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.