A Dose-Finding Study of AG-348 in Sickle Cell Disease

NCT04000165 | Completed Early Phase 1 Results FDA Drug

• 2 other identifiers: 19009719-H-0097
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief Summary

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, blood and urine testing, and an EKG. During the following 5 visits, participants will stay at the clinic for 1 night each. Participants will take study drug in increasing doses up to 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. 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.

Conditions

Sickle Cell Disease

Keywords

HbS polymerization; pyruvate kinase; 2,3- diphosphoglycerate; ATP in red blood cells; acute sickle pain

Outcome Measures

Primary Outcomes (3)

• Number Participants With Most Common Reported Drug Related Adverse Events

  To assess the clinical safety and tolerability of multiple escalating doses of AG-348, an allosteric activator of the enzyme pyruvate kinase, in subjects with stable sickle cell disease (SCD). Safety and tolerability were assessed by frequency and severity of adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) 5.0.

  14 weeks

• Number Participants With Serious Adverse Events That Were Possibly Drug-related Serious Adverse Events

  To assess the clinical safety and tolerability of multiple escalating doses of AG-348, an allosteric activator of the enzyme pyruvate kinase, in subjects with stable sickle cell disease (SCD). Safety and tolerability were assessed by frequency and severity of adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) 5.0.

  14 weeks

• Number Participants With Increase of ≥ 1 g/dL in Hemoglobin

  To assess the clinical safety and tolerability of multiple escalating doses of AG-348, an allosteric activator of the enzyme pyruvate kinase, in subjects with stable sickle cell disease (SCD). Safety and tolerability were assessed by defined as a ≥ 1 g/dL increase in hemoglobin at any dose level compared to baseline.

  14 weeks

Secondary Outcomes (12)

• Change in Hemoglobin at Each Dose Level of AG-348

  14 weeks

• Change in Lactic Acid Dehydrogenase (LDH) at Each Dose Level of AG-348

  14 weeks

• Change in Total Bilirubin at Each Dose Level of AG-348

  14 weeks

• Change in Absolute Reticulocyte Count at Each Dose Level of AG-348

  14 weeks

• Change in Aspartate Aminotransferase (AST) at Each Dose Level of AG-348

  14 weeks

Study Arms (1)

AG-348 in participants with Sickle Cell Disease

EXPERIMENTAL

Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.

Drug: AG-348

Interventions

AG-348 DRUG

This is a nonrandomized, intra-patient dose escalating clinical study. AG-348 will be administered starting at 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.

Also known as: Mitapivat

AG-348 in participants with Sickle Cell Disease

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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:
• Documented pyruvate kinase deficiency
• 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:
• Poorly controlled hypertension (defined as systolic blood pressure \[BP\] \>150 mmHg or diastolic BP \>90 mmHg) refractory to medical management.
• 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.
• Cardiac dysrhythmias judged as clinically significant by the Investigator.
• Heart-rate corrected QT interval-Fredericia's method (QTcF) \>480 msec with the exception of subjects with right or left bundle branch block.
• History of drug-induced cholestatic hepatitis.
• 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.
• 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.
• 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.
• Positive test for human immunodeficiency virus 1 or 2 Ab.
• 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.
• 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.
• Unstable extramedullary hematopoiesis that could pose a risk of imminent neurologic compromise.

Sponsors & Collaborators

• National Institutes of Health Clinical Center (CC): lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Agios Pharmaceuticals, Inc.: collaborator

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (2)

• Le K, Wang X, Chu J, Lundt M, Lee YY, Conrey A, Frey I, Giannini S, Kosinski PA, Hausman JM, Low PS, Jeffries N, Desai SA, Thein SL. Activating pyruvate kinase improves red blood cell integrity by reducing band 3 tyrosine phosphorylation. Blood Adv. 2024 Nov 12;8(21):5653-5662. doi: 10.1182/bloodadvances.2024013504.

  PMID: 39265169 DERIVED

• Xu JZ, Conrey A, Frey I, Gwaabe E, Menapace LA, Tumburu L, Lundt M, Lequang T, Li Q, Glass K, Dunkelberger EB, Iyer V, Mangus H, Kung C, Dang L, Kosinski PA, Hawkins P, Jeffries N, Eaton WA, Lay Thein S. A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease. Blood. 2022 Nov 10;140(19):2053-2062. doi: 10.1182/blood.2022015403.

  PMID: 35576529 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

mitapivat

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Dr. Swee Lay Thein, Chief of Sickle Cell Branch
• Organization: The National Institutes of Health / The National Heart, Lung, and Blood Institute

sweelay.thein@nih.gov

301.402.6699

Study Officials

• Swee Lay Thein, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Swee Lay Thein, M.D.

Study Record Dates

• First Submitted: June 22, 2019
• First Posted: June 27, 2019
• Study Start: July 11, 2019
• Primary Completion: June 21, 2021
• Study Completion: June 21, 2021
• Last Updated: July 12, 2022
• Results First Posted: July 12, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: 6 months after publication date for a period of 5 year

Locations

US (1)