DUPLEX (Phase 3 Study): Study Design & Results

FILSPARI® (sparsentan)

DUPLEX (Phase 3 Study): Study Design & Results

DUPLEX overview

DUPLEX was a large, global, randomized, multicenter, double-blind, active-controlled, Phase 3 FSGS study^{1,
2}

Objective: To evaluate potential long-term nephroprotective effects and safety of sparsentan in pediatric and adult patients with biopsy-proven FSGS or documented genetic mutation in podocyte protein associated with FSGS compared to maximum-labeled dose irbesartan, an ARB^{1,
2}

DUPLEX overview

Endpoints:

Primary:Total eGFR slope (Change from Day 1 to Week 108)³

Secondary³:

Change in eGFR from Week 6 to Week 108
Change in eGFR from baseline to 4 weeks postcessation of randomized treatment at week 112

Safety outcomes³

Post hoc analyses have assessed:

The effect of achieving partial or complete remission of proteinuria (UPCR <0.3 g/g) and progression to kidney failure⁷
The impact of achieving UPCR <0.7 g/g (a clinically meaningful threshold identified by PARASOL) on kidney failure rates⁶
Proteinuria reduction in the pediatric and genetic-associated FSGS subgroups^{8,
9}

Clinical significance:

Safety and efficacy findings from the DUPLEX study support the regulatory approval of sparsentan, the first FDA-approved medicine to reduce proteinuria in adult and pediatric patients aged 8 years and older with FSGS who do not have nephrotic syndrome^{3
-
5*}

Key findings:

Compared to those in the maximum-labeled dose irbesartan group (n=187), patients in the sparsentan group
(n=184) experienced³:

Illustration of a urine sample collection container

Greater reduction in proteinuria at Week 36 with sustained reduction over 108 weeks³

Greater reduction in proteinuria³

Proportion of patients who achieved the FSGS partial remission endpoint (UPCR ≤1.5 g/g and >40% reduction from baseline)^{3,
10}:

Week 36 (sparsentan vs. irbesartan): 42% vs. 26% (Difference: 16%, 95% CI: 4 to 28, P=0.009)
Week 108 (sparsentan vs. irbesartan): 43% vs. 27% (Difference: 15%)

Illustration of a calendar icon with multiple stacked pages

Earlier and more frequent low proteinuria thresholds, including complete remission of proteinuria (UPCR <0.3 g/g)³

Earlier and more frequent low proteinuria thresholds⁷

Proportion of patients who achieved complete remission of proteinuria (UPCR of <0.3 g/g) at any point over 108 weeks⁷:

Sparsentan: 18.5%
Irbesartan: 7.5%
Relative reduction: 2.47 (95% CI: 1.37 to 4.45)

Illustration of two hands holding a medical cross symbol

A comparable safety profile, with the frequency of AEs similar between the two groups³

A comparable safety profile³

The safety profiles were also comparable in subgroup populations^{8,
11}
Heart failure and drug-induced liver injury were not observed with sparsentan³
Most common AEs with sparsentan included peripheral edema, hypotension, and hyperkalemia³

Irrespective of treatment⁶:

Patients who achieved UPCR <0.7 g/g at any time on treatment over 108 weeks were less likely to reach kidney failure vs. those who did not⁶

Patients who achieved UPCR <0.7 g/g at any time on treatment over 108 weeks were less likely to reach kidney failure vs. those who did not⁶

The proportion of patients who progressed to kidney failure⁶:

Achieved UPCR <0.7 g/g: 3.6%
Did not achieve UPCR <0.7 g/g: 11.2%
Relative reduction: 0.52 (95% CI: 0.2 to 1.8)

DUPLEX post hoc proteinuria threshold analysis infographic

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Footnotes:

*Nephrotic syndrome includes the presence of three concurrent criteria: proteinuria greater than 3.5 g/24h (adults) or UPCR >2.0 g/g (pediatric patients <18 years of age), serum albumin <3.0 g/dL, and edema.⁴

Baseline characteristics

Overall population Pediatric subgroup Genetic-associated FSGS subgroup

The overall FSGS patient population was geographically broad and clinically diverse²

Median age²

42 years

Sex²

54% male
46% female

Race²

73% White
13% Asian
7% Black/African American
7% Other race

Proteinuria²

3.0 g/g median UPCR

Nephrotic syndrome⁴

32% of patients

Mean eGFR^2†

64 ± 30 mL/min/1.73 m²

History of hypertension²

64% of patients

Edema²

38% of patients

Footnotes:

Overall population demographics and baseline characteristics³

Data are given as n (%) or median (IQR) unless otherwise noted. Plus–minus values are means ± SD.

^*Race and ethnic group were reported by the patients. Patients could have selected more than one race.³
^†Patients were stratified according to eGFR at screening (≥30 to <60 or ≥60 mL/min/1.73 m² of body-surface area). The two groups were well balanced.³
^‡The UPCR (with both protein and creatinine measured in grams) is the value from the baseline visit. Eligibility was based on the value at screening.³
^§Patients were considered to have a documented history of nephrotic syndrome if the term "nephrotic syndrome" was present in their medical history or if all the following conditions were met at any of the visits before the first dose of the trial drug: UPCT >3.5 (for patients ≥18 years of age) or UPCR >2 (for patients <18 years of age), a serum albumin level of less than 30 g/L, and abnormal edema observed on physical examination.³
^¶Included are pathogenic or likely pathogenic genetic variants.³
^‖The included variants are CD2AP, INF2, LMX1B, NPHS1, NPHS2, TRPC6, and WT1.³
^**These agents were stopped before the washout period.³
^††These agents were started before and were continued after the first dose of the trial drug.³

Pediatric subgroup demographics and baseline characteristics⁸

Data are given as n (%) or median (IQR) unless otherwise noted.

^*For patients aged ≥13 years: Normal BP was defined as SBP <120 and DBP <80 mmHg; elevated BP as SBP 120-129 and DBP <80 mmHg; stage 1 hypertension as SBP 130-139 or DBP 80-89 mmHg; and stage 2 hypertension as SBP ≥140 or DBP ≥90 mmHg. For patients aged <13 years: Normal BP was defined as BP <90th percentile; elevated BP as BP ≥90th to <95th percentile or SBP/DBP of ≥120/80 mmHg to <95th percentile (whichever is lower); stage 1 hypertension as BP ≥95th to <95th percentile +12 mmHg or SBP/DBP of 130/80 to 139/89 mmHg (whichever is lower); and stage 2 hypertension as BP ≥95th percentile +12 mmHg or SBP/DBP of ≥140/90 mmHg (whichever is lower).⁸
^†Genetic variants were evaluated in post hoc analyses after completion of the double-blind period.⁸
^‡None of the patients had identified COL4A3-5 variants.⁸
^§Includes NPHS2, CD2AP, INF2, LMX1B, NPHS1, TRPC6, and WT1 variants.⁸
^¶Medications initiated prior to and continued after first dose of study drug.⁸

Genetic-associated FSGS subgroup demographics and baseline characteristics⁹

Data are given as n (%), median (IQR), or mean (SD) unless otherwise noted.

Efficacy

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FSGS partial remission endpoint at Week 36

Surrogate efficacy endpoint

Proportion of patients who achieved FSGS partial remission endpoint
(UPCR ≤1.5 g/g and >40% reduction from baseline) at Week 36^3*

Summary

Significantly more patients in the sparsentan group achieved FPRE by Week 36 than those in the irbesartan group (42% vs. 26%, Difference: 16%, 95% CI: 4.0 to 28.0)³
Findings were sustained through Week 108³

*The estimated percentages that are shown were derived from an analysis that used a generalized linear model with multiple imputation. The observed number of patients who had partial remission was 39/88 (44.3%) in the sparsentan group and 19/82 (23.2%) in the irbesartan group.³

FSGS partial remission endpoint at Week 108

Prespecified exploratory endpoint

Proportion of patients who achieved FSGS partial remission endpoint
(UPCR ≤1.5 g/g and >40% reduction from baseline) at Week 108^{3,
10*}

Summary

More patients in the sparsentan group achieved the FPRE by Week 36 and findings were sustained through Week 108³
At Week 108, approximately 38% of patients treated with sparsentan and 23% of patients treated with irbesartan achieved the FPRE³

*The estimated proportions reported in the figure are from a generalized linear model analysis with multiple imputation. The observed number of cases was 51/119 (43%) with sparsentan and 35/128 (27%) with irbesartan.¹⁰

Proteinuria thresholds <0.3, <0.7, and <1.5 g/g

Exploratory and post-hoc endpoints

Proportion of patients who achieved UPCR <0.3, <0.7, and <1.5 g/g ^{3,
6,
10}

Summary

More patients in the sparsentan group achieved complete remission of proteinuria (UPCR of <0.3 g/g) and UPCR levels <0.7 g/g and <1.5 g/g compared to the irbesartan group^{3,
6}
The treatment effect of sparsentan was consistent across evaluated key proteinuria thresholds (<0.3, <0.7, and <1.5 g/g)^{3,
6}

Proteinuria (UPCR) at Week 108

Prespecified exploratory endpoint

Change in UPCR from baseline up to Week 108 ³

Summary

Treatment with sparsentan led to greater and sustained reductions in proteinuria compared with irbesartan³
At 108 weeks, there was a mean reduction of proteinuria of 50% from baseline in patients receiving sparsentan vs. 32% in those receiving irbesartan³
The geometric LS mean ratio was 0.74 (95% CI: 0.58 to 0.93)³

Time to complete remission of proteinuria

Exploratory endpoint

Time to complete remission of proteinuria ¹⁰

Summary

Thirty-four (18.5%) patients receiving sparsentan achieved complete remission of proteinuria (UPCR of <0.3 g/g) vs. 14 (7.5%) of those receiving irbesartan³
Patients in the sparsentan group achieved complete remission of proteinuria (UPCR of <0.3 g/g) earlier than those in the irbesartan group^{3,
10}

Time to UPCR <0.7 g/g

Post-hoc exploratory endpoint

Time to UPCR <0.7 g/g⁶

Summary

Sixty-nine (38%) patients receiving sparsentan achieved UPCR <0.7 g/g compared to 40 (21%) patients receiving irbesartan⁶
Sparsentan was associated with a higher probability of achieving UPCR <0.7 g/g⁶

Time to the FSGS partial remission endpoint

Exploratory endpoint

Time to FSGS partial remission endpoint (UPCR ≤1.5 g/g and >40% reduction from baseline) ¹⁰

Summary

Approximately 38% of patients receiving sparsentan achieved the FPRE vs. 23% of those receiving irbesartan^3*
The median time to response was shorter with sparsentan compared to irbesartan (14.1 vs. 109.0 weeks)^{3,
10}

*The estimated proportions reported are from a generalized linear model analysis with multiple imputation. The observed number of cases was 51/119 (43%) with sparsentan and 35/128 (27%) with irbesartan.¹⁰

Estimated eGFR chronic slope or total slope

Primary/Secondary efficacy endpoint (varies by region)*

Chronic slope³

Total slope³

Summary

Numerical differences in eGFR slopes favored the sparsentan group versus the irbesartan group (mL/min/1.73 m²)³
- Chronic slope (sparsentan vs. irbesartan): -4.8 vs. -5.7 (Difference: 0.9, 95% CI: -1.3 to 3.0, P=0.42)³
- Total slope (sparsentan vs. irbesartan): -5.4 vs. -5.7 (Difference: 0.3, 95% CI: -1.7 to 2.4, P=0.75)³

^*Total eGFR slope was the primary endpoint in the US but the secondary endpoint outside the US. Chronic eGFR slope was the primary endpoint outside the US but the secondary endpoint in the US.³

Kidney function (eGFR) at Week 112

Key secondary endpoint

Change in eGFR from baseline to Week 112³

Summary

At Week 112, there was a smaller mean change from baseline in eGFR with sparsentan vs. irbesartan (mL/min/1.73 m²)³
- Sparsentan vs. irbesartan: -10.4 vs. -12.1 (Difference: 1.8, 95% CI: -1.4 to 4.9)³

Composite kidney failure endpoint at Week 108

Exploratory endpoint

Proportion of patients who reached the composite kidney failure endpoint³

Summary

Fewer patients in the sparsentan group reached the composite kidney failure endpoints³
- Confirmed ≥40% reduction in eGFR, kidney failure, or death (sparsentan vs. irbesartan): 20% vs. 23% (Relative risk: 0.87, 95% CI: 0.60 to 1.26)³
- Confirmed ≥50% reduction in eGFR, kidney failure, or kidney death (sparsentan vs. irbesartan): 11% vs. 17% (Relative risk: 0.68, 95% CI: 0.43 to 1.10)³
Fewer patients in the sparsentan group progressed to kidney failure compared to the irbesartan group³

*Renal death is defined as death in a patient who reached kidney failure before initiating renal replacement therapy for whom another cause of death was not reported.¹⁰

Risk of kidney failure

Post hoc exploratory efficacy endpoint

Proportion of patients who progressed to kidney failure^{6,
13}

Summary

Irrespective of treatment arm, fewer patients who achieved complete remission of proteinuria (UPCR of <0.3 g/g) or UPCR <0.7 g/g^‡ reached kidney failure compared to those who did not^{6,
13}
- Achieved complete remission of proteinuria (UPCR of <0.3 g/g) (yes vs. no): 2% vs. 10% (Relative risk: 0.23, 95% CI: 0.03 to 1.85)¹³
- Achieved UPCR <0.7 g/g (yes vs. no): 4% vs. 11% (Relative risk: 0.52, 95% CI: 0.2 to 1.8)⁶

^*Results from post hoc analyses using pooled data irrespective of treatment arm.¹³ ^†Results from post hoc analyses using pooled data irrespective of treatment arm.¹³ ^‡Analysis of patients who achieved vs. did not achieve UPCR <0.7 g/g at any time on treatment.⁶

Proteinuria (UPCR) at Week 108

Without nephrotic syndrome subgroup analysis*

Change in UPCR from baseline up to Week 108 (FAS)^{4,
5,
14†}

Change in UPCR from baseline up to Week 108 in patients with podocyte gene variants

Summary

At 108 weeks, there was a mean reduction of proteinuria of 48% from baseline in patients receiving sparsentan vs. 27% in those receiving irbesartan (Difference: 29%, nominal p-value=0.0075)^{4,
5,
14}

*Nephrotic syndrome includes documentation of nephrotic syndrome in the medical history or the presence of three concurrent criteria: proteinuria greater than 3.5 g/24h (adults) or UPCR >2.0 g/g (pediatric patients <18 years of age), serum albumin <3.0 g/dL, and edema.⁴ ^†Missing data were handled using multiple imputation. Patients who had initiated renal replacement therapy or died were sampled from the worst 5% of the observed proteinuria data. Changes from baseline in log UPCR were analyzed using the mixed models repeated model including treatment, baseline logarithm of UPCR, visit weeks stratification factors, interaction of visit weeks and treatment as factors.⁴

Proteinuria thresholds <0.3, <0.7, and <1.5 g/g

Without nephrotic syndrome subgroup analysis*

Proportion of patients who achieved UPCR <0.3, <0.7, and <1.5 g/g ^14*,†

Summary

More patients in the sparsentan group achieved complete remission of proteinuria (UPCR of <0.3 g/g) and UPCR levels <0.7 g/g and <1.5 g/g compared to the irbesartan group¹⁴

Estimated eGFR chronic slope or total slope

Without nephrotic syndrome subgroup analysis*

Chronic slope¹⁴

Total slope¹⁴

Summary

Differences in eGFR slopes were statistically significant between the sparsentan group versus the irbesartan group (mL/min/1.73 m²)¹⁴
- Chronic slope (sparsentan vs. irbesartan): -3.7 vs. -6.2 (Difference: 2.5, nominal p-value=0.015)¹⁴
- Total slope (sparsentan vs. irbesartan): -4.1 vs. -6.2 (Difference: 2.1, nominal p-value=0.031)¹⁴

*Nephrotic syndrome includes documentation of nephrotic syndrome in the medical history or the presence of three concurrent criteria: proteinuria greater than 3.5 g/24h (adults) or UPCR >2.0 g/g (pediatric patients <18 years of age), serum albumin >3.0 g/dL, and edema.⁴

Kidney function (eGFR) at Week 108

Without nephrotic syndrome subgroup analysis*

Change in eGFR from baseline to Week 108⁴

Summary

At Week 108, there was a smaller mean change from baseline in eGFR with sparsentan vs. irbesartan (mL/min/1.73 m²)⁴
- Sparsentan vs. irbesartan: -11.3 vs. -12.4 (Difference: 1.1, 95% CI: -2.6 to 4.8)⁴

Kidney failure outcome

Without nephrotic syndrome subgroup analysis*

Proportion of patients who reached kidney failure¹⁴

Summary

Fewer patients in the sparsentan group reached kidney failure compared to the irbesartan group (1.6% vs 8.0%, Relative risk: 0.19, nominal p-value=0.0180)¹⁴
Nominal p-values for odds ratio for rates of no event

Proteinuria (UPCR) at Week 108

Pediatric subgroup analysis

Change in UPCR from baseline up to Week 108⁸

Summary

There was a mean reduction of proteinuria of 39.5% from baseline in patients receiving sparsentan vs. 24.9% in those receiving irbesartan⁸
- The geometric LS mean ratio was 0.81 (95% CI: 0.38 to 1.71)⁸
Reductions in UPCR were observed as early as Week 6 and sustained through Week 108 in the sparsentan arm⁸

Proteinuria thresholds <0.3, <0.5, and <1.0 g/g and FSGS partial remission endpoint

Pediatric subgroup analysis

Proportion of patients who achieved low proteinuria thresholds⁸

Summary

Higher proportions of patients in the sparsentan group consistently reached low proteinuria thresholds, including complete remission of proteinuria (UPCR <0.3 g/g), compared with the irbesartan group⁸
- Complete remission of proteinuria (UPCR <0.3 g/g) (sparsentan vs. irbesartan): 12.5% vs. 5.3% (Relative risk: 2.56, 95% CI: 0.23 to 28.43)⁸
- UPCR <0.5 g/g (sparsentan vs. irbesartan): 18.8% vs. 10.5% (Relative risk: 1.80, 95% CI: 0.33 to 9.69)⁸
- UPCR <1.0 g/g (sparsentan vs. irbesartan): 43.8% vs. 21.1% (Relative risk: 2.07, 95% CI: 0.74 to 5.80)⁸
- FPRE (UPCR ≤1.5 g/g and >40% reduction from baseline): 56.3% vs. 36.8% (Relative risk: 1.58, 95% CI: 0.77 to 3.22)⁸

Composite kidney failure endpoint at Week 108

Pediatric subgroup analysis

Proportion of patients who reached the composite kidney failure endpoint⁸

Summary

Fewer patients in the sparsentan group reached the composite kidney endpoint vs. the irbesartan group⁸
- Sparsentan vs. irbesartan: 31.3% vs. 47.4% (Relative risk: 0.64, 95% CI: 0.29 to 1.41)⁸
Fewer patients in the sparsentan group progressed to kidney failure vs. the irbesartan group⁸
- Sparsentan vs. irbesartan: 12.5% vs. 36.8% (Relative risk: 0.31, 95% CI: 0.08 to 1.12)⁸

Proteinuria (UPCR) at Week 108

Genetic-associated FSGS subgroup analysis - Podocyte gene variants

Change in UPCR from baseline up to Week 108 in patients with podocyte gene variants^{9,
15}

Summary

As early as Week 6, sparsentan led to a greater reduction in proteinuria compared to irbesartan⁹
At Week 108, the geometric LS mean percent change from baseline in UPCR was -49.1% for sparsentan (95% CI: -66.3 to -23.1) vs. -27.5% for irbesartan (95% CI: -49.0 to 3.0)¹⁵

Proteinuria (UPCR) at Week 108

Genetic-associated FSGS subgroup analysis - COL4A3-5 variants

Change in UPCR from baseline up to Week 108 in patients with COL4A3-5 variants^{9,
15}

Summary

As early as Week 6, sparsentan led to a greater reduction in proteinuria compared to irbesartan⁹
At Week 108, the geometric LS mean percent change from baseline in UPCR was -48.0% for sparsentan (95% CI: -65.8 to -20.8) vs. -34.1% for irbesartan (95% CI: -55.9 to –1.6)¹⁵

Proteinuria (UPCR) at Week 108

Genetic-associated FSGS subgroup analysis - APOL1 high-risk genotypes

Change in UPCR from baseline up to Week 108 in patients with APOL1 high-risk genotypes^{9,
15}

Summary

As early as Week 6, sparsentan led to a greater reduction in proteinuria compared to irbesartan⁹
At Week 108, the geometric LS mean percent change from baseline in UPCR was –46.2% for sparsentan (95% CI: –75.8 to 19.9) vs. –55.0% for irbesartan (95% CI: –85.2 to 36.7)¹⁵

Time-weighted proteinuria (UPCR) at Week 108

Genetic-associated FSGS subgroup analysis

Time-weighted UPCR change from baseline by genetic and treatment groups⁹

Summary

Compared to irbesartan, sparsentan demonstrated a significant reduction in time-weighted UPCR change from baseline in patients with podocyte gene variants and COL4A3-5 variants⁹
Podocyte gene variants (sparsentan vs. irbesartan): -53.4% vs. -21.5% (Relative change: -32.5 (95% CI: -52.7 to -3.9, P=0.03)⁹
COL4A3-5 variants (sparsentan vs. irbesartan): -59.7% vs. -23.1% (Relative change: -44.9 (95% CI: -63.6 to -16.5, P=0.01)⁹
The reduction in time-weighted UPCR change from baseline was non-significant in patients with APOL1 high-risk genotypes (Sparsentan: -54.3% vs. Irbesartan: -33.8%, Relative change: -27.3 (95% CI: -78.1 to 141.2, P=0.57)⁹

Complete remission of proteinuria

Genetic-associated FSGS subgroup analysis

Proportion of patients with genetic-associated FSGS who reached complete remission of proteinuria (UPCR <0.3 g/g)^⁹

Summary

Sparsentan led to a numerically higher rate of complete remission of proteinuria vs. irbesartan across all genetic subgroups^⁹

Kidney function (eGFR)

Genetic-associated FSGS subgroup analysis

Changes in eGFR by genetic and treatment groups ^⁹

Summary

Changes in eGFR from baseline to Week 108 showed no consistent treatment-related pattern within genetic subgroups^⁹
However, patients with high-risk APOL1 genotypes had numerically less absolute eGFR decline with sparsentan than with irbesartan^⁹

Composite kidney failure endpoint at Week 108

Genetic-associated FSGS subgroup analysis

Proportion of patients who reached the composite kidney failure endpoint^⁹

Summary

Across the three subgroups, the composite kidney outcome* occurred numerically less frequently in patients treated with sparsentan vs. irbesartan^⁹
- Podocyte gene variants (sparsentan vs. irbesartan): 8% vs. 22%^⁹
- COL4A3-5 variants (sparsentan vs. irbesartan): 18% vs. 29%^⁹
- APOL1 variants (sparsentan vs. irbesartan): 11% vs. 40%^⁹

^*Defined as a 40% reduction in eGFR, progression to end-stage kidney disease, or death.⁹

Overall population
- FSGS partial remission endpoint at Week 36: Surrogate efficacy endpoint
- FSGS partial remission endpoint at Week 108: Prespecified exploratory endpoint
- Proteinuria thresholds <0.3, <0.7, and <1.5 g/g -2: Exploratory endpoint
- Proteinuria (UPCR) at Week 108: Prespecified exploratory endpoint
- Time to complete remission of proteinuria: Exploratory endpoint
- Time to UPCR <0.7 g/g: Post-hoc exploratory endpoint
- Time to the FSGS partial remission endpoint: Exploratory endpoint
- Estimated eGFR chronic slope or total slope: Primary/Secondary efficacy endpoint (varies by region)*
- Kidney function (eGFR) at Week 112: Key secondary endpoint
- Composite kidney failure endpoint at Week 108: Exploratory endpoint
- Risk of kidney failure: Post hoc exploratory efficacy endpoint
Without nephrotic syndrome subgroup
- Proteinuria (UPCR) at Week 108: Without nephrotic syndrome subgroup analysis*
- Proteinuria thresholds <0.3, <0.7, and <1.5 g/g: Without nephrotic syndrome subgroup analysis*
- Estimated eGFR chronic slope or total slope: Without nephrotic syndrome subgroup analysis*
- Kidney function (eGFR) at Week 108: Without nephrotic syndrome subgroup analysis*
- Kidney failure outcome: Without nephrotic syndrome subgroup analysis*
Pediatric subgroup
- Proteinuria (UPCR) at Week 108: Pediatric subgroup analysis
- Proteinuria thresholds <0.3, <0.5, and <1.0 g/g and FSGS partial remission endpoint: Pediatric subgroup analysis
- Composite kidney failure endpoint at Week 108: Pediatric subgroup analysis
Genetic-associated FSGS subgroup
- Proteinuria (UPCR) at Week 108: Genetic-associated FSGS subgroup analysis - Podocyte gene variants
- Proteinuria (UPCR) at Week 108: Genetic-associated FSGS subgroup analysis - COL4A3-5 variants
- Proteinuria (UPCR) at Week 108: Genetic-associated FSGS subgroup analysis - APOL1 high-risk genotypes
- Time-weighted proteinuria (UPCR) at Week 108: Genetic-associated FSGS subgroup analysis
- Complete remission of proteinuria: Genetic-associated FSGS subgroup analysis
- Kidney function (eGFR): Genetic-associated FSGS subgroup analysis
- Composite kidney failure endpoint at Week 108: Genetic-associated FSGS subgroup analysis

Safety

TEAEs in overall population TEAEs in pediatric subgroup

Over 108 weeks of treatment, TEAEs were reported with similar frequency in the sparsentan (n=172/184; 93.5%) and irbesartan (n=174/187; 93%) treatment groups³

Adverse events reported in ≥2% of patients on sparsentan

Sparsentan (n=184)

Irbesartan (n=187)

Peripheral
edema^4*

42 (23%)
45 (24%)

Hypotension^4†

38 (21%)
25 (13%)

Hyperkalemia^4*

37 (20%)
21 (11%)

Dizziness^4*

25 (14%)
21 (11%)

Anemia⁴

24 (13%)
10 (5%)

Acute kidney injury⁴

8 (4%)
13 (7%)

Transaminase elevations^4‡

7 (4%)
5 (3%)

In the sparsentan group,
there were NO³:

Instances of heart failure classified as AEs³

Cases of drug-induced liver injury³

Clinically meaningful concerns regarding fluid retention or edema³

Footnotes:

*Includes related terms.^4 †Including orthostatic hypotension.^4 ‡Elevations in ALT or AST greater than 3-fold ULN.⁴

TEAEs in the overall population^{3,
10}

Data are given as n (%).

^*TEAEs were defined as events that were considered to be "related" or "possibly related" to the trial drug by the investigator. Events with missing relationship information were counted as treatment-related events.³
^†AEs that led to death included neuroendocrine carcinoma, subdural hematoma, COVID-19, and suicide (in 1 patient each) in the sparsentan group; and COVID-19 pneumonia, COVID-19, and respiratory distress (in 1 patient each) in the irbesartan group.³
^‡If a patient had more than one event with a given preferred term, the patient was counted only once for that term.^{3,
10}

TEAEs in the pediatric subgroup^8*

Data are given as n (%).

^*All adverse events were coded per the Medical Dictionary for Regulatory Activities version 23.0.⁸
^†New elevation in ALT or AST >3× ULN (with or without elevation of total serum bilirubin to >2× ULN) or 2× increase from baseline in ALT or AST in a patient who had elevated values prior to starting study medication.⁸
^‡Increased serum creatinine of ≥0.3 mg/dL within 48 hours, increased serum creatinine of ≥1.5× baseline that is known or presumed to have occurred within the prior 7 days, or urine volume <0.5 mL/kg/hour for ≥6 hours.⁸

Sparsentan overview

Sparsentan is a novel, non-immunosuppressive, single-molecule,
Dual Endothelin Angiotensin Receptor Antagonist (DEARA)^{16,
17}

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