ENVISION Trial: Sibeprenlimab Reduces 24-Hour UACR in IgA Nephropathy

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Results of the phase 2 ENVISION trial suggest sibeprenlimab could prove useful in the management of IgA nephropathy.

Presented at the American Society of Nephrology’s Kidney Week 2023, results of the trial indicate sibeprenlimab resulted in a significantly greater decrease in proteinuria than placebo at 12 months among patients with IgA nephropathy.

“The results of the current trial showed robust suppression of serum APRIL levels and of galactose-deficient IgA1 levels after administration of intravenous sibeprenlimab,” wrote investigators.¹ “These changes led to significantly greater reductions in proteinuria and greater stabilization of eGFR decline with sibeprenlimab than with placebo, particularly with the higher doses.”

A humanized IgG2 monoclonal antibody, sibeprenlimab binds to and neutralizes a proliferation-inducing ligand (APRIL), which investigators pointed out has been implicated in the pathogenesis of IgA nephropathy. Funded by Visterra, which was acquired by Otsuka Pharmaceuticals in 2018,² the ENVISION trial was launched in with the intent of building on preclinical and phase 1 studies purporting reversible, dose-dependent reductions in the serum levels of IgA, galactose-deficient IgA1, IgG, IgM, and APRIL after administration.¹

With this in mind, the phase 2 ENVISION was designed as a multicenter, double-blind, randomized, placebo-controlled, parallel-group trial and randomized patients with biopsy-confirmed IgA nephropathy who were at high risk for disease progression 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 trial’s primary endpoint was s the change from baseline in the log-transformed 24-hour urinary protein-to-creatinine ratio (UACR) at month 12. The trial also included multiple secondary endpoints of interest, including change from baseline in the estimated glomerular filtration rate (eGFR) at month 12.¹

For inclusion in the study, patients needed to be at least 18 years of age or older, have biopsy-confirmed IgA nephropathy, a 24-hour UACR of at least 0.75, an eGFR of 30 ml/min/1.73m2 a serum IgG level of at least 700 mg per deciliter, an IgM level of at least 37 mg per deciliter, and an IgA level of at least 70 mg per deciliter. Investigators noted patients were also required to be receiving the highest stable dose of treatment with an ACEi/ARB for at least 3 months before screening.¹

A total of 155 patients underwent randomization in the study. Of these, 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 therapy. Of the 155 patients included in the trial, 146 completed the full treatment course, with the mean number of doses received at 11.4 per patient.¹

Upon analysis, a significant linear treatment effect was observed for change from baseline in 24-hour UACR (P <.001). When assessing geometric mean ratio reduction from baseline in 24-hour UACR, results indicated reductions of 47.2% (Standard Error [SE], 8.2), 58.8% (SE, 6.1), 62.0% (SE, 5.7), and 20.0% (SE, 12.6) occurred among the in the sibeprenlimab 2 mg, sibeprenlimab 4 mg, sibeprenlimab 8 mg groups, and placebo group, respectively.¹

Further analysis suggested the least-squares mean change from baseline in eGFR was −2.7 (SE, 1.8), 0.2 (SE, 1.7), −1.5 (SE, 1.8), and −7.4 (SE, 1.8) ml per minute per 1.73 m2 in the sibeprenlimab 2 mg, sibeprenlimab 4 mg, sibeprenlimab 8 mg groups, and placebo group, respectively. In an analysis of safety outcomes, adverse events were observed among 78.6% of the pooled sibeprenlimab groups and 71.1% of the placebo group. According to investigators, adverse events occurring among 5% or more of the sibeprenlimab group were COVID-19, pyrexia, nasopharyngitis, upper respiratory tract infection, headache, hypertension, diarrhea, and muscle spasms.¹

“In the current trial, 12 months of treatment with sibeprenlimab resulted in a significantly greater decrease in proteinuria than placebo in patients with IgA nephropathy,” investigators added.¹

References:

1. Mathur M, Barratt J, Chacko B, et al. A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy. The New England Journal of Medicine. Published online November 2, 2023. Accessed Novembr 2, 2023. doi:10.1056/NEJMe2312324
2. Otsuka pharmaceutical to acquire Visterra. Otsuka Pharmaceutical to Acquire Visterra | Discover Otsuka. July 11, 2018. Accessed November 2, 2023. https://www.otsuka-us.com/discover/articles-1206.