RTRX - Meets primary endpoint (proteinurea):
September 7, 2016
Retrophin Announces Positive Top-Line Results from Phase 2 DUET Study of Sparsentan in Patients with Focal Segmental Glomerulosclerosis
Combined sparsentan treatment group experienced 44.8 percent reduction of proteinuria, more than double the reduction of irbesartan; achieves statistical significance in primary efficacy endpoint
Preliminary safety findings show sparsentan was generally safe and well-tolerated
Conference call scheduled for today at 8:30 a.m. ET
SAN DIEGO, Sept. 07, 2016 (GLOBE NEWSWIRE) -- Retrophin, Inc. (NASDAQ:RTRX) today announced positive top-line results from the Phase 2 DUET study of sparsentan for the treatment of focal segmental glomerulosclerosis (FSGS), a rare kidney disorder without an approved pharmacologic treatment that often leads to end-stage renal disease. 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.
"We are very pleased with the robust top-line results from DUET, which suggest sparsentan could be a significant advancement in the treatment of FSGS," said Stephen Aselage, chief executive officer of Retrophin. "FSGS patients today face poor outcomes with limited medical options; we look forward to working with the FDA to find the most expeditious path forward that would deliver the first approved pharmacologic treatment to the FSGS community."
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.
"The results from DUET serve as proof of concept for sparsentan's novel approach of combining endothelin receptor type A blockade with angiotensin II inhibition for the treatment of FSGS," said Alvin Shih, M.D., executive vice president and head of research & development for Retrophin. "Significant reductions in proteinuria, along with a well-tolerated preliminary safety profile have us excited about being one step closer to providing a new treatment option for patients with FSGS."
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.
The Company plans to present detailed study results, including data from the open label extension, at an upcoming medical meeting or in a peer-reviewed publication.
Conference Call Information
Retrophin will host a conference call and webcast today, Wednesday, September 7, 2016 at 8:30 a.m. ET to discuss the DUET study results. To participate in the conference call, dial +1-855-219-9219 (U.S.) or +1-315-625-6891 (International), confirmation code 76903331 shortly before 8:30 a.m. ET. The webcast can be accessed at www.retrophin.com, on the Events and Presentations page within the Investors section. A replay of the call will be available starting at 11:30 a.m. ET, September 7, 2016 until 11:59 p.m. ET, September 14, 2016. The replay number is +1-855-859-2056 (U.S.) or +1-404-537-3406 (International), confirmation code 76903331.
About the DUET Study
The DUET study is an international, randomized, double-blind, Phase 2 clinical trial assessing the safety and efficacy of sparsentan in 109 patients with focal segmental glomerulosclerosis (FSGS), of which 96 qualified for the evaluable database. The primary endpoint is the reduction of proteinuria, as compared to irbesartan, which is part of a class of drugs used to manage FSGS in the absence of an approved pharmacologic treatment. After a two-week washout period, patients were randomized to receive daily oral doses of 200 mg, 400 mg, and 800 mg of sparsentan or 300 mg of irbesartan. After completing the eight-week treatment period, all patients were eligible to receive sparsentan as part of the study's open-label extension.
About Focal Segmental Glomerulosclerosis (FSGS)
Focal segmental glomerulosclerosis, or FSGS, is a rare disorder without an approved pharmacologic treatment option that is estimated to affect up to 40,000 patients in the U.S. with similar prevalence in Europe. The disorder is defined by progressive scarring of the kidney and often leads to end-stage renal disease. FSGS is characterized by proteinuria, where protein is found in the urine due to a breakdown of the normal filtration mechanism in the kidney. Other common symptoms include swelling in parts of the body known as edema, as well as low blood albumin levels, abnormal lipid profiles, and hypertension.
Reduction in proteinuria is widely regarded to be beneficial in the treatment of FSGS, and may be associated with a decreased risk of progression to end-stage renal disease. In the absence of an approved pharmacologic treatment, FSGS patients are currently managed with angiotensin receptor blockers, angiotensin converting enzyme inhibitors, calcineurin inhibitors, and steroids.
About Sparsentan
Sparsentan could be the first approved pharmacologic treatment for focal segmental glomerulosclerosis, or FSGS, a rare kidney disorder that often leads to end-stage renal disease. Sparsentan's dual mechanism of action combines angiotensin receptor blockade with endothelin receptor type A 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 blockade via angiotensin receptor blockade or angiotensin converting enzyme inhibitors.
The Phase 2 DUET study of sparsentan met the primary efficacy endpoint for the overall treatment group, demonstrating a greater than two-fold reduction of proteinuria compared to irbesartan, after the eight-week, double-blind treatment period. The Company plans to engage the FDA to determine the most expeditious path forward to advance the development of sparsentan towards approval. In 2015, the U.S. Food and Drug Administration and European Commission each granted sparsentan orphan drug designation for the treatment of FSGS.
About Retrophin
Retrophin is a fully integrated biopharmaceutical company dedicated to delivering life-changing therapies to people living with rare diseases who have few, if any, treatment options. The Company's approach centers on its pipeline featuring clinical-stage assets targeting rare diseases with significant unmet medical needs, including sparsentan for focal segmental glomerulosclerosis (FSGS), a disorder characterized by progressive scarring of the kidney often leading to end-stage renal disease, and RE-024 for pantothenate kinase-associated neurodegeneration (PKAN), a life-threatening neurological disorder that typically begins in early childhood. Research exploring the potential of early-stage assets in several rare diseases is also underway. Retrophin's R&D efforts are supported by revenues from the Company's commercial products Thiola®, Cholbam® and Chenodal®.
Commentary:
Meeting the primary endpoint isn't a particular surprise since historically these drug classes are typically additive in proteinurea. But FWIW I'd suggest that there is substantial regulatory risk going forward.
1) Will the FDA provide Accelerated Approval based upon proteinurea? For other, bigger, indications, like Diabetic Nephropathy, I think it is a virtual certainty they would not (for good reason - combining drugs might look good for proteinurea, but actually end up harmful on more important endpoints like GFR etc)? Martin's argument that they would accept proteinurea for FSGS was that FSGS is a substantially more 'proteinuric' disease than most nephropathies (and, or course, that it is an orphan indication)
2) I would suggest that the likelihood of the FDA providing AA on this data will depend substantially on other parameters seen in the trial:
a) GFR change at the end of trial: There is a pretty good chance that the GFR change was substantively worse for the drug than for the SOC (typical with most nephropathy drugs over the first 2 to 4 months). That would (and probably should) make the FDA nervous given history of nephropathy drug combos. The mitigation would potentially be the extension data - e.g. if it flattens in the extension. (Interesting note - I know of only one drug class that seems to avoid this issue.)
b) SAE - particularly edema (the claim is that by being extremely specific to ETA (vs ETB) this won't be an issue - and the (sparse) data for Sparsentan does make this a plausible hypothesis), but the PR says no more than 'no withdrawls due to edema'.
AI
