⚡Sonelokimab stumbles in pivotal HS trials

Good morning — it’s Saturday, October 11, and we’re covering sonelokimab’s Phase 3 results in hidradenitis suppurativa, a lebrikizumab trial in eczema patients who could not be treated with cyclosporin, and more.

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MoonLake’s sonelokimab failed to meet expectations in the two Phase 3 VELA trials for hidradenitis suppurativa, missing a primary endpoint in one study and showing smaller treatment effects than anticipated.

Sonelokimab is a trispecific Nanobody® that blocks IL-17A and IL-17F while also binding albumin to enhance tissue penetration at sites of inflammation.

The VELA-1 and VELA-2 trials randomized 838 adults with moderate-to-severe disease to sonelokimab or placebo.

At Week 16, 35% and 36% of patients on sonelokimab achieved HiSCR75 (≥75% reduction in abscess and nodule counts with no increase in abscesses or draining tunnels) compared with 18% and 26% on placebo. VELA-1 met its primary endpoint (P<0.05), but VELA-2 narrowly missed statistical significance (P=0.053).

The treatment advantage of 10–17% over placebo was considerably smaller than in the earlier Phase 2 MIRA trial, where sonelokimab achieved a 29% margin. That result had fueled expectations the drug could surpass IL-17 competitors bimekizumab (Bimzelx) and secukinumab (Cosentyx).

Despite mixed primary outcomes, both VELA studies met key secondary endpoints. HiSCR50 responses were observed in 52–59% of patients vs 30–43% on placebo. Safety was also favorable. The only imbalance was a higher incidence of oral candidiasis in the active arm (7.3% vs 0.4%).

Even so, MoonLake’s shares dropped more than 80% on the news. The company said it will discuss the results with regulators and review the path to approval.

The findings also cast uncertainty over sonelokimab’s ongoing programs in adolescent hidradenitis suppurativa, palmoplantar pustulosis, and psoriatic arthritis.

> Lebrikizumab improves eczema control when cyclosporin A is not an option: The ADvantage Phase 3b trial, published in the BJD, is the first large-scale study to evaluate lebrikizumab (Ebglyss) in moderate-to-severe eczema when cyclosporin A isn’t an option. The trial enrolled patients who had either failed or were ineligible for the drug. In parts of Europe, cyclosporin is required before advanced therapies are reimbursed. Its long-term use, however, is limited by renal toxicity. Investigators randomized 331 adults and adolescents to lebrikizumab or placebo plus topical corticosteroids, with placebo patients crossing over at Week 16. At that point, 68% of lebrikizumab-treated patients achieved EASI 75 (≥75% improvement in eczema severity) vs 41% on placebo (P<0.001). Responses deepened in the open-label extension, approaching 90% by Week 52. No new safety signals emerged. However, 11% of patients reported conjunctivitis at Week 16, slightly higher than the 5–8% seen in earlier trials. A limitation was the lack of separate analyses for cyclosporin ineligibility versus treatment failure. Still, the findings suggest that the IL-13 inhibitor remains effective in this harder-to-treat population.

> Next-generation TYK2 inhibitor sustains psoriasis clearance through 52 weeks: One-year data from the open-label extension of the Phase 2 STRIDE trial support the sustained efficacy and safety of envudeucitinib (formerly ESK-001) in moderate-to-severe psoriasis. The study enrolled 165 adults who had completed an initial 12-week placebo-controlled phase. Participants began envudeucitinib 40 mg once or twice daily, before a protocol amendment based on emerging data moved all to 40 mg twice daily. By Week 52, 61% achieved a ≥90% reduction in disease severity (PASI 90) while 39% reached complete skin clearance (PASI 100). Efficacy was durable, with 80% of PASI 75 responders who entered the extension maintaining their response through one year. Treatment was generally well tolerated: only 4% discontinued due to adverse events. Rates of acne and folliculitis were ≤3%. Interpretation is limited by the open-label design, modest sample size, and selection of only those who chose to continue into the extension. Envudeucitinib is an oral, highly selective allosteric TYK2 inhibitor that targets the IL-23/Th17 axis and type I interferon signaling. Enrollment is already complete in the Phase 3 psoriasis program, with topline results due in Q1 2026.

> First randomized trial of Mediterranean diet in psoriasis: A dietitian-guided Mediterranean diet program reduced psoriasis severity, but unequal trial design tempered conclusions. The MEDIPSO trial, published in JAMA Dermatology, enrolled 38 adults with mild-to-moderate psoriasis on stable topical therapy. Participants were randomized to a Mediterranean diet program (dietitian visits, educational materials, and weekly extra-virgin olive oil) or standard low-fat diet advice without supervision. At Week 16, 47% of patients in the Mediterranean diet group achieved PASI 75 compared with 0% in the control group (P<0.001). Glycemic control also favored the intervention, with a −4 mmol/mol difference in HbA1c (P=0.01). However, interpretation is limited by the study’s small sample size, open-label design, and multiple comparisons. The intervention arm also received far more support and contact, which likely boosted adherence and engagement and may have introduced a Hawthorne effect. It remains unclear how much of the benefit came from the diet itself or the increased attention. Larger, equal-contact trials are needed to confirm these findings.

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

By Week 140, observed case analyses from three Phase 3 trials (Measure Up 1/2 and AD Up) showed that upadacitinib maintained durable efficacy in moderate-to-severe atopic dermatitis. EASI 75 was achieved by 82–86% on 15 mg and 90–91% on 30 mg. No new safety signals emerged (More)

In the KOHDIAK trial of 631 patients with mild-to-moderate actinic keratosis (≤5 lesions), complete clearance at the end of treatment was higher with KOH 5% solution than with diclofenac 3% gel (45% vs 24%) or placebo (23%). At 6 months, however, clearance rates converged between KOH and diclofenac (38% vs 41%). Most adverse reactions were mild and localized (More)

In a Phase 2 trial of 67 adults with moderate-to-severe hidradenitis suppurativa, HiSCR50 response rates were 49% with eltrekibart and 32% with placebo at Week 16 (P=0.19). Over 80% of eltrekibart responders maintained HiSCR50 through Week 36, suggesting durable benefit. The monoclonal antibody targets CXCR1/2 ligands, chemokines implicated in disease pathogenesis (More)

A case series of 4 patients (6 keloids) found that microinfusion of 5-FU with a tattoo machine reduced Observer POSAS scores from 5 to 2 on a 1–10 scale (higher scores indicate worse scar quality). Benefits persisted at 1 year in two patients. Adverse events were minimal and transient (More)

A review of five randomized withdrawal trials in psoriasis found differences in time to relapse after stopping IL-17 inhibitors. Median time to PASI-90 loss was longest with bimekizumab (24 weeks) and shortest with brodalumab (5 weeks). Secukinumab and ixekizumab were intermediate (16 weeks) (More)