Study to Evaluate how effective and safe the investigationall product, Mitapivat, is when administred to Pediatric Subjects With Pyruvate Kinase Deficiency, who are not receiving regular blood transfusions, followed by a 5-Year Open-label Extension Period, where subjects will be given the option to receive mitapivat for an additional 5 years.

Phase 3

Recruiting

• Conditions: Pyruvate Kinase Deficiency

• Registration Number: 2024-515025-28-00
• Lead Sponsor: Agios Pharmaceuticals Inc.

Brief Summary

To determine the efficacy of treatment with mitapivat compared with placebo, as assessed by the increase in hemoglobin (Hb) concentrations in pediatric subjects with pyruvate kinase deficiency (PK deficiency) who are not regularly transfused.

Detailed Description

Not available

Study Timeline

• Study First Posted: 2024-07-09
• Last Update Posted: 2025-02-21

Recruitment & Eligibility

• Status: Authorised, recruiting
• Sex: Not specified
• Target Recruitment: 14

Inclusion Criteria

Written informed consent from the subject, or the subject’s legally authorized representative, parent(s), or legal guardian, and the subject’s assent, where applicable (informed consent/assent) must be obtained before any study-related procedures are conducted and subjects must be willing to comply with all study procedures for the duration of the study.

Aged 1 to <18 years. Subjects between 12 and 24 months of age must weigh a minimum of 7 kg.

Clinical laboratory confirmation of PK deficiency, defined as documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation, as determined per the genotyping performed by the study central genotyping laboratory

No more than 5 red blood cell (RBC) transfusions in the 52-week period before providing informed consent/assent and no RBC transfusions ≤12 weeks before administration of the first dose of study drug

Hemoglobin concentration ≤10 g/dL for subjects 12 to <18 years of age or ≤9 g/dL for subjects 1 to <12 years of age during the Screening Period. Hemoglobin concentration must be based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the Screening Period.

Receiving folic acid supplementation as part of routine clinical care for at least 21 days before administration of the first dose of study drug, to be continued during study participation

Female subjects who have attained menarche and/or breast development in Tanner Stage 2 must be abstinent of sexual activities that may induce pregnancy as part of their usual lifestyle, or agree to use 2 forms of contraception, 1 of which must be considered highly effective, from the time of informed consent/assent, throughout the study, and for 28 days after the last dose of study drug (including the time required to dose taper). The second form of contraception can include an acceptable barrier method.

Exclusion Criteria

Pregnant or breastfeeding

Subjects with known HIV infection

History of major surgery (including splenectomy) ≤6 months before providing informed consent/assent and/or planning on undergoing a major surgical procedure during the Screening or Double-blind Period

Current enrollment or past participation (within 90 days before the first dose of study drug or a time frame equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational study drug or device

Prior exposure to gene therapy, or bone marrow or stem cell transplantation

Currently receiving hematopoietic stimulating agents; the last dose must have been administered at least 28 days or a time frame equivalent to 5 half-lives (whichever is longer) before randomization

Receiving products that are strong inhibitors of cytochrome P450 (CYP)3A4/5 that have not been stopped for ≥5 days or a time frame equivalent to 5 half-lives (whichever is longer), or strong inducers of CYP3A4 that have not been stopped for ≥28 days or a time frame equivalent to 5 half-lives (whichever is longer), before randomization

Receiving anabolic steroids, including testosterone preparations that have not been stopped for at least 28 days before randomization

Known allergy, or other contraindication, to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, Opadry® II Blue [hypromellose, titanium dioxide, lactose monohydrate, triacetin, and FD&C Blue #2], Opadry® II White [hypromellose, titanium dioxide, lactose monohydrate, and triacetin], and magnesium stearate)

Any medical, hematologic, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data; also included are: • Subjects who are institutionalized by regulatory or court order • Subjects with any condition(s) that could create undue influence (including but not limited to incarceration, involuntary psychiatric confinement, and financial or familial affiliation with the Investigator or Sponsor)

Receiving a pyruvate kinase activator that has not been stopped for ≥52 weeks before providing informed consent/assent

Homozygous for the R479H mutation or have 2 nonmissense mutations, without the presence of another missense mutation, in the PKLR gene as determined per the genotyping performed by the study central genotyping laboratory

History of malignancy

History of active and/or uncontrolled cardiac or pulmonary disease or clinically relevant QT prolongation within 6 months before providing informed consent/assent

Hepatobiliary disorders including, but not limited to: a. Liver disease with histopathological evidence of cirrhosis or severe fibrosis b. Clinically symptomatic cholelithiasis or cholecystitis (subjects with prior cholecystectomy are eligible) c. History of drug-induced cholestatic hepatitis d. Aspartate aminotransferase >2.5× the upper limit of normal (ULN) (unless due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5×ULN (unless due to hepatic iron deposition)

Renal dysfunction as defined by an estimated glomerular filtration rate <60 mL/min/1.73 m2 (bedside Schwartz equation)

Nonfasting triglycerides >440 mg/dL (5 mmol/L)

Active uncontrolled infection requiring systemic antimicrobial therapy

Subjects with known active hepatitis B or hepatitis C virus infection

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Hb response, defined as a ≥1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 12, 16, and 20 during the Double-blind Period. The individual subject’s baseline Hb concentration is defined as the average of all available Hb concentrations collected for that subject during the Screening Period up to the first dose of study drug		Hb response, defined as a ≥1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 12, 16, and 20 during the Double-blind Period. The individual subject’s baseline Hb concentration is defined as the average of all available Hb concentrations collected for that subject during the Screening Period up to the first dose of study drug

Trial Locations

Locations (7)

Ospedale Pediatrico Bambino Gesu; 🇮🇹 Rome, Italy

Universitair Medisch Centrum Utrecht; 🇳🇱 Utrecht, Netherlands

Centre Hospitalier Universitaire De Bordeaux; 🇫🇷 Bordeaux, France

Charite Universitaetsmedizin Berlin KöR; 🇩🇪 Berlin, Germany

Universitaetsklinikum Wuerzburg AöR; 🇩🇪 Wuerzburg, Germany

Hospital Infantil Universitario Nino Jesus; 🇪🇸 Madrid, Spain

Hospital Universitari Vall D Hebron; 🇪🇸 Barcelona, Spain

Ospedale Pediatrico Bambino Gesu

🇮🇹Rome, Italy

Giuseppe Palumbo

Site contact

00390668592406

giuseppe.palumbo@opbg.net