Mitapivat in Membranopathies

Phase 1

• Conditions: erythrocyte membranopathies; MedDRA version: 20.0Level: LLTClassification code: 10015268Term: Erythrocytes abnormal Class: 10005329; Therapeutic area: Diseases [C] - Hemic and Lymphatic Diseases [C15]

• Registration Number: CTIS2023-503271-24-01
• Lead Sponsor: Eurobloodnet Association

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2023-08-23
• Last Update Posted: 22 July 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 25

Inclusion Criteria

Male or female with RBC membranopathy or congenital dyserythropoietic anemia type II (CDAII). Diagnosis must be supported genetically by a ACMG class 3 (VUS), 4 or 5 variant, Age =18 years at the first screening, Average hemoglobin (Hb) concentration (average of at least 2 Hb measurements separated by a minimum of 7 days the during screening period) must be less than 13.0 g/dL for males and 11.0 g/dL for females. Patients with average Hb >10.0 g/dL for males and females must meet at least one of the following additional criteria: a) Splenomegaly (length =12.5 cm) b) Fatigue attributed to hemolysis c) Active hemolysis as evaluated by one or more of the following: haptoglobin, bilirubin, LDH, reticulocytes, Subjects must start or continue taking at least the equivalent of daily 0.8 mg oral folic acid for the duration of the study .Have adequate organ function, as defined by: a) Serum aspartate aminotransferase (AST) =2.5 × ULN (unless the increased AST is assessed by the Investigator as due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase (ALT) =2.5 × ULN. b) Normal or elevated levels of serum bilirubin. In subjects with serum bilirubin > ULN, the elevation must be attributed to hemolysis with or without Gilbert’s syndrome and must not be associated with choledocholithiasis, cholecystitis, biliary obstruction, or hepatocellular disease Elevated bilirubin attributed to hemolysis with or without Gilbert’s syndrome is not exclusionary. c) Estimated glomerular filtration rate =45 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration creatinine, Be willing and able to give written informed consent and to comply to all study procedures for the duration of the study . For women of reproductive potential, have a negative urine or serum pregnancy test during the Screening Period (Day -50 to Day -1). Women of reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy or tubal occlusion; or who have not been naturally postmenopausal (i.e. who have not menstruated at all for at least the preceding 12 months prior to signing informed consent), or has a known diagnosis of hypogonadotropic hypogonadism., For women of reproductive potential as well as men with partners who are women of reproductive potential, be abstinent 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 giving informed consent, during the study, and for A highly effective form of contraception is defined as combined (estrogen and progestin containing) hormonal contraceptives (oral, intravaginal, or transdermal) associated with inhibition of ovulation; progestin-only hormonal contraceptives (oral, injectable, or implantable) associated with inhibition of ovulation; intrauterine device; intrauterine hormone releasing system; bilateral tube occlusion; or vasectomized partner. The second form of contraception can include an acceptable barrier method, which includes male or female condoms with or without spermicide, and cervical cap, diaphragm, or sponge with spermicide. Women of reproductive potential using hormonal contraception as a highly effective form of contraception must also utilize an acceptable barrier method while enrolled in the study and for at least 28 days after their last dose of study drug.

Exclusion Criteria

Known history of pyruvate kinase deficiency (decreased PK activity or two pathogenic PKLR alleles). PK activity and PKLR testing is not required., Are receiving medications that are strong inhibitors of CYP3A4 that have not been stopped for = 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) ; or strong inducers of CYP3A4 that have not been stopped for =4 weeks or a timeframe equivalent to 5 half-lives (whichever is longer), prior to the first dose of study treatment, Are currently receiving hematopoietic stimulating agents (eg, erythropoietins, granulocyte colony stimulating factors, thrombopoietins) that have not been stopped for a duration of at least 28 days prior to the first dose of study treatment., Known allergy to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol) or history of acute allergic reaction to drugs characterized by acute hemolytic anemia, drug-induced liver injury, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson syndrome, cholestatic hepatitis, or other serious clinical manifestations., For men and women of reproductive potential: unwillingness to be abstinent or use double anticonception during the trial period., Receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic or preventive transfusion), defined as more than 5 transfusion episodes in the 12-month period up to the first day of study treatment, and/or have received a transfusion within the past 3 months prior to the first day of study treatment., Have a significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound interpretation of the study data. Such significant medical conditions include, but are not limited to: a. Poorly controlled hypertension (defined as systolic blood pressure >150 mm Hg or diastolic blood pressure >90 mm Hg) refractory to medical management. b. Any history of congestive heart failure; myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; or recent (< 6 months prior to signing informed consent) deep venous thrombosis; or pulmonary or arterial embolism. c. Cardiac dysrhythmias judged as clinically significant by the Investigator. d. Clinically symptomatic cholelithiasis or cholecystitis. Prior cholecystectomy is not exclusionary. Subjects with symptomatic cholelithiasis or cholecystitis may be rescreened once the disorder has been treated and clinical symptoms have resolved. e. History of drug-induced cholestatic hepatitis. f. Severe iron overload as evaluated by the Investigator. This includes cardiac (eg, clinically significant impaired left ventricular ejection fraction) or hepatic (eg, fibrosis, cirrhosis) dysfunction. g. Have a diagnosis of any other congenital or acquired blood disorder or any other hemolytic process, except mild allo-immunization, as a consequence of transfusion therapy. h. Positive test for HBsAg or HCVAb with signs of active hepatitis B or C virus infection. Subjects with hepatitis C may be rescreened after receiving appropriate hepatitis C treatment. i. Positive test for HIV-1 or -2 antibodies. j. Active infection requiring the use of parenteral antimicrobial agents or Grade =3 in severity (per NCI CTCAE) within 2 months prior to the first dose of study treatment. k. Diabetes mellitus judged to be under poor control by the Investigator or requiring >3 antidiabetic

Study & Design

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

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate safety of mitapivat;Secondary Objective: To evaluate the effect of mitapivat on changes in hemoglobin (Hb), To evaluate the long-term effect of mitapivat on Hb, To evaluate the effect of mitapivat on additional measures of Hb response, To evaluate the effect of mitapivat on markers of hemolysis, To evaluate the effect of mitapivat on markers of erythropoiesis, To evaluate the effect of mitapivat on symptoms and impacts, To evaluate the effect of mitapivat on spleen size in non-splenectomized patients;Primary end point(s): Safety of mitapivat in the study population is the main endpoint in this study. The overall safety profile of study drug will be assessed in terms of the following safety and tolerability endpoints:, - Incidence of treatment-emergent adverse events (TEAEs), - Clinical laboratory values, - ECGs (standard 12-lead), - Physical examination findings, - DEXA scans, - Type, incidence, severity and relationship of mitapivat to AE and SAE