Positive interim results from Phase I study for sickle cell disease treatment

Massachusetts-headquartered Fulcrum Therapeutics has announced positive interim results from the ongoing single and multiple-ascending dose (SAD and MAD) Phase I trial with FTX-6058 in healthy adult volunteers.

FTX-6058 is an investigational, potent and selective small molecule inhibitor of EED designed to increase the expression of fetal hemoglobin (HbF) with the potential to treat hemoglobinopathies, such as sickle cell disease and beta-thalassemia. Results from the MAD portion of the trial demonstrated proof of biology as evidenced by a dose proportional induction in HBG mRNA and accompanying increases in HbF-containing reticulocytes (F-reticulocytes).

At 10mg, the highest dose studied to date, the mean changes were 4.5-fold and 4.2-fold respectively. The increases in F-reticulocytes indicate that the HBG mRNA increases observed with FTX-6058 treatment are translating to HbF protein production. Additionally, all FTX-6058 doses in the MAD portion of the trial achieved maximal target engagement as evidenced by decreases in trimethylation at lysine 27 of histone H3 (H3K27me3), a downstream target of the polycomb repressive complex 2 (PRC2). These proof of mechanism results were achieved with once-daily, oral administration of FTX-6058 for 14 consecutive days, which was also generally well-tolerated in all SAD and MAD cohorts completed to date.

“These results with FTX-6058 are very encouraging,” said Julie Kanter, Managing Director and Co-Director at Lifespan Comprehensive Sickle Cell Center at the University of Alabama in Birmingham. “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.”

“We are very pleased with the interim results from this clinical trial of FTX-6058, which demonstrated compelling results across all primary, secondary, and exploratory endpoints included in this study,” said Bryan Stuart, Fulcrum’s President and CEO. “We are excited to have been able to demonstrate proof of mechanism and proof of biology, as evidenced by maximal target engagement and increases in fetal hemoglobin parameters, including HBG mRNA and F-reticulocytes. These PD effects were further supported by predictable pharmacokinetics and being generally well tolerated.”

Stuart continued: “Preclinically, we demonstrated consistent two- to three-fold induction of HBG mRNA and HbF protein both in vitro and in vivo. 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. We look forward to moving this program forward into a trial in people living with sickle cell disease in the fourth quarter of 2021.”

The Phase I randomised, double-blind, placebo-controlled trial is designed to evaluate the safety, tolerability and pharmacokinetics of FTX-6058 (NCT04586985). In the SAD portion of the trial, healthy volunteers have received to date a single oral dose of either placebo or two, four, 10, 20, 30 or 40mg of FTX-6058. In the MAD portion of the trial, healthy volunteers have received to date a single oral dose of placebo or two, six or 10 mg of FTX-6058 daily for 14 consecutive days. Safety assessments are performed regularly throughout the trial.

The trial is also collecting secondary pharmacokinetic measurements, including bioavailability and half-life assessments. Exploratory measures were included to assess target engagement, HBG mRNA changes and F-reticulocyte changes. Target engagement of FTX-6058 was assessed as a change from baseline in H3K27me3/Total Histone H3 ratio in circulating monocytes. Pharmacodynamic parameters assessed include changes in HBG mRNA and F-reticulocytes. Subjects were seen seven to 10 days after the conclusion of study drug or placebo for a safety follow-up.

Results from the MAD cohorts showed maximal target engagement as evidenced by 70% – 80% reduction in baseline H3K27me3 levels. The 10mg dose showed a mean 4.5-fold induction in HBG mRNA at day 14 and mean 4.2-fold increases in F-reticulocytes at the safety follow-up, indicating increased HbF protein expression. The kinetics observed across the target engagement and pharmacodynamic endpoints are consistent with the process of erythropoiesis in healthy individuals. These results demonstrated a time and dose-dependent relationship between target engagement, mRNA induction and F-reticulocyte increases.

There were no serious adverse events reported and no discontinuations. All treatment-emergent adverse events (TEAEs) deemed at least possibly related were mild (Grade 1 or 2) in both the SAD and MAD cohorts. There was one Grade 4 TEAE in the 10mg MAD cohort, which was determined to be unrelated to FTX-6058. No clinically significant changes in safety-related laboratory tests were reported during treatment periods for any of the FTX-6058 dose cohorts included in the analysis.

Based on these results, Fulcrum anticipates initiating enrolment in a clinical trial in sickle cell patients in the fourth quarter of 2021. The Phase Ib trial will be an open-label multi-dose trial starting at 6mg once-daily dosing and will include a treatment period of up to three months. This trial could provide the opportunity to demonstrate HbF protein induction in people living with sickle cell disease and will be used to help inform a potential Phase II/III trial.

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