medwireNews: In “The Great Debate” held at the ACR Convergence 2021 virtual meeting, experts discussed which new add-on treatment option should be used first for patients with active lupus nephritis despite conventional therapy.
Session chair Namrata Singh (University of Washington, Seattle, USA) explained that lupus nephritis “is a leading cause of mortality for patients with lupus.” But the phase 3 BLISS-LN and AURORA 1 trials “helped change the treatment landscape of lupus nephritis,” she added, leading the US FDA to approve both the B-cell activating factor (BAFF) inhibitor belimumab and the calcineurin inhibitor voclosporin as add-on treatment options in 2021.
For the debate, rheumatologist Michelle Petri (Johns Hopkins University School of Medicine, Baltimore, Maryland, USA) argued for the use of belimumab as the preferred first add-on treatment option, while nephrologist Brad Rovin (The Ohio State University, Columbus, USA) advocated for voclosporin in this setting.
Encouraging efficacy results for both drugs
Petri outlined the efficacy data from the BLISS-LN trial, which demonstrated significantly better Primary Efficacy Renal Response (PERR) rates from week 20 and Complete Renal Response (CRR) rates from around week 32 among participants treated with add-on belimumab versus placebo. She pointed out that 2-year efficacy data are available for belimumab, with CRR rates of 30.0% versus 19.7% with placebo at this timepoint, whereas only 1 year of follow-up data is available for voclosporin efficacy.
“It’s not really fair to put these two trials head-to-head because they had different study designs,” with more initial steroid use in the BLISS-LN trial, as well as a higher permitted daily dose of mycophenolate mofetil (up to 3 g vs 2 g in the AURORA trial of voclosporin), said Petri.
“To hit on every single primary and key secondary is so refreshing in this field”
Rovin took delegates through the results of the AURORA trial of voclosporin, as well as those from the phase 2 AURA-LV study. He pooled the findings from both trials, which demonstrated better CRR rates at 6 months (31.7 vs 20.3%) and 1 year (43.7 vs 23.3%) with add-on voclosporin versus placebo. He said that the significantly improved renal outcomes and lower glucocorticoid requirements with voclosporin plus mycophenolate mofetil provide support for the use of the calcineurin inhibitor in clinical practice.
Rovin remarked that the combination of voclosporin and mycophenolate mofetil was “effective in patients of diverse racial and ethnic backgrounds” in a subgroup analysis of the AURORA trial.
Insights from subgroup analyses
Petri also discussed subgroup analyses for belimumab, and remarked that PERR rates at 2 years were not significantly better with the BAFF inhibitor versus placebo in people of Black African ancestry, albeit with point estimates favoring belimumab.
“This has been a controversial point for belimumab efficacy,” unlike in the voclosporin trial, in which the between-group difference for voclosporin versus placebo did reach statistical significance in the 45 Black patients, Petri conceded. She suggested that the different doses of mycophenolate used in the two trials may explain these results.
Protecting kidney function is the most important goal
In addition to the renal benefits seen in BLISS-LN, Petri described evidence from this study and others showing that belimumab has extra-renal benefits for people with lupus, which is “one of the areas where belimumab shines.” Finally, she pointed out that belimumab has shown significant efficacy for the prevention of kidney function decline, which, ultimately, “is the reason why we’re treating lupus nephritis patients.”
And Rovin said: “I totally agree […] that what we’re looking to do in lupus nephritis is […] to protect the kidneys over the long term and avoid the need for renal replacement therapy.”
He described data suggesting potential beneficial effects of voclosporin on renal function, including rapid resolution of proteinuria, which is known to be associated with improved long-term renal outcomes, and preservation of podocytes.
Rovin said that the favorable safety profile of voclosporin provides additional support for its use as an add-on treatment. The pooled analysis of data from AURORA and AURA-LV found similar rates of treatment-related serious adverse events (AEs; 4.5 vs 3.4%) and AEs leading to treatment discontinuation (13.5 vs 13.2%) with voclosporin versus placebo, and there were no treatment-related AEs leading to death.
And Petri highlighted the safety profile as an important benefit of belimumab therapy, noting that a meta-analysis found no increased risk for serious or fatal infection among patients treated with the BAFF inhibitor versus placebo. She said that belimumab has no drug–drug interactions, unlike voclosporin, and commented that the BAFF inhibitor is not associated with increased rates of hypertension or malignancy. She pointed to data showing an imbalance of deaths in the AURA-LV voclosporin trial, which was “never explained,” but could be due to issues with access to care in South Asia, where the deaths mainly occurred.
“I have lots of vulnerable patients [such as those] with infections, patients who have already had a malignancy, where the very clean safety profile of belimumab is going to matter,” she said.
Petri cautioned that it is currently unknown whether belimumab is appropriate to use during pregnancy, with an insufficient number of patients in the Belimumab Pregnancy Registry to draw any conclusions.
“Of course each rheumatologist, or nephrologist for that matter, can make a personalized decision for that particular patient,” but “I would personally be cautious” about the use of belimumab in pregnancy, she said.
A new treatment paradigm?
Although Petri advocated for belimumab in the debate, she said: “I think if our Great Debate is successful, you will feel comfortable using both of these new treatments for lupus nephritis.”
“We don’t want rheumatologists to use belimumab and nephrologists to use voclosporin,” she added, and Rovin agreed.
Petri proposed a new treatment paradigm in which patients could be given belimumab or a calcineurin inhibitor in cases of very active lupus nephritis on biopsy, rather than starting on mycophenolate monotherapy first.
“I think we should be very comfortable using either a calcineurin inhibitor or belimumab right at the get-go,” she said. Alternatively, she suggested that “you could add a calcineurin inhibitor or belimumab at 3 months, or if you’re very conservative, you could add it at 6 months
Thinking along similar lines, Rovin suggested that “the next step may be to just abandon our conventional thinking about how we treat lupus nephritis with standard-of-care therapy […] and see if we can’t think about using these new drugs in a way to protect the kidney over the long term.”
He highlighted the need for “biomarkers that will help us decide which drug is appropriate for which patient,” but also believes that “maybe both drugs are appropriate for a lot of patients, and maybe they can be used together.”
And Petri said “I have no objections, in a patient who isn’t responding, to adding both a calcineurin inhibitor and belimumab [to conventional therapy], but we don’t have any data on when to do that and how to do that, and whether it should be sequential or additive.”
Both speakers agreed that there is a need for further studies to establish whether using both therapies together is beneficial.
Rovin said that “we don’t have the data but the mechanisms of action and the subsequent effects on kidney function are so appealing and so different between the two drugs,” suggesting they could work well together, and called for a trial investigating the combination.
What did the audience think?
In the meantime, which drug should be used first for enhancing lupus nephritis therapy? After watching the presentations from Petri and Rovin, the audience was asked to vote. The majority (70%) plumped for belimumab first, while the remaining 30% said they would favor voclosporin.
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