Pharmacological chaperone is designed to stabilize α-GAL A and restore its activity.

GlaxoSmithKline (GSK) is making a $31 million investment in Amicus Therapeutics and will pay the firm another $30M up front in return for exclusive worldwide development and commercialization rights to the latter’s Phase III-stage Fabry disease therapy, Amigal™ (migalastat HCL). GSK’s investment in Amicus equates to a 19.9% stake in the firm.

Under terms of the deal the two companies will jointly fund Amigal monotherapy development costs, and work together to start clinical evaluation of Amigal combined with enzyme-replacement therapy (ERT) in the treatment of Fabry disease.

Amicus says the $60 million earned from GSK’s up-front payment and share purchase could be boosted by a further $170 million in Amigal development and commercial milestones, plus additional tiered double-digit royalties on future global sales of the drug. “The completion of this agreement with GSK is a transformational event for Amicus,” states John F. Crowley, its chairman and CEO. “With this key strategic alliance with GSK and the added financial strength it provides, Amicus is now uniquely positioned to build shareholder value through our expertise in rare disease drug development.”

Amicus is focused on the development of orally administered drugs known as pharmacological chaperones for the treatment of diseases characterized by protein misfolding. Molecular chaperone drugs are designed to selectively bind and stabilize their target proteins to facilitate protein folding into the correct three-dimensional shape. The firm believes this activity will restore the protein’s correct function, reduce the body’s tendency to identify the misfolded proteins as defective and destroy them, and reduce the tendency for such molecules to aggregate in the cell endoplasmic reticulum and cause proteotoxic effects. While Amicus is initially concentrating on drugs against lysosomal storage disorders, the firm believes its pharmacological chaperone technology will have potential application in a broad range of relevant genetic diseases, including neurodegenerative disorders and other metabolic diseases.

Amigal is the firm’s lead clinical-stage product, it has received orphan drug designation in both the U.S. and Europe. Amigal is designed to to bind to destabilized α-galactosidase A enzyme (α-GAL A) and restore its ability to degrade the globotriaosylceramide (GL-3) substrate in lysosomes. Phase II trials have found that in patients identified as Amigal responders, treatment resulted in increased levels of alpha-Gal A, reduces levels of GL-3 measured in renal interstitial cells, and has a potentially positive impact on renal function. An international placebo-controlled Phase III trial (study 011) was initiated in 2009, and will include about 60 patients. The surrogate primary endpoint is the change in levels of kidney interstitial capillary GL-3. Amicus says a second Phase III trial (study 012) is expected to start before the end of 2010. This 18-month open-label study will compare Amigal with ERT in about 60 Fabry disease patients.

Clinical data on Amicus’ other two lysosomal storage disease candidates have been mixed. In October 2009 the firm confirmed it was unlikely to take its Gaucher disease candidate Plicera™ (afegostat tartrate) into Phase III development as monotherapy, due to disappointing Phase II trial results. The Phase II data showed that while all 18 treated patients experienced an increase in the level of the target enzyme (GCase) as measured in white blood cells, only one exhibited clinically meaningful improvements in key measures of disease. Plicera had been in development by Amicus in partnership with Shire Human Genetic Therapies.

Side effects caused by the Pompe disease candidate AT2200 (1-deoxynojirimycin hydrochloride), meanwhile, have also led Amicus to ditch developing the drug as montherapy, although the firm is looking at possible development of the drug in combination with ERT against Pompe disease. Amicus had started a Phase II trial with AT2220 monotherapy in adults back in June 2008. However, in February 2009 patient enrollment was suspended after two participating patients experienced serious adverse events that were probably related to treatment with the candidate. The AT2200 IND was subsequently placed on clinical hold by FDA.

Having evaluated all data from the two affected subjects and completed additional preclinical studies of AT2220, Amicus then proposed to FDA the start of another Phase I trial to further evaluate the pharmacokinetics of AT2220 in muscle, the key target tissue in Pompe disease. In September 2009 FDA agreed to the proposal and converted the clinical hold of AT2220 to a partial hold. Unfortunately, in May this year the firm reported that pharmacokinetic data from the new trial demonstrated that AT2220 was cleared relatively slowly from muscle tissue. Based on the collective data from this trial and previously completed preclinical and clinical studies of AT2220, Amicus decided not to advance AT2220 as a monotherapy for Pompe disease, but focus on developing the drug in combination with ERT.

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