Pharmacy's future may be in the genes - What's Hot in 2002 - larger pharmaceutical companies are seeking smaller biotechnology partners with genetics know-how

NEW YORK -- Advances in specialty drug development are changing the politics and power of pharmaceuticals. In the age of pharmacogenomics--the study of how genes affect the body's response to drugs--Big Pharma now finds itself courting smaller biotech cousins, rather than the other way around. That's because the smaller biotechs often are the ones with the knowledge, while the larger pharmaceutical companies have the marketing and manufacturing punch.

Some biotech companies are forgoing partnerships with pharmaceutical Goliaths and banding together on their own. Amgen's recently announced intention to acquire Immunex for $16 billion is a prime example of this dynamic in play. Using its specialized knowledge of how elevated levels of a protein called tumor necrosis factor cause pain in rheumatoid arthritis patients, Immunex produced Enbrel (etanercept), an injectible drug that, in spite of sometimes serious side effects, sells so well and fast that it's on perpetual backorder. Enbrel, launched in 1998, owes its existence directly to advancing knowledge of human genetics and researchers who discovered the gene that produces TNF.

In each company's view, Immunex' Enbrel is a perfect fit with Amgen's Neupogen (filgrastim, a white blood cell builder), Aranesp (darbepoetin alfa for chemotherapy-induced anemia) and Epogen (epoetin alfa, another anemia drug). The merger allows Amgen to add another blockbuster drug to its stable, and Immunex can use Amgen's resources to address the production problems that have been holding back Enbrel's sales.

Amgen chairman and chief executive officer Kevin Sharer has predicted that Enbrel will reach $3 billion or more in annual sales as a result of the merger and make Amgen a $10 billion dollar market leader in inflammatory product sales.

"Amgen's experience in bringing successful drugs to market and maximizing their therapeutic and commercial benefits will ensure that Enbrel achieves its full blockbuster potential," Sharer said. "We intend to apply our significant resources and expertise in protein manufacturing to step up production and distribution of Enbrel to meet strong market demand."

Molecular medicine

Another biotech merger in the news is Millennium and COR Therapeutics. The merger of these two companies, according to their spokesmen, "unites COR's cardiovascular expertise, product pipeline and commercial infrastructue for its market-leading anti-platelet cardiovascular product, Integrilin (eptifbatide) injection, with Millennium's genomicbased research, leadership in strategic alliances and product pipeline in oncology, inflammation and metabolic disease." Integrilin, a drug administered during angioplasty to prevent blood clots, works by specifically targeting glycoprotein receptors on blood platelets. It is co-marketed by Schering-Plough.

"Millennium and COR create an unparalleled combination of scientific leadership to bring the next generation of gene-to-patient products to the market based on a knowledge of molecular medicine," Charles Homcy, COR's vice president of research and development, said. Highlights of the newly combined pipeline include the first genomically derived drug targeted for obesity, MLN4760, and several cancer drugs.

Gleevec (ST1571 imatinib mesylate) is another specialized drug made possible by advanced genetic discovery. This chronic myeloid leukemia treatment from Novartis works by targeting an abnormal version of the BCR-ABL gene, a mutation found in nearly all CML patients. So dramatic has Gleevec's affect on CML been that the National Cancer Institute launched a special "Cancer Genome Anatomy Project" to see if other abnormal genes are at the root of other cancers. Novartis also is studying Gleevec's effectiveness for other cancers.

The ability of drugs such as Enbrel, Gleevec and Integrilin to target the genetic cause of disease is what sets them apart from traditional drug therapies and what ultimately will change the face of disease management. The "one-size-fits-all" approach to medication will become obsolete, according to federal supporters of the Human Genome Project, as drugs become tailored to specific populations and people.

The STRENGTH study of cholesterol

Dr. Gualberto Ruano, founder and chief executive officer of Genaissance Pharmaceuticals, predicated doctors will soon perform a blood test to analyze a patient's genetic markers and decide which drug therapies she or he will best respond to before prescribing them. Genaissance is already testing this theory out in its STRENGTH Study. The study, which stands for "Statin Response Examined by Genetic HAP Markers" involves more than 800 patients in 60 medical centers throughout the United States diagnosed with high cholesterol. Each patient is being treated with one of several lipid-lowering agents: Merck's Zocor (simvastatin) or Mevacor (lovastatin), Pfizer's Lipitor (atorvastatin) or Bristol-Myers Squibb's Pravachol (pravastatin). Genaissance researchers will later compare which cholesterol-lowering drug worked best in each patient with the fewest side effects and look for a genetic correlation.

"Preliminary results indicate that most statins work well, but high density lipoprotein levels ["good" cholesterol] are unpredictable," Dr. Ruano said. "But we have found that statin response correlates with a specific haplotype [genetic bar code] marker. In fact, effectiveness in patients with the marker have a 22 percent greater response to statins."

Ruano said discovering that a statin works better in a subset of patients like this can be taken directly to market. "Our application of discoveries from the human genome," he said, "may have broad implications in terms of improving public health and the ability of pharmaceutical companies to differentiate their products."

Product distinction is expected to become increasingly important in drug classes such as statins, where more than one drug fights for best-in-class status and a coveted place on insurance formularies. Genaissance already has research agreements with Pfizer and AstraZeneca to harvest selected data from the company's Genaissance HAP marker database. In addition to the statin HAPs, Genaissance has already discovered more than 80,000 haplotypes from nearly 5,000 genes.

Ruano said interest from major pharmaceutical companies in pharmacogenomic research like his will change the face of pharmaceuticals. "This is an indication that major pharmaceutical companies are moving to adopt haplotype technology to help accelerate the development of new medicines," he said.

"Pharmaceutical companies traditionally have initiated corporate relationships, but now an evolution is taking place," said Bob Esposito, national industry director of biotech and life sciences at KPMG. "Biotechs are becoming stronger and stronger, so they're not as dependent on pharmaceutical companies being their saviors. At the same time, pharmaceutical companies are knocking on their doors."

Pharmaceutical companies are knocking on the door of biotechs because their pipelines depend on it.

"Everyone is grasping for the holy grail, if you will," Esposito said. "What all these companies are looking for is the product that can give them top-line revenue, and generally about 50 percent to 80 percent profit margins. But product pipelines are slim, and the pipeline for blockbuster drugs is even slimmer." Hence, Esposito said, biotech companies that are used to surviving on a day-to-day, "succeed or fail" basis have an advantage over Big Pharma companies that have to justify every decision by the potential for profit.

But the public sector also is very interested in the success of genomic research. The U.S. National Institute of General Medical Sciences, a component of the National Institutes of Health, has established a Pharmacogenetics Research Network to study how genes affect people's responses to antidepressants, asthma drugs and chemotherapy treatments. The government is hoping the public will voluntarily contribute genetic samples to an anonymous information library called "PharmGKB," where scientists can study the links between gene variation and drug response.

The federal government is enthusiastic about genomics for several reasons, including the discovery of more powerful and better-targeted medicines, safer drugs, more accurate methods of determining appropriate drug dosages, advanced screening for disease, better vaccines, expedited drug approvals and the potential to decrease the overall cost of health care. This last point is of particular importance to the federal government and other major health care payors.