Christopher Ritchlin, MD, MPH, discusses the safety and efficacy of bimekizumab in patients with psoriatic arthritis, the BE ACTIVE study, the clinical significance of these results, and his plans for future research on this topic.
Rheumatology Network sat down with Christopher Ritchlin, MD, MPH, who is affiliated with the University of Rochester. Ritchlin is a professor and Chief of the Department of Medicine Allergy/Immunology and Rheumatology. We discussed the safety and efficacy of bimekizumab in patients with psoriatic arthritis (PsA), the BE ACTIVE study, the clinical significance of these results, and his plans for future research on this topic.
Rheumatology Network: Hi, Dr Ritchlin, thank you for joining me today.
Christopher Ritchlin, MD, MPH: Pleasure to be here.
RN: What first sparked your interest in studying the safety and efficacy of bimekizumab in patients with psoriatic arthritis?
CR: Well, I'm going to simplify things and call it bimab, that's an easier word to say. Well, you know that there are agents that are approved for the treatment of psoriatic arthritis and psoriasis that block interleukin-17 (IL-17) A. And it turns out that there is a family of interleukin-17 molecules which are called isoforms. And they are literally different forms of IL-17. And there's A, B, C, D, E, and F molecules that are all part of these isoforms. And it turns out that both A and F promote inflammation. So, the notion that you could develop an antibody that would block not only A but also F raised the question of whether or not that kind of an approach might be more effective than just binding to IL-17 A. Of course, when you're blocking more of those family members, the second question that arises is safety. So, are you able to have a medication that is both more effective and safer than current medicines that are out there in the market? And that's what interested me and that's how we got started.
RN: How does this study add to previous research on this topic?
CR: Well, the phase 2 trial, which was presented a couple of years ago, was the efficacy and safety of bimab in over 200 patients with psoriatic arthritis. In the phase 2 studies, these are dose ranging, so a variety of doses, they had 16 milligrams, 160 milligrams, 320 milligrams, 320 milligrams load and followed by 160. And from this study, they demonstrated that the 160-milligram dose was very effective and safe. And we saw some of the highest responses to for psoriatic arthritis of any agent we've ever seen. Indeed, the primary outcome measure was the American College of Rheumatology (ACR)-50, which is a very high bar, and they achieved this bar and about 50% of the patients. So, this was a really important phase 2 trial. Now I have to underscore that the results that one sees in phase 2 may be somewhat higher than what you observe in phase 3. But nonetheless, these results were very impressive.
RN: Can you tell me a little bit about the BE ACTIVE study design?
CR: Yeah, so the BE ACTIVE study was a double-blind placebo-controlled trial, multiple doses, the doses are previously mentioned, against placebo. And patients that were asked had active psoriatic arthritis. And they were randomized to the doses that I described. And the primary outcome measure was at 12 weeks. And again, the primary outcome measure was the ACR-50, a rather high bar. And they looked at a number of other outcomes such as a Psoriasis Area and Severity Index (PASI) score, which states how much psoriasis a patient has, the degree of swelling in a digit such as dactylitis, inflammation, at where tendons and ligaments attach to bone, which is enthesitis. So, they looked at all of these outcomes. And again, the results were quite impressive. In fact, they were the most impressive results we've seen in a phase 2 trial. They then went on and did an open label trial that we can talk about when you're ready.
RN: Sure, I'm ready. Please tell me more.
CR: After the 12 weeks, the patients that were on placebo, or were on the 16 milligram doses, which are obviously either not known to be effective or very low dose, meaning placebo and 16 milligrams, were randomized to receive either 320 milligrams or 160 milligrams of the bimab. And then when they went into the long-term open label which went out to 4 years. All of the patients were placed on the 160 milligram dose and outcomes were measured out to week 108.
RN: What is the clinical significance of these results?
CR: Well, I think the clinical significance is, first of all, it did show that the strategy of blocking both IL-17 A and IL-17 F was effective. So, the next question that was posed was whether it's safe. So, the safety data showed that probably the most common event was oral candida, which is the fungal infection. This can involve the oral pharynx, and is known to be a side effect that one sees when you use IL-17 A blocking agents. Well, they also saw this in patients who were on bimab, in up to 10% over the full 108 weeks, but they were able to treat this with local topical agents. And patients did not have disseminated disease, which means involvement of other parts of the GI tract, or the lung, etc. So, about 10%, but they were able to treat it locally, in terms of serious infections, or cardiovascular events or malignancies. These were extremely rare and uncommon, even out to 108 weeks.
RN: Were you surprised by the results of the studies?
CR: In a way. When the study was being put together, and I was part of that consultant team, I was concerned that setting such a high bar as the ACR-50 may be problematic for a drug in phase 2B, but they showed that it was achievable. And by about half of the patients. The other outcome measure I should say they looked at was the MDA, or minimal disease activity, which is another high bar. And again, about a half the patients, 50%, achieved this outcome. So, I am very impressed by the outcomes that we're seeing in the phase 2 trial. And it'll be most interested to see if these are recapitulated in the phase 3 trials, which are now ongoing.
RN: Were there any strengths or limitations of the studies that you'd like to discuss?
CR: I think the strength is that they shot high and they achieved their high outcome. So that's a real strength when you're looking at a market that's quite competitive for the treatment of psoriasis and psoriatic arthritis, I think, and what I didn't also mention was they also have trials with this agent in both psoriasis alone, and in ankylosing spondylitis, which has also shown very high treatment responses. So, when you can show that you're effective across a disease spectrum, this is also very helpful and something that I think is a great strength. In terms of weaknesses, I don't see any major weaknesses in the phase 2B trial. They were able to find the dose that they thought was most effective, which was the 160 milligram dose, they were able to carry out a long term extension over 4 years, and show safety and efficacy was maintained. And I think that all in all, it was it was a very well-designed trial that was carried out effectively.
RN: Does your team plan on doing any further research on this topic?
CR: I think that there's going to be a lot of research on this topic. So, the idea that you might be able to interrupt a number of members or isoforms of the IL-17 family is a very attractive strategy. I should mention that Dr Ellen Gravallese, at Harvard, had an abstract at last year's American College of Rheumatology meeting where she looked at the function of IL-17 D, another isoform and found that may actually be anti-inflammatory. So, I think we're going to learn a lot more about these family members of the IL-17 group, and how to best orchestrate therapies that might be able to maintain higher responses and maintain efficacy.
RN: Is there anything else you'd like our audience to know about this drug or psoriatic arthritis before we wrap up?
CR: Well, I think that the important point to underscore is that the response rates that we've seen in psoriatic arthritis with the 13 agents that are currently approved in the United States by the FDA are of the same magnitude of the responses that we saw in the first anti-TNF trial by Philip Mease, in 1999 in 2000, with the drug etanercept. So, I'm saying that for psoriatic arthritis, we have not seen the kinds of increased responses to the newer agents that have been observed in psoriasis. So, this demands for us to think about new targets, new approaches, and thinking outside the box in order to improve our patient outcomes with PsA. This is one strategy that has promised, but I think we need to focus in increasing our attention to new pathways and new molecules. And then the idea of combination biologics is something we are actively entertaining.
RN: Dr Ritchlin, thank you so much for joining me today. I really appreciate it.
CR: Thank you. I enjoyed talking to you.