Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Escalating Multiple Oral Doses of AG-348 in Subjects With Stable Sickle Cell Disease

• ClinicalTrials.gov Identifier: NCT04000165
• Recruitment Status: Recruiting
• First Posted: June 27, 2019
• Last Update Posted: December 6, 2019
• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Tracking Information

• First Submitted Date: June 22, 2019
• First Posted Date: June 27, 2019
• Last Update Posted Date: December 6, 2019
• Actual Study Start Date: July 11, 2019
• Estimated Primary Completion Date: December 31, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 26, 2019)

safety and tolerability [ Time Frame: day 51 ]

frequency and severity of AEs, and changes in laboratory parameters, including levels in hemoglobin, reticulocyte counts, bilirubin and lactate dehydrogenase

• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT04000165 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: June 26, 2019)

PK & PD [ Time Frame: day 51 ]

RBC 2,3-DPG activities from baseline, 2,3-DPG, ATP levels at different doses of AG-348 and change from baseline etc.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Escalating Multiple Oral Doses of AG-348 in Subjects With Stable Sickle Cell Disease
• Official Title: 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

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) o 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 7 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 4 visits participants will stay at the clinic for up to 2 nights. Participants will take study drug in increasing doses for 6 weeks, 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.

Detailed Description

Sickle cell disease (SCD) is a multisystem disorder associated with episodes of acute clinical events and progressive organ damage. Episodic pain, triggered by micro-vasoocclusion induced by sickled red blood cells, is the most common acute complication and the leading cause of hospitalization. Management strategies for SCD have evolved very slowly, and treatment of acute pain is still limited to supportive therapy with opioid medication. Until recently in 2017, the only approved therapy for SCD was hydroxyurea (HU), indicated to reduce frequency of acute painful crises but not universally effective. In addition to HU, transfusions with normal red blood cells are widely used to treat severe sickle crises, but this strategy has limitations (not uniformly accessible, accompanied by risks of alloimmunization, hemolytic transfusion reactions and transfusional iron overload). The only curative treatment is bone marrow transplantation, but this option carries significant risks and is limited by the availability of histocompatible donors.

As the root cause of SCD is polymerization of deoxy-HbS, there is a strong rationale for exploring agents that could inhibit/reduce the polymerization process itself. HbS polymerizes only when deoxygenated, its oxygenation is influenced by a few factors, one key factor being the 2,3- diphosphoglycerate (2,3-DPG) concentration in the red blood cell. Increased intracellular 2,3-DPG decreases oxygen binding and stabilizes the deoxygenated form (T form) of hemoglobin. In addition, increased 2,3-DPG concentration decreases intracellular red cell pH further promoting HbS polymerization. 2,3-DPG is an intermediate substrate in the glycolytic pathway, the only source of ATP production in red blood cells. Pyruvate kinase (PK) is a key enzyme in the final step of glycolysis; PK converts phosphoenolpyruvate to pyruvate, creating 50% of the total red cell ATP that is essential for maintaining integrity of the red cell membrane. Reduced PK activity leads to accumulation of the upstream enzyme substrates, including 2,3- DPG, that favours polymerization of deoxy-HbS. In humans with SCD, and even in sickle carriers who are generally asymptomatic, reduced oxygen affinity will favour deoxygenation of HbS and its polymerisation, and thus sickling. Indeed, the combination of PK deficiency and sickle cell trait causing an acute sickling syndrome has been previously reported in two cases.

Current approaches to reduce HbS polymerization include fetal haemoglobin induction via multiple strategies and drugs that targets HbS polymerization through increasing affinity of hemoglobin for oxygen (eg. Voxelotor / GBT440). Increasing red cell PK (PK-R) activity, leading to a decrease in intracellular 2,3-DPG concentration, presents a potentially attractive therapeutic target for thwarting HbS polymerization and acute sickle pain. AG-348 is a novel, orally bioavailable, small molecule allosteric activator of PK-R, that is currently in Phase II/III clinical trials in humans with PK deficiency (NCT02476916, NCT03548220 / AG348-C-006; NCT03559699 / AG348-C-007). Overview of the preclinical AG-348 data and other data support dose-dependent changes in blood glycolytic intermediates consistent with glycolytic pathway activation at all multiple ascending doses tested, supporting the potential role of AG-348 in the treatment of sickle cell disease. The overall objective of the present study is to determine the clinical safety and tolerability of AG-348 in subjects with SCD.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Basic Science
• Condition: Sickle Cell Disease

Intervention

Drug: AG-348

All subjects will receive an initial dose of 5 mg BID of AG-348 for 2 weeks followed by 2 dose increases, from 5 to 20 mg BID and from 20 to 50 mg BID,depending on safety and tolerability. Specifically, the treating clinician will assess the safety and tolerability of the current dose level before a decision is taken to escalate the dose to the next level.

Study Arms

Experimental: AG-348

Single arm, intrapatient dose escalation Q 2 weeks

Intervention: Drug: AG-348

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 26, 2019): 25
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2020
• Estimated Primary Completion Date: December 31, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

• INCLUSION CRITIERIA:

For enrollment, subjects must meet all of the following criteria during the screening period:

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

5.1.2 Age between 18-70 years

5.1.3 Unequivocal diagnosis of HbSS confirmed by hemoglobin electrophoresis performed on patients at least 90 days after a blood transfusion if previously transfused, or DNA genotyping within 30 days prior to study enrollment

5.1.4 No transfusion in the 90 days prior to the first dose of study drug

5.1.5 Have adequate organ function, as defined by:

1. Serum aspartate aminotransferase (AST) less than or equal to 2.5 (SqrRoot) Upper Limit of Normal (ULN) (unless the increased AST is assessed by the Investigator as due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase (ALT)

   less than or equal to 2.5 (SqrRoot) ULN (unless the increased ALT is assessed by the Investigator as due to hepatic iron deposition).

2. Serum creatinine less than or equal to 1.25 (SqrRoot) ULN. If serum creatinine is >1.25 (SqrRoot) ULN, then glomerular filtration rate (based on creatinine) must be greater than or equal to 60 mL/min.
3. Absolute neutrophil count greater than or equal to 1.0 (SqrRoot) 109/L.
4. Hemoglobin greater than or equal to 7 g/dL
5. Platelet count greater than or equal to 100 (SqrRoot) 109/L.
6. Activated partial thromboplastin time and international normalized ratio less than or equal to 1.5 (SqrRoot) ULN, unless the subject is receiving therapeutic anticoagulants.

5.1.6 For women of reproductive potential, have a negative serum or urine 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 12 months prior to signing informed consent and have an elevated folliclestimulating hormone level indicative of menopause during the screening period).

5.1.7 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, and barrier methods.

5.1.8 Be willing to comply with all study procedures for the duration of the study.

EXCLUSION CRITERIA:

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:

5.2.1 Documented pyruvate kinase deficiency

5.2.2 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-Fridericia's method (QTcF) >450 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 HCVAb, 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 the use of parenteral antimicrobial agents 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 the first dose of study treatment.
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.
18. Have had any prior treatment with a pyruvate kinase activator.
19. Have a prior bone marrow or stem cell transplant.
20. Are currently pregnant or breastfeeding.

21. Are currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4, strong inducers of CYP3A4, strong

    inhibitors of P-glycoprotein (P-gp), or digoxin (a P-gp sensitive substrate medication) 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.

22. 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.

23. 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.

24. Have a history of allergy to AG-348 or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Swee Lay Thein, M.D.; (301) 402-6699; sweelay.thein@nih.gov

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04000165
• Other Study ID Numbers: 190097; 19-H-0097
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
• Study Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborators: Not Provided

Investigators

• Principal Investigator: Swee Lay Thein, M.D.; National Heart, Lung, and Blood Institute (NHLBI)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: December 4, 2019