Modeling Based on NefIgArd Two-Year eGFR Total Slope Predicts Long-Term Clinical Benefit of Nefecon in a Real-World IgA Nephropathy (IgAN) Population
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.020 | 0.018 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.012 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".