Complement Inhibitor Shows Promise for Rare Kidney Disorder

SAN DIEGO — Intravenous ravulizumab (Ultomiris) yielded clinically meaningful reductions in IgA nephropathy-related proteinuria in a small, mid-stage trial.

The 43 patients treated with ravulizumab had a 33.2% greater reduction in average urine protein to creatinine ratio (UPCR) compared with the 22 patients on placebo (P=0.0011), reported James Tumlin, MD, of Emory University in Atlanta, at the American Society of Nephrology Kidney Week meeting.

Patients taking ravulizumab also had a 40.4% reduction in UPCR from baseline — from 1.69 to 1.06 g/g — versus a 10.9% reduction with placebo (1.81 to 1.67 g/g).

“Spot UPCR measurements indicated separation between ravulizumab and placebo as early as week 4, suggestive of an early treatment effect,” the research group wrote in the Journal of the American Society of Nephrology, where the findings were simultaneously published.

During an open-label period from week 26 to 50, participants on ravulizumab maintained their reduction in UPCR, ending with a 41.1% reduction (from 1.69 to 1.07 g/g). Participants initially in the placebo group who crossed over to ravulizumab at week 26 also reaped the benefits, ending with a UPCR reduction of 43.1% (from 1.81 to 1.13 g/g) by the end of week 50.

The annualized estimated glomerular filtration rate (eGFR) slope with ravulizumab was -1.35 mL/min/1.73 m² per year compared with -6.74 mL/min/1.73 m² per year with placebo through 26 weeks. At 50 weeks, the annualized eGFR slope with ravulizumab was -2.34 mL/min/1.73 m² per year. After crossover to ravulizumab at week 26 in the placebo group, the annualized slope was -4.09 mL/min/1.73 m² per year through 50 weeks.

Approved in 2018, the complement inhibitor is already used to treat complement-mediated diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and myasthenia gravis.

It “binds to the C5 molecule and blocks the cleavage to C5a and C5b-9,” Tumlin explained. “We believe it’s an advantage of ravulizumab that it blocks both the lectin classical pathways and alternative complementaries, all of which have been implicated in IgA nephropathy.”

This was one of a handful of new or potential IgA nephropathy therapies discussed at Kidney Week, in addition to the complement inhibitor iptacopan (Fabhalta) and atrasentan, an elective inhibitor of the endothelin type A receptor. Up until the first IgA nephropathy drug — delayed-release budesonide (Tarpeyo) — was approved in December 2021, treatment options “have largely been limited to supportive care, primarily renin-angiotensin system (RAS) blockade and immunosuppression with corticosteroids,” Tumlin’s group pointed out.

In this trial, known as SANCTUARY, 66 patients with biopsy-proven IgA nephropathy, proteinuria ≥1 g/day, and an eGFR ≥30 mL/min/1.73 m² on stable RAS blockade were randomized 2:1 to ravulizumab (intravenous every 8 weeks) or placebo for 26 weeks. All participants had to have two complete and valid 24-hour urine collections during the screening period.

Of the patients, average age was 40, 46% were women, 71% were white, and 21% were Asian. Baseline median 24-hour UPCR was 1.4 g/g and 1.5 g/g in the treatment and placebo groups, respectively, and median baseline eGFR was 74 and 63 mL/min/1.73 m². Stable SGLT2 inhibition was allowed, and was used by nine participants in the ravulizumab arm and four in the placebo arm.

A statistically significant reduction in proteinuria with ravulizumab compared with placebo was also reported in several subgroups of patients, including those with varying proteinuria levels (1.0-2.0 and >2.0 g/day) and eGFR levels (>60-90 and >90 mL/min/1.73 m²).

Biopsy data were not available for participants throughout the trial, Tumlin pointed out.

Most adverse events were generally mild, and the only serious event involved hospitalization due to COVID, which occurred in a patient in the ravulizumab arm. No meningococcal infections occurred, though all participants had to be vaccinated prior to enrollment. No deaths or adverse events leading to withdrawal of the study drug were reported during the study. The most common adverse event in the ravulizumab group was nasopharyngitis.

“We have an ongoing phase III trial that’s currently enrolling for patients with IgA nephropathy at risk of disease progression,” said Tumlin.