Rees, David C, Kilinc, Yurdanur, Unal , Selma, Dampier, Carlton, Pace, Betty S, Kaya, Banu, Trompeter, Sara, Odame , Isaac, Mahlangu, Johnny, Unal, Sule, Brent, Julie, Grosse, Regine, Fuh, Beng R, Inusa, Baba PD, Koren, Ariel, Levin, Carina, McNamara, Elizabeth, Meiser, Karin, Hom, Douglas and Oliver, Stephen (2022) Inhibiting IL-1beta-mediated inflammation in pediatric and young adult patients with sickle cell anemia: a randomized, placebo-controlled, double-blind trial with canakinumab (ACZ885). Blood.

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 pro-inflammatory cytokines, including interleukin 1-beta (IL-1). We hypothesized that IL-1 blockade by canakinumab in patients with SCA would reduce markers of inflammation and clinical disease activity. In this randomized, double-blind, multi-center phase 2a study, patients aged 8-20 years old with SCA (HbSS or HbS0thalassemia), history of acute pain episodes and elevated hsCRP >1.0 mg/L at screening were randomized 1:1 to received 6 monthly treatments with 300 mg s.c. 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 one of the 49 enrolled patients received background hydroxyurea therapy. Although the primary objective (pre-specified reduction of pain) was not met, compared to placebo-arm patients, canakinumab-treated patients had reductions in markers of inflammation, incidence of SCA-related AE and SAE, 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 gain in, restricted to pediatric patients. Canakinumab was well tolerated with no treatment-related SAEs and no new safety finding. These findings demonstrate that the inflammation associated with SCA can be reduced by selective IL-1b blockade by canakinumab with potential for therapeutic benefits. This trial was registered at www.clinicaltrials.gov as NCT02961218.

Item Type:	Article
Keywords:	Sickle cell anemia, inflammasome, clinical trial, canakinumab
Date Deposited:	05 Jul 2022 00:45
Last Modified:	05 Jul 2022 00:45
URI:	https://oak.novartis.com/id/eprint/45503