Etavopivat for Sickle Cell Disease

Overseen By Novo Nordisk

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Novo Nordisk A/S

Must not be taking: Moderate/strong enzyme inhibitors/inducers

Disqualifiers: Pregnancy, Hypersensitivity, Recent investigational drug, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 10 days

29 Participants Needed

Trial Summary

What is the purpose of this trial?

The study aims to test if a new medicine called etavopivat potentially affects other medicines in healthy participants. The purpose of the study is to investigate whether the use of etavopivat affects the breakdown and metabolism of commonly used medicines in the body. During the study, participants will receive etavopivat and five different medicines that are already approved and available on the market, and which can be prescribed by doctors. These marketed medicines are called substrate drugs and they are: digoxin, pitavastatin, metformin, midazolam, and rosuvastatin. During a period of the study, participants will take 2 tablets of etavopivat daily for 10 consecutive days. The study will last for about 34 to 64 days.

Will I have to stop taking my current medications?

Yes, you will need to stop taking most medications, including prescription and non-prescription drugs, 14 days before the study and throughout its duration, except for certain contraceptives, hormone replacement therapy, and occasional acetaminophen use.

What data supports the effectiveness of the drug Etavopivat for treating sickle cell disease?

Research shows that Etavopivat, a drug that activates an enzyme in red blood cells, can help treat sickle cell disease by reducing cell sickling. It works by increasing the cells' ability to carry oxygen and improving their flexibility, which may reduce complications of the disease. ^{1 2 3 4 5}

How does the drug Etavopivat differ 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. Unlike other treatments, it works by decreasing a molecule called 2,3-DPG, which helps red blood cells hold onto oxygen better, potentially reducing blockages in blood vessels. ^{1 2 6 7 8}

Research Team

Clinical Transparency (dept. 2834)

Principal Investigator

Novo Nordisk A/S

Eligibility Criteria

This study is for healthy individuals who may help researchers understand if a new medicine, etavopivat, affects how the body processes other common drugs. Participants should not have sickle cell disease or thalassemia but will contribute to research that could benefit those conditions.

Inclusion Criteria

My weight is over 50 kg.

Considered to be generally healthy based on medical history, physical examination, and results of vital signs, electrocardiogram, and clinical laboratory tests performed during the screening visit, as judged by the investigator

Body mass index (BMI) between 18.5 and 29.9 kilograms per square meter (kg/m^2) at screening

Exclusion Criteria

Known or suspected hypersensitivity to study interventions or related products

I am willing and able to follow all study rules, including diet and medication restrictions.

I can avoid taking certain strong medications and St. John's Wort for 28 days before and during the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive etavopivat and substrate drugs to evaluate pharmacokinetics

10 days

Daily visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Etavopivat

Trial Overview The trial tests whether etavopivat changes how the body breaks down and uses five approved medicines: digoxin (heart medication), pitavastatin and rosuvastatin (cholesterol medications), metformin (diabetes medication), and midazolam (sedative). Participants take etavopivat with these drugs over 10 days.

Participant Groups

Group I: Period 2: etavopivat+midazolam+rosuvastatin Experimental Treatment 3 Interventions

Participants will receive a daily dose of oral etavopivat, single dose of oral midazolam and rosuvastatin.

Group II: Period 2: etavopivat+midazolam Experimental Treatment 2 Interventions

Participants will receive a daily dose of oral etavopivat and single dose of oral midazolam.

Group III: Period 2: etavopivat+digoxin+pitavastatin+metformin Experimental Treatment 4 Interventions

Participants will receive a daily dose of oral etavopivat, single dose of oral digoxin, pitavastatin and metformin.

Group IV: Period 1: midazolam+rosuvastatin Experimental Treatment 2 Interventions

Participants will receive a single dose of oral midazolam and rosuvastatin.

Group V: Period 1: digoxin+pitavastatin+metformin Experimental Treatment 3 Interventions

Participants will receive a single dose of oral digoxin, pitavastatin and metformin.

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 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 series of workshops and educational sessions were organized to empower sickle cell disease (SCD) patients in Europe, allowing them to influence research priorities and enhance their involvement in the scientific community.

These initiatives have improved patient experience and empowerment, benefiting not only patients and caregivers but also health professionals, highlighting the importance of patient-centered approaches in medical research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sickle cell disease: embedding patient participation into an international conference can transform the role of lived experience. Pellegrini, M., Chakravorty, S., Del Mar Manu Pereira, M., et al.[2023]

Patients with sickle cell disease (SCD) experience significant quality of life impairments due to the disease's complications, highlighting the need for effective disease-modifying therapies.

Recent initiatives, such as the ASH Research Collaborative SCD Clinical Trials Network and the Cure Sickle Cell Initiative, aim to improve clinical trial designs and patient-centered outcomes, emphasizing the importance of patient-reported outcomes in evaluating treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical trial considerations in sickle cell disease: patient-reported outcomes, data elements, and the stakeholder engagement framework. Badawy, SM.[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 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]

Voxelotor, a first-in-class therapy for sickle cell disease (SCD), targets the root cause of the disease by preventing sickle hemoglobin polymerization, and has been shown to improve hemoglobin levels and reduce hemolysis in patients.

In a study of 27 patients treated for at least 8 weeks, both clinicians and patients reported significant improvements in health-related quality of life and disease symptoms, indicating voxelotor's positive impact on SCD outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient perception of voxelotor treatment benefit in sickle cell disease. Idowu, M., Haque, A., Williams, EM., et al.[2022]

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. Italy pubmed.ncbi.nlm.nih.gov

New Therapeutic Options for the Treatment of Sickle Cell Disease. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Sickle cell disease: embedding patient participation into an international conference can transform the role of lived experience. [2023]

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

Clinical trial considerations in sickle cell disease: patient-reported outcomes, data elements, and the stakeholder engagement framework. [2022]

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

A Scientific Renaissance: Novel Drugs in Sickle Cell Disease. [2018]

6. 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]

7. 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]

8. England pubmed.ncbi.nlm.nih.gov

Patient perception of voxelotor treatment benefit in sickle cell disease. [2022]