Etavopivat for Sickle Cell Anemia

(FLORAL Trial)

Recruiting at 96 trial locations

Overseen By Novo Nordisk

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Novo Nordisk A/S

Must be taking: Hydroxyurea, Crizanlizumab, Endari

Must not be taking: Voxelotor, Selectin antagonists, Erythropoietin, CYP3A4 inducers

Disqualifiers: Other disorders, Treatment withdrawal, 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

Duration: 260 weeks

325 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you may continue taking hydroxyurea, crizanlizumab, or l-glutamine if you have been on a stable dose. However, you cannot use voxelotor, certain experimental drugs, or strong inducers of CYP3A4 within 2 weeks before joining the trial.

Is Etavopivat safe for humans?

In a study with healthy adults, Etavopivat was generally safe, with most side effects being mild and not causing anyone to stop the study. This suggests it has a good safety profile for further testing in people with sickle cell disease. ^{1 2 3 4 5}

What makes the drug Etavopivat unique for 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 improving red blood cell function. This mechanism is different from other treatments as it directly targets the metabolic pathway to enhance red blood cell health and reduce complications of sickle cell disease. ^{1 2 6 7 8}

What is the purpose of this trial?

Etavopivat is a new medicine under development for treating blood disorders like sickle cell disease and thalassaemia. Sickle cell disease and thalassaemia are inherited blood disorders that affect haemoglobin. Haemoglobin is the protein that carries oxygen through the body. This study is looking into how safe treatment with etavopivat is and how well it works over a long period of time. The study will last for up to 264 weeks, but it will end earlier if etavopivat is approved in the participant's country.

Research Team

Clinical Transparency (dept. 2834)

Principal Investigator

Novo Nordisk A/S

Eligibility Criteria

This trial is for individuals with inherited blood disorders, specifically sickle cell disease or thalassaemia. Participants will be involved in the study for up to 264 weeks unless etavopivat gets approved sooner in their country.

Inclusion Criteria

I am currently taking hydroxyurea, crizanlizumab, or Endari without changing the dose recently.

I have shown improvement with etavopivat treatment as judged by my doctor.

Participant must have ongoing participation in an etavopivat parent study for treatment of sickle cell disease (SCD) or thalassaemia and have completed at least a treatment period of the parent study

Exclusion Criteria

I am on a lower dose or have temporarily stopped my treatment.

I am not taking, nor will I need, strong drugs that affect liver enzymes during the study.

I have not used experimental drugs for blood cell disorders in this or any study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive an oral dose of Etavopivat for the treatment of sickle cell disease or thalassaemia

260 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Participants may continue to receive Etavopivat until it is approved in their country

Up to 264 weeks

Treatment Details

Interventions

• Etavopivat

Trial Overview The study tests long-term safety and effectiveness of a new medication called etavopivat, which aims to treat anemia caused by sickle cell disease and thalassaemia by improving haemoglobin function.

Participant Groups

Group I: Participants ≥ 12 years old with transfusion-dependent thalassaemia Experimental Treatment 1 Intervention

Participants will receive an oral dose of Etavopivat A.

Group II: Participants ≥ 12 years old with sickle cell disease on chronic red blood cell (RBC) transfusions Experimental Treatment 1 Intervention

Participants will receive an oral dose of Etavopivat A.

Group III: Participants ≥ 12 years old with non-transfusion dependent thalassaemia Experimental Treatment 1 Intervention

Participants will receive an oral dose of Etavopivat A.

Group IV: Participants ≥ 11 months to less than (<) 12 years old with sickle cell disease Experimental Treatment 2 Interventions

Participants ≥ 12 years of age will receive an oral dose of Etavopivat A and participants \< 12 years of age will receive an oral dose of Etavopivat B.

Group V: Participants greater than or equal to (≥) 12 years old with sickle cell disease Experimental Treatment 1 Intervention

Participants will receive an oral dose of Etavopivat A.

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

Findings from Research

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]

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]

A Phase I study involving 28 patients with sickle cell disease found that ICA-17043 was well tolerated with no dose-limiting adverse events, indicating a good safety profile for this medication.

The pharmacokinetics showed that the total systemic exposure to ICA-17043 increased with higher doses, and the drug has a long half-life of 12.8 days, suggesting that once-daily dosing could effectively maintain therapeutic levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-escalation study of ICA-17043 in patients with sickle cell disease. Ataga, KI., Orringer, EP., Styles, L., 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]

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 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

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]

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

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

3. Switzerland pubmed.ncbi.nlm.nih.gov

Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Aromatic Aldehydes as Drug Candidates for the Treatment of Sickle Cell Disease. [2022]

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

Safety of short-term valacyclovir as an anti-sickling agent in sickle-cell anemia. [2021]

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

Dose-escalation study of ICA-17043 in patients with sickle cell disease. [2022]

6. 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]

7. 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]

8. 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]