Mitapivat in Membranopathies

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Eurobloodnet Association

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

29 Dec 2023 → ongoing

Decision date (initial)

2023-12-04

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

AGIOS Pharmaceuticals

External identifiers

EU CT number

2023-503271-24-01

ClinicalTrials.gov

NCT05935202

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To evaluate safety of mitapivat

Secondary objectives 7

1. To evaluate the effect of mitapivat on changes in hemoglobin (Hb)
2. To evaluate the long-term effect of mitapivat on Hb
3. To evaluate the effect of mitapivat on additional measures of Hb response
4. To evaluate the effect of mitapivat on markers of hemolysis
5. To evaluate the effect of mitapivat on markers of erythropoiesis
6. To evaluate the effect of mitapivat on symptoms and impacts
7. To evaluate the effect of mitapivat on spleen size in non-splenectomized patients

Conditions and MedDRA coding

erythrocyte membranopathies

Study design 1 period

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 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
2. Age ≥18 years at the first screening
3. 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
4. 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
5. 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
6. Be willing and able to give written informed consent and to comply to all study procedures for the duration of the study
7. 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.
8. 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 13

1. Known history of pyruvate kinase deficiency (decreased PK activity or two pathogenic PKLR alleles). PK activity and PKLR testing is not required.
2. 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.
3. 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.
4. 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.
5. 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.
6. Have had any prior treatment with a pyruvate kinase activator.
7. Have a prior bone marrow or stem cell transplant.
8. Are currently pregnant or breastfeeding or planning to become pregnant during the course of the study.
9. 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.
10. 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
11. 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.
12. 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.
13. For men and women of reproductive potential: unwillingness to be abstinent or use double anticonception during the trial period.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 7

1. 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:
2. - Incidence of treatment-emergent adverse events (TEAEs)
3. - Clinical laboratory values
4. - ECGs (standard 12-lead)
5. - Physical examination findings
6. - DEXA scans
7. - Type, incidence, severity and relationship of mitapivat to AE and SAE

Secondary endpoints 8

1. Hb response (HR) defined as a ≥1 g/dL increase in Hb concentration from baseline (mean of Screening and D0) that is sustained at 2 or more points during fixed dose period 1.
2. Change from baseline in Hb levels to the average of scheduled visits in fixed dose period 2.
3. Average change in mean Hb concentration during Fixed Dose Periods 1 and 2 compared to baseline (mean of Screening and D0)
4. Proportion of subjects who achieve Hb concentration in the sex-associated normal range that is sustained at two or more points in the fixed dose periods 1 and 2
5. Change from baseline in lactate dehydrogenase (LDH), bilirubin, and haptoglobin at the end of fixed dose period 1 and 2.
6. Change from baseline in reticulocytes erythropoietin, erythroferrone, and sTfR at the end of fixed dose period 1 and 2.
7. Change from baseline in in fixed dose periods 1 and 2: • Health related Quality of Life (HRQoL) (SF-36 version 1) • Pyruvate Kinase Deficiency Impact Asessment (PKDIA)
8. Change from baseline in spleen volume in fixed dose periods 1 and 2

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Eurobloodnet Association

Sponsor organisation

Eurobloodnet Association

Address

1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Eurobloodnet Association

Contact name

Andreas Glenthøj

Public contact point

Organisation

Eurobloodnet Association

Contact name

Pr Pierre FENAUX

Third parties 1

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications