乌鸦传媒

COPENHAGEN -- In a phase II study reported here, a small-molecule drug engineered to inhibit interleukin (IL)-17A appeared effective and safe among patients with psoriatic arthritis (PsA).

Half of patients receiving either of two doses of the novel agent, called izokibep (formerly ABY-035), for 16 weeks achieved so-called ACR50 responses -- 50% reduction in PsA symptoms by American College of Rheumatology criteria -- compared with 13% of a placebo group, according to Frank Behrens, MD, of University Hospital & Fraunhofer Institute for Translational Medicine and Pharmacology in Frankfurt, Germany.

Except for injection-site reactions and possibly some excess upper respiratory tract infections, no safety issues were noted in the trial, Behrens told attendees at the (EULAR) annual meeting.

IL-17A is considered a key driver of PsA as well as plaque psoriasis and related conditions, and a number of approved drugs for these illnesses, including secukinumab (Cosentyx) and ixekizumab (Taltz), are designed to block it. Izokibep's developers hope to improve on those agents by increasing the potency -- izokibep has two binding domains, one for each of IL-17A's two subunits -- and also extending its activity in vivo by including a third domain that binds to serum albumin.

As a result, izokibep's binding affinity for IL-17A is dramatically higher than either of the monoclonal antibodies, with a 12-day half-life in circulation. Behrens also said the albumin binding boosts the drug's ability to reach sites of inflammation including joints, skin, and nails.

For the phase II PsA study, 135 individuals were enrolled. They all had active PsA (at least three tender and three swollen joints) despite treatment such as nonsteroidal anti-inflammatory drugs, standard disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate, or tumor necrosis factor inhibitors. Patients were allowed to stay on one standard DMARD during the trial.

Participants were randomized 1:1:1 to either 40 or 80 mg of izokibep or placebo every 2 weeks, with outcomes at 16 weeks as the primary endpoints. Mean age was about 48, and patients had lived with PsA for a mean of 7 years. All were white and half were women.

Safety assessment was the trial's principal goal. There were no serious adverse effects and, with the exception of injection-site reactions, nothing stood out as clearly more common with the active drug versus placebo. Two patients in the 40-mg group and three assigned to 80 mg developed upper respiratory infections, compared with one in the placebo group, but it was impossible to say that the difference wasn't simply due to chance.

Some 25%-30% of the izokibep groups developed injection-site reactions, severe enough in two patients that they dropped out. Behrens noted that there were no dose-limiting effects, and he offered that even higher doses could be tried in future studies.

Besides ACR50 (the primary efficacy endpoint), Behrens and colleagues also examined a range of other outcomes, particularly the Psoriasis Area and Severity Index (PASI) that measures skin involvement in PsA as well as plaque psoriasis. Patients receiving izokibep showed even stronger responses in this measure than in ACR50 -- upwards of 80% of patients in both dosage groups achieved 75% score reductions (PASI75), and 37%-39% saw total clearance of skin lesions (PASI100) at week 16. In contrast, only 13% of the placebo group had PASI75 responses and just 5% reached PASI100.

Similar results were seen for enthesitis, which was assessed in a subset of 43 patients, including 10 in the placebo group. Nearly 90% of the high-dose group and 63% had complete resolution, compared with 10% of those on placebo. Other PsA treatments do well to bring a 60% rate of enthesitis resolution, Behrens said.

Psoriatic arthritis is not the only condition that the drug's developers -- Swedish firm Affibody is the lead but shares marketing rights with a U.S.-based company and one in China -- are targeting for izokibep. Trials are also underway or have been completed in plaque psoriasis, non-anterior uveitis, and ankylosing spondylitis. The firms have not yet said when or whether a phase III trial in PsA may commence.

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