TYK2 inhibitor deucravacitinib shows impressive long-term response in psoriasis

The once-daily, selective tyrosine kinase 2 (TYK2) inhibitor deucravacitinib demonstrated long-term efficacy in psoriasis through week 52 in the phase 3 POETYK PSO-1 and POETYK PSO-2 trials. The results of a withdrawal analysis showed that almost a third of patients who switched to placebo at week 24 still maintained a PASI 75 at 52 weeks.

The small molecule deucravacitinib selectively inhibits TYK2 via an allosteric mechanism by uniquely binding to the regulatory domain rather than to the more conserved active domain where Janus kinase (JAK)1/2/3 inhibitors bind (see Figure). This unique binding provides high functional selectivity for TYK2, which might have advantages regarding tolerability [1].

Figure: Deucravacitinib binds at the regulatory domain of TYK2 in contrast to other kinase inhibitors [1]

ATP, adenosinetriphosphate; TYK2, tyrosine kinase 2.

In the 2 global, phase 3 studies, POETYK PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751), deucravacitinib was significantly more efficacious than placebo and apremilast based on the coprimary endpoint of Psoriasis Area and Severity Index improvement by 75% (PASI 75) and static Physician’s Global Assessment scale clear or almost clear skin (sPGA 0/1) at week 16 [2]. Both studies included patients with moderate-to-severe psoriasis.

To evaluate the long-term efficacy of deucravacitinib, all 666 participants in the PSO-1 study were switched after the double-blind phase (at week 16) from placebo to deucravacitinib and treated until week 52. Assessed were the maintenance of efficacy on continued treatment or switch from placebo to deucravacitinib at week 16 and durability of response through week 52 [3]. Responses achieved at week 16 were maintained to week 52 in patients who received continuous deucravacitinib treatment. “Patients showed a good maintenance of response,” Prof. Richard Warren (University of Manchester, UK) explained. A PASI 90 response was achieved by 35.5% of patients at week 16 and 44.0% at week 52. Similarly, the sPGA 0/1 results of week 16 (53.6%) were maintained through 52 weeks (52.7%). Patients who switched from placebo to deucravacitinib at week 16 achieved comparable PASI 75 and sPGA 0/1 responses to those observed in patients who received continuous deucravacitinib treatment. The agent also showed good efficacy in scalp psoriasis. At the end of the PSO-1 study, more than 40% of patients achieved a quality of life that was no longer impaired by the disease.

In the PSO-2 trial (n=1,020), PASI 75 responders at week 24 were either re-randomised to deucravacitinib and treated until week 52, or re-randomised to placebo for a random withdrawal analysis. PASI 75 and sPGA 0/1 responses were also maintained on continuous treatment through week 52 in most patients. “In the random withdrawal analysis, we detected an impressive maintenance of response,” Prof. Warren said. Of the patients who switched from deucravacitinib to placebo at week 24, 31.3% showed a PASI 75 response at 52 weeks. The median time to loss of PASI 75 response was 12 weeks.

Thus, deucravacitinib, a once-daily oral drug, has the potential to become an efficacious and well-tolerated treatment choice with long-lasting effects for patients with moderate-to-severe psoriasis.

1. 
   
   1. Chimalakonda A, et al. Dermatol Ther. 2021;11:1763–1776.
   2. Armstrong A, et al. Ann Rheum Dis. 2021;80 (suppl 1):795–796.
   3. Warren RB. Deucravacitinib, an oral, selective tyrosine kinase 2 inhibitor, in moderate to severe plaque psoriasis: 52-week efficacy results from the phase 3 POETYK PSO-1 and POETYK PSO-2 trials. D1T01.4C, EADV Congress 2021, 29 Sept–2 Oct.

 

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Posted on 18 November 202130 November 2021