Fulcrum Therapeutics Announces Additional HBG mRNA Induction from Higher Dose Cohorts in Phase 1 Healthy Adult Volunteer Trial of FTX-6058 for Sickle…

Achieved mean 5.6-fold HBG mRNA induction at 20mg and mean 6.2-fold at 30mg after 14 days of once-daily dosing, further supporting potential of FTX-6058 to provide a functional cure

Continues to be well-tolerated at higher doses with no serious adverse events observed to date

New mechanism data demonstrate potent downregulation of BCL11A and MYB, key repressors of fetal hemoglobin

On track to initiate enrollment in Phase 1b clinical trial in people with sickle cell disease and to submit an IND for treatment of other hemoglobinopathies by year-end 2021

Company to review results on conference call, including guest KOL Dr. Gerd Blobel, at 8:00 am ET today

CAMBRIDGE, Mass., Dec. 06, 2021 (GLOBE NEWSWIRE) -- Fulcrum Therapeutics, Inc. (Nasdaq: FULC), a clinical-stage biopharmaceutical company focused on improving the lives of patients with genetically defined rare diseases, today announced positive results from the 20mg and 30mg dose cohorts in healthy adult volunteers in its Phase 1 clinical trial of FTX-6058. The company also shared new preclinical mechanism data showing that FTX-6058 downregulated known repressors of fetal hemoglobin (HbF). FTX-6058 is an investigational oral HbF inducer that is being developed for the treatment of sickle cell disease and other hemoglobinopathies, such as beta-thalassemia.

Data from the 20mg and 30mg dose cohorts demonstrated a mean 5.6-fold induction and a mean 6.2-fold induction in HBG mRNA, respectively, at day 14. These increases were higher than those observed in the previously reported 2, 6 and 10mg dose cohorts. In preclinical studies of FTX-6058, increases in HBG mRNA have consistently translated to the same fold increases in HbF protein. Notably, human genetics show that 2-3-fold increases in HbF are associated with significantly improved outcomes, and even functional cures, in people with sickle cell disease. FTX-6058 has now demonstrated greater than a mean 2-fold induction starting with the 6mg dose.

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Despite progress in the treatment of sickle cell disease, existing therapies either offer limited benefit or, in the case of gene therapy, are not amenable to the great majority of patients and carry certain risks, said Gerd Blobel, MD, PhD, Frank E. Weise III Endowed Chair in Pediatric Hematology at Childrens Hospital of Philadelphia. The strategy of increasing the levels of fetal hemoglobin is based on solid genetic and clinical data. It can substantially reduce mortality and morbidity, and in cases where HbF reaches greater than 25-35% of total hemoglobin, lead to asymptomatic disease. The emerging clinical data on FTX-6058, combined with the new preclinical data showing that it downregulates BCL11A and MYB, two validated HbF repressors, is encouraging.

The data for FTX-6058 continue to exceed our expectations, said Bryan Stuart, Fulcrums president and chief executive officer. We believe the fold increases in HBG mRNA that we have now seen at multiple doses, starting at 6mg once-daily, have the potential to translate to levels of HbF protein that could provide a functional cure for people with sickle cell disease. Additionally, with the new insights into the mechanism of action, there's now a clear relationship between FTX-6058 and HbF induction that further affirms our conviction. We remain on track to begin enrolling people with sickle cell disease in our Phase 1b trial by year-end, with an eye toward reporting initial data, including HbF protein levels, in the second quarter of next year.

FTX-6058 Continues to be Well-Tolerated and Achieved Maximal HBG mRNA Induction at Higher Doses

The Phase 1 randomized, double-blind, placebo-controlled trial was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of ascending doses of FTX-6058 (NCT04586985). In the single-ascending dose (SAD) cohorts, healthy volunteers received one dose of either placebo or 2, 4, 10, 20, 30, 40 or 60mg of FTX-6058. In the multiple-ascending dose (MAD) cohorts, healthy volunteers received a once-daily dose of placebo or 2, 6, 10, 20 or 30mg of FTX-6058 for 14 consecutive days. Each MAD cohort had six subjects on drug and two on placebo. Food effect was also studied in a separate 20mg dose cohort. Exploratory measures were included in the MAD cohorts to assess target engagement, as well as changes in HBG mRNA and HbF-containing reticulocytes (F-reticulocytes). A 6mg dose cohort in people with sickle cell disease was recently added to this trial to further inform PK and pharmacodynamic modeling for future dose selection. All other cohorts in the trial have been completed, and data from the 2-40mg SAD cohorts and 2-10mg MAD cohorts were reported in August 2021.

Consistent with the earlier reported data, FTX-6058 has been generally well-tolerated with no serious adverse events reported to date and there were no discontinuations due to treatment-emergent adverse events (TEAEs) across all SAD and MAD cohorts. Across all cohorts, all TEAEs deemed possibly related to FTX-6058 were mild (Grade 1 or 2) and resolved. There was one Grade 4 TEAE in the 10mg MAD cohort and one Grade 3 TEAE in the food effect cohort, both of which were determined to be unrelated to FTX-6058. Data continued to show dose-proportional PK, with a mean half-life of approximately 6-7 hours in the MAD cohorts, supporting once-daily dosing, and no food effect was observed with FTX-6058. Data from the MAD cohorts continued to show robust target engagement, as evidenced by an approximately 75-95% reduction from baseline in H3K27me3 after 14 days of treatment.

The data also showed higher-fold induction of HBG mRNA at the higher doses, with FTX-6058 achieving maximal rate of HBG mRNA induction in the 20mg and 30mg cohorts. Maximal HBG induction has not yet been achieved with the higher doses of FTX-6058. Persistent HBG mRNA induction was observed for 7-10 days after treatment. F-reticulocytes also increased by a mean of 1.8-fold in the 20mg cohort and a mean of 2.4-fold in the 30mg cohort as of the safety follow up visit, which was seven to 10 days after conclusion of dosing. Increases in F-reticulocytes of any magnitude are a first indicator that HBG mRNA is translating to HbF protein production, which Fulcrum anticipates observing in the Phase 1b trial that will dose people with sickle cell disease for up to three months.

HBG mRNA Mean Fold Induction for FTX-6058 versus Placebo

2mg*

6mg*

10mg*

20mg

30mg

Mean FoldInduction

P-value

Mean FoldInduction

P-value

Mean FoldInduction

P-value

Mean FoldInduction

P-value

Mean FoldInduction

P-value

Day 7

1.28

0.3494

1.94

0.0135

2.08

0.0063

2.06

0.0072

2.29

0.0025

Day 14

1.20

0.5122

2.45

0.0025

3.54

<0.0001

5.63

<0.0001

6.15

<0.0001

Safety Follow-up (Day 21-24)

1.21

0.3736

2.75

<0.0001

3.22

<0.0001

6.45

<0.0001

6.13

<0.0001

F-Reticulocyte Mean Fold Increase for FTX-6058 versus Placebo

2mg*

6mg*

10mg*

20mg

30mg

Mean FoldIncrease

P-value

Mean FoldIncrease

P-value

Mean FoldIncrease

P-value

Mean FoldIncrease

P-value

Mean FoldIncrease

P-value

Day 7

0.53

0.1070

1.02

0.9524

0.83

0.6214

0.71

0.3831

1.50

0.2928

Day 14

0.88

0.6881

1.25

0.4895

2.23

0.0180

1.00

0.9880

1.71

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Fulcrum Therapeutics Announces Additional HBG mRNA Induction from Higher Dose Cohorts in Phase 1 Healthy Adult Volunteer Trial of FTX-6058 for Sickle...