Forma Therapeutics Holdings, Inc. announced etavopivat, the company's investigational oral, once-daily, selective pyruvate kinase-R (PKR) activator, significantly improved anemia and red blood cell (RBC) health with a favorable tolerability and safety profile in patients with SCD. These Phase 1 trial findings, presented in two oral sessions on Dec. 11 at the 63rd American Society of Hematology (ASH) Annual Meeting, support a highly differentiated etavopivat profile to potentially improve the lives of patients with SCD, including increases in hemoglobin, improvements in RBC health, and decreases in vaso-occlusive crises (VOCs). In the open label cohort of a randomized, placebo-controlled Phase 1 trial (NCT03815695), 15 patients received etavopivat 400 mg once daily for up to 12 weeks, with a data cutoff as of Nov. 23, 2021. Significant and sustained improvement in anemia and RBC health: Etavopivat administered for up to 12 weeks reduced anemia by significantly raising and sustaining hemoglobin levels. A hemoglobin increase >1 g/dL was experienced by 73.3% (11/15) of patients (p<0.0001), with a maximal mean increase of 1.5 g/dL. Etavopivat therapy also significantly increased the lifespan of RBCs and decreased hemolysis, as measured by three biomarkers that together indicate enhanced survival of RBCs. Durability of these improvements was sustained throughout the 12 weeks of treatment: absolute reticulocyte count (ARC, p<0.05), indirect bilirubin (p<0.0001), and lactate dehydrogenase (p<0.05). In addition, an analysis of all patients in the 12-week open label cohort showed a decreasing trend in VOCs requiring hospitalization when compared to the rate 12 months prior to trial entry. Of the 15 patients receiving etavopivat, only a single VOC was reported while on treatment, which was precipitated by a grade 3 COVID-19 infection, representing an annualized VOC rate of 0.3. The cohort’s pre-study annualized VOC rate was 0.93 (13 events). Etavopivat was well tolerated, consistent with safety profile of underlying SCD. The primary endpoint of the Phase 1 trial was the incidence, frequency, and severity of adverse events (AEs). In the 12-week open-label extension, most AEs were grades 1 and 2. Two patients reported three serious grade 3 AEs on treatment, including a VOC following a COVID-19 infection unrelated to treatment, and a previously reported deep vein thrombosis. During the four weeks post-treatment, three patients reported four serious AEs, all grade 3 and considered unrelated to etavopivat, including VOC, syncope, and acute chest syndrome and VOC following a respiratory infection. Etavopivat multimodal mechanism of action improved biomarkers of RBC health and SCD in exploratory analyses. Findings from exploratory analyses showed improvements in RBC health and function as measured by biomarkers of SCD during 12 weeks of etavopivat therapy. Etavopivat’s multimodal mechanism of action via PKR activation resulted in increased adenosine triphosphate (ATP), and decreased 2,3-diphosphoglycerate (2,3 DPG), which was sustained during 12 weeks of etavopivat treatment. Four weeks post treatment, ATP and DPG levels gradually returned to pre-treatment levels, suggesting the potential durability of etavopivat on RBC health may persist for 1-4 weeks following the treatment period. Surrogate marker results showed etavopivat normalized the affinity of hemoglobin for oxygen, resulting in improved oxygen release in the peripheral tissues and reducing RBC sickling. Further analysis after two weeks of etavopivat treatment support improved RBC membrane health, with increased levels of two enzymes important to reducing oxidative stress in sickled RBCs: superoxide dismutase activity (SOD, p<0.05) and glutathione reductase activity (GSH, p<0.001), as well as significantly repairing membrane damage, as measured by phosphatidylserine (PS, p<0.01). Additionally, up to 12 weeks of etavopivat showed promising trends in reducing systemic biomarkers of inflammation and coagulation. Significant decreases were observed in TNF-alpha (p<0.001), prothrombin 1.2 (p<0.05), and D-dimer (p<0.01). In addition, improved oxygen delivery was observed as measured by significant decreases in erythropoietin levels (p<0.05).