These subgroup analyses also indicate that the efficacy observed in the overall study population was likely not driven by a single subgroup or set of subgroups. SCD (n=121) was assessed over a median follow-up of 1 year. This pattern of response was also apparent in patients with 2‐4 VOCs in the previous year, no concomitant HU use, and non‐HbSS genotype. The most common genotype was HbSS (94/132, 71.2%); the remaining non‐HbSS patients had HbSC, HbSβ0, HbSβ+, or rare genotypes. Key inclusion criteria included patients 16 to 65 years of age; diagnosis of SCD (HbSS, HbSC, HbSβ0 thalassemia or HbSβ+ thalassemia); and history of 2 to 10 SCPC in the previous 12 months. ZZ performed the analyses and contributed to the interpretation of the findings presented. Antiplatelet agents. Further analysis of annualized days of hospitalization by subgroup was not feasible due to the sample size of the study, given that the overall analysis did not demonstrate statistically significant differences. The cell adhesion molecule P‐selectin plays a key role in the pathogenesis of a vaso‐occlusive crisis (VOC) in patients with sickle cell disease (SCD). P-selectin, an adhesion molecule expressed on activated vascular endothelial cells and platelets, facilitates cell-to-cell and cell-to-endothelium interactions that are involved in the pathogenesis of VOC in SCD. If you do not receive an email within 10 minutes, your email address may not be registered, Patients, care providers and those assessing outcomes were blinded to group assignments. n = 15bb Number of patients included in the subgroup who experienced any VOC during the SUSTAIN study. The purpose of this study is to compare the efficacy and safety of 2 doses of crizanlizumab (5.0 mg/kg and 7.5 mg/kg) versus placebo in adolescent and adult sickle cell disease (SCD) patients with history of vaso-occlusive crisis (VOC) leading to healthcare visit. Non‐drug therapeutic options for patients with SCD include stem cell transplant28 and blood transfusions.29 Stem cell transplant is not a viable option for many patients owing to the lack of suitable donors,30 and although blood transfusions can play a vital role in treating the acute and chronic complications of SCD, they can also cause alloimmunization, hyperhemolytic transfusion reactions, and iron overload.29. Although PSGL‐1 is not present on normal erythrocytes, sickled red blood cells (RBCs) are known to have glycoproteins on their cell surface that can mimic the P‐selectin ligand and mediate adherence to activated endothelial cells expressing P‐selectin.15, 16, Crizanlizumab is a humanized, anti‐P‐selectin monoclonal antibody.17 The 52‐week, phase 2 SUSTAIN study demonstrated that crizanlizumab has a potentially disease‐modifying effect when used for the prevention of VOCs in patients with SCD.17 In this study, crizanlizumab 5 mg/kg significantly reduced the frequency of VOCs by 45% (P = .01), significantly delayed the median time‐to‐first VOC by 2.7 months (P = .001) and second VOC by 5.2 months (P = .02), and appeared to decrease the annualized median rate of days hospitalized (for any cause) by 42% (4.00 vs 6.87 days) vs placebo in SCD patients aged ≥16 years, although the difference was not statistically significant due to large variability (P = .45) but may be considered clinically relevant.17. In the SUSTAIN study, 198 patients met the eligibility criteria, of whom 67 were assigned to receive crizanlizumab 5 mg/kg and 65 to receive placebo (giving a total of 132 patients in the subgroup analyses) (Figure 1). Less severe genotypes include sickle hemoglobin C disease (HbSC) and sickle β+‐thalassemia (HbSβ+), and a number of rare genotypes are also known (eg, sickle‐delta β‐thalassemia). Investigate combination therapies and new drug-delivery models. In SUSTAIN, patients with SCD were randomized to crizanlizumab 2.5 mg/kg, crizanlizumab 5 mg/kg, or placebo intravenously 14 times over 52 weeks. Use the link below to share a full-text version of this article with your friends and colleagues. Sickle cell disease is characterized by the presence of sickle hemoglobin (HbS), chronic hemolysis, recurrent pain episodes (called sickle cellrelated pain crises or vaso-occlusive crises), multiorgan dysfunction, and early death. Demographic parameters were evenly distributed in the treatment groups. Time to first SCPC at 5.0 mg/kg vs. placebo was increased 2.9-fold (medians of 4.1 vs. 1.4 months, p = 0.001, Fig. KIA has received fees for consultancy from Modus Therapeutics and Reprixys Pharmaceuticals Corporation, and has participated in advisory boards for Bioverativ, Global Blood Therapeutics and Novartis Pharmaceuticals Corporation. The primary endpoint was the annual rate of VOC with crizanlizumab vs placebo. 33 The SUSTAIN trial, a multicenter randomized double blind study, showed that crizanlizumab decreased the incidence of VOC by 45% in patients with or without HU. Clinical trials are underway using different gene transfer vectors and cassettes. Abbreviations: HbSS, hemoglobin S; HU, hydroxyurea; VOC, vaso‐occlusive crisis. Patients were randomly assigned to receive 5 mg/kg or 2.5 mg/kg of SelG1 or a placebo intravenously once a month, after an initial loading dose. OAA has participated in advisory boards for Novartis Pharmaceuticals Corporation. Descriptive statistics were used to summarize the number of VOC event‐free patients and types of VOC in the following subgroups: prior VOC events (2‐4 or 5‐10), genotype (HbSS or non‐HbSS), and concomitant HU use (yes or no). It is notable that crizanlizumab increased the likelihood of being VOC event‐free and delayed time‐to‐first and time‐to‐second VOC compared with placebo in patients who had experienced 2‐10 VOCs in the year prior to study entry despite receiving concomitant HU. The rates of treatment‐related (according to investigator judgment) AEs and SAEs were higher in patients treated with crizanlizumab than with placebo, across all subgroups, although the incidence of AEs leading to discontinuation was generally low in both dose groups (0%‐8.0% in the crizanlizumab arm vs 0%‐8.7% in the placebo arm across all subgroups). n = 11bb Number of patients included in the subgroup who experienced any VOC during the SUSTAIN study. Primary Purpose: Treatment. Findings for time‐to‐second VOC were similar to those observed for time‐to‐first VOC. Platelets contribute to SCD pathology through multiple mechanism including formation of intravascular aggregates, release of pro-inflammatory cytokines and activation of coagulation. For all other types of VOC, including ACS, the incidence of events was too low to provide any meaningful subgroup analysis. Thus, HU primarily targets RBCs, whereas crizanlizumab is targeting the vasculature. Over the course of the study, a greater proportion of patients in the crizanlizumab group (n = 24/67; 35.8%) did not experience a VOC, compared with patients in the placebo group (n = 11/65; 16.9%). All efficacy analyses were conducted using the intention‐to‐treat (ITT) population, which included all patients randomized to crizanlizumab 5 mg/kg or placebo. Results: 198 SCD patients were randomized for the 1-year study. SUSTAIN clinical trial data. Kanter:Novartis: Consultancy. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com. In conclusion, this post hoc descriptive analysis of the phase 2 SUSTAIN study demonstrated that crizanlizumab increases the likelihood of being VOC event‐free and delays time‐to‐first VOC across all subgroups assessed. A phase 3 trial showed modest efficacy during acute VOC and a second phase 3 trial is currently ongoing. VOC event‐free patients were defined as those with zero annualized days with a VOC, regardless of whether patients completed the full duration of the study. The randomization was stratified by historical SCPC in the prior year (2-4 or 5-10) and concomitant HU use (yes or no). Patients were excluded if they were undergoing long‐term, RBC transfusion therapy. Uncomplicated VOCs were defined as crises other than ACS, hepatic or splenic sequestration, or priapism. The procedures for the SUSTAIN study have been described in detail.17 In brief, patients received placebo or crizanlizumab at a dose of 2.5 or 5 mg/kg, administered intravenously 14 times over 52 weeks (2 loading doses in the first month followed by monthly infusions thereafter). Rother:Selexys Pharmaceuticals: Equity Ownership, Other: Previous Employment. ACS events were rare in this study. … In the Phase II SUSTAIN study, crizanlizumab 5.0 mg/kg significantly reduced the median annual rate of VOCs compared with placebo (P=0.010). The HU use subgroups were also further categorized by prior VOC events (2‐4 or 5‐10). Primary results were published in The New … In the double‐blind, placebo‐controlled phase 2 SUSTAIN study, crizanlizumab (humanized, anti‐P‐selectin monoclonal antibody) 5 mg/kg significantly lowered the rate of VOC in patients with SCD by 45% vs placebo. The full text of this article hosted at iucr.org is unavailable due to technical difficulties. There were no apparent increases in infections with SelG1 treatment. This post hoc analysis of SUSTAIN shows that in patients with a high number of prior VOCs, on concomitant hydroxyurea and/or with the HbSS genotype, crizanlizumab treatment increases the likelihood of patients being VOC event‐free and delays time‐to‐first VOC. A hierarchical testing procedure was employed (α = 0.05 for high dose vs. placebo, and if significant, low dose vs. placebo). Data obtained so far with a short-term follow-up has been very encouraging. Blood 2016; 128 (22): 1. doi: https://doi.org/10.1182/blood.V128.22.1.1. Kutlar:Novartis Pharmaceuticals: Research Funding. Results showed that even among those who had experienced 5‐10 VOC events in the year prior to study entry, those using concomitant HU, and those with the more clinically severe HbSS genotype, crizanlizumab treatment increased the likelihood of being VOC event‐free compared with placebo. The SUSTAIN study evaluated the safety of SelG1, a first-in-class humanized anti-P-selectin antibody, and its effect on the frequency of SCPC in SCD patients. Sickle cell disease (SCD) is a genetic disorder that predominantly affects individuals of African descent.1 It is characterized by the presence of sickle hemoglobin (HbS), which polymerizes upon deoxygenation, damaging erythrocytes and potentially leading to vaso‐occlusion, multi‐organ damage, and early death.2 Painful vaso‐occlusive crises (VOCs), also known as sickle cell pain crises, are the hallmark of SCD and are the primary cause of hospitalization in SCD.3 VOCs cause pain in the extremities, back, abdomen or chest, and can vary in intensity from mild to excruciating.4 Patients with SCD and frequent VOCs may experience problems with low self‐esteem, anxiety, depression, dissatisfaction with body image, poor school performance, social isolation, decreased participation in normal daily activities, and poor peer and family relationships.4, The most common SCD genotype is homozygous hemoglobin S (HbSS) which, along with sickle β0‐thalassemia (HbSβ0), is generally considered to be the most clinically severe. One priapism event was reported in the placebo arm and none was reported in the crizanlizumab 5 mg/kg arm. Giovanna Russo (GR): Department of Clinical and Experimental Medicine, University of Catania, Catania. Patients with SCD engrafted, had sustained production of the transgene and a decreased number of vaso-occlusive crises. HU is approved for patients who have had 3 or more VOCs in the previous year,18 and this post hoc analysis suggests that crizanlizumab can provide additional benefit compared with HU alone in patients who continue to experience VOCs despite HU treatment. AK has received research funding from Novartis Pharmaceuticals Corporation and from Reprixys Pharmaceuticals Corporation (which was acquired by Novartis Pharmaceuticals Corporation on November 18, 2016), is a member of a data monitoring committee for BlueBird Bio, and Chair of a Data and Safety Monitoring Board for Sancilio & Co. JK has received research support from Reprixys Pharmaceuticals Corporation, has participated in advisory boards and other activities for Novartis Pharmaceuticals Corporation, has participated in advisory boards for BlueBird Bio and Prolong Pharmaceuticals, and has acted as a consultant for AstraZeneca. Despite the substantial burden of VOCs, there are currently few available treatment options and all have important limitations. Patients were randomized to receive placebo, 2.5 mg/kg or 5.0 mg/kg SelG1; patients received their initial dose, a dose 14 days later, and then every 4 weeks through week 50 for a total of 14 doses. This study was sponsored by Novartis Pharmaceuticals. Learn more. SUCCESSOR is a retrospective cohort study of adult patients (≥18 years old) who participated in the SUSTAIN study in the United States to evaluate outcomes related to SCD up to 52 weeks following their completion of the trial. This post hoc analysis evaluated the effect of crizanlizumab 5 mg/kg vs placebo on selected secondary efficacy endpoints and safety assessments. The study will enroll up to 45 patients and follow patients for approximately two years after infusion. Although hydroxyurea (HU) is known to decrease the frequency of SCPC in sickle cell anemia, many patients continue to experience acute painful episodes despite such therapy. The efficacy and safety of crizanlizumab was studied in a 52-week, randomized, multicenter, placebo-controlled, double-blind, Phase II, clinical trial SUSTAIN (NCT01895361). Gene therapies are being developed, and several are now in various stages of early-phase human clinical trials. VOCs were defined as acute episodes of pain that were caused by a vaso‐occlusive event that resulted in a visit to a medical facility and treatment with oral or parenteral opioids or parenteral nonsteroidal anti‐inflammatory drugs. A subgroup analysis of the primary endpoint (annual rate of VOCs) highlighted that a lower frequency of crises was observed with crizanlizumab 5 mg/kg vs placebo regardless of the number of prior VOC events, concomitant hydroxyurea (HU) use or SCD genotype.17 We therefore conducted a post hoc analysis to further evaluate different endpoints in these same subgroups, including the proportion of patients who did not experience a VOC during the study, additional secondary efficacy endpoints and the safety of crizanlizumab 5 mg/kg compared with placebo. The annual rate of days hospitalized at 5.0 mg/kg vs. placebo showed a non-significant, 42% reduction (medians of 4.0 vs. 6.9, p = 0.450). All data are number of event‐free patients/number of patients in subgroup (%). As such, when we refer to the crizanlizumab group in this analysis we are referring to the 5 mg/kg dose. Both the U.S. approval and the new CHMP opinion were based on the results of the SUSTAIN Phase 2 clinical trial (NCT01895361). The primary endpoint, the annual rate of SCPC in the ITT population at 5.0 mg/kg vs. placebo, was reduced 47% (medians of 1.6 vs. 3.0, p = 0.010, Table 1). The drug was approved in the USA26 based on results from a phase 3 study that have recently been published.27 At the time of writing, no additional real‐world experiences are available for this new treatment option. This post hoc descriptive analysis evaluated the proportion of patients who did not experience a VOC during the study in the following subgroups: VOCs in the year prior to study entry (2‐4/5‐10), SCD genotype (HbSS/non‐HbSS), and concomitant hydroxyurea use (yes/no). Rollins:Selexys Pharmaceuticals: Equity Ownership, Other: Previous Employment. This article reviews the evidence pertaining to crizanlizumab in SCD by searching records in Medline, Embase, and International Pharmaceutical Abstracts. Within each subgroup, patients were evenly distributed between the crizanlizumab and placebo arms (see Supporting Information Table S1, for an expanded list of patient characteristics). Working off-campus? Treatment with crizanlizumab 5 mg/kg resulted in a significant decrease in the number of VOCs per year compared with placebo and also resulted in several patients remaining VOC event free during the study; these lower rates of crises were observed regardless of concomitant HU use or SCD genotype, as previously reported.17 This analysis further evaluated the effect of crizanlizumab vs placebo based on different endpoints according to concomitant HU use, SCD genotype, and the number of VOCs in the previous year. The observed reductions in VOCs suggest that P‐selectin inhibition can provide an additional treatment effect and, therefore, meets an existing unmet need based on the currently available treatment options. The funder developed the statistical analysis plan, analyzed and had a role in interpreting the data, provided financial support for medical editorial assistance, and had a role in writing the report. These findings provide supportive evidence that crizanlizumab provides a clinically meaningful treatment benefit when used alone or in combination with HU for the prevention of VOCs. It is a key molecule in the initiation of leukocyte rolling on the vessel wall that leads to firm attachment and extravasation to underlying tissues during inflammation. DKL, RDC, JRF and JMK‐M declared no conflicts of interest.