Background
Phase II (pivotal) double-blind placebo-controlled RCT. 198 patients aged ≥16 years with SCD (any genotype) and ≥2 VOC in the prior 12 months. Randomized 1:1:1 to crizanlizumab 5 mg/kg q4w, crizanlizumab 2.5 mg/kg q4w, or placebo IV for 52 weeks. Crizanlizumab is a monoclonal antibody targeting P-selectin, which mediates adhesion of sickled red cells to endothelium and leukocytes. FDA approved November 2019 under accelerated approval; voluntarily withdrawn by Novartis April 2023 after Phase 3 STAND trial failure.
Interventions and follow up
Arm A: Crizanlizumab 5 mg/kg IV q4w for 52 weeks (loading dose at week 2)
Arm B: Placebo IV q4w for 52 week
Primary endpoint: Annual rate of sickle cell–related pain crises (VOC)
mFollow up: 52 week
Arm B: Placebo IV q4w for 52 week
Primary endpoint: Annual rate of sickle cell–related pain crises (VOC)
mFollow up: 52 week
Results
Annual VOC rate: Median 1.63 (5 mg/kg) vs 2.98 (placebo); rate ratio 0.55, P=.01
Days to first VOC: Significantly prolonged (63.6% vs 40.5% event-free, P=.01)
Uncomplicated pain crises: Median 1.08 vs 2.91 per year (high dose vs placebo)
Days to first VOC: Significantly prolonged (63.6% vs 40.5% event-free, P=.01)
Uncomplicated pain crises: Median 1.08 vs 2.91 per year (high dose vs placebo)
Adverse events
Main adverse events: Grade ≥3 AEs: 45% (high dose) vs 52% (placebo). Arthralgia 7% vs 5%, diarrhea 7% vs 3%, fever 6% vs 5%. Infusion-related reactions grade 1–2 in ~15%. No increase in serious infections. Discontinuation due to AEs: 8% vs 6%.
Conclusions
Crizanlizumab 5 mg/kg reduced annual VOC rate by 45% versus placebo in SCD patients with ≥2 prior VOC, supporting P-selectin as a therapeutic target. FDA approved November 2019; however, confirmatory Phase 3 STAND trial failed, leading to voluntary withdrawal in April 2023.
Key Limitations
Key Limitations: Phase 2 (pivotal) trial, not Phase 3; sample size modest (N=198). Median VOC rate endpoint has high variability; 45% reduction is large but confidence intervals wide. Accelerated approval based on surrogate (VOC rate). Phase 3 STAND trial (N=~400) failed to confirm benefit, with VOC rates similar between arms. STAND included a more diverse population and stricter VOC documentation, raising concerns that SUSTAIN overestimated effect. Concurrent hydroxyurea use (≥35%) could confound results. No OS benefit measured.
Clinical Context
FDA approved November 2019 for adults and children ≥16 with SCD. Novartis voluntarily withdrew crizanlizumab (Adakveo) from the US market in April 2023 after the STAND trial failed to demonstrate VOC reduction. No longer commercially available. Together with voxelotor's 2024 withdrawal, both non-HU/non-transfusion SCD agents have been withdrawn. Hydroxyurea, chronic transfusion, and curative gene therapy (exa-cel, lovo-cel) remain the mainstays of SCD management.
References