GlaxoSmithKline has made an additional $18.6 million investment in Amicus Therapeutics as part of an expansion to the firms’ collaboration on development of Amicus’ pharmacological chaperone migalastat HCL (AT1001) for the treatment of Fabry disease. The investment by GSK, at $6.3 per share of common stock, means the firm now owns 19.9% of Amicus. The latter will also receive a $3.5 million milestone cash payment from GSK relating to achievement of a clinical development milestone earlier this year.

Amicus is developing genetic disease treatments that are based on small molecules, pharmacological chaperones that effectively bind to and stabilize disease-related proteins, helping the protein fold into its correct three-dimensional shape and allowing the protein to be trafficked to and act in the appropriate location in the cell. Pivotal development-stage migalastat HCL (which the firms aim to trade name Amigal) is designed to bind to the destabilized α-galactosidase A enzyme (α-GAL) that causes Fabry disease, and restore its intended biological function of degrading globotriaosylceramide (GL-3) substrate in lysosomes.

Amicus and GSK’s expanded agreement now covers codevelopment of all current and future formulations of migalastat HCL for Fabry disease, including a coformulation of the drug with an investigational enzyme replacement therapy (ERT) currently in preclinical development by GSK and Japanese firm JCR Pharmaceutical. Amicus gains commercial rights to all developed Fabry disease products in the U.S., with GSK retaining all commercial rights to relevant products in the rest of the world.

“Amicus has a very successful track record as our development partner, and long-standing relationships with the Fabry community,” comments Marc Dunoyer, global head of GSK rare diseases. “We look forward to their leadership in the U.S. commercialization of now several potential medicines for patients with Fabry disease. This is an important step in our strategic vision, allowing us to undertake and fund an enlarged scientific program with a view to turning molecules into medicines for rare diseases faster and more effectively than ever before.”

Migalastat HCL monotherapy is currently undergoing two registrational trials (studies 011 and 012) in patients with genetic mutations suitable for chaperone montherapy. Results from study 011 are expected during the third quarter of 2011. A Phase II trial is also ongoing to evaluate Fabry disease therapy that combines migalastat HCL therapy with a coadministered ERT. Positive preliminary data from this study (designated 013) were reported in January.

GSK and Amicus will also now develop a coformulated product comprising migalastat HCL and a preclinical-stage recombinant alpha-Gal-A enzyme (JR-051) ERT, which was originally developed by JCR and licensed to GSK for all non-Japanese markets. The coformulated product is projected to start in clinical studies some time in 2013.

Over the rest of 2012 the firms will continue to share R&D costs for all formulations of migalastat HCL, with Amicus funding 25% and GSK 75% of the costs relating to development of migalastat as monotherapy or for use in combination regimens. This financial split will change to 40/60 from 2013. The costs of developing migalastat-containing coformulations will be split 40/60 between Amicus and GSK, respectively, forthwith.

GSK will be eligible for $20 million in regulatory approval and product milestones for migalastat HCl monotherapy and chaperone-ERT-coadministration, plus potentially up to $35 million within seven years following the launch of a coformulated chaperone-ERT product.

Amicus is also developing pharmacological chaperones for the treatment of Gaucher disease and Pompe disease. The Gaucher disease candidate AT2101 (isofagomine tartrate), is designed to bind to destabilized glucocerebrosidase and restore its ability to degrade glucoerebroside in lysosomes. Phase II trials with AT2101 monotherapy were previously carried out, and an AT2101-ERT combination therapy is in preclinical development.

Amicus’ AT2220 (duvoglostat HCl) is a pharmacological chaperone in development for treating Pompe disease. A Phase II trial evalauting AT2220 coadministered with Genzyme’s Pompe disease ERT Myozyme™/Lumizyme™ (alglucosidase alfa) is in parallel with a trial evaluating alpha-glucosidase ERT-related immunogenicity in Pompe disease.The firm says immune responses occur in a majority of Pompe patients receiving alglucosidase alfa infusions which have the potential to limit treatment outcomes with ERT.

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