Crizanlizumab Treatment Is Associated with Clinically Significant Reductions in Hospitalization in Patients with Sickle Cell Disease: Results from the Sustain Study
Authors: Ataga Kenneth I. , Kutlar Abdullah , DeBonnett Laurie , Lincy Jeremie , Kanter Julie 
Published: November 2019

Background: Sickle cell disease (SCD) is characterized by the presence of sickle hemoglobin (HbS), chronic hemolysis, recurrent pain episodes called vaso-occlusive crises (VOCs), multiorgan dysfunction and early death. VOCs decrease quality of life, are the main cause of healthcare encounters in SCD, and increase the risk of death. New therapies that reduce SCD hospitalizations are desirable given the potential to impact healthcare utilization, but also to reduce disease burden and decrease mortality and morbidity.
The SUSTAIN study (Ataga et al. NEJM 2017), was a Phase 2, multicenter, randomized, placebo-controlled, double-blind, 12-month study to assess safety and efficacy of crizanlizumab (2.5 and 5 mg/kg) with or without hydroxyurea therapy, in patients with SCD and a history of 2-10 VOCs in the previous 12 months (NCT01895361). The primary efficacy endpoint was annual rate of SCD-related pain crises (VOCs) leading to healthcare visit. The key secondary endpoint was annual rate of days hospitalized, regardless of cause. There was a statistically significant 45.3% reduction in median annual rate of VOCs leading to healthcare visit with crizanlizumab 5 mg/kg compared with placebo (1.63 vs 2.98 VOCs/year, P=0.01). There was a 41.8% reduction in median rate of days hospitalized with crizanlizumab 5 mg/kg compared with placebo (4.00 vs 6.87 days/year). Although this difference was not statistically significant (P=0.45), it appears to be clinically relevant.
Methods: A post-hoc analysis of the SUSTAIN data was performed to better characterize the difference in the annual rate of days hospitalized between the crizanlizumab 5 mg/kg and placebo arms, and to compare the distribution of hospitalizations and time to first hospitalization.
Results: As illustrated in Figure 1, a greater proportion of patients in the crizanlizumab arm (46%) were not hospitalized during the trial period (up to end of treatment) than in the placebo arm (35%). Correspondingly, the percentage of patients with ≥1 hospitalization was lower in the crizanlizumab (54%) than the placebo arm (65%). In addition, a trend for delayed time to first hospitalization shown in Figure 1 was further explored with a Kaplan-Meier (KM) analysis (Figure 2).
Figure 2 shows clear separation of the curves, evident from Month 1 of treatment. The median time to first hospitalization was greater with crizanlizumab 5 mg/kg than with placebo (6.3 vs 3.2 months; hazard ratio [HR] 0.683 [95% CI 0.437-1.066]). The apparent improvement in time to first hospitalization is consistent with previously published SUSTAIN results regarding median time to first VOC leading to healthcare visit. Patients treated with crizanlizumab 5 mg/kg were found to experience a longer median time to first VOC leading to healthcare visit than patients on placebo (4.07 vs 1.38 months; HR 0.50 [95% CI 0.33-0.74]).
Conclusions: The primary SUSTAIN results showed that crizanlizumab reduced VOCs leading to a healthcare visit. This analysis demonstrates additional positive trends associated with crizanlizumab treatment compared to placebo, regarding the percentage of patients with no hospitalizations and a delayed time to first hospitalization. Together, these findings provide further evidence that crizanlizumab may have a beneficial impact on reducing hospitalizations.

Disclosures
Ataga: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Modus Therapeutics: Honoraria. Kutlar:Micelle Biopharma: Other: DSMB Chair; Novartis: Consultancy; Global Blood Therapeutics, Inc. (GBT): Research Funding; Novo Nordisk: Research Funding; Bluebird Bio: Other: DSMB Member. DeBonnett:Novartis Pharmaceuticals Corporation: Employment. Lincy:NOVARTIS PHARMA AG: Employment. Kanter:Novartis: Consultancy, Honoraria; Imara: Consultancy; Sangamo: Consultancy, Honoraria; Modus: Consultancy, Honoraria; Guidepoint Global: Consultancy; GLG: Consultancy; Cowen: Consultancy; Jeffries: Consultancy; Medscape: Honoraria; Rockpointe: Honoraria; Peerview: Honoraria; SCDAA: Membership on an entity's Board of Directors or advisory committees; NHLBI: Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy.