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Rheumatology Network interviewed Paul M Peloso, MD, MSc, Chief Medical Officer at Acelyrin, to discuss recent phase 2 data examining the safety and efficacy of izokibep in the treatment of psoriatic arthritis. Izokibep is a unique antibody mimetic and potent interleukin-17A (IL-17A) inhibitor designed to overcome the limitations of existing monoclonal antibodies. In the randomized controlled trial, patients received placebo, bi-weekly 80 milligram izokibep, or bi-weekly 40 milligram izokibep, administered subcutaneously, for 16 weeks. The primary endpoint was the American College of Rheumatology 50 response (ACR50), a standard accepted composite score in psoriatic arthritis.
Rheumatology Network: Why did your team initially decide to study izokibep treatment in patients with psoriatic arthritis?
Paul M Peloso, MD, MSc: We know that there's a large unmet medical need for more effective therapies in psoriatic arthritis. It has multiple manifestations and current therapies don't necessarily manage all of them well. We also know that psoriatic arthritis is largely an L-17 driven illness. And we know that there are 2 approved therapies that target IL-17 that have shown good efficacy already. So, the open question for us was, “Could we do even better than existing therapies and broaden the range of disease features that we could treat well?”
RN: Can you tell me a bit more about the eligibility criteria and trial?
PP: Patients had to meet the definition of the ClASsification for Psoriatic ARthritis (CASPAR) criteria, which means they had to have active tender and swollen joints and a known diagnosis of psoriatic arthritis. The primary time point was week 16. Most trials have their primary endpoint between week 16 and week 24. It's inching backwards as we have more effective therapies and less interest in having patients on placebo longer term.
RN: And what were the ultimate results of the study?
PP: Results showed that the ACR50 primary endpoint was met for both the 40 milligram every other week dose and the 80 milligram every other week dose and had superiority to placebo. They also showed that there was dose improvement going from 40 milligrams to 80 milligrams on the primary endpoint and comparatively. For the ACR50, we were at the very top end of all existing therapies, which suggested that the unique features of izokibep could lead to more robust response.
There were, and always are, because it's a disease of multiple different manifestations, several key secondary endpoints. Results also showed very good improvement on the Psoriasis Area and Severity Index 75 (PASI75), which again was at the top end of the results of existing therapy. One of the pleasant surprises that was anticipated, but you never know until you see the data, was that we had enthesitis responses that were very different than we've seen historically, which fits with the unique nature of izokibep as a molecule.
RN: In your opinion, what is the clinical significance of these results?
PP: If you're a patient living with the chronic pain and inflammation of psoriatic arthritis, you want absence of disease. That's the goal. I always make the point that if you had 20 swollen joints and you got down to 10, you'd be happy that you had less swollen joints. But you'd still say, “Gosh, I still have 10.” So, the impetus is to continue to look for newer therapies.
But there's no question that patient-reported function and patient-reported quality of life improved as the joints, skin, and enthesitis improved. Enthesitis is a core feature of psoriatic arthritis that has been less well-studied for a lot of reasons, but mostly because the therapies we have had haven't been highly effective. We saw results that showed very dramatic effects on enthesitis, which is IL-17 mediated.
The fact that we have a molecule that's much smaller than monoclonal antibodies, is presumably better able to penetrate these inflamed, less vascular tissues, and showing very outsized benefits is really important for patients because all the studies have shown that enthesitis has a real impact on patient-reported quality of life. Improving the joints, improving the skin, and getting robust effects on enthesitis is very exciting for patients.
RN: What are the next steps for your team?
PP: Based on the results of this study, the evident dose response going from 40 mg to 80 mg, and the fact that we didn't have any adverse events that were unexpected or different than the IL-17 inhibitors or different from placebo, we think the right thing to do is to continue to see if we can dose higher. And for the reasons I've already stated, it's great for patients that we that were able to improve them to a significant degree.
The next study will explore whether we can get to higher levels of response and better patient improvement. And, as stated, that's predicated on the fact that we saw dose response. We're not seeing any limitations based on an adverse event point of view and we know we can continue to dose higher with a subcutaneous route of delivery. For the patient’s sake, we hope that we can do even better than we are currently at.
RN: Is there anything else that you would like our audience to know before we wrap up?
PP: I think the findings for enthesitis are clearly important in psoriatic arthritis. But I would also make the point that psoriatic arthritis and axial spondyloarthropathy are related conditions. They fall under the broader umbrella of spondyloarthropathies and so we're very hopeful that these results will translate to patients with related axial spondyloarthropathy as well. Based on the results of the upcoming study that I briefly described, we'll use that to pick the optimal dose for patients, not only in psoriatic arthritis, but also in axial spondyloarthropathy as well.