Etavopivat for Sickle Cell Disease

Overseen by Amy Tang, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Novo Nordisk A/S

Disqualifiers: Chronic transfusion, Severe renal dysfunction, Hepatic dysfunction, Cardiac or pulmonary disease, Chemotherapy, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests etavopivat, a medication aimed at improving blood flow and oxygen use in the brain and muscles, in young patients with sickle cell disease. Etavopivat is being developed for the treatment of sickle cell disease.

Will I have to stop taking my current medications?

The trial allows participants to continue taking hydroxyurea (a medication for sickle cell disease) if the dose has been stable for at least 3 months. The protocol does not specify about other medications, so it's best to discuss with the trial team.

How is the drug Etavopivat different from other treatments for sickle cell disease?

Etavopivat is unique because it is an oral drug that activates an enzyme in red blood cells to increase their energy and flexibility, reducing the sickling of cells that causes pain and complications in sickle cell disease. ^{1 2 3 4 5}

Research Team

Amy Tang, MD

Principal Investigator

Children's Healthcare of Atlanta

Clinical Transparency dept. 2834

Principal Investigator

Novo Nordisk A/S

Eligibility Criteria

This trial is for children aged 12-21 with Sickle Cell Disease, specifically those with hemoglobin SS or S/beta0 thalassemia and a hemoglobin level ≤ 9.0 g/dL. Stable hydroxyurea therapy is okay, but not if they've had recent severe complications like organ dysfunction, transfusions, surgery on stomach/small intestine, or unstable heart conditions.

Inclusion Criteria

Hemoglobin (Hb) ≤ 9.0 g/dL at baseline

I have sickle cell disease with either HbSS or HbS/β0 thalassemia.

I have been on a stable dose of hydroxyurea for 3 months without blood-related side effects.

Exclusion Criteria

I need regular blood transfusions to manage my condition.

Vaso-occlusive crisis (VOC) within 14 days prior to signing the informed consent form

Acute chest syndrome (ACS) within 14 days prior to signing the informed consent form

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

up to 4 weeks

Treatment

Participants receive etavopivat to evaluate its effect on cerebral and muscle hemodynamics

24 weeks

Safety Follow-up

Safety follow-up visit to monitor participants after the last dose of study drug

4 weeks

1 visit (in-person)

End of Study (EOS)

End of study visit to complete all final assessments

8 weeks

1 visit (in-person)

Treatment Details

Interventions

• Etavopivat (Other)

Trial Overview The study tests Etavopivat's effects on brain and muscle blood flow in young patients with Sickle Cell Disease. It's an open-label trial where all participants receive the drug to see how it influences their cerebral hemodynamics.

Participant Groups

Group I: Etavopivat Experimental Treatment 1 Intervention

Single-arm, open-label

Who Is Running the Clinical Trial?

Novo Nordisk A/S

Lead Sponsor

Trials

1,578

Recruited

3,813,000+

Lars Fruergaard Jørgensen

Novo Nordisk A/S

Chief Executive Officer since 2017

MSc in Finance and Business Administration, Aarhus School of Business, Aarhus University, Denmark

Martin Holst Lange

Novo Nordisk A/S

Chief Medical Officer since 2021

MD from University of Copenhagen

Forma Therapeutics, Inc.

Lead Sponsor

Trials

13

Recruited

1,300+

Emory University

Collaborator

Trials

1,735

Recruited

2,605,000+

Dr. R. Donald Harvey

Emory University

Chief Medical Officer

MD from Emory University School of Medicine

Dr. George Painter

Emory University

Chief Executive Officer since 2013

PhD in Synthetic Organic Chemistry from Emory University

Findings from Research

Etavopivat, an investigational oral medication, activates erythrocyte pyruvate kinase, leading to decreased levels of 2,3-diphosphoglycerate (2,3-DPG) and increased hemoglobin-oxygen affinity, which may help reduce sickling of red blood cells in sickle cell disease (SCD).

In studies involving nonhuman primates and healthy human subjects, etavopivat significantly increased ATP production and hemoglobin-oxygen affinity, and it also showed effectiveness in reducing sickling in red blood cells from SCD patients, indicating its potential as a promising treatment for SCD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etavopivat, a Pyruvate Kinase Activator in Red Blood Cells, for the Treatment of Sickle Cell Disease. Schroeder, P., Fulzele, K., Forsyth, S., et al.[2022]

In a phase 3 trial involving 274 patients with sickle cell disease, voxelotor 1500 mg significantly improved hemoglobin levels over 72 weeks compared to placebo, demonstrating its efficacy as a treatment.

Voxelotor also led to notable reductions in hemolysis markers, indicating its potential to alleviate symptoms associated with hemolytic anemia in sickle cell disease, while serious adverse events were infrequent and unrelated to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial. Howard, J., Ataga, KI., Brown, RC., et al.[2021]

Etavopivat, an oral medication being developed for sickle cell disease, was found to be safe in a phase 1 trial with 90 healthy adults, where most side effects were mild and did not lead to discontinuation of the study.

The drug effectively activated erythrocyte pyruvate kinase-R, leading to beneficial changes in hemoglobin-oxygen affinity, with pharmacodynamic effects lasting 48 to 72 hours, supporting its potential for once-daily dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Pharmacokinetics, and Pharmacodynamics of Etavopivat (FT-4202), an Allosteric Activator of Pyruvate Kinase-R, in Healthy Adults: A Randomized, Placebo-Controlled, Double-Blind, First-in-Human Phase 1 Trial. Forsyth, S., Schroeder, P., Geib, J., et al.[2022]

A simulation model based on pharmacokinetic data from 109 patients was developed to recommend dosing for rivipansel in children aged 6-11 years with sickle cell disease, taking into account renal function and disease-specific factors.

The recommended dosing regimen of a 40-mg/kg loading dose followed by a 20-mg/kg maintenance dose every 12 hours is expected to achieve effective drug concentrations, and its efficacy will be validated in an ongoing phase III study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose Selection Based on Modeling and Simulation for Rivipansel in Pediatric Patients Aged 6 to 11 Years With Sickle Cell Disease. Tammara, BK., Harnisch, LO.[2019]

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]

References

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

Etavopivat, a Pyruvate Kinase Activator in Red Blood Cells, for the Treatment of Sickle Cell Disease. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial. [2021]

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

Safety, Pharmacokinetics, and Pharmacodynamics of Etavopivat (FT-4202), an Allosteric Activator of Pyruvate Kinase-R, in Healthy Adults: A Randomized, Placebo-Controlled, Double-Blind, First-in-Human Phase 1 Trial. [2022]

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

Dose Selection Based on Modeling and Simulation for Rivipansel in Pediatric Patients Aged 6 to 11 Years With Sickle Cell Disease. [2019]

5. 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]