New data presented recently at the American College of Rheumatology meeting add to the evidence in support of anifrolumab, which could address unmet need in lupus.
To understand what lupus does to the body, Richard Furie, MD, professor of medicine at the Zucker School of Medicine at Hofstra/Northwell Health, explained it this way:
“Imagine being 25 years old, and suddenly, out of the blue, developing fever, profound fatigue, a disfiguring rash, and joint pain to the point that you couldn't function. That’s what lupus is all about,” he said in an interview with Managed Healthcare Executive® (MHE).
Lupus is a classic autoimmune disease, in that it arrives suddenly in people with a genetic predisposition. Lurie explained that something sets lupus off—an environmental trigger, perhaps a virus. For others, it’s smoking. “What happens is the immune system goes a little haywire and instead of providing protective function, it starts attacking the body,” Lurie explained.
When treating systemic lupus erythematosus (SLE), the most common form of the disease, the choices are limited. For the most part, clinicians use immunosuppressive drugs that limit immune system activity, including hydroxychloroquine—which experienced shortages this year when it was promoted as possible treatment for coronavirus disease 2019 (COVID-19), despite a lack of evidence. This came as patients with autoimmune diseases, including lupus, were found to have a greater vulnerability to COVID19.
The other common therapy is corticosteroids, especially prednisone, but over time, this comes with side effects. The FDA approved belimumab in 2011, the first new drug for SLE in more than 50 years, but the heterogeneity of SLE begs for more choices.
New therapies in the pipeline include anifrolumab, an investigational monoclonal antibody from AstraZeneca, which binds to the type I interferon receptor to block all the type I interferons, the cytokines responsible for inflammation. Between 60% and 80% of adults with SLE have a gene signature that suggests they would type I interferon disease activity.
In its first phase 3 trial, TULIP 1, anifrolumab did not meet its primary end point. TULIP 2 showed superiority across multiple end points for efficacy vs placebo, with both arms receiving standard of care; in addition, pooled results from the trials showed consistent benefits across subgroups by age, gender, race, and age of disease onset.
New data from the TULIP trials was presented this weekend during the American College of Rheumatology Convergence 2020 meeting included findings that showed patients taking anifrolumab had rapid and sustained reduction in skin activity. Pooled data also showed the benefit of anifrolumab across multiple organ domains.
An AstraZeneca spokesman said the company is targeting regulatory approval in the second half of 2021.
For insights, MHE spoke with Furie and Rachele Berria, MD, PhD, vice president for US Medical, BioPharmaceuticals for AstraZeneca.
MHE: Can you discuss how lupus is currently detected, diagnosed, and treated?
Furie: There is incredible heterogeneity with lupus. So, any part of the body can be attacked by the immune system. The way we diagnose it is talking to the patient. It’s a very old-fashioned subspecialty—we actually talk to the patient, we examine the patient, and then we check laboratory tests to make the diagnosis. After that, it's a matter of making a list of the various manifestations that the patient has in ordering them from most severe to least severe. Then, we come up with a therapeutic regimen.
We haven't had that many drugs available to us. The major breakthrough occurred in 1948 with compound E, basically cortisone, and that's transformed a lot of inflammatory diseases. Patients started to do better with lupus in the early 1950s. Then, along came immunosuppressives like azathioprine and then chemotherapy like cyclophosphamide. And then we had our first biologic approved about 10 years ago, but our toolbox is relatively small. There’s still a great unmet need for our patients who have moderate to severe systemic lupus are patients with lupus, kidney disease, and I could go through a whole list of other manifestations, but there remains a huge need.
Berria: One additional peculiarity of lupus is that it does affect mostly women—90% of the patients are women in their childbearing age, so it's on average a 15- to 45-year-old, and the other particular thing about lupus is that it affects minority patients; in order of prevalence, you would see African American, Hispanic patients and Asian patients. You asked about COVID-19—as you know, the minority patients are the ones that are affected the most, because of several reasons. One additional thing that strikes me is that the course of the disease is unpredictable with flares and remission, and this causes not only physical but emotional burden to the patients, including productivity loss. You could quantify the tangible losses for the society on average at around $20,000 for per year [per patient], in fact.
MHE: With lupus and other autoimmune diseases, one of the balancing acts with steroids is that they can bring relief, but in the long term the long term, they can cause damage. Is that the promise with this new therapy, anifrolumab? That you can get the get the therapeutic benefit without some of the problems that you've had with steroids.
Furie: We've had a love hate relationship with steroids forever. They are great medicines, as I mentioned, transformative for inflammatory diseases. But the problem is the toxicity—the side effects of prednisone could fill many, many pages. We basically kind of wrap that all up as damage. They contribute to cataract formation, osteoporosis, something called osteonecrosis, where the bone actually dies. There’s also infection, diabetes, hypertension, cardiovascular risk—a huge list.
So, it’s a rule of thumb is to try to get the patient on the lowest dose of prednisone without allowing the disease to flare, because the disease activity can also contribute to damage—it’s a balancing act between the treatment and the disease. So, a medicine that can reduce disease activity, prevent flares, and prevent damage is an ideal drug.
Berria: At ACR [there will be] a poster publication that shows exactly as Dr. Furie is saying it’s a balancing act—you want to use the least amount of steroids; at the same time, you want to prevent flares. And we showed in this poster that anifrolumab would lead to a cumulative decrease in the corticosteroids dose versus placebo without any increase in flares. In fact, in those patients, where we were able to taper and sustain a relatively low dose of oral steroids during the course of the study, we saw a reduction of over two-fold in terms of reduction of flares.
MHE: With payers, across the autoimmune landscape, the other overarching issue is the question of when to start novel therapies, given cost considerations. There’s the argument that the earlier you treat, the greater the benefit, and the more you prevent the longer-term complications—and perhaps greater long-term costs to the health system.
Berria: Keep in mind that the TULIP 1 and TULIP 2 studies, the pivotal trials, were done to study patients with moderate to severe lupus. They were 52 weeks, and we do have a long-term extension for up to two years. [This] will give us some idea of the long-term safety and tolerability and there's an additional study in lupus nephritis.
Furie: Clinical trials in lupus are relatively short. The ideal clinical trial would be a lifetime—it would be about 50 years with an end point of damage. But what we do know about damage is that activity begets damage. Damage begets more damage. And I hate to put it this way, but damage begets death. So, in a one-year trial or two-year trial, we generally don't see changes in damage. But we know from cohort studies—non-drug development studies—that as one reduces [disease] activity, one can prevent damage accrual. So, with studies like anifrolumab, we certainly showed that activity of the disease goes down. We're not able, because of the duration of the study being short, to show effects on damage. But I think it would be a pretty good surrogate, the reduction in inactivity. We have the long-term extensions, which goes several years, where we don't see damage accrual.