Slide 1: Patients in DUPLEX Achieved Partial or Complete Remission of Proteinuria Earlier and More Often
LB-07 Patients in DUPLEX Achieved Partial or Complete Remission of Proteinuria Earlier and More Often With Sparsentan vs Irbesartan: Implications for Slowing Progression to Kidney Failure in Focal Segmental Glomerulosclerosis (FSGS) James Tumlin,1 Vladimir Tesar,2 Hernán Trimarchi,3 Laura Kooienga,4
Slide 2: Disclosures
Disclosures • JT reports grants from Akebia Therapeutics, Alexion Pharmaceuticals, argenx, AstraZeneca, Aurinia Pharmaceuticals Inc., Dimerix Limited, Humacyte Global Inc., La Jolla Pharmaceutical Company, Mallinckrodt Pharmaceuticals, Medtronic Inc., Otsuka Pharmaceuticals, Palatin Technologies, Pf
Slide 3: Learning Objectives
Learning Objectives 1. Explain how endothelin-1 and angiotensin II contribute to kidney injury in patients with FSGS, emphasizing their role in podocyte damage, proteinuria, and disease progression 2. Discuss the link between proteinuria reduction and kidney survival in patients with FSGS, highlight
Slide 4: FSGS Is Associated With a Substantial Patient, Clinical, and Economic Burden
FSGS Is Associated With a Substantial Patient, Clinical, and Economic Burden • FSGS is a rare, progressive, kidney condition defined by a histological pattern of glomerular and podocyte injury1,2 • FSGS is associated with substantial burden: Substantial risk of progression to kidney failure, with 40
Slide 5: Effective Treatment Options for FSGS Are Limited
Effective Treatment Options for FSGS Are Limited Primary Genetic FSGS- Secondary FSGS FSGS Unidentified FSGS Cause Supportive treatment for persistent proteinuria1 High-dose oral Likely to be steroid Supportive treatment for glucocorticoids (first line)1 resistant2 persistent proteinuria1 Underlying
Slide 6: ET-1 and Ang II Are Key Mediators of Podocyte Damage in FSGS
ET-1 and Ang II Are Key Mediators of Podocyte Damage in FSGS Activation of ET-1 and Ang II4,5 Proteinuria1 Podocyte detachment1 Podocyte injury1 Cell death1 Progression to kidney failure Impaired Initial drivers of podocyte glomerular injury include serum factors, filtration genetic causes, viral ba
Slide 7: In FSGS, sparsentan protects the podocytes by simultaneously blocking ET-1 and Ang-II
In FSGS, sparsentan protects the podocytes by simultaneously blocking ET-1 and Ang-II1-3 Sparsentan is a novel, non-immunosuppressive, Dual Endothelin Angiotensin Receptor Antagonist (DEARA)1,4 ET-1 Sparsentan targets Ang II glomerular injury, reducing proteinuria Sparsentan and preserving kidney fu
Slide 8: Glomerular ETAR Expression Increased in Patients With FSGS
Glomerular ETAR Expression Increased in Patients With FSGS >5-Fold Increase in ETAR Expression Glomerular Endothelium Normal control Patient with FSGS 100 *** Percentage of glomeruli with ETAR-positive endothelium ETAR 50 0 Control FSGS MA-SP-25-0043 04/2025 NATIONAL KIDNEY FOUNDATION ***P<.001. ETA
Slide 9: Proteinuria Reduction in FSGS: Target?
Proteinuria Reduction in FSGS: Target? What endpoint predicts kidney function preservation and kidney health? MA-SP-25-0043 04/20259
Slide 10: PARASOL: An International Initiative to Advance Understanding of Proteinuria and eGFR Endpoints in FSGS
PARASOL: An International Initiative to Advance Understanding of Proteinuria and eGFR Endpoints in FSGS PARASOL: Proteinuria and GFR as Clinical Trial Endpoints in Focal Segmental Glomerulosclerosis N=1626 Trial window (24 months) Follow-up • Biopsy-proven or genetic FSGS • UPCR ≥1.5 g/g All cohort
Slide 11: Proteinuria Endpoints in FSGS
Proteinuria Endpoints in FSGS PARASOL identified proteinuria as a biologically plausible and clinically meaningful endpoint* Reduction in proteinuria at 2 years is strongly associated with lower kidney failure risk Nonresponder UPCR UPCR <1.5 <1.5 g/g g/g and and UPCR <0.3 g/g UPCR <0.5 g/g UPCR UPC
Slide 12: PARASOL: Achieving Proteinuria <0.7 g/g Is Associated With Meaningful Reduction in Kidney Failure Risk
PARASOL: Achieving Proteinuria <0.7 g/g Is Associated With Meaningful Reduction in Kidney Failure Risk PARASOL RaDaR-FSGS Responder survival differences Independent validation of responder survival post index for UPCR <0.7 g/g (all) difference post index for UPCR <0.7 g/g (all) Surv diff. at 84m (95
Slide 13: Sparsentan: DUET and DUPLEX Trials in FSGS
Sparsentan: DUET and DUPLEX Trials in FSGS What is the efficacy of a dual endothelin angiotensin receptor antagonist (DEARA) in the treatment of FSGS? MA-SP-25-0043 04/2025 13
Slide 14: DUET: Study Design
DUET: Study Design Double blind Open-label extension (OLE) Selection criteria 8 weeks ≥4.6 years SPAR:SPAR • Age 8-75 (US) or 18-75 (EU) 200 mg SPAR years 200 mg SPAR 300 mg IRB • Biopsy-proven primary FSGS IRB:SPAR or documented genetic RASi washout mutation (secondary FSGS (2 weeks) SPAR:SPAR 400
Slide 15: Complete Remission of Proteinuria in DUET Open-Label Period
Complete Remission of Proteinuria in DUET Open-Label Period • In the phase 2 DUET study, sparsentan led to rapid proteinuria reductions in the double-blind period that were sustained throughout the open-label period1,2 • 43% of patients achieved complete remission of proteinuria with sparsentan at a
Slide 16: DUPLEX: Study Design
DUPLEX: Study Design DUPLEX (NCT03493685) is a phase 3, randomized, double-blind trial investigating the safety and efficacy of sparsentan vs active control, maximum labeled dose irbesartan in adults and children (aged ≥8 y) with FSGS Washout period Double-blind treatment 4 weeks post cessation 2 we
Slide 17: Patient Demographics and Baseline Characteristics
Patient Demographics and Baseline Characteristics Sparsentan Irbesartan All patients n=184 n=187 N=371 Age, mean (SD), years1 41.7 (16.5) 41.5 (17.3) 41.6 (16.9) <18 years, n (%) 16 (8.7) 19 (10.2) 35 (9.4) Male sex, n (%) 101 (55) 99 (53) 200 (54) eGFR, mean (SD), mL/min/1.73 m2 63.3 (28.6) 64.1 (3
Slide 18: DUPLEX: Reductions in Proteinuria
DUPLEX: Reductions in Proteinuria In the phase 3 DUPLEX study, sparsentan was well tolerated and led to rapid (as early as 6 weeks) and sustained (up to 108 weeks) reductions in proteinuria compared with the active control irbesartan in patients with FSGS1 LS means (95% CI) change from baseline at w
Slide 19: DUPLEX: Risk of Kidney Failure
DUPLEX: Risk of Kidney Failure In DUPLEX study, fewer patients progressed to kidney failure or composite kidney failure endpoints with sparsentan vs maximum labeled dose irbesartan Kidney failure Composite kidney failure endpoints Confirmed ≥40% 20.1% RR, 0.87 6.5% reduction in (95% CI, eGFR, 0.60-1
Slide 20: Achieving Proteinuria Remission
Achieving Proteinuria Remission What is the impact of sparsentan on partial or complete remission of proteinuria, and what is the effect of achieving these outcomes on progression to kidney failure? MA-SP-25-0043 04/2025 20
Slide 21: Analyses
Analyses Analyses by treatment arm • Proportion of patients achieving partial or complete remission of proteinuria at any time through 108 weeks • Time to first partial or complete remission of proteinuria Partial remission of proteinuria: UPCR ≤1.5 g/g and >40% reduction from baseline1* Complete re
Slide 22: Patients Achieved Partial Remission of Proteinuria Earlier and More Often With Sparsentan
Patients Achieved Partial Remission (PR) of Proteinuria Earlier and More Often With Sparsentan vs Maximum Labeled Dose Irbesartan* Median time to PR (Difference, P<.0001†) 0.80 Sparsentan, 14.1 weeks Irbesartan, 109.0 weeks Probability of achieving PR 0.60 Sparsentan (119/184) 64.7% RR, 1.48 Partial
Slide 23: Patients Achieved Complete Remission of Proteinuria Earlier and More Often With Sparsentan
Patients Achieved Complete Remission (CR) of Proteinuria Earlier and More Often With Sparsentan vs Maximum Labeled Dose Irbesartan* Sparsentan Median time to CR 0.20 (NE in either group; Probability of achieving CR difference, P=.0008†) 2.5-fold higher rate of CR Sparsentan (34/184) 18.5% 0.15 with
Slide 24: Patients Who Achieved Partial or Complete Remission Were Less Likely to Reach Kidney Failure
Irrespective of Treatment, Patients Who Achieved Partial or Complete Remission Were Less Likely to Reach Kidney Failure RR, 0.33 30 (95% CI, 0.11-0.95) Patients reaching kidney failure through 108 weeks (95% CI), %† 25 15.9% (27/170) RR, 0.23 (95% CI, 0.03-1.85) 20 9.9% 15 2.1% (32/323) (1/48) 10 3.
Slide 25: Sparsentan Was Well Tolerated, With a Safety Profile Comparable to That of Irbesartan
Sparsentan Was Well Tolerated, With a Safety Profile Comparable to That of Irbesartan The most common TEAEs (≥15% in either group) included COVID-19, hyperkalemia, peripheral edema, and hypotension Sparsentan Irbesartan All patients Patients With TEAEs, n (%) n=184 n=187 N=371 Any TEAEs 172 (93) 174
Slide 26: Conclusions
Conclusions Dual endothelin angiotensin receptor blockade with sparsentan led to partial or complete remission of proteinuria earlier and more often in patients with FSGS than did angiotensin receptor blockade alone with irbesartan Consistent with recently reported results from PARASOL,1 patients wh
Slide 27: Polling question
Polling question Patients with FSGS receiving sparsentan are ____ likely to reach complete remission of proteinuria and therefore are ____ likely to progress to kidney failure A) Less, less B) Less, more C) More, less D) More, more MA-SP-25-0043 04/2025 NATIONAL KIDNEY FOUNDATION SPRING CLINICAL MEE
Slide 28: Acknowledgments
Acknowledgments • This study was funded by Travere Therapeutics, Inc. • Medical writing support was provided under the direction of the authors by Taryn Ralph, PhD, of Nucleus Global, an Inizio company, in accordance with Good Publication Practice guidelines, and was funded by Travere Therapeutics,
Slide 29: Questions?
Questions? MA-SP-25-0043 04/2025