⚡First Oral FASN Inhibitor for Acne

Good morning — it’s Saturday, June 14, and we’re covering a first-in-class oral fatty acid synthase inhibitor for acne, major updates from the 2025 Revolutionizing Atopic Dermatitis (RAD) meeting, and more.

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Denifanstat, an oral once-daily fatty acid synthase inhibitor, met all primary and secondary endpoints in a Phase 3 randomized trial involving 480 patients with moderate-to-severe acne vulgaris.

At Week 12, significantly more patients treated with denifanstat achieved clear or almost clear skin (IGA 0/1 with ≥2-point improvement) compared to placebo (33% vs. 15%). Denifanstat-treated patients also showed greater reductions in inflammatory (−64% vs. −43%) and non-inflammatory (−52% vs. −29%) lesion counts. All comparisons were statistically significant (P < 0.0001).

The drug was well tolerated, with no serious adverse events reported. Mild-to-moderate dry skin and dry eye (each at 6%) were the only adverse events with an incidence greater than 5%.

Denifanstat inhibits fatty acid synthase, the final enzyme in the de novo lipogenesis pathway, to reduce both sebum production and inflammation in acne. It is also under development for metabolic dysfunction-associated steatohepatitis (MASH).

Ascletis holds the rights to denifanstat in China and plans to submit the drug for regulatory approval. Meanwhile, global developer Sagimet has initiated a Phase 1 trial of TVB-3567, a second oral FASN inhibitor in development for acne in the United States.

> DISCOVER Trial Supports Dupilumab for Atopic Dermatitis in Skin of Color: Sanofi and Regeneron presented positive results from the DISCOVER Phase 4 trial at RAD 2025, offering the first large-scale data on dupilumab (Dupixent) in atopic dermatitis among patients with skin of color. The open-label, single-arm study enrolled 120 adolescents and adults, including 82% Black and 11% Asian participants, all with Fitzpatrick skin types IV–VI. At Week 24, 76% achieved at least a 75% improvement in eczema severity (EASI 75), and 53% reported a ≥4-point reduction in itch severity (PP-NRS; range 0–10). Pigmentation scores improved from 5.1 to 2.4 (PHSS; range 0–8). Meanwhile, the percentage of patients who were very or extremely bothered by dry skin dropped from 78% to 18%. Safety findings were consistent with the known profile of dupilumab. The study fills a key clinical knowledge gap and used newly validated tools for assessing pigmentary change and xerosis.

> Avelumab–Cetuximab Combination Delays Progression in Advanced cSCC: Avelumab plus cetuximab significantly prolonged progression-free survival (PFS) compared to avelumab alone in patients with advanced cutaneous squamous cell carcinoma (cSCC), according to a Phase 2 randomized trial. Avelumab blocks PD-L1, while cetuximab is an IgG1 monoclonal antibody targeting EGFR. Among 57 patients, median PFS was 11 months with the combination versus 3 months with avelumab alone (HR, 0.48; 95% CI, 0.23–0.97; P = 0.018). PFS was defined as the time from treatment initiation to disease progression or death. Nine patients in the avelumab monotherapy arm crossed over to combination therapy at progression, achieving a median PFS of 11.3 months. Overall survival favored the combination (HR, 0.78; 95% CI, 0.34–1.80), though the difference was not statistically significant (P = 0.28). Grade ≥3 adverse events were more common with combination therapy (48% vs. 22%), driven by acneiform rash (21%) and infusion-related reactions (21%). Limitations include a small sample size and lower observed efficacy of avelumab relative to other PD-1 inhibitors, such as cemiplimab. These results support preclinical data showing that IgG1 antibodies such as cetuximab can activate innate and adaptive immunity and may synergize with PD-1/PD-L1 blockade to enhance antitumor activity.

> Zoryve Maintains Clearance With Reduced Dosing in Atopic Dermatitis: Roflumilast cream (Zoryve), a selective phosphodiesterase-4 inhibitor, improved skin clearance over time and sustained long-term disease control with twice-weekly maintenance dosing, according to the Phase 3 INTEGUMENT-OLE results in atopic dermatitis. The open-label extension enrolled 1220 participants aged ≥2 years from prior trials. Between Weeks 4 and 56, the percentage of patients achieving clear or almost-clear skin (vIGA-AD 0/1) increased from 29% to 63% in children aged 2–5 years and from 33% to 56% in those aged ≥6 years. At Week 4, 30% of 2–5-year-olds with clear skin (vIGA-AD 0) transitioned to proactive twice-weekly maintenance dosing. Median duration of disease control was 238 days in this group, comparable to the 281 days observed in older children and adults. Application-site pain occured in <1%, with no new safety signals. The findings support roflumilast as a long-term, steroid-sparing option. The 0.05% formulation for treating atopic dermatitis in children aged 2–5 is currently under FDA review.

> Nemluvio Deepens and Sustains Efficacy in Atopic Dermatitis Through Two Years: Galderma presented two-year data from the ARCADIA long-term extension study at RAD 2025, showing sustained and enhanced efficacy of nemolizumab (Nemluvio) in moderate-to-severe atopic dermatitis. Among more than 1,900 patients, 85% achieved at least a 75% reduction in eczema severity (EASI 75), 60% reached clear or almost-clear skin (IGA 0/1), and 70% were itch-free or nearly itch-free by Week 104. Patients new to nemolizumab saw rapid improvement, with nearly half reaching EASI 75 by Week 4. No serious adverse events emerged over the long-term follow-up. Nemolizumab was approved by the FDA in 2024 for use in combination with topical corticosteroids or calcineurin inhibitors, and is also approved for prurigo nodularis. Two-year data in prurigo nodularis will be presented later this year. Watch how nemolizumab targets IL-31 signaling here.

> Selumetinib Shows Modest Response in Adults With NF1-Plexiform Neurofibromas: Selumetinib met its primary endpoint but with modest effect in adults with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas, according to Phase 2 KOMET trial results published in The Lancet. Selumetinib is a selective MEK1/2 inhibitor that blocks the RAS/MAPK pathway to reduce tumor growth. Investigators randomized 145 participants to selumetinib or placebo in 28-day cycles for 12 cycles; placebo patients crossed over after cycle 12 or earlier if progression, with all continuing open-label selumetinib until cycle 16. By that point, selumetinib achieved a 20% objective response rate—defined as ≥20% confirmed shrinkage—versus 5% with placebo (P = 0.01). Among responders, median tumor volume reduction was 37%. In participants with baseline pain scores ≥3, selumetinib reduced PAINS-pNF scores (range 0–10) more than placebo (–2.0 vs –1.3), though the difference was not statistically significant (P = 0.07). Quality of life scores were similar between groups (P = 0.92). No new safety signals emerged. The KOMET trial is ongoing, with outcomes to be assessed over at least 24 months. Selumetinib is already approved in children based on the SPRINT trial.

Quizzes, cases, and perspectives to sharpen your clinical eye.

In the Phase 4 real-world Canadian CAN UpTIMISE study of 108 patients with moderate to severe atopic dermatitis, 66% who switched to upadacitinib after dupilumab failure or intolerance achieved clear or almost-clear skin (vIGA-AD 0/1) by Week 16, with improvements evident by Week 4 (More)

Adding methotrexate to adalimumab did not improve drug survival or disease severity at 1 or 3 years compared to adalimumab monotherapy, according to a target trial emulation cohort study of 1,784 psoriasis patients (More)

In a real-world study of 111 patients with moderate-to-severe psoriasis treated with the oral TYK2 inhibitor deucravacitinib, all who reached at least a 75% reduction in psoriasis severity (PASI 75) at Week 16 maintained their response through Week 52; however, only 67% of those who achieved complete clearance (PASI 100) at Week 16 sustained it at Week 52 (More)

Sebetralstat—an investigational, novel oral plasma kallikrein inhibitor—halted hereditary angioedema attack progression in a median of 19.8 minutes across 1,591 attacks, offering rapid on-demand control even in severe cases (More)

A randomized trial of 40 patients undergoing second intention healing after lower extremity dermatologic surgery showed no significant benefit from compression stockings over standard care (time to complete reepithelialization: 9.5 vs. 10 weeks; P = 0.40) (More)

The FDA has cleared Ascletis’ investigational new drug (IND) application for ASC50, a first-in-class oral IL-17 inhibitor, with a Phase 1 trial launching later this year (More)