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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether the drug mitapivat can safely assist individuals with sickle cell disease (SCD), a condition that causes painful episodes and organ damage. The trial focuses on the long-term safety and tolerability of this medication. Participants will take mitapivat in tablet form twice daily and undergo various health checks. Those who previously participated in a related study, benefited from mitapivat, and have stable SCD without recent transfusions would be well-suited for this trial. As a Phase 1, Phase 2 trial, the research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that mitapivat is likely to be safe for humans?

Research has shown that mitapivat is generally safe and well-tolerated by people with sickle cell disease (SCD). In one study, participants took mitapivat for about 2.5 years and experienced ongoing improvements in key blood markers. Another study found that mitapivat significantly increased hemoglobin levels, the protein in red blood cells that carries oxygen.

These results suggest that mitapivat is usually well-tolerated and has not caused major safety issues so far. However, individual experiences can differ, so potential participants should discuss any concerns with their healthcare provider. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for sickle cell disease, such as hydroxyurea and blood transfusions, Mitapivat works by activating the enzyme pyruvate kinase. This activation helps improve the energy balance in red blood cells, which can potentially reduce the sickling of cells that causes painful crises and other complications. Researchers are excited about Mitapivat because it represents a novel approach that targets the root of the metabolic issue in sickle cell disease, offering hope for better management of the condition with possibly fewer side effects.

What evidence suggests that mitapivat might be an effective treatment for sickle cell disease?

Research has shown that mitapivat yields promising results for people with sickle cell disease (SCD). In studies, about 46% of patients taking mitapivat experienced a significant increase in hemoglobin levels compared to those on a placebo. Over more than two years of follow-up, mitapivat improved anemia and reduced the number of painful episodes often experienced by people with SCD. Long-term use of mitapivat proved safe and well-tolerated. These findings suggest that mitapivat could effectively manage SCD symptoms. ^{1 2 3 5 6}

Who Is on the Research Team?

Swee Lay Thein, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39644907/

Safety and efficacy of mitapivat in sickle cell disease (RISE ... Both treatment groups showed a statistically significant haemoglobin response rate versus placebo (12 [46%] of 26 patients in the mitapivat 50 ...

2. ashpublications.org ashpublications.org/bloodrci/article/1/2/100014/546279/Long-term-mitapivat-treatment-is-safe-and

Long-term mitapivat treatment is safe and efficacious in ... Median of 2.53-year follow-up of mitapivat showed favorable safety and tolerability in patients with SCD. Sustained improvements in Hb, ...

3. agios.com agios.com/agios-eha-2025-data-room/

Agios EHA 2025 Data Room In the study, mitapivat showed sustained efficacy and tolerability over three years, including improvements in anemia, hemolysis, painful vaso-occlusive crises ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S3050598425000149

Long-term mitapivat treatment is safe and efficacious in ... Median of 2.53-year follow-up of mitapivat showed favorable safety and tolerability in patients with SCD. · Sustained improvements in Hb, hemolytic markers, and ...

5. investor.agios.com investor.agios.com/news-releases/news-release-details/agios-completes-enrollment-phase-3-rise-study-mitapivat-sickle

Agios Completes Enrollment of Phase 3 RISE UP Study ... The RISE UP Phase 2 and 3 studies are evaluating the efficacy and safety of mitapivat in sickle cell disease patients who are 16 years of age ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37934880/

One-year safety and efficacy of mitapivat in sickle cell ... Cellularly, the ATP:2,3-DPG ratio and Hb-oxygen affinity significantly increased and RBC sickling (point of sickling) nonsignificantly reduced.