FTX-6058 Shows Promise in Raising Fetal Hemoglobin in Healthy Adults
FTX-6058, an investigational oral treatment being developed by Fulcrum Therapeutics for sickle cell disease (SCD) and beta-thalassemia, was found to be effective at raising the levels of fetal hemoglobin in healthy adults enrolled in a Phase 1 trial, according to new interim results.
Study data also indicated that FTX-6058 was generally well-tolerated, with no serious adverse events reported to date.
“These results with FTX-6058 are very encouraging,” Julie Kanter, MD, co-director of the Lifespan Comprehensive Sickle Cell Center at the University of Alabama at Birmingham, said in a press release. “Tremendous unmet need exists for many people with sickle cell disease and the availability of an effective, tolerable, oral, once-daily treatment option could represent a significant advancement.”
Fetal hemoglobin (HbF), a form of hemoglobin produced during fetal development, is more effective at transporting oxygen throughout the body than its adult counterpart.
SCD and beta-thalassemia are both hemoglobinopathies, or genetic disorders caused by mutations in the gene coding for hemoglobin — the protein in red blood cells responsible for transporting oxygen.
FTX-6058, an oral small molecule designed to boost the production of fetal hemoglobin, is expected to improve oxygen transport throughout the body, thereby alleviating disease symptoms.
The Phase 1 trial will assess the safety, tolerability, and pharmacokinetics of FTX-6058 in healthy volunteers. Pharmacokinetics refers to the movement of a medicine into, through, and out of the body.
Participants were randomly assigned to receive single or multiple ascending doses of FTX-6058 or a placebo. Single dosing started at 2 mg, rising up to 40 mg to date, while multiple ascending doses ranged so far from 2 mg up to 10 mg, once-daily, for 14 days.
The new interim results showed that multiple ascending doses of FTX-6058 led to proportional increases in HbF levels, both at the RNA and protein levels. RNA is the molecule cells use as a template to produce proteins. Increases in HbF protein levels were deduced from observations showing an increase in the number of F-reticulocytes — immature red blood cells that produce HbF.
After being given for 14 days at a dose of 10 mg, FTX-6058 increased HBG RNA levels by more than fourfold compared with a placebo. The number of HbF-producing reticulocytes also increased by more than fourfold at a safety follow-up carried out from days 21 to 24. HBG is the gene that provides instructions for making a portion of HbF.
Both 6 mg and 10 mg doses led to maximal activation of the HBG gene, as shown by a reduction of 70%–80% in the levels of a repressive gene activity marker.
No serious adverse events or discontinuations have been reported. All potentially treatment-related adverse events were mild in both the single- and multiple-ascending dose groups. A single severe adverse event reported in the 10 mg multiple-ascending dose group was deemed to be unrelated to FTX-6058.
Fulcrum is planning to present additional results from the trial at a medical meeting later this year.
“We are very pleased with the interim results from this clinical trial of FTX-6058, which demonstrated compelling results,” said Bryan Stuart, Fulcrum’s president and chief executive officer.
“We are excited to have been able to demonstrate proof of mechanism and proof of biology, as evidenced by … increases in fetal hemoglobin parameters, including HBG mRNA and F-reticulocytes,” Stuart said, adding these effects were further supported by a favorable pharmacological and safety profile.
Based on these interim results, the company is now planning to initiate a Phase 1b trial of FTX-6058 in people with SCD. Enrollment is expected to begin later this year.
Participants will receive multiple doses of the investigational therapy, starting at 6 mg once-daily for up to three months. Data from this study may also be used as the basis for a potential Phase 2/3 trial, provided it demonstrates FTX-6058’s ability to trigger HbF production in SCD patients.
Also, Fulcrum plans to submit a formal request — in the form of an investigational new drug application — to launch a clinical trial to evaluate FTX-6058 in patients with other hemoglobinopathies besides SCD, namely beta-thalassemia, by year-end.
Previous preclinical data “demonstrated consistent 2-3-fold induction of HBG mRNA and HbF protein both in vitro and in vivo,” said Stuart.
“These clinical results reported today not only underscore the consistency observed preclinically, but also demonstrate the first evidence that FTX-6058 can achieve or exceed these preclinical thresholds predicted to provide meaningful clinical benefits to individuals with SCD,” he added. “We look forward to moving this program forward into a trial in people living with sickle cell disease in the fourth quarter of 2021.”