Richard Furie, MD: FDA Approval of Anifrolumab-Fnia for Systemic Lupus

Rheumatology Network sat down with Richard Furie, MD, to discuss the recent FDA approval of anifrolumab-fnia for the treatment of patients with systemic lupus. Furie is a leader in Lupus Research Alliance's Lupus Clinical Investigator Network and the Chief of Rheumatology at Northwell Health. He explains the clinical significance of this FDA approval, the unmet needs of patients with systemic lupus, and the ongoing research in the quest to find a cure.

Rheumatology Network: Hi, Dr Furie. Thank you for joining me today. How did the Lupus Research Alliance (LRA)’s research and pioneering work contribute to the development of anifrolumab-fnia?

Richard Furie, MD: The Lupus Research Alliance has been funding investigators doing basic and translational research. And the interferon pathway has become very hot. They in fact funded I think, a total of about 40 projects. And that came to about $16 million. So, you heard about the drug approval on Monday anifrolumab, but it just didn't pop up like that. There's a lot of basic science and translational research that went into that, not just by LRA investigators, but by investigators around the world. In fact, the whole interferon story started in the 1950s. But it was not until probably the 1970s and 80s that we recognized interferons played a role in systemic lupus.

RN: What are some of the unmet needs in patients with systemic lupus?

RF: There are a lot of unmet needs. Let me just explain a little bit about the disease. So, the typical patient who develops systemic lupus is a young female. It's about a 10-to-1 ratio of females to males. And we see it in kids as young as 1 or 2 years old. And we see it in older people. But the typical age of onset is around 20 to 30 years of age. And we see it all around the world. In the United States, it's estimated that a little over 200,000 patients exist with lupus. And unlike our brethren who do drug development studies on rheumatoid arthritis and psoriatic arthritis, we've struggled with lupus. It's a very difficult disease to do research in as far as clinical research goes because it's so heterogeneous. In lupus, the immune system attacks the body, and it can attack any part of the body. Skin rashes and joint problems are the most common, but there's no organ that's off limits to lupus. So, when you do a clinical study, to try to see if a drug is effective in reducing disease activity, it gets a little tricky because there are so many different manifestations. So, lupus has been a tough nut to crack for sure.

RN: You mentioned interferons, what role do interferons play and systemic lupus?

RF: So, the interferon story actually goes back to the 1950s. In 1957, investigators in London, using a model of influenza virus, noted that there was a substance produced by chicken eggs that inhibited the replication of influenza virus, and they called it viral interference. That got shortened to interferons. So, we knew that interferons were important for host defense against viral infections. It was actually in 1979, that there was a publication from the National Institutes of Health, where they did a survey of various rheumatic disease patients and measured interferons in the blood of these patients. And they in fact found that about 70% of the lupus patients had interferons. But interferon is a very hard thing to measure in blood, at least up until recently. It was in the early 2000s, in fact 2003 to be exact, that the interferon gene signature was developed. And this was a way to identify patients who had activation of their interferon pathway. Because, again, it was very difficult to actually measure interferon and then research beyond that. While there's a lot of research beyond that, 1 area of research was to correlate clinical and serologic findings in our lupus patients to the presence of the interferon gene signature. And in fact there was a correlation. Interferons definitely play a role in systemic lupus. If you survey patients in the modern era, just like they did back in the 1970s, we find that about 70 to 80% of lupus patients have activation of the interferon pathway.

RN: What were the study designs and results of the TULIP-1 and TULIP-2 studies?

RF: TULIP-1 and TULIP-2 were actually fashioned after the phase 2 study in lupus, and I actually presented the phase 2 data around 2015. They were incredibly robust data. And again, we've struggled in lupus clinical trials. So, to have the successful study is unbelievable. But this was not just successful, these are really robust phase 2 data. So, the phase 3 program was modeled after phase 2, but there are a few differences here and there. But TULIP-1 and TULIP-2 at least started out as identically and were fairly identically designed trials. In TULIP-1, there was an extra low dose put in, but the endpoint was the same and the entry criteria was the same. TULIP-1 enrolled quicker and therefore the results were known to the public quicker. And to the shock of the lupus community TULIP-1 failed to reach the endpoint. And we're still trying to figure that out now. But there was another endpoint, a different composite index, where it was successful. And a lot of the secondary endpoints were successful. So, the burning question at the time was, do we change the endpoint of TULIP-2, from the original one (SRI) to the one where it did work in TULIP-2, called Based Composite Lupus Assessment (BICLA). I'm not going to go into the details of those endpoints. And this was the decision was to change it and to look to because the TULIP-2 study had not been completed. So, no one knew about any of the data of TULIP-2. So, it was the change was made before unblinding of TULIP-2. So, in fact, TULIP-2’s endpoint BICLA was successful. But it turns out, ironically, that the other endpoint that was abandoned was also successful. So, we had one outlier, of these composite indexes that we used. And that was in the TULIP-1 trial.

RN: You mentioned being surprised by the results of TULIP-1. Were you surprised by the results of TULIP-2?

RF: No, I as well as, I think everybody in the lupus community had a lot of confidence and that confidence was built around the phase 2 results. So, the outlier, the shock was the result of the TULIP-1 study, but again, looking deeper into the other composite index, looking at a lot of the secondary endpoints, we saw that the drug was effective. So, I would say the results of TULIP-2 were the expected results, the norm, and TULIP-1 was the unexpected.

RN: What is the clinical significance of this FDA approval?

We don't have enough drugs for our lupus patients. There are major unmet needs in lupus, lupus nephritis, moderate and severe extra renal lupus. We need to prevent flares, we need to get patients off steroids and their immunosuppressants. And I would put on that list, remission induction. But we have a very small toolbox. Our toolbox goes back to the 1950s. Steroids, anti-malarials and then later on immunosuppressives. But we've had a love hate relationship with a lot of these medicines, namely with steroids. They've transformed inflammatory disease outcomes, but there's a price to pay. There's a lot of toxicity with steroids. And you could say the same about immunosuppressives. So, we've been looking for new therapies that are more effective, that are safer, and they've been hard to come by and it's not for lack of trying. We've done a lot of clinical trials in lupus, but the only drugs approved have been belimumab, or Benlysta, which was approved in 2011 for SLE. And then we saw something that we will probably never see again and that's back to back approvals by the FDA to drugs for lupus nephritis. And that again was belimumab/Benlysta in December of this past year, and then voclosporin, or LUPKYNIS, in January. And then we had anifrolumab just this week. So, we're making progress, maybe not as quickly as what's happened in rheumatoid arthritis or psoriatic arthritis. But bit by bit we are making progress and what this means for the patients, more choices of medicines, and better outcomes.

RN: Can you tell me a bit about the ongoing research and the quest to find a cure?

RF: Cure in lupus. We're now starting to talk about remission. Generally, what we're attempting to do is reduce disease activity, prevent flares, and spare patients from the side effects of medicines. Cure is a goal for sure. But it may be a way off. So, the effect in lupus is the overactive immune system which is attacking the body. And so, we need to subdue that immune system. And we're just starting to better understand all the different components of the immune system in health and disease, especially lupus, and trying to develop targeted approaches to subduing some of these abnormalities that we see in lupus. So, I'd love to talk about cure, but we're not quite there yet.

RN: Is there anything else that you would like our audience to know before we wrap up?

RF: Oh, I think we covered a fair amount in a short period of time. I don't think so.

RN: Okay, excellent. Well, thank you so much for speaking with me today. I really appreciate it.