Denifanstat for moderate‐to‐severe acne: A Phase 2, randomized, double‐blind, placebo‐controlled trial

Abstract Background Acne vulgaris is a common chronic inflammatory skin disease with largely unmet treatment needs. Patients and Methods This was a multi‐centre, randomized, double‐blind, placebo‐controlled, dose‐escalation Phase 2 trial ( Clinicaltrials.gov ID: NCT05104125) to evaluate the safety, tolerability and efficacy of denifanstat, a first‐in‐class fatty acid synthase inhibitor, in patients with moderate‐to‐severe acne vulgaris. Denifanstat was administered orally at 25 ( n = 45), 50 ( n = 44), 75 ( n = 45) mg or placebo ( n = 45) once daily after dinner for 12 weeks. Results Denifanstat was generally well‐tolerated. Study drug‐related TEAEs were 48.9% (22/45), 47.7% (21/44), 62.2% (28/45) and 48.9% (22/45) in the denifanstat 25, 50 and 75 mg and placebo groups, respectively. The most common TEAEs were dry eye, dry skin, urine protein positive, skin peeling and conjunctivitis (Grade 1 to 2). No serious drug‐related TEAEs occurred. At Week 12, denifanstat demonstrated significantly greater median reductions in total lesion counts versus placebo (25 mg: −53.2% [Q1–Q3: −62.5% to −37.6%]; 50 mg: −61.3% [−78.2% to −29.1%]; 75 mg: −53.1% [−62.4% to −39.2%] vs. placebo: −34.2% [−53.0% to −18.4%]; all p < 0.05). The proportion of participants achieving a ≥ 2‐grade reduction in Investigator's Global Assessment (IGA) for denifanstat 25, 50 and 75 mg and placebo was 31.1% (14/45), 31.8% (14/44), 22.2% (10/45) and 15.6% (7/45), respectively. The difference among the four groups was not significant ( p = 0.336). Conclusion Denifanstat 50 mg once daily for 12 weeks was generally well tolerated and showed potential to reduce total lesion counts in moderate‐to‐severe acne vulgaris. Larger and longer term studies are needed to confirm efficacy and safety.