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Richard Furie, MD, explains the safety and efficacy of BIIB059 for patients with systemic lupus erythematosus (SLE), the study design and background on his upcoming SLE study, and Biogen’s ongoing commitment to including underrepresented groups in its clinical trials.
Rheumatology Network sat down with Richard Furie, MD, Chief of the Division of Rheumatology at Northwell Health and a professor at Zucker School of Medicine at Hofstra/Northwell. We discuss the safety and efficacy of BIIB059 for patients with systemic lupus erythematosus (SLE), the study design and background of TOPAZ-1, a 52-week double-blind, placebo-controlled phase 3 study, and Biogen’s ongoing commitment to including underrepresented groups in clinical trials.
Rheumatology Network: To begin, what initially sparked your team's interest in studying the safety and efficacy of BIIB059 (BIB59)?
Richard Furie, MD: Well, the story goes back a long way and it's about studying interferon. And not sure how much detail you want to know, but I'm going to provide it anyway. So, there are several milestones along the way, but 1957 was 1 of the first milestones. And that's what investigators in England, who were using a model of influenza virus discovered some substance that prevented the replication of influenza virus in chicken eggs. And they called it viral interference, which was shortened to interferon. And then a little bit later, 1979 was the publication from the National Institutes of Health (NIH), where they noted that interferon levels were very high in lupus patients compared to other types of rheumatic disease patients. So, they thought that interferon was important in lupus. Now, we've come to know interferon as something that's very important for viral defense for host defense against viruses. The next major milestone was in the early 2000s, when something called the interferon gene signature was developed. And this was a way of measuring the activation of the interferon pathway in a person. So, we all have interferon in our bodies. And in fact, there are 3 different types of interferon, but we're going to be talking about type 1 interferons today. And so, in the early 2000s, we then were able to detect activation of the interferon pathway. And that opened up a whole line of research. And the short of it is that and the majority of lupus patients, there's activation of the interferon pathway. And we think that activation plays a key role in the pathogenesis of lupus. Now, the burning question that developed around the same time in the early 2000s was, “could you inhibit the interferon pathway?” Could you block it and see lupus activity get better? And so, there were a couple of companies that tried to do that with antibodies against components of the interferon pathway. And they were mixed with a negative result and the other modest result. And there's been further development in that area. And we hopefully will hear from the food and drug administration (FDA) within the next month about a drug called anifrolumab, which blocks the type 1 interferon pathway. But there are other strategies that are being tried to block this pathway. And 1 is with BIB059. So, a little more about the biology interferons, at least the type 1 interferons are primarily made by cells called plasmacytoid dendritic cells (pDCs). For short, we all have pDCs in our body. So, they are the major producers of type 1 interferons. And in lupus, they are mass producers of type 1 interferons. And we find abundance of pDCs in the skin of lupus patients, but also in other organs, like in the kidneys and in the joints. Another strategy would be to try to prevent the pDCs from spewing out all these interferences, which are causing inflammation. And that's what BIB059 does. BIB059 is an antibody that binds a protein on the surface of the plasmacytoid dendritic cell, and that's called BDCA2. When the antibody binds that protein, that protein is internalized in the cell, and the cell no longer makes the type 1 interferons. It also stops making other pro-inflammatory proteins as well. So, another strategy to try to improve lupus activity. The first phase of development was a phase 1 study. And that was done in normal volunteers to establish safety. And then we did a small study small on patients huge on biology 12 patients with lupus who had skin disease, and the skin was a natural target because as I mentioned, pdcs are very abundant in the skin of lupus patients. And we know that the interferon pathway is very active in those lupus patients who have cutaneous disease. So we did a small study, big on biology, small on patients (12 patients enrolled), and that established the safety and it also established efficacy for this approach in treating cutaneous lupus. And that served as the foundation for phase 2 studies. And there were 2 phase 2 studies done. They've been reported at scientific meetings. One focused on the skin, it was a dose-ranging study to establish the appropriate dose to move forward. And the other study looked at lupus more globally focusing on arthritis, skin disease, and other manifestations of lupus. Anyway, both of those studies were successful. And you have to understand lupus is a tough nut to crack as far as drug development and clinical trials. Most of our studies have failed. So, when we see 2 parallel studies in lupus phase to be successful, that's very exciting. And anyway, so those 2 phase 2 studies served as the foundation for the phase three program, which just started
RN: Can you tell me a little bit about the study design and the methods that your team is planning to use in the TOPAZ-1 study?
RF: It's a pretty standard study design. The idea is to take a lupus patient who has active disease. And the way we measure activity is by looking at various organs. And we judge activity based on something called the SLEDAI, the systemic lupus erythematosus disease activity instrument, which is an instrument that's been around for quite a long time. And it's fairly standard to be used in clinical trials. That has been incorporated into a composite index called the SRI, the Systemic Lupus Activity (SLA) responder index, which is basically just a way to discriminate someone who is a responder to an intervention with a drug versus someone who's a non-responder. So, it is dichotomous. The endpoint for this particular study is the SRI at 1 year. And again, it just boils down to seeing improvement in the clinical activity of a patient with active lupus. In order to get into the study, one has to have active lupus. And, again, the goal is to reduce that disease activity safely.
RN: As this study just started, do you have any predictions as to what the results may be?
RF: Oh, I wish I had a crystal ball. Predictions and lupus, that's tough. I mean, again, I'll reiterate that lupus is a tough nut to crack. I would say that 90% of our studies in lupus have failed. We've had just 1 drug approved via the route of a randomized controlled study and systemically best, and that's a drug called belimumab that was approved 10 years ago. We hope another 1 might get approved this summer, but time will tell. We actually had an amazing event in December and January of this year. We had 2 drugs, belimumab and voclosporin, approved for kidney disease and lupus nephritis, which is a whole different treatment algorithm. So those are just 3 approvals so far. And it's not for lack of trying, I can't tell you how many clinical trials have been done. So, we are getting a little better at our designs, and we'll see better outcomes. But to predict is always difficult, except we have evidence of biologic activity for this approach with BIB059, and we have a phase 1 study and 2 phase 2 studies that showed clinical benefit. So if everything keeps going the same way, I would think that the phase 3 program will be successful.
RN: Can you tell me a little bit more about Biogen’s ongoing commitment to including underrepresented groups in its clinical trials?
RF: The disease, systemic lupus, first of all, affects a younger crowd. So, the typical patient who develops systemic lupus is a 25-year-old woman. Women outnumber men about 10 to 1. And then there are certain ethnicities and races that are more commonly involved, and actually more severely involved. And those ethnicities and races include African Americans, Asians, and Hispanics. And it's been the case so far, that minority populations remain, unfortunately, a minority in the clinical trials. So, we would expect 50-60% of our enrollment in a lupus clinical trial to consist of, obviously, it depends where it's being done, African Americans, Hispanics, and Asians. And certainly, with African Americans, that's not been the case. This was first observed with the belimumab trials, many years ago. We were in the phase 3 program and about 15% of the population was composed of African American patients. That's clearly well under the percentage that develop lupus. It's a very challenging issue. There's no question about that. It's just a matter of reaching out to all of our patients. A nd actually at our site, and I'm in Long Island, I would say our African American population composes maybe 40% of our lupus population. And then our clinical trials will match that. So, we're doing better than the rest of the of the United States in that regard.
RN: Are there any strengths or limitations of the study that you'd like to expand upon?
RF: Limitations of the study? Not really, I think there's a solid foundation; we've shown efficacy and safety. So, I think if you were well prepared to advance to phase 3, and it's just a matter of finding the appropriate patients. That is very challenging. There's actually a lot of subjectivity to determining the activity of one's lupus. And that we have these instruments, which I mentioned, the SLEDAI, there still is room for subjectivity. And it's so important to enroll informative patients, because all these studies are set up to compare the intervention with BIB059, versus a placebo, on background therapy. These patients are coming in on steroids, on anti-malarials, on immunosuppressives. And despite the background therapy, they still have active disease while we just need to make sure that they really do in fact, have active disease. So that's one of the big challenges in lupus: ensuring that we have an informative bunch of patients.
RN: After this clinical trial, does your team plan on doing any further research on this topic?
RF: We have a long way to go to conquer lupus. So, I would say absolutely. With lupus, we're talking, in the United States, about 200 to 225,000 patients. And it's a condition that affects the innocent, is the way I put it. A young female out of the blue; there may be no family history, and all of a sudden, they have arthritis, they have bad skin rash, and about half of our patients with lupus will develop kidney disease over time, and kidney disease can be quite devastating. Despite our current therapies, about 15% of our patients will still go on, at about 15 years, to die. I have had countless patients develop strokes and other very serious morbidities. If you focus on lupus nephritis, the worst kind is something called proliferative nephritis. And about 40% of our patients with proliferative nephritis, after 15 years, end up on dialysis and in need of a transplant. So, we have unmet needs like you wouldn't believe and we had to conquer those needs.
RN: Is there anything else that you'd like our audience to know about this study or lupus in general before we wrap up?
RF: It's a very exciting approach to treating lupus and we just have to get through this study and look at the reasons. Sounds easy, but it's easier said than done. This will take a while. And there are a lot of sites around the world that will be participating in this study.
RN: Excellent. Well, Dr Furie, thank you so much for speaking with me today. I really appreciate it.