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Fledgling Genomas Research Links Muscle Genes to Statin Response; Dx In the Works

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Genomas has identified two gene variants associated with patient muscle damage resulting from statin treatment, the company said this week.

Genomas is developing a multi-gene test involving one risk-related SNP in each of the two genes — nitric oxide synthase and angiotensin II receptor-1 — that "interprets the risk that each of the factors conveys for the patient" by using an algorithm that assigns weight to each factor, Gualberto Ruaño, the firm's CEO, told Pharmacogenomics Reporter this week.

The research, which appears in the December issue of the British journal Pharmacogenomics, "is the beginning of [Genomas'] publications on this problem of statin safety," Ruaño said. The final test will interrogate approximately 45 genes, including metabolism gene CYP450 3A5, and should launch in the spring or early summer, he said.

Results of the study, which was conducted as part of a collaboration with the University of California-San Francisco, the Hartford Hospital, and the Yale University School of Medicine, also suggest that statin drugs may affect the contraction control of smooth muscles, and that the drugs directly affect vascular walls, said Ruaño. "That was surprising because to date, most workers in the field thought [the drug's effects] were related to skeletal muscle," he said.

The connection to smooth-muscle genes helps explain the drugs' utility in stabilizing patients after myocardial infarction, among other cardiovascular indications, Ruaño said. "We decided to look at it utilizing a different hypothesis, and that is whether vascular genes are related to the outcome in the context of [creatine kinase] elevation as a surrogate for muscle damage," he said. "What we found is that the two key genes regulating the tone of the vascular smooth muscle are the ones most highly associated with response, namely the nitric oxide synthase and AGTR1 — one is responsible for contraction, the other [is responsible] for dilation."

"We have two such programs: one is on statins, the other is on anti-psychotic agents," each with the goal of preventing side effects or to provide an estimate of patient risk, said Ruaño.

There are six statin drugs on the market: Pfizer's Lipitor, known generically as atorvastatin; Lescol, made by Novartis and Reliant Pharmaceuticals, and known generically as fluvastatin; Mevacor, a product of Merck known as lovastatin; Pravachol, made by Bristol-Myers Squibb known as pravastatin; Zocor, a product of Merck known as simvastatin; and AstraZeneca's Crestor, also known as rosuvastatin.

Statins, especially at high doses, can cause a number of muscle-related side effects, including muscle pain, muscle wasting, and rhabdomyolysis, which involves the rupture of skeletal muscle fibers. This last adverse event is particularly noteworthy because myoglobin, which is released into the blood stream after muscle fiber breaks down, can impair kidney function and lead to kidney failure.

Because sometimes-fatal rhabdomyolysis had occurred in patients taking the statin Baycol, known generically as cerivastatin, Bayer Pharmaceuticals voluntarily removed the drug from the worldwide market in August 2001.

The worldwide market for statins is the largest of any drug class, with most estimates falling in the range of $22 billion to $27 billion. According to the consulting firm IMS Health, the 2004 US statin market totaled $15 billion, showing 12 percent growth during the year. The top-selling statin, Lipitor, brought in US revenues of $7.7 billion in 2004.

— Chris Womack ([email protected])

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