GSK loses its wager as Amigal fails in phase III

Analysis

The crashing of Amicus’s Fabry disease candidate Amigal in its pivotal US phase III trial is a shock for the company, whose share price fell by 44%, but perhaps represents an even nastier surprise for GlaxoSmithKline. The UK giant’s decisions to license Amigal and to take a 20% financial stake in Amicus itself now look rather questionable.

This might not be the end of the road for the drug, though. The interim results show the primary endpoint to have been missed, but signs of success in secondary analyses, if borne out by the full data, might just be enough to allow the drug onto the US market. But even if approval is eventually forthcoming, the companies might have to drop the price significantly to compete with Sanofi’s Fabrazyme, and that could seriously damage their chances of making Amigal profitable.

Responders unknown

Patients with Fabry do not produce the enzyme alpha galactosidase A owing to a genetic mutation, causing build-up of globotriaosylceramide (GL-3) in the blood vessels, kidneys and other organs.

The 67 patients enrolled in the pivotal trial had undergone testing which showed that their mutation was responsive to the drug in vitro. This testing was introduced after mining the phase II data suggested that a particular population responded, although the proportion of Fabry disease patients responsive is not known.

The trial, known as study 011 and also Facets, compared 150mg of Amigal with placebo. Its primary endpoint was the proportion of patients who demonstrated a 50% or greater reduction in kidney interstitial capillary GL-3 after six months, versus placebo.

This criterion was met by 41% of patients in the Amigal group and 28% in the placebo group; but the difference was not statistically significant. Percentage change from baseline of kidney GL-3, a secondary analysis, was 41% with Amigal and 6% with placebo, but again significance was missed. Full 12-month data will be presented at the Lysosomal Disease Network meeting in February.

Niche

The results are not as damning as they first appear. With Fabrazyme, the only therapy on the US market, having unpleasant side effects and requiring infusion, a niche could perhaps be found for Amigal, with its oral delivery route and – reportedly – good safety. Another trial, study 012, is under way and will compare Amigal versus enzyme-replacement therapies, namely Fabrazyme and Shire’s Replagal. Also called Attract, study 012 is designed to support European approval and will report in 2014. 

There is also the prospect of combination with Fabrazyme or Replagal, which Amicus and GSK might explore if they are forced to give up on Amigal as a monotherapy.

Eric Le Berrigaud, an analuyst with Bryan Garnier, said the drug was now unlikely to succeed in monotherapy. He said a combination for a subset of patients was possible, but the target market is very limited. Leerink Swann cut the probability of Amigal’s success as a monotherapy from 75% to 25%, but gave a putative combination a fifty-fifty shot.

Partnering

At least Amicus has a back-up plan: its Pompe’s disease drug, AT2220, won through in phase II two months ago (Orphan drugs can be a route to success, but pricing is a future problem, October 16, 2012). 

But a takeover by GSK, thought possible after the UK company took a 20% equity stake in Amicus, now looks unlikely (Event – Glaxo endorsement puts focus on Amicus phase III result and more, July 19, 2012). In fact, Shire’s 2009 decision to drop rights to both drugs, as well as Plicera, a now-abandoned Gaucher’s candidate, looks very wise. 

AT2220 is currently unpartnered, and with Plicera gone and Amigal perhaps on the way out it might remain a wallflower for some time yet.

Study name Trial ID
Study 011/Facets NCT00925301
Study 012/Attract NCT01218659  

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

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