etavopivat (NN7535) / Novo Nordisk - LARVOL DELTA

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. | Trial completion date: Sep 2027 ➔ Jun 2028

Trial completion date • Cardiovascular • Genetic Disorders • Hematological Disorders • Pediatrics • 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: Mar 2029 ➔ Aug 2029

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

2026 Update on Clinical Trials in β-Thalassemia. (PubMed, Am J Hematol) - "Luspatercept and mitapivat have demonstrated clinically meaningful improvements in hemoglobin levels and reduction of transfusion burden and are now approved in multiple jurisdictions. Additional pyruvate kinase activators, such as etavopivat, are undergoing clinical evaluation...Approved therapies, including betibeglogene autotemcel and exagamglogene autotemcel, have achieved high rates of durable transfusion independence, while emerging platforms aim to further improve efficacy, safety, and accessibility. At the same time, several promising approaches targeting fetal hemoglobin induction, iron metabolism, and ineffective erythropoiesis have failed to demonstrate sufficient clinical benefit despite preclinical proof of concept, highlighting the complexity of therapeutic development in β-thalassemia. Future priorities include refining patient selection, generating real-world and comparative effectiveness data, developing clinically meaningful response criteria, expanding..."

Journal • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Pediatrics

EFFICACY AND SAFETY OF PYRUVATE KINASE-R ACTIVATORS IN SICKLE CELL DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS (EHA 2026) - "Three agents approved 2017–2019 briefly widened options, but crizanlizumab lost European approval in August 2023 (STAND trial: no VOC benefit), and voxelotor was withdrawn globally in September 2024 due to a fatal events imbalance the effectively resetting the field...Mitapivat (RISE UP) and etavopivat (HIBISCUS) have both completed Phase 2 RCTs in SCD, but their evidence has never been pooled...Baseline Hb was 8.4–8.8 g/dL across both trials, with 65–81% of participants receiving concomitant hydroxyurea...Abbreviations: CI, confidence interval; DL RE, DerSimonian-Laird random-effects model; Hb, haemoglobin; PP, per-protocol; PKR, pyruvate kinase-R; RR, risk ratio; SAE, serious adverse event; SCD, sickle cell disease; VOC, vaso-occlusive crisis; WMD, weighted mean difference; Wk, week. Panel A (Hb response) pooled estimate is exploratory given cross-trial heterogeneity in response definitions and timepoints; Panel C VOC rate ratio reflects HIBISCUS per-protocol..."

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

PHASE 1/2 HIBISCUS KIDS STUDY OF ETAVOPIVAT IN PEDIATRIC PATIENTS WITH SICKLE CELL DISEASE: SAFETY AND EFFICACY FINDINGS FROM THE COMPLETE FIRST COHORT (EHA 2026) - P2 | "A concomitant stable dose of hydroxyurea, crizanlizumab, or L-glutamine was permitted. Hb at week 24 is the average between week 24 and week 20. ARC, absolute reticulocyte count; BL, baseline; Hb, hemoglobin; LDH, lactate dehydrogenase; SD, standard deviation."

Clinical • P1/2 data • Cholestasis • Gastroenterology • Genetic Disorders • Hematological Disorders • Hepatology • Infectious Disease • Otorhinolaryngology • Pediatrics • Sickle Cell Disease

ETAVOPIVAT REDUCES TRANSFUSION REQUIREMENTS IN ADULTS AND ADOLESCENTS WITH TRANSFUSION-DEPENDENT ALPHA- OR ΒETA-THALASSEMIA: RESULTS FROM THE OPEN-LABEL PHASE 2 GLADIOLUS STUDY (EHA 2026) - P2, P3 | "Responders were defined as any participant with ≥20% or ≥33% reduction from baseline in RBC units transfused during at least one qualifying 12-week (84-day) interval in the primary treatment period (i.e., Days 2 to 85, 3 to 86, ..., 253 to end of primary treatment period), where baseline was defined as the total number of RBC units transfused from Study Day –83 to Study Day 1. RBC, red blood cell."

Clinical • P2 data • Genetic Disorders • Hematological Disorders • Musculoskeletal Pain • Sickle Cell Disease

ETAVOPIVAT IMPROVES HEMOGLOBIN LEVELS IN ADULTS AND ADOLESCENTS WITH NON-TRANSFUSION-DEPENDENT ALPHA- OR ΒETA-THALASSEMIA: RESULTS FROM THE OPEN-LABEL PHASE 2 GLADIOLUS STUDY (EHA 2026) - P2, P3 | "P-values were not calculated for pharmacodynamic endpoints. 2,3-DPG, 2,3-diphosphoglycerate; ARC, absolute reticulocyte count; ATP, adenosine triphosphate; BL, baseline; CFB, change from baseline; CI, confidence interval; Hb, hemoglobin; LDH, lactate dehydrogenase; LS, least squares; MMRM, mixed model repeated measures; ppts, participants; SD, standard deviation; SE, standard error; sTfR, soluble transferrin receptor."

Clinical • P2 data • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • ERFE

Pyruvate Kinase Activation in the Management of Thalassemia and Sickle Cell Disease. (PubMed, Hemoglobin) - "Although hydroxyurea, luspatercept, and curative approaches such as allogeneic transplantation and gene therapy have expanded the therapeutic landscape, major unmet needs persist because of limited access, variable response, toxicity, cost, and incomplete control of anemia, ineffective erythropoiesis, hemolysis, and/or vaso-occlusion...Mitapivat, a first-in-class oral PK activator, has shown encouraging activity across thalassemia and SCD...Tebapivat and etavopivat, two additional PK activators in earlier stages of development, have also shown promising metabolic, hematologic, and rheologic effects. Overall, PK activation represents a promising disease-modifying strategy in thalassemia and SCD, although optimal patient selection, affordability, and equitable global access will need to be addressed."

Journal • Review • Fatigue • Gene Therapies • Genetic Disorders • Hematological Disorders • Pain • Sickle Cell Disease • Transplantation

HIBISCUS KIDS: A Study to Evaluate the Pharmacokinetics and Safety of Etavopivat in Pediatric Patients With Sickle Cell Disease (clinicaltrials.gov) - P2 | N=95 | Recruiting | Sponsor: Forma Therapeutics, Inc. | N=50 ➔ 95

Enrollment change • Genetic Disorders • Hematological Disorders • Pediatrics • Sickle Cell Disease

Novo Nordisk: Etavopivat is the first in a new class of drugs to meet both co-primary endpoints in the phase 3 HIBISCUS trial, substantially reducing vaso-occlusive crisis events and improving haemoglobin response in sickle cell disease (GlobeNewswire) - "In the trial, people treated with etavopivat demonstrated a superior reduction in the annualised rate of VOCs of 27% compared to placebo. The time to first VOC was significantly prolonged with etavopivat, with a median time to first VOC of 38.4 weeks versus 20.9 weeks for placebo. In addition, etavopivat demonstrated a superior increase in the proportion of people achieving a Hb response greater than 1g/dL at week 24 of 48.7% compared to 7.2% with placebo, corresponding to an adjusted rate difference of 41.2%. Further, as an exploratory analysis, etavopivat significantly reduced the risk of blood transfusion....Novo Nordisk plans to submit for the first regulatory approval of etavopivat in the second half of 2026. The detailed results from the HIBISCUS phase 3 trial will be presented at a scientific conference in 2026."

Filing • P3 data: top line • Sickle Cell Disease

Novo Nordisk’s Etavopivat Trials Put Rare Blood Disorders In Focus (Yahoo Finance) - "The treatment is under ongoing regulatory review, focused on both beta and alpha thalassemia, an area with significant unmet medical need...Etavopivat signals a broader ambition in rare disease care. The stock shows mixed performance, with a 6.5% gain over the past week and 3.6% over the past 30 days, while longer term returns such as a 24.9% decline year to date and 37.0% decline over 1 year point to a more complex backdrop for investors to weigh."

Stock price • Beta-Thalassemia

The Pyruvate Kinase Activator Etavopivat (FT-4202) Limits Pulmonary and Systemic Sequelae of Sepsis in a Mouse LPS Model. (PubMed, Am J Physiol Lung Cell Mol Physiol) - "We conclude that the PKRA FT-4202 protected against systemic and respiratory (capillary permeability and neutrophil influx) features of sepsis induced by LPS in mice. FT-4202 promoted RBC ATP generation and export ex vivo, which could contribute to the favorable effects in LPS-induced sepsis."

Journal • Preclinical • Acute Kidney Injury • Acute Lung Injury • Hematological Disorders • Infectious Disease • Nephrology • Renal Disease • Respiratory Diseases • Septic Shock • IFNG • IL6 • LCN2 • MPO • TNFA

Study of the Effect of Etavopivat on Cerebral Hemodynamic Response in Children With Sickle Cell Disease (clinicaltrials.gov) - P2 | N=12 | Completed | Sponsor: Novo Nordisk A/S | Trial primary completion date: Mar 2025 ➔ Mar 2026

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

Study of the Effect of Etavopivat on Cerebral Hemodynamic Response in Children With Sickle Cell Disease (clinicaltrials.gov) - P2 | N=12 | Completed | Sponsor: Novo Nordisk A/S | Active, not recruiting ➔ Completed

Trial completion • 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=44 ➔ 480

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

4202-HEM-202: A Single Arm, Open Label, Phase 1/2 Study to Evaluate the Pharmacokinetics and Safety of Etavopivat in Pediatric Patients with Sickle Cell Disease (clinicaltrialsregister.eu) - P1/2 | N=9 | Not yet recruiting | Sponsor: Novo Nordisk A/S

New P1/2 trial • Genetic Disorders • Hematological Disorders • Pediatrics • Sickle Cell Disease

HIBISCUS KIDS: 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: Aug 2029 ➔ Feb 2028

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

Basal and stimulated intra-RBC and exported ATP and RBC adhesivity ex vivo in children with sickle cell disease (ASH 2025) - "RBC-specific PK (PKR) activators (PKRAs), such as etavopivat and mitapivat, are now approved in PK deficiency, and are being studied in SCD patients. In contrast, similar exposure to PKRA did not significantly increase intra-RBC ATP in SCD, and ATP export from SS RBCs rose in hypoxia but not after ex vivo PKRA treatment. Ongoing work addresses the determinants of cellular and exported ATP in HC and SCD RBCs (basal and treated) and the basis of the antiadhesive effect of this PKRA on SS RBCs."

Preclinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

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