⚡Next-Generation TYK2 for Psoriasis

Good morning — it’s Saturday, July 19, and we’re covering a novel TYK2 inhibitor in psoriasis, the U.S. launch of Leqselvi for severe alopecia areata, and more

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ESK-001, Alumis’ next-generation TYK2 inhibitor, demonstrated strong efficacy in moderate-to-severe psoriasis in the Phase 2 STRIDE trial published in JAAD.

This highly selective, oral, allosteric TYK2 inhibitor targets the IL-23/Th17 axis and type I interferon signaling. Its unique design maximizes TYK2 inhibition while minimizing off-target effects.

Investigators randomized 227 patients to placebo or one of five ESK-001 doses for 12 weeks, followed by a 4-week observation period.

At Week 12, 59% of patients receiving the highest dose of ESK-001 (40 mg BID) achieved clear or almost clear skin (sPGA 0/1), compared to 8% receiving placebo (P < 0.0001). Additionally, 39% achieved a ≥90% reduction in disease severity (PASI 90) versus 0% on placebo (P < 0.0001).

Responses continued to improve through Week 12 without plateauing and were largely sustained after treatment cessation.

Skin biomarker analyses confirmed normalization of IL-17F and IL-23A expression, supporting the drug’s mechanism.

ESK-001 was well tolerated, with a low discontinuation rate of 3%. The most commonly reported adverse events were headache (6%), upper respiratory tract infections (5%), nasopharyngitis (4%), and acne (2%).

Earlier this year, Alumis completed enrollment in the pivotal ONWARD Phase 3 trials, evaluating ESK-001 in over 1,700 patients with moderate-to-severe psoriasis. Topline results are expected in Q1 2026.

> Leqselvi launches in the US for severe alopecia areata after patent resolution: Sun Pharma has launched deuruxolitinib (Leqselvi), an oral JAK1/2 inhibitor approved at 8 mg twice daily, for adults with severe alopecia areata. Although FDA-approved in July 2024, the drug’s market entry was delayed due to a now-resolved patent dispute with Incyte. Approval was based on data from 1,209 adults enrolled in the pivotal THRIVE-AA1 and THRIVE-AA2 Phase 3 trials. Average baseline scalp hair coverage was 13%, indicating severe disease. At Week 24, 31% of patients receiving deuruxolitinib achieved at least 80% scalp hair coverage (SALT score ≤20), compared to just 1% on placebo (P < 0.0001). Discontinuations due to adverse events were rare, occurring in only 3% of patients; the most frequent adverse events were headache (12%), acne (10%), and nasopharyngitis (8%). Long-term open-label data presented late last year showed continued improvement through Week 68, with 49% achieving SALT ≤20.

> Topical BRAF inhibitor first to show efficacy for EGFR-induced acneiform rash in a randomized trial: Lutris Pharma’s LUT014 gel is the first treatment to demonstrate efficacy for acneiform rash caused by anti-EGFR cancer therapies in a randomized trial. EGFR inhibitors suppress MAPK signaling—specifically the RAS–RAF–MEK–ERK cascade—reducing ERK phosphorylation, which leads to acneiform rash. LUT014, a topical BRAF inhibitor, paradoxically reactivates this pathway by restoring ERK phosphorylation in BRAF–wild-type keratinocytes. The Phase 2 trial enrolled 117 patients with colorectal cancer who developed moderate-to-severe acneiform rash during cetuximab or panitumumab therapy. Patients applied LUT014 gel (0.03% or 0.1%) or placebo once daily for 28 days. Treatment success with high-dose LUT014 was 64% in panitumumab-treated patients and 82% in those on cetuximab, compared to 33% in both placebo arms (P = 0.03 and 0.02, respectively). Treatment success was defined as at least a 1‑grade improvement in rash severity (CTCAE scale; range 0–5) or a minimum 5‑point gain in skin-related quality of life (FACT‑EGFRI‑13; range 0–52). The gel was well tolerated, with fewer adverse events reported than placebo. By reducing this common cutaneous dose-limiting toxicity, LUT014 may help patients remain on full-dose EGFR inhibitor therapy without interruption.

> Real-world study shows high efficacy of oral JAK inhibitors in prurigo nodularis: Oral JAK inhibitors significantly reduced pruritus and nodular severity in patients with prurigo nodularis, according to a retrospective cohort study published in Clinical and Experimental Dermatology. The study included 71 adults treated across 23 Italian centers: 55 with upadacitinib, 12 with abrocitinib, and 4 with baricitinib. Nearly half of the patients had previously received a biologic such as dupilumab or tralokinumab. At Week 16, 95% of patients on upadacitinib, 83% on abrocitinib, and 100% on baricitinib achieved a clinically meaningful reduction in itch severity (≥4-point reduction in PP-NRS; scale 0–10). These improvements were sustained through Week 24. At that point, 81% of patients on upadacitinib and 100% on both abrocitinib and baricitinib achieved clearance or almost-clearance of all nodules (IGA PN-S 0/1). No serious adverse events occurred, and no patients discontinued therapy due to side effects. All three drugs target JAK1, a key mediator of cytokines such as IL-4, IL-13, and IL-31, which drive type 2 inflammation and itch. Interpretation is limited by the study’s retrospective, nonrandomized design and small sample size

> Tofacitinib reduces vitiligo extent more than mini-pulse steroid therapy but not meaningful response rates: A randomized trial published in JAAD found that oral tofacitinib reduced vitiligo extent more than twice-weekly dexamethasone mini-pulse therapy. However, both treatments achieved similar rates of clinically meaningful response. The study enrolled 60 adults with active nonsegmental vitiligo who received treatment for 24 weeks, followed by 12 weeks of observation. At Week 36, the mean reduction in Vitiligo Extent Score (VES) was significantly greater with tofacitinib (32%) than with dexamethasone (17%) (P = 0.03). Despite this, the proportion of patients achieving meaningful clinical improvement (≥50% VES reduction) was similar in both groups (23% with tofacitinib vs. 20% with dexamethasone, P = 0.86). Disease stabilization at Week 24 favored tofacitinib (83% vs 63%) but was not statistically significant (P = 0.19). Adverse effects were more than twice as common with tofacitinib (43% vs 20%, P = 0.08). Interpretation is limited by the study’s small sample size, lack of double-blinding, and multiple statistical comparisons.

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

A 5-year retrospective study of 34 women with female pattern hair loss treated with systemic minoxidil showed progressive gains in hair density over time. By Year 3, 38% achieved a ≥1-point improvement on the Sinclair scale (range 1–5), increasing to 65% by Year 5. Overall, 94% experienced either improvement or stabilization by the end of the study (More)

In a case series of 11 adults with chronic superficial dermatophyte infections persisting for more than 5 years and refractory to at least three oral antifungals, immune defects were identified in 6 patients—including monogenic mutations (CARD9 and FOXN1), IL-17 pathway defects, and Good’s syndrome. Most (10 of 11) achieved partial control with long-term continuous antifungal therapy (More)

In a 5-year real-world study of 1,765 psoriasis patients treated with guselkumab, outcomes were consistent regardless of psoriatic arthritis status. A ≥90% reduction in disease severity from baseline (PASI 90) was reached in 79% of patients without psoriatic arthritis and 80% of those with it, while drug survival remained high in both groups (80% vs. 79%) (More)

A retrospective study of 24 superficial basal cell carcinomas treated with tirbanibulin 1% ointment found a 54% clearance rate (13/24) after two 5-day treatment cycles. Recurrence was low at 6 months, occurring in just one of the 13 patients (8%) who initially cleared (More)

A systematic review of 8 studies involving 123 patients who underwent hair transplantation for inactive primary cicatricial alopecia found that follicular unit graft survival peaked at 83% at 7–12 months, then declined to 40% at 4–6 years (More)