High Risankizumab Induction Dose Rapidly Clears Psoriasis, Reduces Resident Memory Cells

Andrew Blauvelt, MD, MBA

High induction doses of risankizumab (Skyrizi) was associated with rapid and high rates of skin clearance, as well as long-term reduction in tissue-resident memory T 17 (T_RM17) cells among patients with plaque psoriasis in new phase 2 trial data.¹

In a late-breaking session at the American Academy of Dermatology (AAD) 2024 Annual Meeting in San Diego this weekend, investigators from the ongoing KNOCKOUT trial reported that the IL-23 inhibitor risankizumab was associated with significant reduction in patient T_RM17 cell numbers at 52 weeks, as well as a mean improvement in Psoriasis Area Severity Index (PASI) exceeding 80% by 12 weeks—sustained through 52 weeks as well.

The findings, presented by former Oregon Medical Research Center investigator Andrew Blauvelt, MD, MBA, suggest the “knockout therapy” approach with risankizumab in patients with plaque psoriasis may provide a substantial and long-term reduction in disease severity.

“Basically, what we’re showing here is that linking these long-term remissions to knockout of the resident memory (cell) population—we think the persistence of the efficacy is due to the persistent loss of the memory T cells,” Blauvelt said.

KNOCKOUT is an ongoing phase 2, double-blind, single-center study analyzing risankizumab 300 mg and 600 mg doses in the induction of long-term psoriasis remission through reduction of the TRM cell numbers in affected skin. The US Food and Drug Administration (FDA) approved risankizumab for the treatment of moderate to severe psoriasis in adults who are candidates for phototherapy or systemic therapy in April 2019.

Prior interim analyses from the KNOCKOUT trial showed 83% of treated patients achieved skin clearance per PASI 100 at 28 weeks. The rationale for this assessment presented at AAD 2024 was due to the understood “essential role” of IL-23 in psoriasis pathogenesis and TRM cell retention and proliferation.

Adult patients ≥18 years old with moderate to severe psoriasis who met the following criteria were enrolled in the trial:

• Psoriasis onset ≥6 months
• Body Surface Area (BSA) ≥10
• PASI ≥12
• No prior Risankizumab use

Investigators randomized patients 1:1 to either 300 mg or 600 mg subcutaneous risankizumab, with dosing occurring at baseline, then weeks 4 and 16. TRM cells were analyzed by skin biopsies of lesional and non-lesional skin at weeks 0 and 52.

The assessment included 20 patients randomized to either 300 mg (n = 10) or 600 mg (n = 10) doses. Seven (35%) participants were female; mean age was 46.8 years old. Another 16 (80%) participants were White. Baseline mean PASI and BSA were 18.5 and 20.9, respectively. Four patients were lost to either follow-up or withdrawn consent before the week 52 visit.

Blauvelt and colleagues observed that the high risankizumab induction dose was linked to reduced counts of epidermal TRM cells. Lesional inflammatory cells returned to levels observed in non-lesional skin by week 52, as TRM17 cells were significantly reduced.

The team additionally reported fast-acting and significant improvement in PASI 75, 90 and 100 responses from baseline, with mean absolute PASI falling under 5% by week 8 and maintaining that rate through 52 weeks.

Regarding safety, investigators observed no treatment-emergent adverse events related to study treatment, and only 1 serious adverse event, in the 300 mg arm. No new safety signals with risankizumab were observed.

“TRM17 reductions noted with high induction risankizumab dosing may explain the cellular rationale for durability of skin clearance noted in patients with moderate-to-severe psoriasis,” investigators concluded. “Larger prospective studies are needed to further evaluate therapeutic potential of high induction doses of Risankizumab to induce long-term remissions of psoriasis.”

References

1. ^{Blauvelt A, Gudjonsson JE, Matheson R, Jiang R, et al. High Induction Dosing of Risankizumab in Patients with Moderate-to-Severe Plaque Psoriasis: 52 Week Results From the Phase 2 KNOCKOUT Study. Abstract presented at: American Academy of Dermatology (AAD) 2024 Annual Meeting. March 7 – 12, 2024. San Diego, CA.}
2. ^{Gingerich CP. FDA Approves Risankizumab for Plaque Psoriasis. HCPLive. Published online April 24, 2019. https://www.hcplive.com/view/fda-approves-risankizumab-for-plaque-psoriasis}