Though analysts are keen to drill down into data from the phase II DUET study testing sparsentan in focal segmental glomerulosclerosis (FSGS), a rare and idiopathic kidney disorder, the better-than-expected top-line results were sufficient to send shares of Retrophin Inc. (NASDAQ:RTRX) soaring by as much as 44 percent Wednesday, before closing at $20.81, up 27.5 percent. Sparsentan, a dual-acting receptor antagonist of angiotensin and endothelin, bested active comparator irbesartan on the primary endpoint of reducing levels of proteinuria in FSGS patients following eight weeks of treatment.

Awaiting data from the international, randomized, double-blind study, Retrophin has said "pretty consistently over the last year or so [that] we hoped to see a 50 percent improvement over irbesartan," said CEO Stephen Aselage. "What we saw was substantially better than that."

The mean reduction of proteinuria from baseline after eight weeks for all patients treated with sparsentan (n = 64) – 200 mg, 400 mg or 800 mg once daily – was 44.8 percent vs. a mean reduction of 18.5 percent for patients (n = 32) receiving 300 mg once-daily irbesartan (p = 0.006). Patients in the combined 400-mg and 800-mg cohorts of sparsentan (n = 51) was 47.4 percent, compared to a mean reduction of 19 percent in the irbesartan group (n = 25) for those cohorts (p = 0.011).

Breaking out percentages for each individual sparsentan cohort showed positive trends toward benefits, though they did not reach statistical significance, which Alvin Shih, the firm's executive vice president and head of R&D, said was due likely to the small sample sizes in each cohort.

Details from the individual cohorts will be forthcoming, though Shih offered some color on a conference call Wednesday morning. For starters, the 109-patient study was intentionally over-enrolled to ensure an adequate number of subjects who had proteinuria readings at both baseline and eight weeks post treatment with either sparsentan or irbesartan, an angiotensin II receptor antagonist currently used as standard of care for FSGS though it's not approved for that indication. And, in response to an analyst's question, Shih clarified that inclusion criteria called only for patients to have proteinuria levels exceeding 1, which indicated they had active disease, "so we could see a treatment effect." There was no upper level cutoff.

Retrophin also opted to keep it simple, comparing only baseline and eight-week post-treatment measurements.

"Primary FSGS is idiopathic and, as such, can be somewhat unpredictable, and that to us was actually a reason not to get overly cute with the design of the trial and to do all these various stratifications, because we ultimately don't exactly know which factors are important in the prognosis of the disease," Shih explained. "So our approach was to take all comers who had a certain proteinuria level because we knew that was an important factor. Beyond that, the inclusion/exclusion criteria were quite wide."

Of the 109 patients enrolled, 96 completed the double-blind treatment period. Patient ages ran from 8 to 75. All patients who completed the treatment period elected to move into an open-label extension study, Shih said.

All told, only three patients dropped out due to adverse events, two in the sparsentan arm and one in the irbesartan arm, which Shih said was "numerically equivalent."

Sparsentan generally was found to be safe and well-tolerated, with Shih noting no dropouts due to fluid retention or edema. He disclosed one serious adverse event (SAE) considered potentially due to treatment, elaborating during the conference call that the patient in question was a young woman who had chronic anemia – a hemoglobin level around 9 or 10 – and also suffered a gastrointestinal bleed. The SAE, therefore, was "ruled as possibly related," though "likely multifactorial in origin." He added that the patient completed the eight-week study and entered the open-label extension.


Next steps are to complete the further analyses and then take the full dataset to the FDA, which San Diego-based Retrophin hopes to do before the end of this year.

Leerink analyst Joseph Schwartz in a research note increased the probability of sparsentan to 75 percent, though "timing of approval remains unclear." At the time DUET launched in 2013, there were hints of possible accelerated approval based on the data, "but apparently this possibility was hypothetical and the exact bogey was never established (as is often the case during early discussions with the FDA)," Schwartz wrote.

For his part, CEO Aselage said he was confident the DUET results would help Retrophin make a compelling argument. "We'll make our best case, but it's a regulatory decision. I think, for good reason, we are very hesitant to speculate on how FDA might respond to the data."

There currently are no drugs specifically approved to treat FSGS, a disease that frequently leads to end-stage renal disease and is estimated to affect about 40,000 patients in the U.S., with similar prevalence in Europe. It's characterized by progressive scarring to the kidney, specifically to the glomeruli, which act as tiny filters that separate protein in the blood from the urine that is flushed from the body. Other symptoms are associated with FSGS as well, including edema, low blood albumin levels, abnormal lipid profiles and hypertension, but targeting proteinuria – the leaking of protein into the urine – is largely considered an effective way to reduce the risk of progression to end-stage renal disease. Measuring proteinuria levels also makes for a fairly straightforward clinical endpoint.

According to Retrophin, in several forms of kidney disease, endothelin receptor blockade has been shown to have an additive benefit when combined with renin-angiotensin blockade. Sparsentan has orphan status in both the U.S. and Europe for FSGS.

A handful of other drugs are in the works, including DMX-200 from Dimerix Ltd., of Melbourne, Australia, which received feedback from the FDA earlier this year on plans for a potentially registrational trial testing the drug, which combines irbesartan with CCR2 chemokine antagonist propagermanium, in FSGS. Late last year, DEX-M74, an N-acetylmannosamine kinase stimulator in development through a partnership with the NIH and Escala Therapeutics Inc., of New York, started a phase II study and, in March, Bristol-Myers Squibb Co. moved into a phase II study in FSGS with its CTLA-4 costimulatory inhibitor abatacept, which previously gained approval as Orencia for autoimmune disorders.

Retrophin gained rights to sparsentan through a 2012 deal with Ligand Pharmaceuticals Inc., negotiated by founder and now-controversial biotech entrepreneur Martin Shkreli, which included a $1 million up-front payment, up to $75 million in potential milestones and a 9 percent royalty rate. (See BioWorld Today, March 12, 2012.)

Though Retrophin got pulled into the drug pricing brouhaha last year, thanks largely to its previous connection to Shkreli – Retrophin's board fired its former top executive in 2014 – it has, with the exception of a lawsuit filed last year, tried to distance itself from Shkreli, focusing instead on its pipeline, which beyond sparsentan includes RE-024, a replacement therapy targeting pantothenate kinase-associated neurodegeneration (PKAN). (See BioWorld Today, Dec. 11, 2015.)

Described as a life-threatening neurological disorder that typically emerges in childhood, PKAN is estimated to affect only about 5,000 people worldwide. There are no approved treatments. Retrophin has said it plans to start an efficacy trial this year testing RE-024 in PKAN, and Aselage confirmed Wednesday that "we are on track to achieve this milestone by year-end."

With the success of DUET and the planned start of the PKAN study, Retrophin is expected to "hit all the key drivers that will make 2016 a transformational year," he added.

The firm, which boasts three marketed products – Thiola (tiopronin) for the prevention of kidney stones, Cholbam (cholic acid) for bile acid synthesis disorders and Chenodal for treating certain patients with gallstones – posted net product sales of $33.3 million for the second quarter. Its net loss was $13.4 million, or 31 cents per share.

As of June 30, Retrophin had cash, equivalents, marketable securities and notes receivable totaling $315.2 million.