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Short-Term High-Dose Psoriasis Therapy Shows Potential for Long-Term Disease Control

— High response rates out to 52 weeks with IL-23 inhibitor, correlating with eradication of T cells

MedpageToday

SAN DIEGO -- Short-term, high-dose treatment with risankizumab (Skyrizi) induced long-term control of plaque psoriasis in association with eradication of resident memory T cells (TRM), a small proof-of-principle study showed.

Two different doses of the interleukin (IL)-23 inhibitor, administered at baseline, 4, and 16 weeks, led to 75% improvement in the Psoriasis Area and Severity Index (PASI) at 52 weeks in 83% of patients. More than 60% of patients had 90% improvement (PASI 90), and 43% had 100% improvement (PASI 100).

Consistent with IL-23's essential role in plaque psoriasis pathogenesis, the TRM count declined dramatically with treatment and remained at levels similar to normal skin, reported Andrew Blauvelt, MD, of the Oregon Medical Research Center in Portland, at the American Academy of Dermatology meeting.

"When we look at T-cell populations of psoriasis lesions, we can see all kinds of T cells at week zero ... [but] when we look at nonlesional skin at week zero, we see relatively few T-cell populations," said Blauvelt. "At week 52 you can see right away that [lesions] look like nonlesional skin at 52 weeks."

The higher dose of risankizumab essentially eradicated all T cells at week 52, including cells that produce IL-17, another key driver of psoriasis pathogenesis, he continued. A few TRM remained at 52 weeks in patients treated with the lower dose.

"Clinical efficacy was rapid and resulted in high response rates of skin clearance through week 52 with no dose dependency between the groups," said Blauvelt. "High induction doses of risankizumab were well-tolerated, with no new safety signals... . Larger prospective studies are needed to further evaluate the therapeutic potential of high induction doses of risankizumab to induce long-term remissions of psoriasis."

An unidentified member of the audience asked whether the results indicate remission or cure.

"I don't think it's cure," said Blauvelt. "This is a 2-year study, and the patients who were clear at week 52, I think three or four of them were still clear far into the second year. About half of them have trickled back, but it's taking a long time. I expect everybody to kind of trickle back, but it will be interesting to look at the year-2 time point and see if we have anybody at PASI 100."

In response to another question, Blauvelt noted that patients with short disease duration appear to do better with biologic agents and are more likely to maintain response with longer intervals between dosing.

"I personally think that if we use high induction doses like this in patients with short disease duration that we could possibly cure some folks," he said. "It's the hit-hard, hit-early hypothesis. We see it throughout medicine. You don't wait for the disease to establish itself to create those resident memory cells to take root."

Previous studies suggested is driven by TRM. The cells remain in psoriasis lesions even after healing and can induce multiple recurrences at the same site, said Blauvelt. TRM induction and activation might be dependent on IL-23, which would be consistent with long-term remissions observed in some patients after withdrawal of anti-IL-23 treatment.

Early clinical studies of risankizumab evaluated high-dose therapy, and a single dose often lead to long-term remissions.

"The objective of this study was to go back to some of those high doses used in the original phase I studies to see whether a high induction dose of risankizumab can knock out psoriasis, induce long-term remissions, and on a tissue level, see whether [the treatment effect] is due to an effect on the resident memory T-cell population," said Blauvelt.

The single-center study included 20 adults with moderate to severe psoriasis and no prior treatment with risankizumab. Investigators randomized the patients to 300-mg or 600-mg doses, administered at baseline, 4, and 12 weeks. Skin biopsies of lesions and nonlesional skin were obtained at baseline and week 52. The primary endpoint was the change in TRM from baseline to week 52. Secondary endpoints included safety at 52 weeks and PASI 100 at weeks 28, 40, and 52.

Single-cell RNA sequencing analysis showed different distribution of T-cell subgroups at baseline in lesional and nonlesional skin. Follow-up biopsies at week 52 showed a similar distribution of T-cell populations in lesional skin and nonlesional skin at baseline. Notably, TRM 17 cells were significantly reduced at week 52 as compared with baseline in both treatment groups (P=0.04).

Patients randomized to the lower dose of risankizumab had slightly better PASI scores. Both treatment groups achieved PASI 75 responses from week 12 to week 22 and in the 300-mg group at weeks 28 and 34. All patients in the 300-mg group met PASI 90 response criteria at weeks 16, 22, and 28 as did more than 80% of patients in both groups at weeks 34, 40, and 46. All patients in the 300-mg group had PASI 100 responses at week 22, whereas 70-80% of patients in the 600-mg arm achieved PASI 100 by week 28.

A single severe treatment-emergent adverse event occurred in the 300-mg group. No patient discontinued treatment or required dose reduction or interruption.

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined ľֱ in 2007.

Disclosures

The trial was supported by AbbVie.

Blauvelt and several co-investigators reported relationships with multiple pharmaceutical companies, and some reported working for AbbVie.

Primary Source

American Academy of Dermatology

Blauvelt A, et al "High induction dosing of risankizumab in patients with moderate-to-severe plaque psoriasis: 52-week results from the phase II KNOCKOUT study" AAD 2024; Late-Breaking Abstract.