GENEVA (FRONTLINE MEDICAL NEWS) – Nemolizumab, a humanized monoclonal antibody that inhibits interleukin-31 signaling, maintained its early dramatic antipruritic effect in patients with moderate to severe atopic dermatitis (AD) throughout a year-long unblinded extension of a large, high-profile, 12-week, phase 2 randomized trial, Thomas Ruzicka, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

In contrast, the 52-week extension study also showed the improvement in the dermatitis aspect of AD as measured by Eczema Area and Severity Index (EASI) scores was more gradual and less robust.

“Double the number of patients using topical corticosteroids plus nemolizumab reached an EASI 75 response compared with nemolizumab alone. This suggests that concomitant use of nemolizumab and topical steroids may further improve the efficacy of nemolizumab,” said Dr. Ruzicka , professor and chairman of the department of dermatology and allergology at Ludwig Maximilian University in Munich.

The study, 64 weeks in total, also demonstrated that what really matters to patients with moderate or severe AD is relief from the itch. Scores on the Dermatology Life Quality Index showed marked improvement even if their improvement in EASI scores was suboptimal.

“The dermatitis scores improved. But the most concerning symptom to patients is the pruritus; that’s what worsens their quality of life. And this improves dramatically very early in the course of the study,” Dr. Ruzicka explained. “If they drop their itch they are very happy. They don’t care about the redness of the skin so much as the pruritus. This is what really bothers them, as has been shown in epidemiologic studies.”

The original 12-week, phase 2, randomized, double-blind, dose-ranging trial drew extensive attention because it demonstrated convincingly for the first time that the inflammatory cytokine interleukin-31 plays a key role in the pathobiology of AD by promoting skin barrier dysfunction, pruritus, and the inflammatory response in AD – and that a biologic agent, nemolizumab, could inhibit those disease mechanisms ( N Engl J Med. 2017 Mar 2;376[9]:826-35 ).

At a dose of 0.5 mg/kg administered by subcutaneous injection every 4 weeks, nemolizumab, a humanized monoclonal antibody directed against interleukin-31 receptor A, reduced scores on the pruritus visual-analogue scale by 60% as early as 4 weeks and maintained that effect through 12 weeks. At that point, the double-blind study ended and the 52-week extension began. Patients on nemolizumab in the double-blind phase stayed on the same dosage for the extension, while those who’d been on placebo were switched to nemolizumab at 0.1, 0.5, or 2.0 mg/kg every 4 weeks.

A total of 211 patients with moderate to severe AD inadequately controlled by topical therapies enrolled in the extension study. The combined 64-week experience convinced investigators and the sponsor, Chugai Pharmaceutical, that 0.5 mg/kg every 4 weeks is the optimal dose to take forward into planned advanced-stage clinical trials.

“At this dosage the IL-31 receptor is saturated, so higher dosages aren’t needed,” according to Dr. Ruzicka.

By week 64, patients in the 0.5-mg/kg arm of the study showed further gradual improvement in their pruritus visual-analogue score, from a 60% reduction from baseline at 12 weeks to close to an 80% reduction at week 64.

Roughly half of nemolizumab-treated patients achieved an EASI-50 response within the first 4 weeks of the double-blind phase of the study and stayed in that response zone throughout the extension study.

The EASI-75 and -90 responses followed a pattern different from EASI-50. Patients didn’t leap to those more robust levels of response early and then plateau. Instead, the EASI-75 and -90 responses were achieved via a gradual climb in efficacy throughout the study, such that by week 64 roughly 35%-40% of patients on the various nemolizumab dosages had reached EASI-75.

In the extension study, patients were permitted to use a mild topical steroid or topical calcineurin inhibitor as needed, and a potent or very potent topical steroid as rescue medication. Roughly half of participants resorted to any topical steroid at least once during the 64 months. An important new observation gleaned in the long-term study was that the patients who did use topical steroids were twice as likely to reach an EASI 75 response.

Roughly 20% of patients on the three highest dosages of nemolizumab achieved a static Investigator’s Global Assessment score of 0 or 1, meaning clear or almost clear, by week 64.

Scores on the Dermatology Life Quality Index fell steadily over the course of 64 weeks, from a baseline of about 16 to 5 at study’s close.

The side effect profile of nemolizumab was essentially the same as seen in the placebo arm during the double-blind phase. About one-quarter of patients experienced nasopharyngitis over the course of 64 weeks of treatment. A similar fraction reported exacerbations of their atopic dermatitis; however, these events were front-loaded in the first weeks of the initial double-blind study phase and appeared to have been triggered by the drug washout period prior to the patients’ receiving the first dose of nemolizumab, according to Dr. Ruzicka. No new safety signals emerged during the additional 52 weeks of treatment.

The study was funded by Chugai. Dr. Ruzicka reported serving as a paid company adviser.


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