Isis Pharmaceuticals Inc. Carlsbad, Calif.

Drugs that operate at the genetic level are the ultimate promise of all the research directed at identification of the human genome. In August the Food and Drug Administration approved the first drug that blocks the action of a gene, in this case cytomegalovirus (CMV) retinis, a virus that can infect the human eye and can cause blindness. This success is a precursor for application of the same technology in human genes themselves. Developed and manufactured by Isis Pharmaceuticals, fomivirsen sodium intravitreal injectable will be marketed as Vitravene by the Ciba Vision Corp., the eye care division of Novartis AG Its specific indication is the treatment of CMV retinis, a viral infection of the eye in many AIDS patients and others whose immune system is depressed. Injected directly into the eye (locally numbed, painless), the drug works by interfering with the replication mechanism of the retina-destroying cytomegalovirus itself and its ability to manufacture disease-producing proteins. "The other drugs we have to treat CMV retinis all act at the level of proteins, after they have been produced," says Debra Goldstein, assistant professor of ophthalmology, University of Illinois, Chicago and a principal investigator of Vitravene. "So if the virus becomes resistant to one of the drugs, it may become resistant to all of the others. Vitravene acts by a completely different mechanism, at the genetic level, on messenger-RNA level, before proteins are produced. There is no reason for there to be cross resistance. In fact there is no (commercial) drug in the world today that acts at this level of messenger RNA. This is the first one." Fomivirsen is based on a technology called antisense, which holds great promise as a way to make potent drugs of very specific therapeutic action with few side effects. Bits of genetic material itself, antisense drugs bind to the portion of messenger RNA (the sense) that DNA sends out as the carrier of genetic code used to produce proteins. "Antisense drugs prevent the sense message from being used," says Stanley Crooke, Isis CEO. "With antisense we can design drugs based directly on genetic information, so from that standpoint, Vitravene is the first of the new genetic medicines." While proteins are the basic building block of the human body, those produced by virus, bacteria, or other human genes also can cause disease. Because the DNA/messenger RNA/protein production sequence is a constant in virtually all human reproduction mechanisms, including disease mechanisms, successful application of antisense technology to specific gene targets responsible for disease could revolutionize the drug industry. "The most important thing about Vitravene is not so much the product itself, but what it represents," says Crooke. "What makes antisense thrilling is the way the antisense drugs bind to the RNA, they are extraordinarily specific. They are really molecular lasers, as opposed to molecular sledgehammers. And since the process is universal, we can use the technology to make drugs for almost all diseases. We have products in the market that have already shown safety and efficacy, and have markets in the tens of billions of dollars." Drug candidates that act via the antisense mechanism in the Isis pipeline include an anti-inflammatory drug, three anti-cancer drugs, and early-stage others for multiple sclerosis, diabetes, and cardiovascular disease. Just as application of the science behind the antisense mechanism represents a breakthrough in medical technology, so does the manufacturing procedure for its first expression in fomivirsen. Built up one genetic "letter" at a time, then strung together like pearls in a necklace, the process begins with salmon sperm. "Fomivirsen is a brand new technology in every possible way," says Crooke. "Its a new chemistry. Salmon sperm is a great source for DNA, which we extract, break down to its component parts, and chemically modify to build up the genetic information we want back again."