麻豆传媒

VIENNA -- Preliminary results with the investigational interleukin-17A (IL-17A) inhibitor izokibep in a phase IIb/III trial for psoriatic arthritis (PsA) built on earlier positive findings, potentially paving the way toward final approval.

After 16 weeks of treatment in the randomized, placebo-controlled study, 40% and 43% of patients receiving 160 mg of izokibep weekly or biweekly, respectively, achieved the primary endpoint of 50% reduction in symptoms according to American College of Rheumatology criteria (ACR50), said Philip Mease, MD, of the University of Washington in Seattle, compared with 15% of those assigned to placebo (P<0.0001).

Other outcome measures also overwhelmingly favored the novel agent, with little difference in either efficacy or safety between the two doses, he reported at a late-breaking abstract session at the European Alliance of Associations for Rheumatology (EULAR) annual meeting.

Inhibiting IL-17A is a well-recognized means of treating PsA; it's the target for the currently approved drugs secukinumab (Cosentyx) and ixekizumab (Taltz). Izokibep was designed to improve on these agents, both by shrinking the molecule (it's one-tenth the size of a monoclonal antibody) and by including an albumin-binding domain. These features, Mease said, should help it last longer in circulation as well as penetrate "hard-to-access tissues."

The , with 351 patients randomized to the three arms, runs to a full year, but only the 16-week data were ready for presentation, Mease said. He added that it had a fourth arm, with an 80-mg dose given every 4 weeks (as tested in an earlier phase II study), but that group began enrollment much later and only eight patients were available for analysis and thus were excluded.

Roughly half of patients were men and some 95% were white. Disease duration averaged 7 years. Only patients who had failed or were unable to tolerate standard disease-modifying drugs, including tumor necrosis factor inhibitors, were eligible.

Tender and swollen joint counts at baseline averaged about 16.5 and 8.9, respectively. Some 60% had some degree of enthesitis, with mean Leeds Enthesitis Index (LEI) values of 2.9. Health Assessment Questionnaire-Disability Index (HAQ-DI) scores averaged 1.0 at the study's start.

Mease dwelled on two secondary outcomes during his talk. Noting that "multidomain efficacy" was an important goal for any PsA drug, given its range of symptoms, he walked attendees through a slide showing achievement of minimal disease activity. This measure is based on achieving certain targets for seven PsA aspects: swollen and tender joint counts, psoriasis extent, patient-reported pain and global disease activity, HAQ-DI values, and tender entheseal points. Patients who reach five of the seven targets are classified as having minimal disease activity. Mease reported that 41% and 42% of the two izokibep groups did so, versus 14% of the placebo group.

He also spent considerable time discussing effects on enthesitis, as resolution of this aspect of PsA was a key goal. The original protocol called for this to be examined for all patients with any degree of enthesitis at baseline. Essentially no difference was seen between the active drug and placebo for this outcome (47% for placebo, 56% for izokibep every 2 weeks, and 45% for izokibep weekly), which left the investigators puzzled. Mease explained that investigators had used ordinary enthesitis testing procedures as used in normal practice, which involves palpating the joints and looking for a pain reaction from the patient; he called this a "squishy" measure.

Consequently, a post-hoc analysis focused on patients with "high baseline burden" of enthesitis, specifically, those with LEI scores ≥3 and ≥5. This produced more of a difference between arms, but it was still a bit perplexing. For patients with LEI values of ≥3 at baseline, 52% of those assigned to 160-mg dose given every 2 weeks saw resolution, versus 41% and 37% of the weekly izokibep and placebo groups, respectively. Among patients with LEI values of ≥5, resolution occurred in 50% of the biweekly dosing group compared with 22% and 8% of the weekly izokibep and placebo groups, respectively.

Safety findings were similar to those seen in earlier studies. The major concern is injection-site reactions, which occurred in 61% and 46% of the weekly and biweekly dosing groups, respectively, compared with 5% of the placebo group. Mease explained that these were mostly limited to erythema, without pain or induration.

Clinicaltrials.gov lists the trial as having completed last November, but neither Mease nor the sponsor, Los Angeles-based Acelyrin, have indicated when the full 52-week results will be released.

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