Evaluation of Mitapivat Sulfate Safety and Efficacy in Adult Patients with Erythrocyte Membranopathies
- Trial ID
- 2023-503271-24-01
- Protocol
- SATISFY
- Sponsor
- Eurobloodnet Association
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** of mitapivat in adult patients with erythrocyte membranopathies. This is clinically relevant as it aims to ensure that the administration of mitapivat does not pose undue risk to patients, which is a critical consideration in the management of erythrocyte membranopathies.
Secondary objectives include:
- Evaluating the effect of mitapivat on changes in **hemoglobin** (Hb) levels.
- Assessing the long-term effect of mitapivat on Hb.
- Investigating the effect of mitapivat on additional measures of Hb response.
- Evaluating the effect of mitapivat on markers of **hemolysis**.
- Assessing the effect of mitapivat on markers of **erythropoiesis**.
- Evaluating the effect of mitapivat on symptoms and impacts.
- Assessing the effect of mitapivat on spleen size in non-splenectomized patients.
Participants
The clinical trial involves a total of **9 participants** diagnosed with **erythrocyte membranopathies** or congenital dyserythropoietic anemia type II (CDAII). The study population includes both male and female subjects, aged **18 years and older**. Participants were selected based on genetic confirmation of their condition, with specific criteria for hemoglobin levels and organ function. The trial includes individuals with an average hemoglobin concentration below 13.0 g/dL for males and 11.0 g/dL for females, with additional criteria for those with higher hemoglobin levels. Participants are required to maintain a daily intake of at least 0.8 mg of oral folic acid throughout the study. The trial population is characterized by adequate organ function, as defined by specific laboratory parameters, and includes individuals who are part of a vulnerable population. Lifestyle considerations include the requirement for women of reproductive potential to use highly effective contraception methods or maintain abstinence. The selection process ensures that participants are willing and able to comply with all study procedures and provide informed consent.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and efficacy of **mitapivat** in adult patients with **erythrocyte membranopathies**. This study is a Phase 4, randomized, double-blind, controlled trial. The trial is expected to commence on December 21, 2023, and conclude by March 22, 2027. Participants will be involved in the study for a maximum treatment period of 56 days, during which they will receive **Pyrukynd** film-coated tablets containing varying doses of **mitapivat**. The trial will include several key visits: an initial screening visit, multiple follow-up visits, and an end-of-study visit. The screening visit will confirm eligibility based on criteria such as age, hemoglobin levels, and organ function. Follow-up visits will monitor the safety and efficacy of the treatment, assessing parameters like hemoglobin response and changes in laboratory values. The end-of-study visit will evaluate the overall safety profile and any treatment-emergent adverse events. Participants may be withdrawn from the study if they experience significant adverse effects or fail to comply with study procedures. The primary endpoint focuses on the safety of **mitapivat**, while secondary endpoints include hemoglobin response and changes in related biomarkers. The study aims to provide comprehensive data on the safety and therapeutic potential of **mitapivat** in this patient population.
Treatment
The clinical trial involves the administration of **Pyrukynd** film-coated tablets, which contain the active substance **mitapivat**. The trial includes three different dosages of Pyrukynd: 50 mg, 20 mg, and 5 mg. Each dosage is provided in the form of film-coated tablets for **oral use**. The 50 mg tablets have a maximum daily dose of 200 mg, the 20 mg tablets have a maximum daily dose of 40 mg, and the 5 mg tablets have a maximum daily dose of 10 mg. The treatment period for each dosage is up to 56 days. The active substance, mitapivat, is a chemical compound, and the product is manufactured by AGIOS NETHERLANDS B.V. Modifications have been made to the product's label, packaging, and other specifications as per the mitapivat IMPD Version 6.0.
In addition to the experimental medication, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details are not provided in the source data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to evaluate the safety and efficacy of mitapivat in adult patients with erythrocyte membranopathies.
Efficacy
The efficacy of **mitapivat** in the clinical trial will be assessed through a series of secondary endpoints. These endpoints include the **hemoglobin (Hb) response**, defined as a ≥1 g/dL increase in Hb concentration from baseline that is sustained at two or more points during the fixed dose period 1. Additionally, changes from baseline in Hb levels to the average of scheduled visits in fixed dose period 2 will be evaluated. The average change in mean Hb concentration during Fixed Dose Periods 1 and 2 compared to baseline will also be measured. The proportion of subjects achieving Hb concentration within the sex-associated normal range, sustained at two or more points in the fixed dose periods, will be determined.
Further assessments will include changes from baseline in lactate dehydrogenase (LDH), bilirubin, and haptoglobin at the end of fixed dose periods 1 and 2. Changes in reticulocytes, erythropoietin, erythroferrone, and soluble transferrin receptor (sTfR) at the end of these periods will also be analyzed. Health-related Quality of Life (HRQoL) using the SF-36 version 1 and the Pyruvate Kinase Deficiency Impact Assessment (PKDIA) will be evaluated for changes from baseline in fixed dose periods 1 and 2. Additionally, changes in spleen volume during these periods will be assessed. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the therapeutic impact of mitapivat on patients with erythrocyte membranopathies.
Inclusion and Exclusion Criteria
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
- 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, be abstinent as part of their usual lifestyle, or agree to use a highly effective method of contraception, from the time of giving informed consent, during the study. 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. 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. An acceptable barrier method includes male or female condoms with or without spermicide, and cervical cap, diaphragm, or sponge with spermicide. Women using nonhormonal methods of contraception as a highly effective method do not need to use an additional barrier method.
Exclusion Criteria
- 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: 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 agents, including insulin (all insulins are considered 1 agent); use of insulin per se is not exclusionary. l. 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. m. Unstable extramedullary hematopoiesis that could pose a risk of imminent neurologic compromise. n. Severe hepatic issues such as liver fibrosis (F3 or worse), significant cirrhosis or non-alcoholic fatty liver disease (NASH). o.Current or recent history of psychiatric disorder that, in the opinion of the Investigator, could compromise the ability of the subject to cooperate with study visits and procedures.
- Are currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. Participation in registry studies is allowed.
- Have exposure to any investigational drug, device, or procedure within 5 half-lives or 3 months (whichever is longer) to the first dose of study treatment.
- Have had any prior treatment with a pyruvate kinase activator.
- Have a prior bone marrow or stem cell transplant.
- Are currently pregnant or breastfeeding or planning to become pregnant during the course of the study.
- Have a history of major surgery within 6 months prior to signing informed consent. Note that procedures such as laparoscopic gallbladder surgery are not considered major in this context.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Recruiting | 21 Dec 2023 | 14 |
 The Netherlands | Recruiting | 21 Dec 2023 | — |
| Netherlands | — | — | 10 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Pyrukynd 20 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 40 | 212 | PRD10061243 |
Pyrukynd 50 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 200 | 212 | PRD10061251 |
Pyrukynd 5 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 10 | 212 | PRD10061235 |
MITAPIVAT | Test | TABLET | ORAL USE | 200 | 212 | PRD11387021 |