麻豆传媒

The interleukin-17 isoforms -- interleukin-17A and interleukin-17F -- are implicated in the of psoriasis and there is evidence that dual inhibition also blocks interleukin-17F/F. This could lead to more complete suppression of inflammation and superior clinical outcomes compared with inhibition of interleukin-17A alone, according to researchers.

Previously, the phase 3 , , and trials showed that the use of bimekizumab (Bimzelx), a humanized monoclonal IgG1 antibody that selectively inhibits both interleukin-17A and interleukin-17F, led to greater clinical improvements in moderate-to-severe plaque psoriasis compared with the interleukin-12/23 inhibitor ustekinumab (Stelara), the tumor necrosis factor inhibitor adalimumab (Humira), and placebo.

Recently, the BE RADIANT phase 3b trial compared the efficacy and safety of bimekizumab with (Cosentyx), another humanized monoclonal IgG1 antibody that selectively neutralizes interleukin-17A, in patients with moderate-to-severe plaque psoriasis treated over a 48-week period. The investigation was led by Kristian Reich, MD, PhD, from the Center for Translational Research in Inflammatory Skin Diseases at the University Medical Center Hamburg-Eppendorf, in Hamburg, Germany, and reported in the .

The following Q&A discusses the study and its findings in greater detail. The answers are taken from the text of the paper (the researchers did not respond to requests for comment).

How was the study designed?

It is a multicenter, randomized, double-blind, active-comparator-controlled, parallel-group trial conducted across 77 sites in 11 countries. It included a 16-week initial treatment period followed by a 32-week maintenance treatment period. Patients who completed the 48-week double-blind period were eligible for enrollment in an ongoing 96-week open-label extension period.

How many patients were enrolled?

Between June 13, 2018, and May 7, 2019, 743 patients were enrolled. A total of 373 were randomly assigned to receive bimekizumab once every 4 weeks and 370 to receive secukinumab once a week to week 4, followed by once every 4 weeks.

What percentage of patients adhered to the 48-week treatment protocol?

Overall, 92.0% and 87.8% of patients randomly assigned to receive bimekizumab and secukinumab, respectively, completed the trial to week 48.

How was moderate-to-severe psoriasis defined?

Three measures were used: a score of 12 or higher on the 72-point Psoriasis Area and Severity Index (PASI), with higher scores indicating worse disease; psoriasis affecting at least 10% of the body-surface area; and a score of 3 or higher on the 5-point Investigator's Global Assessment (IGA) scale, with 0 representing complete clearance and 4 the most severe psoriasis.

What was found in terms of efficacy?

At 16 weeks and again at 48 weeks, the percentage of patients who had complete skin clearance or a PASI 100 response -- indicating a 100% reduction from baseline in their PASI score -- was higher with bimekizumab than with secukinumab, regardless of the dosing schedule.

At week 16, 230 patients (61.7%) treated with bimekizumab had a PASI 100 response compared with 181 patients (48.9%) who received secukinumab (adjusted risk difference 12.7%; 95% confidence interval [CI], 5.8 to 19.6; P<0.001). At week 48, the difference in treatment response was even more pronounced: 250 patients (67.0%) in the bimekizumab group had a PASI 100 response compared with 171 (46.2%) in the secukinumab group (adjusted risk difference 20.9%; 95% CI, 14.1 to 27.7; P<0.001).

Researchers also found that the proportion of patients with a PASI 90 response and an IGA score of 0 or 1 at week 48 was greater in patients treated with bimekizumab than with secukinumab, regardless of the dosing schedule. Similarly, 77.7% of patients treated with bimekizumab had a score of 0 or 1 on the Dermatology Life Quality Index (DLQI) at week 48, indicating that the impact of psoriasis on their daily lives was either nil or extremely low. By comparison, 70.3% of patients treated with secukinumab had a DLQI score of 0 or 1.

What did safety results show?

Researchers looked at all adverse events (AEs) occurring after the initial dose up to 140 days after the final dose. Their prespecified safety focus included infections, neutropenia, hypersensitivity, depression, major adverse cardiovascular events (MACE), liver function changes or enzyme elevations, cancer, and inflammatory bowel disease.

Overall, the incidence of AEs was similar in the two treatment groups. Through 48 weeks, AEs were reported in 86.1% of patients treated with bimekizumab and in 81.4% of patients treated with secukinumab. Serious AEs were reported in 5.9% and 5.7% of patients, respectively, and AEs leading to treatment discontinuation were reported in 3.5% and 2.7%.

Oral and oropharyngeal candidiasis occurred more frequently with bimekizumab than with secukinumab (19.3% vs. 3.0%). This finding is consistent with the contributions of interleukin-17A and interleukin-17F to against Candida infections at the oral mucosa, and with observations from previous studies of bimekizumab. These cases of candidiasis were predominantly mild or moderate, and more than 85% were treated with antifungal therapy and resolved during the trial.

New diagnoses of inflammatory bowel disease have been reported with interleukin-17A inhibitors, including one case of ulcerative colitis with bimekizumab across the BE READY, BE VIVID, and BE SURE phase 3 trials. In the current trial, one case of ulcerative colitis was reported with bimekizumab and one with secukinumab.

There were two cases of adjudicated MACE in the secukinumab group, and none in the bimekizumab group. There were also two deaths, both during the maintenance period. One death in the bimekizumab group occurred when the patient was struck by a car; and in the secukinumab group, a 70-year-old woman died of asphyxia adjudicated as MACE some 23 weeks after receiving the initial dose.

What is the study's take-home message?

Dual inhibition of interleukin-17A and interleukin-17F with bimekizumab was superior to inhibition of interleukin-17A with secukinumab in the treatment of plaque psoriasis, with more complete clearance of psoriatic lesions through 48 weeks of treatment. Although bimekizumab was more likely to be associated with oral candidiasis than secukinumab, study data suggest that inhibition of both interleukin-17A and interleukin-17F with bimekizumab may provide greater clinical benefit for patients with moderate-to-severe plaque psoriasis than inhibition of interleukin-17A alone.

What's needed now?

Longer and larger trials are required to determine the relative effects of interleukin-17A and interleukin-17F inhibition as compared with inhibition of interleukin-17A alone in psoriasis.