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Proteinuria in urine cup


Exploring Clinical Trial Endpoints in FSGS: Spotlight on Proteinuria

Published on May 9, 2025

Topics: Nephrology FSGS Non-product RWE Newsletter

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Home » RKD News » Proteinuria as a Key FSGS Surrogate Endpoint

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Welcome by Dr. Anna Gaddy

Focal segmental glomerulosclerosis (FSGS) is a rare, progressive kidney condition with no FDA-approved pharmacologic therapies1

FSGS is a histopathologic pattern of injury seen on kidney biopsy, reflecting underlying podocytopathy and characterized by segmental glomerular sclerosis, variable degrees of proteinuria, and, in some cases, nephrotic syndrome.2,3

Proteinuria in FSGS

Figure. Proteinuria in FSGS

Given the lack of approved treatments, there remains a need to address the high clinical, humanistic, and economic burden of FSGS.4-6 While clinical studies are key to identifying effective and safe therapies for FSGS, studies may be met with several challenges.1,7

  • As FSGS is a rare condition, it has a smaller patient population, leading to some studies facing difficulties in patient recruitment1,7
  • FSGS is also a heterogeneous condition, potentially making it difficult to evaluate targeted therapies in a diverse patient population1
  • Historically, there was uncertainty around appropriate clinical trial endpoints7

Topics: Nephrology FSGS


Introduction to FSGS

Understanding FSGS: Tune in to Dr. Trachtman’s overview and clinical insights on FSGS.

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Collaborative efforts within the nephrology community are driving progress in FSGS research and enhancing clinical studies7-10

Advancements in FSGS include:

  • A better understanding of the pathology8
  • A notable increase in emerging investigational therapies8
  • The identification of proteinuria as a primary clinical trial endpoint and a marker of disease progression9,10

In 2018, the Kidney Health Initiative (KHI) Working Group evaluated potential short-term and intermediate endpoints from FSGS studies and identified proteinuria as a key endpoint.7 The KHI and FDA working group believed that achieving complete remission (CR) of proteinuria (<0.3 g/day) could act as a surrogate endpoint for traditional approval of new FSGS therapies.9

Several studies supported achievement of CR of proteinuria as the strongest indicator for a better long-term FSGS prognosis.11-13 Reaching CR of proteinuria was associated with prolonged kidney survival and lower risk of kidney failure in patients with FSGS.12-14

In line with those findings, the 2021 Kidney Disease Improving Global Outcomes (KDIGO) guideline recommended CR of proteinuria as the optimal therapeutic goal for FSGS.3

In 2024, the FDA, NephCure, the International Society of Glomerular Disease (ISGD), the KHI, and the National Kidney Foundation (NKF) partnered to hold the PARASOL Scientific Workshop.15 The objective was to evaluate the use of proteinuria and estimated glomerular filtration rate (eGFR) as surrogate endpoints for kidney failure (KF), as KF is unfeasible to use in clinical trials due to the nature of FSGS.15

Findings from PARASOL suggest that an eGFR slope endpoint is impractical to implement in clinical trials, whereas proteinuria is a biologically plausible and clinically meaningful surrogate endpoint with a strong predictive value for kidney failure risk.10

Considerations for eGFR and proteinuria as FSGS clinical study endpoints

Figure. Considerations for eGFR and proteinuria as FSGS clinical study endpoints2,10

PARASOL data also suggests that using proteinuria as an endpoint could allow for more feasible study sample sizes.10 For example, to detect a treatment effect of 15%, one would only need approximately 210 patients per treatment group, supporting both the assessment of efficacy and the feasibility of conducting trials in the typically small FSGS patient population.10

In addition to highlighting proteinuria as a feasible endpoint for FSGS clinical trials, the PARASOL project set out to better understand proteinuria thresholds by assessing FSGS data from around the world10 

The PARASOL project analyzed data from several participating registries.10 Achieving proteinuria reduction was strongly associated with a significant reduction in risk of kidney failure, and findings were robust across subgroups.10 Similar behavior was seen across proteinuria thresholds ranging from 0.7 to 1.5 g/g.10 For patients with a high risk of FSGS progression, experiencing some level of proteinuria reduction represented substantial biological improvement and slower disease progression.10 Those who achieved CR of proteinuria had the lowest risk of kidney failure within 7 years.10

PARASOL: Proteinuria response thresholds and risk of kidney failure

Figure. PARASOL: Proteinuria response thresholds and risk of kidney failure16

PARASOL data were independently validated in the UK FSGS Registry of Rare Kidney Disease (RaDaR) cohort.10 Overall recent findings regarding endpoints in FSGS are paving the way for significant clinical trial advancements.10

Milestones in IgAN and FSGS

Milestones in IgAN & FSGS: Advancing Understanding and Possibilities

Travere and NKF partnered on a recent episode of Life as a Nephrology Professional. Tune in to hear experts discuss the evolution in IgAN and FSGS care.
Unravel the groundbreaking work in rare kidney disease.

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In recent years, organizations have partnered to advance FSGS research and improve clinical trial design in an effort to tackle the high clinical, humanistic, and economic burden of FSGS. 4-7,9,10,15 Identification of proteinuria reduction as a primary endpoint for FSGS studies has been a pivotal advancement.9,10 Recently, PARASOL and RaDaR demonstrated that proteinuria reduction was significantly associated with improvement of renal outcomes, underscoring the clinical meaningfulness and importance as a primary endpoint.10

References
  1. Trachtman H. Expert Opin Emerg Drugs. 2020;25(3):367-375.
  2. D’agati VD et al. N Engl J Med. 2011;365(25):2398-2411.
  3. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. Kidney Int. 2021;100(4S):S1-S276.
  4. Gipson DS et al. JAMA Netw Open. 2022;5(8):e2228701.
  5. Szklarzewicz J et al. Poster presented at: European Renal Association Congress 2023; June 15-18. 2023; Milan, Italy.
  6. Bensink ME et al. Kidney Med. 2024;6(2):100760.
  7. Gale D. Presented at: American Society of Nephrology Kidney Week 2024. October 24-27, 2024. San Diego, CA.
  8. De Cos M et al. Kidney Int Rep. 2023;8(1):30-35.
  9. Mariani LH et al. Am J Kidney Dis. 2024.
  10. Smith AR. Presented at: American Society of Nephrology Kidney Week 2024. October 24-27, 2024. San Diego, CA.
  11. Troyanov S et al. J Am Soc Nephrol. 2005;16(4):1061-1068.
  12. Troost JP et al. Am J Kidney Dis. 2021;77(2):216-225.
  13. Troost JP et al. Clin J Am Soc Nephrol. 2018;13(3):414-421.
  14. Saleem MA et al. Poster presented at: American Society of Nephrology Kidney Week; November 4-7, 2021. Virtual. PC1529.
  15. Food and Drug Administration. Proteinuria and GFR as Clinical Trial Endpoints in Focal Segmental Glomerulosclerosis: A Scientific Workshop. Accessed 21 March 2025. https://www.fda.gov/drugs/proteinuria-and-gfr-clinical-trial-endpoints-focal-segmental-glomerulosclerosis-scientific-workshop.
  16. Tumlin J et al. Presented at: National Kidney Foundation Spring Clinical Meetings 2025; April 10-13, 2025; Boston, USA. LB-07.

MA-DS-25-0017 | May 2025