During the American College of Rheumatology (ACR) Convergence 2021 conference, the Great Debate compared belimumab versus voclosporin as add-on therapy to mycophenolate in the management of active lupus nephritis. The debate discussed benefits and drawbacks of these two agents, which were newly FDA approved for lupus nephritis in the past year.
Benefits of Belimumab
Dr. Michelle Petri, a professor of Medicine at the Johns Hopkins University School of Medicine and Director of the Hopkins Lupus Center, provided arguments in favor of belimumab. She discussed how the BLISS-LN Phase 3 RCT randomized patients (1:1) to standard of care vs standard of care plus belimumab, with belimumab demonstrating efficacy over standard of care, either mycophenolate or EuroLupus cyclophosphamide dosing.
“For subset analyses, all of the point estimates favored belimumab with one exception, pure Class V [lupus nephritis],” Petri said. She noted the belimumab BLISS-LN trial did have higher glucocorticoid use initially compared to the voclosporin trial and higher dose of mycophenolate, with mycophenolate 3g in the belimumab trial compared to mycophenolate 2g for the voclosporin trial.
For extra-renal lupus, Dr. Petri explained that belimumab has proven benefit in non-renal lupus.
“The benefit of belimumab beyond the kidneys has been proven in the original Phase 3 trials and long-term follow-up,” Dr. Petri said. Additional abstracts at the ACR Convergence 2021 demonstrated efficacy of belimumab for prevention of severe flares and reduction of glucocorticoid use.
Next, Dr. Petri discussed safety concerns of the calcineurin inhibitor class including acute and chronic nephrotoxicity of calcineurin inhibitors (with decreases in GFR observed), infections, increased risk of malignancy, neurologic toxicity, drug-drug interactions, and increases in hypertension, diabetes and hyperlipidemia. While these side effects are seen across the class of calcineurin inhibitors, most were not prominent in the voclosporin trial. She also discussed medication adherence (a significant issue in lupus). Given voclosporin dosing requires a total of six tablets each day, this can be a significant pill burden especially when added to mycophenolate.
In Favor of Voclosporin
Dr. Brad Rovin, Director of Division of Nephrology at the Ohio State University, provided arguments in favor of use of voclosporin with standard therapy for lupus nephritis.
He discussed the AURORA randomized controlled trial of voclosporin vs placebo, added to background of mycophenolate 2g per day, which demonstrated efficacy of voclosporin. This study employed an aggressive steroid taper regimen, with patients tapered down to prednisone 2.5mg/day by Week 16 that may help minimize long-term adverse steroid-related side effects.
Next, Dr. Rovin highlighted that voclosporin was effective in patients of diverse racial and ethnic backgrounds, including Black, Asian and Hispanic/Latinx patients. He showed a graph of the proteinuria (UPC) over time, with dramatic reduction in proteinuria in the voclosporin group; this rapid reduction in proteinuria is due to the effects on the podocyte which are also kidney protective.
A slight decline in GFR was observed in voclosporin, which Dr. Rovin noted, is not nephrotoxicity but actually a reversible, hemodynamic effect. There was an increase in systolic and diastolic blood pressure, again as part of the hemodynamic effects; Dr. Rovin highlighted this was not major and did not persist by the end of the trial.
The major benefits of voclosporin include the dramatic reduction in glucocorticoid requirement, rapid reduction in proteinuria which should translate to fewer flares of nephritis and less accumulation of chronic kidney injury, as well as beneficial non-immunologic effects such as stabilization and protection of the podocytes, Dr. Rovin explained. He also emphasized there were no increase in serious adverse events in the voclosporin trial, and that voclosporin had fewer side effects than traditional calcineurin inhibitors. Finally, he explained that only voclosporin reached statistical significance for Class V lupus nephritis and efficacy for Black patients, though he also acknowledged that belimumab offers prevention of GFR reduction and long-term efficacy.
Dr. Petri and Dr. Rovin both emphasized they do not want only rheumatologists to prescribe belimumab and only nephrologists to prescribe voclosporin, and that both options should be considered in the management of lupus nephritis. For a patient with very low GFR, Dr. Petri advocated considering the GFR protective effect of belimumab and extra-renal manifestations in decision-making – areas “where belimumab shines,” she said. Dr. Rovin also suggested evaluating the effects of both drugs, belimumab and voclosporin, together in future trials to see if the combination of effects may offer even better renal protection by combining the rapid proteinuria reduction and podocyte effects of voclosporin in conjunction with the GFR protection provided by belimumab.
At the conclusion of her talk, Dr. Petri emphasized that it is time to change the way we treat lupus nephritis. If a renal biopsy shows very active lupus nephritis with bad prognostic markers, Dr. Petri explained we should not be using mycophenolate alone and comfortable starting either a calcineurin inhibitor (CNI) or belimumab from the start of treatment. An alternative option in less active disease is to wait for 3 to 6 months and see how the patient does on mycophenolate, and adding a CNI or belimumab at that time versus switching to cyclophosphamide. She encouraged the audience to be comfortable with these new medications.
“It’s time we change the paradigm of how we manage lupus nephritis,” Dr. Petri concluded.
Source: Abstract 6S113. The Great Debate- Enhancing Lupus Nephritis Therapy: Is Your Next Step Belimumab or Voclosporin? ACR Convergence 2021.
Mithu Maheswaranathan, MD, is currently a practicing rheumatologist ay the Duke University School of Medicine. Follow him on Twitter (@MithuRheum).