Efficacy and safety of vixarelimab, a human monoclonal oncostatin M receptor β antibody, in moderate-to-severe prurigo nodularis: a randomised, double-blind, placebo-controlled, phase 2a study

Abstract

Background: Prurigo nodularis is a chronic skin disease characterised by intensely pruritic, hyperkeratotic nodules. Vixarelimab, a human monoclonal antibody, binds to the beta subunit of the oncostatin M receptor, inhibiting signalling of both interleukin 31 and oncostatin M, two cytokine pathways that contribute to pruritus and nodule formation in prurigo nodularis.

Methods: This double-blind, placebo-controlled, phase 2a trial was done at both private and academic dermatology outpatient research clinics across the United States and Canada (n = 40). Patient eligibility criteria included age 18-75 years, physician-documented diagnosis of prurigo nodularis minimum 6 months duration of prurigo nodularis, presence of at least 10 pruritic nodules approximately 0.5-2 cm in size on at least two different anatomical locations (excluding face and scalp) and involving the extremities, and presence of normal-appearing skin between nodules; atopic dermatitis as a comorbidity was exclusionary. Patients were required to have moderate-to-severe pruritus, defined as Worst Itch-Numeric Rating Scale (WI-NRS) score ≥7 at screening and LS-mean weekly WI-NRS score ≥5 for each of the 2 consecutive weeks immediately before randomisation. Participants were randomly assigned (1:1) to receive weekly subcutaneous vixarelimab 360 mg (720 mg loading dose) or placebo using stratification factors (sex and presence of atopy) and block size 4 through the IWRS system. Stratification by atopy status was based on the reported high prevalence of atopy in this population and the potential impact of atopy in the immunopathologic process in prurigo nodularis. Patients, investigators, study sponsor, and site staff were masked to study treatment. The primary efficacy endpoint was least squares (LS)-mean percent change from baseline (PCFB) at Week 8 in weekly average Worst Itch-Numeric Rating Scale (WI-NRS) score. The primary efficacy endpoint was analysed with ANCOVA including treatment as fixed effect, with baseline WI-NRS, and randomisation stratification factor as covariates. All randomised patients who had at least 1 dose of study drug or placebo were included in the Safety Analysis Set. This trial is registered at ClinicalTrials.gov, NCT03816891.

Findings: Of 50 patients randomised between March 11, 2019 and January 31, 2020, 23 vixarelimab recipients and 26 placebo recipients comprised the modified intent-to-treat analysis population (baseline LS-mean [SD] WI-NRS score, 8.3 [1.05]). Outcomes at Week 8 for vixarelimab versus placebo included LS-mean PCFB in WI-NRS score, -50.6% versus -29.4% (LS-mean difference [95% CI], -21.2% [-40.82, -1.60]; p = 0.03); ≥4-point reduction in WI-NRS score, 52.2% (12/23) versus 30.8% (8/26) (p = 0.11); PN-IGA score of 0 or 1, 30.4% (7/23) versus 7.7% (2/26) (p = 0.03); LS-mean PCFB in pruritus VAS score, -54.4% versus -32.6% (p = 0.03); and LS-mean PCFB sleep loss reduction (improvement), -56.3% versus -30.0% (p = 0.02). No deaths, serious TEAEs, or TEAEs leading to dose interruption were reported. The percentage of vixarelimab recipients reporting any TEAE was 91.3% (21/23) versus 76.9% (20/26) of placebo recipients; drug-related TEAEs generally were similar between the two groups (vixarelimab, 43.5% [10/23]; placebo, 38.5% [10/26]).

Interpretation: Vixarelimab demonstrated rapid reduction of pruritus and achievement of clear/almost clear skin in one-third of the patients by Week 8. Relief of itch and clearing of skin nodules represent two important potential therapeutic advances in the management of patients suffering from the debilitating disease Prurigo Nodularis.

Funding: Kiniksa Pharmaceuticals, Ltd.

Keywords: IL-31; Interleukin-31 receptor alpha; Nodular prurigo; Oncostatin M receptor beta; Prurigo nodularis; Pruritus; Vixarelimab.

Fig. 1

Trial profile. ∗One patient had an unclear cause of extremely high immunoglobulin E level, and two patients were outside of the visit windows. ^†One patient was inadvertently randomised but never dosed after the patient was confirmed to be ineligible for the study. mITT = modified intent-to-treat.

Fig. 2

Least squares mean (SE) percent change from baseline and median percent change from baseline in weekly average WI-NRS scores. ∗p < 0.05. ^†p < 0.20. LS = least squares. SE = standard error. WI-NRS = Worst Itch–Numeric Rating Scale.

Fig. 3

Percentages of patients in vixarelimab and placebo groups with clinically meaningful (≥4-point) reductions from baseline in weekly average WI-NRS scores over 8 weeks, by categorical reduction in WI-NRS. ∗p < 0.05. ^†p < 0.20. Vixarelimab vs placebo at time point for total number of patients with WI-NRS reductions ≥4 points. WI-NRS = Worst Itch–Numeric Rating Scale.

Fig. 4

Percentage of PN-IGA responders (score of 0 or 1) and patients with a reduction in PN-IGA score ≥2 points from baseline. ∗p < 0.05. PN-IGA = Prurigo Nodularis Investigator's Global Assessment.

Fig. 5

Representative images of nodule resolution from Day 1 to Week 8 in vixarelimab and placebo recipients. PN-IGA = Prurigo Nodularis Investigator's Global Assessment. WI-NRS = Worst Itch–Numeric Rating Scale.

Fig. 6

Least squares mean (SE) percent change from baseline in A) sleep loss VAS ratings, B) ItchyQoL total score, and C) DLQI total score. ∗p < 0.05. ^†p < 0.20. DLQI = Dermatology Life Quality Index. ItchyQoL = Itchy Quality of Life. LS = least squares. SE = standard error. VAS = visual analogue scale.