Povetacicept Cuts Proteinuria in IgAN: Richard Lafayette, MD, FACP

Povetacicept, a dual inhibitor of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), produced a proteinuria difference of about 50% from placebo at 36 weeks in an interim analysis of patients with IgA nephropathy, with a safety signal that looked no different than placebo, according to Richard Lafayette of Stanford University Medical Center.

In an interview with The American Journal of Managed Care^®, Lafayette discussed how povetacicept works, what the interim findings mean for kidney outcomes, and how the safety profile compares with placebo.

How Povetacicept Targets IgA Nephropathy

Lafayette explained that povetacicept is novel because of a specially designed fusion protein. It is based on the natural receptor for BAFF and APRIL but engineered to be more potent and to have different tissue penetrance. BAFF and APRIL are key cytokines that stimulate B-cell development and survival, including plasmablasts and plasma cells, which make antibodies.

In IgA nephropathy, immune complexes of antibodies, galactose-deficient IgA1, and anti-glycan antibodies deposit in the kidney and start inflammation and injury. Lafayette said the upstream blockade of BAFF and the slightly further downstream blockade of APRIL "work really harmoniously together to quiet the disease."

What the 36-Week Interim Data Show

At the interim analysis, "the most important thing is really that the proteinuria was rapidly and well controlled at around a 50% difference from placebo," Lafayette said. That result suggests a strong effect on renal disease progression and a reduction in long-term risk, Lafayette noted, and it was supported by a dramatic reduction in galactose-deficient IgA1 and a reduction in hematuria.

Lafayette said the FDA uses the 36-week proteinuria reduction as a signal for early drug approval because it has correlated well with long-term benefit and fewer hard outcomes. Proteinuria reduction alone has supported several approvals across different mechanisms of action. When it appears together with large reductions in galactose-deficient IgA1 and resolution of hematuria, Lafayette said, the pattern fits better with disease-modifying potential. That potential has been associated with greater reductions in the risk of progressive kidney failure.

The ultimate outcome in these trials is assessed at 2 years and has been associated with fewer harder endpoints, such as loss of kidney function or the need for kidney replacement treatment. Lafayette said more evidence is needed for povetacicept, but "the hallmarks so far are really promising."

Safety and Place in Treatment

Because these agents affect immune cells and reduce antibody production, infection risk is a natural concern, Lafayette said, since antibodies help protect against infections. However, the injectable agent appears to be well tolerated, with only minor injection reactions. The infection profile looked no different than placebo, with numerically fewer severe adverse events. "So far, it's looking great," Lafayette said.

Lafayette pointed to meta-analyses of agents in this space, which suggest that B-cell modifiers look to be the best class for preserving kidney function while maintaining safety. These agents are often used with conservative therapies such as renin-angiotensin system (RAS) inhibitors and sodium-glucose cotransporter 2 inhibitors, and more than half of the patients in the RAINIER study were taking them.

Lafayette emphasized the value of patients staying in the trial. "We want to have a longer safety record, so the ongoing study is really important, despite the extremely promising findings of the interim analysis," Lafayette said.