Inhibition of the P2X7 receptor is insufficient to mediate disease in hidradenitis suppurativa, but may restore immune exhaustion: Results of a phase 2 randomized controlled trial of AZD9056

Summary: Abstract Body: The NLRP3 inflammasome and the upstream P2X7 receptor are upregulated in hidradenitis suppurativa (HS) skin lesions. However, the role of the P2X7-NLRP3 axis in cytokine dysregulation, immune exhaustion, and clinical disease activity in HS remains unclear. To explore the therapeutic potential of targeting P2X7, we conducted a phase 2 randomized, double-blind, placebo-controlled trial of the small molecule inhibitor AZD9056. Five patients with moderate-to-severe HS received AZD9056 (400 mg daily) for 24 weeks, while seven received a placebo for 12 weeks, followed by a 12-week open-label AZD9056 phase. Tissue and plasma samples were collected at baseline, week 12, and week 24 for Luminex assays. Resting cytokine levels were assessed in blood and skin; peripheral blood monocyte (PBMC) immunophenotyping was performed using flow cytometry, and immune exhaustion was evaluated by cytokine production after LPS+ATP stimulation. Clinical data showed no significant impact of AZD9056 on HS disease activity (HiSCR, IHS4). In line with the lack of clinical response, cytokine levels in skin and blood were also unaffected. However, AZD9056 restored LPS+ATP-stimulated cytokine production in PBMCs (restoring IL-13, IL-1β, IL-6, and TNF-α, all p < 0.05). Flow cytometry revealed reduced Th1/Th17 axis expression following AZD9056 treatment. In this small study, P2X7 receptor inhibition did not improve HS clinical activity or cytokine dysregulation in HS lesions. Nonetheless, P2X7 inhibition restored cytokine production in PBMCs, reversing immune exhaustion, possibly via reduced Th1/Th17 expression. While it does not address HS clinical activity, it may enhance immune responses, meriting further investigation for its role in immune dysfunction in HS and other autoimmune diseases. James M. Kilgour¹, Hal Landy², Alexa B. Kimball³, Joslyn Kirby³, Barbara Gilchrest³, Milan J. Anadkat³, Barry I. Resnik³, Sunil Dhawan³, Mark de Souza², Kavita Sarin¹ 1. Dermatology, Stanford University, Stanford, CA, United States. 2. Phoenicis Therapeutics, Inc., Foxboro, MA, United States. 3. AZD9056 Clinical Trial Investigators, Foxboro, MA, United States. Clinical Research: Interventional Research