Benefit and safety of TYK2 inhibitor ESK-001 for psoriasis in phase 2

ESK-001 demonstrated increasing dose-dependent efficacy over time compared with placebo in primary and secondary Psoriasis Area and Severity Index (PASI) endpoints of the phase 2 STRIDE study. In the open-label extension (OLE), further drug exposure resulted in rising response rates including PASI75 in 90.9% on the highest dose at week 28.

“ESK-001 is a highly selective allosteric TYK2 inhibitor that avoids classic JAK inhibitor liabilities,” Dr Kim Papp (Probity Medical Research, Canada) described the agent assessed in the phase 2 STRIDE study (NCT05600036) [1]. The trial included 228 participants with moderate-to-severe plaque psoriasis receiving placebo or ESK-001 in various dosages between 10 mg daily and 40 mg twice daily over 12 weeks. The OLE with 40 mg ESK-001 once daily or twice daily for all participants followed suit, after a withdrawal of 4 weeks. The overall study cohort had a mean age of 47.8 years and was 82.5% White. The mean PASI score was 17.8, and 36.0% of participants had previous experience with biologics or JAK inhibitors.

At week 12, STRIDE met its primary endpoint PASI75 with dose-dependent response rates ranging from 19.4% (P<0.005 vs placebo) to 64.1% (P<0.0001). PASI90 was reached by 25.6% to 38.5% on the highest 3 dose regimens. Measuring achievement of a static Physician Global Assessment (PGA) of 0/1, all dosages demonstrated increasing trajectories over time, with, for example, 17.9% on 40 mg twice daily at week 4 and 59.0% at week 12.

In the washout period, response rates dropped. However, during the OLE up to week 28, PASI75, PASI90, and PASI100 response rates on ESK-001 40 mg twice daily rose over time from 46.3% to 90.9%, 23.2% to 72.7%, and 6.1% to 36.4%, respectively.

Safety assessments during STRIDE revealed proportions of participants with ≥1 treatment-emergent adverse event (TEAE) of 39.5% in the placebo arm and 39.8% to 64.1% in the ESK-001 groups. Overall, TEAE were mainly mild to moderate in severity. Most frequent were headaches, upper respiratory tract infections, and nasopharyngitis. During the OLE, the rate of ≥1 TEAE was overall 44.5%, with 1.2% of TEAEs entailing treatment discontinuation.

Thus, Dr Papp considered ESK-001 safe and well-tolerated, having a favourable risk-benefit profile in long-term use. Phase 3 development is therefore supported.

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   1. Papp KA. Efficacy and safety of ESK-001, a highly selective oral TYK2 inhibitor, in a phase 2 study in adults with moderate-to-severe plaque psoriasis (STRIDE). LB1, 2024 AAD Annual Meeting, 8–12 March, San Diego, USA.

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Posted on 22 April 202422 April 2024