HOPE (Sickle Cell Disease)

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Vichinsky E, et al. "A phase 3 randomized trial of voxelotor in sickle cell disease". The New England Journal of Medicine. 2019. 381(8):509-519.
PubMedFull textPDFClinicalTrials.gov

Clinical Question

In patients with sickle cell disease, does voxelotor 1500mg increase baseline hemoglobin of patients?

Bottom Line

In a trial of patients with sickle cell disease with at ≥1 vaso-occlusive crisis in the past year, voxelotor increased hemoglobin and reduced hemolysis labs when compared to placebo. There were no improvements in clinical events at 24 weeks.

Major Points

Sickle cell disease is a chronic disease with numerous acute and chronic clinical manifestations that results in premature mortality among persons afflicted by the condition. Despite its commonality, there are few treatment options available to improve improve clinical outcomes. The hallmark of sickle cell disease is polymerization of HbS and resultant sickling of RBCs. This leads to multiple events related to microvascular occlusion (eg, infarctions, pain), intravascular hemolysis (eg, anemia), and adverse inflammation.[1] One of the factors contributing to HgS polymerization is low oxygen. Voxelotor is an oral, targeted therapy that increases hemoglobin's oxygen affinity and reduces hypoxia-related polymerization.[2] Prior to 2019, it had not been assessed in a large trial.

Published in 2019, the Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization (HOPE) trial randomized 274 patients with sickle cell disease and 1-10 vaso-occlusive crises in the prior year, but not in the prior 14 days, to voxelotor 1500 mg or 900 mg PO daily or placebo. The present publication reports only the 24-week follow-up. At 24 weeks, 51% (1500 mg) and 33% (900 mg) doses were associated with ≥1 g/dL increase in hemoglobin. This was observed among only 7% of those receiving placebo. There were also changes in hemolysis laboratory results that are consistent with lower levels of hemolysis. Despite the improvement in biomarkers, there were nearly identical occurrences of vaso-occlusive events in the two voxelotor and placebo groups at 24 weeks. It was reasonably well-tolerated, with overall similar frequency of side effects in each arm. A pre-specified secondary outcome on the ClinicalTrials.Gov listing is noted to be annual vaso-occlusive events at 72 weeks. As of December 2020, these follow-up results have not yet been published.

Despite a lack of clinical benefit, the FDA provided accelerated approval and orphan drug status for voxelotor in November 2019.[3] But without evidence of clinical benefit, there is unclear utility of this drug other than to mildly improving hemoglobin and markers of hemolysis.

Guidelines

As of December 2020, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=274
    • Placebo (n=92)
    • Voxelotor 900 mg PO daily (n=92)
    • Voxelotor 1500 mg PO daily (n=90)
  • Setting: 60 institutions, 12 countries
  • Enrollment: January 2017 to May 2018
  • Follow up: 37-42 weeks
  • Analysis: Intention to treat (per protocol analyses also presented)
  • Primary outcome: Proportion with >1g/dL increase in hemoglobin at 24 weeks

Population

Inclusion Criteria

  • Sickle cell disease (HbSS, HbSC, HbS-beta thal, other sickle hemoglobinopathy variants)
  • Baseline hemoglobin of 5.5 to 10.5 g/dL
  • ≥1 and ≤10 vaso-occlusive crises in prior year

Exclusion Criteria

  • Vaso-occlusive crises in prior 14 days
  • Regular blood transfusions, or one in the prior 60 days

Baseline Characteristics

From the voxelotor 1500 mg group.

  • Demographics: Median age 24 years, 64% women
    • Race: 66% Black, 22% Arab or Middle Eastern, 13% White, 1% Asian
    • Region: N America 38%, Europe 21%, other 41%
  • Disease subtype: homozygous HgS 68%, HbS-β0-thalassemia 20%, HbSβ+-thalassemia 8%, HbSC 3%, other 1%
  • Median hemoglobin: 8.7 g/dL
  • # of vaso-occlusive crises in prior year: One 39%, 2-10 61%
  • On hydroxyurea: 64%

Interventions

  • Participants were randomized to a group:
    • Voxelotor 1500mg
    • Voxelotor 900mg
    • Placebo

Outcomes

Comparisons are voxelotor 1500 mg vs. voxelotor 900 mg vs. placebo.

Primary Outcomes

Proportion with >1g/dL increase in hemoglobin at 24 weeks
51% (95% CI 41 to 61%) vs. 33% (23 to 42%) vs. 7% (1 to 12%)
Voxelotor 1500 mg vs. placebo: P<0.001
Per protocol analysis: 59% vs. 38% vs. 9% (shown in Figure 2A)

Secondary Outcomes

Change in hemoglobin at 24 weeks
+1.1 (95% CI +0.9 to +1.4) vs. +0.6 (+0.3 to +0.8) vs. -0.1 g/dL (-0.3 to +0.2)
Voxelotor 1500 mg vs. placebo: P<0.001
Change in labs of hemolysis at 24 weeks
Indirect bilirubin: -29.1% (−35.9 to −22.2%) vs. −20.3% (−27.1 to −13.6%) vs. −3.2% (−10.1 to +3.8%)
% change in absolute reticulocyte count: −8.0 (−18.1 to +2.1) vs. 5.1 (−4.9 to +15.2) vs. 3.1 (−7.0 to +13.2)
% change in % of reticulocytes: −19.9% (−29.0 to −10.9%) vs. −1.3% (−10.3 to +7.7%) vs. +4.5% (−4.5 to +13.6%)
LDH: −4.5% (−11.9 to +2.8) vs. +1.4% (−5.9 to +8.7) vs. +3.4% (−4.0 to +10.9)

Subgroup Analysis

The primary outcome was similar by age, history of vaso-occlusive crises, use of hydroxyurea, and baseline level of hemoglobin. Details are shown in Figure S1 in the Supplemental appendix.[4]

Adverse Events

Any treatment-emergent adverse events
94% vs. 94% vs. 89%
Grade ≥3: 26% vs. 23% vs. 26%
Serious: 19% vs. 17% vs 16%
Treatment-related: 3% vs. 3% vs. 1%
Vaso-occlusive crises
Annualized incidence rate: 2.77 (2.15 to 3.57) vs. 2.76 (2.15 to 3.53) vs. 3.19/P-Y (2.50 to 4.07)
% with ≥1 crisis: 67% vs. 66% vs. 69%
Non-sickle cell disease-related adverse event
Any: 94% vs. 93% vs. 89%
Headache: 26% vs. 15% vs. 22%
Diarrhea: 20% vs. 17% vs. 10%
Nausea: 17% vs. 16% vs. 10%
Arthralgia: 15% vs. 12% vs. 12%
URI: 14% vs. 18% vs. 11%
Abdominal pain: 14% vs. 14% vs. 8%
Fatigue: 14% vs. 13% vs. 10%
Rash: 14% vs. 11% v.s 10%
Pyrexia: 12% vs. 11% vs. 7%
Pain in extremity: 11% vs. 20% vs. 18%
Back pain: 11% vs. 14% vs. 11%
Vomiting: 11% vs. 13% vs. 12%
Pain: 9% vs. 11% vs. 7%
Non-cardiac chest pain: 8% vs. 13% vs. 9%
Upper abdominal pain: 7% vs. 12% vs. 7%

Criticisms

  • Outcomes were biomarkers alone, no differences in clinical outcomes were noted in this 24-week trial. Differences might be observed in the 72 week follow-up.[5]

Funding

  • Funded by Global Blood Therapeutics, the manufacturers of Oxbryta (brand name of voxelotor), who also provided voxelotor in this study

Further Reading

  1. Chakravorty S & Williams TN Sickle cell disease: a neglected chronic disease of increasing global health importance. Arch Dis Child 2015. 100:48-53.
  2. Metcalf B et al. Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. ACS Med Chem Lett 2017. 8:321-326.
  3. FDA approval press release for voxelotor.
  4. Supplemental appendix.
  5. Thompson A & A Targeted Agent for Sickle Cell Disease - Changing the Protein but Not the Gene. N Engl J Med 2019. 381:579-580.