Abstract Background: In the 52-week SUSTAIN study, which compared the P-selectin inhibitor crizanlizumab with placebo, crizanlizumab 5.0 mg/kg significantly reduced the frequency of sickle cell pain crises (SCPCs) versus placebo (1.6 vs 3.0, P=0.01) and increased the time to first on-treatment SCPC (4.1 vs 1.4 months, P=0.001) in patients with sickle cell disease (SCD) (Ataga KI et al. N Engl J Med 2017;376:429-39). Due to heterogeneity in disease severity and differences in medications used for the treatment of SCD and various other factors, treatment responses may vary between individuals with SCD. Differences in the response to crizanlizumab observed in defined subgroups of patients are of interest to increase understanding of this treatment, and the role of P-selectin in SCD. Aims: This post hoc analysis evaluated the time to first SCPC in subgroups of the SUSTAIN study population to further assess the efficacy of crizanlizumab 5.0 mg/kg and differences in treatment response between those subgroups. Methods: SUSTAIN was a randomized, double-blind, placebo-controlled, Phase II study (NCT01895361). Patients aged 16-65 years with SCD (HbSS, HbSC, HbSβ0-thalassemia, HbSβ+-thalassemia or other genotype) were included if they had experienced 2-10 SCPC events in the previous 12 months. Concomitant use of hydroxyurea (HU) was permitted if the patient had been using it for ≥6 months and at a stable dose for ≥3 months. Patients were randomized 1:1:1 to receive intravenous crizanlizumab 5.0 mg/kg, 2.5 mg/kg or placebo; however, this abstract focuses on the 5.0 mg/kg dose of crizanlizumab versus placebo. Study treatments were administered on days 1 and 15, then every 4 weeks to week 50; the final study visit of the treatment phase was at week 52, with an additional follow-up visit at week 56. The median time to first SCPC after the first dose of study treatment was summarized for patients treated with crizanlizumab 5.0 mg/kg or placebo in the following subgroups: 2-4 or 5-10 SCPC events in the previous 12 months; HbSS or non-HbSS genotype; and HU use (yes or no) at baseline. Hazard ratios (HRs) for crizanlizumab 5.0 mg/kg versus placebo were calculated based on Cox regression analysis, with treatment as a covariate. Results: 67 patients in the intent-to-treat population received crizanlizumab 5.0 mg/kg and 65 received placebo. Overall, more patients who had experienced 2-4 SCPCs (63% in both groups) than 5-10 SCPCs (37% in both groups) in the previous year were enrolled. HbSS was the most common genotype (crizanlizumab 5.0 mg/kg: 70%; placebo: 72%), and more than half of patients were taking HU at baseline (crizanlizumab 5.0 mg/kg: 63%; placebo: 62%). In almost all the subpopulations evaluated, crizanlizumab 5.0 mg/kg significantly (P Conclusions: Treatment with crizanlizumab 5.0 mg/kg significantly delayed the time to first on-treatment SCPC in adults living with SCD compared with placebo in most of the subpopulations investigated, including patients with the HbSS genotype, suggesting a potential for disease modification. Crizanlizumab 5.0 mg/kg was also effective in those individuals taking HU who had still experienced 2-10 SCPCs in the previous year, indicating that P-selectin inhibition provided additional beneficial treatment effect compared with HU alone. Download : Download high-res image (213KB) Download : Download full-size image Disclosures Kanter: Sancillo: Research Funding; Apopharma: Research Funding; MUSC: Other: The site PI for sponsored research conducted at MUSC who receives funds from: Novartis, bluebird bio, GBT, Sancillo, Apopharma, Pfizer; GBT: Research Funding; Pfizer: Research Funding; American Society of Hematology (Sickle Cell Disease Guideline Panel): Membership on an entity's Board of Directors or advisory committees; NHLBI (sickle cell disease research advisory committee): Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kutlar: Novartis: Research Funding; BlueBird Bio: Other: Member of Data Monitoring Committee; Sancilio & Co (OMEG-411-02): Other: Chair of Data and Safety Monitoring Board; Reprixys Pharmaceuticals Corporation (formerly known as Selexys Pharmaceuticals Corporation, which is not affiliated with Selexis S.A.): Research Funding. Liles: Pfizer: Research Funding. Bruederle: Novartis: Employment. Shi: Novartis: Employment. Zhu: Novartis: Employment. Ataga: Reprixys Pharmaceuticals Corporation (formerly known as Selexys Pharmaceuticals Corporation, which is not affiliated with Selexis S.A.): Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Research Funding; Novartis: Honoraria; Global Blood Therapeutics: Honoraria; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees.