Sparsentan in Patients With IgA Nephropathy: A Prespecified Interim Analysis From a Randomised, Double-Blind, Active-Controlled Clinical Trial
Topics: Nephrology IgAN Sparsentan Phase 3 PROTECT
Heerspink HJL, Radhakrishnan J, Alpers CE et al.
10.1016/S0140-6736(23)00569-X
Summary
The PROTECT interim analysis demonstrated reduction in proteinuria and a comparable safety profile with sparsentan in IgA nephropathy versus irbesartan1
Background
IgA nephropathy is an important cause of kidney failure and is the most prevalent primary chronic glomerular disease worldwide.2
Proteinuria is a risk factor for loss of kidney function in patients with IgA nephropathy.2 Treatment of proteinuria >0.5 g/day with renin-angiotensin system inhibitors (RASi) is recommended in treatment guidelines.3
Studies suggest that in addition to activation of the renin-angiotensin system (RAS), endothelin-1 (ET-1) signaling is a potential therapeutic target for renal diseases.4 Combined use of RASis and endothelin type A receptor (ETAR) antagonists have shown additional beneficial effects in experimental models of kidney disease and in those with diabetic and non-diabetic nephropathies.5-8
Sparsentan is a non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist that can be used to reduce proteinuria in adults with IgA nephropathy.9
Aim
The Phase 3 PROTECT study evaluated the long-term efficacy and safety of sparsentan in IgA nephropathy versus irbesartan.1
Approach
PROTECT is a large, international, randomized, double-blind, active-controlled Phase 3 trial of sparsentan versus irbesartan in adults with IgA nephropathy.1 Eligibility criteria included1:
- Biopsy-proven IgA nephropathy
- Proteinuria ≥1.0 g/day
- Maximum tolerated (stable) dose of RASi therapy for ≥12 weeks
Participants were randomized to sparsentan 400 mg once daily (QD) (n=202) or irbesartan 300 mg QD (n=202).
The primary efficacy endpoint was change from baseline to Week 36 in urine protein-creatinine ratio (UPCR).1 Safety endpoints included treatment-emergent adverse events (TEAE) and liver enzyme elevations.1 The data herein are from a prespecified interim analysis and derived from the on-treatment full analysis set, which included all participants who received at least one dose of randomized treatment.1
Read more about the two-year efficacy and safety findings from the PROTECT trial or listen now.
Findings
Baseline demographic and characteristics were well balanced between treatment groups1
- Age (mean): 46.0 years
- Estimated glomerular filtration rate (eGFR) (mean): 57.0 mL/min per 1.73 m²
- Urine protein excretion (mean): 1.8 g/day
- Angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) at maximum labeled dose at screening: 63.5%
The primary endpoint, reduction in UPCR from baseline, was greater with sparsentan versus irbesartan1
At Week 36, the mean change in UPCR was significantly greater in the sparsentan group than in the irbesartan group (-49.8% versus -15.1%, respectively).1 The between group relative reduction was 41% (geometric least squares mean ratio [sparsentan/irbesartan] = 0.59, 95% CI: 0.51-0.69; P<0.0001).1
This reduction was evident at Week 4 of the study and was maintained throughout follow-up.1
The beneficial effect of sparsentan versus irbesartan on UPCR was consistent across subgroups1
Subgroup analysis showed a consistent benefit from sparsentan versus irbesartan among demographic subgroups, and notably, in subgroups stratified by baseline eGFR and urine protein excretion.1
Safety was similar between sparsentan and irbesartan1
TEAEs were mostly similar across treatment groups.1 TEAEs that occurred in a greater proportion (≥4% difference) of patients receiving sparsentan versus irbesartan were, respectively1:
- Peripheral edema: 14% versus 9%
- Hypotension: 14% versus 6%
- Dizziness: 13% versus 5%
There were no cases of heart failure, hepatotoxicity, or severe edema or edema-related discontinuations.1
Key takeaway
The interim analysis of the PROTECT study demonstrated a meaningful antiproteinuric effect of sparsentan in IgA nephropathy versus irbesartan and a comparable safety profile.1
Footnotes
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; ET-1, endothelin-1; ETAR, endothelin type A receptor; QD, once daily; RAS, renin-angiotensin system; RASi, renin-angiotensin system inhibitor; TEAE, treatment-emergent adverse event; UPCR, urine protein-creatinine ratio.
- Heerspink HJL et al. Lancet. 2023;401(10388):1584-1594.
- Wyatt RJ, Julian BA. N Engl J Med. 2013;368:2402-2414.
- Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. Kidney Int. 2021;100(4S):S1-S276.
- De Miguel C et al. Curr Opin Nephrol Hypertens. 2016;25(1):35-41.
- Komers R, Plotkin H. Am J Physiol Regul Integr Comp Physiol. 2016;310(10):R877-R884.
- Trachtman H et al. Drugs Future. 2020;45(2):79.
- de Zeeuw D et al. J Am Soc Nephrol. 2014;25(5):1083-1093.
- Dhaun N et al. Hypertension. 2011;157(4):772-774.
- FILSPARI® (sparsentan) Prescribing Information. San Diego, CA: Travere Therapeutics, Inc. 9/2024.
MA-SP-24-0102 | October 2024