Recent research at Myogen suggests that HDAC inhibitors represent a viable approach to the development of novel, disease-modifying cardiac therapeutics. Myogen scientists have shown that HDAC inhibitors block pathological cardiomyocyte hypertrophy and up-regulate the expression of alpha myosin heavy chain while decreasing beta myosin isoform expression.
Patients with chronic heart failure develop an enlargement of the heart called cardiac hypertrophy. The causes and effects of cardiac hypertrophy have been extensively documented, but the underlying molecular mechanisms that link the molecular signals to cell changes, or cardiac signalling pathways, remain poorly understood.
Muscle cell growth associated with cardiac hypertrophy is caused by changes in gene expression controlled by cardiac signalling pathways that are turned on by pro-hypertrophic hormones (adrenalin, angiotensin II and endothelin I) and by pathophysiologic stimuli (heart attack and high blood pressure) that stretch cardiac muscle cells.
This research has resulted in the discovery of small molecule drugs that halt, or reverse, pathological cardiac remodelling and its underlying gene reprogramming and have the potential to improve the function of the failing heart. Myogen has identified and patented (US 6,706,686) therapeutic uses of HDAC inhibitors for the prevention and treatment of cardiac hypertrophy and heart failure.
The expansion of the collaboration extends research funding for a minimum of three years and includes undisclosed signing fees, milestone payments and royalty payments on sales of products that are successfully commercialised.
Upon the completion of Phase 2 clinical trials of HDACi product candidates Novartis has licensed under the collaboration, Myogen has an option to enter into a co-promotion and profit sharing agreement in certain markets.
This is subject to the company reimbursing Novartis for certain costs incurred through the completion of Phase 2 trials as well as a commensurate portion of future development and marketing costs and the elimination of the associated royalty.
"Through this partnership, we have an exciting opportunity to advance the discovery and development of novel small molecule compounds that selectively inhibit HDACs for treatment of cardiac diseases," said William Freytag, chief executive officer of Myogen.
"This expansion underlies our commitment to work with Myogen and to expand the productive relationship established in 2003," said Dr Jeremy Levin, global head of strategic alliances of Novartis.
Myogen originally entered into a research collaboration in October 2003 with Novartis Institutes for BioMedical Research, an affiliate of Novartis, for the discovery and development of novel drugs for the treatment of cardiovascular disease.