Investigative Oral Targeted Budesonide Significantly Improves Berger Disease Over 9 Months

Richard Lafayette, MD

Credit: LinkedIn

A novel oral, targeted-release formulation of budesonide (Nefecon), which is currently marketed as Tarpeyo, was associated with clinical relevant and durable reductions in parameters of IgA nephropathy versus placebo over 9 months, according to new phase 3 data.¹

Findings from the Calliditas Therapeutics-funded, 2-year NEfIgArd study showed a strong profile for the efficacy, safety and tolerability of the novel budesonide administration, setting the stage for a potential US Food and Drug Administration (FDA) application and approval for use in patients with IgA nephropathy—better known as the rare Berger disease.

A multinational team of investigators, led by Richard Lafayette, MD, a professor in Stanford University’s division of nephrology, conducted the multicenter, randomized, double-blind, placebo-controlled trial assessing oral targeted-release budesonide formulation in adult patients ≥18 years old with primary Berger disease. A chronic immune-mediate kidney disease, IgA nephropathy is associated with a significant rate of kidney failure among patients globally.

“The gut mucosal immune system is implicated in its pathogenesis, and Nefecon is a novel, oral, targeted-release formulation of budesonide designed to act at the gut mucosal level,” investigators wrote.

Eligible NEfIgArd trial patients were diagnosed with Berger disease and had estimated glomerular filtration rates (eGFRs) 35 – 90 mL/min per 1.73 m2 as well as persistent proteinuria—defined as urine protein-creatine ratio ≥0.8 g/g or proteinuria ≥1 g/24 h—despite optimized renin-angiotensin system blockade.

The team enrolled patients across 132 hospital-based clinical settings across 20 countries globally; participants were randomized 1:1 to 16 mg daily oral budesonide or placebo for 9 months. Patients were additionally followed for a 15-month observational follow-up period without treatment. Randomization was stratified base on patient baseline proteinuria, eGFR and region.

Lafayette and colleagues sought a primary efficacy endpoint of time-weighted eGFR average over 2 years, with efficacy and safety analyses completed in the full set of patients. Recruitment ran from September 2018 – January 2021.

A total of 364 patients were randomized to either budesonide (n = 182) or placebo (n = 182). Two-thirds (n = 240 [66%]) were male, and three-fourths (n = 275 [76%]) identified as White.

Time-weight eGFR average change was -2.47 mL/min per 1.73 m2 (95% CI, -3.88 to -1.02) over 2 years for patients receiving budesonide, versus -7.52 mL/min per 1.73 m2 (95% CI, -8.83 to -6.18) among patients receiving placebo. Mean difference between the treatment arms was statistically significant, at 5.05 mL/min per 1.73 m2 (95% CI, 3.24 – 7.38; P <.0001).

Commonly reported adverse events among treated patients included peripheral edema (n = 31 [17%]), hypertension (n = 22 [12%]), muscle spasms (n = 22 [12%]), acne (n = 20 [11%]) and headache (n = 19 [10%]). No treatment-associated deaths were reported among patients.

In an editorial accompanying the phase 3 data, Dr. Borje Haraldsson, of the Institute of Neuroscience and Physiology at the University of Gothenburg in Sweden, emphasized the urgency of identifying viable new treatments for Berger disease—a condition inaccurately considered to be benign in nature.²

“Therapy is mainly supportive and based on blood pressure control and blockade of the renin-angiotensin system,” Haraldsson wrote. “Most patients are treated by a nephrologist, but some are treated by their general practitioner. Considering that almost all patients with IgA nephropathy develop renal failure within their lifetime, it seems evident that these patients need improvements in therapy and disease-modifying therapies.”

Fortunately, investigators concluded their findings indicate a significant benefit with investigative oral budesonide.

“A 9-month treatment period with Nefecon provided a clinically relevant reduction in eGFR decline and a durable reduction in proteinuria versus placebo, providing support for a disease-modifying effect in patients with IgA nephropathy,” the team concluded. “Nefecon was also well tolerated, with a safety profile as expected for a locally acting oral budesonide product.”

References

1. ^{Lafayette R, Kristensen J, Stone A, Floege J, et al. Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial. The Lancet. Published August 14, 2023. DOI: https://doi.org/10.1016/S0140-6736(23)01554-4}
2. ^{Haraldsson B. Phase 3 trial results bring hope for patients with IgA nephropathy. The Lancet. Published August 14, 2023. DOI: https://doi.org/10.1016/S0140-6736(23)01633-1}