Clinical trial NCT03815695: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Sickle Cell Disease
Lead sponsor: Novo Nordisk A/S
Sponsor class: INDUSTRY
Collaborators: name: Medpace, Inc.
First posted: 2019-01-24
Enrollment: 130
Sex: ALL
Minimum age (years): 12
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Single ascending dose escalation and multiple ascending dose escalation study followed by an evaluation of food effects on absorption
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: 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.
timeFrame: Up to 3 weeks of monitoring
measure: Maximum observed plasma concentration (Cmax)
timeFrame: Up to 3 weeks of testing
measure: Time to maximum observed plasma concentration (Tmax)
timeFrame: Up to 3 weeks of testing
measure: Area under the plasma concentration-time curve from time zero until the 24-hour time point (AUC0-24)
timeFrame: Up to 3 weeks of testing
measure: Area under the plasma concentration-time curve from time zero until the last quantifiable time point (AUC0-last)
timeFrame: Up to 3 weeks of testing
measure: Area under the plasma concentration-time curve from time zero to infinity (AUC0-inf)
timeFrame: Up to 3 weeks of testing
measure: Terminal elimination half-life (t1/2)
timeFrame: Up to 3 weeks of testing
measure: Apparent clearance (CL/F)
timeFrame: Up to 3 weeks of testing
measure: Apparent volume of distribution (Vd/F)
timeFrame: Up to 3 weeks of testing
measure: Terminal disposition rate constant (Lz)
timeFrame: Up to 3 weeks of testing
measure: Renal clearance (ClR)
timeFrame: Up to 3 weeks of testing
Secondary outcomes:
measure: 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.
timeFrame: Up to 3 weeks of testing
measure: 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
timeFrame: up to 7 days
measure: Change from baseline heart rate after a single dose of FT-4202 in healthy volunteers
timeFrame: up to 7 days
measure: Change from baseline PR after a single dose of FT-4202 in healthy volunteers
timeFrame: up to 7 days
measure: Change from baseline QRS after a single dose of FT-4202 in healthy volunteers
timeFrame: up to 7 days
measure: Change from baseline T-wave morphology after a single dose of FT-4202 in healthy volunteers
timeFrame: up to 7 days
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Woodland International Research Group (SCD subjects only)
state: Arkansas
city: Long Beach
country: United States
facility: Collaborative Neuroscience Research, LLC (SCD subjects only)
state: California
city: Oakland
country: United States
facility: Pacific Research Partners (SCD subjects only)
state: California
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital Oakland (SCD subjects only)
state: California
city: Miami
country: United States
facility: Advanced Pharma CR, LLC (SCD subjects only)
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta (SCD subjects only)
state: Georgia
city: Augusta
country: United States
facility: Augusta University Medical Center (SCD subjects only)
state: Georgia
city: Chicago
country: United States
facility: University of Illinois at Chicago (SCD subjects only)
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland, Greenebaum Comprehensive Cancer Center (SCD subjects only)
state: Maryland
city: New York
country: United States
facility: Columbia University Medical Center (SCD subjects only)
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute (SCD subjects only)
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center (SCD subjects only)
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center (SCD subjects only)
state: Ohio
city: Cincinnati
country: United States
facility: Medpace Clinical Pharmacology Unit (Healthy Volunteers only)
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center (SCD subjects only)
state: Ohio
city: Tulsa
country: United States
facility: Lynn Institute of Tulsa (SCD subjects only)
state: Oklahoma
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital (SCD subjects only)
state: Tennessee
city: Houston
country: United States
facility: The University of Texas Health Science Center at Houston (SCD subjects only)
state: Texas
Study officials:
affiliation: Forma Therapeutics, Inc.
name: Cameron Trenor, MD
role: STUDY_DIRECTOR
References:
citation: 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.