SPARSENTAN

Sparsentan as an investigational therapeutic candidate for the treatment of focal segmental glomerulosclerosis

Sparsentan is a novel small-molecule candidate in Phase 3 development for the treatment of focal segmental glomerulosclerosis (FSGS). FSGS is a pattern of damage to the glomeruli (filter units) of the kidney with numerous causes that often leads to decline in kidney function and progression to end-stage kidney disease (ESKD). Learn more about FSGS.

The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have granted sparsentan orphan drug designation for FSGS.

MECHANISM OF ACTION

Sparsentan is a single molecule designed to selectively block the receptors of two pathways which are associated with kidney disease progression. The receptors are endothelin 1A and angiotensin II type 1.1

Endothelin I and angiotensin II have a role in kidney function decline by contributing to inflammation and fibrosis in the kidney, changes to the shape of podocytes, podocyte loss, and increased permeability of the glomerular filtration barrier.2 Endothelin I and angiotensin II are also vasoconstrictive, meaning they cause a narrowing of blood vessels and an increase in pressure in the glomeruli.

Proteinuria is a standard measure of disease activity, and a predictor of and contributor to disease progression in FSGS.3,4

The goal of the sparsentan program for FSGS is to develop a well-tolerated, safe and effective treatment that sustainably reduces proteinuria and protects the long-term health of kidneys in people living with FSGS.

PATIENT NEED

FSGS can be characterized by an aggressive clinical course. 50% of patients with nephrotic-range proteinuria who do not reach remission or partial remission will require kidney transplant or dialysis within 5-10 years of diagnosis.5

Patients who are steroid resistant are at a significantly higher risk of disease progression and kidney failure.5,6 For those with primary FSGS (not secondary to another condition) who undergo kidney transplantation, FSGS recurs in the transplanted kidney in approximately 40% of patients.7,8

CLINICAL TRIALS

The DUET and DUPLEX Studies

After completing the double-blind portion of the Phase 2 DUET Study, Travere Therapeutics initiated a global pivotal Phase 3 clinical trial in 2018 to support potential approval of sparsentan for patients with FSGS in the United States and Europe. The DUPLEX Study protocol provides for an unblinded analysis of at least 190 patients performed after 36 weeks of treatment to evaluate the interim efficacy endpoint – the proportion of patients achieving a partial remission, defined as proteinuria reduction of ≥40% from baseline and a urinary protein-to-creatinine ratio of <1.5 g/day.9 The data from this analysis are expected to serve as the basis for submission of a New Drug Application under the Subpart H accelerated approval pathway in the United States and Conditional Marketing Authorization in Europe. Top-line efficacy data from the 36-week interim efficacy endpoint are expected in the first quarter of 2021. The confirmatory endpoint of the DUPLEX Study is the slope of eGFR assessed from baseline to week 108 at the final analysis.


Sources

  1. Trachtman, et al. J Am Soc Nephrol. 2018;29:2745-2754.
  2. Komers and Plotkin. Am J Physiol Regul Integr Comp Physiol. 2016;310:R877-R884.
  3. Abbate M, et al. Am J Pathol 2002; 161:2179–2193.
  4. Abbate M, et al. J Am Soc Nephrol 2006; 17:2974–2984.
  5. Korbet. J Am Soc Nephrol. 2012;23:1769-1776.
  6. KDIGO Clinical Practice Guideline on Glomerular Diseases (Public review draft – June 2020).
  7. D’Agati, et al. N Engl J Med. 2011;365:2398-2411.
  8. Kang, et al. Biomed Res Int. 2016;2016:6832971.
  9. Troost et al. Clin J Am Soc Nephrol. 2018;13:414-421

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