TARPEYO was shown to reduce the loss of kidney function in adults with primary IgAN at risk of disease progression in the NefIgArd trial. While the effect on kidney function that was seen during the 9-month treatment period persisted following completion of treatment, TARPEYO did not change the long-term rate of decline in kidney function. 

NefIgArd Study: A Phase 3, Double-Blind Placebo-Controlled, Randomized Trial in Adults with Primary IgAN

The effect of TARPEYO on proteinuria and kidney function (estimated glomerular filtration rate, eGFR) was assessed in a randomized, double-blind, phase 3, 2-part, multicenter study (NefIgArd, NCT: 03643965) in adults with biopsy-proven IgAN, eGFR ≥35 mL/min/1.73 m2, and proteinuria (defined as either ≥1 g/day or urine protein to creatinine ratio (UPCR) ≥0.8 g/g) who were on a stable dose of maximally-tolerated RAS inhibitor therapy. Patients with other glomerulopathies, nephrotic syndrome, or those who had been treated with systemic immunosuppressive medications were excluded. Patients were randomized 1:1 to either TARPEYO 16 mg once daily or placebo and treated for nine months followed by a 2-week taper of either TARPEYO 8 mg once daily or placebo. Patients were then followed off-treatment for 15 months. The primary endpoint for Part A of the study (interim analysis) was the ratio of UPCR (based on 24-hour urine collections) at 9 months compared to baseline based on the first 199 randomized patients who completed the Month 9 visit. The primary endpoint for Part B of the study (final analysis) was a time-weighted average of the log ratio of eGFR at each time point over 2 years relative to baseline. 

Of the 364 randomized patients evaluated for efficacy, 66% were male, 76% were Caucasian, 23% were Asian, and 20% were from North America. The median age was 43 years (range 20 to 73 years). At baseline, the mean eGFR was approximately 58 mL/min/1.73 m2, with 60% of patients having an eGFR <60 mL/min/1.73 m2. The mean baseline UPCR was 1.5 g/g and 21% of patients had proteinuria >3.5 g/24 hours. Approximately 70% of patients had a history of hypertension and 7% had a history of type 2 diabetes mellitus. At baseline, 98% were treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and <1% of patients were on a sodium-glucose cotransporter 2 (SGLT2) inhibitor. At study entry, the median systolic/diastolic blood pressure was 125/79 mmHg. 

The trial met the prespecified Part A primary endpoint based on an interim analysis of 199 randomized patients who had completed the Month 9 visit. The interim analysis showed a 31% reduction in UPCR in patients treated with TARPEYO 16 mg once daily compared to placebo (95% CI: 16% to 42% reduction; p=0.0001). In the final analysis of 364 patients, the percentage change in UPCR observed at 9 months was consistent with the results in the subset of 199 patients included in the interim analysis. The final analysis of the percentage change in UPCR during the treatment and follow-up phase is shown in Figure 1. 

Figure 1: LS Mean (95% CI) Percentage Change from Baseline in UPCR (g/g) in NefIgArd Study (Full Analysis Set)

Estimated mean percentage change from baseline in UPCR with 95% confidence intervals estimated from a mixed model repeated measures analysis of log-transformed post-baseline to baseline ratios at 3, 6, 9, 12, 18, and 24 months. Analysis included all UPCR data regardless of use of prohibited medication at any point during the study. 

Values reported under the figure are converted to percent reduction from baseline. Relative percent reductions comparing TARPEYO and placebo are estimated from the regression model. 

Abbreviations: UPCR, urine protein to creatinine ratio; CI, confidence interval; LS, least squares. 

In the final analysis of 364 patients, the trial met the prespecified Part B primary endpoint (p<0.0001). The mean change from baseline in eGFR and respective 95% CI for each arm at each scheduled visit during the treatment and follow-up phase is shown in Figure 2. The favorable effect of TARPEYO on eGFR was seen by Month 3 (the earliest assessment) and did not appear to increase in magnitude over two years. At Year 2, there was a 5.9 mL/min/1.73 m2 difference in the mean change from baseline in eGFR between TARPEYO and placebo (95% CI: 3.3 to 8.5 mL/min/1.73 m2; p<0.0001). 

Figure 2: LS Mean (95% CI) Change from Baseline in eGFR (mL/min/1.73 m2) in NefIgArd Study (Full Analysis Set)

Estimated least squares mean change from baseline in eGFR (mL/min/1.73 m2) with 95% confidence intervals estimated from a mixed model repeated measures analysis of post-baseline to baseline differences at 3, 6, 9, 12, 18, and 24 months. Analysis was based on untransformed data and includes all eGFR data regardless of use of prohibited medication at any point during the study. A total of 15 patients in the TARPEYO arm and 20 patients in the placebo arm received rescue medication during the 2-year study. 

Abbreviations: eGFR, estimated glomerular filtration rate; CI, confidence interval; LS least squares 

The treatment effect based on the change from baseline in eGFR at 2 years was consistent across key subgroups, including key demographic (such as age, sex, race) and baseline disease (such as baseline proteinuria) characteristics.