Long-Term Mitapivat for Sickle Cell Disease

Overseen By Swee Lay Thein, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Must not be taking: Voxelotor, Crizanlizumab, CYP3A4 drugs

Disqualifiers: Hypertension, Heart failure, Diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 13

Duration: 48 weeks

15 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications. However, you cannot take certain medications like voxelotor or crizanlizumab within 12 weeks before joining, and you must stop strong inhibitors or inducers of CYP3A4/5 before signing consent. If you're on hydroxyurea or L-glutamine, you can continue if the dose hasn't changed for 12 weeks before joining.

What data supports the effectiveness of the drug Mitapivat for treating sickle cell disease?

Research shows that Mitapivat can improve hemoglobin levels and reduce the rate of painful events in sickle cell disease patients. It works by increasing energy in red blood cells and reducing substances that cause cell sickling, showing promise as a treatment. ^{1 2 3 4 5}

Is mitapivat safe for humans?

Mitapivat has been generally well tolerated in clinical trials for sickle cell disease and other conditions, with mostly mild side effects like headaches and increased liver enzymes. Serious side effects were rare and not directly related to the drug, suggesting it has a tolerable safety profile. ^{1 2 3 4 6}

How does the drug mitapivat differ from other treatments for sickle cell disease?

Mitapivat is unique because it is an oral drug that activates pyruvate kinase in red blood cells, increasing ATP and decreasing 2,3-DPG levels, which helps reduce sickle hemoglobin polymerization and improve red blood cell function. This mechanism is different from other treatments that primarily focus on managing symptoms or complications of sickle cell disease. ^{1 2 3 4 5}

Research Team

Swee Lay Thein, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria

Adults aged 18-70 with Sickle Cell Disease (SCD) who previously participated in NIH study #19H0097 and benefited from it. They must have stable organ function, no recent blood transfusions, and for women of childbearing potential, a commitment to use two forms of contraception. Exclusions include significant heart rhythm issues, uncontrolled medical conditions like hypertension or diabetes, active infections or certain drug allergies.

Inclusion Criteria

I am a woman who can have children and have a negative pregnancy test.

My blood clotting tests are within normal limits, unless I'm on blood thinners.

My organs are functioning well.

Exclusion Criteria

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:

I have had gallstones or gallbladder inflammation but it's treated now.

My high blood pressure is not controlled by medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive a maintenance dose of mitapivat for 48 weeks with regular safety monitoring and evaluation of pharmacokinetics and pharmacodynamics.

48 weeks

10 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments of hemoglobin response and quality of life.

6 weeks

2 visits (in-person)

Open-label extension (optional)

Participants benefiting from the study drug have the option to continue therapy for an additional 5 years.

5 years

Treatment Details

Interventions

• Mitapivat

Trial Overview The trial is testing the long-term safety and effectiveness of mitapivat tablets taken twice daily by people with SCD. It extends a previous study to see if benefits continue or improve over time. Participants will undergo various health assessments including physical exams, blood tests, heart checks (ECG), mobility tests (6-minute walk), echocardiograms for heart/lung function, bone scans (DXA), and health questionnaires.

Participant Groups

Group I: 1 Experimental Treatment 1 Intervention

Subjects will be treated with a maintenance dose of mitapivat previously assessed for safety and tolerability in the Phase I study for an initial 48 weeks and undergo safety monitoring, evaluation of pharmacokinetics and pharmacodynamics, and assessment of secondary laboratory and clinical endpoints at pre-specified intervals during the study period.

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Findings from Research

In a 1-year study involving 10 patients with sickle cell disease, mitapivat was well tolerated and led to a significant increase in hemoglobin levels (mean increase of 1.1 g/dL) and a reduction in vaso-occlusive events from a historical baseline.

The treatment also improved the ATP:2,3-DPG ratio and Hb-oxygen affinity, indicating a potential mechanism for its efficacy in reducing sickling of red blood cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

One-year safety and efficacy of mitapivat in sickle cell disease: follow-up results of a phase 2, open-label study. van Dijk, MJ., Rab, MAE., van Oirschot, BA., et al.[2023]

In a phase II study involving 76 subjects with sickle cell disease, HQK-1001 showed a minimal increase in fetal hemoglobin (Hb F) levels compared to placebo, with only 24% of patients experiencing an increase greater than 3%.

The study also indicated a concerning trend of increased pain crises in the HQK-1001 group, with an average of 3.5 crises per year compared to 1.7 in the placebo group, leading to the conclusion that further daily administration of HQK-1001 is not recommended.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind, placebo-controlled phase II study of the efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease. Reid, ME., El Beshlawy, A., Inati, A., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

One-year safety and efficacy of mitapivat in sickle cell disease: follow-up results of a phase 2, open-label study. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease. [2023]

3. Spain pubmed.ncbi.nlm.nih.gov

Mitapivat for sickle cell disease and thalassemia. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Mitapivat increases ATP and decreases oxidative stress and erythrocyte mitochondria retention in a SCD mouse model. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

A double-blind, placebo-controlled phase II study of the efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease. [2022]