Novel, selective TYK2 inhibitor shows promise for psoriasis

A novel, highly-selective, allosteric tyrosine kinase 2 (TYK2) inhibitor showed remarkable efficacy in patients with psoriasis for an oral agent. On the highest dose of NDI-034858, almost one-third of patients achieved complete skin clearance. The safety profile of this “new kid on the block“ is consistent with experiences from previous trials with TYK2 inhibitors.

Prof. April Armstrong (Keck School of Medicine of University of California, LA, USA) pointed out that TYK2, an essential component in the JAK/STAT signalling pathway, is an important target in psoriasis as it is central to mediating some of the key pathogenic signals that may be increased in patients with psoriasis [1]. The agent NDI-034858 is a highly selective, oral, allosteric inhibitor of TYK2. By selectively inhibiting TYK2, receptor-mediated activation and downstream signal transduction of immune-related cytokines, like IL-6, IL-10, IL-12 and type I interferon, can be prevented.

At this year’s AAD meeting, the results of the phase 2b, randomised, double-blind, placebo-controlled study (NCT04999839) were presented [1]. The 259 participants with moderate-to-severe psoriasis were randomly assigned to receive 1 of 4 doses of this agent or placebo. The primary endpoint was the percentage of patients who achieved a 75% improvement in the Psoriasis Area and Severity Index (PASI) score at week 12.

At this time, a significantly greater proportion of patients achieved PASI75 at doses ≥5 mg (44%, 68%, and 67% with 5 mg, 15 mg, and 30 mg, respectively) versus placebo (6%; P<0.001 for each comparison). “What we learn from this is that 15 mg and 30 mg were superior to 5 mg, and almost 7 out of 10 achieved PASI75 by week 12,” Prof. Armstrong said. Moreover, 46% of patients achieved PASI90 with the higher doses, which was assessed as a secondary endpoint. Almost one-third of patients achieved PASI100 with the highest dose; “an impressive result for an oral agent,” as Prof. Armstrong pointed out.

Adverse event frequency was 53‒62% with no clear dose dependence in the active arms and 44% in the placebo arm. COVID-19 infection was the most frequent adverse event as the study was performed during the pandemic. One patient experienced 2 serious adverse events considered unrelated to treatment. Additionally, participants presented with acne and folliculitis of the truncal area and diarrhoea. Mean lab values and changes from baseline did not reveal adverse trends in cell counts; however, creatine kinase showed some variability in the high doses. These promising results support further studies of the TYK2 inhibitor in psoriasis.

1. Armstrong A. Efficacy and safety results from the randomized, double-blind, placebo-controlled phase 2b trial of TYK2 inhibitor NDI-034858 in moderate-to-severe psoriasis. S025, AAD 2023 Annual Meeting, 17–21 March, New Orleans, USA.

Posted on 15 May 20239 April 2024