Amicus Therapeutics approaches treatment of human genetic diseases by using its pharmacological chaperones, or small molecule drugs that selectively bind to the target protein. Once bound, these molecules increase the protein’s stability and encourage it to fold into the correct 3-D shape.
Amicus’ lead candidate is in Phase III trials to treat Fabry disease. The company, along with partner GlaxoSmithKline (GSK), is conducting a Phase III study and expects preliminary results in mid-2011. In February Amicus announced positive data from its ongoing Phase II extension study. Fifteen subjects have been treated for more than three years, seven subjects have been treated for more than four years, and 17 continue to receive treatment in the ongoing extension study.
Renal function is a key efficacy endpoint for Fabry disease treatments. The trial showed that estimated glomerular filtration rate, a measure of kidney function, remained stable out to 3–4 years for all subjects continuing in the extension study. Reduced 24-hour urine protein levels, another measure of renal function, was observed with a mean 21% and median 34% reduction from baseline in patients identified as responders.
Apart from GSK, another big pharma company made a major commitment in the protein folding space. Pfizer acquired FoldRx Pharmaceuticals in September 2010 for its pipeline of preclinical and clinical products to treat diseases caused by protein misfolding. Lead product, tafamidis, is being developed for TTR amyloidosis, a disease linked to mutations in the transthyretin (TTR) protein.
TTR amyloidosis manifests in two clinical forms: ATTR-PN, a sensory neuropathy that starts in the lower extremities and progresses to include both autonomic and motor dysfunction, and ATTR-CM, characterized by amyloid deposits that infiltrate the heart and result in a potential fatal restrictive cardiomyopathy. ATTR-CM generally occurs in individuals over 60 years of age. ATTR-PN affects about 5,000–10,000 patients worldwide, while ATTR-CM affects about 400,000 patients in the U.S alone.
Tafamidis works to prevent the dissociation of native TTR tetramer into monomers. This results in the inhibition of amyloid fibril formation that leads to amyloid deposition. The last report on clinical investigations was made in 2009. FoldRx said preliminary results from the first randomized, controlled trial showed that treatment significantly halted disease progression in ATTR-PN, reduced the burden of disease after 18 months, and appeared to be safe and well-tolerated.
Pfizer has filed an MAA and is currently in communication with the FDA to define its path for filing in the U.S. Tafamidis has orphan drug designation in both the U.S. and EU as well as Fast Track designation in the U.S. for the treatment of ATTR-PN.