Potential Oral DMT Showing Safety and Signs of Efficacy in Phase 1 Trial

FT-4202 — an investigational treatment for sickle cell disease (SCD) — has a favorable safety profile and the expected biological effects, providing preliminary support of efficacy, according to data from an ongoing Phase 1 clinical trial.

Forma Therapeutics, which is developing FT-4202, plans to start a global Phase 2/3 study in SCD patients later this year.

“FT-4202 represents a potential foundational, disease-modifying therapy for people living with sickle cell disease,” Frank Lee, Forma’s CEO, said in a press release. “These early data are encouraging and demonstrate multi-modal activity in SCD patients.”

The findings, “Phase 1 Single (SAD) and Multiple Ascending Dose (MAD) Study of the Safety, Pharmacokinetics (PK) and Pharmacodynamics (PD) of FT-4202, a PKR Activator, in Healthy and Sickle Cell Disease Subjects,” were presented at the 25th European Hematology Association Annual Congress, which was held virtually.

SCD is characterized by abnormalities in hemoglobin, the protein that carries oxygen through the bloodstream. Such abnormalities cause deoxygenated (not bound to oxygen) hemoglobin to stick together, which ultimately results in stiff and “sickled” red blood cells (RBC) that can clog small blood vessels.

FT-4202 is a small molecule that works by activating the protein pyruvate kinase-R (PKR). This protein helps to lower levels of 2,3-diphosphoglycerate (2,3-DPG) — a byproduct of RBC metabolism that decreases the ability of hemoglobin to bind to oxygen.

By activating the PKR protein, FT-4202 is expected to lower 2,3-DPG levels to reduce the sickling of red blood cells. The therapy may also increase levels of adenosine triphosphate (ATP) — the cellular “energy currency” — improving the overall health and survival of these blood cells.

The experimental therapy recently received orphan drug, fast track, and rare pediatric disease designations from the U.S. Food and Drug Administration for the treatment of SCD.

An ongoing Phase 1 clinical trial (NCT03815695), sponsored by Forma, is evaluating the safety profile of single and multiple ascending oral doses (up to 600 mg daily) of FT-4202 in people with and without SCD. The trial is also assessing the treatment’s pharmacokinetics — its movement into, through, and out of the body — and pharmacodynamics, or the effects of a medication on the body.

Enrollment of up to 150 people, ages 12 to 65, is still ongoing at multiple locations in the U.S. Additional information can be found here.

Previously reported trial results demonstrated that FT-4202 had a good safety profile in healthy volunteers, with the majority of reported side effects being mild in severity.

These new findings are from the first seven SCD patients enrolled in the trial, and given either a single oral dose of FT-4202 (700 mg) or a placebo.

As was seen in the volunteer group,  FT-4202 showed a good safety profile and was well tolerated by patients. All reported adverse events were mild and temporary; the most common side effect was headache.

The pharmacokinetic profile of FT-4202 was similar in people with and without SCD. The medication reached its highest concentration in the blood about an hour after administration, decreasing to about half by 10 to 13 hours post-treatment.

In healthy volunteers, FT-4202 led to significantly reduced levels of 2,3-DPG and greater hemoglobin ability to bind oxygen, while significantly decreasing the number of reticulocytes —immature RBCs found at increased levels in people with SCD. Biological activity was seen as early as 24 hours after administration, and was maintained throughout the 14-day treatment period.

Similar effects were also observed in SCD patients given a single dose.

“Early single dose studies in SCD subjects show an acceptable safety profile with evidence of PD activity translating into favorable biologic effects of increased oxygen affinity … and improved membrane deformability [altered structure] of sickle RBCs,” the researchers wrote.

“We believe these initial findings — showing a positive hemoglobin response, increased oxygen affinity and improved membrane deformability of sickle red blood cells — support continued development of FT-4202 in a global Phase 2/3 trial in SCD patients later this year,” said Patrick Kelly, MD, Forma’s chief medical officer.

“We also look forward to continuing to report data from our ongoing Phase 1 trial throughout the year,” Kelly added.

This trial is expected to end in September.