Etavopivat for Sickle Cell Anemia

(FLORAL Trial)

Recruiting at 115 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

480 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called etavopivat for individuals with sickle cell disease and thalassemia, blood disorders that affect oxygen transport in the body. The goal is to assess the safety and effectiveness of etavopivat over time. Participants take the treatment as a pill, and the study may last up to five years unless the treatment receives approval sooner. Ideal candidates have previously benefited from etavopivat in another study and have managed sickle cell disease or thalassemia with stable treatments. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking treatment.

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 there any evidence suggesting that this trial's treatment is likely to be safe?

Earlier studies have shown that etavopivat is safe and well-tolerated in people with sickle cell disease (SCD) and thalassemia. Initial trials found that most side effects, such as headache and nausea, were mild or moderate, with no serious safety issues identified.

Research on healthy adults also supports the safety of etavopivat. The trial's later stage indicates that previous research found no major safety problems, which is encouraging for those considering joining the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for sickle cell anemia?

Unlike the standard treatments for sickle cell disease, which primarily focus on managing symptoms and preventing complications through pain medications, blood transfusions, and hydroxyurea, Etavopivat offers a novel approach. This treatment is exciting because it works by enhancing red blood cell health and function, potentially reducing the need for frequent transfusions. Researchers are particularly enthusiastic about Etavopivat’s ability to increase hemoglobin levels and improve overall oxygen delivery in the body, which could lead to better quality of life for patients. Additionally, its oral administration makes it more convenient compared to some existing treatments, which often require hospital visits.

What evidence suggests that etavopivat might be an effective treatment for sickle cell disease and thalassaemia?

Research has shown that etavopivat may help treat sickle cell disease by reducing the number of painful episodes caused by blocked blood flow. In earlier studies, patients taking etavopivat experienced a quick and lasting increase in hemoglobin, the protein in red blood cells that carries oxygen, and their red blood cells became healthier. In this trial, participants with sickle cell disease, both transfusion-dependent and non-transfusion-dependent, will receive an oral dose of etavopivat. For thalassemia, etavopivat is under study for its potential to improve the health and lifespan of red blood cells, which could help manage symptoms. Participants with transfusion-dependent and non-transfusion-dependent thalassemia will also receive etavopivat in this trial. Overall, early evidence suggests that etavopivat could effectively manage these blood disorders by improving red blood cell function and reducing complications. ^{1 6 7 8 9}

Who Is on the Research Team?

Clinical Transparency (dept. 2834)

Principal Investigator

Novo Nordisk A/S

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: Participants ≥ 2 years to less than (<) 12 years old with sickle cell disease Experimental Treatment 3 Interventions

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

Group II: Participants ≥ 12 years old with transfusion-dependent thalassaemia Experimental Treatment 2 Interventions

Participants will receive an oral dose of Etavopivat A or C.

Group III: Participants ≥ 12 years old with sickle cell disease transfusion dependent Experimental Treatment 2 Interventions

Participants will receive an oral dose of Etavopivat A or C.

Group IV: Participants ≥ 12 years old with non-transfusion dependent thalassaemia Experimental Treatment 2 Interventions

Participants will receive an oral dose of Etavopivat A or C.

Group V: Participants greater than or equal to (≥) 12 years old with sickle cell disease Experimental Treatment 2 Interventions

Participants will receive an oral dose of Etavopivat A or C.

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

Published Research Related to This Trial

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 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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06612268

NCT06612268 | A Study to Evaluate How Well Etavopivat ... This study is conducted to confirm whether etavopivat works well at reducing the number of Vaso-occlusive crisis VOCs (sickle cell pain crises)

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38640200/

Multicenter, phase 1 study of etavopivat (FT-4202) ... The first study of etavopivat in SCD, 400 mg once daily for 12 weeks was well tolerated, resulting in rapid and sustained increases in Hb, improved red blood ...

3. novonordisk-trials.com novonordisk-trials.com/trials-conditions/all-trials-v2/NN7535-7807.html

A Study to Evaluate How Well Etavopivat Works in People ... This study is conducted to confirm whether etavopivat works well at reducing the number of Vaso-occlusive crisis VOCs (sickle cell pain crises)

4. delta.larvol.com delta.larvol.com/Products/?ProductId=b6463a25-e529-406f-8996-f56e78abdd64

etavopivat (NN7535) / Novo Nordisk Evaluating anti-sickling therapies for sickle cell disease: a microfluidic assay for red blood cell-mediated microvascular occlusion under hypoxia.

5. guidelinecentral.com guidelinecentral.com/clinical-trial/?id=NCT06609226&v=tabular

A Research Study Looking at Long-term Treatment With ... An Open-label, Multi-centre, Rollover Study to Characterise Long-term Safety and Efficacy of Etavopivat in Adults, Adolescents and Children Who Have Sickle Cell ...

6. novonordisk-trials.com novonordisk-trials.com/trials-conditions/all-trials-v2/NN7535-7822.html

A Research Study Looking at Long-term Treatment With ... Etavopivat is a new medicine under development for treating blood disorders like sickle cell disease and thalassaemia.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35019238/

Etavopivat (FT-4202): Safety, PK/PD of Allosteric Activator Safety, Pharmacokinetics, and Pharmacodynamics of Etavopivat (FT-4202), an Allosteric Activator of Pyruvate Kinase-R, in Healthy Adults: A ...

8. adisinsight.springer.com adisinsight.springer.com/drugs/800053945

Etavopivat - Forma therapeutics - AdisInsight - Springer Etavopivat is an orally-available, small molecule pyruvate kinase red blood cell isozyme (PKR) agonist, being developed by Forma ...

9. sigma.larvol.com sigma.larvol.com/product.php?e1=800423&tab=newstrac

etavopivat (NN7535) News Furthermore, early-phase clinical trials of mitapivat and etavopivat have demonstrated the safety and tolerability of PK activators in patients with SCD, and ...