Etavopivat Files on VOC Win but Safety and Precedent Gaps Cap Conviction

Novo Nordisk Submits Etavopivat for Sickle Cell Disease Approval

Novo Nordisk has announced the submission of a New Drug Application (NDA) to the US FDA and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for etavopivat. This investigational, once-daily, orally available therapy is intended for adolescents and adults aged 12 years and older living with sickle cell disease (SCD). The submissions are based on positive efficacy and safety results from the Phase 3 HIBISCUS trial, which demonstrated a 27% reduction in vaso-occlusive crises (VOCs) and a ~4-month delay to the first VOC compared to placebo. If approved, etavopivat, a selective activator of pyruvate kinase red blood cell isozyme (PKR), could offer a new disease-modifying treatment option for SCD patients.

• Regulatory Milestones and Designations: Etavopivat has received significant regulatory support, including Fast Track, Rare Pediatric Disease, and Orphan Drug designations from the FDA, and Orphan Drug designation from the European Commission. These designations underscore the urgent unmet medical need in sickle cell disease and are expected to expedite the review process, with regulatory actions anticipated in 2027 for both the NDA and MAA.
• Pivotal Phase 3 HIBISCUS Trial Design: The NDA and MAA submissions are grounded in the comprehensive HIBISCUS study program, a 52-week efficacy and safety phase 2/3 trial. This pivotal study enrolled approximately 440 adolescents and adults (aged 12 years and over) with SCD who had experienced 2 to 15 VOCs in the prior year, comparing once-daily etavopivat against placebo while allowing standard-of-care treatment.
• Mechanism of Action and Therapeutic Potential: Etavopivat functions as a selective activator of pyruvate kinase red blood cell isozyme (PKR), a key enzyme in glycolysis. By reducing 2,3-DPG levels and increasing ATP production, it improves hemoglobin-oxygen affinity, averting sickle hemoglobin polymerization and sickling, while also preserving red blood cell membrane integrity. These disease-modifying effects aim to reduce VOC events and improve hemoglobin levels.

Addressing the Unmet Needs in Sickle Cell Disease Treatment

Current treatment approaches for sickle cell disease improve survival and reduce complications but remain constrained by toxicity, limited durability, donor and access barriers, and cost. While HLA-matched allogeneic bone marrow transplantation is potentially curative, it has considerable limitations due to potential severe toxicities, and there is still a large area of unmet needs for patients with SCD.

• Transfusion-related toxicity and alloimmunization: Despite overall improvements in blood inventory safety, adverse effects of transfusion are prevalent and include alloimmunization, acute and delayed hemolytic transfusion reactions, and iron overload. Although limited and extended RBC antigen matching reduces antibody formation, the prevalence of RBC alloimmunization in patients with SCD remains high, with RH genetic diversity contributing to Rh alloimmunization, while transfusional iron overload requires automated RBC exchange, noninvasive imaging to monitor iron burden, and iron chelation with parenteral or oral agents.

• Limitations of hydroxyurea: Hydroxyurea, the first approved drug for sickle cell disease, decreases sickle hemoglobin polymerization by inducing fetal hemoglobin, with excellent effects in young children but variable responses in adults that are not curative, and it is not effective in a large proportion of patients. Utilization remains poor in low-resource settings due to lack of availability, inadequate treatment guidance, excessive costs, inadequate knowledge, unawareness of treatment guidelines, non-availability, intensive monitoring, and side effects, with reduction of crisis and safety as motivators and difficulty remembering to take hydroxyurea reported by patients.

• Constraints of newer pharmacologic agents: Several pharmacological agents targeting different mechanisms have been examined in clinical trials and recently US-FDA-approved, including L-glutamine and crizanlizumab, but long term efficacy data and cost is still a concern for the newer agents including L-glutamine, voxelotor and crizanlizumab. Voxelotor was previously US-FDA-approved but has been voluntarily withdrawn from the market as the overall benefit did not outweigh the risks.

• Barriers to hematopoietic stem cell transplantation: Allogeneic hematopoietic stem cell transplantation is limited by donor availability and complicated by graft failure, graft versus host disease and prolonged immune suppression, with use in adults historically limited by transplant-related toxicity. Even with non-myeloablative and reduced-intensity conditioning achieving overall survival above 90% in matched sibling transplants and 2-year OS of 95% with graft failure of just 7% in haploidentical transplantation with post-transplant cyclophosphamide, chronic GVHD incidence of 0% with NMA conditioning, 13-22% with RIC, to 22% in the haploidentical plus PTCy setting, infectious complications, secondary malignancies, and need for close follow-up persist.

• Gene therapy access and manufacturing challenges: Gene therapies based on CRISPR-Cas9 and lentiviral vectors have been very recently approved and have demonstrated durable haemoglobin correction and near-complete resolution of vaso-occlusive events, yet excessive costs are a barrier to widespread use. Challenges include difficulty in obtaining sufficient numbers of autologous hematopoietic stem cell progenitors for genetic manipulation and loss of cells during the manufacturing process, stem-cell mobilisation, fertility preservation, conditioning toxicity, and equitable access, with slow uptake reflecting a complex, resource-intensive intervention in a fragmented care system.

Etavopivat's HIBISCUS Trial Design and Efficacy Data

Key sickle cell disease trials evaluate diverse modalities including transplantation, polymerization inhibition, anti-adhesion therapy, and metabolic modulation across pediatric and adult populations. Designs range from small proof-of-concept studies to large multicenter randomized phase 2 and 3 trials with vaso-occlusive and hemoglobin endpoints.

Etavopivat's Potential Impact on the SCD Treatment Landscape

In the past five years the sickle cell disease treatment landscape expanded beyond hydroxyurea and chronic transfusion with three newer disease-modifying medications, L-glutamine, voxelotor, and crizanlizumab, approved since 2017. L-glutamine reduced vaso-occlusive crisis burden in the pivotal trial (rate ratio, 0.75; 95% confidence interval, 0.62-0.90). Crizanlizumab, an anti-P-selectin monoclonal antibody indicated to reduce the frequency/prevent recurrence of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD) aged ≥16 years, prolonged time to first vaso-occlusive crisis in SUSTAIN (hazard ratio, 0.50; 95% confidence interval, 0.33-0.75). Voxelotor (1500 mg), an oral once-daily sickle haemoglobin polymerisation inhibitor approved in the USA in 2019 for treatment of sickle cell disease in patients aged 12 years and older, primarily improved hemoglobin response (risk ratio, 7.84; 95% confidence interval, 3.52-17.4), with the HOPE trial showing adjusted mean change in haemoglobin concentration from baseline to week 72 of 1·0 g/dL (95% CI 0·7 to -1·3) in the voxelotor 1500 mg group versus 0·0 g/dL (-0·3 to 0·3) in the placebo group, alongside improvements in indirect bilirubin concentrations (-26·6% [95% CI -40·2 to -12·9]) and percentage of reticulocytes (-18·6% [-33·9 to -3·3]).

A second evolution is potentially curative autologous gene addition and gene editing, with gene therapies (Exa-cel and Lovo-cel, 2023) approved after hydroxyurea remained the only approved disease modifying therapy (1998) until FDA approval of L-glutamine (2017) and Crizanlizumab and Voxelotor (2019). Gene addition uses lentiviral vectors to introduce functional or modified β-globin genes into autologous haematopoietic stem cells, whereas gene editing targets regulatory pathways, particularly BCL11A, to reactivate fetal haemoglobin synthesis or correct disease-causing mutations. LentiGlobin for sickle cell disease (bb1111; lovotibeglogene autotemcel) consists of autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified β-globin gene, which produces an antisickling hemoglobin, HbA; in Group C the median total hemoglobin level increased from 8.5 g per deciliter at baseline to 11 g or more per deciliter from 6 months through 36 months after infusion, HbA contributed at least 40% of total hemoglobin and was distributed across a mean (±SD) of 85±8% of red cells, with resolution of severe vaso-occlusive events in all 25 evaluable patients compared with a median of 3.5 events per year (range, 2.0 to 13.5) before enrollment. CRISPR-Cas9 approaches include OTQ923 with targeted disruption of the HBG1 and HBG2 (γ-globin) gene promoters, resulting in fetal hemoglobin as a percentage of total hemoglobin, 19.0 to 26.8%, with fetal hemoglobin broadly distributed in red cells (F cells as a percentage of red cells, 69.7 to 87.8%), and BCL11A erythroid enhancer editing producing high levels of allelic editing, pancellular fetal hemoglobin, transfusion independence, and elimination of vaso-occlusive episodes. Regulatory approvals now include Lyfgenia (lovotibeglogene autotemcel) for sickle cell disease, Zynteglo (betibeglogene autotemcel) for β-thalassemia, and Casgevy (exagamglogene autotemcel) for either sickle cell disease or β-thalassemia.

Postapproval experience has prompted therapy-specific benefit-risk reassessment and highlighted limited real-world uptake. The recent withdrawal of voxelotor from the market and regulatory reassessment of crizanlizumab warrant reassessment, with the STAND phase 3 trial of crizanlizumab 5·0 mg/kg and 7·5 mg/kg showing adjusted annualised rate of vaso-occlusive crises of 2·49 (95% CI 1·90-3·26) in the 5·0 mg/kg group, 2·04 (1·56-2·65) in the 7·5 mg/kg group, and 2·30 (1·75-3·01) in the placebo group, with ratios of 1·08 (95% CI 0·76-1·55, p>0·999) and 0·89 (0·62-1·27, p>0·999) versus placebo and no significant difference in efficacy. Uptake of disease-modifying treatments remained low from 2014 to 2021 despite newer approvals, with total DMT use increasing from 428 of 2188 participants (19.6%) in 2014 to 815 of 2880 patients (28.3%) in 2021, hydroxyurea use increasing from 428 of 2188 participants (19.6%) to 701 of 2880 (24.3%), and in 2021 102 (3.5%) with at least 1 fill for crizanlizumab and 131 (4.6%) with at least 1 fill for voxelotor.