Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of FTX-6058

• ClinicalTrials.gov Identifier: NCT05169580
• Recruitment Status: Recruiting
• First Posted: December 27, 2021
• Last Update Posted: April 19, 2024
• Sponsor: Fulcrum Therapeutics
• Information provided by (Responsible Party): Fulcrum Therapeutics

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Sickle Cell Disease; Sickle Cell Anemia	Drug: FTX-6058 oral capsule(s)	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 70 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Intervention Model Description: Open-label, multiple-dose study.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: December 13, 2021
• Estimated Primary Completion Date: April 2025
• Estimated Study Completion Date: April 2025

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Treatment-Emergent Adverse Events [ Time Frame: Up to approximately 16 weeks of monitoring ]
   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.
2. Plasma Concentrations of FTX-6058 [ Time Frame: Days 1, 14, 28, 42, 56, 70, 84, 88 and 91 ]
   Blood samples will be collected to measure the plasma concentration of FTX-6058 at specified timepoints.

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Call Center; 617-651-8853; clinicaltrials@fulcrumtx.com

Locations

United States, Florida

Foundation for Sickle Cell Disease Research, LLC; Withdrawn

Hollywood, Florida, United States, 33021

University of Miami Health System; Recruiting

Miami, Florida, United States, 33136

United States, Georgia

Visionaries Clinical Research; Withdrawn

Atlanta, Georgia, United States, 30329

Atlanta Center for Medical Research; Withdrawn

Atlanta, Georgia, United States, 30331

Augusta University; Recruiting

Augusta, Georgia, United States, 30912

United States, Maryland

Axon Clinical Research Institute; Withdrawn

Baltimore, Maryland, United States, 21237

United States, New York

Jacobi Medical Center; Recruiting

Bronx, New York, United States, 10461

United States, North Carolina

University of North Carolina at Chapel Hill; Recruiting

Chapel Hill, North Carolina, United States, 27599

United States, Oklahoma

Lynn Health Science Institute; Recruiting

Oklahoma City, Oklahoma, United States, 73112

United States, Virginia

Virginia Commonwealth University; Recruiting

Richmond, Virginia, United States, 23298

Sponsors and Collaborators

Fulcrum Therapeutics

Investigators

• Study Director: William Engelman, MD; Fulcrum Therapeutics

More Information

Publications:

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.

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.

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.

• Responsible Party: Fulcrum Therapeutics
• ClinicalTrials.gov Identifier: NCT05169580
• Other Study ID Numbers: 6058-SCD-101
• First Posted: December 27, 2021
• Last Update Posted: April 19, 2024
• Last Verified: April 2024

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Fulcrum Therapeutics:

Sickle Cell Disease; Sickle Cell Anemia; Pharmacokinetics; Pharmacodynamics; FTX-6058; Open label

Additional relevant MeSH terms:

Anemia, Sickle Cell; Anemia; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Genetic Diseases, Inborn