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Clinical Trials

Date: 2018-10-26

Type of information: Presentation of results at a congress

phase: 2

Announcement: presentation of results at the American Society of Nephrology (ASN) Kidney Week 2018

Company: Retrophin (USA - CA)

Product: sparsentan (RE-021)

Action mechanism:

  • endothelin receptor antagonist/angiotensin receptor blocker. Sparsentan has two separate mechanisms of action, acting as both an Endothelin Receptor Antagonist (ERA) and Angiotensin Receptor Blocker (ARB). Studies in similar nephropathies have shown ERAs and ARBs to both be effective in reducing proteinuria.
  • Ligand  Pharmaceuticals licensed worldwide rights of sparsentan (RE-021) (formerly known as DARA) to Retrophin in 2012, at the time of Retrophin’s formation.
  • About Sparsentan Sparsentan is an investigational product candidate that has a dual mechanism of action that combines angiotensin receptor blockade with endothelin receptor type A blockade. Retrophin is developing sparsentan for the treatment of FSGS, as well as for IgA nephropathy (IgAN), a rare kidney disorder that also often leads to ESRD. In several forms of chronic kidney disease, such as FSGS and IgAN, endothelin receptor blockade has been shown to have an additive beneficial effect on proteinuria in combination with renin-angiotensin blockade via angiotensin receptor blockade or angiotensin converting enzyme inhibitors. Sparsentan has been granted orphan drug designation for the treatment of FSGS by the FDA and European Commission .

Disease: focal segmental glomerulosclerosis (FSGS)

Therapeutic area: Rare diseases - Kidney diseases - Renal diseases

Country: Belgia, Czechia, Italy, USA

Trial details:

  • This study will investigate whether RE-021 (sparsentan), a selective dual-acting receptor antagonist with affinity for endothelin (A type) and angiotensin II receptors (Type 1), is safe and effective in treating patients with focal segmental glomerulosclerosis (FSGS). (NCT01613118)
The Phase 2 DUET Study of sparsentan in FSGS met its primary efficacy endpoint for the combined treatment group, demonstrating a greater than two-fold reduction in proteinuria compared to irbesartan, after the eight-week, double-blind treatment period. Irbesartan is part of a class of drugs used to manage FSGS and IgAN in the absence of an approved pharmacologic treatment. In April 2018 , Retrophin initiated the pivotal Phase 3 DUPLEX Study of sparsentan for the treatment of FSGS. The study includes an interim efficacy endpoint based on proteinuria to serve as the basis for a New Drug Application (NDA) filing for Subpart H accelerated approval of sparsentan in the U.S. and Conditional Marketing Authorization (CMA) consideration in Europe . In addition, Retrophin expects to initiate the pivotal Phase 3 PROTECT Study evaluating the safety and efficacy of sparsentan for the treatment of IgAN during the fourth quarter of 2018. If approved, sparsentan could potentially be the first approved pharmacologic treatment for FSGS and IgAN.

Latest news:

  • • On October 26, 2018, Retrophin announced new data from the ongoing open-label extension of the Phase 2 DUET Study of sparsentan for the treatment of focal segmental glomerulosclerosis (FSGS). These data were presented during an oral session at the American Society of Nephrology (ASN) Kidney Week 2018, being held October 23–28, 2018, in San Diego, CA.
  • As previously reported, the overall sparsentan treatment group demonstrated a greater than two-fold reduction in proteinuria compared to the irbesartan treatment group, after an eight-week, double-blind treatment period in the Phase 2 DUET Study. Additional results showing that patients with FSGS who remained on sparsentan for 40 weeks during the open-label extension period of DUET achieved progressive reduction in proteinuria and stable estimated glomerular filtration rate (eGFR), were reported at ASN Kidney Week 2017 (see below).
  • New findings from the open-label extension of the Phase 2 DUET Study presented at ASN Kidney Week 2018 include:
  • Patients with FSGS who remained on sparsentan for 76 weeks during the open-label period (n=71) achieved additional progressive reduction of proteinuria. In patients who received sparsentan as part of the original eight-week, double-blind treatment period (n=45), median urine protein-to-creatinine ratio (UP/C) was reduced from 2.8 g/g at baseline (week 0) to 0.9 g/g at week 84. Patients who crossed over to sparsentan from the original irbesartan control group (n=26) experienced additional and sustained reduction in proteinuria during the treatment period, with median UP/C decreasing from 2.3 g/g at crossover (week eight) to 1.1 g/g at week 84.
  • An increasing proportion of patients achieved the FSGS partial remission of proteinuria endpoint (FPRE), defined as UP/C: ?1.5 g/g and >40 percent reduction of proteinuria from baseline, with ongoing sparsentan treatment in the open-label extension.
  • In patients who received sparsentan as part of the original eight-week, double-blind treatment period (n=45), the proportion of patients who achieved FPRE increased from 28 percent at week eight to 60 percent at week 84. The proportion of patients who crossed over to sparsentan from the original irbesartan control group (n=26) and achieved FPRE increased from nine percent at week eight to 50 percent at week 84.
  • Treatment with sparsentan in the open-label extension was associated with a stabilization of eGFR out to week 84. The observed beneficial effects of sparsentan on proteinuria were associated with a sustained reduction in mean systolic and diastolic blood pressure.
  • Sparsentan continued to be generally well-tolerated during the open-label extension period. Sixty-two patients continue to receive treatment with sparsentan in the ongoing open-label extension of DUET.
  • • On October 25, 2018, Retrophin announced that the Journal of the American Society of Nephrology (JASN) has published online (doi: 10.1681/ASN.2018010091) the positive results from the Phase 2 DUET Study of sparsentan for the treatment of focal segmental glomerulosclerosis (FSGS). As previously reported, these results demonstrated that the sparsentan treatment group experienced a greater than two-fold reduction of proteinuria compared to the irbesartan treatment group after an eight-week, double-blind treatment period. In the randomized, double-blind, controlled Phase 2 DUET Study, the overall sparsentan treatment group achieved statistical significance in the primary efficacy endpoint, demonstrating a greater than two-fold reduction in proteinuria compared to the irbesartan treatment group, after an eight-week, double-blind treatment period. Treatment with sparsentan resulted in greater reductions in urinary protein-to-creatinine ratio (UP/C) compared with irbesartan when all dose cohorts (44.8 percent versus 18.5 percent; p=0.006) were combined or when the 400 and 800 mg dose cohorts (47.4 percent vs. 19.0 percent; p=0.011) were combined.
  • An analysis of the secondary endpoint of the study showed that during the eight-week, double-blind treatment period, a significantly greater proportion of patients receiving sparsentan (28.1 percent) achieved the FSGS partial remission of proteinuria endpoint (FPRE), defined as UP/C:?1.5 g/g and >40 percent reduction of proteinuria from baseline, compared to irbesartan-treated patients (9.4 percent; p=0.040).
  • In addition, data from patients who were followed out to 48 weeks in the open-label sparsentan treatment period of DUET demonstrated a steady rise in the percentage of patients who achieved FPRE, reaching approximately 60 percent in patients originally randomized to either sparsentan or irbesartan.
  • The data also showed sparsentan was generally well-tolerated during the eight-week, double-blind period, with the overall incidences of treatment-emergent adverse events (TEAEs), drug-related TEAEs, or serious TEAEs similar between the sparsentan and irbesartan groups.
  • • On November 3, 2017, Retrophin announced new data from the ongoing open-label extension of the Phase 2 DUET study of sparsentan for the treatment of focal segmental glomerulosclerosis (FSGS). These data were presented during an oral session at the American Society of Nephrology (ASN) Kidney Week 2017 in New Orleans, LA.
  • As previously reported, the sparsentan treatment group achieved statistical significance in the Phase 2 DUET study’s primary efficacy endpoint, demonstrating a greater than two-fold reduction in proteinuria compared to irbesartan, after an eight-week, double-blind treatment period.
  • New findings from the open-label extension of the Phase 2 DUET study presented at ASN Kidney Week 2017 include:
  • Patients with FSGS who remained on sparsentan for 40 weeks during the open-label period (n=38) achieved progressive reduction in proteinuria.
    • In patients who received sparsentan as part of the original eight-week, double-blind treatment period (n=26), median urine protein-to-creatinine ratio (UP/C) was reduced from 2.7 g/g at baseline (week 0), to 0.7 g/g at week 48.
    • Patients who crossed over to sparsentan from the original irbesartan treatment group (n=12) experienced additional and sustained reduction in proteinuria during the treatment period, with median UP/C decreasing from 2.3 g/g at crossover (week 8), to 1.7 g/g at week 48.
  • The observed beneficial effects of sparsentan on proteinuria were associated with stable estimated glomerular filtration rate (eGFR).
  • Transition to the sparsentan treatment group from the irbesartan group led to further reduction in proteinuria and long-term stability in eGFR.
  • The observed beneficial effects of treatment with sparsentan were similar after the exclusion of data from patients who received new immunosuppression therapy during the open-label extension.
  • Sparsentan continued to be generally safe and well-tolerated during the 40-week open-label extension period, including in patients who transferred from the original irbesartan group.
  • Seventy-four patients continue to receive treatment with sparsentan in the ongoing open-label extension of DUET.
  • • On September 7, 2016, Retrophin announced top-line results from the Phase 2 DUET study of sparsentan for the treatment of focal segmental glomerulosclerosis (FSGS). The study achieved statistical significance in the primary efficacy endpoint for the overall sparsentan treatment group, demonstrating a greater than two-fold reduction of proteinuria compared to irbesartan after the eight-week, double-blind treatment period.
  • In the DUET study, the mean reduction of proteinuria from baseline after eight weeks of treatment for all patients treated with 200, 400, and 800 mg/day of sparsentan (n=64) was 44.8 percent, compared to a mean reduction of proteinuria for all patients receiving 300 mg/day of irbesartan (n=32) of 18.5 percent (p=0.006). Further, the mean reduction of proteinuria from baseline after eight weeks of treatment for all patients treated with 400 mg and 800 mg doses of sparsentan (n=51) was 47.4 percent, compared to a mean proteinuria reduction of 19.0 percent for patients receiving 300 mg of irbesartan (n=25) in these two dose cohorts (p=0.011). The comparison of individual sparsentan dose cohorts to irbesartan showed clear signals of relative improvement, but did not reach statistical significance.
  • Top-line results suggest sparsentan was generally safe and well-tolerated in the DUET study. One serious adverse event, anemia, classified as potentially related to treatment occurred in the sparsentan group but did not result in study discontinuation during the eight-week blinded treatment period. There were no withdrawals due to fluid retention during the eight-week blinded treatment period. All patients who completed the eight-week treatment period entered the ongoing open label extension study, and the vast majority of these patients continue to receive therapy.
  • • On August 4, 2015, Retrophin announced that The Phase 2 DUET study of sparsentan for the treatment of focal segmental glomerulosclerosis (FSGS) continues to enroll toward the target of 100 patients by year-end 2015

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