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A randomized, placebo-controlled, double-blind trial of canakinumab in children and young adults with sickle cell anemia

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David C. Rees, Yurdanur Kilinc, Selma Unal, Carlton Dampier, Betty S. Pace, Banu Kaya, Sara Trompeter, Isaac Odame, Johnny Mahlangu, Sule Unal, Julie Brent, Regine Grosse, Beng R. Fuh, Baba P.D. Inusa, Ariel Koren, Goksel Leblebisatan, Carina Levin, Elizabeth McNamara, Karin Meiser, Douglas Hom & 1 more Stephen J. Oliver

Original languageEnglish
Pages (from-to)2642-2652
Number of pages11
JournalBlood
Volume139
Issue number17
DOIs
Published28 Apr 2022

Bibliographical note

Funding Information: Conflict-of-interest disclosure: D.C.R. is an investigator and steering committee member of the Novartis Solace Kids study for crizanlizumab. J.M. has received research grants from Novo Nordisk and Roche. B.P.D.I. has received educational grants from Novartis, AstraZeneca, Global Therapeutics, and Pfizer and honoraria from Cyclerion, AstraZeneca, and Novartis. A.K. acts as a medical advisor and lecturer for Novartis, Apopharma, and Bristol-Myers-Squibb and has received Novartis financial compensation for clinical studies. E.M., K.M., D.H., and S.J.O. are full-time employees of Novartis Pharma AG. S.J.O. has equity ownership in Novartis Pharma AG. The remaining authors declare no competing financial interests. Publisher Copyright: © 2022 American Society of Hematology

King's Authors

Abstract

Excessive intravascular release of lysed cellular contents from damaged red blood cells (RBCs) in patients with sickle cell anemia (SCA) can activate the inflammasome, a multiprotein oligomer promoting maturation and secretion of proinflammatory cytokines, including interleukin-1β (IL-1β). We hypothesized that IL-1β blockade by canakinumab in patients with SCA would reduce markers of inflammation and clinical disease activity. In this randomized, double-blind, multicenter phase 2a study, patients aged 8 to 20 years with SCA (HbSS or HbSβ0-thalassemia), history of acute pain episodes, and elevated high-sensitivity C-reactive protein >1.0 mg/L at screening were randomized 1:1 to received 6 monthly treatments with 300 mg subcutaneous canakinumab or placebo. Measured outcomes at baseline and weeks 4, 8, 12, 16, 20, and 24 included electronic patient-reported outcomes, hospitalization rate, and adverse events (AEs) and serious AEs (SAEs). All but 1 of the 49 enrolled patients were receiving stable background hydroxyurea therapy. Although the primary objective (prespecified reduction of pain) was not met, compared with patients in the placebo arm, patients treated with canakinumab had reductions in markers of inflammation, occurrence of SCA-related AEs and SAEs, and number and duration of hospitalizations as well as trends for improvement in pain intensity, fatigue, and absences from school or work. Post hoc analysis revealed treatment effects on weight, restricted to pediatric patients. Canakinumab was well tolerated with no treatment-related SAEs and no new safety signal. These findings demonstrate that the inflammation associated with SCA can be reduced by selective IL-1β blockade by canakinumab with potential for therapeutic benefits. This trial was registered at www.clinicaltrials.gov as #NCT02961218.

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