Evaluation of the Safety,Tolerability, Pharmacokinetics, and Pharmacodynamics of Long-term Mitapivat Dosing in Subjects With Stable Sickle Cell Disease: An Extension of a Phase I Pilot Study of Mitapivat

Study point of contact

Ingrid C Frey
(301) 402-6674
[email protected]

Locations

1 United States site

Age

18 to 70 Years

Phase

Phase 1/Phase 2

Study type

Interventional

Gender

All

Interventions

Drug

Compensation

Unknown

About the study

Background:

Sickle cell disease (SCD) is a disorder that causes episodes of acute pain and progressive
organ damage. Ways to manage SCD have evolved slowly. Treatments do not always work.
Researchers want to see if a drug called mitapivat can help people with SCD.

Objective:

To test the long-term tolerability and safety of mitapivat (or AG-348) in people with SCD.

Eligibility:

Adults age 18-70 with SCD who took part in and benefited from NIH study #19H0097.

Design:

Participants will be screened with a medical history and physical exam. They will give a
blood sample. They will have an electrocardiogram to test heart function.

Participants will repeat some of the screening tests during the study.

Participants will complete 6-minute walk tests to measure mobility and function. They will
have transthoracic echocardiograms to measure heart and lung function. They will have
dual-energy X-ray absorptiometry scans to measure bone health. They will complete online
questionnaires that measure their overall health and well-being.

Participants will take the study drug in the form of a tablet twice a day.

Participants will keep a study diary. They will record any symptoms they may have.

Participation will last for about 54 weeks. After 48 weeks, participants can either keep
taking the study drug for 48 more weeks or be tapered off of the study drug to complete the
study. Those who are on the study for 1 year will have 10 study visits. Those who are on the
study for 2 years will have 14 study visits.

participation requirements

– Only subjects completing Study 19H0097 will be screened for eligibility. Eligibility
criteria are identical with the exception of criteria 1.4, 2.2, and 2.3.p.

Subjects will enroll onto the study and undergo screening. Subjects who do not meet any of
the following criteria during screening will not receive the study intervention but will be
counted toward study accrual. Screen failures may be rescreened at a later time.

In order to be eligible to participate in this study, an individual must meet all of the
following criteria:

– 1.1 Have provided signed written informed consent prior to performing any study
procedure, including screening procedures.

– 1.2 Age between 18-70 years

– 1.3 Have previously been enrolled in Study 19H0097 with study drug mitapivat,
completed at least 3 dose escalation levels, and demonstrated clinical benefit from
mitapivat treatment as determined by the PI

– 1.4 No transfusion in the 12 weeks prior to signing consent, or absence of Hb A on
hemoglobin analysis (by high-performance liquid chromatography; HPLC)

– 1.5 Have adequate organ function, as defined by:

– a. Serum aspartate aminotransferase (AST) <=2.5 x Upper Limit of Normal (ULN) (unless the increased AST is assessed by the Investigator as due to hemolysis) and alanine aminotransferase (ALT) <=2.5 x ULN. - b. Serum creatinine <=1.25 x ULN. If serum creatinine is >1.25 x ULN, then
glomerular filtration rate (based on creatinine) must be >=60 mL/min.

– c. Absolute neutrophil count >=1.0 x 10^9power/L.

– d. Hemoglobin >= 7 g/dL

– e. Platelet count >=100 x 10^9/L.

– f. Activated partial thromboplastin time and international normalized ratio <=1.5 x ULN, unless the subject is receiving therapeutic anticoagulants. - 1.6 For women of reproductive potential, have a negative serum pregnancy test during the screening period. 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 1 year prior to signing informed consent and have an elevated follicle-stimulating hormone level indicative of menopause during the screening period). - 1.7 For women of reproductive potential as well as men and their partners who are women of reproductive potential, be abstinent as part of their usual lifestyle, or agree to use 2 effective forms of contraception from the time of giving informed consent, during the study, and for 28 days (both men and women) following the last dose of study treatment. An effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine or subdermal contraceptive implants, and barrier methods. - 1.8 Be willing to comply with all study procedures for the duration of the study.

participation restrictions

– 2.1 Documented pyruvate kinase deficiency

– 2.2 Screening hemoglobin level of >= 11 g/dL

– 2.3 Have a significant medical condition that confers an unacceptable risk to
participating in the study, and/or that could confound the interpretation of the study
data. Such significant medical conditions include, but are not limited to the
following:

– a. Poorly controlled hypertension (defined as systolic blood pressure [BP] >150
mmHg or diastolic BP >90 mmHg) refractory to medical management.

– b. History of recent (within 24 weeks prior to signing consent) decompensated
congestive heart failure; myocardial infarction or unstable angina pectoris;
hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary
or arterial embolism.

– c. Cardiac dysrhythmias judged as clinically significant by the Investigator.

– d. Heart-rate corrected QT interval-Fredericia’s method (QTcF) >480 msec with the
exception of subjects with right or left bundle branch block.

– e. 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.

– f. History of drug-induced cholestatic hepatitis.

– g. Iron overload sufficiently severe to result in a clinical diagnosis by the
Investigator of cardiac (e.g., clinically significant impaired left ventricular
ejection fraction), hepatic (e.g., fibrosis, cirrhosis), or pancreatic (e.g.,
diabetes) dysfunction.

– h. Have a diagnosis of any other congenital or acquired blood disorder, or any
other hemolytic process as defined by a positive direct antiglobulin test (DAT),
except mild allo-immunization as a consequence of transfusion therapy.

– i. Positive test for hepatitis B surface antigen or hepatitis C virus (HCV)
antibody (Ab) with signs of active hepatitis B or C virus infection. If the
subject is positive for HCVAb, a reverse transcriptase-polymerase chain reaction
test will be conducted. Subjects with hepatitis C may be rescreened after
receiving appropriate hepatitis C treatment.

– j. Positive test for human immunodeficiency virus 1 or 2 Ab.

– k. Active infection requiring any use of systemic antimicrobial agents
(parenteral or oral) or Grade >=3 in severity (per National Cancer Institute
Common Terminology Criteria for Adverse Events) within 8 weeks prior to signing
consent.

– l. 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.

– m. History of any primary malignancy, with the exception of: curatively treated
nonmelanomatous 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.

– n. Current or recent history of psychiatric disorder that, in the opinion of the
Investigator or Medical Monitor, could compromise the ability of the subject to
cooperate with study visits and procedures.

– o. Are currently enrolled in another therapeutic clinical trial involving ongoing
therapy with any investigational or marketed product or placebo. SCD subjects on
hydroxyurea or L-glutamine will also be considered, provided that they have been
on an unchanged dose of hydroxyurea or LGlutamine for 12 weeks prior to signing
consent. Use of the newer SCD therapies voxelotor or crizanlizumab will not be
permitted on this study, and subjects who have received voxelotor or
crizanlizumab in the 12 weeks prior to signing consent will be excluded.

– p. Have exposure to any investigational drug (other than the current drug,
mitapivat), device, or invasive procedure within 12 weeks prior to signing
consent. All non-investigational invasive procedures within 12 weeks of signing
consent may be considered as a potential exclusion criteria per the PI s
discretion.

– q. Have had a prior bone marrow or stem cell transplant.

– r. Are currently pregnant or breastfeeding.

– s. Are currently receiving medications that are strong inhibitors of cytochrome
P450 (CYP)3A4 or strong inducers of CYP3A4 that have not been stopped for a
duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever
is longer) prior to signing consent.

– t. Are currently receiving hematopoietic stimulating agents (e.g.,
erythropoietins, granulocyte colony stimulating factors, thrombopoietins) that
have not been stopped for a duration of at least 28 days prior to signing
consent.

– u. Have a history of allergy to sulfonamides if 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.

– v. Have a history of allergy to mitapivat or its excipients (microcrystalline
cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol).

Locations

  • Bethesda, Maryland, United States, National Institutes of Health Clinical Center, 20892 [Recruiting]