JAK1 inhibition: a promising forthcoming treatment option in vitiligo

Selective JAK1 inhibitors in 2 phase 2 trials have shown the potential of these agents in longstanding vitiligo. In both trials, a treatment plateau had not been reached after 52 weeks of continuous therapy with upadacitinib and povorcitinib.

The autoimmune disease vitiligo is characterised by depigmentation of the skin due to progressive loss of melanocytes. Prof. Khaled Ezzedine (University Paris-Est Créteil, France) pointed out that vitiligo’s pathogenesis is largely regulated by interferon-gamma activation of the JAK pathway [1]. A second rationale for using JAK inhibitors in vitiligo is that they can interrupt the process of immune-mediated apoptosis of melanocytes [2]. Therefore, several JAK inhibitors are currently being investigated in phase 2 trials.

Oral JAK1 inhibitor induces increasing repigmentation over time

The JAK1 inhibitor povorcitinib was tested as a treatment for non-segmental vitiligo in a phase 2b trial (NCT04818346) that enrolled 171 participants [1]. In 4 equally powered study arms, the participants were treated with 3 different dosages of povorcitinib (i.e. 15 mg, 45 mg, 75 mg) or placebo once daily over 24 weeks. Thereafter, all participants starting on this regimen continued on 45 mg, and all other participants received 75 mg of the drug for 28 more weeks, which was followed by 6 months of off-treatment follow-up.

The median age of participants was 50 years, and 54.4% were women. Vitiligo was diagnosed at a mean of 19.4 years earlier and about 2 thirds presented a Fitzpatrick skin type of 1-3. At week 24, the change in total body (T) Vitiligo Area Scoring Index (VASI) was significantly higher in all povorcitinib groups than on placebo with least square mean depigmentation improvements of 19.1% (15 mg), 17.8% (45 mg), and 15.7% (75 mg) compared with -2.3% on placebo (P<0.01 for all comparisons to placebo).
Up to week 52, these results in mean change of T-VASI further advanced to 42.7% and 41.3% in those who were on 45 mg and 75 mg povorcitinib from the start. “Even at week 52, we haven’t reached the plateau; this is something very interesting,” Prof. Ezzedine pointed out. A ≥50% reduction (i.e. T-VASI50) was achieved by 15.2% on 45 mg after 6 months and 37.0% at week 52.

With regard to facial (F) VASI, statistical significance was observed in all regimens of povorcitinib, with the highest rate on continued 45 mg from day 1: 36.4% versus 5.1% (P<0.0001 vs placebo) at week 24 and 63.8% after 1 year. F-VASI75 was observed in 45.5–58.6% at the end of the extension period. Prof. Ezzedine also explained that although the sample size for the period without treatment from weeks 52–76 was too small for statistical analysis, the results suggested a maintained durability of response in T-VASI and F-VASI.

As for safety up to week 52, the overall rate of treatment-emergent adverse events on povorcitinib was reported at 89.3%, ≥grade 3 at 16.9%, and serious at 2.4%. “No serious adverse events were considered related to the treatment, and no new safety signals were observed,” Prof. Ezzedine commented, adding that povorcitinib was generally well-tolerated at all doses.

Similar results with upadacitinib

Prof. Thierry Passeron (Centre Hospitalier Universitaire de Nice, France) presented the 52-week results of a multicentre, randomised, double-blind, placebo-controlled phase 2 study of 184 adult patients with non-segmental vitiligo who received 3 different doses of upadacitinib (i.e. 6 mg, 11 mg, and 22 mg once daily). The primary study endpoint was the change in F-VASI from baseline to week 24.

A second study phase continued as a blinded extension from week 24, the time of the primary analysis, until week 52. After 24 weeks, half of the 2 placebo groups were treated with 11 mg and half with 22 mg of upadacitinib until week 52. Of the 185 participants enrolled in the first phase of the study, 165 also participated in the second phase. In most participants, the disease had been present for more than 15 years and a high proportion had active disease – all unfavourable factors in terms of response.

Treatment with upadacitinib resulted in an improvement in F-VASI in all groups, reaching statistical significance at the 2 highest doses. The F-VASI decreased by 34% with 22 mg upadacitinib and by 35.6% with 11 mg upadacitinib. Body lesions also improved, with improvements also reaching significance with the 2 highest doses (-20.7% with 22 mg and - 17.3% with 11 mg).

In both face and body, progressive improvement was seen in repigmentation during the extension phase under therapy with upadacitinib. No plateau had been reached after 52 weeks: At the highest dose, the F-VASI decreased by 69.8% (T-VASI by -49.0%), with 11 mg of upadacitinib F-VASI decreased by 60.7% (T-VASI by 45.4%).

Therapy was also relatively well tolerated with no differences between groups. Venous thromboembolism was not observed. However, 1 patient with multiple cardiovascular risk factors treated with 11 mg upadacitinib had a non-fatal ischemic stroke in the extension phase.

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   1. Ezzedine K. Efficacy and safety of povorcitinib for extensive vitiligo: 52-week results from a double-blinded, placebo-controlled, dose-ranging phase 2b study. D1T01.1A, EADV Congress 2023, 11–14 October, Berlin, Germany.
   2. Qi F, et al. Front Immunol 2021;12:790125.
   3. Passeron T. Efficacy and safety of upadacitinib in a phase 2 randomized, double-blind, dose-ranging study of adults with extensive non-segmental vitiligo. FC02.8, EADV Congress 2023, 11–14 October, Berlin, Germany.

 

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Posted on 28 November, 202315 February, 2024