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High induction doses of risankizumab — at double and quadruple the approved 150 mg dose — produced rapid and durable skin clearance in patients with moderate-to-severe plaque psoriasis while significantly reducing tissue resident memory T cells (TRM) in the just-published phase 2 KNOCKOUT study led by Andrew Blauvelt, MD, MBA.
The small study randomized 20 patients to either 300 mg or 600 mg doses of the interleukin (IL)-23 blocker at weeks 0, 4, and 16. At weeks 28 and 52, 83% and 44% of all patients, respectively, achieved a Psoriasis Areas and Severity Index (PASI) 100 response with no new safety signals, Blauvelt and his co-investigators reported in Nature Communications.
Moreover, while only a minority of patients completed the entire follow-up period of 100 weeks’ duration, it is “intriguing to note,” they reported, that four patients maintained PASI 90 and two patients remained completely clear at 100 weeks — 84 weeks after their last dose of risankizumab (Skyrizi), which is approved for treating plaque psoriasis and psoriatic arthritis.
“This treatment strategy leads to higher short-term efficacy than what has been documented with any other psoriasis treatment, with no worrisome safety issues,” Blauvelt, of Blauvelt Consulting in Annapolis, Maryland, told Medscape Medical News in an e-mail interview. “And complete clearance lasts for a very long time due to knockout of resident memory T cells within the skin.”
Changes in the number and function of TRM cells, which have been shown in prior research to be dependent on IL-23 for their survival, was the primary outcome of the KNOCKOUT study. Single-cell RNA-sequencing of full-thickness skin biopsies performed at weeks 0 and 52 showed a marked reduction of TRM cells in lesional skin at week 52, with numbers that were similar to the number of nonlesional TRM cells at week 0, the authors reported in the study.
Asked to comment on the results, Christopher Griffiths, MD, a psoriasis expert who has written about curing psoriasis, said in an email that the study “confirms the ability of high-dose risankizumab to clear psoriasis” for the longer term in some patients with moderate-to-severe disease, “accompanied by normalization of numbers of CD8+ tissue resident memory T cells and pathogenic cytokines in the previously involved skin.”
“Both the clinical and immunological data point to a break or reversal of the immunological drive that determines persistence of psoriasis,” Griffiths, emeritus professor of dermatology, The University of Manchester, Manchester, and adjunct professor, King’s College London, London, England, told Medscape Medical News.
Also asked to comment on the results, Joel Gelfand, MD, MSCE, director of the psoriasis and phototherapy treatment center, at the University of Pennsylvania, Philadelphia, said the study “challenges clinical practice paradigms regarding dosing of risankizumab” for psoriasis.
“A remarkable aspect of IL-23 inhibition,” he said, “is that there does not appear to be safety issues with increasing doses.” Patients with ulcerative colitis “receive seven times the dose of risankizumab in the first year compared to the dose psoriasis patients receive,” he noted.
“The KNOCKOUT study provides initial evidence that higher doses of [the biologic] may achieve better outcomes for psoriasis patients, possibly mediated by a reduction in pathogenic memory T cells in the skin,” Gelfand said.
One Arm of ‘Hit hard, Hit early’ Hypothesis
The phase 2 study findings come a decade after a phase 1 study of a single high dose of risankizumab revealed long-term clearance. In six of eight patients who entered an optional follow-up extension study, PASI 100 responses were sustained for up to 66 weeks, Blauvelt said during a grand rounds lecture titled “Curing Psoriasis” held at the Department of Dermatology, George Washington University (GWU) School of Medicine and Health Sciences, Washington, D.C, in August 2025.
The new findings also build upon a study published in 2020 by Blauvelt and colleagues — the IMMhance study — which randomized patients to continuous risankizumab therapy vs treatment withdrawal at week 28. Doses were 150 mg — not higher. Still, approximately 10% of patients who were completely clear after three doses (weeks 0, 4 and 16) maintained their PASI 100 status at week 76 — over a year after the last dose.
In the new KNOCKOUT study (in which two patients remained completely clear at 100 weeks), it’s unclear what factors led to the “super-response” in a couple of patients, Blauvelt said in the interview.
Other research published in recent years has shown that patients with a short disease duration (< 1-2 years) respond better to risankizumab and other IL-23 inhibitors than patients with a long duration of disease. But in the KNOCKOUT study, where the mean length of disease course upon entry was over 20 years, “we had only two short-disease duration patients and neither of them were super responders,” he said.
“I do believe, however, that treating short-disease duration patients with knockout therapy will lead to long-term remissions and potential cures in a subset of patients,” said Blauvelt, formerly the president of the Oregon Medical Research Center, who coined the term “KNOCKOUT.”
Blauvelt has long talked about a “hit hard, hit early” treatment approach. The KNOCKOUT study gets part-way there. “To me, ‘hit-hard, hit early’ means treating patients with < 1 year disease duration and hitting with a higher-than-approved dose,” he said in the GWU presentation.
Future answers may lie in research being conducted by the biotechnology company Oruka Therapeutics on a new YTE-modified monoclonal antibody targeting IL-23p19, ORKA-001, Blauvelt said in the presentation.
YTE-modified antibodies have specific mutations that “allow increased binding affinity to FcRN (the neonatal Fc receptor) and allow for antibodies to be taken up by macrophages and spit back out and recycled back into the bloodstream, extending half-life,” he explained. Several YTE-modified antibodies have been approved, including one for respiratory syncytial virus prophylaxis (nirsevimab-alip).
In a phase 1 interim analysis presented at 2025 European Academy of Dermatology and Venerology (EADV) Congress, the mean half-life of ORKA-001 was found to be 100 days, more than triple that of risankizumab.
One phase 2 trial (EVERLAST-A) is underway, and another (EVERLAST-B) is scheduled to begin soon, with “knockout” dosing of 600 mg, with hopes of achieving once-yearly dosing. Patients with short disease duration are not being specifically recruited into either of these studies, Blauvelt said in the interview, and plans for phase 3 enrollment are under discussion now.
In the GWU lecture in August, Blauvelt expressed hope that a subset of short-disease-duration patients would be enrolled in the phase 3 research “so we’ll be able to finally test this hypothesis of hit-hard, hit early.”
Potential for Cure?
According to Griffiths, the KNOCKOUT study data “in part confirm our hypothesis that psoriasis may be curable using a combinatorial approach, one strand of which is high-dose biologics used early in the disease course.”
Griffiths described this combination, personalized approach, which includes early intervention with biologics, cell-based or advanced therapeutics, and lifestyle modification, in a 2024 perspective piece in the Journal of Investigative Dermatology, titled “Curing Psoriasis” — a paper that Blauvelt has called “fascinating.” Cure is defined in the paper as clearance of psoriasis for at least 5 years following withdrawal of treatment.
Studies of cell-based or advanced therapeutics “probably [offer] the best chance of achieving cure,” Griffiths told Medscape Medical News. Studies of their “efficacy and ability to effect immune reset are now underway for severe psoriasis.”
Blauvelt sees early intervention with high-dose biologics as the most “accessible” strategy for now. “We can use what we have now in better ways with better outcomes,” he said in the GWU lecture.
The KNOCKOUT study’s tissue findings bring increased understanding of the role of TRM cells in psoriasis recurrences and “explain in part the biological mechanisms underlying long-term psoriasis remissions after anti-IL-23 treatment,” Blauvelt and his co-authors wrote.
TRM cells are cells that develop in tissues in response to pathogen exposure and are responsible for protecting tissues from reinfection. “In the case of psoriasis, it’s not memory to a pathogen but memory to autoimmune inflammation specific to the disease,” Blauvelt explained in the GWU lecture. “This is why psoriasis always comes back in that elbow or that knee.”
Among the reported tissue findings from the KNOCKOUT study in Nature Communications are downregulation of CD8+TRM17 cell numbers and function and normalization of inflammatory gene expression in keratinocytes after high doses of risankizumab. All tissue data — including “what happens to cell types other than tissue resident memory T cells, such as keratinocytes, dendritic cells, endothelial cells, and fibroblasts” — have been submitted for publication in another journal, Blauvelt told Medscape Medical News.
The patient numbers in the KNOCKOUT study were too small, and baseline disease characteristics too unbalanced, to draw any definitive conclusions comparing remission with the two dosage groups, he and coauthors wrote in the paper.
The KNOCKOUT study was funded by AbbVie, which participated in the trial design, research, analysis, collection, and interpretation of data, and review and approval of the publication. Blauvelt disclosed that he is a scientific adviser/received honoraria from AbbVie and Oruka, among other companies, and he is a stockholder for Oruka. Gelfand disclosed he has served as a consultant for AbbVie, Oruka, and other companies. Griffiths disclosed receiving honoraria and/or research support from AbbVie, Amgen, Boehringer-Ingelheim, Bristol Meyers Squibb, and other companies.
