While many approved and late-stage HIV treatments work by blocking viral replication, a drug in development by Koronis Pharmaceuticals Inc. aims at using the virus' rapid replication against itself.

The company recently entered Phase Ib testing with its lead compound, KP-1461, an oral prodrug of a nucleoside analogue designed to attack HIV from the inside by speeding up mutations that lead to the virus' death. It is the first compound to emerge from Koronis' Selective Viral Mutagenesis platform, which was developed by Larry Loeb and Jim Mullins from the University of Washington, and John Essigmann from the Massachusetts Institute of Technology.

Founded on that platform technology in 1999, the company has spent the past five years developing lead compounds that "target viruses with small genomes that mutate rather quickly," said Don Elmer, chairman of Koronis, adding that "HIV has always been on top of that list."

The biggest challenge in treating HIV has been the virus' eventual resistance to existing therapies, due mostly to its constant mutation. But, in studying the disease, researchers learned that 99.9 percent of the virus isolated from an HIV patient has mutated to the point where it no longer replicates, becoming a dead virus, said John Reno, chief operating officer.

"It was the insight of the inventors of our platform technology that this high mutation rate means the virus probably lives very close to what we call an error threshold," Reno told BioWorld Today. "If we can increase that mutation rate even a fraction of a percent, we might actually push the virus over the edge, and collapse the entire population."

To transform that theory into therapy, Koronis began by identifying nucleoside analogues that can be metabolized by an infected cell. In lab studies, KP-1461 demonstrated its ability to fool the virus into thinking it's a natural nucleoside and incorporating it into a replicating viral genome.

"Our drug sneaks into the viral genome," Reno said, "and, from the inside, it actually rots the virus by causing mutations, until the virus eventually has had enough mutation and is no longer functional."

One of the compound's strengths is its ability to bind to different analogues to provoke mutations. Reno said he sometimes refers to KP-1461 as a "Janus compound" because "if you look at it one way, it'll base pair with one pair, and if you look at it a different way, it'll base pair with a different base."

Other HIV drugs, such as Morrisville, N.C.-based Trimeris Inc.'s Fuzeon or Gilead Sciences Inc.'s Viread and Emtriva, work by inhibiting or blocking viral proteins or functions in the virus. Fuzeon is a viral entry inhibitor partnered with Basel, Switzerland-based F. Hoffmann-La Roche Ltd. Viread and Emtriva are nucleoside reverse transcriptase inhibitor drugs. Those products are aimed at slowing or stopping viral entry, binding or replication.

But KP-1461 is "actually dependent on the virus utilizing the drug," Reno said, "and the virus has to be replicating."

Koronis previously completed a Phase Ia trial of KP-1461 in non-infected volunteers before initiating testing in people with HIV. The multicenter, dose-escalating Phase Ib study is expected to enroll about 40 patients who have failed antiretroviral regimens. The subjects will be randomized into cohorts of 10 to receive KP-1461 or placebo over a two-week period. Primary endpoints of the study are safety, tolerability and pharmacokinetics. Results of the trial are expected early next year.

Although Koronis expects the trial to show some signs of efficacy, Reno said two weeks likely isn't enough time to observe significant effects from the increased mutations.

"Normally, if you're testing an HIV drug such as AZT, you'll see a dramatic reduction in viral load over a short period of time," he said. "Of course, as the virus mutates, the drug eventually becomes less effective."

Koronis' drug is designed "to build up mutations and viral replications," Reno added, "which can take four to six weeks before you start seeing results. But, with our drug, we do not expect to see the virus make a comeback."

After completing the Phase Ib trial, the company expects to begin a Phase II study that likely would take a year to complete. As of now, the company anticipates partnering the product but plans to wait until it is closer to Phase II before making any decisions.

Since inception, Koronis has raised about $14.5 million, and Elmer said an additional $9 million is needed to get KP-1461 through Phase II trials.

In addition to its HIV program, the company is using its platform to develop a therapy for hepatitis C virus, and also might investigate treatments for respiratory syncytial virus, as well as viruses such as the one that causes severe acute respiratory syndrome.