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.