Experimental Drug KP-1461 Steps Up HIV Mutation Rate

	SUMMARY: The investigational nucleoside analog KP-1461 significantly increased the rate of HIV mutation in a Phase 2a clinical trial described in the January 14, 2011, online edition of the open-access journal PLoS ONE. If further studies demonstrate sustained viral load reduction, the drug could become the first antiretroviral agent that works by a mechanism other than suppression of viral replication.

All currently approved antiretroviral drugs work by inhibiting various steps of the HIV lifecycle, for example inhibiting copying of viral genetic material (reverse transcriptase inhibitors) or processing of newly produced viral proteins (protease inhibitors).

Although KP-1461 belongs to the nucleoside/nucleotide analog class, like many current HIV medications, it instead works by accelerating viral mutation so much that HIV is disabled -- a mechanism dubbed "lethal mutagenesis" or "error catastrophe."

KP-1461 has not taken a straightforward path through the drug development process. Preliminary studies indicated that the drug had potent activity against HIV, but repeated laboratory studies failed to reproduce this effect and trials were halted in 2008. Then, in 2009, developer Koronis Pharmaceuticals announced that a comprehensive review confirmed that the drug does show antiviral activity, both in the laboratory and in the body, and said it would proceed with clinical trials.

The recently published study looked at HIV-1 viral sequences from treatment-experienced participants in a Phase 2 clinical trial who received 1600 mg KP1461 twice-daily for 124 days. While plasma viral load did not decrease and overall levels of viral mutation did not increase during this short study, investigators noted that, "the mutation spectrum of HIV was altered." Furthermore, KP-1461 appeared to be safe and well-tolerated.

In the latest analysis, researchers evaluated HIV sequences from 10 treated and 10 untreated patients after 0, 56, and 124 days of KP-1461 or placebo. They found that the number of so-called "private mutations" -- those found in only 1 viral sequence and presumed to have occurred during the most recent rounds of replication -- increased significantly in individuals who received KP-1461 compared with untreated participants after 56 and 124 days. In addition, treated patients had more of certain specific types of mutations.

"These results validate the proposed mechanism of action in humans and should spur development of this novel antiretroviral approach," the study authors concluded.

Below is an edited excerpt from a press release issued by Koronis describing the study and its findings.

Clinical Trial Results Demonstrate Promise for First Non-suppressive HIV Drug

Seattle, WA -- January 19, 2011 -- Recently published Phase 2a clinical trial results (see PLoS One Journal article) show that the frequency of specific, drug-induced mutations in the HIV genome can be significantly increased by administering KP-1461, a drug being developed by Koronis Pharmaceuticals based on its novel Viral Decay Acceleration (VDA) drug mechanism. Koronis is planning a follow-on Phase 2 trial to determine the treatment duration required to achieve a clinically meaningful decrease in a patient's viral load.

"These clinical findings confirm that KP-1461 causes extra mutations to occur in the HIV genome in HIV-infected patients. We believe the accumulation of extra mutations will eventually cause a critical loss of fitness in a patient's HIV population. If clinical results from a longer trial confirm that loss of fitness can reduce a patient's viral load to a clinically meaningful degree, then we believe VDA will become a viable mechanism for an entirely new class of non-suppressive HIV therapeutics," said lead author James Mullins, PhD, Professor of Microbiology and Medicine at the University of Washington.

All approved HIV therapeutics employ suppressive drug mechanisms that inhibit viral enzymatic functions, or block the entry of the virus into uninfected cells. Currently, these suppressive drugs must be administered in a multi-drug cocktail to minimize emergence of drug-resistant HIV strains, and require lifelong administration to ensure continuous suppression of viral replication.

If durable reductions in patient viral populations can be demonstrated in future trials, VDA would become the first clinically-demonstrated non-suppressive drug mechanism against HIV. The possibility of using a non-suppressive drug mechanism such as VDA in HIV treatment would have significant implications for treatment paradigms and could lead to a much wider distribution of anti-HIV drugs throughout the world.

"These results indicate that KP-1461 can increase the frequency of mutations in HIV-1 populations. Importantly, it also appears to be generally safe and well tolerated based on results from the more than 80 patients who have received the drug. While larger studies are obviously needed, the conclusions from this paper certainly underscore the potential for positive clinical effects. This should encourage further development of the VDA mechanism as a new approach for the treatment of HIV-1 infection," said Charles Hicks, MD, Professor of Medicine at Duke University Medical Center, who is also Director of the Duke University Interdisciplinary Research Training Program in AIDS.

The recently published paper (accessible by clicking here) appears in the January 14, 2011 PLoS ONE Journal, an international, peer-reviewed publication produced by the Public Library of Science, and presents an analysis of HIV-1 gene sequences from heavily treatment-experienced HIV-infected volunteers treated with KP-1461 for a 4-month period.

About Koronis

Koronis Pharmaceuticals, Inc., is a privately held biotechnology company developing antiviral therapeutics based on a novel mechanism, Viral Decay Acceleration (VDA). The company's lead product candidate is KP-1461 for the treatment of human immunodeficiency virus (HIV). The company also has products in development for the treatment of hepatitis C and RSV. For more information, please visit www.koronispharma.com.