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Points to Consider for the Efficacy Evaluation of Drugs for IgA Nephropathy (Early Consideration)

2026.02.04

• Early Consideration Papers
• IgA Nephropahty
• PMDA

Introduction to Regulatory Considerations

According to the document “Points to Consider for the Efficacy Evaluation of Drugs for IgA Nephropathy (Early Consideration)” issued by the Pharmaceuticals and Medical Devices Agency (PMDA) on December 24, 2025 (https://www.pmda.go.jp/files/000278438.pdf), Japan has clarified its current regulatory thinking on the clinical efficacy evaluation of drugs for IgA nephropathy to support and accelerate drug development in this area.

IgA nephropathy is one of the most common forms of chronic glomerulonephritis and is characterized by hematuria and proteinuria caused by IgA deposition in the glomerular mesangium. Approximately 40% of patients progress to end-stage renal disease (ESRD) within 20 years after diagnosis. In Japan, IgA nephropathy is designated as an intractable disease, and there remains a significant unmet medical need due to the lack of established disease-modifying therapies.

Currently approved and commonly used treatments, including antiplatelet agents, renin-angiotensin system inhibitors, corticosteroids, and immunosuppressants, have not consistently demonstrated long-term renal outcome benefits. Similar challenges are observed globally, prompting active development of novel therapeutic agents.

Challenges in Efficacy Evaluation

ESRD is considered the gold-standard clinical endpoint for chronic kidney disease (CKD); however, trials using ESRD as the primary endpoint require long observation periods and are often impractical. As a result, alternative endpoints such as estimated glomerular filtration rate (eGFR) change, eGFR slope, and urine protein-to-creatinine ratio (UPCR) have been explored internationally.

Japan’s Early CKD clinical evaluation guideline defines Early CKD as eGFR ≥30 mL/min/1.73 m² and discusses the use of eGFR slope as a surrogate endpoint, including considerations on observation period and clinical relevance. Most IgA nephropathy trials target patients with mild to moderate renal impairment within this Early CKD population.

Use of Surrogate Endpoints

Short-term reduction in proteinuria, assessed by UPCR, has been increasingly recognized as a potential surrogate endpoint that may reasonably predict long-term renal function preservation. Several global Phase 3 studies have adopted trial designs in which UPCR is evaluated at earlier time points, followed by confirmation of eGFR slope over longer observation periods.

In the United States, for example, budesonide received accelerated approval for IgA nephropathy in 2021 based on proteinuria reduction, with full approval subsequently granted upon confirmation of long-term renal outcomes using eGFR data. These global regulatory precedents are referenced in the PMDA’s considerations.

Key Points for Efficacy Evaluation

1. Primary Endpoints: For patients with mild to moderate renal impairment (eGFR ≥30 mL/min/1.73 m²), PMDA recommends using eGFR slope or change in eGFR over an observation period of at least two years as the primary efficacy endpoint. The slope should generally be calculated from treatment initiation.
2. Role of Proteinuria Reduction: If a clinically meaningful reduction in UPCR observed over a shorter period (e.g., around 9 months) can reasonably predict a favorable long-term effect on eGFR slope, such data may support demonstration of efficacy, depending on the totality of evidence.
3. Potential Use of Conditional Approval: Given the high unmet medical need in IgA nephropathy, PMDA indicates that Japan’s conditional approval system may be considered when clinical trials demonstrate a certain level of efficacy and safety. Early and proactive consultation with PMDA is strongly recommended to discuss the applicability of this pathway.

Conclusion

This PMDA document provides important regulatory clarity on acceptable efficacy endpoints and trial designs for IgA nephropathy drug development in Japan. By outlining expectations for eGFR-based endpoints, the potential role of proteinuria as a surrogate marker, and the possible application of conditional approval, Japan aims to promote efficient development while maintaining scientific rigor.