Background: The hallmark of sickle cell disease (SCD) is hemoglobin S (HbS) polymerization upon deoxygenation, resulting in red blood cell (RBC) sickling, oxidative damage, membrane damage, hemolysis, chronic anemia, vaso-occlusions and inflammation. Exacerbating the pathogenesis of SCD, the HbS RBC has 1) increased (↑) 2,3-DPG with decreased (↓) oxygen affinity (↑ P50) and 2) ↓ RBC ATP. FT-4202 is a novel, small molecule allosteric activator of erythrocyte pyruvate kinase (PKR) that increases the activity of both wild type and mutated PKR enzymes, resulting in ↓ 2,3-DPG levels and ↑ ATP levels in RBC. In preclinical safety studies, FT-4202 had no effect on steroidogenesis, low risk of drug-to-drug interactions (DDI) and was well tolerated in vivo at the maximum doses administered. In vitro FT-4202 treatment of RBCs from patients with SCD increased oxygen affinity and shifted the point of sickling by oxygen scan. After 1-week of dosing in vivo Berkeley SCD mouse-models, FT-4202 increased the oxygen affinity of HbS RBC, resulting in reduction of sickling and improved hemoglobin. Based on these results, a first-in-human Phase 1 study evaluating FT-4202 in healthy subjects and subjects with SCD was initiated. The key objectives of this randomized, double-blind, placebo-controlled single (SAD), multiple ascending dose (MAD), and food effects (FE) study are to evaluate the safety and pharmacokinetics/pharmacodynamics (PK/PD) of FT-4202, in healthy and SCD subjects [NCT03815695]. Herein we report the effects of FT-4202 on healthy subjects in this ongoing study.

Methods: SAD cohorts were randomized to receive a single oral dose of FT-4202 or placebo (P). Four healthy SAD cohorts were evaluated (n=8 each; 6 FT-4202, 2 P), at increasing doses of 200, 400, 700, and 1000 mg. Four healthy MAD cohorts (n=12 each; 9 FT-4202, 3 P) received 200 to 600 mg total daily dose for 14 days at QD or BID dosing. In the FE cohort, 10 subjects received 200 mg FT-4202 QD with and without food. Safety assessments included adverse events (AEs), vital signs, ECGs and laboratory parameters. Rich PK/PD blood sampling was performed on Day1 (SAD/MAD/FE) and Day 14 (MAD), up to 72h after the last dose and at the end of study visit. PD parameters included 2,3-DPG, ATP, and P50. Safety data are summarized in a blinded fashion pending enrollment of SCD subjects. To maintain study blind, PK/PD analysis was performed by an unblinded pharmacologist using dummy subject identifiers.

Results: No serious adverse events (SAEs) or AEs leading to withdrawal were reported. In the SAD cohorts, 32 subjects (20 males [M] and 12 females [F]; median age 46 yrs) were enrolled and completed the study. A total of 7 treatment-emergent AEs occurred in 6/32 (19%) subjects during the study: 3 Grade (Gr) 1 and 3 Gr 2 in severity while 1 subject in the 1000 mg FT-4202/P dose cohort experienced an isolated, asymptomatic lipase increase (Gr 3 AE) that occurred 4 days post dose and normalized within 24 hrs. In the MAD cohorts, 48 subjects (28 M; 20 F; median age 46 yrs), were enrolled and completed dosing. 18/48 (38%) of subjects receiving FT-4202/P experienced 31 Gr 1 AEs with the most frequent AE of headache (n=12). In PK assessments, FT-4202 was rapidly absorbed with a median Tmax of 1 hr post-dose. Single dose exposure increased in greater than dose-proportional manner at doses ≥700 mg. In multiple-doses delivered BID or QD, linear PK was observed across all dose levels (100-300 mg BID, 400 mg QD), and exposure remained steady up to day 14, without cumulative effect. FT-4202 exposure under fed/fasted conditions was similar. PD activity was demonstrated at all dose levels evaluated in FT-4202-treated subjects (Table 1). Within 24 hr of a single dose of FT-4202, ↓ 2,3-DPG with a corresponding ↓ P50 was observed. After 14 days of FT-4202 dosing these PD effects were maintained along with ↑ ATP over baseline. PK/PD modeling demonstrated that exposures achieved with FT-4202 150-200 mg BID will result in maximum/sustained PD effect.

Conclusions: FT-4202 has a favorable safety profile in healthy subjects based on preliminary analysis of subjects receiving a single dose up to 1000 mg or multiple doses up to 600 mg/day for 14 days. FT-4202 demonstrated linear and time-independent PK with proof of mechanism (POM) demonstrated based on PD effects. Studies in SCD subjects are ongoing to confirm safety and POM of FT-4202 at doses predicted to achieve maximum PD effect (↓ 2,3-DPG/↓ P50 and ↑ ATP) in the HbS RBC.


Kalfa:FORMA: Other: sponsored research agreement; Agios: Other: local PI of clinical research trial. Kuypers:FORMA Therapeutics: Research Funding. Telen:Forma Therapeutics: Research Funding; Novartis: Other: Member of a safety monitoring committee; Pfizer: Other: Member of a clinical trial steering committee. Estepp:Global Blood Therapeutics, FORMA Therapeutics, Pfizer, Eli Lilly and Co: Research Funding; Daiichi Sankyo, Esperion, Global Blood Therapeutics: Consultancy; ASH, NHLBI: Research Funding. Saraf:Pfizer: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wilson:FORMA Therapeutics: Employment. Ribadeneira:FORMA Therapeutics: Employment. Forsyth:FORMA Therapeutics: Employment. Schroeder:FORMA Therapeutics: Employment. Drake:FORMA Therapeutics: Employment. Polyanskaya:FORMA Therapeutics: Employment. Kelly:FORMA Therapeutics: Employment. Biernat:Medpace, Inc.: Employment.

Author notes


Asterisk with author names denotes non-ASH members.

Sign in via your Institution