Translational importance of IL-31 and clinical trials
The TH2 cytokines IL-4 and IL-13 have recently been identified as central mediators of AD, leading to the development of antibodies targeting IL-4 or IL13, or both, for AD treatment.34,66 In particular, the success of dupilumab, a fully human IgG4κ monoclonal antibody binding to the α- subunit of the interleukin-4 receptor (IL4Rα), validated an essential role of the TH2 (type-2) inflammatory axis in AD. Dupilumab treatment achieved a rapid and robust improvement of skin lesions and pruritus and has been designated as a breakthrough therapy for AD by the US Food and Drug Administration (FDA).67
Considering the multifaceted role of IL-31 in TH2-driven AD, efforts have been intensified to develop agents that efficiently block also the IL-31/IL31RA axis. Early IL-31/IL31RA inhibition approaches in NC/Nga-inbred mice resulted in the first observation of reduced scratching.68 Several follow up studies demonstrated that blocking of IL31RA by a neutralizing antibody effectively prevented itch in AD mouse models and AD patients.69–74 IL-31-dependent pruritic activity has been described in mice, canines, primates and humans despite the low inter-species homology of the cytokine.75–77
Michels et al., demonstrated that subcutaneous administration of lokivetmab, a caninized anti-canine monoclonal anti-IL-31 antibody, alleviates itch symptoms in dogs with AD.77,78 The decrease of itch was stable for over a month and associated with decreased IL-31 serum levels.78 Similar results have been obtained in cynomolgus monkeys, where an AD-like phenotype was caused by administration of human and cynomolgus IL-31.75,79 Moreover, blockage of IL-31 signaling using an anti-IL31RA antibody resulted in significant itch reduction.27714851
In humans, the first data of a clinical phase I/Ib trial assessing the efficacy of a humanized anti-IL31RA monoclonal antibody (CIM331, nemolizumab) revealed a marked dose-dependent reduction of pruritus after a single subcutaneous dose (Table 1).72Nemolizumab inhibited IL-31-mediated cell signaling efficaciously and safely, reduced pruritus to about 50% at week 4, improved sleep efficiency and decreased use of topical hydrocortisone.72 A follow-up trial concluded the safe use of nemolizumab with no significant adverse event in combination with corticosteroid therapy.73 In this phase-II clinical trial, nemolizumab (0.1, 0.5, 2 mg/kg) reduced itch by 43.7%, 59.8%, 63.1%, respectively, compared to 20.9% itch reduction with placebo (P<0.01). Changes in the Eczema Area Severity Index (EASI) score were -23.0%, -42.3%, and -40.9% in the nemolizumab groups versus -26.6% in the placebo group. The affected body surface area (BSA) was reduced by 7.5%, 20.0%, and 19.4% in the nemolizumab groups vs. 15.7% in the placebo group. Thus, nemolizumab every 4 weeks significantly improved pruritus in moderate-to-severe AD, was safe and well tolerated. In contrast, the secondary endpoints (EASI, BSA) were not significantly different in treatment and placebo group at 12 weeks with chosen dosages.80 A phase-IIb clinical trial investigated the effects of nemolizumab (10, 30, and 90 mg) administered every 4 weeks over 24 weeks in adults with uncontrolled moderate-to-severe AD associated with severe pruritus.80 Concomitant topical corticosteroid treatment was allowed. Here, 30 mg nemolizumab was the most efficacious, markedly improving EASI, Investigator’s Global Assessment (IGA), and Peak Pruritus Numerical Rating Scale (ppNRS) vs. placebo group already at week 8, but not week 24, with an overall acceptable safety profile. A phase-III follow-up extension study investigated Japanese adult patients with moderate-to-severe AD and pruritus treated with nemolizumab (60 mg, every 4 weeks) versus placebo over 16 weeks.74 Here, nemolizumab reduced the median VAS score by 42.8% vs. placebo (21.4%, P<0.001). Mean EASI score, Dermatology Life Quality Index (DLQI) score also improved in nemolizumab group compared to the placebo group. Injection site reaction was the most frequent adverse event. Finally, a recent phase-II, long-term extension study was published in moderate-to-severe atopic dermatitis.71 Improvement of itch was observed at week 64 with 0.5-mg/kg nemolizumab. No long-term safety concerns were identified. Since AD is a clinically heterogeneous disease it will be important to better understand the subtypes of AD which will profit the most from the current and future therapies targeting IL-4, -13 and -31.