Clinical trial NCT05169580: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Pociredir
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Sickle Cell Disease
Sickle Cell Anemia
Keywords: Sickle Cell Disease
Sickle Cell Anemia
Pharmacokinetics
Pharmacodynamics
Pociredir
Open label
Lead sponsor: Fulcrum Therapeutics
Sponsor class: INDUSTRY
First posted: 2021-12-27
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: Open-label, multiple-dose study.
Primary purpose: TREATMENT

Brief summary: This is a study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of Pociredir in participants with sickle cell disease.

Detailed description: This is a Phase 1 multicenter, international, open-label study evaluating the safety, tolerability, pharmacokinetics (PK), fetal hemoglobin (HbF) induction and biological activity of Pociredir 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. A maximum of 3 participants with SCD HbSC+ genotype may be enrolled in each cohort.

Cohort 1 will receive 6 milligrams (mg) of Pociredir 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 Pociredir as measured by the frequency of adverse events and to evaluate single and multiple-dose pharmacokinetics of Pociredir in participants with sickle cell disease. Secondary endpoints include evaluating the effect of Pociredir on fetal hemoglobin induction in peripheral blood and evaluating the effects of Pociredir on hemolysis in participants with sickle cell disease.

Eligibility criteria: Key Inclusion Criteria:

* Participant is 18 to 65 years of age, inclusive at the time informed consent is obtained.
* Documented SCD at the time of screening (S/S, S/β0, S/β+, and S/C only) as confirmed through review of medical records or HPLC.
* Participants who meet at least one the following criteria:

  1. ≥4 to 10 episodes of SCD pain crisis over 12 months, or ≥2 to 5 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
  3. ≥2 of the following events over the previous 12 months:i. ACS ii. Hepatic or splenic sequestration iii. Priapism
  4. Tricuspid regurgitant jet velocity (TRV) ≥ 3.0 meter/second(m/s) OR TRV ≥ 2.5 m/s + N-terminal pro b-type natriuretic peptide (NT-proBNP) plasma level ≥ 160 picogram per milliliter; OR documented ongoing pulmonary hypertension diagnosed from previous echocardiogram or right-sided heart catheterization with mean pulmonary artery pressure \> 25 millimeter of mercury;
  5. SCD-related chronic kidney disease (CKD)
  6. 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) but have shown to be unresponsive and/or intolerant or ineligible AND
* Previous experience with a stable dose of voxelotor, crizanlizumab, and/ or L-glutamine but have shown to be unresponsive and/or intolerant or ineligible
* Per Investigator's recommendation, participants may continue crizanlizumab and/or L-glutamine but must be on a stable dose for at least 6 months
* 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:

  1. Absolute neutrophil count ≥ 1.5 × 10\^9 per liter (/l)
  2. Platelets ≥ 80 × 10\^9/l
  3. Absolute reticulocyte count at screening ≥ 100 x 10\^9/l.

Key Exclusion Criteria:

* Sickle cell complication requiring care from a medical provider in hospital or emergency care setting 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 therapeutic phlebotomies, 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 has 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, or have received HU, within 60 days prior to initiating study drug.

Primary outcomes:
measure: Treatment-Emergent Adverse Events
timeFrame: Up to approximately 16 weeks of monitoring
measure: Plasma Concentrations of Pociredir
timeFrame: Days 1, 14, 28, 42, 56, 70, 84 and 91
Secondary outcomes:
measure: Change from Baseline in percentage fetal hemoglobin (%HbF) biomarkers in peripheral blood
timeFrame: Baseline and at Days 1, 14, 28, 42, 56, 70, 84, 91, and 112
measure: Change from Baseline in % Reticulocytes
timeFrame: Baseline and at Days 1, 14, 28, 42, 56, 70, 84, 91, and 112
measure: Change from Baseline in Absolute Reticulocyte Count
timeFrame: Baseline and at Days 1, 14, 28, 42, 56, 70, 84, 91, and 112
measure: Change from Baseline in Red cell distribution width
timeFrame: Baseline and at Days 1, 14, 28, 42, 56, 70, 84 and 91
measure: Change from Baseline in unconjugated bilirubin
timeFrame: Baseline and at Days 1, 14, 28, 42, 56, 70, 84 and 91
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences (UAMS)
state: Arkansas
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Hollywood
country: United States
facility: Foundation for Sickle Cell Disease Research, LLC
state: Florida
city: Miami
country: United States
facility: University of Miami Health System
state: Florida
city: Atlanta
country: United States
facility: Sonar Research Center
state: Georgia
city: Atlanta
country: United States
facility: Visionaries Clinical Research
state: Georgia
city: Atlanta
country: United States
facility: Atlanta Center for Medical Research
state: Georgia
city: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Baton Rouge
country: United States
facility: Our Lady of the Lake Hospital
state: Louisiana
city: Baltimore
country: United States
facility: Axon Clinical Research Institute
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Madison
country: United States
facility: Mississippi Center for Advanced Medicine
state: Mississippi
city: Bronx
country: United States
facility: Jacobi Medical Center
state: New York
city: Jamaica
country: United States
facility: Queens Hospital Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Oklahoma City
country: United States
facility: Lynn Health Science Institute
state: Oklahoma
city: Houston
country: United States
facility: University of Texas Houston
state: Texas
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Abuja
country: Nigeria
facility: National Hospital, Abuja
city: Ibadan
country: Nigeria
facility: University of Ibadan
city: Kaduna
country: Nigeria
facility: Barau Dikko Teaching Hospital
city: Johannesburg
country: South Africa
facility: Charlotte Maxeke Johannesburg Academic Hospital
Study officials:
affiliation: Fulcrum Therapeutics
name: Adeyemi Adenola, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.