Wall Street Journal - July 9, 2004
Amir Efrati, Staff Reporter of The Wall Street Journal

In a study published today in Science, a Merck & Co. compound that blocks integrase was successful in rhesus monkeys infected with simian-human immunodeficiency virus (SHIV), reducing the level of the virus to one-hundredth or less of the level found in untreated monkeys. SHIV is a hybrid of the human and monkey versions of the retrovirus.

The result, while still early, could bring new hope for AIDS patients who have developed a resistance to existing drugs.

"It's been years since we've seen a new class of oral drugs to treat HIV and a new class would be very important for our patients," says Paul Volberding, president of the HIV Medicine Association, which is part of Infectious Diseases Society of America.

Merck says it has begun testing the integrase drug in humans in Phase I studies, which test safety and tolerability of the drug in healthy people.

The integrase enzyme splices a section of the viral DNA into a human white cell's long DNA strand. Once that happens, the human cell is tricked into copying the viral DNA, thus perpetuating the disease.

Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, a branch of the National Institutes of Health, says the monkey study "isn't reason for massive celebration," but "we're on the road to getting an integrase inhibitor." Any drug that might be developed from this approach -- and risks remain that it could fail -- probably wouldn't be approved for use until the end of the decade.

A record five million people world-wide were infected with HIV last year and three million died, according to the United Nations. The number of U.S. residents living with AIDS is roughly 900,000, according to latest figures from the Centers for Disease Control and Prevention.

The new integrase inhibitor would be used in combination with other oral drugs as part of the cocktail treatments given to HIV patients. It could be used on patients in any stage of the virus but would work best in stages where the immune system is relatively strong, says Steven D. Young, a Merck researcher and one of the authors of the monkey study.

Harold Varmus, one of the first scientists to research integrase in the 1980's and who is now president of Memorial Sloan-Kettering Cancer Center in New York, says the Merck study looks "very promising" and provides the "proof of principle" that the enzyme is a useful drug target.

Scientists discovered integrase, one of three enzymes that helps the AIDS virus multiply, in the late 1980's and studied it intensely as a potential target for drugs. Two other enzymes, protease and transcriptase, long ago gave up their secrets to drug researchers, and drugs that block them are the foundation for current AIDS treatments. Integrase inhibitor research, however, was filled with dead ends and failures mainly because the enzyme wasn't well understood.

There are three classes of oral compounds for HIV treatment that are combined into drug cocktails to target protease and transcriptase, says Daria J. Hazuda, a 15-year Merck researcher and lead author of the monkey study. Once the virus develops resistance, "it would be beneficial to have another regimen where you could introduce new compounds that the body has never seen before," she says.

A more recent class of AIDS treatment, called fusion inhibitors, is an injected drug. It isn't widely used -- it costs more than $20,000 a year. Merck, based in Whitehouse Station, N.J., says it doesn't know how much the integrase drug would cost. Merck is funding the research.

In addition to the fusion inhibitors, at least five pharmaceuticals companies are working on a drug that blocks the binding of the virus to a receptor called CCR5 on human cells. CCR5 helps usher HIV into cells of the human immune system. Pfizer Inc., and Schering-Plough Corp. are currently in Phase II trials.

A few years ago, Merck's Dr. Hazuda and her colleagues made a breakthrough in their integrase research by finding compounds known as "diketo acids" that inhibited integrase in test tubes. The compounds became the basis for designing a drug. The findings were published in a 2000 issue of Science, setting off a rush by pharmaceutical companies to find new drug candidates against the enzyme.

Bristol-Myers Squibb Co., GlaxoSmithKline PLC and Gilead Sciences Inc. are racing Merck to develop an inte grase-inhibitor drug. Today, Merck is furthest along. Results for one of its inhibitor compounds are due early next year.

The integrase enzyme's function is to carry and paste a section of the viral DNA into a human white cell's long DNA strand, which is analogous to adding letters into the middle of a long word when using a word processor. The human cell then copies the viral DNA. The inhibitor sticks to the integrase, preventing the virus from embedding itself in human DNA. This causes the enzyme to bend the viral DNA into a circle, which is then "chewed up" by the human cell, Merck's Dr. Young says.

One hurdle was that diketo acids were chemically unstable. Drs. Hazuda and Young experimented with thousands of synthesized compounds until 2002, when they found safer compounds that could be tested on monkeys.

"We needed to understand what it was about diketo acids that made them effective as inhibitors and design molecules that had better drug-like" characteristics, Dr. Young says.

GlaxoSmithKline, which last year terminated a previous clinical study of an integrase inhibitor in collaboration with the Japanese pharmaceutical, Shionogi & Co., is in pre-clinical stages on a new compound. Bristol-Myers Squibb and Gilead Sciences are still in exploratory development on its inhibitor.

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