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ACR Convergence 2021—The Great Debate at the meeting sparked a thoughtful discussion on the future of lupus nephritis treatment strategies, with experts saying clinicians should be open to new ways of approaching patient care.
In the past year, approvals of the monoclonal antibody belimumab and the calcineurin inhibitor voclosporin for use in lupus nephritis (when combined with standard therapy) have given physicians new treatment possibilities, but they are now faced with the question of which regimen to use.1,2
Michelle Petri, MD, MPH, professor of medicine at Johns Hopkins University, Baltimore, and director of the Hopkins Lupus Cohort, underscored belimumab’s “clean” safety profile and beneficial effects on glomerular filtration rate (GFR). She also said clinicians should be comfortable being more aggressive in their approach.
Dr. Petri
“You need to feel comfortable using both of these new treatments,” she said. “It’s time to change our paradigm. If, at the time of biopsy, it is a bad biopsy with lots of bad prognostic markers, I don’t think we should be using mycophenolate (MMF) alone. I think we should be very comfortable starting either a calcineurin inhibitor or belimumab.”
Dr. Petri and Brad Rovin, MD, a nephrologist and professor of medicine at Ohio State University, Columbus, who reviewed voclosporin’s benefits, delved into the details of both treatments. They highlighted the following five points:
1. Response Rates
In the phase 3 trial for belimumab, those in the treatment group, who received standard care plus belimumab, had a one-year complete renal response (i.e., a ratio of urinary protein to creatinine of <0.5, an eGFR that was no worse than 10% below the pre-flare value or ≥90 ml per minute per 1.73 m2, and no use of rescue therapy) rate (CRR) of 32.2%, compared with 26.9% for the placebo group, although Dr. Petri said the differences were better just before and after the 52-week landmark.1 At two years, belimumab’s CRR was 30%, compared with 19.7% for placebo. In a voclosporin trial, the CRR for the drug was 41%, compared with 23% for placebo.2 There was no two-year randomized clinical trial for voclosporin.
2. GFR Protection
The GFR was well protected by belimumab, which Dr. Petri suggested was one of the most important findings in the trial. From three to four months after treatment, the GFR was considerably better in patients treated with belimumab than in patients who received only standard care, she said.
“Why is this important? The FDA [U.S. Food & Drug Administration] has now accepted GFR trajectory as a surrogate for end-stage kidney disease in trials,” she said. “Why are we treating the patient? We’re trying to prevent end-stage kidney disease.”
Patients in the voclosporin trial tended to see a reduction in GFR, but Dr. Rovin noted the curve remained flat, without a continuing decline over time. This is the result of kidney blood flow changes brought on by the therapy, he said.
“The reason the GFR declines is that glomerular perfusion is slightly decreased by the calcineurin inhibitor,” he said. “That decrease in intraglomerular pressure also tends to result in a benefit in terms of glomerular sclerosis over the long term.”
3. Rapid Proteinuria Decrease from Voclosporin
Dr. Rovin
The voclosporin trial showed proteinuria began to drop in a matter of days, which Dr. Rovin said is likely due to the drug’s protective effects on podocytes, the epithelial cells that coat glomerular capillaries.2 Early remission tends to lead to better preservation of kidney function over time, he said.
“Time is nephrons,” Dr. Rovin said.
4. Efficacy in African Americans
Although the primary efficacy renal response favored belimumab over placebo in the pivotal trial in this subset, the result wasn’t statistically significant. Voclosporin’s response rate was statistically significant among African Americans, however.
Dr. Petri said this could have to do with the study’s entry criteria. An MMF dose of up to 3 g was allowed in the belimumab trial, but the limit was 2 g in the voclosporin trial. In her experience, African Americans tend to do better with the 3 g dose, she said. This methodology difference could help explain the belimumab result.
“The delta is always going to be affected by how good the comparison group is,” she said.
5. Safety
Dr. Petri said the data on safety favors belimumab in nearly every category (i.e., nephrotoxicity, infection, cardiovascular risk factors, malignancy and drug-drug interactions), and she suggested there might be adherence advantages because the infusions allow for an objective measure of adherence.
Dr. Rovin offered a caveat in interpreting this observation: “[Although] Dr. Petri presented a side-effect profile that may not have appeared to be as clean as belimumab, one of the issues with that is most of these side effects are coming from the transplant literature, where the calcineurin inhibitors are literally lifelong medications as long as you have the allograft. So the expectation, at least in my mind, is that we’re not going to be using voclosporin on a long-term basis.”
The Takeaways
How should clinicians incorporate these therapies into their care?
Dr. Petri suggested they should consider a calcineurin inhibitor or belimumab with MMF right away if patients have a renal biopsy that is “very active.” Or clinicians could wait three months, or even six months, if they’d like to use a particularly conservative approach.
For patients who are particularly vulnerable in terms of safety factors or for whom GFR is a primary consideration, belimumab is likely the better option, she said. And for those with extra-renal lupus, it’s important to remember that this is where “belimumab shines,” she said.
If an immediate effect on proteinuria is the primary goal, voclosporin showed greater improvement at one year.
“What I’m asking you to do is change,” she said. “I’m going to change my own pattern of behavior and add belimumab or voclosporin earlier.”
Dr. Rovin suggested that with voclosporin’s rapid proteinuria effects and belimumab’s long-term protection of GFR, the two therapies might work well together. Aspects of both drugs “are really beneficial to the kidney.”
“What I’m looking for is, really, a way to take this to the next step,” he said.
“I have no objections, in a patient who isn’t responding, to adding both a calcineurin inhibitor and belimumab,” Dr. Petri said. “We don’t have any data on when to do that and how to do that and whether it should be sequential or additive. We need to collect these data. But again, given belimumab has such a great safety profile, I think it is an easy choice to add [it].”
Both doctors said identifying biomarkers to help guide treatment and simplify these choices should be the ultimate goal.
“I hope … what we’re going to see in the end are biomarkers that will help us decide which drug is appropriate for which patient,” Dr. Rovin said. “But maybe both drugs are appropriate for a lot of patients. And maybe they can be used together.”
Thomas Collins is a freelance medical writer based in Florida.
References
- Furie R, Rovin BH, Houssiau F, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020 Sep 17;383:1117–1128.
- Rovin BH, Teng YKO, Ginzler EM, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): A double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2021 May 29;397:2070–2080.
