ESK-001 makes good STRIDEs for plaque psoriasis

In the phase II dose-ranging STRIDE trial presented at AAD 2024, ESK-001, a highly-selective and potentially best-in-class allosteric tyrosine kinase 2 (TYK2) inhibitor, demonstrated favourable efficacy and safety signals for the treatment of adults with moderate-to-severe plaque psoriasis.

The study met its primary endpoint of PASI75* at week 12, as well as key secondary efficacy endpoints at all clinically relevant ESK-001 doses tested, the investigators noted. There were also clear dose-dependent responses observed, consistent with increasing levels of target inhibition.

A total of 228 participants were randomized across five ESK-001 doses (40 mg BID, 20 mg BID, 40 mg QD, 20 mg QD, and 10 mg QD) or placebo for 12 weeks, with a 4-week treatment withdrawal follow-up period. [AAD 2024, abstract 56715]

At week 12, more than half of those on the three higher ESK-001 doses achieved PASI75 (64, 56, and 56 percent for 40 mg BID, 20 mg BID, and 40 mg QD, respectively, vs zero percent [placebo]; p<0.001 for all). Favourable PASI75 responses were also seen with the 20-mg QD (33 percent; p<0.001 vs placebo) and 10-mg QD doses (19 percent; p<0.005).

ESK-001 40 mg BID also yielded better PASI90* and PASI100* responses vs placebo (38 percent vs 0 percent; p<0.001 and 15 percent vs 0 percent; p<0.05, respectively), as did the 20-mg BID dose (26 percent vs 0 percent; p<0.001 and 10 percent vs 0 percent; p<0.05).

ESK-001 was well tolerated with no treatment-related serious adverse events (AEs). The researchers noted similar incidences of treatment-related AEs (TRAEs) between ESK-001 and placebo. Discontinuation rate owing to AEs was low (<3 percent). The most common AEs were headache, upper respiratory tract infection, and nasopharyngitis.

A new treatment alternative

“Since starting my clinical practice years ago, I have witnessed the challenges faced by psoriasis patients. I see, and I feel, the very negative impact psoriasis has on their quality of life,” shared STRIDE investigator Dr Kim Papp from Probity Medical Research, Waterloo, Ontario, Canada, in a press release. [https://www.alumis.com/news/press-releases/030924]

“Well tolerated and safe oral treatments with biologic-like efficacy would represent a true innovation in the treatment of psoriasis. I am excited about the possibility of TYK2 inhibitors achieving that goal,” Papp continued.

“[These results] for ESK-001 support its potential as a new treatment option in moderate-to-severe psoriasis. I am thrilled to see how this treatment may offer hope and relief for … patients who need more effective options,” he added.

Dr Jörn Drappa, Chief Medical Officer, Alumis, echoed Papp’s sentiments. “We are very excited about the risk-benefit profile observed in our phase II programme. These highly promising data support the potential for a best-in-class profile of ESK-001 in psoriasis.”

Open-label extension

In the ongoing open-label extension phase (n=164) evaluating ESK-001 40 mg QD and 40 mg BID, 90 percent of evaluable patients on the BID dose achieved PASI75, with a continued favourable safety profile after 16 weeks of treatment. Moreover, 57 percent of those on the BID dose achieved PASI90, while a third achieved PASI100.

“We were pleased to see that ESK-001 was able to maximally inhibit the target safely, and this translated to a high degree of clinical improvement at week 12 that continued to increase over time,” said Drappa.

The results support the planned initiation of phase III trials in the second half of 2024.

“Doses that did not achieve maximum target inhibition led to a significant reduction in long-term efficacy,” noted Martin Babler, President and Chief Executive Officer, Alumis. “This gives us confidence as we prepare to initiate phase III trials with the goal of offering an oral treatment with greater efficacy as compared to existing treatments, not only for patients with psoriasis but for other immune-mediated diseases as well.” [https://www.alumis.com/news/press-releases/030924]