IgA nephropathy

A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy

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Abstract

BACKGROUND

A proliferation-inducing ligand (APRIL) is implicated in the pathogenesis of IgA nephropathy. Sibeprenlimab is a humanized IgG2 monoclonal antibody that binds to and neutralizes APRIL.

METHODS

In this phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial, we randomly assigned adults with biopsy-confirmed IgA nephropathy who were at high risk for disease progression, despite having received standard-care treatment, in a 1:1:1:1 ratio to receive intravenous sibeprenlimab at a dose of 2, 4, or 8 mg per kilogram of body weight or placebo once monthly for 12 months. The primary end point was the change from baseline in the log-transformed 24-hour urinary protein-to-creatinine ratio at month 12. Secondary end points included the change from baseline in the estimated glomerular filtration rate (eGFR) at month 12. Safety was also assessed.

RESULTS

Among 155 patients who underwent randomization, 38 received sibeprenlimab at a dose of 2 mg per kilogram, 41 received sibeprenlimab at a dose of 4 mg per kilogram, 38 received sibeprenlimab at a dose of 8 mg per kilogram, and 38 received placebo. At 12 months, the geometric mean ratio reduction (±SE) from baseline in the 24-hour urinary protein-to-creatinine ratio was 47.2±8.2%, 58.8±6.1%, 62.0±5.7%, and 20.0±12.6% in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. At 12 months, the least-squares mean (±SE) change from baseline in eGFR was −2.7±1.8, 0.2±1.7, −1.5±1.8, and −7.4±1.8 ml per minute per 1.73 m2 in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. The incidence of adverse events that occurred after the start of administration of sibeprenlimab or placebo was 78.6% in the pooled sibeprenlimab groups and 71.1% in the placebo group.

CONCLUSIONS

In patients with IgA nephropathy, 12 months of treatment with sibeprenlimab resulted in a significantly greater decrease in proteinuria than placebo.

FDA accepts, grants priority review of new treatment for IgA nephropathy

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Travere Therapeutics Inc. announced the FDA has accepted and granted priority review of its new drug application under subpart H for accelerated approval of sparsentan for treatment of IgA nephropathy.

According to the company press release, sparsentan is a dual endothelin angiotensin receptor antagonist that targets the endothelin A receptor and the angiotensin II subtype 1 receptor.

FDA-sign_323811316
Source: Adobe Stock

“For decades, people living with IgA nephropathy have had limited treatment options while facing a progression toward end-stage kidney disease. If approved, sparsentan would be the first FDA-approved non-immunosuppressive treatment option for IgA nephropathy, and we aspire to ultimately position sparsentan as a new standard of care,” Eric Dube, PhD, president and CEO of Travere Therapeutics, said in the release.

In the ongoing, phase 3 PROTECT study, researchers examined sparsentan in 404 patients with proteinuria to determine the effectiveness of treatment. After 36 weeks of treatment, researchers found sparsentan was well-tolerated and achieved a mean reduction in proteinuria from baseline of 49.8%.

The FDA assigned a Prescription Drug User Fee Act target action date of Nov. 17 for sparsentan.

“Acceptance of the NDA and being granted priority review brings us one step closer to potentially delivering sparsentan to the IgA nephropathy community before the end of this year, and we look forward to continuing to work with the FDA throughout the review process,” Dube concluded.

Oral methylprednisolone treatment reduces risk of kidney function decline vs. placebo

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Compared with placebo, oral methylprednisolone treatment reduced the risk of kidney function decline among patients with IgA nephropathy at high risk of progression, according to data published in JAMA.

However, investigators found serious adverse events correlated with high-dose oral methylprednisolone.

Infographic showing treatment results
Data were derived from Lv J, et al. JAMA.2022;doi:10.1001/jama.2022.5368.

“Although there have been advances in understanding the pathogenesis of IgA nephropathy, highlighting its immunological basis, no disease-specific therapy has been proven to prevent kidney failure,” Jicheng Lv, MD, from the renal division in the department of medicine at Peking University First Hospital in Beijing and colleagues wrote. They added, “The Therapeutic Effects of Steroids in IgA Nephropathy Global (TESTING) study was designed to determine the effects of oral methylprednisolone on the risk of major kidney outcomes, as well as adverse effects, in people with IgA nephropathy and proteinuria.”

In an international, multicenter, double-blind, randomized clinical trial, researchers examined 503 patients (mean age was 38 years; 39% were women) with IgA nephropathy, proteinuria greater than or equal to 1 g per day and eGFR of 20 mL/min/1.73 m² to 120 mL/min/1.73 m² following at least 3 months of “optimized background care.” All patients received care from one of 67 centers in Australia, Canada, China, India and Malaysia between May 2012 and November 2019. Researchers followed up on patients until June 2021.

Researchers randomized patients in a 1:1 ratio to receive either oral methylprednisolone (n=136) or placebo (n=126). After randomization, researchers identified an excess of serious infections among patients and reduced oral methylprednisolone doses from 0.6 mg/kg per day to 0.8 mg/kg per day, maximum 48 mg per day, weaning by 8 mg per day per month to 0.4 mg/kg per day, maximum 32 mg per day, weaning by 4 mg per day per month. In addition to the dose reduction, researchers gave subsequent patients antibiotic prophylaxis for pneumocystis pneumonia (121 in the oral methylprednisolone group and 120 in the placebo group).

Using an adjusted Cox model, researchers determined the effect of treatment on the primary end point of a composite of 40% decline in eGFR, kidney failure or kidney disease-related death. Similarly, the Kaplan-Meier method created survival curves.

Analyses revealed the primary end point occurred in 28.8% of the methylprednisolone group and 43.1% in the placebo group. Among the 503 patients, 493 completed the trial. Both doses of methylprednisolone reduced risk of kidney function decline, but more serious adverse events correlated with the intervention than placebo (10.9% vs. 2.8%); the occurrence of serious adverse events increased as the dosage increased (16.2% vs. 3.2%).

“The observed kidney benefits showed no significant heterogeneity of treatment effect between a reduced-dose regimen and the original full-dose protocol. However, the incidence of serious adverse events was increased with oral methylprednisolone and the reduced-dose regimen had fewer adverse events compared with the full-dose regimen,” Lv and colleagues wrote. “Overall, these data suggest that a 6- to 9-month course of oral corticosteroids effectively protected kidney function in people with IgA nephropathy and that this benefit can be realized with a reduced-dose protocol with a lower risk of adverse events.”