SCD is genetic disease characterized by abnormal hemoglobin molecules in red blood cells (RBCs). As a result, these blood cells become sickle-shaped and unable to carry oxygen efficiently. This leads to symptoms like chronic hemolytic anemia as red blood cells are destroyed, and vaso-occlusive crises due to the obstruction of small blood vessels.
These symptoms can cause severe pain, inflammation, organ damage, and early death. They also greatly affect a person’s quality of life.
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 the RBCs. Its levels are higher in the RBCs of SCD patients. For this reason, lowering 2,3 DPG levels can increase hemoglobin’s oxygen binding capacity.
Pyruvate kinase-R (PKR) is a key metabolic enzyme that utilizes 2,3 DPG as a substrate. By raising the activity of PKR, the levels of 2,3 DPG can be lowered, and the binding of oxygen to hemoglobin can be increased.
Moreover, one of the by-products 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 red blood cells.
FT-4202 is a small chemical molecule that is designed to bind to PKR in the RBCs and increases its activity. As a result, 2,3 DPG levels decrease. This increases the affinity of hemoglobin for oxygen in the sickled RBCs, and helps them deliver more oxygen to different tissues and organs in the body.
When oxygen affinity increases, the sickling of the RBCs decreases. FT-4202 could, therefore, also alleviate other symptoms of SCD like vaso-occlusive crises.
Because FT-4202 activates PKR, it may also increase the production of ATP, and the cells’ energy levels. This should further improve the health of the sickled RBCs as well as their longevity.
FT-4202 in clinical trials
A Phase 1 randomized, placebo-controlled, double-blind, single- and multiple-ascending dose study (NCT03815695) is assessing the safety, pharmacokinetics (movement in the body), and pharmacodynamics (effects on the body) of FT-4202 first in healthy volunteers and then in SCD patients.
The single-ascending dose (SAD) study tested a dose range of FT-4202 in healthy participants and analyzed safety and pharmacokinetics. People in at least two SAD groups were then enrolled in a two-week multiple-ascending dose (MAD) study.
Forma presented results of this part of the study at the 62nd annual meeting of the American Society of Hematology (ASH) in San Diego, California in December 2019.
A total of 32 healthy volunteers received a single oral dose up to 1,000 mg of FT-4202 or a placebo, and 48 healthy volunteers received multiple oral doses up to 600 mg per day of FT-4202 or a placebo for 14 days.
A favorable safety profile with only grade 1 (mild) treatment-emergent adverse events was recorded during this part of the study. The maximal ATP response was obtained at doses of 50 mg or more twice daily, or 150 mg once daily; the maximal 2,3-DPG response was obtained at doses of 150 mg or more twice daily, or 400 mg once daily.
The pharmacokinetic findings were linear and time-independent, demonstrating maximal changes being achieved within a single dose of FT-4202 over a 24-hour period, as well as sustained maximal change for a 14-day period for multiple ascending doses.
The trial is currently recruiting SCD patients in the U.S. to conduct a planned second part; contact information is available here. It is expected to finish by September 2020.
Last updated: Jan. 31, 2020
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