FT-4202, a potential disease-modifying oral treatment for sickle cell disease (SCD), is well-tolerated in people with SCD and induces improvements in several red blood cell parameters, early clinical trial data indicate.
The results observed in this initial group of patients support the efficacy of Forma Therapeutics‘ investigational medication, as well as the dosing of a second group with a higher daily dose.
The findings were revealed in “FT-4202, an Allosteric Activator of Pyruvate Kinase-R, Demonstrates Proof of Mechanism and Proof of Concept after a Single Dose and after Multiple Daily Doses in a Phase 1 Study of Patients with Sickle Cell Disease,” a presentation at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, held recently online.
“We are pleased to present our clinical proof-of-concept data and continue to see potential for FT-4202 to improve the lives of people living with sickle cell disease,” Patrick Kelly, MD, chief medical officer of Forma, said in a press release.
SCD is characterized by abnormal hemoglobin, the molecule used by red blood cells to ferry oxygen throughout the body. The abnormal hemoglobin, called hemoglobin S (HbS), can’t bind oxygen as well as normal hemoglobin, and it can form clumps in red blood cells that cause the cells to take on the “sickle” shape that gives the disease its name.
FT-4202 is an orally available small molecule that works by activating an enzyme called pyruvate kinase-R (PKR) in red blood cells. This enzyme decreases levels of 2,3-diphosphoglycerate (2,3-DPG), a metabolic byproduct that prevents hemoglobin from binding to oxygen. As such, the investigational medication is expected to help HbS hold on to oxygen more effectively, thus decreasing sickling.
The activation of PKR by FT-4202 also is expected to increase energy levels in red blood cells, thereby improving their health and survival.
The therapy has been named an orphan drug in the European Union.
Forma is funding an ongoing Phase 1 clinical trial (NCT03815695) to evaluate FT-4202 in up to 150 healthy adults and SCD patients. Results from the first part of the trial, reported previously, showed the investigational medication to be well-tolerated in people who do not have SCD.
At the ASH presentation, researchers reported data for 16 SCD patients who participated in the trial. Of them, seven received a single treatment dose — five were assigned to receive 700 mg of FT-4202 and two were given a placebo — and nine received daily treatment for two weeks. Among the nine, seven were given 300 mg daily of FT-4202 and two received a daily placebo.
The data continue to support a good safety profile for FT-4202: no serious adverse events have been reported, nor have there been any such events leading to treatment discontinuation. Four of the participants who received FT-4202 reported mild adverse events, specifically joint pain, headache, palpitations, and nausea.
In both groups, FT-4202 resulted in decreased 2,3-DPG levels in red blood cells and increased levels of energy, resulting in improved red blood cell function and less sickling. Other markers of red blood cell damage also indicated that the treatment improved red blood cell health.
Notably, patients receiving the single dose of FT-4202 experienced an increase in hemoglobin levels by roughly 0.9 g/dL one day after administration, relative to those given a placebo. Among those given daily FT-4202 for 14 days, six (86%) experienced increases in hemoglobin levels by more than 1 g/dL (median 1.2 1 g/dL) after the two weeks of dosing.
“These results are remarkable for a Phase 1 study, and they’re encouraging for sickle cell patients,” said Marilyn J. Telen, MD, a professor at Duke University School of Medicine and a study investigator.
“The absence of serious treatment-related adverse events, together with increased hemoglobin and reduced markers of hemolysis among the group receiving FT-4202, indicate a potential impact on overall red blood cell health and support further studies,” Telen said.
These data indicate that the investigational medication is working as expected. Based on the promising data observed in the multiple-dose group, the trial is enrolling a second group of patients who will receive a 600 mg oral dose of FT-4202 or placebo, also for 14 days.
The trial is currently recruiting participants at multiple locations in the U.S.; more information is available here. Patients who complete dosing in this group may then enter a 12-week, open-label part where all will receive a daily 400 mg oral dose of FT-4202.
Forma is also planning a global Phase 2/3 clinical trial (NCT04624659) to further test FT-4202 in adults and adolescents with SCD. That trial is not yet recruiting participants, but will investigate two doses of FT-4202, versus a placebo, among 344 patients, ages 12-65.
“As we prepare to initiate Forma’s pivotal Phase 2/3 trial, we plan to evaluate whether the combined ability of FT-4202 to increase hemoglobin levels in red blood cells and bring about improved red blood cell health will meaningfully reduce the frequent painful vaso-occlusive crises these patients endure,” Kelly said.
A vaso-occlusive crisis, or VOC, occurs when small blood vessels are blocked, preventing oxygen supply to tissues and causing injury. VOCs, the most common complication of sickle cell anemia, can be acutely painful and often lead to emergency department visits and hospitalization.
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