Canakinumab in children and young adults with sickle cell anaemia

May 2022 Science Jolien Blokken

A recent phase IIa study assessed the safety and efficacy of the interleukin 1-β neutralising antibody canakinumab in children and young adults with sickle cell anaemia (SCA), chronic pain, and inflammation. Although participants receiving the study drug did not experience a significant reduction in average daily pain, a promising reduction of multiple biomarkers of inflammation, number and duration of hospitalisations, and other patient-reported outcomes of pain and fatigue was reported.

KEY MESSAGES FOR CLINICAL PRACTICE

  1. Canakinumab treatment of sickle cell anaemia did not meet its primary endpoint of a clinically relevant reduction in average daily pain.
  2. Canakinumab in combination with hydroxyurea was well tolerated and reduced systemic inflammation with potential for clinical benefits.

Excessive intravascular release of lysed cellular contents from damaged red blood cells (RBCs) in patients with sickle cell anaemia (SCA) can activate the inflammasome, a multiprotein oligomer promoting maturation and secretion of proinflammatory cytokines, including interleukin-1β (IL-1β). It was hypothesised that IL-1β blockade by canakinumab in patients with SCA would reduce markers of inflammation and clinical disease activity.

In this randomised, double-blind, multicentre phase IIa 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 randomised (1:1) to receive six 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, hospitalisation rate, adverse events (AEs) and serious AEs (SAEs). All but one 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 adverse events and SAEs, and number and duration of hospitalisations 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 paediatric patients. Canakinumab was well tolerated with no treatment-related SAEs and no new safety signals. These findings demonstrate that the inflammation associated with SCA can be reduced by selective IL-1β blockade by canakinumab with potential for therapeutic benefits.

DISCUSSION BY PROF. DR. JAN PHILIPPÉ (GHENT UNIVERSITY)

This article is part of the Editor’s Pick of Prof. Dr. Jan Philippé. In the Editor’s Pick, we provide a snapshot of pivotal studies published in recent issues of the most important international journals focusing on haematology. The selection of the study discussed here was made by Prof. Dr. Jan Philippé (Senior full professor, University Hospital Ghent/ University Ghent). In addition to the key highlights of the article, an expert opinion by Prof. Philippé is included.

The past five years have witnessed a proliferation of new treatment approaches for SCA. Seminal studies in humanised transgenic sickle cell mice have dissected a plethora of pathways that link the polymerisation of mutated sickle haemoglobin (HbS), the condicio sine qua non for the emergence of the SCA phenotype, to a wide spectrum of vasculotoxic effects and end organ damage. Each of the pathogenic mechanisms of SCA, including endothelial dysfunction, cellular hyperadhesion, ischemia-reperfusion injury, oxidative stress, and sterile inflammation, are now becoming prime targets for new classes of biological agents. Two recently approved drugs, L-glutamine and the anti-P-selectin monoclonal antibody crizanlizumab, target oxidative stress and hyperadhesion, respectively, and lead to a reduction in the rate of vaso-occlusive pain episodes (VOEs).

With canakinumab, Rees et al. have now opened a new front in the fight against SCA by targeting sterile inflammation. Sterile inflammation is indeed rising to prominence as a druggable pathogenic mechanism in multiple fields, in particular in cardiovascular diseases, in which the deleterious effects of a pro-inflammatory milieu compound those of haemostatic activation and hyperlipidaemia. Anti-inflammatory biologicals, whose therapeutic indications were initially confined to rare inflammatory conditions, are being piloted as agents to combat disparate conditions ranging from diabetes to coronary artery disease. In addition to the novelty of testing an anti-inflammatory drug in SCA, the study by Rees et al. also stands out for the authors’ choice of a somewhat questionable yet intriguing outcome measure. Assessing the impact of new drugs on the incidence of VOEs—typically defined as acute SCA-related pain that leads to a health care encounter—has become a standard approach in clinical research over the past decades, but the incorporation of patient-reported outcomes into the design of clinical trials has lagged. Yet pain is a quintessentially subjective outcome measure, and its inherent complexity bears a nuanced investigative approach, particularly in children, whose report of daily pain may never reach the ears of their health care providers. Thus, although it was unusual, the choice of average daily pain measured by an electronic patient-reported outcome device (eDiary) as the primary outcome measure was wise.

The study may spur research on the nebulous link between inflammation and pain in SCA. Chronic pain, in particular, is a recalcitrant symptom and a frustrating complication for individuals who have SCA to live with and for health care providers to treat, particularly because its underlying pathology is often elusive. This knowledge gap is not merely an academic concern, and it explains why we have no effective drugs to control chronic pain in SCA, and indeed in most other diseases. The results of this study, even though they are preliminary, highlight the possible role of sterile inflammation in chronic pain, and offer new potential areas of investigation. With sickling of red blood cells being an incessant process in the microcirculation, we can posit that background ischemia-reperfusion events and their downstream inflammatory cascades may incite a low level of daily pain. Alternatively, we may invoke neuroinflammation as a primary effector of pain in SCA, in which overproduction of inflammatory cytokines such as IL-1β, tumour necrosis factor, and interferon-γ lead to recruitment of immune cells, tissue damage, and both central and peripheral sensitisation, with the attendant activation of nociceptive receptors and hyperalgesia. This latter hypothesis opens many research avenues with the prospect of modulating both central and peripheral neuroinflammation to alleviate pain.

References

Rees DC, Kilinc Y, Unal S, et al. A randomized, placebo-controlled, double-blind trial of canakinumab in children and young adults with sickle cell anemia. Blood. 2022;139(17):2642-52.

Novelli E. Extinguishing the fire in sickle cell anemia. Blood. 2022;139(17):2578-80.

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