Merck Integrase/Pfizer CCR5 & New HIV Drugs Spark Care Revolution
Merck, Pfizer HIV Drugs May Spark a Second Revolution in Care
By John Lauerman and Allan Dodds Frank
Feb. 15 (Bloomberg) -- To look at him, you wouldn't know Mark McClelland is dying.
McClelland, a ramrod-straight 6-foot-4 (1.9 meters), easily strides up the San Francisco hill to his house and tussles playfully with his golden retriever. While McClelland has a form of HIV that's overcome all seven drugs he now takes, he can smile because hope is on the horizon.
Pfizer Inc., Merck & Co. and others are in the final stages of developing drugs that offer unique ways to bar HIV from infecting human cells. For the 65,000 people in the U.S. whose virus, like McClelland's, is resistant to three or more drug types, the new therapies promise to spur the first revolution in care in a decade. The debut of combination therapy in 1996 doubled life expectancy for patients. This latest generation of treatments offers new options to hold off the opportunistic infections that occur when HIV leads to deadly AIDS.
``I've been a guinea pig for a long time, and it doesn't bother me,'' says McClelland, 45, who was told in 1995 that the single drug he was taking was failing. Then, he was saved by the new drug cocktails. Now, he says, `I'm just happy, happy that there may be two powerful drugs out there that I can take at the same time. It's very exciting.''
The new therapies -- including Pfizer's experimental maraviroc and Merck's MK-0518, both now in late-stage testing -- blunt HIV's ability to evade drugs through rapid, constant mutation. They hit the virus with previously unseen weapons that may give drugmakers six or more years in which to develop even more powerful weapons, infectious disease doctors say.
`Generations of Therapy'
``These drugs will provide additional generations of therapy and give us time to find more new drugs and potential targets,'' said Daniel Kuritzkes, a Harvard University researcher who treats HIV patients at Brigham and Women's Hospital in Boston. ``It is really a major advance.''
The new treatments can also be vital in helping keep the disease under control as U.S. officials this month begin a push to make HIV testing routine in emergency rooms, clinics and doctor's offices, potentially adding as many as 100,000 newly diagnosed patients. Almost one in five of those patients might be infected with strains able to beat at least one of the major types of drugs that currently keep AIDS at bay, experts say.
HIV attacks the immune system, leaving the body vulnerable to the infections and tumors that make AIDS, or acquired immune deficiency syndrome, lethal.
Pfizer, based in New York, learned this week that maraviroc will receive accelerated review and, along with Merck's MK-0518, may be cleared for U.S. sale this year. The two drugs will enter an estimated $5.9 billion market, according to Wolters Kluwer Health, which gathers data on the industry.
Once approved, maraviroc may generate $145 million in 2008, and Merck's new drug may raise about $50 million, said Barbara Ryan, a Deutsche Bank analyst. The therapies may cost users about $5,000 a year each, she said, based on prices of current drugs.
HIV has proven to be a formidable opponent for drug designers. The virus's attack begins when it attaches itself to a cell surface molecule, called a receptor, and uses one of its proteins to force its way into the cell.
Once there, HIV makes an enzyme called reverse transcriptase to convert its genetic material into DNA that's integrated into the human cell, tricking it into making new viral proteins. Those proteins are then chopped up by an enzyme called protease into chunks that bud out of the original cell and invade others.
In 1996, researchers combined use of the three existing families of drugs as a way to limit the virus's ability to overcome any one roadblock. As a result, the life expectancy of diagnosed patients jumped to about 24 years from less than 10 years over a period of just a few years, according to studies.
``One of the most remarkable things I've ever experienced was in 1996 when desperately ill patients got better overnight,'' says Steven Deeks, a University of California San Francisco AIDS specialist at San Francisco General Hospital, who helps treat McClelland. ``With these drugs, we could see that happen again in 2007,'' he says.
Doctors now estimate that as many as 65,000 U.S. HIV patients are resistant to all three major medication classes and in worsening health. Like McClelland, many of these so-called salvage patients, as they're sometimes called, began getting treatment more than 10 years ago, before combination therapy became common, Harvard's Kuritzkes said.
``They became resistant because their virus wasn't fully suppressed to begin with; their regimens weren't sufficiently potent,'' he said. ``Others are failing therapy because they just aren't taking their drugs regularly.''
Years to Overcome
What the new drugs offer is a chance to attack the virus in ways that may take HIV years to overcome through mutation.
Pfizer's maraviroc is the first drug to block a receptor called CCR5, or chemokine receptor 5, one of two cellular entry points used by HIV strains. Since Pfizer plans to test patients to identify those whose CCR5 receptors are active, the drug is the first form of personalized medicine for the disease, said Kate Robins, a Pfizer spokeswoman.
Merck, the Whitehouse Station, New Jersey-based maker of Crixivan for HIV, used a different strategy with MK-0518, preventing the virus from integrating its genes to human cellular DNA.
Early-stage trials have already suggested that MK-0518, as part of a three-drug regime, is at least as effective as Bristol- Myers Squibb Co.'s Sustiva, a therapy on the market today that works by interrupting HIV's ability to make the reverse transcriptase enzyme.
In developing MK-0518, Merck sifted through several hundred thousand potential drugs during a 10-year search for one with the potential to safely inhibit the DNA-knitting enzyme called integrase, said Daria Hazuda, a Merck researcher. The company scrapped two other drugs of the same type in 2005 because they caused liver damage in dogs.
Earlier studies showed ``outstanding activity'' by the drug in dealing with triple-class resistance, Hazuda said. Now Merck is scheduled to present new findings on MK-0158 at the 14th annual Conference on Retroviruses and Opportunistic Infections in Los Angeles Feb. 25-28, the biggest meeting of the year on new treatments for HIV and AIDS.
The latest trial will ``confirm the efficacy that we saw and presented'' earlier, Hazuda says.
Doctors are also anticipating positive results, says John Bartlett, director of a Johns Hopkins University HIV clinic in Baltimore. ``The drug is unprecedented in its ability to control the virus, and appears to have no obvious toxicity,'' he said.
Still, as long as patients skip doses, HIV will find ways to evade drugs, said Chris Petropoulos, chief scientific officer for San Francisco-based Monogram Biosciences Inc., which is working with Pfizer to develop tests for the CCR5 receptor.
``None of the new drugs is going to be a solution,'' he said. ``Over the last 10 years, new drugs that have come into favor are usually replaced within just five or six years.''
Until there's a cure, and there is none on the horizon, a steady supply of new drugs, such as maraviroc and MK-0518, will be needed because of the virus's extraordinary ability to mutate, said Anthony Fauci, director of the Bethesda, Maryland-based National Institute of Allergy and Infectious Diseases.
``Even under the best of circumstances, there will always be a gradual emergence of resistance,'' Fauci said. ``You're going to need a pipeline.''
Several companies have products on the horizon that may fulfill that need.
Panacos Pharmaceuticals Inc., based in Watertown, Massachusetts, plans this year to begin the final phase of human testing needed for market clearance on its experimental drug, beviramat. The drug is the only one in development to stop the virus in taking the final step it needs to become infectious, called ``maturation,'' according to Chief Operating Officer Graham Allaway.
``They can't spread the infection to new cells, and actually, they're cleared from the bloodstream,'' he says.
The maker of the top-selling Truvada HIV drug, Foster City, California-based Gilead Sciences Inc., is also developing an integrase inhibitor like Merck's. And Johnson & Johnson's Tibotec Pharmaceuticals unit, based in Belgium, is testing a similar drug to Sustiva that's been shown in early studies to be active against resistant strains.
Two U.S. government agencies, the Bethesda, Maryland-based National Institutes of Health and the Atlanta-based Centers for Disease Control and Prevention, may also present data at the Los Angeles meeting from new programs to study HIV resistance. The U.S. Centers for Disease Control and Prevention estimates that about two-thirds of 1.1 million Americans with HIV get care.
Shape of Virus
HIV's resistance to drugs arises from its ability to quickly mutate. One mutation referred to by scientists as K103N, for instance, changes the shape of a ``pocket'' on the virus that some drugs were designed to hook into as they seek to disable the bug.
Before combination treatment became routine in 1996, patients quickly developed lasting resistance to single drugs. A national survey conducted by Doug Richman, of the University of San Diego, in 1996 through 1998 found that almost four of five U.S. HIV patients had resistance to at least one medication, if not more.
That rate has probably dropped since then, said Rhoda Schmuecking of Synovate Healthcare, a unit of London-based Aegis Group Plc that tracks resistance in HIV patients. Synovate estimates that fewer than half of all patients in treatment who were tested had resistance to one drug in 2006, she said.
Resisting a Class
While many mutations can interfere with the work of a single drug, some are more powerful. K103N allows viruses to resist not only Bristol's Sustiva, but the whole class of drugs related to it, including Pfizer's Rescriptor and Viramune, made by Ingelheim, Germany-based Boehringer Ingelheim GmbH.
Still, any interruption in dosing raises the risk that a new resistant strain will emerge, said Bartlett, of Johns Hopkins.
``You miss a high blood pressure medicine and take it again, your blood pressure comes right down,'' he said. ``You mess around like that with HIV drugs, once you get resistance, it's like a diamond, it's forever.''
With the arrival of the new drugs, patients like McClelland say they are hoping they'll gain the chance to kill off the resistant viruses that have crippled their immune systems.
He recently joined a study that will allow him to use Merck's MK-0518 along with an experimental drug that's in earlier development from Johnson & Johnson's Belgium-based Tibotec unit. His doctors will also test to see if the Pfizer's maraviroc would be effective on him.
Doctors keep track of a person's ability to overcome infection by measuring their T-cells, white blood cells that play a critical role in the body's disease-fighting immune system. An immune system that's operating normally may have T-cell levels of 600 to 1,500 per cubic millimeter of blood.
McClelland said the amount of T-cells in his body is below the level that can be detected. That means his immune system won't be able to fight off the infections and tumors of AIDS.
``I'm hoping to get to at least 100 T-cells'' as a result of the new drugs, he said. ``That could be realistic. I'm looking forward to getting them and having that come true.''