Denifanstat, a fatty acid synthase inhibitor achieved significant clinical improvement in moderate-to-severe acne vulgaris: a review of mechanistic and clinical data

Background and Aims:bExcess sebum production via increased de novo lipogenesis (DNL) contributes to acne pathogenesis. Fatty acid synthase (FASN) is the key enzyme in the DNL pathway. Inhibition of FASN reduces sebum production and directly decreases inflammation by disrupting the key inflammatory signaling pathway. Denifanstat (deni), an oral FASN inhibitor, was tested in preclinical models and evaluated for treatment of moderate-to-severe acne in Phase 3 clinical trials in China. Methods: ASC40-303 (NCT06192264) was a 12-week, randomized, double-blind, placebo (pbo)-controlled Phase 3 trial of deni 50 mg once daily (n=240) vs pbo (n=240) followed by ASC40-304 (NCT06248008) an open-label extension (OLE) in which participants from both arms (n=240) received deni 50 mg through week 52 to assess long-term safety and efficacy. In preclinical studies, primary human cells were isolated from human blood, and sebocytes were Meisen CTCC Hum-280 and SZ95. Results: Deni directly inhibited DNL and reduced triglyceride production in human sebocyte cell lines. Deni reduced sebum palmitic acid, sapienic acid, and triglycerides in human skin sebum samples collected via non-invasive sebutape. FASN inhibitors also reduced pro-inflammatory cytokine production and decreased Th17 cell development. In ASC40-303, deni met all primary and secondary endpoints and demonstrated significant treatment success (defined as clear or almost clear skin with a ≥2-point IGA improvement) versus pbo (33.2% vs 14.6%; p<0.0001). Mean lesion count reductions were greater with deni: total lesions −57.4% deni vs −35.4% pbo (p<0.0001), inflammatory lesions −63.5% deni vs −43.2% pbo (p<0.0001), and non-inflammatory lesions −51.9% deni vs −28.9% pbo (p<0.0001). After 4 weeks of deni treatment, all parameters showed a statistically significant benefit. In ASC40-304 OLE, efficacy continued to improve through week 52. IGA treatment success was 57.8% in deni/deni patients and 55.6% in pbo/deni patients at the end of treatment. Total, inflammatory, and non-inflammatory lesion count reductions in deni/deni and pbo/deni groups were -73.0%, and -70.7%, and -78.1% and -75.8%, and -68.3%, and -65.5%, respectively. Deni was generally well-tolerated in ASC40-303/304 trials. Two categories of treatment related adverse events (AEs) had an incidence of 5% or more: in ASC40-303, dry eye at 10.9% in deni vs 8% in pbo, and dry skin at 6.3% (deni) vs 2.9% (pbo), and in the 239 patients receiving deni up to 52 weeks in ASC40-304: dry skin at 7.1% and dry eye at 5.9%, the incidence in the 40 week OLE alone was 2.5% for dry skin and 2.1% for dry eye. All deni-related AEs were mild or moderate; grade 1 hair thinning was experienced by 1 deni-treated patient during OLE. Conclusion: Deni demonstrated significant efficacy compared to pbo in a 12-week trial, with significant improvements demonstrated as early as 4 weeks and further clinical improvement evident through week 52. Deni was generally well-tolerated without drug related serious AEs or grade ≥3 AE. These clinical and preclinical mechanistic results demonstrate that FASN inhibition can offer a novel oral therapeutic approach for acne, targeting its pathogenesis by reducing de novo lipogenesis, sebum production, and inflammation.