FILSPARI (sparsentan) – PROTECT (Phase 3 Study): Study Design & Results

FILSPARI® (sparsentan)

PROTECT (Phase 3 Study): Study Design & Results

PROTECT overview

PROTECT is a large, international, randomized, double-blind, active-controlled Phase 3 trial¹

Objective: To evaluate the long-term efficacy and safety of sparsentan in slowing kidney function decline in patients with IgA nephropathy who are at high risk of progression due to proteinuria ≥1 g/day despite treatment with RASi¹

Clinical significance:

Sparsentan could be used as a long-term foundational therapy for IgA nephropathy to reduce proteinuria and preserve kidney function¹

Key findings:

Compared to maximum labeled dose irbesartan (n=202), sparsentan (n=202) demonstrated^1*:

Maintenance of rapid and superior reduction of proteinuria¹

Reduction in UPCR at Week 110 compared to baseline³:

Sparsentan: 40%
Irbesartan: 2%
Relative reduction: 38% (95% CI: 52% to 73%; P<0.0001)

Better preservation of kidney function that accrued year on year^{1,
2}

Between group eGFR difference between sparsentan and
irbesartan (mL/min/1.73 m²)⁴:

Year 1: 1.9 (95% CI: 0.1 to 3.7, P=0.0401)
Year 2: 3.8 (95% CI: 1.6 to 6.1, P=0.0008)

Better projected eGFR data suggesting prolonged kidney survival^{1,
2}

A patient may theoretically reach dialysis (eGFR<10 mL/min/1.73 m² )^{2,
5}:

Sparsentan: After 15.7 years
Irbesartan: After 11.2 years

A comparable safety profile¹

PROTECT highlights infographic

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Footnotes:

*The target doses (sparsentan 400 mg and irbesartan 300 mg) were reached by 192 (95%) patients in the sparsentan group and 196 (97%) patients in the irbesartan group.¹

Baseline characteristics

View table

Well-balanced demographic, clinical and biochemical characteristics, and concomitant medication status⁶

Mean age^{5,
6}

46 years
(range 18-76)

Sex⁵

70% male
30% female

Race⁵

67% white
28% Asian
1% Black or African American

Mean eGFR^{5,
6}

57 mL/min/1.73 m²

Proteinuria⁵

1.2 g/g mean UPCR

49 (12%) patients
had UPE > 3.5 g/24 hours

History of hypertension⁵

~78% of patients

History of diabetes or IFG⁵

11% of patients

Hematuria⁵

56% of patients

Demographics and baseline characteristics^1,6

Data are mean (SD), n (%), or median (IQR). Percentages might not sum to 100 because of rounding.

^*Patients might have selected more than one race.
^†Age at IgA nephropathy diagnosis is derived on the basis of the year of diagnosis and year of birth.
^‡Time from initial biopsy is derived based on the year of the initial kidney biopsy and year of signed informed consent.
^§eGFR was determined using the Chronic Kidney Disease Epidemiology formula.
^¶Patients progressed from chronic kidney disease stage 3 to 4 between randomization and first dose of study drug.
^||ACEi and ARB treatment at screening; RASi were prohibited during the study.
^**Baseline concomitant medications were started before and continued after the initial dose of study medication.
^††Antihypertensive medications exclude ACEi, ARBs, aldosterone blockers, and aliskiren.

Efficacy

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Proteinuria (UPCR) at Week 36

Primary endpoint

Change in UPCR from baseline up to Week 36^{5,
7}

Summary

There was a mean reduction of proteinuria of 45% from baseline vs.15% in those receiving irbesartan⁵
The mean percent change in UPCR from baseline by sparsentan was significantly greater vs. irbesartan, corresponding to a 35% reduction (95% CI: 23% to 45%, P<0.0001)⁵

Proteinuria (UPCR) at Week 110

Other prespecified secondary efficacy endpoint

Changes in UPCR from baseline up to Week 110^{3,
5}

Summary

There was a mean reduction of proteinuria of 40% from baseline in patients receiving sparsentan vs. 2% in those receiving irbesartan^{3,
5}
The mean percent change in UPCR from baseline by sparsentan was significantly greater vs. irbesartan, corresponding to a 38% relative reduction³
- The geometric LS mean ratio was 0.62 (95% CI: 0.52 to 0.73, P<0.0001)³

Time to complete remission of proteinuria at Week 110

Prespecified exploratory endpoint

Time to achieve complete proteinuria remission²

Summary

Sixty-two (31%) patients receiving sparsentan achieved complete remission (UPE <0.3 g/day) vs. 23 (11%) of those receiving irbesartan¹
Patients in the sparsentan group achieved complete remission earlier and more frequently than those in the irbesartan group¹

Complete and partial remission of proteinuria at Week 110

Prespecified exploratory endpoint

Complete and partial proteinuria remission²

Summary

More patients in the sparsentan group achieved complete remission (UPE <0.3 g/day) and partial remission (UPE <1.0 g/day) of proteinuria compared to the irbesartan group¹
Findings for partial remission were consistent with observations for complete remission⁸

^*The proportion of patients achieving UPE <0.5 g/day was a post hoc assessment²

Estimated eGFR chronic slope or total slope at Week 110

Prespecified key secondary efficacy endpoint

Chronic slope⁹

Total slope⁹

Summary

Sparsentan showed a statistically significant reduction vs irbesartan in the rate of eGFR decline^{5,
9}
- Total slope (sparsentan vs. irbesartan): -3.0 vs. -4.2 (Difference: 1.2, 95% CI: 0.2 to 2.1, P=0.0168)⁹
- Chronic slope (sparsentan vs. irbesartan): 2.9 vs. -4.2 (Difference: 1.3, 95% CI: 0.3 to 2.3, P=0.0087)⁹

Kidney function (eGFR) at Week 110

Other prespecified secondary efficacy endpoint

Change in eGFR by visit up to Week 110^{4,
5*†}

Summary

At Week 110, there was a lower absolute change from baseline in eGFR with sparsentan vs. irbesartan^{4,
5}
Sparsentan vs. irbesartan: -6.1 vs. -9.9 (Between-group difference: -3.8, 95% CI: 1.6 to 6.1)⁴

^*eGFR was calculated using the CKD-EPI equation. Baseline was defined as the last non-missing observation on or prior to the start of dosing. The analysis includes eGFR data during the double-blind period up to Week 110 regardless of treatment discontinuation or immunosuppressive therapy initiation.⁵

^†The treatment benefit with sparsentan on the rate of change in eGFR through Week 110 was not evident in patients with an eGFR ≥90 mL/min/1.73 m²; however, there was a small number of patients in this subgroup.⁵

Composite kidney failure endpoint at Week 110

Other prespecified secondary efficacy endpoint

Time to reach the composite kidney failure endpoint^1*

Summary

Eighteen (9%) patients receiving sparsentan reached the composite kidney failure endpoint vs. 26 (13%) of those receiving irbesartan¹

*Defined as confirmed 40% reduction in eGFR, end-stage kidney disease, or death.¹

Potential long-term impact of improved eGFR slope

Additional analysis

Potential long-term impact of improved eGFR slope^{2,
5*}

Summary

Projected eGFR slopes for sparsentan and irbesartan were derived from the PROTECT study^{1,
2}

^*Baseline eGFR was set to equal 57 mL/min/1.73 m² (0 years), reflecting the mean eGFR of all patients (N=404) reported in this study.²

^†ACEi and/or ARB.²

^‡Mean of observed chronic or total slopes for SOC ACEi/ARB as reported in 5 randomized controlled trials in IgA nephropathy.²

^§DAPA-CKD was a multicenter, double-blind, placebo-controlled, randomized trial designed to assess the effects of dapagliflozin on kidney and cardiovascular outcomes in patients with CKD, with or without type 2 diabetes. Data in this graph reflects patients with IgA nephropathy.¹⁰

^¶This study was a prospective, open-label, randomized-controlled trial designed to assess the effect of adding a 6-month course of corticosteroids to long-term ramipril use on renal survival and function.¹¹

^#TESTING was a multicenter, double-blind, randomized-controlled trial designed to assess the effect of oral methylprednisolone on kidney function in patients with IgA nephropathy.¹²

^**HKVIN was a multicenter, double-blind, placebo-controlled, randomized trial designed to assess the therapeutic role of valsartan in patients with IgA nephropathy.¹³

^††NefIgArd was multicenter, double-blind, placebo-controlled, randomized trial designed to assess the effect of Nefecon on kidney function in patients with IgA nephropathy.¹⁴

Use of systemic IST through Week 110

Prespecified exploratory endpoint

Use of IST in patients on sparsentan and irbesartan⁵

Summary

IST was initiated more frequently in the irbesartan group compared to the sparsentan group⁵
- Sparsentan: 7 (3%) patients
- Irbesartan: 18 (9%) patients

Proteinuria (UPCR) at Week 36

Primary endpoint
Proteinuria (UPCR) at Week 110

Other prespecified secondary efficacy endpoint
Time to complete remission of proteinuria at Week 110

Prespecified exploratory endpoint
Complete and partial remission of proteinuria at Week 110

Prespecified exploratory endpoint
Estimated eGFR chronic slope or total slope at Week 110

Prespecified key secondary efficacy endpoint
Kidney function (eGFR) at Week 110

Other prespecified secondary efficacy endpoint
Composite kidney failure endpoint at Week 110

Other prespecified secondary efficacy endpoint
Potential long-term impact of improved eGFR slope

Additional analysis
Use of systemic IST through Week 110

Prespecified exploratory endpoint

Safety

View TEAEs View Serious TEAEs

Sparsentan (n=202)

Irbesartan (n=202)

Hyperkalemia^5*

34 (17%)
27 (13%)

Hypotension⁵

33 (16%)
13 (6%)

Peripheral
edema^5*

33 (16%)
29 (14%)

Dizziness^5*

32 (16%)
14 (7%)

Anemia⁵

16 (8%)
9 (4%)

Acute kidney injury⁵

12 (6%)
5 (2%)

Transaminase elevations^5†

7 (3.5%)
8 (4%)

In the sparsentan group, there were NO cases of¹:

Discontinuations due to heart failure¹

Serious hepatic TEAEs or DILI¹

Serious TEAEs of drug-related edema or discontinuations due to edema¹

Footnotes:

*Includes related terms.⁵

^†Elevations in ALT or AST >3X ULN.⁵

TEAEs¹

^*Abnormal liver function test results that met the following criteria: new elevation in ALT or AST of more than 3X ULN with or without elevation of total serum bilirubin of more than 2X ULN; and twofold increase in ALT or AST above the baseline value in patients who had elevated values before taking study medication.¹
^†One patient in the irbesartan group died due to a severe adverse event of cardiorespiratory arrest that was considered not to be related to study drug.

Serious TEAEs¹

Sparsentan overview

Sparsentan is a novel, non-immunosuppressive,
Dual Endothelin Angiotensin Receptor Antagonist (DEARA)^{14,
15}

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FILSPARI® (sparsentan)

PROTECT (Phase 3 Study): Study Design & Results

PROTECT overview

Clinical significance:

Key findings:

Baseline characteristics

Well-balanced demographic, clinical and biochemical characteristics, and concomitant medication status 6

Mean age 5, 6

Sex 5

Race 5

Mean eGFR 5, 6

Proteinuria 5

History of hypertension 5

History of diabetes or IFG 5

Hematuria 5

Demographics and baseline characteristics 1,6

Footnotes

Efficacy

Chronic slope 9

Total slope 9

Safety

Hyperkalemia 5*

Hypotension 5

Peripheral edema 5*

Dizziness 5*

Anemia 5

Acute kidney injury 5

Transaminase elevations 5†

In the sparsentan group, there were NO cases of 1 :

TEAEs 1

Serious TEAEs 1

Sparsentan overview

Search for information about a product,
therapeutic area or event

Well-balanced demographic, clinical and biochemical characteristics, and concomitant medication status⁶

Mean age^{5,
6}

Sex⁵

Race⁵

Mean eGFR^{5,
6}

Proteinuria⁵

History of hypertension⁵

History of diabetes or IFG⁵

Hematuria⁵

Demographics and baseline characteristics^1,6

Chronic slope⁹

Total slope⁹

Hyperkalemia^5*

Hypotension⁵

Peripheral
edema^5*

Dizziness^5*

Anemia⁵

Acute kidney injury⁵

Transaminase elevations^5†

In the sparsentan group, there were NO cases of¹:

TEAEs¹

Serious TEAEs¹