WASHINGTON – A series of investigating whether high-dose IL-23 inhibition can target resident memory T cells and thereby induce long-term remission, Andrew Blauvelt, MD, MBA, reported at the annual research symposium of the National Psoriasis Foundation.
Understanding and trying to target resident memory T (Trm) cells has become a hot topic in psoriasis research, with possible importance for psoriatic arthritis as well. The cells, which normally develop within tissues in a pathogen-specific manner and persist after infections resolve, have been found in healed psoriatic skin and are believed to be responsible for recurrences of psoriasis at the same sites previously affected by the disease. Research suggests, moreover, that Trm cells are dependent on IL-23 for their survival, said Dr. Blauvelt, an investigator with the Oregon Medical Research Center, Portland.
Dr. Andrew Blauvelt
Using an approach he has coined “knockout” therapy, 20 adult patients at the center were randomized 1:1 in double-blinded dosing to receive 300 mg or 600 mg of risankizumab (two and four times the standard initial doses, respectively) at 0, 4, and 16 weeks, and were seen every 4-6 weeks in a double-blinded follow-up period. Skin biopsies of lesional and nonlesional skin were collected at weeks 0 and 52 for RNA sequence analysis to evaluate changes in Trm cell number and effector function.
At week 28, almost all patients – 94% – achieved a Psoriasis Area and Severity Index 90 score, and 83% achieved PASI 100. At week 52, of the 18 still-enrolled patients, 69% had PASI 90 scores and 43% maintained PASI 100 scores. “We’re not curing psoriasis, but that is incredible to have 43% still clear 9 months after the last dose,” Dr. Blauvelt said.
The findings are interim results that pool the two doses of risankizumab (Skyrizi). An evaluation of maintenance of efficacy with the 300-mg versus 600-mg doses and results of the skin biopsies will be presented at the 2024 annual meeting of the American Academy of Dermatology, he said. Patients who have not had recurrences are being followed up to week 100 (unblinded).
Skin biopsy findings together with levels of clearance will “add insight as to whether high-dose IL-23 inhibition is associated with higher levels of complete clearance (i.e., PASI 100) over long periods of time, and whether remissions are associated with more profound knock-down of Trm cells,” Dr. Blauvelt wrote in an editorial on Trm cells in psoriasis published in the Journal of Psoriasis and Psoriatic Arthritis.
Risankizumab was approved by the Food and Drug Administration for moderate to severe plaque psoriasis in 2019, and for active psoriatic arthritis in 2022.
Impact of IL-23 inhibition
A 2021 study, Dr. Blauvelt noted in his presentation, showed that the IL-23 inhibitor guselkumab (Tremfya) reduced the number of Trm cells in healed psoriatic skin, while the IL-17A inhibitor secukinumab (Cosentyx) did not affect Trm cells.
Other researchers have concluded that local IL-23 is required for the proliferation and retention of Trm cells in the skin, he said, noting also that, as a class, IL-23 blockers “are associated with the longest disease-free intervals” in patients with psoriasis.
Dr. Christopher T. Ritchlin
Research showing loss of Trm cells in biopsies of cleared skin is “incredibly important,” as is data showing that IL-23 may be “a critical survival factor” for Trm cells, said Christopher Ritchlin, MD, MPH, a rheumatologist and director of the clinical immunology research unit at the University of Rochester (N.Y.) Medical Center, who attended the NPF meeting and was asked to comment on the growing interest in Trm cells. He did not hear Dr. Blauvelt’s presentation but has followed Trm research in psoriasis.
Measuring Trm cells in synovial tissue of patients with psoriatic disease is, in fact, on the agenda of a new research team coled by Dr. Ritchlin that is part of the Autoimmune and Immune-Mediated Diseases Program of the Accelerating Medicine Partnership – a public-private partnership that aims to collect and analyze troves of biological data in order to illuminate the cellular and molecular interactions leading to autoimmune diseases.
“Resident memory T cells have been thought to be cells that are constrained to being resident in the tissue, and while that’s largely true, there’s more recent data showing that they actually can dedifferentiate and go back to the lymph node and then go back to the joint again,” Dr. Ritchlin noted in an interview. “So it’s a more complicated story,” but nonetheless targeting the cells is a concept worth exploring therapeutically.
Moving toward a cure?
The high induction doses of risankizumab in Dr. Blauvelt’s phase 2 “knockout” study were well tolerated through week 40, with safety profiles similar overall to those reported in previous studies of risankizumab and “no new safety signals,” Dr. Blauvelt said at the meeting.
(At baseline, patients had a mean disease duration of 21 years, a mean affected BSA of 21, and a mean PASI of 18.5. Seven had prior treatment with biologic medications, though not in the prior 4 months and not with risankizumab.)
In lieu of a cure, which is still possible in the next 10 years, he said, patients are eager for longer-term remission and the ability to break away from established regular dosing. After publication of a phase 1 study of risankizumab, in which a notable number of patients experienced complete skin clearance up to 1 year following a single high dose, “we started getting numerous calls in our [clinical trials] office from patients who said ‘I want to be on that drug that you give once a year,’ ” Dr. Blauvelt said. (The high dosing was not investigated any further in phase 2 and 3 research, he added.)
While the “knockout” study adopts a “hit hard” approach, it is also possible that a strategy to hit both hard and early after disease onset may induce long-term remission and/or cure of the disease. “I’m talking about using the best things first. There are hints that if we treat early, maybe we can keep [psoriasis] from becoming a chronic disease, keep it from ‘setting up shop’ if you will,” he said, noting that the “hit hard, hit early” concept is not unique to dermatology.
During a discussion period, Dr. Blauvelt said that in a future iteration of the “knockout” study, he would like to evaluate risankizumab in patients with disease duration under 12 months. It may also be valuable to look not only at Trm cells, but more broadly at other elements of the tissue architecture before and after treatment.
Among other strategies for achieving long-term remission and/or cure is the expansion of regulatory T cells, which work to “control inappropriate immune responses” and calm inflammation. Defects in the number and function of regulatory T cells are associated with psoriasis and other autoimmune diseases, and it appears in early research from other investigators that low-dose IL-2 can induce the expansion of regulatory T cells and improve psoriasis. “Keep tuned,” Dr. Blauvelt said.
Dr. Blauvelt disclosed ties with numerous pharmaceutical companies. Dr. Ritchlin had no disclosures.