Potential shift to IgA nephropathy treatment…'Nefecon'

Targeting the Peyer’s patches…targets the underlying causes of the disease

Improved proteinuria·eGFR…"Early intervention is increasingly important"

The treatment landscape for IgA nephropathy (IgAN) is likely to shift from a focus on conservative management toward targeted therapies that address the disease's underlying cases.

While treatments centered on renin-angiotensin system (RAS) inhibitors, aimed at blood pressure control and reduction of proteinuria, have shown limitations, a local immunomodulatory therapy targeting the Peyer’s patches (immune tissue in the ileum) has demonstrated efficacy in reducing proteinuria and protecting renal function, drawing attention to a potential paradigm shift in treatment strategies.

On the 26th, Everest Medicines hosted a media session at the Plaza Hotel in Jung-gu, Seoul, to highlight the clinical value of 'Nefecon (micronized budesonide),' a targeted treatment for IgA nephropathy.

IgA nephropathy is a primary glomerular disease characterized by the deposition of immunoglobulin A (IgA) within the glomeruli, which induces inflammation and a decline in kidney function. It accounts for approximately 40% of glomerulonephritis cases in South Korea and is known to commonly manifest in individuals in their 20s to 40s who are socially and economically active. Unlike conventional chronic kidney disease (CKD), which frequently occurs in the elderly population in association with diabetes and hypertension, IgAN is distinct in its onset among a relatively younger ages.

Although disease progression varies across patients, persistent proteinuria and renal decline carry a high risk of progression to end-stage renal disease (ESRD). The recurrence rate remains at 20% to 60% even after kidney transplantation, and some studies report that the average life expectancy is shortened by approximately 10 years, with a mortality rate roughly twice as high as that of the general population.

Jung Pyo Lee, Department of Nephrology, Boramae Medical Center

In particular, proteinuria and a depressed estimated glomerular filtration rate (eGFR) are recognized as key indicators of disease progression and elevated cardiovascular risk. A British cohort study reported that a considerable number of cases progressed to kidney failure within 10 to 15 years post-diagnosis, demonstrating that patients with higher baseline proteinuria faced a substantially increased risk of ESRD or mortality.

Previously, the management of IgA nephropathy has centered on supportive care aimed at slowing the rate of renal deterioration rather than modifying the disease itself. Renin-angiotensin system (RAS) inhibitors designed for blood pressure and proteinuria control. While RAS inhibitors help reduce proteinuria by lowering intraglomerular pressure, they limitations because they do not directly target the underlying pathogenesis.

Professor Jung Pyo Lee explained, "While a renal biopsy is vital for a definitive diagnosis of IgA nephropathy, it cannot be practically performed on every patient. Global guidelines recommend a biopsy when proteinuria exceeds 0.5g. However, in real-world clinical practice, RAS inhibitors or SGLT-2 inhibitors are prioritized when proteinuria is under 0.5g. Immunotherapy is considered when proteinuria reaches 1g or more, and there are approximately 10,000 severe patients who would be eligible candidates for Nefecon therapy."

Nefecon is a targeted therapeutic designed to modulate the mucosal immune response implicated in the pathogenesis of IgA nephropathy. It is engineered to locally deliver the active drug to the Peyer's patches in the terminal ileum, a recognized primary anatomical site where IgAN originates.

Through this mechanism, it downregulates the production of galactose-deficient IgA1 (Gd-IgA1), a key pathogenic biomarker, thereby suppressing abnormal immune cascades. It was explained that while conventional supportive therapies focus mainly on reducing proteinuria and controlling blood pressure, Nefecon distinguishes itself as a 'disease-modifying' approach that modulates the core progression of the disease.

The drug-delivery mechanism is also key. It delivers the drug to the target tissue utilizing a dual formulation technology that integrates delayed-release and sustained-release profiles. The budesonide component is specifically designed to minimize systemic exposure, as the vast majority of the active pharmaceutical ingredient is cleared by extensive first-pass hepatic metabolism. According to the presented data, its impact on the HPA axis (hypothalamic-pituitary-adrenal axis) was also relatively limited.

Nefecon was designated as the second product under the Ministry of Food and Drug Safety (MFDS)'s Global Innovative Product on Fast Track (GIFT) program in November last year, and it secured approval in the United States in 2021 under the brand name 'Tarpeyo.'

Professor Lee explained, "IgA nephropathy features a high proportion of young patients, and the risk of progressing to ESRD fluctuates depending on the severity of proteinuria and renal function decline. It is critical to consider early immunological interventions in high-risk patients."

Confirmed effectiveness in proteinuria·renal function protection 

Professor Jung-ho Shin, Division of Nephrology, Chung-Aug University Hospital

The clinical value of Nefecon was validated through the global Phase 3 NefIgArd study.

NefIgArd was a global, randomized, double-blind, placebo-controlled study conducted in patients with primary IgA nephropathy who exhibited persistent proteinuria despite optimized RAS inhibitor therapy. Patients were randomized to receive either Nefecon or a placebo for 9 months, followed by a 15-month observational follow-up period.

The clinical results showed that Nefecon significantly reduced levels of the core pathogenic biomarker Gd-IgA1 by 34% compared to the placebo group.

Proteinuria was reduced by up to 51.3% at 3 months post-treatment completion, and the preservation effect on eGFR was robustly maintained throughout the 15-month post-treatment follow-up period.

Notably, a modeling analysis based on the eGFR slope from the NefIgArd study generated predictive data suggesting that Nefecon treatment could delay the onset of kidney failure and the initiation of dialysis by up to 12.8 years.

From a safety perspective, the most frequently reported adverse events (AEs) included peripheral edema, hypertension, muscle cramps, and acne development.

Professor Shin stated, "The key feature of IgA nephropathy management lies in long-term preservation of renal function and delaying progression to ESRD, rather than short-term reduction of proteinuria alone. Nefecon is different from conventional conservative therapies as it directly addresses the disease pathogenesis by targeting mucosal immune responses."

Professor Shin added, "The clinical data confirmed that the eGFR preservation benefit was sustained even after treatment cessation, and the modeling analysis supported its potential to delay progression to renal failure. It is now time to consider the necessity of earlier therapeutic intervention in high-risk patients."