PHILADELPHIA — An investigational humanized IgG2 monoclonal antibody reduced proteinuria in adults with immunoglobulin A (IgA) nephropathy at high risk for disease progression despite standard treatments, a randomized phase II trial found.
In a dose-dependant manner, intravenous sibeprenlimab led to significantly greater decreases in 24-hour urinary protein-to-creatinine ratio at 12 months compared with placebo, with geometric mean ratio reductions ranging from 47.2% to 62% versus 20%, respectively (P<0.001), meeting the trial’s primary endpoint, reported Mohit Mathur, MD, of drugmaker Visterra in Waltham, Massachusetts.
More patients on sibeprenlimab achieved clinical remission by this point as well (7.9-26.3% vs 2.6% with placebo) and safety outcomes were comparable between groups, according to findings of the so-called ENVISION trial presented here at the American Society of Nephrology’s Kidney Week and simultaneously published in the New England Journal of Medicine.
If confirmed in an ongoing global phase III study, sibeprenlimab may provide IgA nephropathy patients with “a much needed safe and efficacious alternative that can modify the course of this disease and reduce the risk of progression to end-stage kidney failure,” Mathur told MedPage Today.
In this study, sibeprenlimab also helped stabilize estimated glomerular filtration rate (eGFR) decline throughout the year, with average changes of -2.7 to 0.2 mL/min/1.73 m2 from baseline across the three doses tested versus a -7.4 mL/min/1.73 m2 decline with placebo.
“A recent long-term cohort study showed that almost all the patients with IgA nephropathy were at risk for progression to kidney failure within their expected lifetime unless a rate of eGFR loss of 1 mL/min/1.73 m2 per year or lower was maintained,” Mathur pointed out, adding that the eGFR stabilization in the study emphasizes “the potential beneficial impact of sibeprenlimab on the long-term outcomes in patients with IgA nephropathy.”
The agent acts by binding to and neutralizing proliferation-inducing ligand (APRIL) activity.
“Multiple lines of evidence support a key role for APRIL and galactose-deficient IgA1 (Gd IgA1) in the pathogenesis of IgA nephropathy,” said Mathur. “Blocking APRIL activity presents a potential method of treatment to reduce circulating levels of Gd IgA1 and associated immune complexes.”
When data from the phase III sibeprenlimab study and trials of other therapeutic interventions are available, “we will have a more refined understanding of how this treatment will fit within the overall treatment landscape,” said Mathur.
The first non-immunosuppressive therapy for this rare condition, sparsentan (Filspari), was FDA approved in February. Budesonide (Tarpeyo) — an immunosuppressant — was also approved in December 2021 as the very first drug to reduce proteinuria in primary IgA nephropathy.
The four-arm ENVISION trial randomized 155 patients at 98 centers across 15 nations in a 1:1:1:1 manner to three doses of sibeprenlimab (8 mg, 4 mg, or 2 mg per kg of body weight) or placebo, administered monthly for a total of 12 doses; nearly all patients in each arm finished the full treatment course.
Overall, patients had a median age of 39 years, 57% were men, roughly three-fourths were Asian, and 23% were white.
All participants had biopsy-confirmed disease and were already receiving standard of care treatment — the highest dose of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) associated with minimal side effects. Inclusion criteria included having a 24-hour urinary protein-to-creatinine ratio of at least 0.75 g of protein/g of creatinine (or a urinary protein level of ≥1.0 g per day) and at least an eGFR of 30 mL/min/1.73 m2.
The primary efficacy endpoint was 24-hour urinary protein-to-creatinine ratio at 12 months. At this point, the highest dose showed the greatest geometric mean ratio reduction from baseline:
- 8 mg: 62%
- 4 mg: 58.8%
- 2 mg: 47.2%
- Placebo: 20%
Secondary endpoints included changes at 9 and 16 months, along with clinical remission (decrease in urinary protein excretion to below 300 mg per day), change in eGFR at month 12, and pharmacodynamics.
Reductions in proteinuria continually dropped until around month 9, and then levels were maintained with the two higher doses through month 16, while levels slowly started to rebound with the 2-mg dose. Across all three doses, more patients on sibeprenlimab achieved clinical remission by 12 months (26.3%, 12.2%, and 7.9% in the 8-mg, 4-mg, and 2-mg groups, respectively) compared with placebo (2.6%).
For eGFR decline, sibeprenlimab showed better stabilization throughout the year, with changes from baseline of -1.5, 0.2, and -2.7 mL/min/1.73 m2 in the 8-mg, 4-mg, and 2-mg groups, as compared with an average -7.4 mL/min/1.73 m2 decline in the placebo group.
Pooled sibeprenlimab and the placebo group had a similar incidence of serious adverse events (4.3% vs 5.3%) and risk of infection (49.6% vs 55.3%). Adverse events that occurred in 5% or more of the sibeprenlimab group included COVID-19, pyrexia, nasopharyngitis, upper respiratory tract infection, headache, hypertension, diarrhea, and muscle spasm, though most were reported as mild or moderate.
The trial was funded by Visterra, a member of the Otsuka family of companies.
Mathur is employed by Visterra. Other study authors reported ties with industry.
New England Journal of Medicine
Source Reference: Mathur M, et al “A phase 2 trial of sibeprenlimab in patients with IgA nephropathy” N Engl J Med 2023; DOI: 10.1056/NEJMoa2305635.