Background:

Sickle cell disease (SCD) is a serious and life-threatening inherited hemoglobin (Hb) disorder caused by a single amino acid substitution in the beta (β)-globin gene (β s c.20A>T; rs334). Sickle cell disease affects millions of people worldwide. The homozygous form (HbSS) occurs in most cases and represents approximately 88% to 96% in certain areas of Africa. Preliminary data indicate that mitapivat may reduce Hemoglobin S polymerization, sickling, and hemolysis. Therefore, in this study mitapivat is a therapeutic candidate for the treatment of adult patients with SCD with the potential to provide clinical benefit by both improvement of anemia and reduction in sickle cell pain crises (SCPCs).

The only current curative treatment approach for some patients with SCD is bone marrow transplant. However, a lack of histocompatible donors, concerns about transplantrelated morbidity and mortality, and pre-existing conditions (organ dysfunction or alloimmunization) often preclude patients from pursuing this treatment option. For decades, hydroxyurea was the only disease-modifying therapy available for patients with SCD. Hydroxyurea is indicated to reduce the frequency of painful crises; however, its use  is limited by its safety profile, which includes myelosuppression (neutropenia and thrombocytopenia) and gastrointestinal toxicity. Reduced fertility has been reported as a longterm adverse effect.

Justification/Rationale:

The use  of curative options for SCD is currently limited to a small subgroup of patients who are deemed fit for bone marrow transplantation and have available donors. The treatment options for SCD are not universally effective or globally available, tend to address only a single component of the disease, or are limited by their safety profile. Therefore, a significant unmet medical need exists for safe and effective therapies for the treatment of SCD that result in both an improvement in anemia and reduction in sickle cell–related crises.

Mitapivat is a small molecule, oral activator of wild-type (WT) and mutant forms of the RBC-specific form of pyruvate kinase (PKR). Activation of PKR has potential application in the treatment of hemolytic anemias, including SCD, which are characterized by increased metabolic demands or by defects in glycolysis that contribute to the shortened life span of the RBC. Decreases in PKR function, exemplified in patients with pyruvate kinase deficiency, leads to dysfunctional RBCs that are characterized by defective glycolysis, including a build-up of 2,3-DPG and PEP with decreased levels of ATP. However, there is evidence that the activation of the normal (WT) PKR enzyme can play a role in other hemolytic anemias such  as SCD.

Main Objectives: Phase 2:

1. To determine the recommended Phase 3 dose of mitapivat by evaluating the effect of 2 dose levels of mitapivat versus placebo on:

• Anemia in subjects with sickle cell disease (SCD)

• Safety

Phase 3: 1. To determine the effect of mitapivat versus placebo on:

• Anemia in subjects with sickle cell disease (SCD)

• Sickle cell pain crises (SCPCs) in subjects with SCD

Secondary objectives:

Phase 2:

1. To evaluate the effect of 2 doses of mitapivat versus placebo on:

• Anemia
• Markers of hemolysis and erythropoiesis
• Patient-reported fatigue
• Sickle cell pain crises (SCPCs)

2. To evaluate the pharmacokinetic and pharmacodynamic effects of mitapivat.

Phase 3:

1. To evaluate the effect of mitapivat versus placebo on:

• Anemia in subjects with SCD

• Markers of hemolysis

• Markers of erythropoiesis

• Patient-reported fatigue

• Additional clinical efficacy measures related to SCPC

Methods:

Overall Study design

This is a Phase 2/3, double-blind, randomized, placebo-controlled, global, multicenter study evaluating the efficacy and safety of mitapivat versus placebo in subjects with SCD using an operationally seamless design. The Phase 2 portion is a double-blind, randomized, placebo-controlled, dose-finding study evaluating 2 dose levels of mitapivat (50 mg BID and 100 mg BID) versus placebo to select the dose of mitapivat to be evaluated in the Phase 3 portion. The Phase 3 portion is a double-blind, randomized, placebo-controlled study evaluating the efficacy and safety of mitapivat at the selected Phase 3 dose versus placebo. Subjects who complete the Double-blind Period in eitherthe Phase 2 or Phase 3 portion will have the option to receive mitapivat in the Open-label Extension Period. A total of 267 subjects (69 in Phase 2 and 198 in Phase 3)

will be randomized in this study. The initiation of the Phase 3 portion will be based on prespecified go/no-go criteria and dose selection criteria. Subjects who participate in the

Phase 2 portion of the study are not eligible to participate in the Phase 3 portion of the study.

Study outcomes:

The primary outcome, or endpoint, for the phase 2 study is hemoglobin (Hb) response, defined as a ≥1.0 g/dL increase in average Hb concentration from Week 10 through Week 12 compared with baseline and safety defined as adverse events (AEs) and serious adverse events (SAEs). The primary outcome for the phase 3 study is Hemoglobin (Hb) response, defined as a ≥1.0 g/dL increase in average Hb concentration from Week 24 through Week 52 compared with baseline and annualized rate of sickle cell pain crises (SCPCs) in subjects with SCD.

Study duration:

The duration of participation of a subject in the Phase 2 portion is up to 4.5 years (236 weeks). The duration of participation of a subject in the Phase 3 portion is up to 5.3 years (276 weeks). The end of the study is defined as the time at which all subjects complete all study visits, are lost to follow-up, have withdrawn consent for further participation in the study, or when the Sponsor terminates the study.