G.P.101

• Published in: Neuromuscular disorders : NMD 2014-10, Vol.24 (9), p.825-825
• Main Authors: Milne, J, Donovan, J, Sweeney, L, Sleeper, M, Hammers, D, Jirousek, M, Curtis, M
• Format: Article
• Language: English
• Subjects: Neurology
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2014.06.115

In DMD, inflammation is driven by elevated NF-κB in muscle and occurs early in life, with resident immune cells driving muscle degeneration. Corticosteroids block inflammation and delay loss of ambulation and onset of cardiac and respiratory failure, but chronic use has significant adverse effects. CAT-1004 is a novel compound that inhibits NF-κB and is in development to treat chronic inflammation in DMD. In the mdx mouse model, CAT-1004 reduced muscle inflammation and degenerating fibers, and increased regenerating muscle fibers. In the Golden Retriever Muscular Dystrophy (GRMD) model, a single dose of CAT-1004 reduced both baseline and lipopolysaccharide (LPS) induced NF-κB activity and production of plasma TNF-α. Long term mdx and GRMD studies have demonstrated improvement in muscle function such as diaphragm. In long term mdx mouse studies, cumulative distance run increased. Preclinical studies did not identify dose limiting toxicities of CAT-1004 at equivalent doses several-fold higher than clinical doses. Phase 1 clinical studies assessed single doses of CAT-1004 (300 mg to 6000 mg, n = 52) and multiple doses for 14 days (500 mg to 4000 mg, n = 44). In a single dose study ( n = 9), CAT-1004 effects on NF-κB activity were evaluated after ex vivo stimulation of peripheral blood mononuclear cells with LPS. Safety was evaluated by adverse events, laboratories, physical exam and EKG. Subjects tolerated CAT-1004 well, with no clinically significant changes in EKG, physical exam, or laboratories. Most common adverse events were headaches and diarrhea. Biomarkers at both the gene and protein level demonstrated significant inhibition at multiple points in the NF-κB pathway following CAT-1004. A single dose of CAT-1004 produced a 70 percent reduction in NF-κB activity, in peripheral blood mononuclear cells. Phase 2 studies of CAT-1004 in DMD patients are planned. CAT-1004 may represent a steroid-sparing approach to slow muscle degeneration and improve function in DMD patients.