About the research

Summary

Aim

To determine the estimated glomerular filtration rate (eGFR) trajectories of patients who achieved complete remission (CR) of proteinuria (<0.3 g/d) or urinary protein excretion (UPE) <0.5 g/d at any time during the 110-week PROTECT trial
versus those who did not¹

This treatment agnostic analysis will determine whether these levels of proteinuria reduction were associated with
favorable outcomes¹

Figure. PROTECT study design

PROTECT is a large, international, randomized, double-blind, active-controlled Phase 3 trial to assess the efficacy and safety 
of sparsentan versus irbesartan¹

About the figure

Participants were randomly assigned to the treatment, sparsentan or active-controlled, maximum labeled dose irbesartan group¹

Study included a 110-week double-blind treatment period and 4 weeks of study drug withdrawal. Interim analysis occurred at 36 weeks. Two-year follow-up occurred at 110 weeks¹

Key findings

Patients who achieved proteinuria remission had similar demographics compared to those who did not except baseline UPE was lower and baseline eGFR was higher in patients who achieved remission¹

Overall, 21.0% (85/404) and 37.4% (151/404) of patients achieved CR and UPE <0.5 g/d, respectively¹

Achieving CR and UPE <0.5 g/d was more common among patients receiving sparsentan than maximum labeled
dose irbesartan¹

The majority of patients who achieved proteinuria remission had been randomized to the sparsentan group, and the majority who did not had been randomized to the maximum labeled dose irbesartan group¹

Figure. Patients achieving CR or UPE <0.5 g/d by treatment assignment at any time from baseline through Week 110

Patients were three times more likely to achieve CR with sparsentan compared to maximum labeled dose irbesartan (73% [62/85] verus 27% [23/85])¹

UPE <0.5g/d was achieved in 68% (103/151) of patients with sparsentan versus 32% (48/151) with irbesartan¹

eGFR preservation was more evident in patients who achieved CR or UPE <0.5 g/d versus those who did not¹

Figure. Absolute change from baseline in eGFR at each study visit in patients who achieved A) CR or B) UPE <0.5 g/day^a

At any time through Week 110, in patients who achieved CR or UPE <0.5 g/day, eGFR acutely dropped in the first few weeks but stabilized through Week 110¹

In patients who never achieved CR or UPE <0.5 g/d, eGFR showed a smaller acute drop after which it steadily declined through Week 110<sup>1

a</sup>Change from baseline in eGFR by visit using a mixed model for repeated measures (MMRM) with on-study values and baseline UPE adjustment.¹

About the figure

At 2 years (Week 110), patients achieving CR experienced a slower kidney function decline than those who did not (-4.0 versus -8.9, Difference: 4.9)¹

At 2 years (Week 110), patients achieving UPE <0.5 g/day experienced a slower kidney function decline than those who did not (-4.3 versus -10.0, Difference: 5.7)¹

The rate of eGFR decline, represented by the chronic and total eGFR slopes,* was slower in patients who achieved CR or UPE <0.5 g/d versus those who did not¹

Notably, in patients who achieved CR at any time through Week 110, the mean rate of kidney function decline
(eGFR chronic slope) was below the therapeutic goal of <1.0 mL/min/1.73 m² per year¹

Table. Total and chronic eGFR slopes from any time through Week 110^b,c

Patients achieving CR experienced a 4.1 difference in chronic slope (95% CI: 2.98 to 5.23, P<0.0001) versus those who did not¹

Patients achieving UPE <0.5 g/d experienced a 4.0 difference in chronic slope (95% CI: 3.04 to 4.91, P<0.0001) versus those who did not^1
 
aBaseline (Day 1) eGFR is included as a response variable and covariate.^{1 b}Based on on-study data.^{1 c}eGFR slopes were assessed using linear mixed effects model and adjusted for baseline log transformed UPE.¹

About the figure

Patients achieving CR experienced a 3.5 difference in total slope (95% CI: 2.41 to 4.63, P<0.0001) versus those who did not¹

Patients achieving UPE <0.5 g/d experienced a 3.5 difference in total slope (95% CI: 2.55 to 4.40, P<0.0001) versus those who did not¹

Markedly fewer patients who achieved CR or UPE g/d reached composite kidney failure (KF)^† endpoint¹

Figure. Kaplan-Meier plot for time to reach the composite KF endpoint in patients who achieved A) CR or B) UPE <0.5 g/d at any time through Week 110

Of patients who achieved CR or UPE <0.5 g/d, 1 (1.2%) and 6 (4.0%) respectively reached the composite KF^† endpoint¹

Of those who did not achieve CR or UPE <0.5 g/d, 43 (13.5%) and 38 (15.0%) respectively did not achieve the composite KF^†

Treatment-emergent adverse events (TEAE) occurred in 79 (93%) patients who achieved CR versus 285 (89%) who did not achieve CR¹

The most common TEAEs were:

TEAEs of interest were comparable between groups:

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Footnotes

*eGFR chronic slope was measured from Week 6 to Week 110 following the initial acute effect of randomized treatment.^4-7 eGFR total slope was measured over the full double-blind study period 
(i.e., Day 1 to Week 110).^{4 †}The composite KF endpoint was defined as confirmed 40% eGFR decline, end-stage kidney disease (initiation of renal replacement therapy or sustained eGFR <15 mL/min per 1.73 m²), or mortality due to any cause.^{1 ‡}This study overlapped with the COVID-19 pandemic.

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CI, confidence interval; COVID-19, coronavirus disease 2019; CR, complete remission; DEARA, Dual Endothelin Angiotensin Receptor Antagonist; eGFR, estimated glomerular filtration rate; IgA, immunoglobulin A; KF, kidney failure; MMRM, mixed model for repeated measures; SOC, standard of care; TEAE, treatment-emergent adverse event; UPE, urine protein excretion.

MA-SP-24-0138 | October 2024