FTX-6058 is an experimental small molecule treatment for sickle cell disease (SCD) being developed by Fulcrum Therapeutics. It aims to treat patients by raising levels of fetal hemoglobin in cells.
SCD is a rare blood disorder caused by mutations in the HBB gene. This gene contains the instructions necessary for cells to produce beta-globin. Beta-globin is an integral part of hemoglobin, the molecule in red blood cells that transports oxygen throughout the body.
Mutations in the HBB gene lead to an abnormal beta-globin protein and results in the formation of hemoglobin S (HbS). HbS molecules stick together and lead to the sickling of red blood cells.
How does FTX-6058 work?
FTX-6058 is a small molecule, meaning oral, therapy that researchers designed to increase the production of fetal hemoglobin (HbF). HbF is the predominant form of hemoglobin during development in the womb. Its amount slowly decreases throughout infancy as the adult version of hemoglobin, hemoglobin A (HbA) replaces it.
Researchers hope that increasing the amount of HbF — fetal hemoglobin is more effective at carrying oxygen in cells than its adult version — will help to prevent the sickling of red blood cells, and ease disease symptoms by improving blood flow and oxygen transport.
Preclinical studies in healthy and SCD donor cells showed an “absolute 8–18% increase in HbF” upon treatment with FTX-6058, the company reported, and its use in a mouse model of SCD safely raised HbF levels higher than hydroxyurea, a U.S. Food and Drug Administration approved disease treatment that also targets fetal hemoglobin.
FTX-6058 in clinical trials
A randomized and placebo-controlled Phase 1 clinical trial (NCT04586985) is investigating the safety, tolerability, and pharmacokinetics (movement in the body) of FTX-6058 in healthy adults. It is enrolling around 88 individuals, ages 18 to 55, at its single site in Kansas to participate in one of trial’s four parts.
In Part A, six groups of five people will each receive a single oral dose of FTX-6058 or a placebo. Successively higher single doses, ranging from 2 mg up to 90 mg, will be given to some in each group (with others getting a placebo).
Up to four groups, each with eight people, will make up Part B. Here, doses ranging from 2 mg up to 20 mg will be given to select participants in each group daily for two weeks.
Researchers will evaluate the effects of fat-rich foods on the metabolism of FTX-6058 in Part C. Ten people will receive half the maximum tolerated dose of FTX-6058 determined in Part A 30 minutes after a high-fat meal, followed by another dose without food about seven days later.
In Part D, FTX-6058 in addition to midazolam, a sedative, will be given to 16 people to determine how the treatment affects the body’s ability to make CYP3A, an enzyme involved in the metabolism and clearance of drugs (midazolam is an established probe of CYP3A activity). Midazolam will be given as a syrup on day one and day 12, and FTX-6058 capsules — at the highest tolerated dose seen in Part B — on days three through 12. CYP3A levels will be measured at the start and end of this part to evaluate changes.
This trial is due to conclude in September 2021.
Researchers are also investigating FTX-6058 as a treatment for beta-thalassemia, another rare blood disorder caused by mutations in the HBB gene.
Last updated: Jan. 28, 2021
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