Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of FTX-6058

• Status: Recruiting
• Trial end date: 2022-11-01
• Target enrollment: 0
• Participant gender: All

Summary

This is a study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of FTX-6058 in subjects with sickle cell disease.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Fulcrum Therapeutics

Criteria

Inclusion Criteria:

1. Subject is 18 to 65 years of age at the time informed consent is obtained. For subjects under the age of 18, informed consent will be collected according to applicable local regulations.

2. Subject has signed and dated informed consent before any study-specific procedures are performed and is willing and able to comply with the study procedures and restrictions.

3. Subjects, who if female and of childbearing potential, agree to use 2 highly effective methods of contraception or practicing abstinence starting at the time of the informed consent form (ICF) signing to 90 days after the last dose of study drug, and, who if male, agree to use 2 methods of contraception or practice abstinence from the time of informed consent form (ICF) signing to 90 days after the last dose of study drug

4. Body mass index (BMI) between 18 and 32 kg/m2, inclusive at screening, and with a minimum weight of 50 kg

5. Confirmed SCD at the time of screening (SS and S/β0 genotypes only)

6. If on hydroxyurea (HU) at time of first dose of study drug, a stable dose for a minimum of 3 months is required. If not on HU at time of first dose of study drug, the subject must have been off HU for a minimum of 60 days.

7. HbF ≤20% of total Hb at screening by high performance liquid chromatography (HPLC).

8. SCD characterized by both of the following:

• Total hemoglobin between 5.5 and 12 g/dL at screening

• 0-6 Vaso-Occlusive Crisis (VOC) episodes over the 12 months prior to screening. A VOC is defined as any event that requires an acute care visit for IV fluid or IV opioid administration.

9. Subject must meet both of the following laboratory values prior to Week 1 Day 1:

• Absolute neutrophil count ≥1.5 × 109/L

• Platelets ≥80 × 109/L

10. Absolute reticulocyte count at screening higher than 100 × 109/L

11. Subjects must have a negative polymerase chain reaction for SARS-CoV-2 at screening.

Exclusion Criteria:

1. Major surgery, hospitalization, infection, significant bleeding, cerebrovascular accident or seizure, or transfusion within 14 days prior to study enrollment through conclusion of study follow-up period; elective surgery planned for the time period of the trial.

2. Sickle cell complication requiring hospitalization in the past 14 days or > 6 total VOCs over the past 12 months requiring hospitalization for ≥ 24 hours.

3. Use of voxelotor within 60 days prior to starting study drug

4. Use of anticoagulants, L-glutamine, crizanlizumab, or medications that induce or inhibit cytochrome P4503A4 (CYP3A4) within 14 days prior to first dose of study drug or anticipated need for any of these medications during the study.

5. Participation in any other investigative treatment studies other than with FTX-6058 within the past 60 days.

6. History of bone marrow transplant or human stem cell transplant or gene therapies.

7. Vaccination (including against COVID-19) in the previous 30 days.

8. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3× the upper limit of normal (ULN) or albumin <2.0 mg/dL or direct (conjugated) bilirubin ≥1.5 mg/dL or prothrombin time >1.5 ULN.

9. Subjects with end stage renal disease defined as glomerular filtration rate (GFR) <10 mL/min/1.73m2 using Schwartz formula or serum creatinine >1.2 mg/dL and calculated creatinine clearance <30 mL/min. Subjects on dialysis of any kind are excluded.

10. Subjects with abnormal laboratory results or medical history indicative of any significant medical disease that, in the opinion of the Investigator, would preclude the subject's participation in the study or potentially obscure the interpretation of the scheduled assessments. Screening laboratory assessments may be repeated up to twice at the discretion of the Investigator.

11. Subjects being treated with antiretroviral agents (such as didanosine and stavudine) because of a higher risk for potentially fatal pancreatitis, hepatic failure, hepatitis, and severe peripheral neuropathy when co-administered with HU.

12. Infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C such that subjects are currently on therapy or will be placed on therapy during the trial

13. Subjects receiving regularly scheduled transfusions to reduce levels of sickle hemoglobin (HbS), or any subject who has been transfused in the last 60 days.

14. Clinically diagnosed substance use disorder for alcohol or other illicit drugs of abuse. A positive urine drug screen for illicit drugs of abuse (other than opioids and marijuana/ tetrahydrocannabinol [THC]/ cannabidiol [CBD]) is exclusionary.

15. Pregnant or lactating female; or female of childbearing age unable or unwilling to comply with birth control or abstinence during the course of the study.

16. Febrile illness in the 7 days prior to baseline visit

17. Subject is investigative site personnel or member of their immediate family (spouse, parent, child or sibling whether biological or legally adopted).

18. Heart rate corrected QT interval-Frederica's method (QTcF) >450 msec male and >470 msec female.