerated basis based on improvements in hemoglobin levels as a surrogate endpoint reasonably likely to predict clinical benefit.  Continued approval for this indication may be contingent upon verification and description of the clinical benefit in a confirmatory study which is currently ongoing and is evaluating cerebral blood flow velocity. Adakveo does not treat the underlying cause of SCD and is only available through intravenous administration, not in oral form.

Prior to the approval of Oxbryta and Adakveo for SCD, there were only two FDA-approved drugs in the United States to treat SCD: Hydroxyurea, or HU, and Endari (L-glutamine); and only one approved drug in the European Union:  HU. These therapies have significant limitations in their safety, dosing regimen, efficacy and long-term effects.

HU, an oral chemotherapy that induces HbF and decreases sickling of the RBC, was first approved by the FDA for the treatment of SCD in 1998 and approved in the European Union in 2007. Despite numerous benefits, HU remains a suboptimal therapy for several reasons:

Endari, an oral powder form of L-glutamine, was approved by the FDA in 2017. L-glutamine is an amino acid precursor to nicotinamide adenine dinucleotide, or NAD, and is thought to reduce the oxidative stress that is present in patients with SCD. In September 2019, Emmaus Life Sciences, Inc. withdrew its marketing application to the European Medicines Agency, or EMA, for Endari.

Blood transfusions are another suboptimal treatment option for patients with SCD. Transfusions can transiently bolster hemoglobin levels by adding functional RBCs but can lead to several complications that include iron overload, adverse immune response and transmission of transfusion-associated infections. Due to the lack of uniform accessibility to blood transfusions, they are not widely employed for the treatment of SCD. Allogeneic hematopoietic stem cell transplant, or HSCT, is available as a potentially curative treatment for SCD and acts by halting sickled RBC production from the affected marrow and replacing it with healthy hematopoietic stem cells from a matched donor. HSCT is rarely used due to the difficulty in finding a matched donor, the potential for infection and an approximately 5% mortality rate. The possibility of increased mortality risk relegates this to a last option, often utilized only in the most severe cases.

Due to the limitations of existing therapies, we believe there remains a critical need to develop new preventative therapies that are easy to access, safe for long-term use and address the multiple aspects of SCD pathology.

Emerging Modalities

There has recently been an increased focus on the development of new treatments for SCD with a spectrum of different approaches, but none address the multifactorial pathology of SCD with an oral once-a-day tablet. These approaches can be broadly categorized as follows:

Anti-Polymerization Agents: Anti-polymerization agents, such as Oxbryta, are designed to prevent polymerization of hemoglobin and sickling of RBCs by increasing hemoglobin’s affinity for oxygen and maintaining hemoglobin in an oxygenated state. However, approaches that are solely focused on reducing polymerization may not address the complex symptomology of SCD and the clinical impact of Oxbryta on VOCs remains a question.

HbF Inducers:  HbF inducers seek to reactivate production of HbF in an effort to enhance hemoglobin-oxygen affinity.  Examples include FTX-6058, under development by Fulcrum Therapeutics, Inc., or Fulcrum, and EPI-01, under development by Novo Nordisk A/S, or Novo Nordisk (in collaboration with EpiDestiny, Inc., or EpiDestiny).

PKR Activators:  Pyruvate kinase-R, or PKR, is an enzyme that is involved in the conversion of sugar into energy and is critical for the survival of RBCs. Mutations in PKR cause deficiencies in this process which results in a shortened lifespan for RBCs.  This has led to the hypothesis that PKR activation can overturn this deficiency and may lead to a therapeutic benefit in patients with SCD.  Examples include mitapivat (AG-348), under development by Agios Pharmaceuticals, Inc., or Agios, and etavopivat (FT-4202), which is under development by Forma Therapeutics, Inc., or Forma.  

Selectin Inhibitors: Pan selectin and specific P-selectin inhibitors, such as Adakveo, are designed to reduce adhesion of WBCs to the endothelial cell wall and reduce VOCs; however, selectin inhibitors do not ultimately prevent the sickling of RBCs in SCD. Furthermore, Adakveo requires lengthy infusion treatments every three to four weeks. Global Blood Therapeutics, Inc, or GBT, is also developing inclacumab, a specific P-selectin inhibitor that was previously under development for non-SCD indications.  

Gene Therapy/Editing: Gene-based therapy is an innovative and potentially curative approach to SCD treatment. Like HSCT, gene therapy for SCD involves several pre-treatment steps that can include chemotherapy, which carry significant standalone risks. bluebird bio, Inc., or bluebird, and Aruvant Sciences, Inc., or Aruvant, are each developing gene therapies which aim to deliver a functional copy of the human beta-globin gene.  Gene editing, including CRISPR-Cas9, is an alternative approach to gene modification that has recently advanced in clinical development. Examples of gene editing approaches include CTX-001, currently in development by CRISPR Therapeutics AG, or CRISPR (in collaboration with Vertex Pharmaceuticals Incorporated, or Vertex).  Numerous questions remain with respect to the gene editing approach, including off-target mutagenesis and the ultimate potential reach of such therapeutics. More studies are needed to establish durability and safety of these potential treatments.

The Role of Phosphodiesterase-9 in SCD

Tovinontrine is being developed to inhibit PDE9. PDE9 decreases cGMP, an active signaling molecule that plays an important role in vascular biology. Lower levels of cGMP, as found in patients with SCD, are associated with reduced blood

flow, increased inflammation, greater cell adhesion and reduced nitric oxide-mediated vasodilation.  In addition, PDE9 is highly expressed in cells of interest in SCD, specifically reticulocytes, which are an important cell type for HbF induction. Furthermore, PDE9 has high expression in WBCs and in areas where RBCs are formed.  In preclinical studies, PDE9 inhibitors have been shown to increase cGMP concentrations, induce HbF and F-cells, reduce WBC activation and adhesion across other cell types and modulate adhesion mediators.  This was further demonstrated in preclinical SCD models of tovinontrine, where we observed that tovinontrine is a potent cGMP inducer and had a multimodal mechanism of action, acting to increase HbF expression in RBCs, reduce RBC sickling and decrease expression of WBC adhesion molecules.

Our Solution for Sickle Cell Disease: Tovinontrine as a Differentiated PDE9 Inhibitor

Our approach to address SCD is fundamentally distinct from other therapies. Tovinontrine is being developed to directly and potently inhibit PDE9, which represents a differentiated approach to increase cGMP levels, with a selectivity for PDE9 that we believe will make it amenable for long-term use. We believe tovinontrine may have advantages over other therapies in SCD, including a multimodal approach and an oral, once daily dosing regimen. In addition, tovinontrine tablets have been shown to be stable at high temperatures and in humid conditions, potentially enabling worldwide access, including in areas where SCD and ß-thalassemia are endemic.

We believe tovinontrine has several differentiating features relative to other PDE9 inhibitors:

Highly Potent PDE9 Inhibitor: Tovinontrine is a highly potent PDE9 inhibitor, as measured by induction of cGMP across escalating doses. Tovinontrine has been designed to rapidly increase cGMP, which translates to HbF induction and potentially reduced WBC adhesion.

Differentiated Selectivity and Tolerability Profile: Tovinontrine is highly specific to PDE9 and not selective for other phosphodiesterase family members. Toxicology studies of tovinontrine, including fertility and juvenile studies, support its potential benefit as a long-term therapy in adults and children. We believe this selectivity will allow us to optimize dose while minimizing off-target effects.

Minimal Brain Penetration: Tovinontrine was observed to have minimal brain penetration in preclinical in vivo models relative to other PDE9 inhibitors that have been studied. We believe this will reduce the potential impact of PDE9 inhibition on central nervous system development and function.

Drug Product Stability: Tovinontrine tablets have been shown to be stable at high temperatures and in humid conditions, potentially enabling worldwide access, including in underserved regions where SCD and β-thalassemia are endemic.

Preclinical and Healthy Volunteer Data

In preclinical SCD models, we observed that tovinontrine is a potent cGMP inducer and had a multimodal mechanism of action, acting to increase HbF expression in RBCs, reduce RBC sickling and decrease expression of WBC adhesion molecules.

In an SCD in vitro model, we measured the ability of tovinontrine to increase cGMP levels in an RBC cell line as compared to HU. In this study, we observed that tovinontrine induced cGMP production in a dose-dependent manner at an approximately 30-fold lower drug concentration than HU. In addition, at an equivalent drug concentration of 10 µM of tovinontrine, we observed an approximately ten-fold increase in cGMP levels as compared to HU. We also evaluated tovinontrine in a mouse model of SCD that expresses human sickle hemoglobin. We observed that tovinontrine demonstrated statistically significant increases in F-cells, statistically significant decreases in the percentage of sickled RBCs and decreases in markers of hemolysis, or destruction of RBCs, and WBC adhesion.

In 2016, we initiated a Phase 1 randomized, double-blind, placebo-controlled clinical trial of tovinontrine in healthy volunteers.  In that trial, single and multiple ascending doses of tovinontrine were reported to be well tolerated to a maximum dose of 4.5 mg/kg per day and no serious adverse events were reported.  In 2021, we conducted a second healthy volunteer clinical trial of tovinontrine to explore higher doses of tovinontrine. This single ascending dose followed by a multiple dose trial tested doses of up to 13 mg/kg per day.  The results demonstrated that doses of up to 8 mg/kg per day were well tolerated and no dose limiting toxicities or serious adverse events were reported at any dose tested.

Phase 2a Clinical Trial of Tovinontrine in SCD

Our Phase 2a clinical trial was a randomized, double-blind, placebo-controlled clinical trial in adult patients with SCD and was conducted at clinical centers in the United States and the United Kingdom. The trial evaluated the safety, tolerability, pharmacokinetics, or PK, and exploratory pharmacodynamic, or PD, and clinical outcomes of escalating doses of tovinontrine administered once daily for 16 to 24 weeks, either as a monotherapy or in combination with HU. A total of 93 patients were dosed in the trial, of which 58 patients were on monotherapy and 35 patients were treated in combination with HU.  Patients on treatment in the monotherapy arm received an escalating dose of tovinontrine of up to 200 mg per day, while patients in the combination arm received an escalating dose of tovinontrine of up to 100 mg per day in addition to HU.

The data from the Phase 2a clinical trial demonstrated that tovinontrine was well tolerated as a monotherapypharmaceutical and in combination with HU at all dose levels. Changes in SCD-related biomarkers were variable across the trial. A post-hoc analysis of the pooled results further showed that when compared to placebo (N=30), patients on tovinontrine (N=63) had:

Phase 2a Open Label Extension of Tovinontrine in SCD

We biotechnology industries are conducting a four-year OLE clinical trial which allows patients from the Phase 2a clinical trial to enroll in a long-term safety and tolerability study of tovinontrine following completion of the Phase 2a clinical trial.  Patients in the OLE clinical trial initially received a once-daily dose of tovinontrine of 200 mg and have subsequently been escalated to a once-daily dose of up to 400 mg.

In December 2021, we presented 12-month data from the OLE trial at the American Society of Hematology (ASH) Annual Meeting. Of the 26 subjects enrolled, 21 were evaluable at month 12 (as of the data cut-off).  Tovinontrine was generally well-tolerated as a monotherapy as well as in combination with HU. There were no clinically significant changes in lab safety data, electrocardiogram data or vital signs, and no patients discontinued from the study due to adverse events.

The median annualized VOC rate was reduced by 38% in subjects previously in the placebo group in the Phase 2a clinical trial (N=7), with median annualized VOC rates of 5.0 (Phase 2a) and 3.1 (OLE) per year, with a median duration of treatment of 6.4 months and 11.6 months, respectively.

The low median annualized VOC rate for tovinontrine-treated patients in the Phase 2a clinical trial was maintained in subjects in the OLE clinical trial (N=14), with median annualized VOC rates of 0 (Phase 2a) and 2.0 (OLE) per year, with a median duration of treatment of 6.4 months and 11.8 months, respectively.

22% (4/18) of evaluable patients had an absolute increase in HbF greater than 3%. 47% (9/19) of patients had an absolute increase in F-cells greater than 6%, and F-cell increases were observed in 18 out of 19 evaluable patients.

Ardent Phase 2b Clinical Trial of Tovinontrine in SCD

We are currently conducting the Ardent Phase 2b clinical trial of tovinontrine in SCD, a randomized, double-blind, placebo-controlled, multicenter study of approximately 115 adult patients with SCD. Patients were initially randomly assigned in a 2:1 ratio to receive either low dose tovinontrine (once daily dose of 200 mg or 300 mg based on patient weight) or placebo.  In the first quarter of 2021, an independent data monitoring committee for the Ardent trial recommended opening of the high dose tovinontrine treatment arm following review of available safety and tolerability data.  After this point, patients were randomly assigned in a 1:2:1 ratio to receive low dose tovinontrine (once daily dose of 200 mg or 300 mg based on patient weight), high dose tovinontrine (once daily dose of 300 mg or 400 mg based on patient weight) or placebo.  We completed enrollment in the Ardent trial in the third quarter of 2021.

The planned primary efficacy endpoint of the Ardent trial is annualized rate of VOCs, and the trial is powered for statistical significance with respect to this endpoint. We decided to change the primary endpoint of the Ardent trial from HbF response, defined as an increase of ≥3% in HbF, to annualized rate of VOCs following a written recommendation from the FDA in November 2021.  HbF response will continue to be evaluated as one of two key secondary endpoints, with an

evaluation of time to first VOC as the other key secondary endpoint.  In addition, other secondary endpoints include the evaluation of the effect of tovinontrine versus placebo on (i) the percent of patients who are VOC-free, time to second VOC, VOC-related hospitalizations, (ii) HbF-associated biomarkers, (iii) indices of red cell hemolysis, (iv) indices of WBC adhesion, and (v) quality of life measures.

We plan to conduct an interim analysis from the Ardent trial of patients who have reached at least 24 weeks of dosing and expect to report data related to the primary endpoint from this interim analysis in the first week of April 2022.  We expect to report final data from the Ardent trial through 52 weeks of treatment in the second half of 2022.  

In the second quarter of 2022, we expect to initiate long-term OLE clinical trial of tovinontrine for patients who complete the Ardent Phase 2b clinical trial in SCD.  In addition to patients from the Ardent trial, we expect patients from the ongoing Phase 2a OLE trial to roll over into this new OLE trial, resulting in one OLE trial with patients from both the Phase 2a clinical trial and the Ardent Phase 2b clinical trial.

β-thalassemia Disorder Overview

β-thalassemia is a rare inherited RBC disorder. Unlike patients with SCD, patients with β-thalassemia have a mutation that causes the absence or decreased synthesis of the beta globin subunit of hemoglobin, thereby creating an over-abundance of the alpha globin subunit. This causes the formation and aggregation of insoluble clumps that lead to ineffective RBC production and a reduction in the number of functioning RBCs. Furthermore, the RBCs that do survive have shorter lifespans and are smaller, paler and less efficient at transporting oxygen throughout tissues of the body. Oftentimes, RBCs of smaller size, measured as mean corpuscular volume, is a first indication of β-thalassemia prior to genotyping. If left untreated, β-thalassemia causes severe anemia, splenomegaly, skeletal abnormalities, organ failure and early death.

β-thalassemia presents as a spectrum of disease, with patients categorized based on hemoglobin levels and clinical manifestations. Although β-thalassemia can be classified as “major,” “intermedia,” and “minor,” a more recent classification is based on a patient’s dependency on blood transfusion. Most β-thalassemia major patients are classified as TDT, while intermedia and minor patients are classified as NTDT. TDT patients have a transfusion regimen that is well established and generally lifelong. NTDT patients are a clinically diverse group, with transfusions required intermittently during periods of RBC stress, such as pregnancy, infection, surgery, times of rapid growth and sometimes later in life.

As in SCD, a promising way to address the missing or decreased presence of the beta globin subunit is to induce HbF production. In addition to resolving persistent anemia, HbF induction rectifies the missing or mutated beta globin subunit and thereby reduces the overabundance of free-floating alpha globin subunits. These benefits have the potential to result in increased functional RBC production, higher hemoglobin levels, reduced hemolysis and the reduction of adhesion and inflammation. In addition to HbF induction, independent research suggests activation of the nitric oxide-cGMP signaling pathway may induce RBC production, which is associated with increases in RBC counts and hemoglobin levels. We believe this is an important mechanism of action to that could be relevant in reducing disease burden. Furthermore, adhesion mediators are also highly upregulated in patients with β-thalassemia and may contribute to the increased number of clots in their blood vessels, known as a hypercoagulability state. Specifically, data show that two adhesion markers, ICAM-1 and VCAM-1, are over-expressed in patients with β-thalassemia as compared to controls. Furthermore, there is evidence that WBCs in patients with β-thalassemia express higher levels of CD11b and CD18, two important biomarkers in the WBC activation cascade.

Addressable Patient Population

The prevalence of β-thalassemia globally is estimated to be 288,000, with an incidence of 60,000 births per year. The total combined prevalence of β-thalassemia in the United States and European Union is estimated to be approximately 19,000 patients. Of the patients currently treated in the United States and European Union, we believe approximately 50% and 10%, respectively, are transfusion dependent. β-thalassemia is especially prevalent in developing countries of Africa, South Asia, Southeast Asia, the Mediterranean region and the Middle East. Although historically prevalent in Mediterranean North Africa and South Asia, thalassemias are now encountered in other regions as a result of changing migration patterns. As such, there is a growing focus on developing new therapeutics aimed at improving quality of life for this significant unmet medical need.

Approved and Emerging Modalities and Their Limitations

Approved Treatments

Blood transfusions have been the standard of care treatment for β-thalassemia. The risks associated with transfusions are similar to those seen in the SCD population, but higher frequency of use often results in iron overload toxicities, a secondary complication of this treatment. Over time, iron becomes trapped in the tissues of vital organs, which can lead to diabetes, cirrhosis, osteoarthritis, heart attack and hormone imbalances. If not addressed, excess iron can result in organ failure and death. There are several approved agents that remove iron from the body, known as iron chelators, but they have significant challenges including high costs, the requirement for frequent monitoring, therapy complications and patient incompatibility.

HSCT is a potential curative therapy for β-thalassemia and has demonstrated successful outcomes across patient types. However, as in SCD, there are numerous barriers to use, including increased mortality risk, that have limited its broader adoption. Recently, the European Commission granted conditional marketing authorization for Zynteglo, a gene therapy approach to β-thalassemia for patients 12 years and older with TDT and for whom HSCT is appropriate, but a donor has not yet been matched or been made available. The long-term efficacy of the therapy remains unknown, as do many of the associated risks.

In November 2019, the FDA approved Reblozyl (luspatercept-aamt) for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions. Reblozyl was approved by the European Commission in June 2020 to treat adult patients with transfusion-dependent anemia associated with ß-thalassemia.  Reblozyl is a modified receptor protein that promotes RBC maturation and increases overall RBC production, but does not address other cell types implicated in β-thalassemia. Reblozyl is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia. Reblozyl is the first and only FDA-approved erythroid maturation agent, representing a new class of therapy which works by regulating late-stage RBC maturation to help patients reduce their RBC transfusion burden.

Emerging Modalities

There has been increased development of new treatments for β-thalassemia, but no clinical-stage program addresses the full spectrum of the disease in an oral, once-a-day tablet. These treatments can be broadly categorized into the following approaches:

RBC Maturation: Clinical stage programs in this category generally are aimed at promoting RBC maturation and/or increasing overall RBC production, but do not address other cell types implicated in b-thalassemia. Several molecules targeting this pathway to treat chronic anemia associated with ineffective erythropoiesis and iron overload are in development. These include IONIS-TMPRss6-LRx, under development by Ionis Pharmaceuticals, Inc., or Ionis Pharmaceuticals, SLN-124, under development by Silence Therapeutics PLC, or Silence Therapeutics, and VIT-2763, under development by Vifor Pharma Ltd, or Vifor.

Gene Therapy/Editing: As with SCD, gene therapy and gene editing approaches are also being developed as potential curative therapies for b-thalassemia. beti-cel is a gene therapy treatment in development by bluebird, while CTX-001 is a gene editing therapy currently in development by CRISPR (in collaboration with Vertex). Gene therapy involves pretreatment regimens associated with standalone risk which may limit its use in broad patient populations, and gene editing approaches still have many unanswered questions, including off-target mutagenesis.

PKR Activators: Drug candidates are being developed that activate PKR, an enzyme that is involved in the conversion of sugar into energy and is critical for the survival of RBCs.  Examples include mitapivat, under development by Agios, and etavopivat, under development by Forma in TDT and NTDT patients with ß-thalassemia.

Our Solution for β-thalassemia: Tovinontrine as a Differentiated PDE9 Inhibitor

PDE9 is a potent and highly selective mechanism that uniquely targets cGMP degradation, making it a promising pathway to increase cGMP, reactivate HbF, enhance RBC production, enable RBC maturation, and reduce WBC activation in β-thalassemia. We believe tovinontrine is a differentiated PDE9 inhibitor that is highly potent, selective for its target, minimally brain penetrating, and is delivered in an oral, once-a-day therapy, which could be used globally.

Preclinical Data of Tovinontrine in ß-thalassemia

We conducted preclinical studies in a ß-thalassemia mouse model that recapitulates the human NTDT condition. This mouse model lacks a functional beta globin subunit, leading to deficits in hemoglobin and RBCs, as well as slowed RBC maturation. After 30 days of treatment at two different doses, we observed that tovinontrine induced statistically significant increases in functional hemoglobin and total RBC counts in a dose dependent way, with the 60mg/kg dose outperforming the 30mg/kg dose. Allometric scaling to reflect dose conversion from mouse to human indicates that the 30mg/kg mouse dose is equivalent to a human dose of approximately 2.4mg/kg and the 60mg/kg mouse dose is equivalent to a human dose of approximately 4.9mg/kg.

Promotion of RBC maturation, a key mechanistic component in reducing ß-thalassemia pathology, was also observed in preclinical studies. After 30 days of once-a-day treatment with 30 mg/kg and 60 mg/kg of tovinontrine, we observed that erythroblast maturation was significantly improved as reflected by an increase in the amount of Ery.C, which is the population of mature erythroblasts, in comparison to Ery.B, which are more immature erythroblasts. These changes were also associated with a decrease on the ratio of Ery.B to Ery.C, otherwise known as a maturation index, where lower ratio indicates progression to maturity.

Forte Phase 2b Clinical Trial of Tovinontrine in ß-thalassemia

We are currently conducting the Forte Phase 2b clinical trial of tovinontrine in ß-thalassemia, a randomized, double-blind, placebo-controlled trial, evaluating the safety and tolerability of tovinontrine in approximately 120 adult patients with ß-thalassemia.  Similar to the Ardent SCD trial, patients were initially randomly assigned in a 2:1 ratio to receive either low dose tovinontrine (once daily dose of 200 mg or 300 mg based on patient weight) or placebo.  In the first quarter of 2021, an independent data monitoring committee for the Forte trial recommended opening of the high dose tovinontrine treatment arm following review of available safety and tolerability data.  After this point, patients have been randomly assigned in a 1:2:1 ratio to receive low dose tovinontrine (once daily dose of 200 mg or 300 mg based on patient weight), high dose tovinontrine (once daily dose of 300 mg or 400 mg based on patient weight) or placebo.

In addition to safety, for TDT patients, we are evaluating the effect of tovinontrine versus placebo in reducing the number of RBC units transfused in any 12-week interval as compared to the 12-week interval prior to randomization, known as the transfusion burden. For NTDT patients, we are evaluating the effect of tovinontrine versus placebo on HbF and hemoglobin, or Hb. The Forte trial will also examine additional exploratory efficacy endpoints as well as additional safety and PK endpoints.

In November 2021, we conducted a pre-specified protocol-driven interim analyses in approximately 43 TDT patients, 35 of whom completed at least 12 weeks of treatment and were in the analysis population for transfusion burden.  The median baseline transfusion burden in each of the high dose tovinontrine and placebo groups was 7.5 RBC units/12 weeks. Furthermore, 54% of the subjects in the analysis population (19/35) had the more severe β⁰/β⁰ genotype.  The interim data demonstrated tovinontrine was well-tolerated, with the most frequent adverse events (at least 10% of subjects in pooled tovinontrine dose groups) being nausea, headache and dizziness. Four (9.3%) patients discontinued due to adverse events considered at least possibly related to study drug.

The proportion of patients who had at least a33% reduction in transfusion burden (of at least 2 units) in any 12-week interval as compared to the 12-week interval prior to randomization was greater in the high dose tovinontrine group (7/8) versus placebo, despite an unexpectedly high response rate in the placebo group (8/12). Additionally, the proportion of patients who had at least a 33% reduction in transfusion burden (of at least 2 units) in any 14-week interval as compared to the 12-week interval prior to randomization was also greater in the high dose tovinontrine group (5/8) versus the placebo group (5/12).  Low dose tovinontrine did not show a higher response rate when compared to the placebo group. No substantial differences between groups were observed in transfusion burden response rate using a fixed interval (weeks 13-24). RBC markers were not evaluable in these regularly transfused subjects.

We expect to report data from an additional interim analysis in approximately 50 TDT patients and 30 NTDT patients through 24 weeks of dosing in the first week of April 2022 and final data from the Forte trial in the second half of 2022.

HFpEF Disease Overview

HFpEF, also known as diastolic heart failure, is typically caused by abnormalities of cardiac filling, which leads to symptoms such as shortness of breath, exercise intolerance and fluid retention. Characteristics of HFpEF are heterogeneous, but commonly include ventricular hypertrophy, diastolic dysfunction, endothelial dysfunction, insulin resistance, and inflammation. Comorbidities, such as hypertension, anemia, chronic kidney disease, diabetes, and obesity, are also common

in HFpEF, which are thought to contribute to its development.  HFpEF accounts for approximately half of all cases of heart failure and is becoming the predominant form of heart failure over time.   Prevalence in the United States is estimated to be approximately 3-4 million patients.  In contrast to heart failure with reduced ejection fraction, or HFrEF, there are relatively few treatment options to improve symptoms and outcomes for patients.

Our Solution for HFpEF: Tovinontrine as a Differentiated PDE9 Inhibitor

cGMP is known to play a pivotal role in cardiovascular and metabolic health. For example, increased cGMP signaling promotes vasodilation, natriuresis, diuresis, insulin sensitivity and lipolysis, and can inhibit cardiac hypertrophy, inflammation and adverse platelet-leukocyte-endothelial interactions. Therefore, increasing cGMP by PDE9 inhibition may be an attractive target for the treatment of HFpEF.  We believe tovinontrine is a differentiated PDE9 inhibitor that is highly potent, selective for its target, minimally brain penetrating, and is delivered in an oral, once-a-day therapy.

Preclinical Data of Tovinontrine in HFpEF

We conducted in vivo studies with tovinontrine in three different established mouse models for HFpEF in collaboration with the Necker Institute of Paris, France. In the first model, we tested whether tovinontrine could prevent the development of HFpEF induced by unilateral nephrectomy and six-week continuous infusion of d-aldosterone.  Tovinontrine was administered at doses of 60 mg/kg or 100 mg/kg concurrently with d-aldosterone for six weeks.  The results showed that tovinontrine significantly attenuated the development of cardiac and cardiomyocyte hypertrophy and limited the increase in biomarkers of myocardial inflammation and fibrosis.  Congruent findings were obtained in the second model, in which mice received continuous infusion of angiotensin II for six weeks to produce the HFpEF phenotype.  Tovinontrine was administered at doses of 60 or 100 mg/kg concurrently with angiotensin II infusion for six weeks.  The results showed that tovinontrine attenuated cardiac and cardiomyocyte hypertrophy and limited the increase in biomarkers of myocardial inflammation and fibrosis.  In addition to these two preventive models, a third model was employed to test the therapeutic potential of tovinontrine to treat prevalent HFpEF.  In this study, 20 week-old diabetic prone obese mice that displayed the HFpEF phenotype were assigned to receive vehicle or tovinontrine at 60- or 100-mg/kg for eight weeks. The mice treated with tovinontrine displayed significantly less cardiomyocyte hypertrophy and lower levels of biomarkers of myocardial inflammation and fibrosis.  In the control arms of all three models, we found increased myocardial transcript levels of PDE9, atrial natriuretic peptide, or ANP, and B-type natriuretic peptide, or BNP.  In all three models, we found that tovinontrine significantly reduced PDE9, ANP and BNP transcript levels in a dose-dependent manner.  

Planned Phase 2 Clinical Trial of Tovinontrine in HFpEF

In the second quarter of 2022, we expect to dose the first patient in the SP₉IN Phase 2 clinical trial of tovinontrine in HFpEF.  The SP₉IN trial will be a randomized, placebo-controlled trial of approximately 170 patients 45 years of age or older with enriched PDE9 expression and persistent symptoms of HFpEF.  Patients will receive either tovinontrine (twice daily dose of 300 mg or 400 mg based on patient weight) or placebo for 16 weeks.  The primary endpoint will be the change in NT-proBNP levels, with secondary endpoints that include safety and tolerability as well as quality of life measures such as Kansas City Cardiomyopathy Questionnaire (KCCQ) and New York Heart Association (NYHA) classification. Exploratory measures are expected to include a clinical composite score, 6-minute walk test and evaluation of cardiac structure and function.

IMR-261 (formerly CXA-10)

Overview

We have commenced research activities for IMR-261 (formerly CXA-10), an oral, clinic-ready activator of Nrf2.  Nrf2 coordinates the expression of antioxidant genes in response to oxidative stress, regulates inflammation, inhibits the NF-kB pathway and has been shown to increase HbF.  Prior to its acquisition by us, IMR-261 was evaluated by Complexa, Inc. in Phase 2 clinical trials in FSGS and PAH, and independent medical literature suggests potential in a broad array of RBC diseases, including disorders of hemoglobin and iron overload diseases.  We have initiated work on drug product manufacturing for IMR-261 as we explore potential clinical development paths in hemoglobinopathies, iron disorders and potentially other areas.

Preclinical Data for IMR-261

We evaluated IMR-261 in preclinical studies using in-vitro cell cultures and in-vivo mouse models of SCD and b-thalassemia. In CD34+ cells from sickle cell and healthy donors, high dose IMR-261 increased HbF expression by approximately 7-fold versus placebo, whereas lower dose IMR-261 increased HbF expression by approximately 4-fold versus placebo. Furthermore, an approximately 3-fold increase in F-cells was seen in both high dose and low dose groups when compared to placebo. In the Townes mouse model of SCD, high dose IMR-261 induced HbF by approximately 2.2-fold when compared to placebo (8.3 ng/ml versus 3.7 ng/ml). In addition, high dose tovinontrine significantly decreased select markers of hemolysis and increased Hb by approximately 1.1 g/dL when compared to placebo (8.7 g/dL versus 7.6 g/dL).

In a separate experiment in Townes SCD mice that assessed VOC reduction after administration of TNF-alpha, IMR-261 significantly reduced the presence of RBC on occluded vessels when compared to placebo. IMR-261 was also tested in a mouse model of b-thalassemia (Hbb^th1/th1) and showed significant increases in Hb and improvements in ineffective erythropoiesis at the high dose.

License and Acquisition Agreements

Tovinontrine – Exclusive License with Lundbeck

In April 2016, we entered into an agreement, or the Lundbeck Agreement, with H. Lundbeck A/S, or Lundbeck, for a worldwide license under certain patent rights and certain know-how owned or otherwise controlled by Lundbeck within the field of prevention, treatment or diagnosis of hemoglobinopathy disorders and/or other diseases or disorders, excluding diseases or disorders of the central nervous system, which we refer to as the Lundbeck Field. The Lundbeck Agreement was amended in July 2016 and October 2017.

The Lundbeck Agreement grants us an exclusive license under the licensed technology, including the right to grant sublicenses with certain restrictions, to research, develop, make, have made, use, sell, have sold, offer to sell, import, export and commercialize any product comprising or containing certain PDE9 inhibitors, in the Lundbeck Field. We call such products Lundbeck Licensed Products. Subject to certain restrictions, under the agreement, we grant Lundbeck a non-exclusive, irrevocable, perpetual, worldwide, sub-licenseable, and fully paid-up right and license under patent rights we control to the extent necessary for Lundbeck to research, develop, make, have made, use, sell, have sold, offer to sell, import, export and commercialize Lundbeck Licensed Products outside of the Lundbeck Field.

The Lundbeck Agreement also grants us a non-exclusive license under the licensed technology to research and develop, and make, have made, use, import and export for purposes of enabling such research and development, enhancements, improvements, modifications or derivatives to licensed products, until but not beyond a specified pre-commercialization developmental stage with respect to each such enhancement, improvement, modification or derivative. We have the right to request that Lundbeck grant us an exclusive development and commercialization license to one or more compounds identified through these activities as a back-up compound.

As partial consideration for the licenses granted under the Lundbeck Agreement, we issued an aggregate of 443,271 shares of our common stock to Lundbeck between April 2016 and August 2017. We are also obligated to make milestone payments to Lundbeck aggregating up to (i) $23.5 million upon the achievement of specified clinical, regulatory and first commercial sale milestones by any licensed product and (ii) $11.8 million upon the achievement of specified clinical, regulatory and first commercial sale milestones by any Imara product that is or comprises a PDE9 inhibitor but is not a Lundbeck Licensed Product, which is referred to as a PDE9 Product, if any. We are obligated to pay tiered royalties of low-to-mid single-digit percentages to Lundbeck based on our, and any of our affiliates’ and sublicensees’, net sales of Lundbeck Licensed Products, and tiered royalties of low single-digit percentages to Lundbeck based on our, and any of our affiliates’ and sublicensees’, net sales of PDE9 Products, if any. The royalties are payable on a product-by-product and country-by-country basis. Our obligation to make royalty payments extends with respect to a Lundbeck Licensed Products in a country until the later of ten years after the first commercial sale of that Lundbeck Licensed Product in that country and the expiration of the last-to-expire valid claim of a patent or patent application licensed from Lundbeck covering the Lundbeck Licensed Product or any constituent licensed compound in that country. Our obligation to make royalty payments extends with respect to a PDE9 Product in a country until the ten years after the first commercial sale of such PDE9 Product in that country. To date pursuant to this agreement, we have made cash payments to Lundbeck of $1.8 million consisting of an upfront payment and ongoing milestone payments.

The Lundbeck Agreement obligates us to use commercially reasonable efforts to develop, seek regulatory approval for, manufacture, market and otherwise commercialize at least one licensed product, in accordance with a development plan and a development milestone timetable specified in the Lundbeck Agreement. We have the option to extend the development milestone timetable up to two times by agreeing to additional payment obligations.

Both we and Lundbeck have the right to terminate the Lundbeck Agreement if the other party materially breaches the Lundbeck Agreement and fails to cure such breach within specified cure periods or in the event the other party undergoes certain bankruptcy events. Lundbeck may terminate the Lundbeck Agreement if we or any of our affiliates, sublicensees or subcontractors bring specified patent challenges against Lundbeck or assist others in bringing such a patent challenge against Lundbeck and fail to cease such challenge within a specified period of time. We have the right to terminate the Lundbeck Agreement for our convenience at any time on six months’ prior written notice to Lundbeck.

IMR-261 – Asset Purchase Agreement with Complexa (assignment for the benefit of creditors), LLC

In October 2020, we entered into an asset purchase agreement, or the Complexa APA, with Complexa (assignment for the benefit of creditors), LLC, or Complexa ABC, pursuant to which we acquired all of Complexa ABC’s right, title and interest in and to the assets comprising the Nrf2 program, including CXA-10 (subsequently renamed IMR-261), previously held by Complexa, Inc.  Complexa, Inc. had previously assigned all such assets to Complexa ABC pursuant to a general assignment entered into in August 2020 between Complexa, Inc. and Complexa ABC.

As consideration for the assets acquired under the Complexa APA, we made a one-time payment of approximately $0.1 million and agreed to pay up to an additional approximately $3.8 million in milestone payments based on the achievement of specified clinical and commercial sale milestones as set for the in the Complexa APA.   As part of the acquisition, Complexa ABC assigned to us all of its rights under license agreements with The UAB Research Foundation and the University of Pittsburgh, each as discussed below.

IMR-261 – Exclusive License Agreement with UAB Foundation

In October 2020, we took assignment to an exclusive license agreement, or the UAB Agreement, originally entered into between The UAB Research Foundation, or UAB, and Complexa, Inc. in April 2012.  The UAB Agreement grants us an exclusive worldwide license to practice and fully exploit certain patent rights and to make, have made, develop, use, lease, offer to sell, sell, import and export products covered by such patents within the field of human therapeutics and diagnostics.  We call such products UAB Licensed Products.  We have the right to grant sublicenses with certain restrictions, including obtaining the consent of UAB, which consent may not be unreasonably withheld, conditioned or delayed.

We are obligated to make milestone payments to UAB aggregating up to approximately $0.3 million upon the achievement of specified commercial sale milestones by any UAB Licensed Product and to pay a low single-digit percentage royalty to UAB based on our, and any of our affiliates’ and sublicensees’, net sales of UAB Licensed Products, if any, subject to a minimum annual royalty payment specified in the UAB Agreement.  Our obligation to make royalty payments extends with respect to a UAB Licensed Product until the expiration of the last-to-expire valid claim of a patent licensed from UAB covering the UAB Licensed Product.  The patents subject to the license under the UAB Agreement only have valid claims in the United States. The royalties are payable on a product-by-product basis.

The UAB Agreement obligates us to use commercially reasonable efforts to develop, manufacture, commercialize and market at least one UAB Licensed Product, in accordance with a development plan and a development milestone timetable specified in the UAB Agreement.

The UAB Agreement expires based upon the expiration of the last-to-expire valid claim of a patent licensed from UAB.  We have the right to terminate the UAB Agreement for our convenience at any time on 90 days’ prior written notice to UAB.  UAB has the right to terminate the UAB Agreement if, amongst other reasons, we are in material default of the UAB Agreement and fail to cure such breach within specified cure periods or in the event we undergo certain bankruptcy events.

IMR-261 – Non-Exclusive License Agreement with University of Pittsburgh

In October 2020, we took assignment to an exclusive license agreement, or the Original Pittsburgh Agreement, originally entered into between University of Pittsburgh – Of the Commonwealth System of Higher Education, or University

of Pittsburgh, and Complexa, Inc. in August 2014.   The Original Pittsburgh Agreement was terminated in its entirety in November 2020 and in May 2021, we and the University of Pittsburgh entered into a new license agreement, or the New Pittsburgh Agreement, to replace the Original Pittsburgh Agreement.  The New Pittsburgh Agreement was amended in December 2021.

The New Pittsburgh Agreement grants us a non-exclusive worldwide license to make, have made, manufacture, research, develop, use, sell, offer for sale and commercialize certain products covered by certain patents within the field of hemoglobinopathies, red cell anemias and iron disorders.  We call such products Pittsburgh Licensed Products. We have the right to grant sublicenses with certain restrictions, including obtaining the consent of Pittsburgh, which consent may not be unreasonably withheld.

As partial consideration New Pittsburgh Agreement, we made upfront payments aggregating to less than $0.1 million.  We are obligated to make milestone payments to the University of Pittsburgh of up to approximately $0.3 million in the aggregate upon the achievement of specified clinical and commercial sale milestones by any Pittsburgh Licensed Product and to pay a low single-digit percentage royalty to the University of Pittsburgh based on our, and any of our affiliates’ and sublicensees’, net sales of Pittsburgh Licensed Product, if any, subject to a minimum annual royalty payment specified in the New Pittsburgh Agreement.  Our obligation to make royalty payments extends with respect to a Pittsburgh Licensed Products until the expiration of the last-to-expire valid claim of a patent licensed from the University of Pittsburgh covering the Pittsburgh Licensed Product.  The patents subject to the license under the New Pittsburgh Agreement only have valid claims in the United States.

The New Pittsburgh Agreement obligates us to use commercially reasonable efforts to develop and obtain FDA approval for Pittsburgh Licensed Products, in accordance with a development milestone timetable specified in the New Pittsburgh Agreement.

The New Pittsburgh Agreement expires upon the expiration of the last-to-expire valid claim of a patent licensed from the University of Pittsburgh.  We have the right to terminate the New Pittsburgh Agreement for our convenience at any time on 90 days’ prior written notice to the University of Pittsburgh.  The University of Pittsburgh has the right to terminate the New Pittsburgh Agreement if, amongst other reasons, we default in the performance of any of our obligations under the New Pittsburgh Agreement and fail to cure such breach within specified cure periods or in the event we undergo certain bankruptcy events.

Competition

The biopharmaceutical industry is characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products. While we believe that our technology, knowledge,the expertise of our team, and our development experience and scientific resourcesknowledge provide us with competitive advantages, we face potentialincreasing competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic institutions, and governmentgovernmental agencies and public and private research institutions. Any productProduct candidates that we successfully develop and commercialize willmay compete with existing therapies and new therapies that may become available in the future.

Our

Many of our competitors, mayeither alone or with their collaborators, have significantly greater financial resources, established presence in the market, and expertise in research and development, manufacturing, preclinical and clinical testing, obtaining regulatory approvals and reimbursement and marketing approved products than we do. These competitors may also compete with us in recruiting and retaining qualified scientific sales, marketing and management personnel, andin establishing clinical trial sites and patient registration for clinical trials.trials, and in acquiring technologies complementary to, or necessary for, our programs. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. Additional mergers and acquisitions may result in even more resources being concentrated in our competitors. Our commercial potential could be reduced or eliminated if our competitors develop and commercialize products that are safer or more effective, have fewer or less severe side effects, and are more convenient or less expensive than products that we may develop. Our

competitors also may obtain FDA or other regulatory approval for their products more rapidly than we can, which could result in our competitors establishing a strong market position before we are able to enter the market or could otherwise make the development or commercialization of our products more complicated. The key competitive factors affecting the success of all of our programs are likely to be efficacy, safety and patient convenience.

If our lead product candidate tovinontrine is

There are currently six BCR-ABL TKIs FDA approved for the indications that we are currently targeting, it will likely competeuse in CML: Novartis AG’s Gleevec (imatinib), Tasigna (nilotinib), and Scemblix (asciminib), Bristol Myers Squibb’s Sprycel (dasatinib), Pfizer’s Bosulif (bosutinib), and Takeda’s Iclusig (ponatinib). Most of these BCR-ABL inhibitors target additional tyrosine kinases, which can lead to debilitating side effects. Iclusig (ponatinib) is indicated for patients with CML who have resistance or intolerance to at least two prior TKIs. It is also approved for patients with the currentlyT315I mutation. However, due to its off-target kinase activity, this agent carries four black box warnings and is poorly tolerated requiring dose reductions that limit its efficacy. Scemblix (asciminib) is a fourth generation TKI by Novartis AG recently approved by the FDA. It is designed to allosterically inhibit BCR-ABL by binding to the myristoyl pocket, which is remote from the active site and is a novel mechanism. Other BCR-ABL TKIs under investigation include Sun Pharma Advanced Research Company’s vodobatinib, Ascentage Pharma’s olverembatinib, Terns Pharmaceutics, and others at various stages of development.

There are no approved TKIs for HER2 mutant NSCLC. Enhertu (fam-trastuzumab deruxtecan), an antibody drug conjugate, marketed drugsby AstraZeneca and if approved,Daiichi-Sankyo, received accelerated approval from the therapiesFDA for this patient population in development discussed below.

Sickle Cell Disease

Approved drug treatmentsAugust 2022. Most of the investigational TKIs for SCD focus primarily on the management of anemiathis population are all dual EGFR and reduction of VOCs. Until November 2019, there were only two drug treatments approvedHER2 inhibitors such as Spectrum’s poziotinib, Takeda’s mobocertinib, Black Diamond’s BDTX-189 and Jiangsu HengRui Medicine Co., Ltd’s pyrotinib. These dual EGFR and HER2 inhibitors have been dose-limited in the United States: HUclinic by EGFR-related toxicities such as GI and Endari;skin-related toxicities. As such, their therapeutic utility is often limited. Pyrotinib is being investigated in a Phase 3 pivotal trial. Bayer received FDA Breakthrough Therapy designation and only oneincreased their trial's sample size to advance BAY2927088 in patients with HER2 mutant NSCLC that have progressed on a prior systemic agent with no other approved treatment. Boehringer Ingelheim initiated a pivotal study with Zongertinib (BI-1810631), a HER2-specific TKI, in newly diagnosed patients with HER2 mutant NSCLC. Other TKIs are in late stage research for HER2 mutant NSCLC including Nuvalent’s NVL-330, Entos’ IAM-H1 and an undisclosed compound being developed by Cogent Biosciences.

For HER2 amplified and overexpressing tumors, such as BRC, there are several FDA-approved antibodies, antibody drug treatmentconjugates, and TKIs. For example, Genentech’s Herceptin (trastuzumab) and Perjecta (pertuzumab) are approved HER2-antibodies. Approved HER2-antibody drug conjugates include Genentech’s Kadcyla (ado-trastuzumab emtansine) and Daiichi Sankyo’s Enhertu (fam-trastuzumab deruxtecan). Approved TKIs for HER2 BRC include Puma’s Nerlynx (neratinib), Novartis AG’s Tykerb (lapatinib), and Seagen’s Tukysa (tucatinib). Several of these drugs are approved for other HER2-driven indications such as gastric and colorectal cancer. Furthermore, Roche’s ZN-A-1041/RG6596 is a HER2 selective TKI in the European Union:  HU. HU, marketed under trade names including Droxia by Bristol-Myers Squibb Company,early-stage development for HER2 BRC.

Finally, there are numerous other investigational therapies, spanning many modalities that are being evaluated preclinically and in clinical trials for various HER2-altered cancers.

Manufacturing

We do not own or operate, and currently have no plans to establish, any manufacturing facilities. We rely, and expect to continue to rely, on third parties to manufacture our product candidates for preclinical and clinical testing, as well as in generic form, is approved for the treatmentcommercial manufacturing should any of anemia relatedour product candidates obtain marketing approval. We also rely, and expect to SCD,continue to reduce the frequency of

VOCsrely, on third parties to package, label, store and distribute our investigational product candidates, as well as our commercial products should marketing approval be obtained. We believe that this strategy allows us to maintain a more efficient infrastructure by eliminating the need for blood transfusions. Endari, marketed by Emmaus Life Sciences, Inc., is an oral powder form of L-glutamine approvedus to reduce severe complications associated withinvest in our own manufacturing facilities, equipment and personnel while also enabling us to focus our expertise and resources on the disorder.

In November 2019, the FDA granted accelerated approval for Oxbryta (voxelotor) for the treatment of SCD in patients 12 years of agediscovery and older and its label was subsequently expanded to include patients four years of age and older. Oxbryta is an oral therapy taken once daily and is the first approved treatment that directly inhibits sickle hemoglobin polymerization. In February 2022, the European Commission approved Oxbryta for the treatment of hemolytic anemia in patients with SCD 12 years of age and older.  In addition, in November 2019, the FDA approved Adakveo (crizanlizumab), to reduce the frequency of VOCs in adult and pediatric patients aged 16 years and older with SCD. Adakveo received conditional approval in the European Union in October 2020 for the prevention of recurrent VOCs in SCD patients aged 16 years and older.  Adakveo is administered intravenously and binds to P-selectin, which is a cell adhesion protein that plays a central role in the multicellular interactions that can lead to vaso-occlusion.

Blood transfusions are also used to treat SCD and can transiently bolster hemoglobin levels by adding functional RBCs. There are a number of limitations associated with this therapeutic approach, including limited patient access and serious complications such as iron overload. The only potentially curative treatment currently approved for severe SCD is HSCT. However, this treatment option is not commonly used given the difficulties of finding a suitable matched donor and the risks associated with the treatment, which include an approximately 5% mortality rate. HSCT is more commonly offered to pediatric patients with available sibling-matched donors.

Tovinontrine could face competition from a number of different therapeutic approaches in development for patients with SCD. For example, there are a number of companies in clinical development for gene editing/therapy treatments, including bluebird, Aruvant, CRISPR (in collaboration with Vertex), Sangamo Therapeutics, Inc. (in collaboration with Sanofi), Intellia Therapeutics, Inc. (in collaboration with Novartis), Graphite Bio, Inc. and Editas Medicine, Inc. There are also several companies advancing therapeutic approaches outside of gene editing/therapy, including GBT, Agios, Forma, Vifor, Novo Nordisk (in collaboration with EpiDestiny), Fulcrum, CSL Ltd. and Pfizer.

ß-thalassemia

Until November 2019, there were no approved drug therapies for ß-thalassemia in the United States. The current standard of care for many patients with ß-thalassemia has been frequent blood transfusions to manage anemia. A potentially curative therapy for ß-thalassemia is HSCT, which is associated with serious risk and is limited to patients with a suitable donor.

In November 2019, the FDA approved Reblozyl for the treatment of anemia in adult patients with ß-thalassemia who require regular RBC transfusions. Reblozyl was approved by the European Commission in June 2020 to treat adult patients with transfusion-dependent anemia associated with ß-thalassemia. Reblozyl is a modified receptor protein that promotes RBC maturation and increases overall RBC production, but does not address other cell types implicated in ß-thalassemia. Reblozyl is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia. Reblozyl is dosed subcutaneously and is administered every three weeks in an outpatient setting.

In June 2019, the European Commission granted conditional marketing authorization for Zynteglo, a gene therapy developed by bluebird bio for the treatment of adult and adolescent patients with transfusion-dependent ß-thalassemia and with certain genotypes. Bluebird bio submitted its rolling BLA to the FDA which it has announced that it plans to complete in 2021.

Tovinontrine could face competition from a number of different therapeutic approaches that are in development as a therapeutic option for patients with TDT or NTDT ß-thalassemia. For example, there are a number of companies in clinical development for gene editing/therapy treatments, including bluebird, CRISPR (in collaboration with Vertex) and Ionis Pharmaceuticals. There are also several companies advancing therapeutic approaches outside of gene editing/therapy, including Agios, Forma, Silence Therapeutics and Vifor.

HFpEF

In the area of HFpEF, tovinontrine could face competition from Entresto (marketed by Novartis) and Jardiance (marketed by Eli Lilly & Co.) which are currently the only FDA-approved therapies for HFpEF.  We are also aware of several drugs approved for other indications that are likely to seek near-term marketing approval for the treatment of HFpEF including Farxiga (Astra Zeneca, PLC), Invokana (Johnson & Johnson) and Zynquista (Lexicon Pharmaceuticals, Inc).  In

addition, Bristol-Myers Squibb Co., Cytokinetics, Inc., Acceleron Pharma, Inc., Palatin Technologies, Inc., Cardurion Pharmaceuticals, Inc. and TransThera Biosciences Co., Ltd., among potentially other companies, are also developing therapeutic approaches for patients with HFpEF.

Intellectual Property

We strive to protect and enhance the proprietary technology, inventions and improvements that are commercially important to the development of our business, including by seeking, maintainingproduct candidates.

To date, we have obtained the custom-manufactured starting materials for active pharmaceutical ingredients ("APIs") manufacture from Pharmaron and defending patent rights, whether developed internally or licensedHande Sciences and our good manufacturing practice ("GMP") APIs from third parties.Pharmaron. The drug product for the ELVN-001 program is manufactured at Latitude Pharmaceuticals Inc., and Quotient Sciences, and the drug product for the ELVN-002 program is manufactured at CoreRx. We also relycould contract with other contract manufacturing organizations ("CMOs") for the starting materials as the raw materials we use are commonly used and are available from multiple sources. We are in the process of developing our supply chain for each of our product candidates and intend to put in place framework agreements under which third-party CMOs will generally provide us with necessary quantities of APIs and drug product on trade secrets, know-how, continuing technological innovationa project-by-project basis based on our development needs.

As we advance our product candidates through development, we plan to explore adding backup suppliers for the APIs and in-licensing opportunitiesdrug product for each of our product candidates in order to develop, strengthen and maintain our proprietary position in our field.protect against any potential supply disruptions.

Intellectual Property

Our future commercial success depends in part on our ability to:to obtain and maintain patent and other proprietary or intellectual property protection for commercially importantour product candidates, technology inventions and know-how, to operate without infringing the proprietary or intellectual property rights of others and to prevent others from infringing our proprietary or intellectual property rights. We expect that we will seek to protect our proprietary and intellectual property position by, among other methods, pursuing and obtaining patent protection in the United States and in jurisdictions outside of the United States related to our business; defendproprietary technology, inventions, improvements and enforce inproduct candidates that are important to the development and implementation of our business. We may also rely on trade secrets, know-how, trademarks, continuing technological innovation and licensing opportunities to develop and maintain our proprietary and intellectual property rights, in particularposition.

As of January 1, 2024, our patent rights; preserve the confidentiality of our trade secrets;portfolio includes issued and operate without infringing, misappropriating or violating the valid and enforceable patents and proprietary rights of third parties. Our ability to stop third parties from making, using, selling, offering to sell or importing any products we develop may depend on the extent to which we have rights under valid and enforceable patents or trade secrets that cover these activities.

The patent positions of biopharmaceutical companies like ours are generally uncertain and can involve complex legal, scientific and factual issues. We cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or whether the claims of any issued patents will provide sufficient proprietary protection from competitors. We also cannot ensure that patents will issue with respect to anypending patent applications that we or our licensors may file in the future, nor can we ensure that any of our owned or licensed patents or future patents will be commercially useful in protecting our product candidates and methods of manufacturing the same. In addition, the coverage claimed in a patent application may be significantly reduced before a patent is issued, and its scope can be reinterpreted and even challenged after issuance. As a result, we cannot guarantee that any products we develop will be protected or remain protectable by enforceable patents. Moreover, any patents that we hold may be challenged, circumvented or invalidated by third parties. See “Risk Factors—Risks Related to Our Intellectual Property” for a more comprehensive description of risksown related to our intellectual property.HER2 and BCR-ABL programs.

We generally file

For our HER2 program, we have six patent applicationsfamilies with claims directed to our key programs in an effort to secure our intellectual property positions vis-a-vis these programs.  The intellectual property portfolio for tovinontrine and IMR-261, is summarized below. Prosecution is a lengthy process, during which the scope of the claims initially submitted for examination by the U.S. Patent and Trademark Office may be significantly narrowed before issuance, if issued at all. We expect this may be the case with respect to some of our pending patent applications referred to below.

Tovinontrine (IMR-687)

The patent portfolio for our tovinontrine program includes at least six published patent families. As of December 31, 2021, we owned, co-owned, or held exclusive license rights to numerous patent and patent applications, including at least six issued or allowed U.S. patents, nine U.S. pending non-provisional patent applications, 82 issued or allowed non-U.S. patents, including five European patent applications which have been validated among individual European Patent Convention nations, 95 non-U.S. pending patent applications, and four pending Patent Cooperation Treaty, or PCT, applications relating to our tovinontrine program. These patents and patent applications comprise the following patent families:

The issued patents include coverage of the tovinontrine composition of matter. The issued patents include US 9,643,970 (exclusively licensed to us from Lundbeck A/S), which issued May 2017. This U.S. patent and related international family members are directed to the tovinontrineHER2 selective inhibitory compounds as composition of matter, including racemic mixtures. The expected expiry date of US 9,643,970, including 63 days of Patent Term Adjustment, based on a 20-year term, is December 2032, absent any other patent term extensions available.

The issued patents also include US 9,434,733 (exclusively licensed to us from Lundbeck A/S), which issued September 2016. This U.S. patent and related international family members areas well as claims directed to the alternative PDE9 inhibitor compositions of matter, including racemic mixtures. The expected expiry date, based on a 20-year term is January 2033, absent any patent term extensions available.

The issued patents also include US 10,513,524 (exclusively licensed to us from Lundbeck A/S), which issued December 2019. This U.S. patent and related international family members provide further protection for the tovinontrine

composition of matter, including the enantiomer, in addition to coverage of therapeutic methods of treating sickle cell disease with tovinontrine . The expected expiry date, based on a 20-year term, is July 2036, absent any patent term extensions available.

The pending applications include an additional patent family directed to therapeutic methods with a priority filing date of July 2016. A patent in Morocco has been allowed in this patent family, and the expected expiry date of this patent family, based on a 20-year term, is June 2037, absent any patent term extensions available.

The pending applications also include a patent family directed to process chemistry for manufacturing with a priority date of May 2017. No patents have issued in this patent family, and the expected expiry date of this patent family, based on a 20-year term, is May 2038, absent any patent term extensions available.

The PCT applications include a patent family directed to polymorphs of tovinontrine with a priority filing date of May 2018. No patents have issued in this patent family, and the expected expiry date of this patent family, based on a 20-year term, is May 2039, absent any patent term extensions available.

The pending PCT applications also include a PCT application directed to solid dose formulations of tovinontrine with a priority filing date of August 2018. No patents have issued in this patent family, and the expected expiry date of this patent family, based on a 20-year term, is August 2039, absent any patent term extensions available.

The pending PCT applications also include a PCT application directed to liquid solution formulations of tovinontrine with a priority filing date of April 2019. No patents have issued in this patent family, and the expected expiry date of this patent family, based on a 20-year term, is April 2040, absent any patent term extensions available.

The pending PCT applications also include a PCT application directed to therapeutic methods of treating thalassemia with a priority date of May 2019. No patents have issued in this patent family, and the expected expiry date of this patent family, based on a 20-year term, is May 2040, absent any patent term extensions available.

While we believe that the specific and generic claims contained in our owned and licensed pending U.S., non-U.S., and PCT applications provide protection for the claimed pharmaceutical compositions and methodscombinations comprising such compounds and uses of use, third parties may nevertheless challenge such claims.

IMR-261

compounds, e.g., for treatment of cancers, such as NSCLC, including cancers associated with E20IMs. The patent portfolio for our IMR-261 programfirst family includes at least four published patent families.  As of December 31, 2021, we owned, co-owned, or held exclusive license rights to numerous patent and patent applications, including at least seven issued or allowedone pending U.S. patents, one U.S.non-provisional application. The second family includes pending non-provisional patent applications 20 non-U.S. pending patent applications,in the U.S. and two pending PCT application relatingin Europe. Any patents that may issue from the first or the second family are expected to our IMR-261 program. These patents and patent applications comprise the following patent families:

The issued patents include coverage of the IMR-261 composition of matter. The issued patents include US 8,309,526 (exclusively licensed to us from UAB), which issued November 13, 2012. The expected expiry date of US 8,309,526, based on a 20-year term, is April 2025, absent any other patent term extensions available.

The issued patents also include four patents (US 7,776,916, US 9,522,156, US 9,006,473 and 9,867,795, each exclusively licensed to us from UAB), which issued between August 17, 2010 and January 16, 2018. These U.S. patents provide coverage of therapeutic methods of treating certain inflammatory and vascular diseases, including sickle cell disease, with IMR-261. The expected expiry date of these patents, based on a 20-year term, ranges between April 2025 and March 2027, absent any patent term extensions available.

The pending applications include a patent family directed to therapeutic methods of treating certain diseases, including sickle cell disease, at specified doses, with a priority date of October 2015. No patents covering therapeutic methods of treating sickle cell disease have issuedexpire in this patent family, and the expected expiry date of this patent family, based on a 20-year term, is October 2036, absent any patent term extensions available.

The PCT applications include a patent family directed to therapeutic methods of treating certain diseases, including sickle cell disease, at additional specified doses, with a priority filing date of May 2020. No patents have issued in this patent family, and the expected expiry date of this patent family, based on a 20-year term, is May 2041, absent any patent term extensions available.

In addition to the above, we have licensed on a non-exclusive basis from the University of Pittsburgh, rights to U.S. issued patents covering pharmaceutical compositions of nitro oleic acids, including IMR-261.  The expected expiry date of these patents, based on a 20-year term, is in mid-2028, absent any otheradjustment, patent term extensions, available.or terminal disclaimers. The third family includes a pending Patent Cooperation Treaty ("PCT") application. The fourth family includes one issued U.S. patent that expires in 2042; pending non-provisional applications in the U.S., Argentina, and Taiwan; and a pending PCT application. Any patents that may issue from the third or the fourth family are expected to expire in 2042, absent any patent term adjustment, patent term extensions, or terminal disclaimers. The fifth family includes a pending PCT application. Any patents that may issue from the fifth family are expected to expire in 2043, absent any patent term adjustment, patent term extensions, or terminal disclaimers. The sixth family includes a pending U.S. provisional application. Any patents that may issue from the sixth family are expected to expire in 2044, absent any patent term adjustment, patent term extensions, or terminal disclaimers. Any patents that may issue from our pending patent applications are expected to expire between 2041-2043, absent any patent term adjustments or patent term extensions for regulatory delay.

For the BCR-ABL program, we own three patent families with claims directed to BCR-ABL tyrosine-kinase inhibitory compounds as composition of matter, as well as claims directed to pharmaceutical compositions and combinations comprising such compounds and uses of such compounds, e.g., treatment of CML, acute myeloid leukemia ("AML"), acute lymphoblastic leukemia ("ALL"), or mixed phenotype acute leukemia, including refractory leukemias associated with a T315I mutation in BCR-ABL. The first family includes two issued U.S. patents that expire in 2041; and pending non-provisional applications in the U.S., Australia, Brazil, Canada, China, Europe, Israel, India, Japan, Republic of Korea, Mexico, New Zealand, Singapore, and South Africa. The second family includes pending non-provisional applications in the U.S., China, Europe, Israel, India, Japan, Republic of Korea, and Mexico. Any patents that may issue from the first or the second family are expected to expire in 2041, absent any patent term adjustment, patent term extensions, or terminal disclaimers. The third family includes a pending U.S. non-provisional application. Any patents that may issue from the third family are expected to expire in 2042, absent any patent term adjustment, patent term extensions, or terminal disclaimers. The term of individual patents depends upon the legal term of thefor patents in the countries in which they are obtained.granted. In most countries in which we file, the patent term is generally 20 years from the earliest date of filing a non-provisional patent application.

In the United States, the term of a patent covering an FDA-approved drugterm may, in certain cases, be eligiblelengthened by patent term adjustment, which compensates a patentee for administrative delays by the USPTO in examining and granting a patent term extension underor may be shortened if a patent is terminally disclaimed over a commonly owned patent or a patent naming a common inventor and having an earlier expiration date. Additionally, the Drug Price Competition and Patent Term Restoration Act of 1984 as compensation for the loss of(“Hatch-Waxman Act”) permits patent term during the FDA regulatory review process. The periodextension of extension may be up to five years butbeyond the expiration date of a U.S. patent as partial compensation for the length of time a drug is under regulatory review while a patent that covers the drug is in force. The length of the patent term extension is related to the length of time the drug is under regulatory review. Patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval. Onlyapproval, only one patent among those eligible for an extensionapplicable to each regulatory review period may be extended and only those claims covering the approved drug, a method for using it or a method for manufacturing it may be extended.

Similar provisions are available in Europethe EU and in certain other foreign jurisdictions to extend the term of a patent that covers an approved drug. It is possible that issued U.S. patents covering tovinontrine may be entitled to patent term extensions. IfIn the future, if and when our use of drugproduct candidates receive approval by the FDA or the drug candidate itself receive FDA approval,foreign regulatory authorities, we intend

expect to apply for patent term extensions on issued patents covering those products, if available, to extend the term of patents that cover the approved use or drug candidate. We also intend to seek patent term extensions in any jurisdictions where available, however,available. However, there is no guarantee that the applicable authorities, including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and, even if granted, the length of such extensions. For more information regarding the risks related to our intellectual property, see the section “Risk Factors—Risks Related to Our Intellectual Property” included elsewhere in this Annual Report on Form 10-K. Expiration dates referred to above are without regard to potential patent term extension or other market exclusivity that may be available to us.

In addition to patent protection, we also rely upon unpatented trade secretson trademarks and confidential know-howother proprietary information and continuing technological innovation to develop and maintain our competitive position. However, trade secrets and confidential know-how are difficult to protect. We seek to protect ourand maintain the confidentiality of proprietary information in part, using confidentiality agreements with any collaborators, scientific advisors, employees and consultants and invention assignment agreements with our employees. We also have agreements requiring assignment of inventions with selected consultants, scientific advisors and collaborators. These agreements may not provide meaningful protection. These agreements may also be breached, and we may not have an adequate remedy for any such breach. In addition, our trade secrets and/or confidential know-how may become known or be independently developed by a third party, or misused by any collaborator to whom we disclose such information. Despite any measures taken to protect our intellectual property, unauthorized parties may attempt to copy aspects of our productsbusiness that are not amenable to, or to obtain or use information that we regard as proprietary.do not consider appropriate for, patent protection. Although we take steps to protect our proprietary information, including through contractual means with our employees and consultants, third parties may independently develop the same or similarsubstantially equivalent proprietary information and techniques or may otherwise gain access to or disclose our proprietary information. As a result,technology. Thus, we may not be unableable to meaningfully protect our trade secrets and proprietary information. See “RiskIt is our policy to require our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors to execute confidentiality agreements upon the commencement of employment or consulting relationships with us. These agreements provide that all confidential information concerning our business or financial affairs developed or made known to the individual during the course of the individual’s relationship with us is to be kept confidential and not disclosed to third parties except in specific circumstances. Our agreements with employees also provide that all inventions conceived by the employee in the course of employment with us or from the employee’s use of our confidential information are our exclusive property. However, such confidentiality agreements and invention assignment agreements can be breached, and we may not have adequate remedies for any such breach. For more information regarding the risks related to our intellectual property, see the section titled “Risk Factors—Risks Related to Our Intellectual Property” forProperty” included elsewhere in this Annual Report on Form 10-K. The patent positions of biotechnology companies like ours are generally uncertain and involve complex legal, scientific and factual questions. Our commercial success will also depend in part on not infringing upon the proprietary rights of third parties. It is uncertain whether the issuance of any third- party patent would require us to alter our development or commercial strategies, alter our products or processes, obtain licenses or cease certain activities. Our breach of any license agreements or our failure to obtain a more comprehensive description of risks relatedlicense to proprietary rights required to develop or commercialize our intellectual property.

Manufacturing

We currently contract withfuture products may have a material adverse impact on us. If third parties for the manufacture of our product candidates for preclinical studiesprepare and clinical trials and intend to do so in the future. We do not own or operate manufacturing facilities for the production of clinical or commercial quantities of our product candidates. We currently have no plans to build our own clinical or commercial scale manufacturing capabilities. To date, our third-party manufacturers have met our manufacturing requirements. We expect third-party manufacturers to be capable of providing sufficient quantities of our program materials to meet anticipated clinical-trial scale demands. To meet our projected needs for commercial manufacturing, third parties with whom we currently work will need to increase their scale of production or we will need to secure alternate suppliers. We believe that there are alternate sources of supply that can satisfy our clinical and commercial requirements, although we cannot be certain that identifying and establishing relationships with such sources, if necessary, would not result in significant delay or material additional costs. Although we rely on contract manufacturers, we have personnel with manufacturing experience to oversee our relationships with contract manufacturers.

Sales and Marketing

In light of our stage of development, we have not yet established a commercial organization or distribution capabilities. We have retained worldwide commercial rights for our product candidates. If our product candidates receive marketing approval, we plan to commercialize themfile patent applications in the United States and Europe and potentially other international regions with our own sales force.that also claim technology to which we have rights, we may have to participate in derivation proceedings in the USPTO to determine priority of invention. For more information, see the section titled “Risk Factors—Risks Related to Our IntellectualProperty” included elsewhere in this Annual Report on Form 10-K.

Government Regulation and Product ApprovalsRegulations

Government authorities in the United States at the federal, state and local level and in other countries and jurisdictions, such as the European Union, or EU, extensively regulate, among other things, the research, development, testing, manufacture, pricing, quality control, approval, labeling, packaging, storage, recordkeeping, labeling,record-keeping, promotion, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, marketing and export and import of drug and export of biopharmaceuticalbiological products. The processesGenerally, before a new drug can be marketed, considerable data demonstrating its quality, safety and efficacy must be obtained, organized into a format specific for obtaining marketing approvals ineach regulatory authority, submitted for review and approved by the regulatory authority.

U.S. Drug Development

In the United States, the FDA regulates drugs under the Federal Food, Drug, and in foreign countriesCosmetic Act ("FDCA"). Drugs also are subject to other federal, state and jurisdictions, along withlocal statutes and regulations. The process of obtaining regulatory approvals and the subsequent compliance with applicableappropriate federal, state, local and foreign statutes and regulations and other regulatory authorities, requirerequires the expenditure of substantial time and financial resources.

Approval and Regulation of Drugs in the United States

In the United States, drug products are approved and regulated under the Federal Food, Drug and Cosmetic Act, or FDCA, and applicable implementing regulations and guidance. A company, institution or organization that takes responsibility for the initiation and management of a clinical development program for such products, and for their regulatory approval, is typically referred to as a sponsor.  The failure of a sponsor Failure to comply with the applicable regulatoryU.S. requirements at any time during the product development process, approval process or post-market may resultsubject an applicant to administrative or judicial sanctions. These sanctions could include, among other actions, the FDA’s refusal to approve pending applications, withdrawal of an approval, a clinical hold, untitled or warning letters, product recalls or market withdrawals, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement and civil or criminal penalties. Any agency or judicial enforcement action could have a material adverse effect on us.

Our product candidates are considered small molecule drugs and must be approved by the FDA through the new drug application ("NDA") process before they may be legally marketed in delaysthe United States. The process generally involves the following:

The data required to support an NDA are generated in two distinct developmental stages: preclinical and clinical. The preclinical and clinical testing and approval process requires substantial time, effort and financial resources, and we cannot be certain that any approvals for any current and future product candidatecandidates will be approved by the FDA:granted on a timely basis, or at all.

Preclinical Studies and IND

Before a sponsor begins testing a product candidate with potential therapeutic value in humans, the product candidate enters theThe preclinical testing stage. Preclinical tests includedevelopmental stage generally involves laboratory evaluations of productdrug chemistry, formulation and stability, as well as other studies to evaluate among other things,toxicity in animals, which support subsequent clinical testing. The sponsor must submit the toxicityresults of the preclinical studies, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND. An IND is a request for authorization from the FDA to administer an investigational product candidate.to humans and must become effective before human clinical trials may begin.

Preclinical studies include laboratory evaluation of product chemistry and formulation, as well as in vitro and animal studies to assess the potential for adverse events and in some cases to establish a rationale for therapeutic use. The conduct of the preclinical tests and formulation of the compounds for testing must comply withstudies is subject to federal regulations and requirements, including GLP regulations and standards and the United States Department of Agriculture’s Animal Welfare Act, if applicable. Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity and long-term toxicity studies may continue after the IND is submitted.

The IND and IRB Processes

for safety/toxicology studies. An IND is a request for FDA authorization to administer such investigational product to humans. Such authorizationsponsor must be secured prior to interstate shipment and administration of any product candidate that is not the subject of an approved NDA. In support of a request for an IND, sponsors must submit a protocol for the clinical trial, and any subsequent protocol amendments must be submitted to the FDA as part of the IND application. In addition, the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical trials,studies, among other things, must be submitted to the FDA as part of an IND. The FDA requires a 30-day waiting periodSome long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue after the filing of each IND before clinical trials may begin. This waiting period is designed to allowsubmitted. An IND automatically becomes effective 30 days after receipt by the FDA, to review the IND to determine whether human research subjects will be exposed to unreasonable health risks. At anyunless before that time during this 30- day period, the FDA may raiseraises concerns or questions aboutrelated to one or more proposed clinical trials and places the conduct of the trials as outlined in the IND and impose a clinical hold or partialtrial on clinical hold. In thissuch a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. As a result, submission of an IND may not result in the FDA allowing clinical trials can begin.to commence.

Following commencement

Clinical Trials

The clinical stage of development involves the administration of the investigational product to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCP requirements, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters to be used to monitor subject safety and assess efficacy. Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND. Furthermore, each clinical trial must be reviewed and approved by an IRB for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB must also approve the informed consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed. There also are requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries. A sponsor who wishes to conduct a clinical trial outside of the United States may, but need not, obtain FDA authorization to conduct the clinical trial under an IND, the FDA may also placeIND. If a foreign

clinical hold or partial clinical hold on that trial. A clinical hold is an order issued by the FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. A partial clinical hold is a delay or suspension of only part of the clinical work requested under the IND. For example, a specific protocol or part of a protocol is not allowed to proceed, while other protocols may do so. No more than 30 days after imposition of a clinical hold or partial clinical hold, the FDA will provide the sponsor a written explanation of the basis for the hold. Following issuance of a clinical hold or partial clinical hold, an investigation may only resume after the FDA has so notified the sponsor that the investigation may proceed. The FDA will base that determination on information provided by the sponsor correcting the deficiencies previously cited or otherwise satisfying the FDA that the investigation can proceed.

A sponsor may choose, but is not required, to conduct a foreign clinical study under an IND. When a foreign clinical study is conducted under an IND, all FDA IND requirements must be met unless waived. When a foreign clinical studytrial is not conducted under an IND, the sponsor must ensure thatmay submit data from the study complies with certain regulatory requirements ofclinical trial to the FDA in order to use the study as support forof an NDA. The FDA will generally accept a well-designed and well-conducted foreign clinical trial not conducted under an IND or applicationif the trial was conducted in accordance with the FDA requirements for marketing approval. The FDA’suse of foreign clinical trials, including the requirements set forth at 21 CFR 312.120, the laws and regulations are intended to help ensureof the foreign regulatory authorities where the trial was conducted, such as the European Medicines Agency ("EMA"), whichever provides greater protection of the human subjects, enrolledand with GCP and GMP requirements, and the FDA is able to validate the data through an onsite inspection, if deemed necessary, and the practice of medicine in non-INDthe foreign clinical studies, as well ascountry is consistent with the quality and integrity ofUnited States.

Clinical trials in the resulting data. They further help ensure that non-IND foreign studiesUnited States generally are conducted in three sequential phases, known as Phase 1, Phase 2 and Phase 3, and may overlap.

Post-approval trials, sometimes referred to as Phase 4 clinical trials, are conducted after initial marketing approval. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication. In additioncertain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.

Progress reports detailing the results of the clinical trials, among other information, must be submitted at least annually to the foregoingFDA. The sponsor is also responsible for submitting written IND requirements, an IRB representing each institution participatingsafety reports, including reports of serious and unexpected suspected adverse events, findings from other studies suggesting a significant risk to humans exposed to the drug, findings from animal or in vitro testing that suggest a significant risk for human subjects, and any clinically significant increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, if at all. The FDA or the sponsor may suspend or terminate a clinical trial must review and approveat any time on various grounds, including a finding that the plan for any clinical trial before it commences at that institution, and the IRB must conduct continuing review and reapprove the study at least annually. The IRB must review and approve, among other things, the study protocol and informed consent informationresearch subjects or patients are being exposed to be provided to study subjects. An IRB must operate in compliance with FDA regulations. Anan unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the product candidatedrug has been associated with unexpected serious harm to patients.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee, or DSMB.committee. This group provides a recommendation as toauthorization for whether or not a trial may move forward at designated check pointscheck-points based on access that only the group maintains to availablecertain data from the study. Suspension or termination of development during any phase of clinical trials can occur if it is determined that the participants or patients are being exposed to an unacceptable health risk. Other reasons for suspension or termination may be made by us based on evolving business objectives and/or the competitive climate.

Expanded Access to an Investigational Drug for Treatment Usetrial.

Expanded access, sometimes called “compassionate use,” is the use of investigational new drug products outside of clinical trials to treat patients with serious or immediately life-threatening diseases or conditions when there are no comparable or satisfactory alternative treatment options. The rules and regulations related to expanded access are intended to improve access to investigational drugs for patients who may benefit from investigational therapies. FDA regulations allow access to investigational drugs under an IND by the company or the treating physician for treatment purposes on a case-by-case basis for: individual patients (single-patient IND applications for treatment in emergency settings and non-emergency settings); intermediate-size patient populations; and larger populations for use of the drug under a treatment protocol or Treatment IND Application.

When considering an IND application for expanded access to an investigational product with the purpose of treating a patient or a group of patients, the sponsor and treating physicians or investigators will determine suitability when all of the following criteria apply: patient(s) have a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition; the potential patient benefit justifies the potential risks of the treatment and the potential risks are not unreasonable in the context or condition to be treated; and the expanded use of the investigational drug for the requested treatment will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the product or otherwise compromise the potential development of the product. Sponsors of one or more investigational drugs for the treatment of a serious disease(s) or condition(s) must make publicly available their policy for evaluating and responding to requests for expanded access for individual patients.

There is no obligation for a sponsor to make its drug products available for expanded access; however, as required by the 21st Century Cures Act, or Cures Act, passed in 2016, if a sponsor has a policy regarding how it responds to expanded access requests, it must make that policy publicly available. Sponsors are required to make such policies publicly available upon the earlier of initiation of a Phase 2 or Phase 3 trial; or 15 days after the investigational drug or biologic receives designation as a breakthrough therapy, fast-track product, or regenerative medicine advanced therapy.

In addition, on May 30, 2018, the Right to Try Act, was signed into law. The law, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase I clinical trial and that are undergoing investigation for FDA approval. Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program. There is no obligation for a drug manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act, but the manufacturer must develop an internal policy and respond to patient requests according to that policy.

Human Clinical Trials in Support of an NDA

Clinical trials involve the administration of the investigational product candidate to human subjects under the supervision of a qualified investigator in accordance with GCP requirements, which include, among other things, the requirement that all research subjects provide their informed consent in writing before their participation in any clinical trial. Clinical trials are conducted under written clinical trial protocols detailing, among other things, the objectives of the study, inclusion and exclusion criteria, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.

Human clinical trials are typically conducted in three sequential phases, but the phases may overlap or be combined. Additional studies may also be required after approval.

Phase 1 clinical trials are initially conducted in a limited population to test the product candidate for safety, including adverse effects, dose tolerance, absorption, metabolism, distribution, excretion and pharmacodynamics in healthy humans or in patients. During Phase 1 clinical trials, information about the investigational drug product’s pharmacokinetics and pharmacological effects may be obtained to permit the design of well-controlled and scientifically valid Phase 2 clinical trials.

Phase 2 clinical trials are generally conducted in a limited patient population to identify possible adverse effects and safety risks, evaluate the efficacy of the product candidate for specific targeted indications and determine dose tolerance and optimal dosage and dosage schedule. Multiple Phase 2 clinical trials may be conducted by the sponsor to obtain information prior to beginning larger and more costly Phase 3 clinical trials. Phase 2 clinical trials are well controlled, closely monitored and conducted in a limited patient population.

Phase 3 clinical trials proceed if the Phase 2 clinical trials demonstrate that a dose range of the product candidate is potentially effective and has an acceptable safety profile. Phase 3 clinical trials are undertaken within an expanded patient population to further evaluate dosage, provide substantial evidence of clinical efficacy and further test for safety in an expanded and diverse patient population at multiple, geographically dispersed clinical trial sites. A well-controlled, statistically robust Phase 3 clinical trial may be designed to deliver the data that regulatory authorities will use to decide whether or not to approve, and, if approved, how to appropriately label a drug. Such Phase 3 studies are referred to as “pivotal.”

In some cases, the FDA may approve an NDA for a product candidate but require the sponsor to conduct additional clinical trials to further assess the product candidate’s safety and effectiveness after approval. Such post-approval trials are typically referred to as Phase 4 clinical trials and are conducted either as post-marketing commitments or post-marketing requirements. These studies are used to gain additional experience from the treatment of a larger number of patients in the intended treatment group and to confirm a clinical benefit in the case of drugs approved under accelerated approval regulations. Failure to exhibit due diligence with regard to fulfilling post-marketing commitments or post-marketing requirements could result in withdrawal of approval for products.

A clinical trial may combine the elements of more than one phase and the FDA often requires more than one Phase 3 trial to support marketing approval of a product candidate. A company’s designation of a clinical trial as being of a particular phase is not necessarily indicative that the trial will be sufficient to satisfy the FDA requirements of that phase because this determination cannot be made until the protocol and data have been submitted to and reviewed by the FDA. Generally, pivotal trials are Phase 3 trials, but they may be Phase 2 trials if the design provides a well-controlled and reliable assessment of clinical benefit, particularly in an area of unmet medical need.

Progress reports detailing the status and a brief description of available results of the clinical trials must be submitted at least annually to the FDA. In addition, IND safety reports must be submitted to the FDA for any of the following: serious and unexpected suspected adverse reactions; findings from other studies or animal or in vitro testing that suggest a significant risk in humans exposed to the product; and any clinically important increase in the case of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.

Finally, sponsors of clinical trials are required to register and disclose certain clinical trial information on a public registry (clinicaltrials.gov) maintained by the U.S. National Institutes of Health, or NIH. In particular, information related to the product, patient population, phase of investigation, study sites and investigators and other aspects of the clinical trial is made public as part of the registration of the clinical trial. Both the NIH and the FDA have recently signaled the government’s willingness to begin enforcing those requirements against non-compliant clinical trial sponsors.  The failure to submit clinical trial information to clinicaltrials.gov, as required, is a prohibited act under the FDCA with violations subject to potential civil monetary penalties of up to $10,000 for each day the violation continues.

Concurrent with clinical trials, companies oftenusually complete additional animal safety studies and theyalso must also develop additional information about the chemistrychemical and physical characteristics of the investigational drug as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process, as performed by the manufacturing facility, must be capable of consistently producing quality batches of theour product candidate and, among other things, must develop methods for testing the identity, strength, quality, purity, and potency of the final drug.candidates. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that theour product candidate doescandidates do not undergo unacceptable deterioration over itstheir labeled shelf life.

Pediatric Studies

UnderWe may be required to develop and implement additional clinical trial policies and procedures designed to help protect subjects from public health concerns, such as COVID-19 infection. To the Pediatric Research Equity Actextent the FDA issues additional guidance and policies, compliance with such changes may materially impact our business and clinical development timelines. Changes to existing policies and regulations can increase our compliance costs or delay our clinical plans.

NDA Review Process

Following completion of 2003, or PREA, an NDA or supplement thereto must containthe clinical trials, data that are adequateis analyzed to assess whether the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which theinvestigational product is safe and effective. Sponsors must also submit pediatric study plans prioreffective for the proposed indicated use or uses. The results of preclinical studies and clinical trials are then submitted to the assessment data. Those plans must containFDA as part of an outline of theNDA, along with proposed pediatric study or studies the sponsor planslabeling, chemistry and manufacturing information to conduct, including study objectives and design, any deferral or waiver requestsensure product quality and other information required by regulation. The sponsor,relevant data. In short, the FDA, and the FDA’s internal review committee must then review the information submitted, consult with each other and agree upon a final plan. The FDA or the sponsor may request an amendment to the plan at any time.

For drugs intended to treat a serious or life-threatening disease or condition, the FDA must, upon the request of a sponsor, meet to discuss preparation of the initial pediatric study plan or to discuss deferral or waiver of pediatric assessments. In addition, the FDA will meet early in the development process to discuss pediatric study plans with sponsors,

and the FDA must meet with sponsors by no later than the end-of-phase 1 meeting for serious or life-threatening diseases and by no later than ninety (90) days after the FDA’s receipt of the study plan.

The FDA may, on its own initiative or at the request of the sponsor, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements. A deferral may be granted for several reasons, including a finding that the product or therapeutic candidate is ready for approval for use in adults before pediatric trials are complete. Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation, although the FDA has recently taken steps to limit what it considers abuse of this statutory exemption in the PREA.

Rare Pediatric Disease Priority Review Voucher Program

With enactment of the Food and Drug Administration Safety and Innovation Act in 2012, and subsequent passage of the Advancing Hope Act of 2016, Congress authorized the FDA to award priority review vouchers to sponsors of certain rare pediatric disease product applications that meet the criteria specified in the law. This provision is designed to encourage development of new drug and biological products for prevention and treatment of certain rare pediatric diseases. Specifically, under this program, a sponsor who receives an approval for a drug or biologic for a “rare pediatric disease” may qualify for a voucher that can be redeemed to receive a priority review of a subsequent marketing application for a different product. The sponsor of a rare pediatric disease drug product receiving a priority review voucher may transfer (including by sale) the voucher to another sponsor. The voucher may be further transferred any number of times before the voucher is used, as long as the sponsor making the transfer has not yet submitted the application.

For the purposes of this program, a “rare pediatric disease”NDA is a (a) serious or life-threatening disease in which the serious or life-threatening manifestations primarily affect individuals aged from birth to 18 years, including age groups often called neonates, infants, children, and adolescents; and (b) rare disease or conditions within the meaning of the Orphan Drug Act. A sponsor may choose to request rare pediatric disease designation, but the designation process is entirely voluntary; requesting designation is not a prerequisite to requesting or receiving a priority review voucher. In addition, sponsors who choose not to submit a rare pediatric disease designation request may nonetheless receive a priority review voucher if they request such a voucher in their original marketing application and meet all of the eligibility criteria.

In December 2016, the Cures Act extended the Rare Pediatric Disease Priority Review Voucher Program, authorizing the FDA to award vouchers through September 30, 2022, limited to drugs with rare pediatric disease designation granted by September 30, 2020. On September 30, 2020, Congress provided a short-term extension of the Priority Review Voucher Program. On December 27, 2020, the Rare Pediatric Disease Priority Review Voucher Program was further extended. Under the current statutory sunset provisions, after September 30, 2024, the FDA may only award a voucher for an approved rare pediatric disease product application if the sponsor has rare pediatric disease designation for the drug, and that designation was granted by September 30, 2024. After September 30, 2026, the FDA may not award any rare pediatric disease priority review vouchers.

Submission and Filing of an NDA

In order to obtain approval to market athe drug product in the United States for one or more specified indications and must contain proof of safety and efficacy for a marketingdrug.

The application must be submitted to the FDA that provides sufficient data establishing the safety, purityinclude both negative and potencyambiguous results of the proposed drug product for its intended indication. The application includes all relevant data available from pertinent preclinical studies and clinical trials, together with detailed information relating to the product’s chemistry, manufacturing, controls and proposed labeling, among other things.as well as positive findings. Data canmay come from company-sponsored clinical trials intended to test the safety and effectivenessefficacy of a product’s use of a product, or from a number of alternative sources, including studies initiated by independent investigators. To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety purity and potencyefficacy of the druginvestigational product to the satisfaction of the FDA.

The FDA approval of an NDA ismust be obtained before a vehicle through which sponsors formally propose that the FDA approve a new product for marketing and saledrug may be legally marketed in the United States for one or more indications. Every new drug product candidateStates.

Under the Prescription Drug User Fee Act ("PDUFA"), as amended, each NDA must be accompanied by a user fee. The FDA adjusts the subject ofPDUFA user fees on an approved NDA before it may be commercialized in the United States. Under federal law, the submission of most NDAs is subject to an application user fee, which for federal fiscal year 2022 is $3,117,218 for an application requiring clinical data. The sponsor of an approved NDA isannual basis. PDUFA also subject toimposes an annual program fee which for federal fiscal year 2022 is $369,413. Certain exceptions andeach marketed human drug. Fee waivers or reductions are available for somein certain circumstances, including a waiver of these fees, such as an exception from the application fee for the first application filed by a small business. Additionally, no user fees are assessed on NDAs for products withdesignated as orphan designation anddrugs, unless the product also includes a waivernon-orphan indication.

The FDA reviews all submitted NDAs before it accepts them for certain small businesses.

Following submission of an NDA, the FDA conducts a preliminary review of the application within 60 days of receipt and must inform the sponsor at that time or before whether an application is sufficiently complete to permit substantive review. If the FDA determines that the application is incomplete, it will issue a Refuse to File, or RFT, letterfiling and may request additional information and studies. In this event,rather than accepting the applicationNDA for filing. The FDA must be resubmitted with the additional information and is subject to review before the FDA accepts itmake a decision on accepting an NDA for filing.

filing within 60 days of receipt. Once the submission is accepted for filing, the FDA begins an in-depth substantive review. The FDA hasreview of the NDA. Under the goals and policies agreed to specified performance goals in the review process of NDAs but the review process and the Prescription Drug User Fee Act, or PDUFA, goal date may be extended by the FDA for three additional months to consider new information or clarification provided by the sponsor to address an outstanding deficiency identified byunder PDUFA, the FDA following the original submission. Under that agreement, 90% of applications seeking approval of New Molecular Entities, or NMEs, are meant to be reviewed withinhas 10 months, from the filing date, onin which to complete its initial review of a new molecular-entity NDA and respond to the applicant, and six months from the filing date of a new molecular-entity NDA designated for priority review. The FDA does not always meet its PDUFA goal dates for standard and priority NDAs, and the review process is often extended by FDA requests for additional information or clarification.

Before approving an NDA, the FDA accepts the application for filing, and 90% of applications for NMEs that have been designated for “priority review” are meant to be reviewed within six monthswill conduct a pre-approval inspection of the filing date.

In connectionmanufacturing facilities for the new product to determine whether they comply with its review of an application, the FDA typically will inspect the facility or facilities where the product is or will be manufactured. These pre-approval inspections may cover all facilities associated with an NDA submission, including component manufacturing, finished product manufacturing and control testing laboratories.cGMP requirements. The FDA will not approve an applicationthe product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and are adequate to assure consistent production of the product within required specifications. Additionally, before approving an NDA, theThe FDA will typically inspect one or morealso may audit data from clinical sitestrials to assureensure compliance with GCP and the integrity of the data supporting the application.

In addition, as a condition of approval,requirements. Additionally, the FDA may require a sponsor to develop a REMS. A REMS uses risk-minimization strategies beyond the professional labeling to ensure that the benefitsrefer applications for novel drug products or drug products which present difficult questions of the product outweigh the potential risks. To determine whether a REMS is needed, the FDA will consider the size of the population likely to use the product, the seriousness of the disease, the expected benefit of the product, the expected duration of treatment, the seriousness of knownsafety or potential adverse events and whether the product is a new molecular entity.

The FDA may refer an application for a novel productefficacy to an advisory committee, or explain why such referral was not made. Typically, an advisory committee istypically a panel of independent experts, includingthat includes clinicians and other scientific experts, that reviews, evaluatesfor review, evaluation and provides a recommendation as to whether the application should be approved and under what conditions.conditions, if any. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

Fast Track, Breakthrough Therapy, Priority Review and Regenerative Advanced Therapy Designations

decisions on approval. The FDA likely will reanalyze the clinical trial data, which could result in extensive discussions between the FDA and the applicant during the review process. After the FDA evaluates an NDA, it will issue an approval letter or a Complete Response Letter. An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications. A Complete Response Letter indicates that the review cycle of the application is authorizedcomplete, and the application will not be approved in its present form. A Complete Response Letter usually describes all of the specific deficiencies in the NDA identified by the FDA. The Complete Response Letter may require additional clinical data, additional pivotal Phase 3 clinical trial(s) and/or other significant and time-consuming requirements related to designate certainclinical trials, preclinical studies and/or manufacturing. If a Complete Response Letter is issued, the applicant may either resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application. Even if such data and information are submitted, the FDA may decide that the NDA does not satisfy the criteria for approval. Data obtained from clinical trials are not always conclusive and the FDA’s interpretation of data may differ from our interpretation.

Orphan Drugs

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug or biological product intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making the product available in the United States for this type of disease or condition will be recovered from sales of the product.

Orphan drug designation must be requested before submitting an NDA. After the FDA grants orphan drug designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Orphan drug designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.

If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan drug exclusivity, which means that the FDA may not approve any other applications to market the same drug for the same indication for seven years from the date of such approval, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity by means of greater effectiveness, greater safety or providing a major contribution to patient care or in instances of drug supply issues. However, competitors may receive approval either for a different product for the same indication or the same product for a different indication but that could be used off-label in the orphan indication. Orphan drug exclusivity also could block the approval of one of our products for expedited reviewseven years if a competitor obtains approval before we do for the same product, as defined by the FDA, for the same indication for which we are seeking approval, or if a product candidate is determined to be contained within the scope of the competitor’s product for the same indication. If one of our products designated as an orphan drug receives marketing approval for an indication broader than that which is designated, it may not be entitled to orphan drug exclusivity. Orphan drug status in the EU has similar, but not identical, requirements and benefits.

Expedited Development and Review Programs

The FDA has a fast track program that is intended to expedite or facilitate the process for reviewing new drugs that meet certain criteria. Specifically, new drugs are eligible for fast track designation if they are intended to address an unmet medical need in the treatment oftreat a serious or life-threatening disease or condition. These programs are referred to as Fast Track designation, Breakthrough Therapy designation, Priority Review designation and Regenerative Advanced Therapy designation. None of these expedited programs change the standards for approval but they may help expedite the development or approval process of product candidates.

Specifically, the FDA may designate a new product for Fast Track review if it is intended for the treatment of a serious or life-threatening disease or condition and it demonstratespreclinical or clinical data demonstrate the potential to address unmet medical needs for such a disease orthe condition. For Fast Track products, sponsors may have greater interactiontrack designation applies to both the product and the specific indication for which it is being studied. The sponsor can request the FDA to designate the product for fast track status any time before receiving NDA approval, but ideally no later than the pre-NDA meeting with the FDA.

Any product submitted to the FDA for marketing, including under a fast track program, may be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval. Any product is eligible for priority review if it treats a serious or life- threatening condition and, if approved, it would provide a significant improvement in safety and effectiveness compared to available therapies.

A product may also be eligible for accelerated approval, if it treats a serious or life-threatening condition and generally provides a meaningful advantage over available therapies. In addition, it must demonstrate an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality ("IMM"), which is reasonably likely to predict an effect on IMM or other clinical benefit. As a condition of approval, the FDA may initiate review of sectionsrequire that a sponsor of a Fast Track product’s NDA beforedrug receiving accelerated approval perform adequate and well- controlled post-marketing clinical trials. The FDA may withdraw drug approval or require changes to the applicationlabeled indication of the drug if confirmatory post-market trials fail to verify clinical benefit or do not demonstrate sufficient clinical benefit to justify the risks associated with the drug. If the FDA concludes that a drug shown to be effective can be safely used only if distribution or use is complete. This rolling reviewrestricted, it may require such post-marketing restrictions as it deems necessary to assure safe use of the product.

Additionally, a drug may be availableeligible for designation as a breakthrough therapy if the FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that a Fast Track product may be effective. The sponsor must also provide, and the FDA must approve, a schedule for the submission of the remaining information, and the sponsor must pay applicable user fees. However, the FDA’s time-period goal for reviewing a Fast Track application does not begin until the last section of the application is submitted. In addition, the Fast Track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trial process.

Second, a new product may be designated as a Breakthrough Therapy if it is intended, alone or in combination with one or more other drugs or biologics, to treat a serious or life-threatening disease orlife- threatening condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over availablecurrently approved therapies on one or more clinically significant endpoints, suchendpoints. The benefits of breakthrough therapy designation include the same benefits as substantial treatment effects observed early in clinical development. Thefast track designation, plus intensive guidance from the FDA to ensure an efficient drug development program. Fast track designation, priority review, accelerated approval and breakthrough therapy designation do not change the standards for approval, but may take certain actions with respect to Breakthrough Therapies, including holding meetings with the sponsor throughoutexpedite the development process; providing timely advice to theor approval process. Even if a product sponsor

regarding development and approval; involvingqualifies for one or more senior staff in the review process; assigning a cross-disciplinary project lead for the review team and taking other steps to design the clinical trials in an efficient manner.

Third,of these programs, the FDA may designate a product for Priority Review if it treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness. The FDA determines, on a case-by-case basis, whether the proposed product represents a significant improvement when compared with other available therapies. Significant improvement may be illustrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment-limiting product reaction, documented enhancement of patient compliance that may lead to improvement in serious outcomes, and evidence of safety and effectiveness in a new subpopulation. A Priority Review designation is intended to direct overall attention and resources to the evaluation of such applications and to shorten the FDA’s goal for taking action on a marketing application from ten months to six months.

With passage of the Cures Act in December 2016, Congress authorized the FDA to accelerate review and approval of products designated as Regenerative Advanced Therapies. A product is eligible for this designation if it is a regenerative medicine therapy that is intended to treat, modify, reverse or cure a serious or life-threatening disease or condition and if preliminary clinical evidence indicateslater decide that the product hasno longer meets the potential to address unmet medical needsconditions for such diseasequalification or condition. The benefits of a Regenerative Advanced Therapy designation include early interactions with the FDA to expedite development and review, benefits available to breakthrough therapies, potential eligibility for Priority Review and accelerated approval based on surrogate or intermediate endpoints.

Accelerated Approval Pathway

The FDA may grant accelerated approval to a product for a serious or life-threatening condition that provides meaningful therapeutic advantage to patients over existing treatments based upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. The FDA may also grant accelerated approval for such a condition when the product has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, or IMM, and that is reasonably likely to predict an effect on IMM or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments. Products granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval.

For the purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit. Surrogate endpoints can often be measured more easily or more rapidly than clinical endpoints. An intermediate clinical endpoint is a measurement of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on IMM. The FDA has limited experience with accelerated approvals based on intermediate clinical endpoints but has indicated that such endpoints generally may support accelerated approval where the therapeutic effect measured by the endpoint is not itself a clinical benefit and basis for traditional approval, if there is a basis for concluding that the therapeutic effect is reasonably likely to predict the ultimate clinical benefit of a product.

The accelerated approval pathway is most often used in settings in which the course of a disease is long and an extended period of time is required to measure the intended clinical benefit of a product, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly. Thus, accelerated approval has been used extensively in the development and approval of products for treatment of a variety of cancers in which the goal of therapy is generally to improve survival or decrease morbidity and the duration of the typical disease course requires lengthy and sometimes large trials to demonstrate a clinical or survival benefit. Thus the benefit of accelerated approval derives from the potential to receive approval based on surrogate endpoints sooner than possible for trials with clinical or survival endpoints, rather than deriving from any explicit shortening of the FDA approval timeline, as is the case with priority review.

The accelerated approval pathway is usually contingent on a sponsor’s agreement to conduct, in a diligent manner, additional post-approval confirmatory studies to verify and describe the product’s clinical benefit. As a result, a product candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of Phase 4 or post-approval clinical trials to confirm the effect on the clinical endpoint. Failure to conduct required post-approval studies, or to confirm a clinical benefit during post-marketing studies, would allow the FDA to initiate expedited proceedings to withdraw approval of the product. All promotional materials for product candidates approved under accelerated regulations are subject to prior review by the FDA.

The FDA’s Decision on an NDA

After evaluating the application and all related information, including the advisory committee recommendations, if any, and inspection reports of manufacturing facilities and clinical trial sites, the FDA will issue either a Complete Response Letter, or CRL, or an approval letter.  To reach this determination, the FDA must determine that there is substantial evidence that the drug product is effective and that its expected benefits outweigh its potential risks to patients. This “benefit-risk” assessment is informed by the extensive body of evidence about the product’s safety and efficacy in the NDA.

A CRL generally outlines the deficiencies in the submission and may require substantial additional testing or information in order for the FDA to reconsider the application. If and when those deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the NDA, the FDA will issue an approval letter. The FDA has committed to reviewing such resubmissions in two or six months depending on the type of information included. Even with submission of this additional information, the FDA ultimately may decide that the application doestime period for FDA review or approval will not satisfy the regulatory criteria for approval. If a CRL is issued, the sponsorbe shortened.

Post-Approval Requirements

Any drug products manufactured or distributed by us or our partners pursuant to FDA approvals will have one yearbe subject to respond to the deficiencies identifiedpervasive and continuing regulation by the FDA, at which time the FDA can deem the application withdrawn or, in its discretion, grant the sponsor an additional six month extension to respond.

An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications. It may limit the approved indications for use of the product. The agency may also require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including, distribution restrictions or other risk management mechanisms, including a REMS, to help ensure that the benefits of the product outweigh the potential risks. REMS can include medication guides, communication plans for health care professionals, and elements to assure safe use, or ETASU. ETASU can include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring and the use of patent registries. The FDA may prevent or limit further marketing of a product based on the results of post-market studies or surveillance programs. After approval, many types of changes to the approved product, such as adding new indications, changes and additional labeling claims, are subject to further testing requirements and FDA review and approval.

Post-Approval Regulation

If regulatory approval for marketing of a product or new indication for an existing product is obtained, the sponsor will be required to comply with all regular post-approval regulatory requirements as well as any post-approval requirements that the FDA may have imposed as part of the approval process. The sponsor will be required to report, among other things, certainrecord-keeping requirements, reporting of adverse reactions and manufacturing problems toexperiences with the drug, providing the FDA providewith updated safety and efficacy information, drug sampling and complydistribution requirements, complying with certain electronic records and signature requirements concerningand complying with FDA promotion and advertising requirements. The FDA strictly regulates labeling, advertising, promotion and other types of information on products that are placed

on the market and imposes requirements and restrictions on drug manufacturers, such as those related to direct-to-consumer advertising, the prohibition on promoting products for uses or in patient populations that are not described in the product’s approved labeling, known as “off-label use,” industry-sponsored scientific and educational activities and promotional activities involving the internet. Although physicians may prescribe legally available drugs for off-label uses, manufacturers may not market or promote such uses. Prescription drug promotional materials must be submitted to the FDA in conjunction with their first use. Further, for certain types of modifications made to the drug, including changes in indications, labeling requirements. Manufacturersor manufacturing processes or facilities, the applicant may be required to submit and certainobtain FDA approval of their subcontractorsa new NDA or NDA supplement, which may require the development of additional data or preclinical studies and clinical trials.

Drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with ongoing regulatory requirements, including cGMP regulations which impose certain procedural and documentation requirements upon manufacturers.

A product may also be subject to official lot release, meaning that the manufacturer is required to perform certain tests on each lot of the product before it is released for distribution. If the product is subject to official release, the manufacturer must submit toother laws and regulations. In addition, the FDA samplesmay impose a number of each lot, together withpost-approval requirements as a release protocol showing a summarycondition of approval of an NDA. For example, the history of manufacture ofFDA may require post-marketing testing, including Phase 4 clinical trials, and surveillance to further assess and monitor the lotproduct’s safety and the results of all of the manufacturer’s tests performed on the lot. effectiveness after commercialization.

The FDA may also perform certain confirmatory testsplace other conditions on lotsapprovals including the requirement for REMS, to assure the safe use of some products before releasing the lotsproduct. A REMS could include medication guides, physician communication plans or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools. Any of these limitations on approval or marketing could restrict the commercial promotion, distribution, prescription or dispensing of products. Product approvals may be withdrawn for distribution. Finally, the FDA will conduct laboratory research related to the safety, purity, potency and effectiveness of pharmaceutical products.non-compliance with regulatory standards or if problems occur following initial marketing.

Once an approval is granted, the

The FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical trialsstudies to assess new safety risks;risks or imposition of distribution restrictions or other restrictions under a REMS program. Other potential consequences include, among other things:

The FDA strictly regulates the marketing, labeling, advertising and promotion of prescription drug products that are placed on the market. This regulation includes, among other things, standards and regulations for direct-to-consumer advertising, communications regarding unapproved uses, industry-sponsored scientific and educational activities, and promotional activities involving the Internet and social media. Promotional claims about a drug’s safety or effectiveness are prohibited before the drug is approved. After approval, a drug product generallyDrugs may not be promoted only for uses that are notthe approved byindications and in accordance with the provisions of the approved label. The FDA as reflected inand other agencies actively enforce the product’s prescribing information. In the United States, health care professionals are generally permitted to prescribe drugs for such uses not described in the drug’s labeling, known as off-label uses, because the FDA does not regulate the practice of medicine. However, FDAlaws and regulations impose rigorous restrictions on manufacturers’ communications, prohibiting the promotion of off-label uses. It may be permissible, under very specific, narrow conditions, foruses, and a manufacturer to engage in nonpromotional, non-misleading communication regarding off-label information, such as distributing scientific or medical journal information as part of bona fide scientific exchange. In September 2021, the FDA published final regulations which describe the types of evidencecompany that the agency will consider in determining the intended use of a drug product.

If a company is found to have improperly promoted off-label uses it may becomebe subject to adverse public relationssignificant liability.

Other U.S. Regulatory Matters

Pharmaceutical manufacturers are subject to various healthcare laws, regulation, and administrative and judicial enforcement by the FDA,federal government and by authorities in the Departmentstates and foreign jurisdictions in which they conduct their business. Our conduct, including that of Justice, or the Office of the Inspector General of the Department of Health and Human Services, or HHS,our employees, as well as state authorities. This could subject a company to a range of penalties that could have a significant commercial impact,our business operations and relationships with third parties, including civilcurrent and criminal finesfuture arrangements with healthcare providers, third- party payors, customers, and agreements that materially restrict the manner in which a company promotes or distributes drug products. The federal government has levied large civil and criminal fines against companies for alleged improper promotion, and has also requested that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.

Pediatric Exclusivity

The Best Pharmaceuticals for Children Act provides an incentive of additional marketing exclusivity in the United States to sponsors who voluntarily complete certain pediatric clinical studies. If granted, pediatric exclusivity provides for the attachment of an additional six months of regulatory exclusivity to the term of any patent or existing regulatory exclusivity, including the orphan drug exclusivity. This six-month exclusivityothers may be granted if an NDA sponsor submits pediatric data that fairly respond to a pediatric written request from the FDA for such data. The data do not need to show the product to be effective in the pediatric population studied; rather, if the clinical trial is deemed to fairly respond to the FDA’s request, the additional protection is granted. If reports of requested pediatric studies are submitted to and accepted by the FDA within the statutory time limits, whatever statutory or regulatory periods of exclusivity or patent protection cover the product are extended by six months.

Orphan Drug Designation and Exclusivity

Under the Orphan Drug Act, the FDA may designate a drug product as an “orphan drug” if it is intended to treat a rare disease or condition, generally meaning that it affects fewer than 200,000 individuals in the United States, or more in cases in which there is no reasonable expectation that the cost of developing and making a product available in the United States for treatment of the disease or condition will be recovered from sales of the product. A company must seek orphan drug designation before submitting an NDA for the candidate product. If the request is granted, the FDA will disclose the identity of the therapeutic agent and its potential use. Orphan drug designation does not shorten the PDUFA goal dates for the regulatory review and approval process, although it does convey certain advantages such as tax benefits and exemption from the PDUFA application fee.

If a product with orphan designation receives the first FDA approval for the disease or condition for which it has such designation or for a select indication or use within the rare disease or condition for which it was designated, the product generally will receive orphan drug exclusivity. Orphan drug exclusivity means that the FDA may not approve another sponsor’s marketing application for the same drug for the same condition for seven years, except in certain limited circumstances. Orphan exclusivity does not block the approval of a different product for the same rare disease or condition, nor does it block the approval of the same product for different conditions. If a drug designated as an orphan drug ultimately receives marketing approval for an indication broader than what was designated in its orphan drug application, it may not be entitled to exclusivity.

Orphan drug exclusivity will not bar approval of another product under certain circumstances, including if a subsequent product with the same drug for the same condition is shown to be clinically superior to the approved product on the basis of greater efficacy or safety, or providing a major contribution to patient care, or if the company with orphan drug exclusivity is not able to meet market demand. This is the case despite an earlier court opinion holding that the Orphan Drug Act unambiguously required the FDA to recognize orphan drug exclusivity regardless of a showing of clinical superiority.

In September 2021, the Court of Appeals for the 11th Circuit held that, for the purpose of determining the scope of market exclusivity, the term “same disease or condition” in the statute means the designated “rare disease or condition” and could not be interpreted by the FDA to mean the “indication or use.” Thus, the court concluded, orphan drug exclusivity applies to the entire designated disease or condition rather than the “indication or use.” It is unclear how this court decision will be implemented by the FDA.

Patent Term Restoration and Extension

A patent claiming a new drug product may be eligible for a limited patent term extension under the Hatch-Waxman Act, which permits a patent restoration of up to five years for patent term lost during product development and the FDA regulatory review. The restoration period granted on a patent covering a product is typically one-half the time between the effective date the IND for the clinical investigation and the submission date of an application, plus the time between the submission date of an application and the ultimate approval date. Patent term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s approval date. Only one patent applicable to an approved product is eligible for the extension, and the application for the extension must be submitted prior to the expiration of the patent in question. A patent that covers multiple products for which approval is sought can only be extended in connection with one of the approvals. The United States Patent and Trademark Office reviews and approves the application for any patent term extension or restoration in consultation with the FDA.

Health Care Law and Regulation

Health care providers and third-party payors play a primary role in the recommendation and prescription of drug products that are granted marketing approval. Arrangements with providers, consultants, third-party payors and customers are subjectexpose us to broadly applicable fraud and abuse anti-kickback, false claims laws, patient privacyand other healthcare laws and regulations, which may constrain the business or financial arrangements and other health carerelationships through which we research, as well as, sell, market, and distribute any products for which we obtain marketing approval. The applicable federal, state and foreign healthcare laws and regulations that may constrainaffect our ability to operate include, but are not limited to: