Sibeprenlimab Shows Promise for IgA Nephropathy

Sibeprenlimab significantly reduces proteinuria in patients with high-risk IgA nephropathy (IgAN), according to trial results published in The New England Journal of Medicine.

In the international phase 2, double-blind ENVISION trial (ClinicalTrials.gov number, NCT04287985), investigators randomly assigned 155 patients with biopsy-confirmed IgAN to receive intravenous sibeprenlimab monthly at a dose of 2, 4, or 8mg/kg or placebo. Despite standard care renin-angiotensin-aldosterone system (RAAS) blockade, patients had a baseline 24-hour urinary protein-to-creatinine ratio (uPCR) of 0.75 g/g or more (or a urinary protein level of 1.0g or more per day). Their serum antibody levels were at least IgG 700mg/dL, IgM 37mg/dL, and IgA 70mg/dL. Participants were required to have a baseline estimated glomerular filtration rate (eGFR; mL/min/1.73m²) of at least 30. Patients with a MEST-C score of T2 or C2 or secondary causes of IgAN were among those excluded.

At 12 months, 24-hour uPCR had decreased 47.2%, 58.8%, and 62.0% from baseline in the sibeprenlimab 2, 4, and 8 mg groups, respectively, compared with 20.0% in the placebo group, investigators led by Mohit Mathur, MD, of Visterra in Waltham, Massachusetts, the drug’s sponsor, reported. Clinical remission to proteinuria less than 300 mg/d occurred in 7.9%, 12.2%, and 26.3% of the sibeprenlimab groups, respectively, compared with 2.6% of the placebo group. Proteinuria reduction was maintained through 16 months (5 months after the last drug dose) in the sibeprenlimab 4 and 8mg groups, but not the 2 mg group.

More stable eGFR was observed in all sibeprenlimab groups at 12 months compared with the placebo group: -2.7, 0.2, -1.5 vs -7.4, respectively, Dr Mathur’s team reported.

Sibeprenlimab is a IgG2 monoclonal antibody that selectively binds to a proliferation-inducing ligand (APRIL). Over 12 months of drug treatment circulating levels of APRIL and galactose-deficient IgA1 decreased. By 16 months, however, during the off-drug period, free APRIL and IgA1 levels had returned to baseline levels.

The adverse events rate did not differ between the sibeprenlimab and placebo groups (78.6% vs 71.1%). The most common adverse events in the sibeprenlimab group were COVID-19, pyrexia, nasopharyngitis, upper respiratory tract infection, headache, hypertension, diarrhea, and muscle spasm. Infection risk appeared no higher with the drug than with placebo.

“The results of the initial clinical sibeprenlimab trial showed that sibeprenlimab selectively inhibited APRIL and did not affect the level of B-cell activating factor of the tumor necrosis factor α family (BAFF), thus avoiding lymphocyte depletion and its potential consequences, which have been associated with dual inhibition of APRIL and BAFF,” the investigators noted.

An ongoing phase 3 trial (ClinicalTrials.gov number, NCT05248646) is underway.

In an accompanying editorial, Kevin V. Lemley, MD, PhD, of Keck School of Medicine of USC, and Richard J. Glassock, MD, of the University of California, Los Angeles, commented:

“The degree of reduction in proteinuria with sibeprenlimab was consistent with substantial protection of kidney function, which is supported by the stabilization of the eGFR, at least over the course of the trial.

“The fact that the reduced APRIL levels were not sustained after sibeprenlimab was stopped suggests that long-term treatment would be needed by most patients. Thus, the possibility of the eventual development of antibodies against sibeprenlimab remains.”

The editorialists noted that sodium glucose cotransporter 2 inhibitors were not included as background therapy in this trial, but should be studied in this setting in the future.

Disclosure: This research was supported by Visterra. Please see the original reference for a full list of disclosures.

This article originally appeared on Renal and Urology News