denotes an abstract that is clinically relevant.
denotes that this is a recommended PHD Trainee Session.
denotes that this is a ticketed session.Session: 114. Sickle cell Disease, Sickle Cell Trait and Other Hemoglobinopathies, Excluding Thalassemias: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
clinical trials, Research, Clinical Research, Adverse Events
Methods: Safety was assessed based on two clinical program data pools. Pool 1 comprised data from the crizanlizumab-treated groups from 3 Phase 2 studies (SUSTAIN [NCT01895361], SOLACE-adults [NCT03264989], and the pediatric SOLACE-Kids [NCT03474965]) and 1 Phase 3 study (STAND [NCT03814746]) in patients with SCD, with a history of VOCs leading to a healthcare visit. Pool 2 included data from the SUSTAIN and STAND treatment groups and the corresponding placebo group. Adverse events (AEs) were summarized by preferred term /system organ class and seriousness/severity per MedDRA version 23.1, with severity assessed based on CTCAE v5. Based on both its mechanism of action and the fact that crizanlizumab is a mAb, AEs of special interest (AESIs) included infections, infusion-related reactions (IRRs, events typically occurring within 24 hours of the recent crizanlizumab infusion), effects on hemostasis, and immunogenicity (antidrug antibodies [ADAs]). Pooled incidences of treatment-related AEs (TRAEs), suspected to be related to study treatment, were also evaluated.
Results: In Pool 1, 245 patients received crizanlizumab 5.0 mg/kg (median age: 24 years [range,12-65]; 54.3% female), with 66.1% having 1 to 4 VOCs and 33.1% having ≥5 VOCs (VOC data were missing for 0.8% patients) at baseline. Pool 2 had 150 patients in the 5.0 mg/kg treatment group (median age: 27 years [range, 12-64]) and 147 patients in the placebo group (median age: 26 years [range, 12-68]). Median crizanlizumab exposure was 87.4 weeks (range, 2-228) in Pool 1, 54.1 weeks (range, 51.9-93.9) in Pool 2 treatment group and 53.3 weeks (range: 50.3-86.0) in the Pool 2 placebo group. The use of crizanlizumab in combination with hydroxyurea/hydroxycarbamide did not result in meaningful differences in safety profile.
Most frequently reported AE in Pool 1 were headache (25.7%), pyrexia (22.9%), arthralgia (18.4%), nausea (16.7%), and COVID-19 (15.9%). In Pool 2 (treatment group vs. placebo), the most common AEs were headache (21.3% vs. 17.7%), pyrexia (19.3% vs. 17.7%), and nausea (17.3% vs. 10.2%).
Infection events were observed in 62.4% and 56.7% of patients in the Pool 1 and 2 treatment groups, respectively, and in 55.1% in the placebo group (Table 1). The most common infections in Pool 1 were COVID-19 (15.9%), upper respiratory tract infections (12.7%), and urinary tract infections (11.8%). No increased risk or severity of infection was found in patients treated with crizanlizumab.
IRRs occurred in 38.8% of Pool 1, 36.7% of the Pool 2 treatment group, and 27.9% of the placebo group. Most common IRRs were headache and nausea (Table 1). IRRs with grade ≥3 occurred in 3.3% of patients in Pool 1, with no grade 4 or 5 events. Bleeding-related events were observed in 16.7% of Pool 1 patients; epistaxis (3.7%) was the most reported. Treatment-induced ADA were reported in 0.8% (n=2) of patients in Pool 1, confirming the low immunogenic potential of crizanlizumab.
TRAEs were observed in 31.8% patients in Pool 1, 34.7% in the Pool 2 treatment group, and 24.5% in the placebo group. Among the patients in Pool 1, 10 (4.1%) experienced grade 3 or higher TRAEs. The most reported TRAEs are listed in Table 1. Treatment-related serious AEs occurred in 10 patients (4.1%), with 7 (2.9%) experiencing ≥ grade 3 AEs in Pool 1.
Treatment discontinuation due to AEs occurred in 3.3% of patients in Pool 1, 2.7% in the Pool 2 treatment group, and 3.4% in the placebo group. Five on-treatment deaths were reported across the four studies and were considered not related to crizanlizumab by the investigator (myocardial infarction, multiple organ dysfunction, endocarditis, meningitis bacterial, and sepsis [1 patient each]).
Conclusion: This pooled analysis of crizanlizumab 5.0 mg/kg in patients with SCD and a history of VOCs showed that crizanlizumab was well tolerated, with a favorable safety profile. Most AEs were mild to moderate, and the discontinuations due to AEs were infrequent. No new safety concerns were identified.
Disclosures: Kutlar: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT/Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma/Novo-Nordisk: Research Funding; Akira Bio: Membership on an entity's Board of Directors or advisory committees, Research Funding. Joshi: Novartis Healthcare Private Limited: Current Employment. Brueckner: Novartis Pharma AG: Current Employment. Kanter: Bausch: Consultancy; Chiesi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Watkins, Lourie, Roll & Chance: Consultancy; Vertex: Consultancy; Guidepoint Global: Honoraria; ECOR-1: Consultancy; Fulcurm: Consultancy; Glycomimetics: Membership on an entity's Board of Directors or advisory committees; Austin Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; BEAM: Consultancy, Research Funding; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; HRSA: Research Funding; NHLBI: Research Funding; CDC: Research Funding; National Alliance of Sickle Cell Centers: Other: President. Liles: Annexon Biosciences: Other: Clinical trial activity (Principal investigator or sub-investigator); Alpine Immune Sciences: Other: Clinical trial activity (Principal investigator or sub-investigator); Abbvie: Other: Clinical trial activity (Principal investigator or sub-investigator); Astex Pharmaceuticals: Other: Clinical trial activity (Principal investigator or sub-investigator); Baxalta: Other: Clinical trial activity (Principal investigator or sub-investigator); BeiGene: Other: Clinical trial activity (Principal investigator or sub-investigator); Bioverativ: Other: Clinical trial activity (Principal investigator or sub-investigator); CSL Behring: Other: Clinical trial activity (Principal investigator or sub-investigator); Celgene: Other: Clinical trial activity (Principal investigator or sub-investigator); Delta-Fly Pharma: Other: Clinical trial activity (Principal investigator or sub-investigator); Exact Sciences: Other: Clinical trial activity (Principal investigator or sub-investigator); Forma Therapeutics: Other: Clinical trial activity (Principal investigator or sub-investigator); Global Blood Therapeutics: Other: Clinical trial activity (Principal investigator or sub-investigator); Immunovant: Other: Clinical trial activity (Principal investigator or sub-investigator); Incyte: Other: Clinical trial activity (Principal investigator or sub-investigator); Janssen Pharmaceuticals: Other: Clinical trial activity (Principal investigator or sub-investigator); NeoImmuneTech: Other: Clinical trial activity (Principal investigator or sub-investigator); Novartis: Other: Clinical trial activity (Principal investigator or sub-investigator); Novo Nordisk: Other: Clinical trial activity (Principal investigator or sub-investigator); Partner Therapeutics: Other: Clinical trial activity (Principal investigator or sub-investigator); Pharm-Olam: Other: Clinical trial activity (Principal investigator or sub-investigator); Principia Biopharma: Other: Clinical trial activity (Principal investigator or sub-investigator); Salix Pharmaceuticals: Other: Clinical trial activity (Principal investigator or sub-investigator); Sanofi-Aventis: Other: Clinical trial activity (Principal investigator or sub-investigator); Takeda: Other: Clinical trial activity (Principal investigator or sub-investigator); Vifor Pharma: Other: Clinical trial activity (Principal investigator or sub-investigator). Lincy: Novartis Pharma AG: Current Employment. Manjare: Novartis Healthcare Private Limited: Current Employment. Heeney: Agios: Other: podcast speaker; Novartis: Research Funding; Novartis, FORMA Therapeutics, Global Blood Therapeutics, Oric Pharma and Bluebird Bio and Pharmacosmos, Weatherden, Blueprint Medicines, Alexion, Bluebird Bio and Pharmacosmos: Consultancy; Vertex/CRISPR: Other: Membership of a data and safety monitoring board. de Montalembert: Novartis: Membership on an entity's Board of Directors or advisory committees; Addmedica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: ASH meeting 2022 support. Keefe: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA: Current Employment, Other: Eligible to receive stocks. Marfo: Novartis Pharma AG, Basel, Switzerland: Current Employment. Ataga: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vertex: Other: Data Monitoring Committee; Sanofi: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Consultancy, Honoraria; Agios Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; FDA: Research Funding; NHLBI: Research Funding; Fulcrum Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Research Funding; Hillhurst Biopharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
OffLabel Disclosure: This is an abstract based on the pooled safety analysis including data from 3 Phase 2 studies (SUSTAIN [NCT01895361], SOLACE-adults [NCT03264989], and the pediatric SOLACE-Kids [NCT03474965]) and 1 Phase 3 study (STAND [NCT03814746]). Crizanlizumab is approved to reduce the frequency of or prevent recurrent vaso-occlusive crises in patients aged 16 years and older, with sickle cell disease. STAND and SOLACE-Kids studies include data from patients aged 12 years and older patients with SCD. So, this abstract includes information or discussion of off-label use of crizanlizumab.