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

• ClinicalTrials.gov Identifier: NCT03815695
• Recruitment Status: Completed
• First Posted: January 24, 2019
• Last Update Posted: July 15, 2022
• Sponsor: Forma Therapeutics, Inc.
• Collaborator: Medpace, Inc.
• Information provided by (Responsible Party): Forma Therapeutics, Inc.

Tracking Information

• First Submitted Date: December 21, 2018
• First Posted Date: January 24, 2019
• Last Update Posted Date: July 15, 2022
• Actual Study Start Date: December 11, 2018
• Actual Primary Completion Date: December 17, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 13, 2019)

• 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. [ Time Frame: Up to 3 weeks of monitoring ]
• Maximum observed plasma concentration (Cmax) [ Time Frame: Up to 3 weeks of testing ]
• Time to maximum observed plasma concentration (Tmax) [ Time Frame: Up to 3 weeks of testing ]
• Area under the plasma concentration-time curve from time zero until the 24-hour time point (AUC0-24) [ Time Frame: Up to 3 weeks of testing ]
• Area under the plasma concentration-time curve from time zero until the last quantifiable time point (AUC0-last) [ Time Frame: Up to 3 weeks of testing ]
• Area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) [ Time Frame: Up to 3 weeks of testing ]
• Terminal elimination half-life (t1/2) [ Time Frame: Up to 3 weeks of testing ]
• Apparent clearance (CL/F) [ Time Frame: Up to 3 weeks of testing ]
• Apparent volume of distribution (Vd/F) [ Time Frame: Up to 3 weeks of testing ]
• Terminal disposition rate constant (Lz) [ Time Frame: Up to 3 weeks of testing ]
• Renal clearance (ClR) [ Time Frame: Up to 3 weeks of testing ]

Original Primary Outcome Measures (submitted: January 22, 2019)

• 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. [ Time Frame: Up to 3 weeks of monitoring ]
• Maximum observed plasma concentration (Cmax) [ Time Frame: Up to 3 weeks of testing ]
• Time to maximum observed plasma concentration (Tmax) [ Time Frame: Up to 3 weeks of testing ]
• Area under the plasma concentration-time curve from time zero until the 24-hour time point (AUC0-24) [ Time Frame: Up to 3 weeks of testing ]
• Area under the plasma concentration-time curve from time zero until the last quantifiable time point (AUC0-last) [ Time Frame: Up to 3 weeks of testing ]
• Area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) [ Time Frame: Up to 3 weeks of testing ]
• Terminal elimination half-life (t1/2) [ Time Frame: Up to 3 weeks of testing ]
• Apparent clearance (CL/F) [ Time Frame: Up to 3 weeks of testing ]
• Apparent volume of distribution (Vd/F) [ Time Frame: Up to 3 weeks of testing ]
• Terminal disposition rate constant (Lz) [ Time Frame: Up to 3 weeks of testing ]
• Renal clearance (ClR) [ Time Frame: Up to 3 weeks of testing ]

Current Secondary Outcome Measures (submitted: March 13, 2019)

• 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. [ Time Frame: 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 [ Time Frame: up to 7 days ]
• Change from baseline heart rate after a single dose of FT-4202 in healthy volunteers [ Time Frame: up to 7 days ]
• Change from baseline PR after a single dose of FT-4202 in healthy volunteers [ Time Frame: up to 7 days ]
• Change from baseline QRS after a single dose of FT-4202 in healthy volunteers [ Time Frame: up to 7 days ]
• Change from baseline T-wave morphology after a single dose of FT-4202 in healthy volunteers [ Time Frame: up to 7 days ]

Original Secondary Outcome Measures (submitted: January 22, 2019)

• Change from baseline in the levels of 2,3-diphosphoglycerate (DPG) and adenosine triphosphate (ATP) in the red blood cells (RBCs) of healthy adults after single and multiple doses of FT-4202. [ Time Frame: 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 adult healthy volunteers [ Time Frame: up to 7 days ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A SAD/MAD to Assess the Safety, PK/PD of FT-4202 in Healthy Volunteers and Sickle Cell Disease Patients
• Official Title: A Randomized, Placebo-controlled, Double Blind, Single Ascending and Multiple Ascending Dose Study to Assess the Safety, Pharmacokinetics and Pharmacodynamics of FT-4202 in Healthy Volunteers and Sickle Cell Disease Patients
• 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.
• Detailed Description: This is a first-in-human (FIH), Phase 1 study of FT-4202 that will characterize the safety, PK and PD of FT-4202 after a single dose and after repeated dosing first in healthy adult volunteers and then in adolescents or adults with sickle cell disease (SCD). Initially, a dose range of FT-4202 in single ascending dose (SAD) escalation cohorts will be explored in healthy subjects. Enrollment of healthy subjects into 2-week multiple ascending dose (MAD) escalation cohorts will be initiated once the safety and PK from at least two SAD cohorts is available to inform the doses for the 2-week MAD portion of the study. The MAD cohorts will then run in parallel to the single dose cohorts. A single dose cohort of healthy subjects is planned to understand food effects (FE) on the PK of FT-4202. After the SAD and FE studies in healthy subjects are completed, the safety, PK, and PD of a single dose of FT-4202 that was found to be safe in healthy subjects will then be evaluated in SCD subjects. Multiple dose studies in SCD subjects will then be initiated upon completion of MAD studies in healthy volunteers.
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

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

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

randomized double blind

Primary Purpose: Treatment

Condition

• Healthy Volunteers
• Sickle Cell Disease

Intervention

• Drug: FT-4202/Placebo
  Healthy volunteer subjects will receive FT-4202/placebo and monitored for side effects while undergoing pharmacokinetics and pharmacodynamic studies
• Drug: FT-4202
  Healthy volunteer subjects will receive FT-4202 with or without food and undergo pharmacokinetic studies
• Drug: FT-4202/Placebo
  SCD subjects will receive FT-4202/placebo and monitored for side effects while undergoing pharmacokinetics and pharmacodynamic studies
• Drug: FT-4202
  SCD subjects will receive FT-4202 and monitored for side effects while undergoing pharmacokinetics and pharmacodynamic studies

Study Arms

• Experimental: Single ascending dose cohorts in healthy subjects
  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.
  Intervention: Drug: FT-4202/Placebo
• Experimental: Multiple ascending dose cohorts in healthy subjects
  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.
  Intervention: Drug: FT-4202/Placebo
• Experimental: Food Effect Cohort in healthy subjects
  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.
  Intervention: Drug: FT-4202
• Experimental: Single ascending dose cohorts in SCD subjects
  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.
  Intervention: Drug: FT-4202/Placebo
• Experimental: Multiple ascending dose cohorts in SCD subjects
  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.
  Intervention: Drug: FT-4202/Placebo
• Experimental: 12-week dosing cohort in SCD subjects
  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
  Intervention: Drug: FT-4202

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 21, 2021): 130
• Original Estimated Enrollment (submitted: January 22, 2019): 98
• Actual Study Completion Date: December 17, 2021
• Actual Primary Completion Date: December 17, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

SCD Key Inclusion Criteria:

• 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

SCD Key Exclusion Criteria:

• 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

HEALTHY VOLUNTEER Inclusion Criteria: [NOTE: no longer recruiting subjects for this portion of the study]

• 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

HEALTHY VOLUNTEER Exclusion Criteria: [NOTE: no longer recruiting subjects for this portion of the study]

• 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
• History of clinically significant cardiac diseases including condition disturbances
• Abnormal hematologic, renal and liver function studies
• History of drug or alcohol abuse

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years to 65 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03815695
• Other Study ID Numbers: 4202-HVS-101
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Forma Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Forma Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Medpace, Inc.

Investigators

• Study Director: Patrick Kelly, MD; Forma Therapeutics, Inc.

• PRS Account: Forma Therapeutics, Inc.
• Verification Date: July 2022