article252

HOPE (Sickle Cell Disease)

"Voxelotor in Patients with Sickle Cell Disease (HOPE Trial)".
The New England Journal of Medicine. 2019.

Clinical Question

Does voxelotor, an HbS polymerization inhibitor, increase hemoglobin levels and reduce markers of hemolysis in patients with sickle cell disease?

Bottom Line

Voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis, consistent with inhibition of HbS polymerization, indicating its disease-modifying potential in sickle cell disease.

Major Points

Voxelotor, a novel agent that inhibits sickle hemoglobin (HbS) polymerization, was evaluated in the Phase 3 HOPE trial for its ability to increase hemoglobin levels and reduce hemolysis in patients with sickle cell disease. The trial showcased voxelotor's ability to improve anemia and reduce hemolysis markers significantly better than placebo, suggesting its potential as a disease-modifying therapy.

Guidelines

As of the last knowledge update for this summary, specific guidelines reflecting the findings from the HOPE trial had not been published.

Design

- Multicenter, phase 3, double-blind, randomized, placebo-controlled trial
- N=274 participants with sickle cell disease
- 1500 mg daily voxelotor (n=90)
- 900 mg daily voxelotor (n=92)
- Placebo (n=92)
- Screening period: 28 to 35 days
- Treatment period: up to 72 weeks, with a follow-up visit at 4 weeks after the last dose
- Enrollment: January 2017 - May 2018
- Analysis: Intention-to-treat
- Primary efficacy analysis: Completed when the last participant reached week 24

Population

- Inclusion Criteria: Confirmed sickle cell disease, aged 12-65 years, hemoglobin level 5.5-10.5 g/dL, 1-10 vaso-occlusive crises in the previous 12 months
- Exclusion Criteria: Regular red-cell transfusion therapy, transfusion in the past 60 days, hospitalization for vaso-occlusive crisis within 14 days before informed consent
- Most participants had sickle cell anemia
- Approximately two-thirds were receiving hydroxyurea

Interventions

- Randomization 1:1:1 to 1500 mg voxelotor, 900 mg voxelotor, or placebo, administered orally once daily

Outcomes

- Primary Outcome: The percentage of participants who had a hemoglobin response, defined as an increase from baseline of more than 1.0 g/dL at week 24. Significantly more participants achieved this in the 1500 mg voxelotor group (51%) compared to the placebo group (7%).
- Secondary Outcomes: The 1500 mg voxelotor group showed significant reductions in indirect bilirubin and percentage of reticulocytes, indicating reduced hemolysis. Voxelotor also demonstrated a rapid pharmacodynamic and biological effect, with improvements ongoing at a steady state throughout the treatment period.

Criticisms

- Longer-term follow-up is required to fully characterize voxelotor's effects on vaso-occlusive crisis incidence and other clinical outcomes.

Funding

The trial was funded by Global Blood Therapeutics.