Etavopivat for Sickle Cell Disease

(GLADIOLUS Trial)

Recruiting at 35 trial locations

Overseen By Novo Nordisk

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Forma Therapeutics, Inc.

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

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new oral medicine called etavopivat in patients with sickle cell disease or thalassemia. The medicine helps red blood cells produce energy more efficiently. The goal is to reduce the need for blood transfusions and increase hemoglobin levels.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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}

Research Team

Clinical Transparency (dept. 2834)

Principal Investigator

Novo Nordisk A/S

Eligibility Criteria

This trial is for individuals with thalassemia or sickle cell disease who consent to participate and agree to use contraception if applicable. It's not for those who are pregnant, breastfeeding, have significant liver issues (high ALT or bilirubin levels), HIV, active hepatitis B/C, severe kidney dysfunction, recent malignancies requiring intense treatment unless considered cured of certain cancers, or unstable heart/lung conditions.

Inclusion Criteria

I have been receiving monthly blood transfusions for at least 2 years to prevent or treat a stroke.

I am using or willing to use birth control methods if I can have children.

I regularly receive blood transfusions to prevent or because of a previous stroke.

Exclusion Criteria

I have an active hepatitis B or C infection.

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

I am HIV positive.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive etavopivat to evaluate safety and clinical activity, with a focus on reducing red blood cell transfusions and increasing hemoglobin levels

12 weeks

Extended Treatment

Continued evaluation of etavopivat's effects on liver iron concentration, hemoglobin levels, and serum ferritin levels

48 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Etavopivat

Trial Overview The study tests Etavopivat tablets in a Phase 2 trial to see if they're safe and effective for patients with thalassemia or sickle cell disease. The goal is to reduce the need for red blood cell transfusions and increase hemoglobin levels in participants.

Participant Groups

Group I: Etavopivat 400 mg daily - Thalassemia with transfusions Experimental Treatment 1 Intervention

Patients with thalassemia on chronic red blood cell transfusions

Group II: Etavopivat 400 mg daily - Thalassemia Experimental Treatment 1 Intervention

Patients with thalassemia not on chronic red blood cell transfusions

Group III: Etavopivat 400 mg daily - SCD with transfusions Experimental Treatment 1 Intervention

Patients with sickle cell disease on chronic red blood cell transfusions

Who Is Running the Clinical Trial?

Forma Therapeutics, Inc.

Lead Sponsor

Trials

13

Recruited

1,300+

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 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]

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

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

One-year safety and efficacy of mitapivat in sickle cell disease: follow-up results of a phase 2, open-label study. [2023]

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. 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]