Phase 1 Trial of Oral FTX-6058 to Promote Fetal Hemoglobin Set to Open

FTX-6058, an investigational oral treatment being developed by Fulcrum Therapeutics for sickle cell disease (SCD) and beta-thalassemia, is entering a Phase 1 clinical trial in healthy volunteers, the company announced.

The trial (NCT04586985), not yet enrolling, aims to recruit 88 adults at its single Altasciences Clinical Kansas site. The goal is to determine the treatment’s safety and tolerability, as single and multiple ascending doses, as well as the effect of foods on its metabolism.

“A major unmet need remains for many sickle cell patients, and the availability of an effective and safe small molecule treatment option could represent a significant advancement,” Robert J. Gould, PhD, president and CEO of Fulcrum Therapeutics, said in a press release. “We believe FTX-6058 offers a differentiated approach to a potential treatment.”

SCD and beta-thalassemia are both genetic disorders caused by mutations in the gene coding for hemoglobin, the protein in red blood cells responsible for transporting oxygen. While in SCD a mutated form of this protein deforms the shape of the red blood cells, the production of hemoglobin is reduced in beta-thalassemia.

FTX-6058 is an oral small molecule designed to compensate for the lack of the adult hemoglobin by increasing the levels of fetal hemoglobin — a form of hemoglobin produced during fetal development that is more effective at transporting oxygen than its adult counterpart.

By raising fetal hemoglobin levels, FTX-6058 is expected to improve oxygen transport throughout the body, alleviating disease symptoms.

Preclinical studies in patient-derived red blood cells showed that FTX-6058 increased fetal hemoglobin levels by about 8–18%, a greater increase than the 5% thought to be clinically beneficial to sickle cell patients. After treatment, up to 30% of total hemoglobin in these cells was fetal hemoglobin.

In animal models of disease, the treatment also increased protein levels at a greater extent than hydroxyurea, an approved SCD medication, and showed a profile that supports once-daily use.

“We are excited about the preclinical data that showed elevations of fetal hemoglobin up to 30% of total hemoglobin. Should this elevation be seen in sickle cell patients, it has the potential to address multiple symptoms, including painful crises and anemia,” Gould said.

The upcoming Phase 1 trial will be divided in four parts to assess the safety and tolerability of FTX-6058 in healthy volunteers. In Parts A and B, participants will be randomly assigned to a placebo or to ascending doses of FTX-6058. Treatment will be given in a single dose in Part A, while those in Part B will take it daily for two weeks.

A total of six groups, each containing five people, will be included in Part A, with dosing starting at 2 mg and rising up to 90 mg. Part B, with up to four groups (eight people each), will test doses ranging from 2 mg up to 20 mg.

In Part C, researchers will evaluate the effects of fat-rich foods on FTX-6058’s metabolism. A total of 10 people will take FTX-6058 within 30 minutes of a high-fat meal, followed by a second dose of the therapy, given without food about seven days later (after washout period). The dose used in this part will be half of the highest tolerated dose in Part A.

Finally, 16 people in Part D will be given FTX-6058 plus the sedative midazolam to assess the therapy’s ability to induce CYP3A, an important molecule for drug clearance from the body. (Midazolam is considered a “gold standard” probe for CYP3A activity.)

In addition to safety and tolerability, researchers will also evaluate the treatment’s pharmacokinetics (its movement into, through, and out of the body), as well as changes in fetal hemoglobin production.