GNE myopathy, previously known as hereditary inclusion body myopathy, is a rare genetic disorder characterized by progressive muscle weakness that results in severe incapacitation. GNE myopathy has been traced to specific mutations in the GNE gene and the biochemical pathways this gene affects within muscle cells. There are no approved therapies for GNE myopathy, and treatment is limited to palliative care. This purpose of this project is to develop a small molecule (DEX-M74) specifically targeted to address the biochemical pathway deficits caused by the GNE mutations that lead to muscle wasting.
GNE myopathy is a rare adult-onset muscular disorder characterized by progressive muscle weakness, resulting in severe incapacitation within 10 to 20 years after onset. GNE myopathy is a genetic disorder that has been traced to mutations in the gene GNE. GNE encodes an enzyme that catalyzes the first two steps in the biosynthesis of sialic acid (SA). The subsequent deficiency of SA production is presumed to cause decreased sialylation of muscle glycoproteins, resulting in muscle degeneration.
Recent studies have implicated the SA precursor N-acetyl-D-mannosamine (ManNAc, or DEX-M74) as a potential therapeutic agent for the treatment of GNE myopathy. The National Human Genome Research Institute at NIH filed a patent application on the use of ManNAc for the treatment of GNE myopathy, and it filed an Investigational New Drug application with the Food and Drug Administration (FDA) in 2007 to conduct a Phase 2/3 clinical trial testing the safety and efficacy of ManNAc in GNE myopathy patients. The FDA issued a hold on this clinical trial, citing the need for additional pre-clinical studies.
Public Health Impact
There are no FDA-approved therapies for GNE myopathy, and treatment is limited to palliative care. There is a clear, high-priority unmet medical need. NIH owns related intellectual property for the use of ManNAc to treat GNE myopathy patients and has designed a Phase 2/3 clinical trial to test its safety and efficacy. The regulatory affairs support required to move this project forward will provide important information adaptable to future TRND projects in the rare disease space.
TRND supported the completion of animal toxicology studies and generated required data on the manufacturing processes to produce the final drug product. This work allowed TRND to gain FDA approval to lift the clinical hold and initiate human trials. To gather information on the disease and enable clinical trial design, TRND scientists began a natural history study of GNE myopathy disease progression in 2011. Since the clearance from the FDA, TRND scientists have concluded a Phase 1 and Phase 2 clinical study in GNE myopathy patients at the NIH Clinical Center. In 2015, Altamira Bio, Inc. (now Escala Therapeutics) acquired a license and entered into a Cooperative Research and Development Agreement (CRADA) with NIH to continue the development of DEX-M74 for GNE myopathy, as well as other disorders characterized by decreased sialylation. Escala plans to commence a Phase 2/3 clinical trial to demonstrate efficacy of DEX-M74 in GNE myopathy patients in 2017.
Mutation in the Key Enzyme of Sialic Acid Biosynthesis Causes Severe Glomerular Proteinuria and Is Rescued by N-acetylmannosamine • Journal of Clinical Investigation • June 2007
Hereditary Inclusion Body Myopathy: A Decade of Progress • Biochimica et Biophysica Acta • September 2009
U.S. Patent No. 60/932,451 filed 30 May 2008: N-acetyl Mannosamine as a Therapeutic Agent Huizing, M.; Gahl, W.A.; Manoli, I.; Klootwijk, E.