Risankizumab and the KNOCKOUT Study, with Andrew Blauvelt, MD, MBA

Late-breaking data presented at the American Academy of Dermatology (AAD) 2024 Annual Meeting in San Diego, CA this weekend showed a high induction dose of risankizumab (Skyrizi) is associated with significantly improved skin area severity among patients with moderate to severe plaque psoriasis at 52 weeks.

The findings from the phase 2 KNOCKOUT trial, presented by former Oregon Medical Research Center investigator Andrew Blauvelt, MD, MBA, additionally showed a significant reduction in treated patients’ resident memory T (TRM)17 cell numbers over the same duration—indicating that intervening with the interleukin 23 (IL-23) inhibitor risankizumab with a few strong, timely doses may provide a more durable treatment response in psoriasis.

In the first segment of an interview with HCPLive at AAD 2024, Blauvelt discussed the conceptualization of the KNOCKOUT study. He noted that the first in-human, phase 1 trial to assess Risankizumab in patients with psoriasis tested a high, single dose.

“So, we had that experience and publication where we saw that just a single dose of that drug led to really dramatic levels of clearance and long-term remissions of psoriasis with one dose, but then the drug got developed at a much lower dose and more on a regular basis, as is done often with drug development,” Blauvelt said. “And that original study, people kind of forgot about it.”

Blauvelt additionally recalled the developing understanding of TRM cells as a contributor to psoriasis clearance, even after successful treatment.

“it's pretty clear now that that cell is the cell that stays in the skin and then after a while, if the treatment is withdrawn or stopped or interrupted in any way, that's the cell that stirs things up again,” Blauvelt explained. “It gets psoriasis going again. And that's actually the reason why psoriasis occurs in the exact same spots over and over again.”

In recent years, dermatologists have come to understand that IL-23 inhibition may mitigate the TRM cell based on clinical outcomes showing a longer duration of disease management with IL-23 inhibitors. This led to Blauvelt proposing a trial studying a higher dose of risankizumab’s effect on the memory T cell, associated with long-term Psoriasis Area Severity Index (PASI) benefit.

“I like the name of the study—I came up with "KNOCKOUT’,” Blauvelt said. “People in boxing, they get up off of the mat, but sometimes they stay down for a long time. So, we wanted to knock down psoriasis, see how long it could stay on the mat, if you will. We didn't really expect to cure it, but maybe knock it out for a long time.”