436 Nemolizumab monotherapy was associated with significant improvements in prurigo activity score in adult patients with moderate-to-severe prurigo nodularis: results from a phase 3 trial (OLYMPIA 2)

Abstract Prurigo nodularis (PN) or chronic nodular prurigo is a debilitating, and severely pruritic neuroimmune skin disease, predominantly characterized by the presence of multiple pruriginous nodules symmetrically distributed in large areas of the trunk and extremities. Other pruriginous lesions such as papules, plaques and umbilicated lesions can also be present. Prurigo nodularis dramatically reduces quality of life among patients, including disruption of physical, emotional and psychosocial domains. Therapeutic goals are primarily to reduce pruritus and improve lesion healing. Interleukin-31 (IL-31) is a neuroimmune cytokine highly expressed in PN lesional skin that bridges the immune and nervous systems, functioning as a central mediator of main pathophysiological processes in PN. Prurigo nodularis has a unique immunophenotype, with recent studies revealing activation of Type-2-inflammation, and also induction of Th17 and Th22 pathways. Nemolizumab, an IL-31 receptor alpha antagonist, was shown to downregulate these pathways and was associated with significant improvements in pruritus and lesion healing in patients with PN in a phase-2-trial. Here, the authors report additional outcomes on excoriations and healing of pruriginous lesions from the OLYMPIA 2 phase-3-study after 16 weeks of treatment with nemolizumab. This study aims to assess the safety and efficacy of nemolizumab compared with placebo in ≥18-year-old patients with moderate-to-severe PN after a 16-week treatment period. OLYMPIA 2 (NCT04501679) was a phase 3, global, multicenter, double-blind study in adults with PN presenting ≥20 nodules, Investigator’s Global Assessment (IGA) score ≥3 (range 0–4) and Peak Pruritus Numerical Rating Scale (PP-NRS) score ≥7.0 (range: 0–10). Patients were randomized (2 : 1) to receive nemolizumab (n = 183) or matching placebo (n = 91). Following an initial 60 mg loading dose, patients weighing 75% healed lesions (PAS item 5b) (55.2% vs. 16.5%; P < 0.0001 at W16) and <20 pruriginous lesions (PAS item 2) (54.6% vs. 22.0%; P < 0.0001 at W16) at each visit, from baseline through W16. Treatment-emergent adverse events (AEs) were reported in 61.2% of nemolizumab-treated patients and 52.7% of placebo-treated patients, while serious AEs were reported in 2.2% of nemolizumab-treated patients and 5.5% of placebo-treated patients. Nemolizumab monotherapy (without TCS or TCI) demonstrated a significant reduction of pruritus as well as excoriations and number of pruriginous lesions after 16 weeks of treatment in patients with moderate-to-severe PN. The safety profile was consistent with that previously observed

Phase 3 Trial of Nemolizumab in Patients with Prurigo Nodularis.

BACKGROUND Prurigo nodularis is a chronic, debilitating, and severely pruritic neuroimmunologic skin disease. Nemolizumab, an interleukin-31 receptor alpha antagonist, down-regulates key pathways in the pathogenesis of prurigo nodularis. METHODS In this phase 3, double-blind, multicenter, randomized trial, we assigned adults with moderate-to-severe prurigo nodularis to receive an initial 60-mg dose of nemolizumab followed by subcutaneous injections of 30 mg or 60 mg (depending on baseline weight) every 4 weeks for 16 weeks or matching placebo. The primary end points were an itch response (a reduction of ≥4 points on the Peak Pruritus Numerical Rating Scale [PP-NRS; scores range from 0 to 10, with higher scores indicating more severe itch]) and an Investigator's Global Assessment (IGA) response (a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4] and a reduction from baseline to week 16 of ≥2 points). There were five key secondary end points. RESULTS A total of 274 patients underwent randomization; 183 were assigned to the nemolizumab group, and 91 to the placebo group. Treatment efficacy was shown with respect to both primary end points at week 16; a greater percentage of patients in the nemolizumab group than in the placebo group had an itch response (56.3% vs. 20.9%; strata-adjusted difference, 37.4 percentage points; 95% confidence interval [CI], 26.3 to 48.5), and a greater percentage in the nemolizumab group had an IGA response (37.7% vs. 11.0%; strata-adjusted difference, 28.5 percentage points; 95% CI, 18.8 to 38.2) (P<0.001 for both comparisons). Benefits were observed for the five key secondary end points: itch response at week 4 (41.0% vs. 7.7%), PP-NRS score of less than 2 at week 4 (19.7% vs. 2.2%) and week 16 (35.0% vs. 7.7%), and an improvement of 4 or more points on the sleep disturbance numerical rating scale (range, 0 [no sleep loss] to 10 [unable to sleep at all]) at week 4 (37.2% vs. 9.9%) and week 16 (51.9% vs. 20.9%) (P<0.001 for all comparisons). The most common individual adverse events were headache (6.6% vs. 4.4%) and atopic dermatitis (5.5% vs. 0%). CONCLUSIONS Nemolizumab monotherapy significantly reduced the signs and symptoms of prurigo nodularis. (Funded by Galderma; ClinicalTrials.gov number, NCT04501679; EudraCT number, 2019-004789-17.)

Risk of COVID-19 after natural infection or vaccinationResearch in context

Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health

Risk of COVID-19 after natural infection or vaccinationResearch in context

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health