A Pilot Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Escalating Multiple Oral Doses of AG-348 in Subjects With Stable Sickle Cell Disease

Study point of contact

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

Locations

1 United States site

Age

18 to 70 Years

Phase

Early Phase 1

Study type

Interventional

Gender

All

Interventions

Drug

Compensation

Unknown

About the study

Background:

Sickle Cell Disease (SCD) is an inherited blood disorder. People with SCD have abnormal
hemoglobin in their red blood cells. Researchers are investigating the safety and efficacy of
an investigational medicine called AG-348 (mitapivat sulfate) to determine if it will help
people with SCD.

Objective:

To test the tolerability and safety of AG-348 in people with SCD.

Eligibility:

People ages 18 and older with SCD.

Design:

Participants will have 8 visits over approximately 14 weeks. At the first visit participants
will be screened with a medical history; a physical exam; and blood, urine, and heart tests.
At the following 5 visits participants will stay at the clinic for 1 night each. Participants
will take study drug in increasing doses upto visit 6, after which the drug will be tapered
off. All visits will include physical exam, blood, and urine tests. The last visit will occur
4 weeks after stopping the drug and also includes a heart test. Participants will provide DNA
from the blood samples they provide. The DNA will be tested for an inherited gene that can
cause differences in response to the study drug. Researchers may also test other genes to see
if they can find any genes that interact with SCD.

participation restrictions

Subjects who meet any of the following criteria during screening will not receive AG348 and
will not be counted toward the final enrollment count for statistical purposes:

1. Documented pyruvate kinase deficiency

2. 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:

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

management.

2. History of recent (within 6 months prior to signing informed consent) congestive
heart failure; myocardial infarction or unstable angina pectoris; hemorrhagic,
embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial
embolism.

3. Cardiac dysrhythmias judged as clinically significant by the Investigator.

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

5. 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.

6. History of drug-induced cholestatic hepatitis.

7. 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.

8. 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.

9. 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 HCV Ab, a reverse transcriptase-polymerase chain reaction test will
be conducted. Subjects with hepatitis C may be rescreened after receiving
appropriate hepatitis C treatment.

10. Positive test for human immunodeficiency virus 1 or 2 Ab.

11. Active infection requiring any use of systemic antimicrobial agents (parenteral
or oral) or Grade greater than or equal to 3 in severity (per National Cancer
Institute Common Terminology Criteria for Adverse Events) within 2 months prior
to signing informed consent.

12. 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.

13. 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.

14. Unstable extramedullary hematopoiesis that could pose a risk of imminent
neurologic compromise.

15. 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.

16. Are currently enrolled in another therapeutic clinical trial involving ongoing
therapy with any investigational or marketed product or placebo. Sickle cell
anemia subjects on hydroxyurea or L-glutamine will also be considered, provided
that they have been on an unchanged dose of hydroxyurea or L-Glutamine for three
months prior to enrollment.

17. Have exposure to any investigational drug, device, or invasive procedure within 3
months prior to the first dose of study treatment. All noninvestigational
invasive procedures within 3 months of starting study treatment may be considered
as a potential exclusion criteria per the PI s discretion.

18. Have had any prior treatment with a pyruvate kinase activator.

19. Have received crizanlizumab or voxelotor in the 12 weeks prior to signing consent

20. Have a prior bone marrow or stem cell transplant.

21. Are currently pregnant or breastfeeding.

22. 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 the first dose of AG-348.

23. 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 the first dose of study
treatment.

24. 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.

Locations

  • Bethesda, Maryland, United States, National Institutes of Health Clinical Center, 20892 [Recruiting]
Last updated 2021-07-03 Enroll Now