Etavopivat for Sickle Cell Disease

(HIBISCUS Trial)

Recruiting at 231 trial locations

Overseen By Novo Nordisk

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Forma Therapeutics, Inc.

Must not be taking: Voxelotor, Erythropoietin, CYP3A4/5 inducers

Disqualifiers: HIV, Hepatitis B/C, Renal dysfunction, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

450 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a drug called etavopivat to see if it can help people with sickle cell disease. The drug aims to improve blood health and reduce pain by making red blood cells work better. The study includes patients aged 12 to 65.

Will I have to stop taking my current medications?

The trial requires that if you are taking hydroxyurea, crizanlizumab, or L-glutamine, you must be on a stable dose for a certain period before starting the study. You cannot use voxelotor, certain experimental drugs, or erythropoietin within 28 days before starting the study. The protocol does not specify other medications, so check with the study team for more details.

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial. If you are on voxelotor, erythropoietin, or certain experimental drugs, you must stop them at least 28 days before starting the study. If you are taking hydroxyurea, crizanlizumab, or L-glutamine, you must be on a stable dose for a specific period before the trial.

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 improve their flexibility, which helps prevent them from becoming sickle-shaped. This mechanism is different from other treatments that primarily focus on reducing pain or preventing complications. ^{1 2 3 4 5}

How is the drug Etavopivat unique in treating sickle cell disease?

Etavopivat is unique because it is an oral drug that activates pyruvate kinase in red blood cells, which helps reduce sickling by increasing hemoglobin's ability to bind oxygen and boosting energy levels in the cells. This mechanism is different from other treatments as it directly targets the red blood cells' metabolism to improve their function and reduce complications of sickle cell disease. ^{1 2 3 4 5}

Research Team

Clinical Transparency (dept. 2834)

Principal Investigator

Novo Nordisk A/S

Eligibility Criteria

This trial is for adults and adolescents with sickle cell disease who have had at least 2 pain crises in the past year. They must be on a stable dose of certain medications, not pregnant or breastfeeding, without severe liver, kidney, heart or blood vessel problems. Participants need to use effective contraception.

Inclusion Criteria

I have been on a stable dose of hydroxyurea for at least 90 days.

I have had at least 2 pain crises due to sickle cell in the last year.

Provision of consent

Exclusion Criteria

I have severe kidney problems or am on long-term dialysis.

My liver tests show high levels of ALT and bilirubin.

I have an active hepatitis B or C infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Double-blind Treatment

Participants receive either etavopivat or placebo to evaluate efficacy on hemoglobin and vaso-occlusive crises

52 weeks

Regular visits as per study protocol

Open-label Extension

Participants may enter an open-label extension period to continue receiving etavopivat

112 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Etavopivat

Trial Overview The study tests low and high doses of Etavopivat tablets against placebo tablets to see if they can increase hemoglobin levels and reduce pain crises caused by blocked blood vessels in patients with sickle cell disease.

Participant Groups

Group I: Open label etavopivat Experimental Treatment 1 Intervention

Open label etavopivat

Group II: Double blind placebo Experimental Treatment 1 Intervention

Double blind placebo

Group III: Double blind etavopivat Low Dose Experimental Treatment 2 Interventions

Double blind etavopivat Low Dose

Group IV: Double blind etavopivat High Dose Experimental Treatment 2 Interventions

Double blind etavopivat High Dose

Who Is Running the Clinical Trial?

Forma Therapeutics, Inc.

Lead Sponsor

Trials

13

Recruited

1,300+

Novo Nordisk A/S

Industry 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

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]

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]

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]

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. 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]

3. 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]

4. 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]

5. 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]