What is SCD?
SCD is a genetic disease characterized by abnormal hemoglobin molecules in red blood cells (RBCs). As a result, red blood cells that are normally oval take on a sickle shape and turn stiff, and are unable to carry oxygen efficiently. Resulting symptoms include chronic hemolytic anemia as red blood cells are destroyed, and vaso-occlusive crises due to stiff sickled cells obstructing small blood vessels. Severe pain, inflammation, and organ damage are common to patients.
How does FT-4202 work?
A metabolic intermediate called 2,3 diphosphoglycerate (2,3 DPG) is a key negative regulator of oxygen binding to hemoglobin in RBCs. Its levels are higher than usual in red blood cells of SCD patients. For this reason, lowering 2,3 DPG levels is thought to be a way of increase hemoglobin’s oxygen-binding capacity.
Pyruvate kinase-R (PKR) is a key metabolic enzyme that utilizes 2,3 DPG as a substrate. Raising the activity of PKR can lower the levels of 2,3 DPG and increase oxygen binding to hemoglobin.
In addition, a by-product of PKR activity is ATP, the energy currency of all cells and a key signaling molecule. PKR as such plays an important role in the energy supply of RBCs.
FT-4202 is a small molecule that researchers designed to bind to PKR in red blood cells to increase its activity. As a result, 2,3 DPG levels decrease. This raises hemoglobin’s affinity for oxygen in sickled RBCs, helping them to deliver more oxygen to tissues and organs.
When oxygen affinity increases, the sickling of the RBCs decreases. As such, FT-4202 is thought to alleviate such symptoms of SCD as its painful vaso-occlusive crises.
As FT-4202 also activates PKR, it may increase ATP production to raise the cells’ energy levels — making RBCs healthier and likely to survive longer in the body.
FT-4202 in clinical trials
A Phase 1 randomized and placebo-controlled trial (NCT03815695) is assessing the safety, pharmacokinetics (movement in the body), and pharmacodynamics (effects on the body) of oral FT-4202 at single- and multiple-ascending doses.
The single-ascending dose (SAD) phase of this study tested a dose range of FT-4202 in healthy people, and analyzed safety and pharmacokinetics. Researchers then enrolled a new group in a two-week multiple-ascending dose (MAD) study. This first trial phase is now complete, and the trial’s second phase, in SCD patients, is underway.
Forma presented the results of this first part at the 61st annual meeting of the American Society of Hematology (ASH) in San Diego in December 2019.
A total of 32 healthy volunteers received a single oral dose of up to 1,000 mg of FT-4202 or a placebo, and 48 healthy volunteers were given multiple oral doses up to 600 mg per day of FT-4202 or a placebo for 14 days.
A favorable safety profile was recorded, with only grade 1 (mild) treatment-emergent adverse event during this phase. Maximal ATP response was evident at doses of 50 mg or more twice daily, or 150 mg once daily. The maximal 2,3-DPG response was at doses of 150 mg or more twice daily, or 400 mg once daily.
Pharmacokinetic findings were linear and time-independent.
Researchers then presented data on a first group of nine patients at the 62nd ASH meeting in December 2020. Results here found six of seven patients treated with FT-4202 at a 300 mg daily dose for 14 days achieved increases of hemoglobin greater than 1 g/dL. Changes in several biomarkers also indicated lower levels of hemolysis (sickled red blood cell rupture).
This trial is currently recruiting eligible SCD patients, ages 12 to 65, at sites across the U.S.; information is available here. Subsequent patients groups will be treated at ascending doses, or randomized to a placebo. Researchers expect the study to conclude in September 2021.
Forma Therapeutics is also running a pivotal Phase 2/3 clinical trial (NCT04624659) into the safety and efficacy of FT-4202 compared to a placebo. Its main goals are changes from baseline (study start) in hemoglobin levels of RBCs at 24 weeks of treatment, and in the rate of vaso-occlusive crises at one year.
The study is recruiting up to 344 SCD patients, ages 12 to 65, at four U.S. sites; more information is here.
In its initial Phase 2 portion, trial researchers will randomize patients 1:1:1 to one of two daily dose levels of FT-4202 (200 mg or 400 mg) or to a placebo.
An analysis of the these results will determine the optimal dose to be given patients enrolled into the trial’s Phase 3 portion, which runs for 52 weeks (one year). Patients here will be randomized 1:1 to FT-4202 at that dose or to a placebo. After these 52 weeks, those who complete the randomized trial will have the option of entering an open-label extension, where all will be given the therapy at its optimal dose once a day for 52 weeks.
The U.S. Food and Drug Administration has given FT-4202 fast track, rare pediatric disease, and orphan drug designations as a potential SCD treatment. The European Medicines Agency also designated it an orphan drug. These designations all aim to speed and support the advancement of a promising therapy for rare diseases through testing and regulatory review.
Last updated: Jan. 27, 2021
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