Interleukin-1 alpha (IL-1α) is constitutively expressed in epithelial cells located at barrier sites, such as skin, lung, and gut. Upon cellular death, injury or infection, IL-1α is released. Serum levels of IL-1α are largely undetectable in healthy volunteers (HV), or atopic dermatitis (AD) and hidradenitis suppurativa (HS) patients, while levels in the skin, especially in the epidermis and exudates from HS tunnels, are highly concentrated. Bermekimab (BMK) is a first-in-class fully human anti-IL-1α monoclonal antibody that has been tested in Phase-2A AD and HS studies. To support understanding of PK/PD relationships, we developed a human skin explant model to assess proteomic and transcriptomic effects of IL-1α blockade on injury-induced inflammation. After 24-hours culture, IL-1α was detected in the media. Ex vivo IL-1α blockade resulted in significant decreases of CXCL1, IL-8, GCSF and IL-6 levels compared to untreated 24-hours samples (p<0.05 for all analytes), and consistent reduction of 73 genes (N=10 donors). Next, we utilized this model to measure post-treatment skin PD effects in HV receiving a single dose of BMK in a Phase 1 study (NCT04544813). BMK exhibited linear PK following a single IV (400-1200mg) or SC (200-800mg) administration. Consistent with ex vivo blockade, CXCL1, IL-8, GCSF and IL-6 were reduced in culture media from post-dose versus pre-dose skin explants with significantly higher % reduction of IL-8 and IL-6 observed in the 800mg compared to the 200mg SC cohorts (p<0.05 for both analytes). Down-regulation of the same 73 genes in skin explants were also observed. These data support the relevance of IL-1α as a key skin alarmin driving tissue injury inflammation, and BMK reduces the downstream skin injury responses. Clinical research evaluating BMK in inflammatory skin diseases is ongoing.

ESDR037 - Bermekimab, Anti-Interleukin-1α Antibody, Inhibits Skin Injury Induced Response in Healthy Volunteers

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.