Guselkumab a Hit in Phase III for PsA Save

The monoclonal antibody guselkumab (Tremfya), which binds the interleukin (IL)-23 p19 subunit, was effective for psoriatic arthritis in two large clinical trials, providing comprehensive benefits for this heterogeneous disorder, investigators reported in The Lancet.

In one of the trials, DISCOVER-1, a 20% improvement on the response criteria established by the American College of Rheumatology (ACR20) at week 24 was achieved by 59% of patients receiving 100-mg subcutaneous guselkumab every 4 weeks and by 52% of those given the monoclonal antibody every 8 weeks compared with 22% of those randomized to placebo. These represented differences versus placebo of 37% (95% CI 26-48%, P0.0001) and 30% (95% CI 19-41%, P0.0001), respectively, according to Atul Deodhar, MD, of Oregon Health and Science University in Portland, and colleagues.

In the second study, DISCOVER-2, ACR20 responses at week 24 were seen in 64% of both guselkumab groups compared with 33% of those in the placebo group, which represented percentage differences versus placebo of 31% (95% CI 22-39%) for the every 4-weeks-group and 31% (95% CI 23-40%) for the every-8-weeks group (P0.0001 for both), according to Philip J. Mease, MD, of the University of Washington in Seattle, and colleagues.

DISCOVER-1 included 381 patients who were either biologic-naive or who had previously received tumor necrosis factor (TNF) inhibitor treatment, while DISCOVER-2 enrolled 741 patients who were all biologic-naive.

"The efficacy of the drug in the musculoskeletal domains -- by which I mean peripheral arthritis, enthesitis, and dactylitis -- were consistent between the two trials even though they were different trial populations," Mease told MedPage Today. "The results were consistent with what we have come to expect from the best performing drugs in psoriatic arthritis."

The pathogenesis of the myriad clinical manifestations of psoriatic arthritis continue to be elucidated, he and his colleagues explained. "The IL-23/T-helper cell 17 pathway -- via downstream IL-17 expression -- appears crucial to skin manifestations. IL-23 can also induce IL-22, a cytokine implicated in enthesitis and bone formation and, in part via IL-17A and TNF induction, elicit the joint symptoms and damage that are hallmarks of psoriatic arthritis."

Guselkumab is approved for the treatment of moderate-to-severe psoriasis. The drug's manufacturer, Janssen, funded the two currently reported pivotal trials.

DISCOVER-1

DISCOVER-1 took place at 86 sites in 13 countries. Participants' mean age was 48, and the majority were white. Average duration of psoriatic arthritis was almost 7 years, and mean numbers of swollen and tender joints at baseline were approximately 10 and 19, respectively. Baseline scores on the Psoriasis Area and Severity Index (PASI) averaged 8.5.

More than half were taking methotrexate and nonsteroidal anti-inflammatory drugs. Thirty-one percent had received one TNF inhibitor and 4% had been treated with two.

At week 24, 36% and 30% of patients in the every-4-weeks and every-8-weeks groups had achieved ACR50 responses compared with 9% of the placebo group, while ACR70 responses were seen in 20%, 12%, and 6%, respectively.

Similar results were seen for patients with and without prior exposure to TNF inhibitors. For those who had previously used these agents, ACR20 responses were seen in 58% and 56% of the every-4-weeks and every-8-weeks groups, respectively, while for those who had not previously received treatment with a biologic, the numbers were 60% and 50%, respectively.

A 75% improvement on the PASI at week 24 was seen in 86% and 76% of the every-4-weeks and every-8-weeks groups compared with 14% of the placebo group, and minimal disease activity was observed in 30%, 23%, and 11%, respectively. Minimal disease activity combines joint, skin, and entheseal activity with pain and physical function, the investigators noted.

Physical function was determined via the Health Assessment Questionnaire-Disability Index. Mean changes from baseline at week 24 were -0.40 (95% CI -0.48 to -0.31) in the every-4-weeks group and -0.32 (95% CI -0.41 to -0.24) in the every-8-weeks group compared with -0.07 (95% CI -0.16 to -0.01) in the placebo group (P0.0001 for both).

The most common adverse events were nasopharyngitis, upper respiratory tract infections, and increases in liver enzymes.

The study findings "provide strong evidence that guselkumab provides a novel mechanism of action, via targeting the p19 subunit of IL-23, to treat the diverse clinical manifestations of psoriatic arthritis," the investigators concluded.

DISCOVER-2

DISCOVER-2 enrolled patients from 118 sites in 13 countries, and will continue to week 100.

Participants' mean age was 45, almost all were white, and disease duration was 5.5 years. The average number of swollen and tender joints were 12 and 21, respectively, and baseline PASI was 9.9.

At week 24, ACR50 responses were seen in 33% of the every-4-weeks group and 31% of the every-8-weeks group compared with 14% of the placebo group, while ACR70 responses were observed in 13%, 19%, and 4%, respectively.

PASI75 responses were seen in 78%, 79%, and 23%, while minimal disease activity was reported in 19%, 25%, and 6%, respectively.

Patients in the trial also underwent radiography of the hands and feet at baseline and at week 24. Those in the every-4-weeks group had significantly smaller changes on radiographic scores by week 24 compared with placebo (0.29, 95% CI -0.05 to 0.63, vs 0.95, 95% CI 0.61-1.29, P=0.011), but differences were nonsignificant for the every-8-weeks group (0.52, 95% CI 0.18-0.86, P=0.072).

The data on dactylitis and enthesitis were pooled from the two DISCOVER trials. Changes in the dactylitis score at week 24 were -5.97 (95% CI -6.84 to -5.11) and -6.10 (95% CI -6.92 to -5.27) in the every-4-weeks and every-8-weeks groups, respectively, compared with -4.21 (95% CI -5.05 to -3.36) in the placebo group.

On the Leeds enthesitis index, changes in score from baseline at week 24 were -1.59 (95% CI -1.79 to -1.38) and -1.52 (95% CI -1.73 to -1.31) in the every-4-weeks and every-8-weeks groups compared with -1.02 (95% CI -1.22 to -0.82) in the placebo group.

Significant improvements also were seen on measures of disability and quality of life for the guselkumab groups.

The most common adverse events were upper respiratory tract infections, nasopharyngitis, bronchitis, and liver enzyme elevations. Serious infections were reported in 1% of the every-4-weeks group and in less than 1% of the every-8-weeks and placebo groups. There were no cases of Candida or opportunistic infections.

"There was no malignancy signal and no cardiovascular signal, and the serious infection rate was low," Mease said. "We also didn't see any flares of inflammatory bowel disease, which has occasionally been seen in the IL-17 inhibitor class," he said. "It really was a pretty pristine safety profile."

"Guselkumab was well tolerated and demonstrated robust efficacy in DISCOVER-2 across clinical domains crucial to achieving psoriatic arthritis remission, including reducing structural damage progression," the investigators concluded.

What's Next

"There will probably be some discussion when the application is made for approval for psoriatic arthritis about the frequency of dosing," Mease said. The application will be for both dose frequencies, the every-4-weeks and every-8-weeks regimens.

"That is partly based on the fact that, whereas the every-4-weeks dosing achieved statically significant inhibition of structural damage progression, the every-8-weeks dosing just missed the statistically significant separation. Sometimes the agency will only give you the smallest effective dose or frequency. We don't know whether or not both frequencies will be accepted," he said.

"In the dermatology space," Mease continued, "the standard dosing for psoriasis is every 8 weeks. But in psoriatic arthritis to get a little more oomph for the best structural damage inhibition in the most severe patients we would probably want to have the option of using it every 4 weeks."

Both studies were funded by Janssen Research and Development.

The authors reported financial relationships with Janssen, AbbVie, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, UCB, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Galapagos, Almirall, Genentech, Gilead, Sun Pharmaceuticals, Avotres Therapeutics, Beiersdorf, Dermira, Incyte, Reddy Labs, Valeant, Xbiotech, AstraZeneca, Cyxone, Daiichi, Eisai, Regeneron, Roche, Sanofi, Takeda, and Leo Pharmaceuticals; several co-authors are employees of Janssen.

Primary Source: The Lancet.  Deodhar A, at al "Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFα inhibitor treatment (DISCOVER-1): a double-blind, randomized, placebo-controlled phase 3 trial" Lancet 2020; 395: 1115-1125.