A host of psoriatic arthritis symptoms can be improved by the investigational interleukin (IL)-17 blocker izokibep, according to the results of a phase 2 trial presented at the annual European Congress of Rheumatology.
Around half of all participants in the trial who were treated with izokibep achieved a 50% or higher improvement in American College of Rheumatology response criteria (ACR50) at week 16, the trial’s primary endpoint. This was highly significant (P = .0003) when compared to the control group, where only 13% of patients given a placebo achieved an ACR50.
There was also a significant improvement in skin symptoms, as assessed by the Psoriasis Area and Severity Index (PASI) and resolution of enthesitis in 88% of patients given the highest dose of izokibep.
Aurelie Najm, MD, PhD, of the Institute of Infection, Immunity and Inflammation at the University of Glasgow, who tweeted about the main results, said that the data also looked “promising for the enthesitis domain” with a “safety profile similar to that observed in PsO [psoriasis].”Peter Taylor, MA, PhD, FRCP, FRCPE, of the University of Oxford in England, said: “The improvements demonstrated in arthritis, psoriasis, and enthesitis are exciting relative to responses reported for the current standard of care.”
He continued, in a statement issued jointly by Affibody, Acelyrin, and Immagene Biopharmaceuticals – the three companies assessing izokibep’s therapeutic potential – that the drug “seems promising” and that he was “eager to see its continued development for patients.”
Small and potent, a novel IL-17 inhibitor
Izokibep is an antibody mimetic that inhibits IL-17A designed to “overcome the limitations of monoclonal antibodies,” according to its developers.
Due to its small molecular size – reportedly about one-tenth of the size of a monoclonal antibody – they say that levels of high drug exposure can be achieved from a single, subcutaneous injection rather than an intravenous infusion, which is needed for monoclonal antibodies.
Moreover, izokibep’s small size means it could potentially reach target tissues “that may otherwise be inaccessible to the much larger monoclonal antibodies.”
So far more than 300 patients have been treated with izokibep, some for up to 3 years, but not all have had psoriatic arthritis. Indeed, the drug has been tested in patients with psoriasis, and there are a few actively recruiting trials including one in ankylosing spondylitis, another in noninfective uveitis, and one in the rare and painful skin condition hidradenitis suppurativa.
Testing two doses of izokibep in psoriatic arthritis
The trial presented at the EULAR 2022 Congress tested two doses of izokibep – 40 mg and 80 mg – given by subcutaneous injection every 2 weeks – against placebo in 135 adult patients with active psoriatic arthritis. For inclusion in the trial patients had to have at least three swollen and at least three tender joints and have had an inadequate response to prior therapy including nonsteroidal anti-inflammatory drugs, conventional synthetic disease-modifying antirheumatic drugs, or tumor necrosis factor inhibitors.
Principle investigator Frank Behrens, MD, of Goethe University Frankfurt, Germany, reported that it was a multicenter effort conducted at 22 European sites with the primary endpoint being an ACR50 response at 16 weeks. This was met by 52% of patients given the 80-mg dose of izokibep, 48% of patients given the 40-mg dose of izokibep, and just 13% of patients who had been randomized to placebo.
ACR20 and ACR70 response were one of several key secondary endpoints tested, again at 16 weeks, with a respective 75%, 60%, and 20% of patients in each group achieving the lower response target and 20%, 32%, and 5%, achieving the more stringent response target.
“Izokibep demonstrated a robust efficacy in the musculoskeletal arthritic domains, but also in the extra-articular musculoskeletal domain,” Dr. Behrens said.
Not only that, but the values were “at the top end” of what’s been demonstrated for drugs currently regarded as the standard of care.
More than 80% of patients achieved a PASI75 response and 57% a PASI50 response with the two doses of izokibep, and 63%-88% achieved a resolution of enthesitis. The latter was measured using the Leeds Enthesitis Index.
There was also improvement in quality of life, measured using the Psoriatic Impact of Disease questionnaire, with a percentage increase beyond the MCID of 31%-41% with izokibep versus 12% for placebo.
“These are the first data of the phase 2 study in psoriatic arthritis,” Dr. Behrens reported.
“The safety profile was consistent with placebo,” with the only “standout aspect” being a higher number of injection-site reactions with izokibep versus placebo; but there were no serious infections, no serious adverse events,” he added.
“The interesting thing is from the preclinical research there was no dose-limiting toxicity with izokibep, therefore, I think the plan in the future is maybe to increase the dose to optimize treatment outcome based on the really robust effectiveness we see here in the first study in this clinical trial,” he said.
As a small study, stratifying results by gender wasn’t an option, Dr. Behrens noted in answering a question during the discussion period, but might be something that will be included in future and larger trials based on the post-hoc findings of other IL-17 trials.
Moving forward, the next step will involve a phase 2b/3 pivotal study which will likely include a higher dosing regimen of 160 mg once weekly alongside the twice-weekly dosing used in this trial.
Izokibep is an investigational treatment being developed by Affibody AB, Sweden, and ACELYRIN, USA. All three companies funded the phase 2 trial and were involved in the study design, conduct and reporting of results.
Dr. Behrens and Dr. Taylor were investigators in the study.
Dr. Behrens disclosed he was a shareholder of Pfizer, Sanofi, GlaxoSmithKline, Gilead Sciences, Inc. and Novartis; part of the speakers’ bureau for Amgen, Horizon, Lilly, Novartis, Pfizer, Sanofi, Genzyme, Flexion and AbbVie; a consultant of AbbVie, Boehringer Ingelheim, Flexion, Janssen, Pfizer, Sanofi, Regeneron, SUN Pharma Advanced Research, Gilead Sciences, Inc.; and had received grant or research support from Pfizer, Janssen, Chugai, Celgene and Roche
Dr. Taylor acknowledged grant or research support from: Celgene and Galapagos, and acted as a consultant for AbbVie, Biogen, Bristol Myers Squibb, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Nordic Pharma, Pfizer, Roche, Sanofi and UCB.