Etavopivat could offer ‘great benefit’ in sickle cell disease
Key takeaways:
- Etavopivat reduced the annualized vaso-occlusive crises rate vs. placebo.
- The agent increased hemoglobin levels, reduced patient-reported fatigue and improved hemolysis markers.
SAN DIEGO — Etavopivat reduced the annualized vaso-occlusive crises rate vs. placebo for people with sickle cell disease, according to study data presented at ASH Annual Meeting and Exposition.
The agent also increased hemoglobin levels, reduced patient-reported fatigue and improved hemolysis markers, results of the HIBISCUS trial showed.
If a confirmatory phase 3 trial of etavopivat (Novo Nordisk) is successful, the agent has the potential to be a second-line therapy to hydroxyurea — or first-line treatment for those who are intolerant of hydroxyurea, researcher Julie Kanter, MD, told Healio.
“We’re certainly hopeful. This is a very exciting mechanism of action and could offer great benefit,” said Kanter, professor of medicine and pediatrics and director of the adult sickle cell program at The University of Alabama at Birmingham. “However, I don’t think it’s going to be for everyone, and that is an important point. Sickle cell disease is not a noncomplicated disorder. You can’t take any drug that has only been given to a hundred people and expect it to affect everyone the same way.”
Background
Etavopivat is an oral activator of the red blood cell pyruvate kinase isozyme. Prior studies showed the agent decreased 2,3-diphosphoglycerate levels and increased adenosine triphosphate levels in red blood cells.
Results of a phase 1 study showed etavopivat conferred sustained and rapid increases in hemoglobin levels, as well as reduced markers of hemolysis over a 12-week period.
Kanter and colleagues conducted the randomized phase 2/phase 3 HIBISCUS trial to further evaluate the efficacy and safety of etavopivat for sickle cell disease.
The trial included 60 people aged 12 to 65 years (mean age, 33.5 years; 32% male; 12% adolescents; 90% HbSS genotype) with any sickle cell disease genotype.
All study participants had hemoglobin levels of 5.5 g/dL to 10.5 g/dL at screening and had experienced at least two but no more than nine vaso-occlusive crises requiring a visit to a medical setting in the past year.
Researchers randomly assigned trial participants 1:1:1 to one of three regimens — etavopivat 200 mg (n = 21), etavopivat 400 mg (n = 20) or placebo (n = 19) — once daily for 1 year.
Study protocol permitted standard care, including stable dosing of hydroxyurea at least 90 days prior, crizanlizumab (Adakveo, Novartis) or L-glutamine at least 1 year prior.
Researchers reported a mean baseline hemoglobin level of 8.4 g/dL (standard deviation, 1.16), and participants had a mean 3.3 (standard deviation, 1.78) vaso-occlusive crises in the prior 12 months.
A majority of patients in each treatment group used concomitant hydroxyurea.
Annualized vaso-occlusive crisis rate over 52 weeks and hemoglobin response — defined as greater than 1 g/dL increase from baseline at week 24 — served as primary endpoints.
At ASH, Kanter presented 52-week results of the primary efficacy analysis for the intent-to-treat population, as well as the per-protocol population, defined as a minimum 80% protocol compliance and completion of the double-blind period with no major protocol deviations.
Key findings
The intent-to-treat analysis showed annualized vaso-occlusive rates of 1.07 (95% CI, 0.49-2.37) with etavopivat 200 mg, 1.06 (95% CI, 0.46-2.46) with etavopivat 400 mg and 1.97 (95% CI, 0.89-4.36) with placebo. Vaso-occlusive rate ratios for etavopivat vs. placebo were 0.55 (95% CI, 0.24-1.26) with 200 mg and 0.54 (95% CI, 0.23-1.26) with 400 mg.
A per-protocol analysis showed annualized vaso-occlusive rates of 0.66 (95% CI, 0.28-1.58) with etavopivat 200 mg, 0.7 (95% CI, 0.29-1.66) with etavopivat 400 mg and 1.77 (95% CI, 0.9-3.5) with placebo. Vaso-occlusive rate ratios for etavopivat vs. placebo were 0.37 (95% CI, 0.16-0.85) with 200 mg and 0.39 (95% CI, 0.17-0.9) with 400 mg.
Results showed longer median time to first vaso-occlusive crisis with etavopivat (33.6 weeks for each dose group) than placebo (16.9 weeks).
Researchers reported higher rates of hemoglobin response in the intent-to-treat population at week 24 with etavopivat 200 mg (38.1%) and etavopivat 400 mg (25%) than placebo (10.5%). Hemoglobin response among patients assigned etavopivat began as early as week 2 and persisted over 1 year.
Researchers also reported higher rates of hemoglobin response at week 24 with etavopivat 200 mg (46%) and 400 mg (33%) than placebo (13%). Results showed mean changes in hemoglobin levels from baseline to week 24 of 1.11 g/dL in the etavopivat 200 mg group and 0.73 g/dL in the etavopivat 400 mg group vs. 0.15 g/dL in the placebo group.
All hemolysis biomarkers declined from baseline in both etavopivat groups at week 24, with decreases in lactate dehydrogenase levels being sustained through 1 year.
PROMIS Fatigue Scale scores showed improvements for people assigned etavopivat.
Kanter characterized etavopivat as well tolerated, noting researchers observed no new safety signals.
Six people in each etavopivat group and three people assigned placebo discontinued their assigned study drug early. Two of the discontinuations in the 200-mg etavopivat group occurred after adverse events.
The majority of adverse events observed were mild to moderate and resolved without action, according to investigators.
Serious adverse events occurred among five people assigned etavopivat 200 mg — with one case of hepatic enzyme increase potentially being drug related — and four people assigned etavopivat 400 mg, with one case of hemoglobin decrease being potentially drug related. One cerebrovascular accident deemed unrelated to therapy occurred in the 200 mg group.
Three serious adverse events occurred in the placebo group.
Next steps
The data and safety monitoring board selected 400 mg daily etavopivat for evaluation in a confirmatory phase 3 trial.
Kanter emphasized she believes hydroxyurea should remain standard first-line therapy, with the acknowledgment that not everyone with sickle cell disease can tolerate it.
“Access to an oral therapy like etavopivat could be a first [option] before some of the genetic therapies that are truly transformative, but not everyone wants those therapies, is able to get them or will be able to afford them,” Kanter said during a press briefing. “To have another novel therapy that can improve hemoglobin and perhaps also decrease adhesion is really important, and I think it will be an excellent second-line therapy — and perhaps for some people, first-line therapy.”
Kanter also highlighted the need to re-evaluate the endpoints used in studies of sickle cell disease treatments.
“Much to my dismay, the primary endpoint [in HIBISCUS] is annualized vaso-occlusive crisis rate over 52 weeks,” Kanter said. “Vaso-occlusive crisis remains the main reason we see individuals coming to the emergency department at the hospital, and it really impacts their care. But it’s a very hard endpoint to measure. Pain is very nebulous. Sickle cell disease causes multiorgan complications. It’s not all about pain, even though that’s often what becomes our focus.”
Kanter noted that not all individuals with sickle cell disease seek acute care for pain. Access to medicines at home, being under the care of a sickle disease specialist and even pain tolerance contribute to that decision.
“Historically, phase 2 studies will show improvement in vaso-occlusive crises because there are fewer centers, fewer patients and more homogeny in practice,” Kanter said. “When we get to phase 3 — especially in a multinational setting — we’re equating things that no longer equate. Vaso-occlusive crises for a 20-year-old in Ghana may not be the same as vaso-occlusive crises for a 20-year-old in Alabama based on what they may or may not have access to and the therapies that are available to them.”
This makes vaso-occlusive crises “an incredibly difficult measure to standardize,” Kanter said.
“And it’s not the right measure for what patients are experiencing,” she said. “We need to focus on patient-reported outcomes. There’s no reason we can’t use these as endpoints. We can do it with pain interference and pain function measures, which ask questions like ‘How much as your pain affected you today or this week?’
“Using that is a much more reliable measure — not just of outcomes, but also to capture those individuals who may not come to the hospital but still experience really detrimental quality of life,” Kanter said.
Perspective
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I am a huge fan of getting new drugs for this disorder.
Etavopivat and another agent — mitapivat (Pyrukynd, Agios) — both look very promising. They seem to raise hemoglobin, which is important, but more important is what they do in terms of how patients feel and the crises they experience.
The results of this study suggest etavopivat will decrease vaso-occlusive events. That could be huge, because we don’t have many options for that other than hydroxyurea.
Dr. Kanter’s comments about pain are important, too, because it is such a complex endpoint. If someone gets a bone marrow transplant and is cured of sickle cell disease, they still have pain for a while after transplant — perhaps up to a year. The explanation I’ve heard is that the brain has to be rewired from a lifetime of pain and it takes time to reset things. With that context, it’s easy to see why — if pain is the key outcome — it can be hard to figure out whether a person truly is improving.
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Delicou S, et al. Abstract 179. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2024; San Diego.