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Some people are infected by HIV strains that are already resistant to FDA-approved drugs because they were transmitted by someone who developed resistance while receiving antiretroviral therapy. As a result, these patients often fail therapy.
Despite best efforts to bring breakthrough HIV/AIDS therapies and drug cocktails to market, the industry has yet to overcome patients' resistance to them. Of the 334,000 patients in the United States who are projected to receive Highly Active Antiretroviral Therapy (HAART) in 2006, 60 percent (204,000) will develop resistance to at least one drug in this triple-drug therapy, according to the consulting firm Easton Associates.
While researchers continue to hunt for new AIDS drugs, Graham Allaway, chief operating officer of Panacos Pharmaceuticals, is focusing on developing a treatment for patients failing therapy due to resistance.
In partnership with the University of North Carolina and the National Institutes of Health, Allaway is spearheading Panacos' efforts to develop PA-457, a compound that made news last summer when a 10-day clinical trial found that it reduced the amount of HIV in the blood by 90 percent.
PA-457 represents a new therapy that works by inhibiting the virus maturation process. So, after treatment, the virus released from HIV-infected cells becomes non-infectious. PA-457 is also unique because it has activity against HIV strains that are resistant to current therapies, and functions as a once-daily oral drug.
Like others working in HIV/AIDS drug research and development, Allaway says a vaccine would be the penultimate breakthrough in the HIV space—but may still be some 20 years away. Until one is discovered, Allaway will continue to chip away at developing effective treatments. In addition to PA-457, Allaway has played an integral role in the discovery of the HIV entry inhibitor PRO-542 and the HIV fusion receptor CCR5.
Pharm Exec: How did you become involved with HIV research?
Allaway: I did my postdoctoral work in virology. But I became really involved in HIV when I joined Progenics Pharmaceuticals in 1990. I find all viruses interesting, but I was drawn to HIV because it poses such huge medical issues around the world. In addition, HIV has a number of interesting characteristics that are specific to it, making it so difficult to develop vaccines and drugs that have long-term efficacy.
What's the problem with currently available treatments?
There are three major classes of FDA-approved HIV drugs: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). These drugs have provided huge benefits for HIV-infected patients since they were introduced in the '90s. Before then, the disease rapidly progressed to AIDS.
Unfortunately, people who are treated with a combination of these drugs over time almost always develop resistance to one or more of them. Drugs within each class typically suffer from cross-resistance, so when the virus becomes resistant to one protease inhibitor, it will often become resistant to others in the same class. Some people are actually infected by strains that are resistant to FDA-approved drugs because they were transmitted from someone who developed resistance while receiving antiretrovirals. As a result, these patients fail therapy.
How does drug resistance actually happen?
Many viruses can develop resistance. But drug resistance can be particularly problematic with HIV, because the virus mutates so rapidly. The rapid mutation rate results in the appearance of many different strains of the virus, some of which may have differences in the sequence of their protease or reverse transcriptase enzymes, making them less susceptible to drugs that bind to those enzymes.
What are the benefits of PA-457?
We recently completed a Phase IIa study, where we treated HIV-infected patients once a day for 10 days. We saw a very dramatic reduction in virus levels, though we need to test it in longer-term studies to make sure that toxicities don't appear on longer-term dosing. In addition, our data indicate that PA-457 would not be subject to metabolic interactions with currently approved HIV drugs, reducing the chance of drug-drug interactions when used in combination therapy. We plan to file an NDA in 2008 and then market the drug in 2008 or 2009. We will move into pivotal Phase III clinical trials in 2007.
How has fast-track status changed the drug's development process?
By granting it fast-track status, FDA recognizes the value of PA-457 to treat drug resistance. With a fast-tracked drug, FDA provides more input for development, including greater access to its expertise and resources on a regular basis. We are working collaboratively with FDA to design the best clinical trial plan to bring the drug to market, keeping safety at the forefront. That status also makes us eligible for faster ways of getting the drug approved. It can enable priority FDA review and accelerated approval mechanisms so that when we file an NDA, we can speed the approval process and start marketing PA-457 sooner.
What are the future development plans for the drug?
We're also developing the drug potentially as a first-line therapy for patients. PA-457 could be very beneficial for the so-called "salvage treatment" patients who have failed most other treatments and are looking for new options. This therapy could extend their lifespan and control their disease.
Panacos is testing PA-457 for long-term safety. What's the current tolerance for adverse events of HIV therapy?
Safety is critical. But for those who are suffering from a life-threatening disease, there may be a tradeoff. A drug's ability to delay the disease and extend a patient's life can be very powerful. Sometimes, patients will accept some toxicities if the drug holds a lot of promise. In fact, there are a number of drugs on the market approved for HIV infection that have significant toxicities. This is a real problem for HIV-infected patients, as these drugs can have major side effects. Yet, some patients will accept the repercussions because the drug can help their disease state.
The goal of new HIV drug development is to identify drugs that not only have efficacy against resistant strains, but also have a better safety profile than the currently approved drugs.
What does the future of the HIV drug pipeline look like? Can we expect to see more innovations?
Absolutely. Over the last several years, there have been major breakthroughs in our understanding of how the virus replicates. As more detailed mechanisms are understood at the biochemical and cellular level, we can glean more potential new targets for drug intervention.
At the same time, it's very difficult to go from a potential target to a drug. As time goes on, there will be new drugs targeting new points in the lifecycle and providing new treatment regimens.
However, the real breakthrough would be a vaccine. Despite a huge effort in this area, we aren't close to developing one. The virus mutates so rapidly and we still don't really understand what kind of vaccine needs to be developed. A vaccine could potentially have a huge worldwide impact, especially since so many people living with HIV can't afford the ongoing treatment required of the disease. A vaccine, however, could likely provide protective immunity at a lower cost.
Graham Allawayis COO of Panacos Pharmaceuticals, which recently merged with Vitex Technologies. Prior to the merger, Allaway was co-founder of Panacos, which grew out of a former Nasdaq company, Boston Biomedica. There, Allaway served as vice president for drug discovery. He has also worked at Manchester Biotech in the UK, where he was CEO, and at Progenics Pharmaceuticals, where he led drug discovery.