During the American College of Rheumatology (ACR) Convergence 2020, several presentations discussed data on the use of anifrolumab to treat patients with systemic lupus erythematosus (SLE). DocWire News interviewed Richard Furie, MD, Professor, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, to discuss two abstracts, Early and Sustained Reduction in Severity of Skin Disease with Anifrolumab Treatment in Patients with Active SLE Measured by the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI): Pooled Data from 2 Phase 3 Studies, and Comprehensive Efficacy of Anifrolumab Across Organ Domains in Patients with Active SLE: Pooled Data from 2 Phase 3 Trials.
DocWire News: What prompted you to undertake this research?
Dr. Furie: The abstracts that we’re going to talk about are sub-analyses of the parent studies [of] anifrolumab, and I should provide a little bit of background about Anifrolumab. It’s a monoclonal antibody against the type one interferon receptor, and we’ve actually known since … wow, it goes back a long time, to the 1970s, that interferons were important in lupus. And the burning question has been for the last 20 years or so whether inhibiting the interferon pathway would provide an improvement in disease activity in lupus patients. All right, but back to the studies. So it was actually a year ago that the TULIP studies were presented at the ACR meeting. I was the global principal investigator for TULIP-1 and Eric Morand for TULIP-2, and TULIP-2 was a positive study. TULIP-1 did not hit the endpoint, but there were a lot of secondaries that were positive.
Both studies have been published, and again, the presentations—and there are actually a lot of presentations at the ACR meeting this year; I forget exactly how many, seven or eight, that are all sub-analyses of the parent studies. Now why did we do these sub-analyses? Well, it really revolves a lot around the heterogeneity of lupus. And I like to use the analogy of snowflakes. When we outline therapy for a patient, it’s got to be customized, focusing on the most severe manifestation. Some people will say that lupus is a thousand different diseases, and there’s probably some truth to that. So no two patients are alike, just like snowflakes. Some might have severe arthritis, some may have rash, some may have kidney disease, and the list goes on and on. So when a new therapy comes along, clinicians need to know if it preferentially treats certain manifestations. And that was analyzed in the studies that we’ll talk about. So it’s a look at which organ systems responded to intervention with anifrolumab.
DocWire News: What are some of the key takeaways from this research?
Dr. Furie: The Organ Domain study was presented by Eric Morand, and he’s sleeping right now so we won’t wake him up. He’s in Australia, so what time is it there? It’s probably around 3:00 a.m., but he was the lead author on this particular abstract. And basically he and his colleagues evaluated responses in the various domains that are components of British Isles Lupus Assessment Group (BILAG) and SLE Disease Activity Index (SLEDAI). Those are two activity indices that are components of the composite outcome measures that we used in the parent studies known as BILAG-Based Composite Lupus Assessment (BICLA) and SLE Responder Index (SRI). And at one year, greater numbers of patients with anifrolumab treatment improved in the mucocutaneous and musculoskeletal domains. Now why did we focus on those domains? Well, those are the most common clinical manifestations. And when patients enter into a clinical research trial focusing on extrarenal manifestations, most of the patients will have arthritis or rash or both. Now I don’t recall the exact differences at one year between the groups, but I think there were around 10 or 15% in favor of anifrolumab over placebo.
You have to remember, in our studies, placebo is not just placebo. Placebo is probably more appropriately, or the least in that group, is more appropriately called standard of care. Patients come in on their background therapies and those therapies could be steroids, anti-malarials, immunosuppressives, and then they’ll have either anifrolumab or placebo added. Then focusing on arthritis, there were higher percentages of patients who were treated with anifrolumab who achieved the end point, which was a 50% reduction in the tender and swollen joint counts.
The bottom line is that there was evidence that anifrolumab worked for arthritis and also skin disease, but focusing on skin disease, there’s yet another presentation, and that was by another investigator, Victoria “Vicky” Werth, who presented the ability of anifrolumab to reduce cutaneous disease activity using a measure called Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). At week 12, which was the endpoint for this sub analysis, 46% of the cohort who entered the study with a high CLASI activity score, and that was 10 or greater, responded at a level of 50% reduction in the activity score, whereas in the placebo group, the value was 25%. So it was 46% versus 25%, and that’s a very significant difference. These findings confirmed actually what we saw in phase two, that cutaneous lupus responds very nicely to anifrolumab, and not only does it respond nicely, it responds quickly. And that’s why the endpoint of 12 weeks was chosen in this sub-analysis.
DocWire News: Did any of the study’s findings surprise you? Although perhaps not their responsiveness, but any other surprises?
Dr. Furie: A quick and robust skin response, as I mentioned, was predicted by the phase two study. Now arthritis, which is another major manifestation of lupus, it’s very difficult to assess, as joint tenderness and swelling are incorporated into the outcome measures, but the swelling and tenderness is not as exuberant as what we see in rheumatoid arthritis. So there may be a lot greater subjectivity in doing these assessments, and this could explain the more modest results in some of the variable responses in the musculoskeletal domain.
DocWire News: What limitations did the studies have?
Dr. Furie: I can’t think of too many. Maybe for skin, it would be nice to know which types of cutaneous lupus the patients had. For example, there’s acute cutaneous, there’s subacute cutaneous, and there’s chronic cutaneous. If you go back many years, they were all lumped together. It just says “cutaneous lupus,” but these days we’re actually starting to separate the three types. So it would have been nice to have had the subtypes known, basically to see if the responses were the same across all three groups or whether there were differential responses. And for arthritis, as I mentioned—but this is not really a study specific issue—we do need better tools that can be applied to these large global studies that we use. It’s all just palpating the joint, assessing for tenderness, and assessing for swelling. There is technology available, such as ultrasound and MRI, but for a large global study, that would create logistic nightmares.
DocWire News: Are there any future research plans in the pipeline for this?
Dr. Furie: Right now everybody’s hard at work converting these abstracts into papers that will provide a lot more detail. There’s a ton of data that still needs to be analyzed. For example, it would be great to know about the molecular signatures and how they predict response, but the key is awaiting a decision from the FDA regarding the approval of this drug.
DocWire News: It sounds like everybody’s got their hands full then.
Dr. Furie: Absolutely.
DocWire News: Is there any last closing comments or information, Dr. Furie, that you’d like to add?
Dr. Furie: Just speaking to lupus drug development in general, wwe started in the early 1990s, and we’ve only had one drug approved for lupus via the route of a randomized controlled trial. And it’s not for lack of trying, it’s just lupus is an incredibly difficult nut to crack. And I could go on for hours about why that is the case. Patients need safer therapies, more efficacious therapies. So I think we’re finally seeing the light at the end of the tunnel. There were three positive lupus nephritis trials, and it could very well be that two of them will lead to drug approvals for lupus kidney disease. Now we didn’t really talk about that, but that’s probably the most severe common manifestation of lupus. But we do need drugs for our patients with extrarenal disease, and I think the totality of the anifrolumab data would create reasons to approve the drug. So I view this program as a success and we’ll see what the regulatory authorities see next year.
DocWire News: That sounds great. It sounds like a lot of exciting things, hopefully, to be coming out in the near future then.
Dr. Furie: So all these efforts—and we have been trying for a long time—will translate into better outcomes for our patients, no doubt.
DocWire News: Well thank you for all you’re doing for them and thank you for taking the time, again, to chat with us about it.
Dr. Furie: All right. You’re welcome.