Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of FTX-6058

A Phase 1 Open-Label, Multiple-Dose Study to Evaluate Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of FTX-6058 in Subjects With Sickle Cell Disease (SCD)

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

Study Overview

• Status: Recruiting
• Conditions: Sickle Cell Disease; Sickle Cell Anemia
• Intervention / Treatment: Drug: FTX-6058 oral capsule(s)

Detailed Description

This is a Phase 1 multicenter, open-label study evaluating the safety, tolerability, pharmacokinetics (PK), fetal hemoglobin (HbF) induction and biological activity of FTX-6058 in participants 18-65 years of age, inclusive, with SCD.

Participants will receive 12 weeks of dosing with 4 weeks of follow-up. Approximately 10 participants will be enrolled in each cohort.

Cohort 1 will receive 6 milligrams (mg) of FTX-6058 by mouth once daily. Doses for subsequent cohorts will be determined following review by the Data Monitoring Committee [DMC]. A total of seven cohorts may be included. Cohort 2 will be dosed at 2 mg once daily by mouth, and cohort 3 will be dosed at 12 mg once daily by mouth. The Sponsor will reinitiate enrolment in the 3rd cohort (12 mg cohort) with the updated inclusion and exclusion criteria. Based on review of available safety and biomarker data and with the recommendation of the DMC, a subsequent 4th cohort of 20 mg and potentially a 5th cohort of 30 mg may be initiated. Additional cohorts using alternative dosing schedules may be considered based on available data.

The primary endpoints of the study are to evaluate the safety and tolerability of FTX-6058 as measured by the frequency of adverse events and to evaluate single and multiple-dose pharmacokinetics of FTX-6058 in participants with sickle cell disease. Secondary endpoints include evaluating the effect of FTX-6058 on fetal hemoglobin induction in peripheral blood and evaluating the effects of FTX-6058 on hemolysis in participants with sickle cell disease.

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Call Center; Phone Number: 617-651-8853; Email: clinicaltrials@fulcrumtx.com

Study Locations

• United States
  • Florida
    • Hollywood, Florida, United States, 33021
      • Withdrawn
      • Foundation for Sickle Cell Disease Research, LLC
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami Health System
  • Georgia
    • Atlanta, Georgia, United States, 30331
      • Withdrawn
      • Atlanta Center for Medical Research
    • Atlanta, Georgia, United States, 30329
      • Withdrawn
      • Visionaries Clinical Research
    • Augusta, Georgia, United States, 30912
      • Recruiting
      • Augusta University
      • Contact: Krystle Stone; Phone Number: 706-723-0008; Email: kstone6@augusta.edu
  • Maryland
    • Baltimore, Maryland, United States, 21237
      • Withdrawn
      • Axon Clinical Research Institute
  • New York
    • Bronx, New York, United States, 10461
      • Recruiting
      • Jacobi Medical Center
      • Contact: Raven Dwyer, MPH; Phone Number: 718-918-7070; Email: dwyerr1@nychhc.org
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Recruiting
      • University of North Carolina at Chapel Hill
      • Contact: David Wichlan; Phone Number: 919-966-6876; Email: dwichlan@med.UNC.edu
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Recruiting
      • Lynn Health Science Institute
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Recruiting
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Participant is 18 to 65 years of age, inclusive at the time informed consent is obtained.

• Participants who meet at least one the following criteria:

  1. ≥4 episodes of SCD pain crisis over 12 months, or ≥2 over 6 months prior to screening
  2. ≥2 episodes of SCD pain crisis plus at least one of the following over previous 12 months:

  i. Acute chest syndrome (ACS) ii. Hepatic or splenic sequestration iii. Priapism c. ≥2 of the following events over the previous 12 months: i. ACS ii. Hepatic or splenic sequestration iii. Priapism d. SCD-related pulmonary arterial hypertension e. SCD-related chronic kidney disease (CKD) f. Meet medical criteria to receive (e.g., post-cerebrovascular accident) but are contraindicated for chronic transfusions (e.g., alloimmunization, transfusion reactions)

• Previous experience with Hydroxyurea (HU) use for at least 6 months at the maximum tolerated dose but have shown to be unresponsive and/or intolerant or ineligible AND
• Previous experience with a stable dose of voxelotor, crizanlizumab, or L-glutamine for at least 6 months but have shown to be unresponsive and/or intolerant or ineligible
• Documented SCD at the time of screening (S/S, S/β0 and S/β+ genotypes only).
• Documented HbF ≤ 20% of total Hb.
• Total Hb ≥ 5.5 g/dL and ≤ 12 g/dL (males) or ≤ 10.6 g/dL (females) at screening.

• Participant must meet both of the following laboratory values at screening:

  • Absolute neutrophil count ≥ 1.5 × 10^9 per liter (/L)
  • Platelets ≥ 80 × 10^9/L
• Absolute reticulocyte count at screening ≥ 100 x 10^9/L.

Key Exclusion Criteria:

• Sickle cell complication requiring care from a medical provider in the 14 days prior to starting study drug.
• History of bone marrow transplant or human stem cell transplant or gene therapies.
• Participants with a history of severe renal disease defined as estimated glomerular filtration rate < 30 mL/min/1.73m^2. Participants on dialysis of any kind are excluded.
• Participants receiving regularly scheduled transfusions or any participant who has been transfused within 60 days prior to initiating study drug.
• Participant with active malignancy, or history of cancer (except for squamous cell skin cancer, basal cell skin cancer, and stage 0 cervical carcinoma in situ, with no recurrence for the last 5 years), or with an immediate family member with known or suspected familial cancer syndrome. Known presence of a chromosomal abnormality or genetic mutation that may put the participant at an increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
• Participant currently on HU, voxelotor, crizanlizumab, and/ or L-glutamine or have received HU, voxelotor, crizanlizumab, and/ or L-glutamine within 60 days prior to initiating study drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: FTX-6058 oral capsule(s) in Sickle Cell participants; Cohort 1 will receive 6 mg of FTX-6058 by mouth once daily. Cohort 2 will be dosed at 2 mg once daily by mouth, and cohort 3 will be dosed at 12 mg once daily by mouth. The Sponsor will reinitiate enrolment in the 3rd cohort (12 mg cohort) with the updated inclusion and exclusion criteria. Based on review of available safety and biomarker data and with the recommendation of the DMC, a subsequent 4th cohort of 20 mg and potentially a 5th cohort of 30 mg may be initiated. A total of seven cohorts may be included. Following the first cohort, doses for all subsequent cohorts will be determined following DMC review of the safety and pharmacokinetic data observed in participants from the prior and ongoing cohorts. Alternate dosing schedules may be evaluated in some of the cohorts.

Drug: FTX-6058 oral capsule(s); Participants will receive FTX-6058

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-Emergent Adverse Events	To evaluate the safety and tolerability of FTX-6058 in adult participants with sickle cell disease based on the frequency of adverse events (AEs) and changes in clinically significant laboratory test results, vital signs and electrocardiograms (ECGs) parameters.	Up to approximately 16 weeks of monitoring
Plasma Concentrations of FTX-6058	Blood samples will be collected to measure the plasma concentration of FTX-6058 at specified timepoints.	Days 1, 14, 28, 42, 56, 70, 84, 88 and 91

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in percentage fetal hemoglobin (%HbF) biomarkers in peripheral blood	The percentage of HbF will be measured in peripheral whole blood by high performance liquid chromatography (HPLC).	Baseline and at Days 1, 14, 28, 42, 56, 70, 84, 88, 91, and 112
Change from Baseline in % Reticulocytes	The percentage of reticulocytes will be measured in peripheral whole blood by flow cytometry.	Baseline and at Days 1, 14, 28, 42, 56, 70, 84, 88, 91, and 112
Change from Baseline in Absolute Reticulocyte Count	The absolute reticulocyte count will be measured in peripheral whole blood by microscopy/cytometry.	Baseline and at Days 1, 14, 28, 42, 56, 70, 84, 88, 91, and 112
Change from Baseline in Red cell distribution width	Blood samples will be collected for the analysis of hematology parameter: red cell distribution width	Baseline and at Days 1, 14, 28, 42, 56, 70, 84 and 91
Change from Baseline in unconjugated bilirubin	Blood samples will be collected for the analysis of clinical chemistry parameter: unconjugated bilirubin	Baseline and at Days 1, 14, 28, 42, 56, 70, 84 and 91

Collaborators and Investigators

• Sponsor: Fulcrum Therapeutics
• Investigators: Study Director: William Engelman, MD, Fulcrum Therapeutics

Publications and helpful links

General Publications

• Piel FB, Steinberg MH, Rees DC. Sickle Cell Disease. N Engl J Med. 2017 Apr 20;376(16):1561-1573. doi: 10.1056/NEJMra1510865. No abstract available.
• Ngo DA, Aygun B, Akinsheye I, Hankins JS, Bhan I, Luo HY, Steinberg MH, Chui DH. Fetal haemoglobin levels and haematological characteristics of compound heterozygotes for haemoglobin S and deletional hereditary persistence of fetal haemoglobin. Br J Haematol. 2012 Jan;156(2):259-64. doi: 10.1111/j.1365-2141.2011.08916.x. Epub 2011 Oct 24.
• Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med. 2013 Jan 1;3(1):a011643. doi: 10.1101/cshperspect.a011643.
• Saraf SL, Molokie RE, Nouraie M, Sable CA, Luchtman-Jones L, Ensing GJ, Campbell AD, Rana SR, Niu XM, Machado RF, Gladwin MT, Gordeuk VR. Differences in the clinical and genotypic presentation of sickle cell disease around the world. Paediatr Respir Rev. 2014 Mar;15(1):4-12. doi: 10.1016/j.prrv.2013.11.003. Epub 2013 Nov 15.
• Steinberg MH, Chui DH, Dover GJ, Sebastiani P, Alsultan A. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood. 2014 Jan 23;123(4):481-5. doi: 10.1182/blood-2013-09-528067. Epub 2013 Nov 12.

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2021
• Primary Completion (Estimated): April 1, 2025
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: December 14, 2021
• First Submitted That Met QC Criteria: December 23, 2021
• First Posted (Actual): December 27, 2021

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Sickle Cell Disease; Pharmacodynamics; Open label; Sickle Cell Anemia; FTX-6058
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell
• Other Study ID Numbers: 6058-SCD-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No