Early research at Myogen Inc. suggesting the connection of histone deacetylase to heart disease has led to the expansion of a 2003 drug discovery collaboration with Basel, Switzerland-based Novartis AG.

The companies agreed to include Myogen's HDAC inhibitor program in their existing research efforts to discover and develop disease-modifying drugs in cardiovascular indications. At the same time, Denver-based Myogen also is expecting undisclosed payments from Novartis relating to three development milestones stemming from the existing collaboration.

The 2003 agreement included $5 million in signing fees, three years of research funding and potential milestones totaling up to $17.1 million. Novartis will retain rights to any compounds discovered, though Myogen has the option, following completion of Phase II trials, to receive either royalties on product sales or enter a co-promotion and profit-sharing arrangement. A similar agreement will apply to the newly included HDAC program, with undisclosed signing fees, research funding and milestone payments to Myogen.

After Phase II trials of any HDAC inhibitor compounds, Myogen again can choose to buy back into the product with a co-promotion option, an important aspect of the deal for Myogen, given the potential market size for cardiovascular drugs. The American Heart Association estimates that 70 million Americans suffer from one or more types of cardiovascular disease.

"The long-term future of this company was in this area of understanding heart failure," said Derek Cole, director of investor relations for Myogen, adding that the company didn't want to possibly lose future benefit by signing a "typical deal" that included only a royalty option.

Founded in 1996, Myogen focuses on determining the molecular basis of cardiovascular diseases and collaborates with academic institutions such as the University of Colorado, as well as the University of Texas Southwestern Medical Center, where much of the early HDAC research was done.

While HDACs - enzymes that remove an acetyl group from histones and allow histones to bind DNA to inhibit gene transcription - are implicated in several diseases and have become a popular target for drug development efforts for several other companies, the concentration primarily has been in oncology. Cambridge, Mass.-based Gloucester Pharmaceuticals Inc. has an HDAC inhibitor in pivotal trials for the treatment of cutaneous T-cell lymphoma, and Tarrytown, N.Y.-based Aton Pharma Inc., which was acquired last year by Whitehouse Station, N.J.-based Merck & Co. Inc., has two HDAC compounds - suberoylanilide hydroxamic acid and pyroxamide - in clinical development for cancer. Other firms' HDAC programs are in preclinical development, including San Diego-based Syrrx Inc. and Nutley, N.J.-based Hoffmann-La Roche Inc., which are collaborating on an early stage HDAC program in cancer. (See BioWorld Today, Dec. 2, 2004.)

Myogen's work on HDACs for cardiovascular disease was "driven largely out of our research laboratory and out of our collaborator, Dr. Eric Olson, and his laboratory at the University of Texas Southwestern Medical Center," Cole said.

Early research has shown that HDAC inhibitors can "block cardiomyocyte hypertrophy and increase the expression of alpha myosin chain," he said. "We believe that can help lead to some targets that will basically halt or reverse some of cardiac remodeling and gene reprogramming."

HDAC inhibitors also complement the late-stage compounds in Myogen's pipeline, which were in-licensed as part of the company's focus to create drugs for treating the disease rather than just the symptoms, Cole said.

The company expects to report preliminary results in July from two Phase III studies of enoximone, a Type III-selective phosphodiesterase inhibitor administered to more than 1,800 patients with advanced heart failure. Myogen's marketed product, Perfan I.V., is an intravenous formulation of enoximone for acute decompensated heart failure.

Results from Phase III studies of ambrisentan also are expected this year. An oral ETA-selective endothelin receptor antagonist, ambrisentan is designed for patients with pulmonary arterial hypertension. Myogen announced earlier this year that results from one of its trials would be delayed six months due to difficulty finding treatment-na ve patients. (See BioWorld Today, Feb. 4, 2005.)

Myogen also has an ongoing Phase IIb trial of darusentan, an oral ETA-selective endothelin receptor antagonist, as a therapy for patients with hypertension that cannot be controlled by other anti-hypertensive products.

The company posted a net loss of $18.3 million, or 51 cents per share, for the first quarter. As of March 31, it had cash, cash equivalents and investments totaling $101.6 million. Shares of Myogen (NASDAQ:MYOG) rose 13 cents Thursday to close at $7.16.