etavopivat (NN7535) / Novo Nordisk - LARVOL DELTA

Hibiscus 2 (Trial-in-Progress): A global, Phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of etavopivat in adolescents and adults with sickle cell disease (ASH 2025) - P3 | "Study population: PwSCD of any genotype and aged ≥12 years are eligible if they have moderate-to-severe anemia, Hb ≥5.0–≤10.0 g/dL at screening, and 2–15 VOC episodes in the year before screening.Concomitant hydroxyurea and/or L-glutamine use is permitted if PwSCD have received stable dosing andare compliant with treatment before screening. Key exclusion criteria are chronic transfusion therapy,use of erythropoiesis-stimulating agents, voxelotor, or crizanlizumab before starting study intervention,and hepatic dysfunction...Study status HIBISCUS 2 is enrolling participants at sites in Australia, Belgium, Brazil, Canada, Colombia, France,Ghana, Greece, India, Italy, Kenya, Lebanon, the Netherlands, Nigeria, Oman, Saudi Arabia, Spain, Turkey,Uganda, the United Kingdom, and the United States. The results from this confirmatory study will provideadditional evidence that etavopivat has the potential to delay or prevent VOCs, enhance Hb levels, andreduce fatigue in PwSCD."

Clinical • P3 data • Anemia • Genetic Disorders • Hematological Disorders • Hepatology • Liver Failure • Sickle Cell Disease

Etavopivat in adolescents with sickle cell disease: Emerging safety and efficacy findings from the first cohort of the ongoing Phase 1/2 hibiscus kids study (ASH 2025) - P2 | "Stable dose concurrent therapy with hydroxyurea,crizanlizumab and L-glutamine was permitted.Safety endpoints included serious adverse events (SAEs), treatment-emergent adverse events (TEAEs),etavopivat discontinuations, dosing interruptions, and dose reductions. In this preliminary analysis of the HIBISCUS Kids study, the first to investigate a PKR activatorin a pediatric SCD population including children younger than 12 years, etavopivat was relatively welltolerated by adolescents. Cohort 1 enrollment and dosing are complete; weight-based dosing with agranule formulation has begun for cohort 2, children aged 6–<12 years. The study is expected to providefurther insights into the safety, tolerability, and potential clinical benefits of etavopivat in youngerchildren, including those as young as 6 months."

Clinical • P1/2 data • Anemia • Cholestasis • Genetic Disorders • Hematological Disorders • Hepatology • Infectious Disease • Malaria • Sickle Cell Disease

Hospital Utilization in Sickle Cell Disease Patients: A One-Year Retrospective Study in Urban Underserved Communities (ASH 2024) - "The average age was 20.3 years.Black patients, compared to Hispanic patients, had more ED visits (13.5 vs 4.6, p=0.101), more readmissions (4.2 vs 2.4, p=0.052), and longer LOS (5.3 vs 3.0 days, p=0.267).Regarding medication use, 78.6% of patients (N=24) were taking Hydroxyurea, 3.6% (N=1) were receiving Voxelotor, and 7.1% (N=2) were enrolled in the clinical trial (Etavopivat). Lack of regular hematologist follow-up and presence of psychiatric disorders were associated with increased healthcare utilization. These findings emphasize the need for improved access to hematology follow-up and integrated psychiatric care, to enhance the quality of life for SCD patients."

Retrospective data • Bipolar Disorder • CNS Disorders • Depression • Genetic Disorders • Hematological Disorders • Mental Retardation • Mood Disorders • Psychiatry • Sickle Cell Disease

FORTITUDE: A Phase 2 Open-Label Study in Progress to Evaluate Etavopivat for the Treatment of Anemia in Patients with Lower-Risk Myelodysplastic Syndromes (ASH 2023) - P2 | "Erythropoiesis-stimulating agents and other drugs, including lenalidomide, luspatercept and imetelstat (an investigational product), can lead to RBC transfusion independence and improve Hb levels in many patients; however, responses are generally transient and novel treatments are needed for this population...Additional exclusion criteria include prior treatment with azacitidine; decitabine; erythropoietin, other hematopoietic growth factor treatment or lenalidomide within 30 days of Day 1 or anticipated to be required during the study; and luspatercept within 30 days of Day 1 for NTD patients and within 16 weeks of Day 1 for TD patients...Summary: Etavopivat is a novel, investigational, once-daily, selective PKR activator with the potential to improve RBC health and lifespan. This phase 2 study will assess the safety of etavopivat and its impact on Hb levels and RBC transfusion burden in patients with LR-MDS and anemia."

Clinical • P2 data • Acute Myelogenous Leukemia • Anemia • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Sickle Cell Disease • TP53

Biologic Assessment of RBC Biology and Neutrophil Activation: Correlation with Sickle Cell Disease Activity (ASH 2023) - "A subset of samples were examined for RBC reactive oxygen species (ROS) content and adhesivity to laminin with and without stimulation by epinephrine...Interestingly, we also found that RBC [ATP] was lower in the RBCs of patients with higher total Hb, while it was higher in individuals with higher retic counts, suggesting that more long-lived RBCs have diminished [ATP], despite the fact that both [ATP] and total Hb have been reported to rise substantially after treatment with pyruvate kinase activators etavopivat and mitapivat...Similarly, senicapoc, which also reduces hemolysis, although by a different mechanism, failed to lessen VOE frequency...Anti-adhesive agents (crizanlizumab, rivipansel, sevuparin) have thus far failed to yield marked improvements in VOE frequency, but our results suggest that, in order to decrease the frequency of VOEs, it is not sufficient to reduce sickling and hemolysis. On the other hand, higher HbF levels were associated with lower admission..."

Cardiovascular • Genetic Disorders • Hematological Disorders • Pulmonary Arterial Hypertension • Pulmonary Disease • Renal Disease • Respiratory Diseases • Sickle Cell Disease • MMP9

Etavopivat Reduces Incidence of Vaso-Occlusive Crises in Patients with Sickle Cell Disease: HIBISCUS Trial Phase 2 Results through 52 Weeks (ASH 2024) - P3 | "Permitted standard of care included stable dosing with hydroxyurea (HU; ≥90 days prior), crizanlizumab, or L-glutamine (≥12 months prior). Etavopivat was well tolerated. Based on the totality of data, proof of concept was established for etavopivat in SCD."

Clinical • P2 data • Cardiovascular • CNS Disorders • Fatigue • Genetic Disorders • Hematological Disorders • Insomnia • Sickle Cell Disease • Sleep Disorder

Pyruvate Kinase Thermostability Is Associated with Red Blood Cell Adhesion, Deformability and Oxygen Affinity in Patients with Sickle Cell Disease (ASH 2023) - P1, P2, P2/3, P3 | "Currently there are several clinical trials ongoing investigating the efficacy of PK activation by small molecules such as mitapivat (NL8517, NCT04000165, NCT05031780), AG-946 (NCT04536792) and etavopivat (NCT04624659, NCT04987489). This study shows for the first time a significant correlation between PK thermostability in sickle RBCs and RBC functions, such as adhesion, deformability and oxygen affinity. Our results suggest that enhancing the activity and stability of PK, with PK activators, is an attractive target in SCD that might improve other pathophysiological targets outside RBC metabolism. Future studies are needed to explore how activation of PK will affect these altered sickle RBC properties in vivo."

Clinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Pyruvate Kinase Activators in Sickle Cell Anemia: A Systematic Review and Single-Arm Meta-Analysis (ASH 2024) - "Three studies administered Mitapivat (n=76), and one administered Etavopivat (n=23). However, the small sample size, observed heterogeneity, and variations in concurrent hydroxyurea use highlight the need for larger, comparative trials to confirm these findings and assess PK activators relative to existing treatments. Future research should focus on more extensive and homogeneous cohorts to validate these results and investigate long-term outcomes."

Retrospective data • Review • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Etavopivat Increases Arterial Hemoglobin-Oxygen Saturation during Moderate and Severe Hypoxia: A Mechanistic Phase 1 Trial in Healthy Volunteers (ASH 2024) - "Increased Hb-O2 affinity, together with maintenance of a high FO2Hb under hypoxic conditions, demonstrates etavopivat's ability to promote oxygen exchange and subsequent delivery. Together with projected improvement of RBC health, also achieved via PKR activation, this indicates a potential clinical benefit with etavopivat for hemoglobinopathies and beyond."

Clinical • P1 data • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

GLADIOLUS: A Study of Etavopivat in Patients With Thalassemia or Sickle Cell Disease (clinicaltrials.gov) - P2 | N=53 | Completed | Sponsor: Forma Therapeutics, Inc. | Active, not recruiting ➔ Completed

Trial completion • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Evaluating anti-sickling therapies for sickle cell disease: a microfluidic assay for red blood cell-mediated microvascular occlusion under hypoxia. (PubMed, Lab Chip) - "Additionally, the HOI assay effectively assessed the efficacy of therapeutic agents, including hemoglobin-oxygen affinity modifiers (GBT021601, GBT440) and protein kinase R (PKR) activators (PKR-3, FT4202), which significantly reduced OI in SCD RBCs. Notably, combination therapies showed enhanced effectiveness, highlighting the assay's potential for optimizing treatment regimens. This study establishes the chemically induced hypoxia OcclusionChip assay as a reliable and clinically useful tool for evaluating RBC deformability in SCD, with significant potential to improve personalized treatment strategies and thus patient outcomes."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Hibiscus 2: A Study to Evaluate How Well Etavopivat Works in People With Sickle Cell Disease (clinicaltrials.gov) - P3 | N=408 | Recruiting | Sponsor: Novo Nordisk A/S | Trial completion date: Sep 2028 ➔ Apr 2029

Trial completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

FLORAL: A Research Study Looking at Long-term Treatment With Etavopivat in People With Sickle Cell Disease or Thalassaemia (clinicaltrials.gov) - P3 | N=480 | Recruiting | Sponsor: Novo Nordisk A/S | N=325 ➔ 480 | Trial completion date: Nov 2029 ➔ Dec 2030 | Trial primary completion date: Nov 2029 ➔ Dec 2030

Enrollment change • Trial completion date • Trial primary completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

A Study on the Effect of Etavopivat on Heart Rhythm in Healthy Participants (clinicaltrials.gov) - P1 | N=33 | Completed | Sponsor: Novo Nordisk A/S | Not yet recruiting ➔ Completed

Trial completion • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

A Research Study on Etavopivat in Participants With and Without Liver Disease (clinicaltrials.gov) - P1 | N=48 | Completed | Sponsor: Novo Nordisk A/S | Recruiting ➔ Completed

Trial completion • Hepatology

A Research Study of the Effect of Etavopivat on Other Drugs in Healthy Participants (clinicaltrials.gov) - P1 | N=37 | Completed | Sponsor: Novo Nordisk A/S | Recruiting ➔ Completed

Trial completion • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

HIBISCUS 3: A Phase 2 Open-label Study to Evaluate the Activity of Etavopivat on Transcranial Doppler Velocities in Pediatric Patients With Sickle Cell Disease Who Are at Increased Risk for Primary Stroke (clinicaltrials.gov) - P2 | N=27 | Recruiting | Sponsor: Forma Therapeutics, Inc. | N=46 ➔ 27 | Trial completion date: May 2026 ➔ Sep 2027 | Trial primary completion date: Jul 2025 ➔ Sep 2027

Enrollment change • Trial completion date • Trial primary completion date • Cardiovascular • Genetic Disorders • Hematological Disorders • Pediatrics • Sickle Cell Disease

Study of the Effect of Etavopivat on Cerebral Hemodynamic Response in Children With Sickle Cell Disease (clinicaltrials.gov) - P2 | N=12 | Active, not recruiting | Sponsor: Forma Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

A Study to Evaluate the Pharmacokinetics and Safety of Etavopivat in Pediatric Patients With Sickle Cell Disease (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Forma Therapeutics, Inc. | Trial primary completion date: Feb 2029 ➔ Aug 2029

Trial primary completion date • Genetic Disorders • Hematological Disorders • Pediatrics • Sickle Cell Disease

A Study on the Effect of Etavopivat on Heart Rhythm in Healthy Participants (clinicaltrials.gov) - P1 | N=26 | Not yet recruiting | Sponsor: Novo Nordisk A/S

New P1 trial • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

GLADIOLUS: A Study of Etavopivat in Patients With Thalassemia or Sickle Cell Disease (clinicaltrials.gov) - P2 | N=60 | Active, not recruiting | Sponsor: Forma Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

FLORAL: A Research Study Looking at Long-term Treatment With Etavopivat in People With Sickle Cell Disease or Thalassaemia (clinicaltrials.gov) - P3 | N=325 | Recruiting | Sponsor: Novo Nordisk A/S | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

A Research Study of the Effect of Etavopivat on Other Drugs in Healthy Participants (clinicaltrials.gov) - P1 | N=29 | Recruiting | Sponsor: Novo Nordisk A/S | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

A Study of Etavopivat in Adults and Adolescents With Sickle Cell Disease (HIBISCUS) (clinicaltrials.gov) - P3 | N=450 | Active, not recruiting | Sponsor: Forma Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Hibiscus 2: A Research Study to Evaluate How Well Etavopivat Works in People With Sickle Cell Disease (clinicaltrials.gov) - P3 | N=408 | Recruiting | Sponsor: Novo Nordisk A/S | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Hematological Disorders • Sickle Cell Disease