Imsidolimab, a novel IgG4 IL36 receptor antagonist, was effective and well tolerated in patients with GPP

Summary: Generalized pustular psoriasis is a rare, severe disease characterized by debilitating flares of non-infectious pustular and erythematous skin lesions, with systemic impacts that can be life threatening. The pathogenesis of GPP is attributed to excessive activity of interleukin 36 pathway, often caused by mutations in the <i>IL36RN</i> gene. Imsidolimab is a novel high affinity humanized immunoglobulin IgG4 mAb that antagonizes IL36 signaling. The efficacy of imsidolimab was investigated in GPP patients in 2 global Phase 3 studies, GEMINI-1 and GEMINI-2. In GEMINI-1, a randomized, double-blind, placebo (PBO) controlled, GPP patients received a single IV dose of 300mg or 750mg imsidolimab, or PBO. Primary efficacy at Wk 4 was achievement of GPPPGA score of clear/almost clear (0/1) across GPP disease attributes. GPPPGA responders, partial responders, or those needing rescue therapy could enroll in GEMINI-2. GPPPGA 0/1 was achieved in 53.3% of patients in the 300mg and 750mg groups, vs 13.3% of patients on PBO. Among PBO patients that received RT in GEMINI-2, 55.6% attained GPPPGA of 0/1 at Wk 4. No responders re-randomized to imsidolimab had a GPP flare through Wk 24, and all maintained GPPPGA score of 0/1, vs 62.5% flared and 75.0% lost GPPPGA 0/1 response in PBO. No PBO cross-over patients had a flare. There were no SAEs leading to discontinuation nor treatment-related SAEs. Both single IV and monthly SC imsidolimab demonstrated clinically meaningful results and prevented GPP flares. In GEMINI-1, the most common TEAE observed in 2 patients in the 750mg treatment group was headache. In GEMINI-1 a total of 1 case of ADA (1/30, 3.3%) was reported. In contrast, a total of 23 cases of ADAs (23/50, 46%) were reported among patients who had received at least 1 dose of spesolimab. Imsidolimab has demonstrated effectiveness in GPP with a well tolerated and safe profile after a single dose<i>.</i> Targeting IL36 signaling with imsidolimab represents a promising therapeutic option. Sandra P. Smieszek¹ 1. Genetics, Vanda Pharmaceuticals Inc, Vanda Pharmaceuticals Inc, Washington, DC, US, corporate/pharma, Washington, DC, United States. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics