Experts Debate Merits of Dual Therapy for Lupus Nephritis

Thomas R. Collins

August 19, 2021

With the approval by the US Food and Drug Administration of the calcineurin inhibitor voclosporin (Lupkynis) in January and belimumab (Benlysta) a month before that, clinicians now have new options for treating lupus nephritis in combination with a background immunosuppressive agent, such as mycophenolate mofetil.

But which combination should clinicians choose?

Dr Brad Rovin

Brad Rovin, MD, a nephrologist with the Ohio State University Wexner Medical Center, Columbus, Ohio, who worked on the phase 3 voclosprin trial, pointed to that drug's fast reduction in proteinuria in a session of the Pan American League of Associations for Rheumatology (PANLAR) 2021 Annual Meeting. That effect on proteinuria is likely due to its effect on podocytes, special epithelial cells that cover the outside of capillaries in the kidney, he said.

These crucial cells have an elaborate cytoskeleton that is stabilized by the protein synaptopodin, which can be subject to harm from calcineurin. But because voclosporin blocks calcineurin, synaptopodin is protected, which consequently protects podocytes and the kidney, Rovin said.

"There's a lot of data in the nephrology literature that suggests as you lose podocytes, you actually can develop glomerular sclerosis and loss of renal function," he said. "In fact, if you lose a critical number of podocytes, then no matter what you do, the kidney is likely to progress to end-stage kidney disease.

"The way I think about it now is, what else do these drugs add? And this idea of preserving the histology of the kidney is really important, and this can be done with voclosporin," Rovin said.

Belimumab is also hailed as an effective tool, particularly for the prevention of flares. In the trial leading to its approval, just under 16% of patients experienced a renal-related event or death over 2 years, compared with 28% of the group that received placebo. Those receiving belimumab had a 50% greater chance of reaching the primary efficacy renal response, which was defined as a ratio of urinary protein to creatinine of 0.7 or less, an estimated glomerular filtration rate that was no worse than 20% below the pre-flare value or at least 60 mL/min/1.73 m2, and no use of rescue therapy for treatment failure.

Dr Richard A. Furie

The endpoints in the belimumab lupus nephritis trial were "quite rigorous," Richard A. Furie, MD, said in the same session at the meeting. Patients with class V lupus nephritis were included in the trial, although disease of this severity is known to be particularly difficult to treat, he noted.

"There's little question that our patients with lupus nephritis will benefit from such a therapeutic approach" with belimumab and mycophenolate, said Furie, professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, in Hempstead, New York. "But regardless of which combination clinicians use, we are making advances, and that means better outcomes for our patients with lupus and lupus nephritis."

Graciela Alarcon, MD, MPH, professor emeritus of medicine at the University of Alabama at Birmingham, who moderated the discussion, said there is no sure answer regarding the best choice for clinicians.

"As long as there's no head-to-head comparison between the two new compounds, I don't think that the question can be answered," she said.

Indeed, the answer for many clinicians might be that for certain patients, dual therapy isn't necessary, Furie said.

"The fundamental question, before we choose the second drug, is whether a second drug should be chosen," he said. "There's a lot of people in the community who are just sticking to the old-fashioned algorithm and that is just choosing one drug, like mycophenolate.... Others might pick a second drug, but not until they see that mycophenolate is not doing an effective job."

All agreed that the response rates are still not optimal for patients with lupus nephritis, even with these new combinations — they are still only in the 30% to 40% range.

"We haven't really boosted the response rate to where we want it to be, at least as measured by our current measurements and composite renal response," Rovin said.

With voclosporin's protective effects and belimumab's flare prevention, the two could potentially be used together at some point, he suggested.

"I think these two drugs show us the possibility that we might use them together and get rid of the older drugs, and really minimize the older drugs and then use them on a longer-term basis to preserve kidney function, as well as keep the lupus in check," he said.

Pan American League of Associations for Rheumatology (PANLAR) 2021 Annual Meeting: Presented August 15, 2021.

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