SDPA Presents 20th Annual Fall Dermatology Conference–Abstracts and Posters
November 16-20, 2022, Miami, FL
8. Exposure–Response Analysis Demonstrates Response to Tapinarof is Driven by Local Effects at Sites of Application
James Del Rosso1, Scott Guenthner2, H. Chih-ho Hong3, John E. Jett4, Philip M. Brown4, David S. Rubenstein4, Stephen C. Piscitelli4
1JDR Dermatology Research, Las Vegas, NV, USA; 2The Indiana Clinical Trials Center, Plainfield, IN, USA; 3University of British Columbia and Probity Medical Research, Surrey, BC, Canada; 4Dermavant Sciences, Inc., Morrisville, NC, USA
Introduction: Tapinarof is a first-in-class, non-steroidal, topical, aryl hydrocarbon receptor agonist approved by the Food and Drug Administration for the treatment of plaque psoriasis in adults and under investigation for the treatment of plaque psoriasis in children down to 2 years of age, and for atopic dermatitis (AD) in adults and children down to 2 years of age. Tapinarof cream 1% once daily (QD) demonstrated significant efficacy versus vehicle and favorable tolerability in adults with plaque psoriasis in two 12-week trials, PSOARING 1 and 2. In PSOARING 3, the long-term extension trial, tapinarof was effective, well tolerated, and demonstrated a durable response, with a ~4-month remittive effect off therapy. Tapinarof cream 1% QD under maximal use conditions in patients with extensive psoriasis resulted in minimal systemic exposure. This exposure–response analysis evaluated the hypothesis stating no relationship between tapinarof plasma exposure and efficacy or safety.
Methods: Analyses included 587 patients with pharmacokinetic data across four clinical trials: a phase 2b trial in AD with 5%–35% body surface area (BSA) involvement (NCT02564055); a phase 2a maximal-use trial in plaque psoriasis with ≥20% BSA (NCT04042103); and the phase 3 trials in plaque psoriasis with 3%–20% BSA, PSOARING 1 (NCT03956355) and PSOARING 2 (NCT03983980). Tapinarof was measured in plasma with a highly sensitive assay (picograms [10–12 g]/mL]). Plasma concentrations were evaluated for relationships with disease and tapinarof dose (0.5%, 1%) and application frequency (QD, twice daily). Pharmacokinetic parameters were minimum and maximum tapinarof plasma concentrations. Adverse events of special interest (AESIs) were folliculitis, contact dermatitis, and headache. Efficacy endpoints in psoriasis trials included Physician Global Assessment and Psoriasis Area and Severity Index scores. Exposure–efficacy was not assessed for AD.
Results: Tapinarof plasma exposure was low overall and undetectable in most samples. No trends in tapinarof systemic concentrations were observed regardless of disease, or concentration or frequency of topical tapinarof application. In addition, there was no relationship between systemic concentration and %BSA in a separate analysis of the maximal-use trial, with %BSA ranging from 21%–46%. There was no relationship between plasma concentrations and efficacy endpoints. Furthermore, there was no relationship between plasma exposure and AESIs of folliculitis, contact dermatitis, or headache.
Conclusions: An exposure–response analysis across four trials demonstrated no relationships between tapinarof plasma concentrations and efficacy or safety. These findings are consistent with the clinical pharmacology of tapinarof and demonstrate that the skin is the site of drug action after topical application, with minimal systemic absorption following application, and no dependence on systemic activity for therapeutic effects.
Funding Support: Dermavant Sciences, Inc.