Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of FTX-6058

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

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.

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)

Conditions
-----------------
Sickle Cell Disease, Sickle Cell Anemia

Intervention / Treatment
-----------------
* Drug: FTX-6058 oral capsule(s)


Participation Criteria
=================
Eligibility 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: ≥4 episodes of SCD pain crisis over 12 months, or ≥2 over 6 months prior to screening ≥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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Open-label, multiple-dose study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FTX-6058 oral capsule(s) in Sickle Cell participants<br>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)<br>* Participants will receive FTX-6058<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sickle Cell Disease, Sickle Cell Anemia, Pharmacokinetics, Pharmacodynamics, FTX-6058, Open label