Novel Agent Nemolizumab Reduced Pruritus, Improved Atopic Dermatitis
Blockade of interleukin (IL)-31RA with the novel monoclonal antibody nemolizumabin patients whose moderate-to-severe atopic dermatitis (AD) was not adequately controlled by topical therapy was associated with a reduction in pruritus and improvement in dermatitis scores in a randomized, double-blind, placebo-controlled, multicenter study. IL-31 is known to play a key role in the pathophysiology of AD, and its inhibition with nemolizumab (previously called CM1331) represents a novel approach in treatment of AD. In presenting the data at AAD 2016, Jon M. Hanifin, MD, Oregon Health and Science University, Portland, Oregon, USA, stated this is the first study to demonstrate that inhibiting pruritus led to an improvement in AD.
In the 12-week phase 2 study [NCT01986933], 264 patients were randomized 1:1:1:1 to placebo every 4 weeks (Q4W) or one of four regimens of subcutaneous nemolizumab (0.1, 0.5, or 2.0 mg/kg Q4W, or 2.0 mg/kg Q8W). A total of 216 (81.8%) of patients completed the study.
The study patients were 35 years old on average, about one-half were women, and they had AD that did not respond adequately to at least 4 consecutive weeks of topical corticosteroids or calcineurin inhibitors, or they had a history of intolerance or inability to take standard topical treatment. At baseline, the patient groups were well balanced, including the dermatitis scores, which were quite high for the pruritus visual and verbal scores (Table).
At 12 weeks, the primary endpoint of pruritus, as measured by the Visual Analogue Score (VAS), was reduced by 20.1% with placebo, 41.5% with the 0.1 mg/kg dose of nemolizumab (p=0.0027), 61.2% with the 0.5 mg/kg dose (p<0.0001), and 60.5% with the 2.0 mg/kg Q4W dose (p<0.0001). All data are mean scores for the per protocol population and exclude data after rescue therapy, which was not allowed until after Week 4.
Notably, the significant reductions in pruritus VAS scores with nemolizumab were seen at Week 1, and continued to fall progressively until Week 12, except for a slight uptick with the 0.1 mg/kg dose.
Nemolizumab was associated with a dose-dependent increase in the proportion of patients with a 50% improvement in pruritus (VAS50), reaching nearly 70% with the 2.0 mg/kg dose, 60% with the 0.5% mg/kg dose, and about 40% with the 0.1 mg/kg dose, compared with about 20% with placebo, at Week 12. Likewise, there was a dose-dependent improvement in the Verbal Rating Score, with nearly 70% of the 0.5 mg/kg dose group and 65% of the 2.0 mg/kg dose group reporting scores ≤1.
The secondary endpoint of change in the eczema area and severity index (EASI) score also showed significant improvement with nemolizumab, with the greatest reduction in the 0.5 mg/kg treatment group (by 44.6%, compared with 20.9% with placebo).This improvement was observed with each dosing regimen as early as Week 1. The same pattern was seen for the static Investigator’s Static Global Assessment (ISGA)≤1, with a 20.9% improvement with the 0.5 mg/kg compared with 4.7% with placebo, and responses in each group at Week 1.
Sleep latency and total sleep time were also improved with treatment, according to exploratory analyses. The baseline mean time to sleep onset of 31-42 minutes was reduced by one-half, and baseline total sleep time of 5.2-5.5 hours was improved by about 50-60 minutes with nemolizumab.
This novel drug was well tolerated, and the frequency of adverse events (AEs) were similar across the study groups. The proportion of patients who withdrew from treatment was 1.9% in the placebo group, and 9.4%, 5.6%, and 7.7% in the 0.1, 0.5, and 2.0 mg/kg Q4W, and 5.8% in 2.0 mg/kg Q8W. The most common AEs were exacerbations of AD and nasopharyngitis.
The higher frequency of AD flares may be related to rescue therapy not being allowed until after Week 4, stated Dr. Hanifin, and only if both the IGA and pruritus scores were not improved. In relation to safety, he noted that the risk of immune suppression seemed to be low, and that peripheral edema should be carefully monitored in future study of this drug.
The interruption of the itch-scratch cycle with nemolizumab appears to be the driver for the improvement in the EASI and ISGA dermatitis scores, and the improvement in sleep also demonstrated improvement in pruritus. The safety, tolerability, improvement in quality of life, and efficacy in improving AD, as early as one week, suggest that nemolizumab should be a new treatment option for patient with AD inadequately controlled by topical agents.