Psoriasis control maintained with less frequent guselkumab dosing

A 16-week dosing interval for the IL-23 inhibitor guselkumab appears to sufficiently keep psoriasis controlled among patients who have achieved complete skin clearance shortly after starting standard treatment with the drug, according to the phase IIIb GUIDE clinical trial.

The primary endpoint of noninferiority of extended guselkumab dosing (ie, every 16 weeks) vs every 8 weeks was met, with more than 90 percent of patients having maintained almost clear skin (Psoriasis Area and Severity Index [PASI] score <3) at week 68 regardless of treatment frequency (91.9 percent vs 92.6 percent; odds ratio [OR], 0.92, 90 percent confidence interval [CI], 0.45–1.87; p=0.001). [JAMA Dermatol 2024;doi:10.1001/jamadermatol.2024.2463]

The analysis included 297 super responders (mean age 39.4 years, 68 percent male), that is patients who had Psoriasis Area and Severity Index (PASI) score of 0 at weeks 20 and 28 after receiving subcutaneous injections of 100 mg guselkumab at weeks 0, 4, 12, and 20. Of these patients, 149 (50.2 percent) were randomly assigned to subsequently receive guselkumab every 16 weeks and 148 to continue receiving treatment every 8 weeks for maintenance of disease control.

Clinical, immunologic effects

The proportion of patients with PASI score ≤1 and PASI score 0 remained consistent through week 68, although the numbers were higher with the 8-week dosing interval (PASI ≤1: 89.9 percent vs 79.2 percent; p=0.01; PASI 0: 81.1 percent vs 69.1 percent; p=0.02).

Nevertheless, the rates of PASI 75/90 responses were high and comparable between the every-16-weeks and every-8-weeks dosing arms (PASI 75: 94.0 percent vs 92.6 percent; p=0.63; PASI 90: 85.9 percent vs 91.9 percent; p=0.10). Mean PASI (0.4 vs 0.1, respectively) and affected body surface area (0.4 percent vs 0.2 percent) remained low through week 68 with both dosing intervals.

According to the investigators, these clinical effects corresponded with changes in immunologic parameters, including blood and skin biomarkers associated with psoriasis. “We showed that IL-17A, IL-17F, IL-22, and β defensin (BD)–2 serum levels were reduced as early as week 4 with guselkumab treatment and remained suppressed through week 68. In turn, lesional skin CD8-positive tissue-resident memory T (TRM)–cells were normalized to nonlesional skin levels by week 28.”

Finally, the clinical and immunologic outcomes were in line with those reported by patients. For instance, more than three-fourths of patients reported that psoriasis had no impact at all on their quality of life (Dermatology Life Quality Index [DLQI] 0/1: 77.9 percent vs 83.1 percent; p=0.25).

“Our findings suggest that early skin clearance with guselkumab is accompanied by rapid and sustained suppression of TRM cells in lesional skin, after which an extended dosing interval effectively controlled disease activity in super responders,” the investigators said.

“Whether non–super responders are capable of maintaining long-term disease control with an extended dosing interval was not studied in the GUIDE clinical trial. Achievement of early and complete skin clearance at two consecutive visits, representing a high level of stability of response to treatment, may be a critical indicator for effective control of disease activity with an extended dosing interval,” they added.

Well-tolerated

In terms of safety, 70.2 percent of patients overall experienced a treatment-emergent adverse event (TEAE), with the most common being nasopharyngitis and headache. TEAEs led to treatment discontinuation in 11 patients (1.3 percent). The frequency of treatment-emergent serious AEs was similar between the every-16-weeks and every-8-weeks dosing arms (6.3 percent vs 4.7 percent).

None of the patients had tuberculosis or inflammatory bowel disease, and the rates of candidiasis and major adverse cardiovascular events were low. Drug-related TEAEs were documented in 14.1 percent of patients with the 16-week dosing interval and in 17.6 percent with the 8-week dosing interval.

“Guselkumab was well-tolerated, [and] no new safety signals were identified,” the investigators said.

No need to continue regular dosing

The findings in GUIDE mirror those in the PSTELLAR trial, wherein extending ustekinumab dosing intervals to every 24 weeks from the standard dosing of every 12 weeks was feasible and maintained disease control in roughly 25 percent of patients with psoriasis, noted authors of an accompanying editorial. [JAMA Dermatol 2024;doi:10.1001/jamadermatol.2024.2462; Br J Dermatol 2017;177:1552-1561]

“In [PSTELLAR], patients who were 100 percent clear at week 28 (ie, super responders to ustekinumab) were the most likely ones to be able to maintain disease control with dosing every 24 weeks, essentially a similar conclusion as reported now in the GUIDE study,” wrote Dr Andrew Blauvelt of Blauvelt Consulting, Lake Oswego, Oregon, US, and colleagues.

“In other words, most patients achieving clear skin at week 28 [in GUIDE] do not need to continue on regular dosing. Injections can be spaced out in these patients deemed super responders, resulting in half as many injections over time, without losing efficacy,” they added.

Blauvelt and colleagues also pointed to the significance of examining how guselkumab affected the immune system in GUIDE. “Understanding drug effects on TRM is important, and decreased TRM cells have been shown to be a feature of drugs with long-term remission rates following withdrawal, as recently highlighted in the KNOCKOUT study,” wherein the clinical and immunologic effects of high induction doses of another IL-23 inhibitor, risankizumab, was examined. [AAD 2024, abstract LB1703, Blauvelt A, et al] 

“Clinical and biomarker results from the GUIDE study and those recently reported for PSTELLAR and KNOCKOUT suggest that IL-23 inhibition may offer the possibility of extended dosing, as-needed dosing, long-term remissions, and possibly cure, all of which are exciting possibilities for the future treatment of patients with psoriasis. Additionally, varied dosing strategies would better suit the needs of patients in real-world practice settings, in addition to reducing unnecessary health care costs,” they said.