Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Novo Nordisk A/S
Disqualifiers: Chronic transfusion, Severe renal dysfunction, Hepatic dysfunction, Cardiac or pulmonary disease, Chemotherapy, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial tests etavopivat, a medication aimed at improving blood flow and oxygen use in the brain and muscles, in young patients with sickle cell disease. Etavopivat is being developed for the treatment of sickle cell disease.
Will I have to stop taking my current medications?
The trial allows participants to continue taking hydroxyurea (a medication for sickle cell disease) if the dose has been stable for at least 3 months. The protocol does not specify about other medications, so it's best to discuss with the trial team.
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 flexibility, reducing the sickling of cells that causes pain and complications in sickle cell disease.
12345Eligibility Criteria
This trial is for children aged 12-21 with Sickle Cell Disease, specifically those with hemoglobin SS or S/beta0 thalassemia and a hemoglobin level ≤ 9.0 g/dL. Stable hydroxyurea therapy is okay, but not if they've had recent severe complications like organ dysfunction, transfusions, surgery on stomach/small intestine, or unstable heart conditions.Inclusion Criteria
Hemoglobin (Hb) ≤ 9.0 g/dL at baseline
I have sickle cell disease with either HbSS or HbS/β0 thalassemia.
I have been on a stable dose of hydroxyurea for 3 months without blood-related side effects.
Exclusion Criteria
I need regular blood transfusions to manage my condition.
Vaso-occlusive crisis (VOC) within 14 days prior to signing the informed consent form
Acute chest syndrome (ACS) within 14 days prior to signing the informed consent form
+12 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
up to 4 weeks
Treatment
Participants receive etavopivat to evaluate its effect on cerebral and muscle hemodynamics
24 weeks
Safety Follow-up
Safety follow-up visit to monitor participants after the last dose of study drug
4 weeks
1 visit (in-person)
End of Study (EOS)
End of study visit to complete all final assessments
8 weeks
1 visit (in-person)
Participant Groups
The study tests Etavopivat's effects on brain and muscle blood flow in young patients with Sickle Cell Disease. It's an open-label trial where all participants receive the drug to see how it influences their cerebral hemodynamics.
1Treatment groups
Experimental Treatment
Group I: EtavopivatExperimental Treatment1 Intervention
Single-arm, open-label
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Emory University Children's Healthcare of AtlantaAtlanta, GA
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Who Is Running the Clinical Trial?
Novo Nordisk A/SLead Sponsor
Forma Therapeutics, Inc.Lead Sponsor
Emory UniversityCollaborator
References
Etavopivat, a Pyruvate Kinase Activator in Red Blood Cells, for the Treatment of Sickle Cell Disease. [2022]Etavopivat is an investigational, oral, small molecule activator of erythrocyte pyruvate kinase (PKR) in development for the treatment of sickle cell disease (SCD) and other hemoglobinopathies. PKR activation is proposed to ameliorate the sickling of SCD red blood cells (RBCs) through multiple mechanisms, including reduction of 2,3-diphosphoglycerate (2,3-DPG), which consequently increases hemoglobin (Hb)-oxygen affinity; increased binding of oxygen reduces sickle hemoglobin polymerization and sickling. In addition, PKR activation increases adenosine triphosphate (ATP) produced via glycolytic flux, which helps preserve membrane integrity and RBC deformability. We evaluated the pharmacodynamic response to etavopivat in nonhuman primates (NHPs) and in healthy human subjects and evaluated the effects in RBCs from patients with SCD after ex vivo treatment with etavopivat. A single dose of etavopivat decreased 2,3-DPG in NHPs and healthy subjects. Hb-oxygen affinity was significantly increased in healthy subjects after 24 hours. After daily dosing of etavopivat over 5 consecutive days in NHPs, ATP was increased by 38% from baseline. Etavopivat increased Hb-oxygen affinity and reduced sickling in RBCs collected from patients with SCD with either homozygous hemoglobin S or hemoglobin S and C disease. Collectively, these results demonstrate the ability of etavopivat to decrease 2,3-DPG and increase ATP, resulting in increased Hb-oxygen affinity and improved sickle RBC function. Etavopivat is currently being evaluated in clinical trials for the treatment of SCD. SIGNIFICANCE STATEMENT: Etavopivat, a small molecule activator of the glycolytic enzyme erythrocyte pyruvate kinase, decreased 2,3-diphosphoglycerate in red blood cells (RBCs) from nonhuman primates and healthy subjects and significantly increased hemoglobin (Hb)-oxygen affinity in healthy subjects. Using ex vivo RBCs from donors with sickle cell disease (SCD) (homozygous hemoglobin S or hemoglobin S and C genotype), etavopivat increased Hb-oxygen affinity and reduced sickling under deoxygenation. Etavopivat shows promise as a treatment for SCD that could potentially reduce vaso-occlusion and improve anemia.
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]For decades, patients with sickle cell disease have had only a limited number of therapies available. In 2019, voxelotor (1500 mg), an oral once-daily sickle haemoglobin polymerisation inhibitor, was approved in the USA for the treatment of sickle cell disease in patients aged 12 years and older on the basis of HOPE trial data. To further describe the applicability of voxelotor as a treatment for this chronic illness, we report the long-term efficacy and safety of this drug at 72 weeks of treatment; the conclusion of the placebo-controlled HOPE trial.
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]Etavopivat (FT-4202) is an orally administered, small-molecule allosteric activator of erythrocyte pyruvate kinase-R (PKR) in clinical development for the treatment of sickle cell disease and other hemoglobin disorders. This randomized, placebo-controlled, double-blind, first-in-human combination single-ascending dose and multiple-ascending dose phase 1 trial (NCT03815695) evaluated the safety and pharmacokinetics/pharmacodynamics of etavopivat in 90 healthy adult subjects. In 4 single-ascending dose cohorts, 8 participants were randomized 3:1 to a single oral dose of either etavopivat (n = 6) or placebo (n = 2). In four 14-day multiple-ascending dose cohorts, 12 participants were randomized 3:1 to 14 days of etavopivat (n = 9) or placebo (n = 3). In these studies, most treatment-emergent adverse events were of mild severity (grade 1) and none led to study discontinuation. Etavopivat exhibited a linear and time-independent pharmacokinetic profile (at doses ≤400 mg) and elicited the expected pharmacodynamic effects of PKR activation (decreased 2,3-diphosphoglycerate and increased adenosine triphosphate) and evidence of improved hemoglobin-oxygen affinity. In addition, pharmacodynamic responses were durable with effects continuing for 48 to 72 hours after the last dose, thereby supporting once-daily dosing. Food appeared to have no clinically meaningful effects on etavopivat exposure, thus facilitating administration with or without food. In conclusion, the evaluation of etavopivat in healthy subjects demonstrated proof of mechanism (PKR activation) without significant adverse events. This study also allowed for the selection of dose levels, projected to have an acceptable safety profile and provide therapeutic benefit, for evaluation in future trials in patients with sickle cell disease.
Dose Selection Based on Modeling and Simulation for Rivipansel in Pediatric Patients Aged 6 to 11 Years With Sickle Cell Disease. [2019]This modeling and simulation exercise aimed to provide dosing recommendations for rivipansel phase III studies in children aged 6-11 years with sickle cell disease (SCD). Pharmacokinetic data from 109 patients aged 12-51 years who received rivipansel (2-40 mg/kg) in previous studies (three phase I and one phase II) were integrated to build a three-compartmental simulation model. Renal clearance simulations across the age range accounted for renal function development and postulated hyperfiltration in SCD. Simulated demographic distributions for the pediatric SCD population were used to predict concentration-time profiles from three dosing regimens, which were then compared against efficacious average steady-state concentrations observed in phase II. A dosing regimen comprising a 40-mg/kg loading dose followed by a 20-mg/kg maintenance dose every 12 hours was selected, as it will likely provide an efficacious concentration range. Its validity will be confirmed in the ongoing phase III study.
One-year safety and efficacy of mitapivat in sickle cell disease: follow-up results of a phase 2, open-label study. [2023]Targeting the primary pathogenic event of sickle cell disease (SCD), polymerization of sickle hemoglobin (HbS), may prevent downstream clinical events. Mitapivat, an oral pyruvate kinase (PK) activator, has therapeutic potential by increasing adenosine triphosphate (ATP) and decreasing 2,3-diphosphoglycerate (2,3-DPG), a glycolytic red blood cell (RBC) intermediate. In the previously reported 8-week dose-finding period of this phase 2, investigator initiated, open-label study, mitapivat was well tolerated and showed efficacy in SCD. Here, the 1-year fixed-dose extension period is reported in which 9/10 (90%) included patients 16+ years with SCD (HbSS, HbS/β0 or HbS/β+) continued with mitapivat. Mostly mild treatment-emergent adverse events (most commonly: transaminase increase and headache) were still reported. Apart from the reported non-treatment-related serious adverse event (SAE) of a urinary tract infection in the dose-finding period, one non-treatment-related SAE occurred in the fixed-dose extension period in a patient who died of massive pulmonary embolism due to COVID-19. Importantly, sustained improvement in Hb level (mean increase: 1.1 +/- 0.7 g/dL; p=0.0014) was seen, which was accompanied by decreases in markers of hemolysis. In addition, the annualized rate of vaso-occlusive events reduced significantly from a historic baseline of 1.33 +/- 1.32 to 0.64 +/- 0.87 (p=0.0489) when combining the dose-finding period and fixed-dose extension period. Cellularly, the ATP/2,3-DPG ratio and Hb-oxygen affinity significantly increased, and RBC sickling (Point of Sickling) non-significantly reduced. Overall, this study (https://www.clinicaltrialsregister.eu/ NL8517; EudraCT 2019-003438-18) demonstrated 1-year safety and efficacy of treatment with mitapivat in SCD, supporting further evaluation in ongoing phase 2/3 study (RISE UP, NCT05031780).