A SAD/MAD to Assess the Safety, PK/PD of FT-4202 in Healthy Volunteers and Sickle Cell Disease Patients

NCT03815695 | Completed Phase 1 FDA Drug

• 1 other identifier: 4202-HVS-101
• Study Type: interventional
• Target: 130
• Locations: 1 country
• Sites: 18

Brief Summary

FT-4202 is an oral small-molecule agonist of pyruvate kinase red blood cell isozyme (PKR) being developed for the treatment of hemolytic anemias. This initial study will characterize the safety, tolerability and the pharmacokinetics/pharmacodynamics (PK/PD) of a single ascending dose and multiple ascending doses of FT-4202 in the context of Phase 1 studies in healthy volunteers and sickle cell disease patients. The effects of food on the absorption of FT-4202 will also be evaluated in healthy volunteers.

Conditions

Healthy Volunteers; Sickle Cell Disease

Outcome Measures

Primary Outcomes (11)

• Incidence, frequency, and severity of adverse events (AEs) per CTCAE v5.0 of a single ascending dose and multiple ascending doses of FT-4202 in adult healthy volunteers and SCD patients.

  Up to 3 weeks of monitoring

• Maximum observed plasma concentration (Cmax)

  Up to 3 weeks of testing

• Time to maximum observed plasma concentration (Tmax)

  Up to 3 weeks of testing

• Area under the plasma concentration-time curve from time zero until the 24-hour time point (AUC0-24)

  Up to 3 weeks of testing

• Area under the plasma concentration-time curve from time zero until the last quantifiable time point (AUC0-last)

  Up to 3 weeks of testing

• Area under the plasma concentration-time curve from time zero to infinity (AUC0-inf)

  Up to 3 weeks of testing

• Terminal elimination half-life (t1/2)

  Up to 3 weeks of testing

• Apparent clearance (CL/F)

  Up to 3 weeks of testing

• Apparent volume of distribution (Vd/F)

  Up to 3 weeks of testing

• Terminal disposition rate constant (Lz)

  Up to 3 weeks of testing

• Renal clearance (ClR)

  Up to 3 weeks of testing

Secondary Outcomes (6)

• Change from baseline in the levels of 2,3-diphosphoglycerate (DPG) and adenosine triphosphate (ATP) in the red blood cells (RBCs) of healthy volunteers and SCD patients after single and multiple doses of FT-4202.

  Up to 3 weeks of testing

• Model-based estimate of change from baseline QT interval corrected using Fridericia's correction formula (QTcF) and 90% confidence interval at the estimated Cmax after a single dose of FT-4202 in healthy volunteers

  up to 7 days

• Change from baseline heart rate after a single dose of FT-4202 in healthy volunteers

  up to 7 days

• Change from baseline PR after a single dose of FT-4202 in healthy volunteers

  up to 7 days

• Change from baseline QRS after a single dose of FT-4202 in healthy volunteers

  up to 7 days

Study Arms (6)

Single ascending dose cohorts in healthy subjects

EXPERIMENTAL

Healthy volunteer subject cohorts randomized 6:2 receiving a single dose of FT-4202 or placebo. The first cohort will receive 200 mg of FT-4202 or placebo. Dose escalation will occur if FT-4202 or placebo is tolerated. The maximum dose of FT-4202 or placebo will be 1500 mg.

Drug: FT-4202/Placebo

Multiple ascending dose cohorts in healthy subjects

EXPERIMENTAL

Healthy volunteer subject cohorts randomized 9:3 to receive FT-4202 or placebo for 14 days continuous dosing. The first cohort will receive 100 mg of FT-4202 or placebo daily X 14 days. The maximum dose of FT-4202/placebo will be 600 mg FT-4202/placebo daily for 14 days.

Drug: FT-4202/Placebo

Food Effect Cohort in healthy subjects

EXPERIMENTAL

Health Volunteer subject cohort of 10 subjects who will receive a single dose of FT-4202 with food and without food. Dose will be administered per the protocol defined dose.

Drug: FT-4202/Placebo

Single ascending dose cohorts in SCD subjects

EXPERIMENTAL

Sickle cell disease subject cohort randomized 6:2 receiving a single dose of FT-4202 or placebo. The dose of FT-4202/placebo administered will be a dose that was found to be safe in healthy subjects.

Drug: FT-4202/Placebo

Multiple ascending dose cohorts in SCD subjects

EXPERIMENTAL

Sickle cell disease subject cohorts randomized 9:3 to receive FT-4202 or placebo for 14 days continuous dosing. The dose of FT-4202/placebo administered will be a dose less than the maximum tolerable dose evaluated in MAD healthy volunteers.

Drug: FT-4202/Placebo

12-week dosing cohort in SCD subjects

EXPERIMENTAL

Sickle cell disease subjects cohort to receive up to 84 consecutive daily doses of open-label FT-4202. The dose of FT-4202 administered will not exceed the highest dose evaluated in the MAD SCD subject cohorts

Drug: FT-4202/Placebo

Interventions

FT-4202/Placebo DRUG

Participants will receive FT-4202/placebo and monitored for side effects while undergoing pharmacokinetics and pharmacodynamic studies

Also known as: Etavopivat

12-week dosing cohort in SCD subjects; Food Effect Cohort in healthy subjects; Multiple ascending dose cohorts in SCD subjects; Multiple ascending dose cohorts in healthy subjects; Single ascending dose cohorts in SCD subjects; Single ascending dose cohorts in healthy subjects

Eligibility Criteria

• Age: 12 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Must be between 12 and 65 years of age
• Previously diagnosed sickle cell disease (hemoglobin electrophoresis or genotype)
• Must have a minimum body weight of 40 kg (88 lbs) at the Screening Visit
• Must have the ability to understand and sign written informed consent (and assent where applicable), which must be obtained prior to any study-related procedures being completed
• All male and female patients of child bearing potential must agree to use medically accepted contraceptive regimen during study participation and for 90 days after last study drug administration
• Must be willing to abide by all study requirements and restrictions

You may not qualify if:

• Had more than 6 episodes of vaso-occlusive crisis (VOC) within the past 12 months that required a hospital, emergency room, or clinic visit
• Had a least one episode of acute chest syndrome in the last 6 months
• Received any of the following approved therapies for use in SCD:
• Hydroxurea (HU): excluded if started HU \< 90 days prior to Day 1 of study treatment
• Adakveo®: excluded if received an infusion within 14 days prior to Day 1 of study treatment
• Oxbryta®: excluded if received a dose within 7 days prior to start of Day 1 of study treatment
• Received a red blood cell transfusion within 30 days of starting the study drug
• Hemoglobin \< 7.0 g/dL or \> 10.5 g/dL
• Unable to take and absorb oral medications
• Subjects must be between 18 and 60 years of age
• Subjects must have the ability to understand and sign written informed consent, which must be obtained prior to any study-related procedures being completed
• Subjects must be in general good health, based upon the results of medical history, a physical examination, vital signs, laboratory profile, and a 12-lead ECG
• All males and females of child bearing potential must agree to use medically accepted contraceptive regimen during study participation and up to 90 days after
• Subjects must be willing to abide by all study requirements and restrictions
• Evidence of clinically significant medical condition or other condition that might significantly interfere with the absorption, distribution, metabolism, or excretion of study drug, or place the subject at an unacceptable risk as a participant in this study

Sponsors & Collaborators

• Forma Therapeutics, Inc.: lead
• Medpace, Inc.: collaborator

Study Sites (18)

Woodland International Research Group (SCD subjects only)

Little Rock, Arkansas, 72211, United States

Location

Collaborative Neuroscience Research, LLC (SCD subjects only)

Long Beach, California, 90806, United States

Location

Pacific Research Partners (SCD subjects only)

Oakland, California, 94607, United States

Location

UCSF Benioff Children's Hospital Oakland (SCD subjects only)

Oakland, California, 94609, United States

Location

Advanced Pharma CR, LLC (SCD subjects only)

Miami, Florida, 33147, United States

Location

Children's Healthcare of Atlanta (SCD subjects only)

Atlanta, Georgia, 30342, United States

Location

Augusta University Medical Center (SCD subjects only)

Augusta, Georgia, 30912, United States

Location

University of Illinois at Chicago (SCD subjects only)

Chicago, Illinois, 60612, United States

Location

University of Maryland, Greenebaum Comprehensive Cancer Center (SCD subjects only)

Baltimore, Maryland, 21201, United States

Location

Columbia University Medical Center (SCD subjects only)

New York, New York, 10032, United States

Location

Levine Cancer Institute (SCD subjects only)

Charlotte, North Carolina, 28204, United States

Location

Duke University Medical Center (SCD subjects only)

Durham, North Carolina, 27710, United States

Location

University of Cincinnati Medical Center (SCD subjects only)

Cincinnati, Ohio, 45219, United States

Location

Medpace Clinical Pharmacology Unit (Healthy Volunteers only)

Cincinnati, Ohio, 45227, United States

Location

Cincinnati Children's Hospital Medical Center (SCD subjects only)

Cincinnati, Ohio, 45229, United States

Location

Lynn Institute of Tulsa (SCD subjects only)

Tulsa, Oklahoma, 74135, United States

Location

St. Jude Children's Research Hospital (SCD subjects only)

Memphis, Tennessee, 38105, United States

Location

The University of Texas Health Science Center at Houston (SCD subjects only)

Houston, Texas, 77030, United States

Location

Related Publications (2)

• Saraf SL, Hagar R, Idowu M, Osunkwo I, Cruz K, Kuypers FA, Brown RC, Geib J, Ribadeneira M, Schroeder P, Wu E, Forsyth S, Kelly PF, Kalfa TA, Telen MJ. Multicenter, phase 1 study of etavopivat (FT-4202) treatment for up to 12 weeks in patients with sickle cell disease. Blood Adv. 2024 Aug 27;8(16):4459-4475. doi: 10.1182/bloodadvances.2023012467.

  PMID: 38640200 DERIVED

• Forsyth S, Schroeder P, Geib J, Vrishabhendra L, Konstantinidis DG, LaSalvia K, Ribadeneira MD, Wu E, Kelly P, Kalfa TA. Safety, Pharmacokinetics, and Pharmacodynamics of Etavopivat (FT-4202), an Allosteric Activator of Pyruvate Kinase-R, in Healthy Adults: A Randomized, Placebo-Controlled, Double-Blind, First-in-Human Phase 1 Trial. Clin Pharmacol Drug Dev. 2022 May;11(5):654-665. doi: 10.1002/cpdd.1058. Epub 2022 Jan 12.

  PMID: 35019238 DERIVED

MeSH Terms

Conditions

Anemia, Sickle Cell

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Cameron Trenor, MD

  Forma Therapeutics, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: randomized double blind
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Single ascending dose escalation and multiple ascending dose escalation study followed by an evaluation of food effects on absorption

Study Record Dates

• First Submitted: December 21, 2018
• First Posted: January 24, 2019
• Study Start: December 11, 2018
• Primary Completion: December 17, 2021
• Study Completion: December 17, 2021
• Last Updated: April 10, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (18)