Safety and Efficacy of Mitapivat Sulfate in Adult Patients With Erythrocyte Membranopathies

NCT05935202 | Not Yet Recruiting Phase 2

• 1 other identifier: SATISFY
• Study Type: interventional
• Target: 25
• Locations: 2 countries
• Sites: 2

Brief Summary

This is a prospective exploratory multicentre pilot study designed to study the safety and efficacy of mitapivat in RBC membranopathies and CDAII

Conditions

Hereditary Red Blood Cell Disorder (Disorder)

Outcome Measures

Primary Outcomes (2)

• Safety and tolerability of mitapivat in adult patients with erythrocyte membranopathies

  Frequency and severity of AEs and laboratory parameters of mitapivat in adult patients with erythrocyte membranopathies

  Up to 56 weeks

• Percentage of Participants With AEs and SAEs, Graded by Severity

  The severity of all AEs will be graded by the Investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) on a 5-point severity scale (Grade 1 through Grade 5) where Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening and Grade 5 is fatal.

  Up to 56 weeks

Secondary Outcomes (1)

• Hb response (HR)

  24 weeks

Study Arms (1)

Mitapivat

EXPERIMENTAL

subjects who enter the Dose Escalation Period will receive an initial dose of 50 mg mitapivat BID. After 4 weeks dose will be increased from 50 mg BID to 100 mg BID unless dose-limiting side effects have occurred or maximum allowed Hb levels have been reached. Subjects who safely tolerate mitapivat may be eligible to continue in two consecutive 24-week Fixed Dose Periods, allowing patients to remain on their tolerated dose of mitapivat for up to 48 weeks after dose escalation. During the Fixed Dose Periods, the dose may not exceed the maximum dose that was used during Dose Escalation Period. 8 weeks: Dose Escalation Period 24-week: Fixed Dose Period 1 24-week: Fixed Dose Period 2

Drug: Mitapivat sulfate

Interventions

Mitapivat sulfate DRUG

Subjects enrolled Maximum dose: will receive Mitapivat during 56 weeks Starting dose: 50 mg BD Maximum dose: 100 mg BD

Also known as: AG-348

Mitapivat

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Splenomegaly (length ≥12.5 cm)
• Fatigue attributed to hemolysis
• 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:
• 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.
• 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.

You may not qualify if:

• Known history of pyruvate kinase deficiency (decreased PK activity or two pathogenic PKLR alleles). PK activity and PKLR testing is not required.
• 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:
• Poorly controlled hypertension (defined as systolic blood pressure \>150 mm Hg or diastolic blood pressure \>90 mm Hg) refractory to medical management.
• 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.
• Cardiac dysrhythmias judged as clinically significant by the Investigator.
• History of drug-induced cholestatic hepatitis.
• 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.
• 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.
• 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.
• Positive test for HIV-1 or -2 antibodies.
• 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.
• History of any primary malignancy, with the exception of: curatively treated non-melanomatous skin cancer; curatively treated cervical or breast carcinoma in situ; or other primary tumor treated with curative intent, no known active disease present, and no treatment administered during the last 3 years.
• Unstable extramedullary hematopoiesis that could pose a risk of imminent neurologic compromise.
• Severe hepatic issues such as liver fibrosis (F3 or worse), significant cirrhosis or non-alcoholic fatty liver disease (NASH).

Sponsors & Collaborators

• EuroBloodNet Association: lead

Study Sites (2)

Copenhagen University Hospital - Rigshospitalet

Copenhagen, 1054, Denmark

Location

Department of Internal Medicine, University Medical Center Utrecht

Utrecht, 3454, Netherlands

Location

Related Publications (1)

• Glenthoj A, van Beers EJ, van Wijk R, Rab MAE, Groot E, Vejlstrup N, Toft N, Bendtsen SK, Petersen J, Helby J, Chermat F, Fenaux P, Kuo KHM. Designing a single-arm phase 2 clinical trial of mitapivat for adult patients with erythrocyte membranopathies (SATISFY): a framework for interventional trials in rare anaemias - pilot study protocol. BMJ Open. 2024 Jul 30;14(7):e083691. doi: 10.1136/bmjopen-2023-083691.

  PMID: 39079928 DERIVED

MeSH Terms

Interventions

mitapivat

Study Officials

• Andreas Glenthøj, MD/PhD

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

• Pierre FENAUX, MD/PhD

  Hôpital Saint Louis

  STUDY CHAIR

Central Study Contacts

Fatiha CHERMAT, PhD

CONTACT

+33171207059; fatiha.chermat-ext@aphp.fr

Pierre FENAUX, MD/PhD

CONTACT

+33171207022; pierre.fenaux@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 11, 2023
• First Posted: July 7, 2023
• Study Start: December 21, 2023
• Primary Completion: July 15, 2025
• Study Completion (Estimated): December 15, 2026
• Last Updated: December 26, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1); NL (1)