JAK1 inhibitor shows promising long-term efficacy in PN

Povorcitinib effectively reduced pruritus and skin lesions in patients with prurigo nodularis (PN) in a phase 2 randomised-controlled trial. Even participants who did not respond by week 16 saw marked improvements when treatment was continued through week 40.

PN is a debilitating inflammatory skin disease with severely itching lesions, pain, stinging, and burning sensations [1]. The condition has been linked to inflammatory pathways involving the JAK/STAT signalling axis [2], and more specifically JAK1. This was the rationale for Dr Shawn Kwatra (Johns Hopkins University School of Medicine, MD, USA) and colleagues to test the selective JAK1 inhibitor povorcitinib in a 40-week phase 2 study (NCT05061693) to assess its long-term efficacy and safety in patients with PN [3].

The randomised, double-blind trial included 146 participants with moderate-to-severe PN who were treated with oral once-daily povorcitinib at 3 different doses (i.e. 15 mg, 45 mg, or 75 mg) for 16 weeks, , followed by a 24-week extension phase. The primary endpoint was a ≥4-point reduction in the Itch Numerical Rating Scale (itch-NRS4) at week 16, which is considered clinically relevant. Moreover, secondary endpoints included the time to itch-NRS4 and the percentage of participants achieving Investigator Global Assessment (IGA)-Treatment Success (TS) of PN lesions.

At week 16, the itch-NRS4 endpoint was met in 36% of participants on 15 mg povorcitinib, 44% on 45 mg, and 57% on 75 mg, compared with 8% in the placebo group (all P<0.01). In the subsequent single-blind extension period, composite responders (i.e. itch-NRS4 and IGA-TS) were treated with 45 mg povorcitinib for another 24 weeks, whereas partial or non-responders received a 75 mg dose until week 40. Most responders retained the itch-NRS4 response, including those that went from 75 mg in the double-blind phase to 45 mg in the extension period, and 88% of responders at week 16 achieved both endpoints (i.e. itch NRS4 response and IGA-TS) at week 40.

The study also showed that participants in the composite non-responder group improved during the extension period: 34% did show an itch-NRS4 response at week 16, whereas 70% showed a response by week 40 when switched to 75 mg povorcitinib, highlighting the importance of longer-term treatment. This is particularly true for nodule improvement. Regarding this endpoint, only 11% in the composite non-responder group achieved an IGA-TS in week 16, compared with 51% in week 40. “Itch improvement happens faster, and skin lesions can take a little longer to improve,” Dr Kwatra commented.

Safety was generally good, with few serious adverse events reported. Thus, povorcitinib is a promising novel oral treatment for patients with PN, with the potential for early and long-term disease control.

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   1. Aggarwal P, et al. Clin Exp Dermatol. 2021;46(7):1277-1284.
   2. Agrawal D, et al J Cosmet Dermatol. 2022;21(9):4009-4015.
   3. Kwatra SG, et al. Efficacy and safety of oral povorcitinib in patients with prurigo nodularis: 40-week results from a randomised, double-blind, placebo-controlled phase 2 study. D2T01.3F, EADV Congress 2024, 25–28 September, Amsterdam, the Netherlands.

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Posted on 6 November 2024