KNOCKOUT Trial: Revolutionising psoriasis treatment with high-dose therapy
Medicom interviewed Dr Andrew Blauvelt about the phase 2 KNOCKOUT trial (NCT05283135), which he presented as a late-breaking abstract at the American Academy of Dermatology (AAD) 2024 Annual Meeting in San Diego, CA, USA [1]. The 52-week results showed that a high induction dose of risankizumab is associated with significantly improved skin area severity among patients with moderate-to-severe plaque psoriasis. The primary outcome was long-term reduction in tissue-resident memory T 17 (TRM17) cells among patients with plaque psoriasis.Thank you so much for your time, Dr Blauvelt. Could you introduce yourself and share a bit about your work and research focus?
“My pleasure. I'm Dr Andrew Blauvelt, a dermatologist based in Portland, Oregon. My career has traversed three phases: starting as a physician-scientist at the NIH for 12 years, then as a professor of dermatology and immunology at Oregon Health and Science University, and for the past 13 years, I've been heavily involved in clinical trials at the Oregon Medical Research Center, focusing primarily on clinical trial work.”
You've recently discussed the KNOCKOUT study in psoriasis. Can you elaborate on its primary objectives and the findings?
“The KNOCKOUT study was initially an investigator-initiated grant, born from my idea and protocol, and later funded by AbbVie and the National Psoriasis Foundation. It turned into a collaborative study focusing on high induction doses of risankizumab for moderate-to-severe plaque psoriasis. Our main interest was in observing the effects of high doses (600 mg, as opposed to the standard 150 mg dose), inspired by a phase 1 study where significant and prolonged skin clearance was noted. This study aimed to explore the potential of high induction dosing to 'knockout' psoriasis, specifically targeting the IL-23 pathway and its effect on resident memory TRM17 cells believed to be responsible for psoriasis recurrences.”
Were there any innovative endpoints in this trial?
“Yes, our primary endpoint was quite novel. We looked at the loss of resident memory T cells at week 52, aiming to correlate long-term remissions with the reduction of these cells. We hypothesised that higher doses would result in a greater loss of these cells and thus longer remission periods.”
What were the major findings of the study?
“The study revealed 3 key outcomes: firstly, the high efficacy of the 600 mg induction dose in significantly reducing resident memory T cells at week 52. Secondly, we observed remarkable short-term clearance rates, with 83% of patients achieving complete clearance at week 28. Lastly, we noted long-term remission in a significant portion of patients, with 43% remaining clear at week 52, showcasing the potential of this dosing strategy for prolonged disease management.”
Did the study address safety concerns with such high doses?
“Indeed, safety was a crucial aspect of our study. IL-23 inhibitors, including risankizumab, are known for their favourable safety profiles. Our study's safety data mirrored this, with no significant side effects observed beyond what's expected in the general population, affirming the safety of high induction dosing.”
What implications do these findings have for psoriasis treatment?
“The implications are substantial. This approach, by significantly increasing the clearance rate with a pre-existing drug through altered dosing and scheduling, hints at a shift towards less frequent, more effective treatments. This method has garnered significant interest from patients and could disrupt the current treatment paradigm, offering a novel, highly effective treatment strategy for psoriasis.”
How do you see this treatment model moving forward?
“It's a bit in flux currently. The likelihood may be greater for a new entrant in the pharmaceutical industry to adopt high induction dosing for an IL-23 inhibitor from the outset, rather than established players revising the dosing strategies of their current drugs. There's a buzz about advancing this approach, so it's an exciting time for psoriasis treatment.”
- Blauvelt A, et al. High Induction Dosing of Risankizumab in Patients with Moderate-to-Severe Plaque Psoriasis: 52 Week Results From the Phase 2 KNOCKOUT Study. LB1, AAD 2024 Annual Meeting, 8–12 March, San Diego, USA.
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