10-K

imra-10k_20201231.htm

10-K

imra-10k_20201231.htm

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2020

Commission File Number 001-39247

IMARA INC.

(Exact name of Registrant as specified in its charter)

116 Huntington Avenue, 6th Floor Boston, Massachusetts 02116

(Address of principal executive offices) (Zip Code)

Registrant’s telephone number, including area code: (617) 206-2020

Securities registered pursuant to Section 12(b) of the Act:

Title of each class Trading Symbol(s) Name of each exchange on which registered

Common stock, par value $0.001 per share IMRA The Nasdaq Stock Market LLC

Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes☐No☒

Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes☐No☒

Indicate by check mark whether the Registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the Registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes☒No☐

Indicate by check mark whether the Registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the Registrant was required to submit such files). Yes☒No☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer ☐ Accelerated filer ☐

Non-accelerated filer ☒ Smaller reporting company ☒

Emerging growth company ☒

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☐

Indicate by check mark whether the Registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes☐No☒

The aggregate market value of the voting and non-voting common equity held by non-affiliates of the Registrant, based on the closing price of the shares of common stock on the Nasdaq Global Select Market on June 30, 2020 was $190,476,799.

The number of shares of Registrant’s Common Stock outstanding as of March 1, 2021 was 17,575,248.

Table of Contents

Page

PART I

Item 1. Business 4

Item 1A. Risk Factors 49

Item 1B. Unresolved Staff Comments 95

Item 2. Properties 95

Item 3. Legal Proceedings 95

Item 4. Mine Safety Disclosures 95

PART II

Item 6. Selected Financial Data 96

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 107

Item 8. Financial Statements and Supplementary Data 107

Item 9A. Controls and Procedures 107

Item 9B. Other Information 108

PART III

Item 10. Directors, Executive Officers and Corporate Governance 109

Item 11. Executive Compensation 114

Item 14. Principal Accountant Fees and Services 134

PART IV

Item 15. Exhibits and Financial Statement Schedules 135

CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS AND INDUSTRY DATA

This Annual Report on Form 10-K contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, that involve substantial risks and uncertainties. All statements, other than statements of historical fact, contained in this Annual Report on Form 10-K, including statements regarding our strategy, future operations, future financial position, future revenue, projected costs, prospects, plans and objectives of management, are forward-looking statements. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “would,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.

The forward-looking statements in this Annual Report on Form 10-K include, among other things, statements about:

• the impact of the ongoing COVID-19 pandemic and our response to it;

• our commercialization, marketing and manufacturing capabilities and strategy;

• the impact of government laws and regulations;

We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. In addition, statements that “we believe” and similar statements reflect our beliefs and opinions on the relevant subject. These statements are based upon information available to us as of the date of this 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-looking 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, and you are cautioned not to give undue weight to such data. Industry publications and third-party research, surveys and studies generally indicate that their information has been obtained from sources believed to be reliable, although they do not guarantee the accuracy or completeness of such information. Our estimates of the potential market opportunities for our product candidates include several key assumptions based 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.

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.

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. Our pipeline is built on the differentiated therapeutic potential of our initial product candidate, IMR-687, which is an oral, once-a-day, potentially disease-modifying treatment for sickle cell disease, or SCD, and β-thalassemia. IMR-687 is a highly selective, potent small molecule inhibitor of phosphodiesterase-9, or PDE9, that has a multimodal mechanism of action that acts primarily on red blood cells, or RBCs, and has the potential to act on white blood cells, or WBCs, adhesion mediators and other cell types that are implicated in these disorders. We recently completed a Phase 2a clinical trial of IMR-687 in adult patients with SCD and are currently conducting an open label extension, or OLE, clinical trial, which allows patients from the Phase 2a clinical trial to continue into a long-term four-year trial to test safety and measure tolerability of IMR-687. In the second quarter of 2020, we initiated a Phase 2b clinical trial for the treatment of patients with SCD and a Phase 2b clinical trial for the treatment of patients with β-thalassemia. We are currently enrolling patients in each Phase 2b clinical trial and expect to report interim data from each of these trials in the second half of 2021. We continue to evaluate the impact of the COVID-19 pandemic on these Phase 2b clinical trials, and therefore, our estimated timelines for these clinical trials could be delayed. Our goal is to leverage IMR-687’s differentiated mechanism of action, its ease of administration and stable drug properties to potentially serve a broad range of patients suffering from hemoglobinopathies around the world, including those in underserved regions. In addition, we recently completed preclinical research of IMR-687 in heart failure with preserved ejection fraction, or HFpEF, and are developing a Phase 2 protocol to support potential future clinical development of IMR-687 in this indication.

Hemoglobinopathies are a diverse range of rare inherited genetic disorders in which there is abnormal production or absence of hemoglobin, the iron-containing protein in RBCs responsible for transporting oxygen in the blood. Hemoglobinopathies can be broadly categorized into two groups. The first group of hemoglobinopathies, which includes SCD, results from structural abnormalities in hemoglobin that cause RBCs to become inflexible and elongated, ultimately blocking blood flow to organs, which can lead to vaso-occlusive crises, or VOCs. SCD is characterized by debilitating pain, progressive multi-organ damage and early death. The second group of hemoglobinopathies, which includes β-thalassemia, results from decreased or absent production of hemoglobin, thereby producing smaller, paler RBCs that do not deliver adequate oxygen to vital tissues. β-thalassemia is often grouped into two subsets: patients who are non-transfusion dependent, or NTDT, or patients who are transfusion dependent, or TDT. If left untreated, β-thalassemia causes severe anemia, splenomegaly, skeletal abnormalities, organ failure and early death. Both groups of hemoglobinopathies share similar pathophysiology and have limited treatment options, which results in a significant unmet medical need for patients. The global prevalence of SCD and β-thalassemia are estimated to be approximately 4.4 million and 288,000 patients, respectively. SCD and β-thalassemia are both designated as rare diseases in the United States and the European Union. For SCD, prevalence is estimated to be approximately 100,000 patients in the United States and 134,000 patients in the European Union. For β-thalassemia, total combined prevalence in the United States and the European Union is estimated to be approximately 19,000 patients.

Our product candidate, IMR-687, is a highly selective and potent small molecule inhibitor of PDE9. PDE9 selectively degrades cyclic guanosine monophosphate, or cyclic GMP, an active signaling molecule that plays an important role in vascular biology. Lower levels of cyclic GMP 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 cyclic GMP levels, which is associated with reactivation of fetal hemoglobin, or HbF, a natural hemoglobin produced during fetal development. 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. Increasing cyclic GMP is associated with lower WBC activation and reduced adhesion across various cell types, both of which also contribute to SCD. Finally, activation of the nitric oxide-cyclic GMP pathway has been shown to induce red cell maturation and production, which are particularly relevant in treating β-thalassemia. We believe IMR-687 has several differentiating features that make it an optimal therapeutic for SCD and β-thalassemia, as supported by our preclinical data:

Managing hemoglobinopathies and their various clinical manifestations is complex and patients have had limited treatment options. In November 2019, the U.S. Food and Drug Administration, or FDA, approved OxbrytaTM (voxelotor) and Adakveo® (crizanlizumab) for the treatment of SCD, which are important milestones for patients with SCD as previously approved therapies for SCD all have significant limitations, including safety concerns, complex dosing regimens, variable response rates and potential adverse effects from long term use. We believe that IMR-687’s differentiated mechanism of action that seeks to increase HbF in patients with SCD, and the association between increases in HbF and reductions in disease risk, have the potential to provide IMR-687, if approved, with competitive advantages over Oxbryta, where the correlation between increases in hemoglobin and disease risk is being tested in a post-approval confirmatory trial, and Adakveo, which is administered intravenously and does not target RBC sickling.

There are no currently approved oral therapies for β-thalassemia; however, in November 2019, the FDA approved REBLOZYLTM (luspatercept-aamt), which is dosed subcutaneously, for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions. Blood transfusions are used to treat both SCD and β-thalassemia, but are suboptimal due to limited patient access and potential serious complications that include iron overload, adverse immune response and transmission of transfusion-associated infections. Allogeneic hematopoietic stem cell transplant, or HSCT, is a potentially curative treatment for both disorders, but is rarely used due to the difficulty in finding a matched donor and an approximately 5% mortality rate. More recent approaches to treating both disorders are emerging, such as gene therapy and gene editing, with promising early clinical data being observed in each. These approaches, however, are complex, costly, difficult to administer and potentially only suitable for a limited subset of patients.

Based on promising preclinical data and data from a Phase 1 clinical trial of IMR-687 in healthy volunteers, in 2018 we initiated our Phase 2a randomized, double-blinded, placebo-controlled clinical trial of IMR-687 in adult patients with SCD. The goals of this trial were to evaluate the safety, tolerability, pharmacokinetics, or PK, exploratory pharmacodynamics, or PD, and clinical outcomes of IMR-687 administered once daily for 16 or 24 weeks in two populations of patients with SCD: one on monotherapy IMR-687 and one on background hydroxyurea, or HU, in combination with IMR-687 to test drug-drug interaction.

In January 2021, we reported final results from the Phase 2a clinical trial. The results showed a lower rate of vaso-occlusive crises/sickle cell-related pain crises, or VOCs/SCPCs, as part of the safety analysis, and VOC-related hospitalizations in specified monotherapy IMR-687 treated patients, as compared to placebo. Changes in HbF and F-cells varied across patient populations in the clinical trial. The results further showed IMR-687 was well tolerated as a monotherapy and in combination with HU.

We are also conducting an OLE clinical trial, which allows patients from the Phase 2a trial to continue into a long-term, four-year trial to evaluate safety and tolerability of IMR-687. A review of approximately 12 patients with evaluable PD biomarker data for at least four months of treatment on the OLE clinical trial as of December 31, 2020, demonstrated increases in both HbF and F-cells and minimal changes in total hemoglobin.

In the second quarter of 2020, we initiated a Phase 2b clinical trial of IMR-687 in adult patients with SCD and a Phase 2b clinical trial of IMR-687 in adult patients with ß-thalassemia. We are currently enrolling patients in each trial and expect to report interim data from each of these trials in the second half of 2021. Based on the supportive safety and PK data from the Phase 2a interim analyses, we designed the Phase 2b clinical trials to evaluate higher doses, longer treatment periods, and additional clinical endpoints as compared to the Phase 2a clinical trial.

In addition to our clinical programs with IMR-687 in patients with SCD and β-thalassemia, in the second quarter of 2020, we commenced preclinical development of IMR-687 in HFpEF. Published literature suggests that the inhibition of PDE9, and resulting increases in cyclic GMP through natriuretic peptide modulation, can serve as an attractive target for the prevention and treatment of vascular disease, including HFpEF. An exploratory analysis co-led by Vanderbilt University Medical Center, or VUMC, on data from the second interim analysis from our Phase 2a clinical trial of IMR-687 demonstrated the potential of IMR-687 to reduce N-terminal pro-B-type natriuretic peptide, or NT-proBNP, a well-established biomarker of cardiovascular risk in patients with SCD. In April 2020, we entered into an agreement with the Necker Institute of Paris, France to conduct preclinical studies with IMR-687 in HFpEF. The preclinical data from three established mouse models for HFpEF suggest potential benefits of IMR-687 across several relevant cardiac biomarkers. We are collaborating with VUMC and have engaged additional key opinion leaders in heart failure, with the aim of developing a Phase 2 protocol to support potential future clinical development of IMR-687 in this indication.

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 for the treatment of hemoglobinopathies. 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.

There are several genetic variations of SCD, including:

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 and 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. We believe that the protective aspects of naturally occurring HbF supports the development of therapies that induce HbF as a means to treat SCD.

The image below depicts how RBCs can change shape in low oxygen environments. In healthy individuals, there is no change to the hemoglobin organization or RBC structure. In SCD, hydrophobic interactions with the hemoglobin subunits lead to polymerization and cause RBC distortion. In cells with reactivated HbF, polymerization is avoided because HbF reduces the ability of mutated hemoglobin to polymerize.

Reactivation of HbF occurs in immature RBCs, known as erythroblasts and reticulocytes. These cells are found in the bone marrow and have the cellular machinery to produce HbF. Once HbF is induced in nascent RBCs, they eventually grow into mature RBCs that contain HbF. Mature RBCs that are already in circulation are not viable targets for HbF induction because they do not contain DNA. Over time, these mature RBCs without HbF die out and are replaced by newly mature RBCs that contain HbF, further increasing the population of HbF containing RBCs. This time course can be up to 120 days, which is the lifespan of a normal RBC, or substantially shorter, as sickled RBCs live for only eight to 40 days. Therapies that increase HbF must focus on immature RBCs to ensure HbF is increasingly part of the mature and circulating RBC population.

Measuring the reactivation of HbF is accomplished in two interrelated ways. The first assay confirms if an RBC contains HbF, in which case it is known as an F-cell. We believe that measurements of the percentage of F-cells relative to total RBCs, which we refer to as %F-cells, establish whether a therapy is reactivating HbF production. The second assay quantifies the amount of HbF across RBCs, expressed as a percentage of total hemoglobin, or HbF%. Increasing HbF% is key to addressing SCD disease pathology and ultimately drives the improved hemoglobin-oxygen affinity. As illustrated in the graphic below, which is based on data from 242 pediatric patients with SCD across various genotypes, the relationship between %F-cells and HbF% is exponentially correlated in that linear increases in %F-cells yield multi-fold increases in HbF%.

Relationship Between %F-cells and HbF%

While %F-cells increases are important measurements, absolute increases in HbF% ultimately drive reduction in disease risk. We commissioned a third-party to perform a systematic literature review and series of quantitative meta-analyses to identify evidence for clinical outcomes associated with HbF% in patients with SCD. Statistically significant associations between HbF% and clinical outcomes in SCD were found for the following: mortality, stroke, acute chest syndrome, pain, blood transfusion, retinopathy and splenomegaly. The figure below shows how absolute increases in HbF% are associated with reduced disease risk across several of these parameters.

Association Between Increases in HbF% and Disease Risk

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 and clinical pathology. The following image describes the role of each of these cells and how they may be implicated in SCD.

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. These include P-selectin, E-selectin, vascular cell adhesion molecule 1, or VCAM-1, and intercellular adhesion molecule 1, or ICAM-1.

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 adults and children 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. The accelerated approval of Oxbryta was based on clinically meaningful and statistically significant improvements in hemoglobin levels, accompanied by reductions in red blood cell destruction, known as hemolysis. 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 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.

While these two approvals are important milestones for patients with SCD, we believe that there remains a significant unmet need for SCD therapies. Oxbryta was approved 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: HU and L-glutamine (marketed as Endari). 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. In the seminal trial for HU that led to its approval, patients on average saw increased HbF induction of 3.2% over a two-year treatment period, which resulted in improved clinical outcomes, such as reduction of acute chest syndrome. Despite these benefits, HU remains a suboptimal therapy for several reasons:

Due to HU’s various limitations, only approximately 30% and 22% of patients with SCD in the United States and certain countries in Europe, respectively, are treated with HU. Of those patients treated with HU in the United States, approximately 50% discontinue use within six months.

Endari, an oral powder form of L-glutamine, was approved by the FDA in 2017, becoming the first new FDA-approved treatment for SCD in nearly 20 years. 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. 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: Oxbryta is 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: In addition to IMR-687, several other novel HbF inducers are in clinical development. Fulcrum Therapeutics, Inc. is in Phase 1 clinical development of FTX-6058, a small molecule embryonic ectoderm development inhibitor designed to induce expression of HbF. Novo Nordisk A/S (in collaboration with EpiDestiny, Inc.) is in Phase 1 clinical development of EPI-01, a DNA methyltransferase inhibitor.

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 (and potentially ß-thalassemia). Agios Pharmaceuticals, Inc. is developing mitapivat (AG-348), which is in Phase 1/2 clinical development, and Forma Therapeutics, Inc. is developing FT-4202, which is in Phase 3 clinical development.

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. is developing inclacumab, a specific P-selectin inhibitor that was previously under development for non-SCD indications. In preclinical studies, inclacumab demonstrated longer duration of exposure and greater inhibition of platelet-leukocyte aggregation as compared to Adakveo, which may create the potential for quarterly dosing, but inclacumab has yet to be tested in SCD patients (although Global Blood Therapeutics has reported that a Phase 3 clinical trial is planned for 2021).

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. Recent data from a gene therapy trial indicated that chemotherapeutic pre-treatment resulted in a patient with SCD developing myelodysplastic syndrome, where the blood-forming cells in the bone marrow become abnormal. bluebird bio, Inc. and Aruvant Sciences, Inc. are each developing gene therapies which aim to deliver a functional copy of the human beta-globin gene (LentiGlobin, which is in Phase 3 clinical development, and ARU-1801, which is in Phase 2 clinical development, respectively). 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 Phase 2 clinical development by CRISPR Therapeutics AG (in collaboration with Vertex Pharmaceuticals, Incorporated), BIVV-003, currently in Phase 1/2 clinical development by Sangamo Therapeutics, Inc. (in collaboration with Sanofi), and OTQ923, currently in Phase 1/2 clinical development by Intellia Therapeutics, Inc. (in collaboration with Novartis). 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

IMR-687 is being developed to inhibit PDE9. PDE9 decreases cyclic GMP, an active signaling molecule that plays an important role in vascular biology. Lower levels of cyclic GMP, as found in patients with SCD, are associated with reduced blood flow, increased inflammation, greater cell adhesion and reduced nitric oxide mediated vasodilation. The figure below illustrates the role of PDE9 inhibition and its potential benefits on SCD pathophysiology. Nitric oxide, a chemical that supports blood vessel health, drives increases in a broadly expressed enzyme, soluble guanyl cyclase, or sGC, which drives the conversion of Guanosine-5’-triphosphate, or GTP, into cyclic GMP. Cyclic GMP levels are decreased by the PDE9 enzyme, which actively converts cyclic GMP to GMP. Increasing cyclic GMP by inhibiting PDE9 has several potential advantageous downstream impacts, including to increase HbF, reduce cell adhesion, decrease WBC activation and ultimately increase nitric oxide levels.

Novel cyclic GMP Degrader: PDE9 belongs to a family of 11 cyclic nucleotide phosphodiesterases, or PDEs. In general, PDEs degrade both cyclic GMP and cyclic adenosine monophosphate, or cAMP. However, PDE9 solely degrades cyclic GMP, has the highest affinity for cyclic GMP of all PDEs, and does not degrade cAMP. Inhibiting PDE9 offers a novel way to increase cyclic GMP levels by limiting cyclic GMP degradation. We believe that other approaches that increase cyclic GMP levels without addressing its degradation, such as HU, are unlikely to confer persistent and robust increases in cyclic GMP. Conversely, preventing degradation of cyclic GMP by targeting PDE9 may enable long-term benefits that include sustained HbF induction, reduced activation of WBCs, positive effects on other cell types and reduced cell adhesion.

High Expression in SCD Cells of Interest: 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. A potential drawback of inhibiting PDE9 for the treatment of SCD is that PDE9 is also highly expressed in the brain, which in part explains why PDE9 inhibitors have been extensively studied in neurodegenerative diseases. While several PDE9 inhibitors have been shown to be well-tolerated in adults, preclinical data suggests that brain penetrant PDE9 inhibition causes mice to have changes in fear response, which may reflect memory impairment. This could be concerning in pediatric patients with SCD who continue to have ongoing brain development. Thus, any PDE9 inhibitor broadly targeting SCD should minimally cross the blood-brain barrier.

Multimodal Method of Action: In preclinical studies, PDE9 inhibitors have been shown to increase cyclic GMP concentrations, induce HbF and F-cells, reduce WBC activation and adhesion across other cell types and modulate adhesion mediators. A brain penetrant PDE9 inhibitor developed by Bayer known as BAY73-6691, which was originally developed for the treatment of neurodegenerative diseases, was observed to increase cyclic GMP and HbF transcription in a representative human cell line for SCD. Furthermore, BAY73-6691 was observed to reduce WBC activation and adhesion to endothelial cells in patient-derived WBCs, however development was subsequently discontinued and we are not aware of any further development of this compound. Another brain penetrant PDE9 inhibitor developed by Pfizer known as PF-04447943

was originally developed for Alzheimer’s disease and tested in patients with SCD. In Pfizer’s Phase 1b clinical trial in patients with SCD, there were some reductions in adhesion markers but no significant HbF induction was observed. Development of PF-04447943 was subsequently discontinued and we are not aware of any further development of this compound.

Our Solution for Sickle Cell Disease: IMR-687 as a Differentiated PDE9 Inhibitor

Our approach to address SCD is fundamentally distinct from other therapies. IMR-687 is being developed to directly and potently inhibit PDE9, which represents a differentiated approach to increase cyclic GMP levels, with a selectivity for PDE9 that we believe will make it amenable for long-term use. We recently completed a Phase 2a randomized, double blinded, placebo-controlled clinical trial of IMR-687 in adult patients with SCD and we are currently conducting a Phase 2b clinical trial in this patient population. We believe IMR-687 may have advantages over other therapies, including speed of onset of HbF induction, a multimodal approach and a once daily dosing regimen. In addition, IMR-687 has 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 IMR-687 has several differentiating features relative to other PDE9 inhibitors:

Highly Potent PDE9 Inhibitor: IMR-687 is a highly potent PDE9 inhibitor, as measured by induction of cyclic GMP across various doses. We have specifically studied the potency of PDE9 inhibition of IMR-687 as compared to HU and analogues of BAY73-6691 and PF-04447943 by analyzing cyclic GMP levels across various doses in an in vitro assay. We studied analogues of BAY73-6691 and PF-04447943 because BAY73-6691 and PF-04447943 are proprietary compounds to which we did not have direct access. The analogues we used were based on the well-defined crystal structures of BAY73-6691 and PF-04447943 that are publicly available in published patent filings. When compared to these agents, IMR-687 was observed to be more potent across all dose groups.

Differentiated Selectivity and Tolerability Profile: IMR-687 is a highly selective PDE9 inhibitor. We compared the selectivity of IMR-687 and an analog of PF-04447943 against a panel of related PDEs. We chose not to test BAY73-6691 or an analog thereof because BAY73-6691’s lack of potency led us to conclude there was little merit to further testing. For the isoform PDE9A1, IMR-687 was observed to be more than eight times more selective than the PF-04447943 analog and for the isoform PDE9A2, IMR-687 was observed to be more than four times more selective than the same compound. Isoforms are functionally similar proteins within each PDE family that have slightly different genetic coding. We believe the selectivity of IMR-687 will allow us to optimize dose while minimizing off-target effects. IMR-687 has exhibited lower interaction with other PDE family members compared to the PF-04447943 analog, or did not have measurable inhibition.

We also conducted toxicology studies of IMR-687. In a 26-week female rat infertility study and in early embryonic development studies, once-daily dosing of IMR-687 was observed to be well tolerated with no effects on fertility or embryonic development at any dose level studied. In addition to standard adult animal toxicology studies, a juvenile rat study was completed where once daily administration of IMR-687 was observed to be well tolerated with no indication of toxicity.

Minimal Brain Penetration: We are developing IMR-687 specifically because it was observed to have low brain penetration in animal models. We believe this will reduce the potential impact of PDE9 inhibition on central nervous system, or CNS, development and function. Historically, most early PDE9 inhibitors were developed for potential CNS indications and thus were specifically designed to cross the blood-brain barrier. We observed in a mouse model that while plasma concentrations were similar, brain exposure to levels of IMR-687 were observed to be five times lower than those seen with the PF-04447943 analog at 10mg/kg.

Additionally, IMR-687 showed no effect on locomotor activity or in a classical fear conditioning mouse model of learning and memory. In contrast, the brain penetrant PF-04447943 analog was observed to significantly increase conditioned fear responses in mice at an equivalent dose.

Drug Product Stability: IMR-687 has been observed to exhibit a durable shelf life at both standard and elevated room temperature and humidity conditions. For example, at standard room temperature and humidity conditions, we have observed consistent stability results at doses of 50 mg, 100 mg, and 200 mg at the 24-month time point. In addition, we have observed consistent stability results under accelerated stress conditions that mimic the high heat (40° Celsius, 104° Fahrenheit) and increased humidity (75%) of the tropics. We believe this observed stability of IMR-687 provides us with a potential opportunity to treat patients in areas where other treatments may not be accessible, including in the tropical climates where SCD and β-thalassemia are endemic.

Preclinical and Phase 1 Data

In preclinical SCD models, we observed that IMR-687 is a potent cyclic GMP inducer and had a multimodal mechanism of action, acting to increase RBC HbF expression, reduce RBC sickling and decrease expression of WBC adhesion molecules.

In an SCD in vitro model, we measured the ability of IMR-687 to increase cyclic GMP levels in an RBC cell line as compared to HU. In this study, we observed that IMR-687 induced cyclic GMP 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 IMR-687, we observed an approximately ten-fold increase in cyclic GMP levels as compared to HU. We also evaluated IMR-687 in a mouse model of SCD that expresses human sickle hemoglobin. We observed that IMR-687 demonstrated statistically significant increases in HbF-positive RBCs, statistically significant decreases in the percentage of sickled RBCs and decreases in markers of hemolysis, or destruction of RBCs, and WBC adhesion.

In our Phase 1 randomized, double-blind, placebo-controlled clinical trial in healthy volunteers, single and multiple ascending doses of IMR-687 were reported to be well tolerated to a maximum dose of 4.5 mg/kg per day and no serious adverse events were reported.

IMR-SCD-102: SCD Phase 2a Clinical Trial

Our Phase 2a clinical trial was a randomized, double-blind, placebo-controlled clinical trial in adult patients with the HbSS and HbS/ß-0 thalassemia genotypes of SCD and was conducted at clinical centers in the United States and the United Kingdom. The trial evaluated the safety, tolerability, PK and exploratory PD and clinical outcomes of IMR-687 in two groups of SCD patients: patients receiving IMR-687 administered as a monotherapy agent once daily for 24 weeks and patients receiving IMR-687 administered at lower doses in combination with HU for 16 weeks. The design of the Phase 2a trial separated out the monotherapy and combination arms into separate sub-studies. The combination sub-study was purposefully designed in consultation with the FDA, taking into account HU and IMR-687’s overlap in the nitric oxide-cyclic GMP pathway, which ultimately drives cyclic GMP expression. This low-dose, short duration sub-study was thus created to test how the two drugs interact when dosed in combination. Patients in the combination sub-study were required to have been receiving HU for at least 60 days prior to screening and then continue to receive the same dose of HU throughout the duration of the trial. A total of 93 patients were dosed in the trial, of which 58 patients were dosed in the monotherapy sub-study and 35 patients were dosed in the combination sub-study.

We initially commenced the monotherapy sub-study with patients receiving IMR-687 at doses of 50 mg or 100 mg through 12 weeks and then escalating to higher doses of 100 mg or 200 mg, respectively, through 24 weeks if approved by the Safety Review Committee, or SRC, after review of vital signs and treatment emergent adverse events, or TEAEs. After dosing 40 monotherapy patients (referred to as Pop A), in the second quarter of 2019 we amended the trial protocol for the monotherapy sub-study to (i) accelerate the time of dose escalation for the 100 mg/200 mg dose group from week 13 to the end of the first month, (ii) allow for patients to be administered the higher dose for five months instead of three months and (iii) eliminate the 50 mg/100 mg dose group. Following the amendment of the protocol, we dosed a further 18 patients (referred to as Pop A1) in the monotherapy sub-study. All patients in the monotherapy sub-study who were dosed with placebo continued to receive placebo for the duration of the trial.

We initially commenced the combination sub-study with patients receiving IMR-687 at an initial dose of 50 mg on top of a stable dose of HU, with escalation after one month to 100 mg for the remaining portion of the trial (through week 16) upon SRC approval. After dosing 21 combination patients (referred to as Pop B), in the second quarter of 2019, we amended the trial protocol for the combination sub-study to extended dosing for an additional month. Following the amendment of the protocol, we dosed a further 14 patients (referred to as Pop B1) in the combination sub-study. All patients in the combination sub-study who were dosed with placebo continued to receive placebo for the duration of the trial. The design of the Pop A/A1 and B/B1 sub-studies are shown in the graphics below.

We conducted two planned interim analyses of data from our Phase 2a clinical trial as described below.

November 2018 Interim Analysis

The first interim analysis was blinded at the individual patient level and consisted of an evaluation of low dose IMR-687 in at least 18 patients that had completed one month of treatment in the Pop A monotherapy sub-study and was carried out as pre-specified in the protocol. The data cut-off for this interim analysis was October 8, 2018. At 13 weeks, we observed an increase of approximately 110% from baseline in the percentage of F-cells in the group receiving 100 mg of IMR-687 as monotherapy. We also observed decreases in absolute reticulocytes and percent reticulocytes in the 100 mg IMR-687 monotherapy group. The data for WBC and adhesion markers were inconclusive. Blinded safety and tolerability data as of the data cutoff date showed that treatment with IMR-687 was reported to be generally well tolerated, with no clinically significant changes in WBC counts and no evidence of neutropenia.

August 2019 Interim Analysis

The second interim analysis was triggered when at least 18 patients completed the 24 weeks of dosing in this trial in the Pop A monotherapy sub-study and had a cut-off date of July 8, 2019. Patients in the Pop B combination sub-study were evaluated for the first time to measure safety and PK related to HU being dosed in combination with IMR-687. In the second interim analysis, IMR-687 was generally reported to be well tolerated across all doses in the monotherapy and combination sub-studies.

All Comers Analysis (n=37)

The first analysis involved all Pop A monotherapy patients, regardless of where they were in the trial, referred to as all comers. We observed a statistically significant (p=0.022) increase in F-cells for the IMR-687 high dose cohort (100 mg/200 mg) compared to placebo after 24 weeks of dosing. We observed a relative increase in F-cell percentage of 18.1 percentage points, with the mean values for the absolute percentage of F-cells observed in patients increasing from 13.6% to 31.7%. We observed a mean absolute increase in HbF% of 1.7 percentage points in the IMR-687 high dose cohort (100 mg/200 mg) after 24 weeks of dosing. Patients in the IMR-687 high dose cohort had a mean baseline HbF% of 6.7%, which increased to 8.4% after 24 weeks of dosing.

In addition, we observed a mean increase in mean corpuscular volume of 4.3 femtoliters in the IMR-687 high dose cohort. While we saw individual changes in other related downstream RBC biomarkers (including variable responses in reticulocytes, LDH, indirect bilirubin and hemoglobin) and white cell adhesion biomarkers (including sP-selectin, sE-selectin, iVCAM-1 and iCAM-1), we did not see consistent trends across the mean values.

Completer Analysis (n = 18)

The second analysis was a pre-specified protocol-driven analysis of the efficacy parameters for the 18 completers. For the measurements of F-cells, 100% of completers showed an increase in F-cells and no completer saw a decrease in F-cells in the high dose arm (100 mg/200 mg). While there was more variability in the lower dose arm (50 mg/100 mg), most completers saw F-cell increases, though they did not have the magnitude of increases as observed for the higher dose (100 mg/200 mg). Placebo completers, as expected, showed the most variability in changes in F-cells, with 50% showing increases in F-cells and 50% showing decreases, netting out to an overall slight decrease in F-cells. These data allowed us to create a relevant PK/PD model to potentially provide greater understanding of how dose impacts efficacy markers, including F-cells and HbF%.

Pharmacokinetics (PK) Summary

PK data from the monotherapy sub-study were analyzed to compare IMR-687 exposure for patients in the Phase 2a trial to exposure observed in preclinical studies and in healthy volunteers in the multiple ascending dose stage of our Phase 1 trial, in each case through an analysis of Area Under the Curve0-24, or AUC0-24, which measures drug concentration in blood plasma over the first 24 hours following dosing. As shown in the far-left column of the figure below, a preclinical female dog model established a No Observed Adverse Effect Level, or NOAEL, which is the highest experimental point that does not have adverse effects, of 90,239 hours x ng/mL, or h x ng/mL. As shown in the second-from-left column of the figure below, the 6 mg/kg highest dose in the fasted single ascending dose stage of our Phase 1 trial resulted in a mean exposure of 31,000 h x ng/mL. As shown in the set of middle columns of the figure below, exposure in the fed multiple ascending dose stage of the trial ranged from 5,630 h x ng/mL at a dose of 1 mg/kg to 23,930 h x ng/mL at a dose of 4.5 mg/kg, which was the maximum tolerated dose, or MTD. As shown in the far-right columns of the figure below, mean exposure in the interim analysis of the Phase 2a trial ranged from 2,880 h x ng/mL at the 50 mg dose to 16,300 h x ng/mL at the 200 mg dose. Also as reflected in the far-right columns in the figure below, we generated a PK model based on these values that predicted exposure of 21,976 h x ng/mL and 32,000 h x ng/mL for possible future higher doses of 300 mg and 400 mg, respectively. The observed mean exposure for 200 mg dosing of IMR-687 in the interim analysis of the Phase 2a trial and the predicted exposure for 300 mg dosing of IMR-687 are below the mean exposure at the 4.5 mg/kg MTD in the multiple ascending dose stage of our Phase 1 trial and are less than 25% of the NOAEL observed in preclinical dog experiments. While the predicted exposure for 400 mg dosing of IMR-687 surpasses the mean exposure at the 4.5mg/kg MTD in the multiple ascending dose stage of our Phase 1 trial, it is substantially lower than the established female dog NOAEL. We believe the exposure data we have observed to date and the exposure data predicted by our PK modeling support our decision to increase dosage to 300 mg, and potentially 400mg, in our ongoing Phase 2b clinical trial in SCD.

The second interim analysis also included analyses of additional PK exposure metrics from the monotherapy sub-study, including Cmax values, which are the peak concentrations achieved by a drug, and concentrations of a drug after 24 hours, or C24 values. The C24 parameter provides an understanding of target coverage over a 24-hour period and is particularly

important when matched with the measure of inhibitory concentrations above 90%, or IC90. We estimated an IC90 value of 160 ng/mL for IMR-687 from the in vitro dose-response curve using IMR-687 in combination with the isolated PDE9 enzyme. Patients in the 50 mg/100 mg group of the monotherapy sub-study were, on average, above this estimated IC90 for approximately six to 12 hours, depending on dose, and patients in the 100 mg/200 mg group were, on average, above this estimated IC90 for approximately 12 to 17 hours, depending on dose. Our PK modeling predicts that a 300 mg dose of IMR-687 will result in concentrations above the estimated IC90 for approximately 22 hours and a 400 mg dose will result in concentrations above the estimated IC90 for over 24 hours. In addition, the Cmax and C24 levels observed for 200 mg dosing and predicted for 300 mg dosing of IMR-687 were below those observed at the 4.5 mg/kg MTD dose in the multiple ascending dose stage of our Phase 1 trial. Our PK modeling predicts that the Cmax and C24 levels for 400 mg dosing of IMR-687 will be higher than those observed at the 4.5 mg/kg MTD in the multiple ascending dose stage of the Phase 1 trial.

Examination of the of the PK for the combination of IMR-687 + HU as compared to HU alone was the key objective for the combination sub-study of the Phase 2a trial and was recommended by the FDA in our pre-IND discussions. We measured HU PK on its own prior to the commencement of combination dosing as well as HU PK following the commencement of combination dosing at weeks five and 17. The PK data in the second interim analysis indicated that treatment with IMR-687 + HU did not result in changes in the HU PK observed prior to combination dosing and that there were no drug-drug interactions between IMR-687 and HU, which we believe supports our use of higher doses of IMR-687 in combination with HU in our Phase 2b clinical trial of IMR-687 in SCD. These findings also allowed us to combine monotherapy and combination dosing into a single trial population for our ongoing Phase 2b clinical trial of IMR-687 in SCD.

PK/PD Modeling with Completer Data

Noncompartmental PK results were combined with the completer data from the second interim analysis to establish PK/PD correlations for use in connection with our Phase 2b trials. There were two key correlations that helped us better understand HbF response in light of the PK data. The first of these was the correlation between F-cell response data and PK data. We defined responders as patients that had a ≥7% increase from baseline, which included all patients from the 100 mg/200 mg dose group and one patient from the 50 mg/100 mg dose group (total n=6). PK/PD analysis showed that completers that responded to IMR-687 had both higher median AUC0-24 and Cmax values with respect to IMR-687 as compared to completer non-responders. Although the median C24 values were similar for all completers, the 25th and 75th percentile values were higher for responders.

The second correlation we examined was between HbF response data and PK data. We defined responders as patients that had a ≥1% absolute increase in HbF from baseline, which included three patients from the 100 mg/200 mg dose group and one patient from the 50 mg/100 mg dose group (n =4). Similar to what we observed in our analysis of the F-cell data, PK/PD analysis showed that completers that responded to IMR-687 had higher median AUC0-24 levels as compared to non-responders. While the median C24 and Cmax values were similar for all completers, the 25th and 75th percentile values for C24 were higher for responders.

Future dose modeling predicts that exposure in AUC0-24, Cmax and C24 for IMR-687 should increase with dose levels above 200 mg and should achieve drug concentration levels above the estimated IC90 for approximately 22 hours at a 300 mg dose and over 24 hours at a 400 mg dose. We believe this PK/PD modeling further justifies our evaluation of higher doses of IMR-687 in our Phase 2b clinical trials.

January 2021 Topline Results

In January 2021, we disclosed topline results of the Phase 2a clinical trial, which are summarized below. We are continuing to conduct additional analyses with respect to this data, including final PK data, and expect to report results from these additional analyses at a future medical meeting in 2021.

As described above, in the second quarter of 2019 we amended the trial protocol for the monotherapy sub-study to create Pop A1, which was comprised of patients who received either placebo or IMR-687 at a once-daily dose of 100 mg through 4 weeks and then 200 mg for an additional 20 weeks (24 weeks total). At the same time, we amended the trial protocol for the combination sub-study to create Pop B1, which was comprised of patients who received either placebo or IMR-687 once-daily at 50 mg on top of a stable dose of standard of care HU, with escalation after 4 weeks to 100 mg for an additional 20 weeks (24 weeks total). None of the patients enrolled in Pop A1 or Pop B1 were included as part of the August 2019 interim analysis described above.

Summary of Safety and Tolerability Data

Overall, the data demonstrated that IMR-687 was well tolerated as a monotherapy and in combination with HU at all dose levels. In the monotherapy sub-studies (Pop A and Pop A1), the most frequent adverse events in the IMR-687 treatment arm included sickle cell anemia with crisis, nausea, headache and back pain. In the combination sub-studies (Pop B and Pop B1), the most frequent adverse events in the IMR-687 + HU treatment arm included headache, sickle cell anemia with crisis, nausea, fatigue and ocular icterus. There were no observed clinically significant shifts in vital signs or electrocardiogram data, including no hypotension or neutropenia in either the monotherapy or combination arms.

A 30% lower rate of VOCs/SCPCs, as part of the safety analysis, was observed in the Pop A1 IMR-687 treatment group when compared to placebo. 58% of patients (7 of 12 patients, 9 events total) experienced at least one VOC/SCPC in the Pop A1 IMR-687 treatment group as compared to 83% (5 of 6 patients, 14 events total) in the placebo population. Furthermore, the rate of VOC-related hospitalizations was lower in the Pop A1 IMR-687 treatment group when compared to placebo. 33% of patients (4 of 12) experienced one VOC-related hospitalization in the Pop A1 IMR-687 treatment group as compared to 66% (4 of 6) in the placebo population. There were no meaningful differences in VOCs/SCPCs or VOC related hospitalizations, between the Pop B1 IMR-687 + HU and HU + placebo groups.

Population A1 Monotherapy (n=18)

Biomarker results showed minimal changes in F-cells, HbF levels and total Hb levels from baseline through week 24. However, a dose-dependent increase in HbF (1.3% absolute increase) was seen when patients dose escalated from 100 mg to 200 mg, starting after 4 weeks (n=10) and through 24 weeks (n=7). One of seven evaluable patients (14%) in Pop A1 recorded an absolute increase in HbF percentage from baseline of greater than 1% (increase of 3.2%). Placebo patients from Pop A1 did not have evaluable week 24 PD biomarker results due in part to missing study visits and are therefore not included in the table below. Biomarkers related to hemoglobin, hemolysis, inflammation, and cardiac stress are summarized below for the IMR-687 treatment arm:

Parameter Baseline Value (n=12)* Week 24 Value (n=7)* Percent Difference

HbF percentage (%) 8.8 8.7 -1.1%

Markers of Hemolysis

Percent reticulocytes (%) 10.4 7.4 -28.8%

Markers of Inflammation & Cardiac Stress

* With respect to F-cell percentage, n=9 at baseline and n=6 at Week 24.

Population B1 Combination Therapy (n=14)

Biomarker results in IMR-687+HU treated patients showed an overall increase in F-cells and HbF levels from baseline to week 24, while Hb levels did not meaningfully change. Three of the eight evaluable patients (33%) had absolute increases in HbF percentage of greater than 1%, with a mean absolute increase in HbF percentage of 4.3% in that subset of patients. There was a single placebo patient from Pop B1, as other patients did not have evaluable week 24 pharmacodynamics biomarker data due in part to missing study visits. Therefore, this single patient is not included in the table below.

Biomarkers related to hemoglobin, hemolysis, inflammation, and cardiac stress are summarized below for the IMR-687+HU treatment arm:

Parameter Baseline Value (n=10)* Week 24 Value (n=8)* Percent Difference

Markers of Hemolysis

Indirect bilirubin (μmol/L) 34.9 37.9 8.6%

Markers of Inflammation & Cardiac Stress

* With respect to F-cell percentage, n=8 at baseline and n=7 at Week 24.

Population A Monotherapy (n=40)

Subsequent to the August 2019 interim analysis described above, four additional patients completed 24 weeks of dosing in the Pop A monotherapy arm. A completers analysis in this group showed that the high dose of IMR-687 (100 mg/200 mg) resulted in an absolute increase in F-cell percentage of 13.3% from baseline (p=0.025) and a mean absolute increase in HbF percentage from baseline of 0.9%. Three of the eight evaluable patients (38%) in Pop A recorded absolute HbF percentage increases of greater than 1%, with a mean absolute increase in HbF percentage of 3.1% in that subset of patients.

We are in the process of conducting multiple post-hoc analyses of the Phase 2a clinical trial data that include, amongst other analyses, reviewing pooled data across the sub-studies from the trial. Preliminary review of certain of these analyses demonstrate potential benefits from IMR-687 with respect to certain SCD biomarkers, including F-Cells. We expect to report results from these analyses at a future medical meeting.

Phase 2a Open Label Extension

We 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 IMR-687 following completion of the Phase 2a clinical trial. The OLE clinical trial was initially designed so that patients were administered a daily dose of 100 mg of IMR-687, and in the second quarter of 2020, a protocol amendment increased the daily dose to 200 mg. Patients from the combination sub-study continue to receive the same dose of HU that they received while on the Phase 2a clinical trial throughout the duration of the OLE clinical trial. Based on the tolerability profile of IMR-687 observed thus far in the OLE clinical trial, the safety review committee, or SRC, has approved, subject to the contingency below, dose escalation in the OLE clinical trial to a minimum daily dose of 300mg, with certain patients being eligible for a daily dose of 400mg based upon their weight. This weight-based approach is similar to that being used in our ongoing Ardent Phase 2b clinical trial in SCD. The SRC approved the dose adjustments contingent on the independent data monitoring committee, or DMC, for the Ardent Phase 2b clinical trial in SCD opening the higher-dose IMR-687 arm of that trial. We expect the Ardent Phase 2b clinical trial DMC to make a decision on opening the higher dose arm in March 2021.

We conducted a preliminary review of 24 patients enrolled in the OLE clinical as of December 31, 2020. As of data cutoff date, approximately 12 of these patients had evaluable PD biomarker data for at least four months of treatment on the OLE clinical trial. We organized the patients with evaluable PD biomarkers into two sub-groups. The first sub-group, which we refer to as the treatment interrupted sub-group, was comprised of approximately 8 patients who initiated treatment on the OLE clinical trial more than 12 weeks after completing treatment for the Phase 2a clinical trial. The second sub-group, which we refer to as the direct roll-over sub-group, was comprised of approximately 4 patients who initiated treatment on the OLE clinical trial within 12 weeks of completing treatment for the Phase 2a clinical trial. For purposes of analyzing PD biomarker results, patients in the direct roll-over sub-group were analyzed using the baseline value from the Phase 2a clinical trial, while patients in the treatment interrupted sub-group were analyzed using a new baseline established upon initiation of the OLE clinical trial.

Four-Month Data Review

Overall, data from the 24 patients enrolled in the OLE clinical trial as of December 31, 2020 demonstrated that IMR-687 was well tolerated. The most common adverse events (in more than 5% of subjects) were sickle cell anemia with crisis, headache, pain in extremity, nausea, upper abdominal pain and back pain, and were generally consistent with those observed in the Phase 2a clinical trial. 16 of the 24 patients (67%) experienced at least one adverse event, with a majority of the adverse events being mild or moderate in severity. There were no observed clinically significant shifts in vital signs, safety laboratory data, or electrocardiogram data.

Biomarker results demonstrated increases in both HbF and F-cells after four-months of treatment in both the treatment interrupted sub-group and the direct roll-over sub-group. Specifically, there was a mean absolute increase in HbF percentage of 1.7% and 2.3% in the treatment interrupted sub-group and direct roll-over sub-group, respectively, and a mean absolute increase in F-cells of 5.9% and 10.2% in the treatment interrupted sub-group and the direct roll-over sub-group, respectively, in each case after four months of treatment. There were minimal changes in total Hb in both sub-groups. Patients in the treatment interrupted sub-group also demonstrated improvements in several markers of hemolysis after four months of treatment, whereas the direct roll-over sub-group showed variable changes in these measures.

The preliminary biomarker results for the OLE clinical trial are shown in the table below.

Parameter Treatment Interrupted Sub-Group Direct Roll-Over Sub-Group

Reticulocytes (%) -6.0% (n=9) 19.0% (n=4)

Absolute reticulocyte count (×109/L) -8.2% (n=9) 11.5% (n=4)

Indirect bilirubin (μmol/L) -25.5% (n=8) 23.0% (n=4)

LDH (U/L) -4.8% (n=9) 6.3% (n=4)

NTproBNP (ng/L) -55.0% (n=3) N/A*

CRP (mg/L) 27.9% (n=3) N/A*

* Patients in the direct roll-over sub-group did not have data for NTproBNP or CRP as of December 31, 2020.

We are in the process of analyzing outcomes with respect to VOCs from the OLE clinical trial and expect to report this information at a future medical meeting.

Case Narratives

In the third quarter of 2020, we presented case narratives on the first two patients in the OLE clinical trial to complete at least six-months of treatment. Below we have provided an update on each of these two patients who remain on the OLE clinical trial as of the filing of this Annual Report on Form 10-K.

Patient #1 was part of the Pop A monotherapy sub-study of the Phase 2a clinical trial and enrolled in the OLE clinical trial shortly following completion of the Phase 2a clinical trial and was therefore a direct roll-over patient. As of December

31, 2020, Patient #1 had been on the OLE clinical trial for approximately 18 months (and on IMR-687 for 24 months) and has shown continued increases in levels of HbF and F-cells, as well as improvements in several SCD disease biomarkers.

The table below presents biomarker results for this patient at baseline, 12 months on study (as presented in the third quarter of 2020) and 18 months on study (the most recent OLE visit for this patient):

* As Patient #1 was a direct roll-over patient, baseline was established using the baseline of the Phase 2a clinical trial (mean of screening and randomization values).

In addition, a comparison of VOC data for the 24-month period that Patient #1 has been on IMR-687 (six months on the Phase 2a and 18 months on the OLE) versus information from a retrospective review of the patient’s medical records for the 24-month period prior to initiation of IMR-687 indicate potential benefits of IMR-687. In the 24-month period on IMR-687, the patient had a 64% reduction (55 to 20 events) in reported VOCs, as compared to the 24-month period prior to IMR-687 administration.

Patient #2 was part of the HU combination sub-study in the Phase 2a clinical trial and was randomized to the placebo dose group, and therefore never received IMR-687 during the Phase 2a clinical trial. The patient started the OLE clinical trial 14 months after completing the Phase 2a clinical trial, and was therefore a treatment interrupted patient, but remained on a stable HU dose (3000mg daily) during this interim period and while on the OLE clinical trial. As of December 31, 2020, we had data on Patient #2 through eight months of treatment, reflecting the most recent OLE visit for this patient. Patient #2 has shown sustained increases in levels of HbF and F-cells over baseline, however this patient has also shown increasing variability in other SCD biomarkers subsequent to the original case narrative presented in August 2020.

The table below presents biomarker results for this patient at baseline, four months on study (as presented in the third quarter of 2020) and eight months on study (the most recent OLE visit for this patient):

* As Patient #2 was a treatment interrupted patient, baseline was reestablished upon initiation of the OLE clinical trial (to the extent each are available, mean of baseline at screening and initiation of treatment).

In addition, a comparison of VOC data for Patient #2 for the eight-month OLE clinical trial period versus information from a retrospective review of the patient’s medical records for the eight-month period prior to initiation of the OLE clinical trial indicate potential benefits of IMR-687 being administered in combination with HU. In the eight-month period on IMR-687, the patient had a 69% reduction (16 to 5 events) in reported VOCs, as compared to the eight-month period prior to IMR-687 administration.

We caution that the case narratives reflect data from only two patients at specified intervals in the OLE clinical trial and reported VOC comparisons involve retrospective reviews of the patients’ medical records. As a result, we cannot assure you that future data on these patients will continue to be favorable or that data on other patients in the OLE clinical trial will demonstrate potential benefit of IMR-687. We plan to present more data on these patients at future medical meetings.

Ardent Phase 2b Clinical Trial of IMR-687 in SCD

In the second quarter of 2020, we initiated a Phase 2b clinical trial, which we refer to as the Ardent trial, of IMR-687 in SCD and enrollment is ongoing. The Ardent trial is designed as a randomized, double-blind, placebo-controlled, multicenter study of approximately 99 patients, aged 18 to 65 years with SCD and one to 12 VOC episodes within the 12 months preceding enrollment. Patients concomitantly receiving a stable dose of HU according to the patient’s established treatment plan are eligible for enrollment. Patient randomization will be stratified by use of HU as well as by region. We plan to utilize weight-based dosing due to the possible wide range of patient weights in the trial and the increased drug exposure resulting from our use of 300 mg and 400 mg doses. We believe this use of weight-based dosing will more precisely manage drug exposure and tolerability, so that patients with below average weights do not receive too high of a dose and patients with above average weight do not receive too low of a dose. The lower-dose IMR-687 arm will test a range of 3.0 mg/kg up to 4.5 mg/kg (including up to a 300 mg dose) and patients will be randomly assigned in a 2:1 ratio to receive either IMR-687 or placebo. The higher-dose IMR-687 arm will test a range of 4.5mg/kg up to 6.7 mg/kg (including up to a 400 mg dose). Prior to enrolling the higher-dose IMR-687 arm, the independent DMC will review the then-available safety and tolerability data and, if the DMC recommends inclusion of the higher dose, randomization will then proceed in a 1:2:1 ratio (IMR-687 lower dose, IMR-687 higher dose or placebo). We expect the DMC to make a decision on opening the higher-dose IMR-687 arm in March 2021. The dose levels to be administered in the Ardent trial are designed to provide meaningful exposure to IMR-687 that could be up to two-fold that employed in the Phase 2a trial and utilize the 300 mg and potentially 400 mg dose for the first time.

The planned primary efficacy objective of the Ardent trial is to evaluate the proportion of patients with HbF response, defined as an increase of ≥3% in HbF from baseline to week 24, compared to placebo, and the trial is powered for statistical significance with respect to this endpoint. Planned secondary objectives include the evaluation of the effect of IMR-687 versus placebo on (i) HbF-associated biomarkers, (ii) indices of red cell hemolysis, (iii) indices of WBC adhesion, (iv) the incidence of VOCs in relation to HbF levels, and (v) quality of life measures. In addition, the Ardent trial will examine exploratory clinical endpoints, based in part, on the published FDA-ASH Guide to Clinical Development of Sickle Cell Disease Therapies. While the primary efficacy endpoint for the trial will assess results after 24 weeks of treatment, patients will continue on treatment through 52 weeks to provide data for additional exploratory endpoints and to measure the incidence of VOCs over the course of a one-year period. Following the completion of 52 weeks of dosing in the trial, patients will be eligible to enroll in an open-label extension study. In addition, there are pre-specified interim analyses planned in the trial, with the first such interim analysis being conducted when 33 patients have reached 24 weeks of dosing. We expect to report data from this first interim analysis in the second half of 2021.

Our systematic literature review and series of meta-analyses support our belief that HbF has the potential to predict clinical benefit and thus could serve as a surrogate endpoint for accelerated approval in SCD. Drugs that could qualify for accelerated approval are those that treat a serious or life threatening condition, generally provide a meaningful advantage over available therapies, and 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, or IMM, that is reasonably likely to predict an effect on IMM or other clinical benefit.

In the first quarter of 2020, we held a face-to-face Type B meeting with the FDA under our Fast Track designation for IMR-687 to discuss both the potential for HbF to serve as a surrogate endpoint for accelerated approval as well as the design of later stage SCD trials seeking to establish the effect of HbF on important clinical outcomes in SCD. In the preliminary meeting comments, the FDA recommended that we conduct a Phase 2b dose finding trial instead of a Phase 2b/3 trial design that we proposed. At the Type B meeting, the FDA commented that our revised Phase 2b trial design and approach to data collection to support HbF as a potential surrogate endpoint was acceptable. The FDA also stated that it would welcome further discussion as the data from the Phase 2b trial matures to discuss the concept of the acceptability of HbF and a potential threshold of 3% from baseline as an acceptable surrogate endpoint. The FDA stressed the importance of defining clear and strong assumptions and having robust results, which would be evaluated by the FDA to test if 3% HbF or higher would provide meaningful clinical benefit and therefore constitute an acceptable surrogate endpoint for a future pivotal trial of IMR-687 in SCD.

Pediatric Development Program of IMR-687 in SCD

We currently anticipate initiating our pediatric clinical program of IMR-687 in SCD in the first half of 2021. We expect to conduct a Phase 1/2 clinical trial in adolescents (12-17 years old) comprised of a single ascending dose, followed by a 36-week multiple dose expansion phase. In December 2020 we held a Type C meeting with the FDA, during which the agency expressed general alignment with the overall clinical trial design and indicated the study could be submitted with the adult study data in the same NDA.

SAD/MAD Clinical Study in Health Volunteers

In the first half of 2021, we expect to initiate a single ascending dose, or SAD, followed by a multiple dose clinical trial of IMR-687 to explore the safety, tolerability, and PK of higher doses of IMR-687. This short duration study in healthy volunteers under fed conditions will sequentially assess doses of IMR-687 up to 800 mg per day administered once daily or twice daily. Based on the safety, tolerability and PK profile observed in the SAD portion of the trial, the multi-dose portion of the trial will evaluate multiple doses of IMR-687 at the maximum tolerated dose observed for both the once daily and twice daily administrations from the SAD portion of the trial.

β-thalassemia Disorder Overview

β-thalassemia, which is part of the second group of hemoglobinopathies, 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. Like in SCD, infants with β-thalassemia major do not present clinical symptoms of their disorder until age six to 24 months, and sometimes later, when their HbF is replaced by mutated adult hemoglobin. Natural history data show that patients with β-thalassemia who have high HbF levels, due to hereditary persistence of HbF, have less severe forms of the disorder. In addition, genetic variations associated with increased HbF production have been shown to correlate with reduced β-thalassemia severity.

The image below depicts how RBCs and hemoglobin can change as a result of gene mutations in β-thalassemia. In healthy individuals, there are equal amounts of alpha globin and beta globin subunits, which form normal hemoglobin. In β-thalassemia, the absence and/or mutation of beta globin subunits cause excessive alpha subunits that often aggregate into clusters. In cells with reactivated HbF, the gamma subunit reduces the effects of free-floating alpha chains and may improve hemoglobin efficiency and RBC health.

The potential of HbF induction has been observed through off-label use of HU to treat patients with β-thalassemia and has been explored in numerous clinical trials in both NTDT and TDT patients. Most of these efforts were not randomized controlled trials, and many of them lacked a placebo comparator. Nevertheless, HbF induction by HU showed promising early response in TDT and NTDT patients. In fact, there are numerous documented cases both in clinical trials and in off-label real world use where TDT patients have a reduced need for transfusions with continued HU treatment. Despite these observed benefits, and similar to SCD, there continue to be limitations with HU as a therapy in β-thalassemia, including its toxicity, dosing schedule and potential long-term effects.

In addition to HbF induction, independent research suggests activation of the nitric oxide-cyclic GMP 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. In preclinical SCD studies, we observed that IMR-687 reduced levels of CD11a and CD11b and CD18.

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 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, which includes the key regulators hepcidin and ferroportin, are in Phase 2 clinical development in patients with b-thalassemia to treat chronic anemia associated with ineffective erythropoiesis and iron overload. These include IONIS-TMPRss6-LRx, an antisense drug under development by Ionis Pharmaceuticals, andVIT-2763, a ferroportin inhibitor under development by Vifor Pharma.

Gene Therapy/Editing: As with SCD, gene therapy and gene editing approaches are also being developed as potential curative therapies for b-thalassemia. Lentiglobin is a gene therapy treatment in Phase 3 clinical development by bluebird bio, while CTX-001 and ST-400 are gene editing therapies currently in Phase 2 clinical development by CRISPR Therapeutics AG (in collaboration with Vertex Pharmaceuticals, Incorporated) and Sangamo Therapeutics, Inc. (in collaboration with Sanofi), respectively. 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. Agios Pharmaceuticals, Inc. is evaluating mitapivat in a Phase 2 clinical trial in non-transfusion-dependent patients with ß-thalassemia. Forma Therapeutics has reported that it plans to initiate clinical development of its PKR activator, FT-4202, in patients with ß-thalassemia.

Our Solution for β-thalassemia: IMR-687 as a Differentiated PDE9 Inhibitor

PDE9 is a potent and highly selective mechanism that uniquely targets cyclic GMP degradation, making it a promising pathway to increase cyclic GMP, reactivate HbF, enhance RBC production, enable RBC maturation, and reduce WBC activation in β-thalassemia. We believe IMR-687 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 IMR-687 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 IMR-687 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 IMR-687, we observed that erythroblast maturation was significantly improved as a result of increasing 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.

We believe the NTDT mouse model provides promising in vivo proof of concept that IMR-687 can improve the RBC-mediated aspects of ß-thalassemia. In addition, we believe the preclinical activity observed in NTDT models will translate to TDT preclinical models and supports clinical development in both populations. While SCD and ß-thalassemia are distinct hemoglobinopathies, they share similar pathophysiology and symptomology which support our strategy of developing IMR-687 across these indications.

Forte Phase 2b Clinical Trial of IMR-687 in ß-thalassemia

In the second quarter of 2020, we initiated a randomized, double-blind, placebo-controlled Phase 2b clinical trial, which we refer to as the Forte trial, in adult patients with ß-thalassemia and enrollment is ongoing. The trial will evaluate the safety and tolerability of IMR-687 in approximately 60 TDT patients and approximately 60 NTDT patients. Additionally, for TDT patients, we plan to evaluate the effect of IMR-687 versus placebo in reducing the average number of days between red blood cell transfusions, or transfusion burden, and change in iron load rate as the result of transfusion, for the treatment period as compared to the 12 weeks prior to screening. Frequent transfusions in TDT patients lead to iron overload, which is a common complication often leading to the development of organ damage and increased mortality in these patients. Accordingly, improvement in iron load rate is an important measure of an effective therapy for TDT patients. For NTDT patients, we plan to evaluate the effect of IMR-687 versus placebo on HbF as well as on anemia. The Forte trial will also examine additional exploratory efficacy endpoints as well as additional safety and PK endpoints.

The Forte trial will consist of a retrospective data collection period, a screening period, a double-blind treatment period and a safety follow-up period. Similar to our Phase 2b trial of IMR-687 for SCD, we plan to utilize weight-based dosing. We believe this use of weight-based dosing will more precisely manage drug exposure and tolerability, so that patients with below average weights do not receive too high of a dose and patients with above average weight do not receive too low of a dose. The lower-dose IMR-687 arm will test a range of 3.0mg/kg up to 4.5mg/kg (including up to a 300 mg dose) and patients will be randomly assigned in a 2:1 ratio to receive either IMR-687 or placebo. The higher-dose IMR-687 arm will test a range of >4.5mg/kg up to 6.7mg/kg (including up to a 400 mg dose). In January 2021, an independent DMC reviewed available safety and tolerability data and recommended inclusion of the higher dose arm. Going forward, randomization will proceed in a 1:2:1 ratio (IMR-687 lower dose, IMR-687 higher dose, or placebo). Safety and tolerability will be assessed after 24 weeks of dosing. There are pre-specified protocol-driven interim analyses planned in the trial, with the first such interim analysis being conducted when 30 patients have reached 24 weeks of dosing and an additional interim analysis being conducted when 30 patients have reached 36 weeks of dosing. We expect to report data from the first interim analysis in the second half of 2021.

Preclinical Pipeline

We are advancing a pipeline of development-stage programs utilizing IMR-687 targeting additional indications, including HFpEF, for which we began preclinical research in the second quarter of 2020. Heart failure affects approximately 26 million people worldwide. HFpEF represents almost half of all cases of heart failure with approximately 2.5-3 million affected adults in the United States alone. Pathophysiologic characteristics of HFpEF include ventricular hypertrophy, diastolic dysfunction, endothelial dysfunction, insulin resistance and inflammation and many of these have also been described in SCD. Cyclic GMP is known to play a pivotal role in cardiovascular and metabolic health. For example, increased cyclic GMP signaling promotes vasodilation, natriuresis, diuresis, insulin sensitivity and lipolysis, and can inhibit cardiac hypertrophy, inflammation and adverse platelet-leukocyte-endothelial interactions, the latter of which have also been implicated in SCD. Therefore, increasing cyclic GMP by PDE9 inhibition may be an attractive target for the treatment of HFpEF and a natural extension from our lead program in SCD. To investigate this hypothesis, we leveraged our existing clinical program in SCD and tested IMR-687 in preclinical models of HFpEF.

In October 2020, the results of an exploratory analysis co-led by VUMC on data from the second interim analysis from our Phase 2a clinical trial of IMR-687 in adult patients with SCD were presented. The exploratory analysis examined the potential of IMR-687 to reduce cardiovascular risk in patients with SCD. We measured plasma concentrations of NT-proBNP, a well-established biomarker of cardiovascular risk (higher levels associate with greater risk). We found patients treated with IMR-687 in combination with HU saw a mean decrease in NT-proBNP of 27.3% from baseline over four months. In contrast, patients on background HU alone saw a mean increase in NT-ProBNP levels of 27% from baseline over four months. The magnitude of this difference in treatment effect was more pronounced among patients with higher baseline NT-proBNP levels. Specifically, among patients with baseline NT-proBNP values greater than 400 pg/ml, treatment with IMR-687 in combination with HU led to a mean reduction of 67.9% from baseline in NT-proBNP over four months, as compared with a mean increase of 28.0% from baseline in patients who received HU alone. As SCD is a condition characterized by acute and chronic vasculopathy as well as high cardiovascular morbidity and mortality, this exploratory analysis by VUMC provides exploratory human data supporting our belief that PDE9 inhibition with IMR-687 may serve as an attractive target for the prevention and treatment of cardiovascular disease, such as HFpEF.

To compliment the observed human data, we also entered into an agreement with the Necker Institute of Paris, France in the second quarter of 2020 to conduct in vivo studies with IMR-687 in three different established mouse models for HFpEF. In the first model we tested whether IMR-687 could prevent the development of HFpEF induced by unilateral nephrectomy and six-week continuous infusion of d-aldosterone. IMR-687 was administered at doses of 60 mg/kg or 100

mg/kg concurrently with d-aldosterone for six weeks. The results showed that IMR-687 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. IMR-687 was administered at doses of 60 or 100 mg/kg concurrently with angiotensin II infusion for six weeks. The results showed that IMR-687 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 IMR-687 to treat prevalent HFpEF. In this study, twenty-week-old diabetic prone obese mice that previously displayed the HFpEF phenotype were assigned to receive vehicle or IMR-687 at 60- or 100-mg/kg for eight weeks. The mice treated with IMR-687 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, providing possible evidence for HFpEF being a condition of PDE9 excess. In all three models, we found IMR-687 significantly reduced PDE9, ANP and BNP transcript levels in a dose-dependent manner.

We are collaborating with VUMC and have engaged additional key opinion leaders in heart failure, with the aim of developing a Phase 2 protocol with the potential to establish proof-of-concept of IMR-687 in the treatment of patients with HFpEF. Additionally, we have begun work on a new formulation of IMR-687 that potentially could be used in this indication.

Exclusive License Agreement

In April 2016, we entered into an 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, including those directly or indirectly related to hemoglobinopathies, which we refer to as the field. This agreement was amended in July 2016 and October 2017.

The 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 field. We call such products 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 licensed products outside of the field.

The 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 agreement, we issued 167,523 shares of our common stock to Lundbeck in April 2016. We issued 127,002 shares of our common stock to Lundbeck in December 2016 and 148,746 shares of our common stock in August 2017 as a result of antidilution provisions contained in the exclusive license agreement triggered by subsequent closings of our series A preferred stock financing. 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 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 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 licensed product in a country until the later of ten years after the first commercial sale of that 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 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 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 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 agreement if the other party materially breaches the 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 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 agreement for our convenience at any time on six months’ prior written notice to Lundbeck.

Competition

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

Our competitors may have significantly greater financial resources, established presence in the market, 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, and establishing clinical trial sites and patient registration for clinical trials. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

If our lead product candidate, IMR-687, is approved for the indications that we are currently targeting, it will likely compete with the currently marketed drugs and, if approved, the therapies in development discussed below.

Sickle Cell Disease

Approved drug treatments for SCD focus primarily on the management of anemia and reduction of VOCs. Until November 2019, there were only two drug treatments approved in the United States: HU and Endari. HU, marketed under trade names including DROXIA by Bristol-Myers Squibb Company, as well as in generic form, is approved for the treatment of anemia related to SCD, to reduce the frequency of VOCs and the need for blood transfusions. Endari, marketed by Emmaus Life Sciences, Inc., is an oral powder form of L-glutamine approved to reduce severe complications associated with the disorder.

In November 2019, the FDA granted accelerated approval for Oxbryta (voxelotor) for the treatment of SCD in adults and children 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 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 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.

These two recent approvals represent important milestones for patients with SCD. We believe that IMR-687’s differentiated mechanism of action that seeks to increase HbF in patients with SCD, and the association between increases in HbF and reductions in disease risk, have the potential to provide IMR-687, if approved, with competitive advantages over Oxbryta, where the correlation between increases in hemoglobin and disease risk is being tested in a post-approval confirmatory trial, and Adakveo, which is administered intravenously and does not target RBC sickling. Further, IMR-687 acts primarily on red blood cells and has the potential to act on white blood cells, adhesion markers and other cell types that are implicated in SCD. We believe that IMR-687’s multimodal mechanism-of-action has the potential to demonstrate significant benefit to patients with SCD.

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.

IMR-687 could face competition from a number of different therapeutic approaches in development for patients with SCD. For example, bluebird bio has reported that it plans to submit a biologic license application, or BLA, for LentiGlobin for the treatment of SCD in 2022 based on the results of its ongoing Phase 2 clinical trial. Aruvant Sciences, Inc. is developing ARU-1801, a gene therapy treatment in Phase 2 clinical development. There are also several gene editing approaches to treating SCD under evaluation, including CTX-001, currently in Phase 2 clinical development by CRISPR Therapeutics AG (in collaboration with Vertex Pharmaceuticals, Incorporated), BIVV-003, currently in Phase 1/2 clinical development by Sangamo Therapeutics, Inc. (in collaboration with Sanofi), and OTQ923, currently in Phase 1/2 clinical development by Intellia Therapeutics, Inc. (in collaboration with Novartis). There are also several therapeutic approaches under development outside of gene editing/therapy. Novo Nordisk A/S (in collaboration with EpiDestiny, Inc.) is evaluating EPI-01, a small molecule designed to increase production of HbF, in Phase 1 clinical trials. Fulcrum Therapeutics, Inc. is developing FTX-HbF, a small molecule designed to upregulate HbF. Agios Pharmaceuticals, Inc. is developing the PKR activator mitapivat (AG-348), which is in Phase 1/2 clinical development, and Forma Therapeutics, Inc. is developing the PKR activator FT-4202, which is in Phase 3 clinical development. In addition, Syros Pharmaceuticals, Inc., in collaboration with Global Blood Therapeutics, is using its gene control platform to discover and develop product candidates to activate gamma globin expression to induce the production of HbF for the treatment of SCD.

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 (luspatercept-aamt) for the treatment of anemia in adult patients with ß-thalassemia who require regular RBC transfusions. 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.

IMR-687 could face competition from a number of different therapeutic approaches that are in development as a therapeutic option for patients with transfusion-dependent or non-transfusion-dependent ß-thalassemia.

For example, Ionis Pharmaceuticals and Vifor Pharma have ongoing Phase 2 trials to evaluate therapies targeting RBC maturation (IONIS-TMPRss6-LRx andVIT-2763, respectively). Agios Pharmaceuticals, Inc. is evaluating mitapivat, a PKR activator, in a Phase 2 clinical trial in non-transfusion-dependent patients with ß-thalassemia. Forma Therapeutics has reported that it plans to initiate clinical development of its PKR activator, FT-4202, in patients with ß-thalassemia. Sangamo (in collaboration with Sanofi) is conducting a Phase 1/2 clinical trial of ST-400, which uses a genome-edited cell therapy approach designed to produce functional RBCs using HbF. CRISPR Therapeutics AG, in collaboration with Vertex, is conducting a Phase 1/2 clinical trial of CTX-001, which uses a gene editing approach to upregulate the expression of HbF, in patients with transfusion-dependent ß-thalassemia. Syros Pharmaceuticals, Inc., in collaboration with Global Blood Therapeutics, is using its gene control platform to identify and develop product candidates to activate gamma globin expression to induce the production of HbF for the treatment of ß-thalassemia.

We believe that IMR-687’s differentiated mechanism of action and oral route of administration have the potential to provide IMR-687, if approved, with competitive advantages over approved therapies for ß-thalassemia, including REBLOZYL.

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, maintaining and defending patent rights, whether developed internally or licensed from third parties. We also rely on trade secrets, know-how, continuing technological innovation and in-licensing opportunities to develop, strengthen and maintain our proprietary position in our field.

Our future commercial success depends, in part, on our ability to: obtain and maintain patent and other proprietary protection for commercially important technology, inventions and know-how related to our business; defend and enforce in our intellectual property rights, in particular our patent rights; preserve the confidentiality of our trade secrets; 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 any 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 risks related to our intellectual property.

We generally file patent applications directed to our key programs in an effort to secure our intellectual property positions vis-a-vis these programs. As of December 31, 2020, 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, five U.S. pending non-provisional patent applications, 29 issued or allowed non-U.S. patents, including four European patent applications which have been validated among individual European Patent Convention nations, 76 non-U.S. pending patent applications, and three pending Patent Cooperation Treaty, or PCT, applications.

The intellectual property portfolio for our most advanced program as of December 31, 2020, 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.

IMR-687

The patent portfolio for our IMR-687 program includes at least six published patent families. As of December 31, 2020, 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, five U.S. pending non-provisional patent applications, 29 issued or allowed non-U.S. patents, including four European patent applications which have been validated among individual European Patent Convention nations, 76 non-U.S. pending patent applications, and three pending PCT applications relating to our IMR-687 program. These patents and patent applications comprise the following patent families:

The issued patents include coverage of the IMR-687 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 IMR-687 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, of US 9,643,970, 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 are directed to the alternative PDE9 inhibitor compositions of matter, including racemic mixtures. The expected expiry date, based on a 20-year term, of US 9,434,733, 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 IMR-687 composition of matter, including the enantiomer, in addition to coverage of therapeutic methods of treating sickle cell disease with IMR-687. The expected expiry date, based on a 20-year term, of US 10,513,524 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 IMR-687 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 IMR-687 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 IMR-687 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 methods of use, third parties may nevertheless challenge such claims.

The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most countries in which we file, the patent term is 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 drug may, in certain cases, be eligible for a patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984 as compensation for the loss of patent term during the FDA regulatory review process. The period of extension may be up to five years, but cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval. Only one patent among those eligible for an extension 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 Europe and in certain other jurisdictions to extend the term of a patent that covers an approved drug. It is possible that issued U.S. patents covering IMR-687 may be entitled to patent term extensions. If our use of drug candidates or the drug candidate itself receive FDA approval, we intend to apply for patent term extensions, 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, there is no guarantee that the applicable authorities, including the FDA, will agree with our assessment of whether such extensions should be granted, and even if granted, the length of such extensions.

In addition to patent protection, we rely upon unpatented trade secrets and confidential know-how 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 our 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 products or to obtain or use information that we regard as proprietary. Although we take steps to protect our proprietary information, third parties may independently develop the same or similar proprietary information or may otherwise gain access to our proprietary information. As a result, we may be unable to meaningfully protect our trade secrets and proprietary information. See “Risk Factors—Risks Related to Our Intellectual Property” for a more comprehensive description of risks related to our intellectual property.

Manufacturing

We currently contract with third parties for the manufacture of our product candidates for preclinical studies 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 them in the United States and Europe and potentially other international regions with our own sales force.

Government Regulation and Product Approvals

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, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of biopharmaceutical products. The processes for obtaining marketing approvals in the United States and in foreign countries and jurisdictions, along with compliance with applicable statutes and regulations and other regulatory authorities, require 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. The failure of an applicant to comply with the applicable regulatory requirements at any time during the product development process may result in delays to the conduct of a study, regulatory review and approval and/or administrative or judicial sanctions.

An applicant seeking approval to market and distribute a new drug in the United States generally must satisfactorily complete each of the following steps before the product candidate will be approved by the FDA:

Preclinical Studies

Before an applicant begins testing a product candidate with potential therapeutic value in humans, the product candidate enters the preclinical testing stage. Preclinical tests include laboratory evaluations of product chemistry, formulation and stability, as well as other studies to evaluate, among other things, the toxicity of the product candidate. The conduct of the preclinical tests and formulation of the compounds for testing must comply with federal regulations and requirements, including GLP regulations and standards. 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

An IND is a request for FDA authorization to administer such investigational product to humans. Such authorization 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, applicants 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, among other things, must be submitted to the FDA as part of an IND. The FDA requires a 30-day waiting period after the filing of each IND before clinical trials may begin. This waiting period is designed to allow the FDA to review the IND to determine whether human research subjects will be exposed to unreasonable health risks. At any time during this 30- day period, the FDA may raise concerns or questions about the conduct of the trials as outlined in the IND and impose a clinical hold or partial clinical hold. In this case, the IND sponsor and the FDA must resolve any outstanding concerns before clinical trials can begin.

Following commencement of a clinical trial under an IND, the FDA may also place a 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 study is not conducted under an IND, the sponsor must ensure that the study complies with certain regulatory requirements of the FDA in order to use the study as support for an IND or application for marketing approval. The FDA’s regulations are intended to help ensure the protection of human subjects enrolled in non-IND foreign clinical studies, as well as the quality and integrity of the resulting data. They further help ensure that non-IND foreign studies are conducted in a manner comparable to that required for IND studies.

In addition to the foregoing IND requirements, an IRB representing each institution participating in the clinical trial must review and approve 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 information to be provided to study subjects. An IRB must operate in compliance with FDA regulations. 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 candidate has been associated with unexpected serious harm to patients.

Additionally, some trials are overseen by an independent group of qualified experts organized by the trial sponsor, known as a data safety monitoring board or committee, or DSMB. This group provides a recommendation as to whether or not a trial may move forward at designated check points based on access that only the group maintains to available 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.

Information about clinical trials must be submitted within specific timeframes to the National Institutes of Health, or NIH, for public dissemination on its ClinicalTrials.gov website.

Expanded Access to an Investigational Drug for Treatment Use

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.

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.

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.

Concurrent with clinical trials, companies often complete additional animal studies and they must also develop additional information about the chemistry 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 must be capable of consistently producing quality batches of the product candidate and, among other things, must develop methods for testing the identity, strength, quality, purity, and potency of the final drug. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

Pediatric Studies

Under the Pediatric Research Equity Act of 2003, an NDA or supplement thereto must contain data that are adequate to assess 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 the product is safe and effective. Sponsors must also submit pediatric study plans prior to the assessment data. Those plans must contain an outline of the proposed pediatric study or studies the applicant plans to conduct, including study objectives and design, any deferral or waiver requests and other information required by regulation. The applicant, 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 applicant 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 an applicant, 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 applicant, 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. Additional requirements and procedures relating to deferral requests and requests for extension of deferrals are contained in the Food and Drug Administration Safety and Innovation Act, or FDASIA, in 2012. Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation.

Rare Pediatric Disease Priority Review Voucher Program

With enactment of the FDASIA 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” 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 21st Century 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.

Review and Approval of an NDA

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