Belimumab and voclosporin are highlighted as key contributors to the lupus nephritis treatment landscape.
Alvin Wells, MD, PhD: Two of our newest drugs that we use to treat lupus nephritis are belimumab and voclosporin. These 2 drugs work completely differently. Belimumab is a monoclonal antibody. It’s an injectable drug given IV [intravenously] or underneath the skin, and it targets a factor on the B cell called BLyS [B lymphocyte stimulator]. With the angry B cell that’s turning, it allows that cell to calm down, and that cell then undergoes apoptosis, which is cell death. It’s slowly taken up and removed by the liver and the spleen. Voclosporin is a completely different drug. As an immunologist, one thing I like about it is it works on 2 different mechanisms. It first targets the T cells by dampening that T cell that can’t present antigen in the B cell, and then the B cell isn’t able to go all haywire. That’s one mechanism. The other mechanism of action is the podocytes. The podocytes look like a scrubbing bubble that binds to the membrane inside of the kidneys. When those podocytes are damaged, the kidney becomes leaky. Voclosporin stabilizes that, and therefore that dam becomes more intact. That’s what we do.
One of the other things we’ve seen here is that as we talk about treating patients with lupus nephritis, we want to get their proteinuria under control as quickly as possible. [We want to] decrease [the proteinuria] by 25% at 3 months and by 50% at 6 months. If you don’t hit that target, you need to make some adjustments. Of the 2 agents, belimumab takes a little more time to work. We have data from voclosporin showing that at about 29 days—within 1 month—patients begin to show a decrease in their proteinuria. I go back to what my nephrology colleagues taught me: when you think about the nephron inside the kidney, time is nephron. The longer it takes to get that patient under control, you can imagine that you’re picking off these nephrons and causing damage that in some cases we might not be able to gain back.
The different FDA-approved drugs that treat lupus nephritis have different mechanisms. They have different onsets of action and adverse effect profiles. At the end of the day, as a rheumatologist, it’s good to have different tools in our armamentarium. But when I tell my patients what drug I like to use, I personalize it. I say, “If you were somebody like my young daughter, I’m not going to wait to let your nephrons be picked off. I want to get your disease under control.” That’s my target: 50% decrease of the proteinuria by 6 months, and maintaining that control in that setting with a low dose of steroids. Now we have data to support that treatment regimen.
The 2 drugs approved for lupus nephritis—belimumab and voclosporin—play different roles. Belimumab was approved first for patients with systemic lupus, and it mainly treats the mucocutaneous lesions, skin rash, sores in the nose and mouth, and arthritis, the musculoskeletal. Those are the 2 main things that we see. Studies showed that it may work in some patients with lupus nephritis to get kidney function and get this under control. If I have a patient who has all those other features, I might start with that drug. If they develop kidney disease, then we might have to add other agents on top of that to get them under control.
Voclosporin is only approved for lupus nephritis. If I have a patient on 1 drug and their skin disease and joints are under control but they develop kidney disease, we’re going to use voclosporin on top of that. When we talk about this, I always like to say that the FDA recommends that voclosporin be used in the background setting with corticosteroids and mycophenolate. We can use it with other drugs or other immunosuppressive drugs, but that’s why we study. Not with cyclophosphamide or other agents, but with corticosteroids and mycophenolate. At the end of the day, as a rheumatologist, I’m going to do what I can to get a patient’s lupus nephritis under control as quickly as possible and use all the tools in my armamentarium to make sure that patient’s kidney function is preserved as long as possible.
Some studies have come out that show the impact of belimumab in treating patients with lupus nephritis and the impact on proteinuria. These studies showed that it might make an impact. For patients with protein in their urine, you can see a decrease in that over time. Some patients take a longer time than others to see that respond. Some patients can have a quick response. One challenge we’ve seen as we talk about patients on belimumab is that even though they’re treating their other mucocutaneous and musculoskeletal symptoms, some patients could still break through with their therapy and develop kidney disease. But the studies have shown that the drug works. It’s impactful for systemic lupus and lupus nephritis.
We still want some long-term studies. We’ve done some propensity matching scores that say that based on some other cohorts out there—such as Toronto, Canada—you see a better response when you add belimumab on top of the standard of care—for the most part, mycophenolate, hydroxychloroquine, and corticosteroids. Will that preserve the renal function long-term? We still need studies. We still need to have some randomized trials. But at least we have a hint that in some patients treated with belimumab, they may respond with their renal disease as well.
When you look at these studies that are coming out, I always ask: what impact does it have on a treatment regimen? Belimumab has allowed us to [decrease the steroid dose]. I always ask my colleagues, “Is your patient doing well?” They say, “Yes, my patient is under control.” I say, “Tell me what drugs they’re on.” They say, “They’re on hydroxychloroquine, 10 mg of prednisone, and belimumab. I say, “If your patients are on more than 7.5 mg of prednisone, that patient isn’t under control, because now the goal is to get that patient’s steroid dose down.”
With every 1-mg increase of prednisone, the steroid, there’s a 3% chance that you can have organ damage. The organ could be the eye causing cataracts, the bone causing osteoporosis, or the pancreas causing diabetes. We see all those things. That’s where belimumab has helped out, allowing us to taper down the prednisone to get some patients as low as possible to make sure their renal function is going to be preserved as long as possible.
Transcript edited for clarity.