Modeling Based on NefIgArd Two-Year eGFR Total Slope Predicts Long-Term Clinical Benefit of Nefecon in a Real-World IgA Nephropathy (IgAN) Population

Background: Nefecon, a targeted-release budesonide formulation, is approved for the treatment of patients (pts) with immunoglobulin A nephropathy (IgAN). Data from the full Phase 3 NefIgArd trial showed that 9 months of Nefecon 16 mg/d preserved estimated glomerular filtration rate (eGFR) and reduced urine protein-creatinine ratio (UPCR) vs placebo. These effects were maintained during the 15-month off-drug follow-up period, indicating that Nefecon is disease-modifying. We conducted a modeling analysis to predict the potential long-term benefit of Nefecon on clinical outcome (i.e., a composite endpoint of end stage renal disease, eGFR <15 mL/min/1.73m2, or sustained doubling of serum creatinine) in a real-world IgAN population. Methods: In the final analysis of the NefIgArd trial, there was a treatment benefit in 2-year eGFR total slope of 2.78 mL/min/1.73m2 per year (95% confidence interval [CI] 1.39-4.17) with Nefecon vs placebo (linear spline mixed-effect model). This difference was applied to a published linear regression between treatment effects for the change in 2-year eGFR total slope and the log hazard ratio (HR) of clinical outcome, based on a meta-analysis involving >60K CKD pts (Inker et al. JASN 2019;30:1735-45). Median time to clinical outcome for a reference group receiving supportive standard of care (SoC) only was estimated by modeling long-term registry data from pts at Leicester General Hospital (LGH), UK, matching NefIgArd-recruited pts to individual LGH pt records based on their baseline UPCR and eGFR. Time to clinical outcome for SoC pts was estimated using a Weibull model. Results: 352/364 NefIgArd pts were matched with 886 unique records from 192 LGH pts, which contained 287 clinical outcome event-times from 68 LGH pts. The NefIgArd 2-year eGFR total slope translated to a log HR for clinical outcome of 0.38 (95% CI 0.21-0.63), a 62% risk reduction vs placebo. Median time to clinical outcome was estimated at 9.6 years in SoC pts and 22.4 years in Nefecon-treated pts (median delay 12.8 [95% CI 4.8-27.9] years). 52% of SoC pts were predicted to have a clinical outcome within 10 years vs 24% of Nefecon-treated pts. Conclusions: Modeling analyses indicate that the clinical benefit seen with Nefecon predicts a substantial delay in progression to kidney failure. Funding: Commercial Support - Calliditas Therapeutics

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