FT-4202, FORMA’s Experimental SCD Therapy, Fares Well in Phase 1 Trial of Healthy Volunteers

FT-4202, FORMA Therapeutics’ experimental disease-modifying therapy for sickle cell disease (SCD), shows a favorable safety and pharmacokinetic profile in healthy volunteers, according to data from a Phase 1 clinical trial.

Patient recruitment is open for the second part of the trial (NCT03815695). Information about trial locations, all in the U.S., is available here.

Trial findings were presented in an oral presentation, “Phase 1 Single (SAD) and Multiple Ascending Dose (MAD) Studies of the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of FT-4202, an Allosteric Activator of Pyruvate Kinase-R, in Healthy and Sickle Cell Disease Subjects,” at the 2019 American Society of Hematology (ASH) Annual Meeting in Orlando, Florida.

FT-4202 is a novel selective activator of red blood cells’ pyruvate kinase-R (PKR), an enzyme that plays an important role in cells’ metabolism. By increasing the activity of PKR, FT-4202 reduces the levels of 2,3-diphosphoglycerate (2,3-DPG), a byproduct of red blood cells’ metabolism that decreases hemoglobin’s affinity to oxygen.

Lower levels of 2,3-DPG potentially reduce the sickling of red blood cells, a hallmark of SCD.

In addition to increasing hemoglobin’s affinity to oxygen, FT-4202 also boosts the production of adenosine triphosphate (ATP) in red blood cells, improving their overall health and survival. ATP is a small molecule used as “fuel” (energy) by all cells.

These two effects combined are expected to lead to an increase in the levels of hemoglobin and to reduce the frequency of painful vaso-occlusive crises (VOCs).

“The growing pipeline of new SCD medicines, both recently approved and under investigation, is very encouraging for these patients, however there is still an unmet need to address the complexity of this disease,” Frank Lee, CEO of FORMA Therapeutics, said in a press release.

“We are encouraged by the potential ability of FT-4202 to address multiple biological events in the cascade that ultimately leads to painful vaso-occlusive crises and organ damage,” Lee said.

FORMA is currently investigating the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) properties of FT-4202 in this first-in-human Phase 1 trial (NCT03815695). PK and PD essentially refer to the interactions between the body and a specific compound. PK interactions are analyzed to understand how a medication is absorbed, distributed, metabolized, and then eliminated from the body. PD studies the effects of the drug in the body.

The randomized, double-blind, placebo-controlled trial is investigating the effects of single- and multiple-ascending doses of FT4202, first in a group of healthy volunteers and then in patients with SCD. The first part of the study in healthy volunteers is complete. Patient recruitment for the second part of the trial is underway in several sites across the U.S.

During the meeting, FORMA presented data from the first group of healthy volunteers who were treated with FT-4202. The findings include data from 32 subjects who received a single oral dose of the medication (up to 1,000 mg), or a placebo; and from 48 who received multiple oral doses of FT-4202 (up to 600 mg daily), or a placebo, for 14 days.

Findings revealed that FT-4202 had a favorable safety and tolerability profile, with the majority of adverse events (side effects) reported as only mild (grade 1) in severity. PK/PD properties also were favorable, with FT-4202 triggering a fast response within 24 hours of its administration (single dose group), which was kept until the end of the 14-day treatment period (multiple dose group).

Analyses also confirmed FT-4202 increased the levels of ATP in healthy red blood cells, reaching a maximal response when administered at doses higher than 50 mg twice a day, or higher than 150 mg once a day.

The effects of the medication on the levels of 2,3-DPG also were confirmed, with maximal responses seen when FT-4202 was administered at doses higher than 150 mg twice a day, or higher than 400 mg once a day.

“The safety and tolerability profile observed in this study is exciting, as are the PK/PD data that confirm FT-4202 activates PKR with a simultaneous effect on hemoglobin oxygen affinity and ATP levels in healthy volunteers,” said Patrick Kelly, MD, chief medical officer of FORMA Therapeutics.

“These data correlate with findings from in vitro [in the lab] studies of blood from patients with sickle cell disease, and we have now identified a well-tolerated dose range with PKR activity lasting up to three days following the last dose,” Kelly said.