Drug KP-1461 Steps Up HIV Mutation Rate
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.
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).
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."
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
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.
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.
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.
results validate the proposed mechanism of action in humans
and should spur development of this novel antiretroviral approach,"
the study authors concluded.
is an edited excerpt from a press release issued by Koronis
describing the study and its findings.
Trial Results Demonstrate Promise for First Non-suppressive
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
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
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.
affiliations: Departments of Microbiology, Medicine, Pathology,
and Biostatistics, University of Washington, School of Medicine,
Seattle, WA; Koronis Pharmaceuticals, Redmond, WA; Departments
of Chemistry and Biological Engineering, Massachusetts Institute
of Technology, Cambridge, MA.
Mullins, L Heath, JP Hughes, and others. Mutation of HIV-1
Genomes in a Clinical Population Treated with the Mutagenic
Nucleoside KP1461. PLoS ONE 6(1): e15135 (Abstract).
January 14, 2011 (Epub).
Pharmaceuticals. Clinical Trial Results Demonstrate Promise
for First Non-suppressive HIV Drug. Press release. January