Sparsentan for FSGS
Sparsentan is a novel product candidate with dual mechanism of action, currently being evaluated in a Phase 3 study which, if successful, has the potential to be the first FDA-approved pharmacologic treatment for focal segmental glomerulosclerosis (FSGS), a serious kidney disorder that often leads to end-stage renal disease.1
FSGS is defined by progressive scarring of the kidney and characterized by proteinuria, where protein is found in the urine due to a breakdown of the normal filtration mechanism in the kidney.2,3 The disorder is estimated to affect up to 40,000 patients in the U.S. with a similar prevalence in Europe.4
Sparsentan's dual mechanism of action combines angiotensin receptor blockade with endothelin receptor blockade. In several forms of chronic kidney disease, endothelin receptor blockade has been shown to have an additive beneficial effect on proteinuria in combination with renin-angiotensin inhibition.4,5,6,7,8,9
In the second quarter of 2018, we initiated DUPLEX (FSGSDUPLEX.com), a pivotal Phase 3 clinical trial of sparsentan in FSGS, which is designed to include an interim analysis of proteinuria to serve as the basis for an NDA filing for Subpart H accelerated approval of sparsentan. The confirmatory endpoint of the study is expected to compare changes from baseline in estimated glomerular filtration rate or, eGFR, which is widely regarded as the best overall measure of kidney function.
In 2016, we announced positive results from the Phase 2 DUET study of sparsentan showing the overall sparsentan treatment group achieved statistical significance in the study's primary efficacy endpoint, reduction of proteinuria. The study also showed that a significantly greater proportion of patients receiving sparsentan achieved modified partial remission of proteinuria, compared to irbesartan-treated patients. Sparsentan was generally safe and well-tolerated in the study, and the incidence of adverse events was comparable across the sparsentan and irbesartan treatment groups. The most common treatment-emergent adverse events in the study were headache, hypotension, dizziness, edema, nausea, diarrhea, vomiting and upper abdominal pain.10
In 2015, the FDA and European Commission both granted sparsentan orphan drug designation for the treatment of FSGS. In the U.S., this status provides Retrophin with development and regulatory incentives, as well as seven years of marketing exclusivity, if sparsentan is approved for FSGS. Similarly, sparsentan is eligible for a single marketing authorization that is valid in all EU countries and 10 years of market exclusivity in the region, upon approval for FSGS.
Visit ClinicalTrials.gov to learn more about the sparsentan clinical program.
Sparsentan for IgAN
We are also advancing the development of sparsentan in IgA nephropathy (IgAN), a rare, immune complex mediated chronic glomerular disease characterized by proteinuria and variable rates of progressive renal failure.
IgAN is estimated to affect more than 100,000 people in the United States and greater numbers in Europe and Asia. Most patients are diagnosed between the ages of 16 and 35 years; an estimated 40 to 50 percent of these patients progress to end-stage renal disease within 15 years of diagnosis. Currently, there are no FDA-approved treatments for IgAN.11
In the fourth quarter of 2018, we initiated the PROTECT Study (NCT03762850), a global, pivotal Phase 3 clinical trial evaluating the long-term nephroprotective potential of sparsentan for the treatment of IgAN. The PROTECT Study, which is expected to enroll approximately 280 patients with IgAN, is designed to include a primary efficacy endpoint evaluating changes in proteinuria to serve as the basis for an NDA filing for Subpart H accelerated approval of sparsentan in the U.S., as well as an application for Conditional Marketing Authorization (CMA) in Europe. Secondary efficacy endpoints are expected to evaluate changes in estimated glomerular filtration rate, or eGFR, which is widely regarded as the best overall measure of kidney function.
- Middleton, et al. Nephrology Rounds 2007; 5(4).
- D’Agati, et al. N Engl J Med 2011;365:2398-411.
- The National Kidney Foundation. Focal Glomerulosclerosis. Available at: https://www.kidney.org/atoz/content/focal. Last accessed: July 28, 2016.
- Data on file. San Diego, CA: Retrophin, Inc.; July 2016.
- Mann, et al. J Am Soc Nephrol. 2010 Mar;21(3):527-35.
- Weber, et al. The Lancet, Volume 374, Issue 9699, 1423-1431.
- Kohan, et al. J Am Soc Nephrol 22: 763–772, 2011.
- De Zeeuw D et al. J Am Soc Nephrol. 2014 May;25(5): 1083-1093.
- Dhaun, et al. Hypertension 2011; 58: e11-e12.
- Trachtman H, Nelson P, Radko K on behalf of the DUET Investigators. Efficacy and Safety of Sparsentan, a Dual Angiotensin II and Endothelin Type A Receptor Antagonist, in Patients with Focal Segmental Glomerulosclerosis: A Phase 2 Trial (DUET). Presented at the American Society of Nephrology Kidney Week Meeting; November 15-20 2016, Chicago, IL.
- Pietro A. Canetta et al. CJASN 2014;9:617-625.