Restoring Retrophin’s reputation


As Martin Shkreli awaits the possible filing of yet more criminal charges against him and beguiles the hours by going on Tinder dates, his former company Retrophin appears to be quietly getting on with developing innovative drugs for rare diseases.

Whether it is doing so successfully will become clearer when a phase II trial of its lead project, sparsentan, in focal segmental glomerulosclerosis reports later this year. If the study hits it is just possible that Retrophin will be able to file on the results, giving the group sole access to a market worth nearly $1bn.

In fact sparsentan has the potential to bring in more revenue than Retrophin’s currently marketed products combined, despite the steep price increases the company has instituted for these over the past few years.


Focal segmental glomerulosclerosis (FSGS) is scar tissue in the glomeruli of the kidney. Its cause is often unknown although it can be associated with drug use, obesity or infection. According to Retrophin it affects up to 40,000 patients in the US and a similar number in Europe.

Sparsentan is a dual angiotensin II and endothelin A receptor antagonist. Endothelin-1 can exacerbate proteinurea and contribute to glomerular capillary hypertension and excessive protein filtration, and it is thought that endothelin A inhibition could be nephroprotective.

The Duet phase IIb trial will randomise 100 patients with primary FSGS to one of three doses of sparsentan – 200mg, 400mg and 800mg once daily for eight weeks – against an active comparator, irbesartan, as a single oral dose of 150mg for the first week, then 300mg for the remaining seven weeks. The primary endpoint is change in urine protein/creatinine ratio.

A 50% relative improvement in proteinuria over irbesartan ought to be considered clinically relevant. But the drug must achieve this without causing oedema, a common side effect with endothelin receptor antagonists. Finding the right dose will be crucial, and even then it seems likely that patients will have to be carefully chosen to filter out those with severe chronic kidney disease or congestive heart failure, and even the selected patients will have to receive concomitant diuretics.


According to analysts at Leerink, previous trials of sparsentan in different kidney diseases saw 12-week oedema prevalence of 3.5%, 6.9%, 10.7% of patients with 200, 400 and 800mg doses, compared with 1.7% and 3.5% for irbesartan. Encouragingly, four-week rates were much lower, at 0% and 2.6% for 200 and 500mg, respectively.

The eight-week Duet study may therefore be able to reduce proteinuria significantly without causing an unacceptable degree of fluid retention.

Proteinuria is of course a surrogate endpoint. Still, if Duet hits it is possible, though certainly not assured, that Retrophin may be able to use the data to file for accelerated approval.

Analysts from BMO Capital Markets write that Retrophin could soon begin a phase II extension study to further support an accelerated approval filing, adding that some patients ought to have been taking sparsentan for several years by the time of the NDA filing, addressing any potential long-term efficacy and safety concerns. They add that approval could come next year; Leerink analysts suggest 2018.

The peak market for sparsentan is pitched at about $950m-$1bn, and the Leerink analysts forecast sales of around $600m for sparsentan based on a 65% probability of success. They assume a price of $150,000 per patient per year, which payers might not baulk at given that FSGS does not often respond to standard of care – the alternative is the expense associated with kidney failure.


Sparsentan is not the only rare disease drug Retrophin has in the clinic. Its other compound, RE-024, will enter a phase II/III efficacy trial for pantothenate kinase-associated neurodegeneration in the second half of this year, and again Retrophin hopes to go straight for approval.

Leerink analysts put the market opportunity for RE-024, which works by increasing levels of coenzyme A to restore patients’ muscular function, at $250m and have assigned it a 50% probability of launch in 2019.

But it is the Duet results that provide the inflection point for the company. If positive, they will boost its share price but perhaps more importantly shift the way the company is viewed: from its association with its founder to a respectable developer of innovative drugs.

Study Trial ID
Duet NCT01613118

To contact the writer of this story email Elizabeth Cairns in London at or follow @LizEPVantage on Twitter

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