Complement Inhibitor Shows Early Promise in IgA Nephropathy

Pam Harrison

June 09, 2021

A first-in-class oral inhibitor of the alternative complement pathway that drives the pathogenesis of primary glomerulonephritis, iptacopan (LNP023, Novartis), is showing early promise as the first targeted therapy for the treatment of IgA nephropathy, a phase 2, dose-ranging study suggests.

"At the moment, we only have the option of optimized supportive care, which consists of maximally tolerated ACE inhibitors/ARB blockers and rigorous blood pressure control," Jonathan Barratt, MD, PhD, of John Walls Renal Unit, Leicester General Hospital, UK, told a press briefing during the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 2021 Virtual Congress.

"So there is a significant unmet need in this disease, and what we show in this study is that if we inhibit this alternative pathway with iptacopan for 90 days we see a significant, dose-dependent reduction in proteinuria and a trend towards stabilization of kidney function. This early reduction in proteinuria is a key marker of drug efficacy in IgA nephropathy," he added.

Commenting on the study, Perry Wilson, MD, associate professor of medicine, Yale University School of Medicine, New Haven, Connecticut, observed that a new treatment for glomerular disease is "always exciting" as these have been few and far between over the past few decades.

"IgA nephropathy, a common form of glomerulonephritis, has been tricky to treat because of a widely varying presentation from asymptomatic individuals to those with rapidly progressive kidney failure," Wilson told Medscape Medical News in an email. 

"This study shows that a new drug, iptacopan, may have promise in those most severely affected by IgA nephropathy," he added. 

Wilson cautioned however that the primary endpoint in this early stage trial — a reduction in proteinuria — is a surrogate outcome. "We'd all love to see whether the use of this drug can reduce the time to end-stage kidney disease (ESKD)," he added. 

Nevertheless, "proteinuria is a powerful risk factor for ESKD and we'll be watching the upcoming phase 3 trial with great interest," he enthused.

Patients at High Risk for Progression

A total of 112 patients with IgA nephropathy at high risk for disease progression were assigned to various doses of active therapy or placebo and treated for 90 days. The maximum dose assigned was iptacopan 200 mg twice a day. For study inclusion, patients had to have > 0.75 grams/day of proteinuria and an estimated glomerular filtration rate (eGFR) in excess of 30 mL/min/1.73m2.

At the end of a 90-day treatment interlude, patients treated with iptacopan 200 mg twice a day had a 23% reduction in proteinuria compared with placebo (P = .038), Barratt reported.

The mean change in eGFR over the same treatment interval was –3.3 mL/min/1.73m2 for patients taking placebo, he noted, compared with virtually no change in eGFR for those on active therapy.   

There was also no difference in the dose-dependent occurrence of adverse events between the two treatment groups, and over 90% of adverse events seen in iptacopan-treated patients were mild.

Importantly, because infections are a cause for concern in the setting of complement inhibition, there were no serious infections and no infections caused by encapsulated bacteria in patients who received active therapy.

As Barratt noted in an interview with Medscape Medial News, investigators expect they will see a bigger drop in proteinuria with longer-term treatment with iptacopan, but it is still too early to predict any further outcomes with certainty.

"If you look at the current trials, they are all looking at outcomes at 9 months, so this is very early days to be looking at outcomes in what is a progressive disease," he explained.

"It's encouraging, it's moving in the right direction, but we don't yet know if the proteinuria will continue to drop with prolonged dosing," he emphasized. Similarly, it's premature to be looking at eGFR as an outcome at 90 days in a disease that takes years to progress, he added.

IgA Nephropathy Is Most Common Primary Glomerulonephritis Worldwide

However, what is clear is that there is a real need for a targeted therapy for IgA nephropathy, which is the most common primary glomerulonephritis worldwide.

"The disease also affects young adults in their 20s and is associated with an up to 50% risk of developing ESKD over the next 20 years, which means that...[they] end up facing dialysis in their 40s or the need to have a kidney transplant. And there is a real risk that the disease will recur in their new kidney and they will lose their graft over time as well," Barratt noted.

This is because the kidney is "an innocent bystander" in the disease process: the pathology leads to scarring and loss of kidney function caused by IgA molecules circulating in the bloodstream, which are deposited in the kidney.

Evidence suggests that complement activation has a hand in both disease onset and progression. Indeed, the alternative complement pathway is found to be activated in 75% to 90% of patients with IgA nephrology, whereas the lectin complement pathway is activated in 17% to 25% of the same patient group.

Iptacopan selectively inhibits factor B, an essential component of C3 and C5 convertase, blocking their activity and thus inhibiting the alternative complement pathway.

"These early findings require confirmation in the phase 3 APPLAUSE study, but they are very encouraging and suggest that this drug may well protect long-term kidney function," Barratt urged.

The phase 3 APPLAUSE study is about to begin. Patients with IgA nephropathy at high risk for disease progression will again be randomized to iptacopan 200 mg twice a day or placebo for a total treatment interval of 24 months.

The study was funded by Novartis. Barratt has reported serving as a consultant or being on advisory boards for Alnylam, Astellas, BioCryst, Calliditas, Chinook, Dimerix, Novartis, Omeros, Travere Therapeutics, Vera Therapeutics, and Visterra. He has also reported receiving grants from Calliditas, Chinook, Dimerix, Novartis, Omeros, Travere Therapeutics, Vera Therapeutics, and Visterra. Wilson has reported no relevant financial relationships.

ERA-EDTA 2021. Abstract 2457. Presented June 6, 2021.

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