Viral
Genetic Variations Predict Response to HIV Maturation Inhibitor Bevirimat  To
date, studies of the investigational HIV maturation inhibitor bevirimat
(formerly known as PA-457) have produced mixed results. Maturation inhibitors
work by preventing HIV particles from properly assembling and budding out of infected
cells to form functional new viral particles that can infect additional cells.
Last
week, Panacos Pharmaceuticals announced completion of a Phase 2b study of bevirimat
that provided information about viral factors that predict good response to the
drug. Specifically, individuals whose HIV has specific genetic patterns in its
Gag protein achieved greater reductions in viral load over the course of the 2
week study. Data
were presented at the recent 17th International HIV Drug Resistance Workshop in
Sitges, Spain. The results will be used to determine inclusion criteria for a
planned Phase 3 trial of bevirimat. Below
is an edited excerpt of a Panacos press release announcing the findings: Panacos
Announces Results of Bevirimat Prospective Study, which Confirm Patient Response
Predictors  WATERTOWN,
Mass. -- June 17, 2008 -- Panacos Pharmaceuticals, Inc. (NASDAQ: PANC) today announced
the completion of a Phase 2b prospective study of bevirimat in treatment-experienced
and treatment-naive patients that confirms the recently discovered factors that
predict response to bevirimat, its lead HIV maturation inhibitor. With 14 days
of bevirimat treatment, patients with the predictors of response had a statistically
significant higher mean viral load reduction than patients with polymorphisms
(variants) at Gag amino acid positions 369, 370 or 371.
Treatment-experienced
patients who had the predictors of response had a mean viral load reduction of
-1.10 log10 copies/mL with individual responses up to -2.03 log10 copies/mL. In
contrast, treatment-experienced patients whose virus had the polymorphisms (variants)
at Gag amino acid positions 369, 370 or 371 had a mean viral load reduction of
-0.65 log10 copies/mL. In the group of treatment-naive patients, which was not
subdivided by patients with the response predictors and those without the predictors,
the mean viral load reduction overall was -1.04 log10 copies/mL. For those treatment-naive
patients with the response predictors, the mean viral load reduction was -1.16
log10 copies/mL.
All patients achieved the target blood level required
for optimal response with the 300 mg bevirimat dose administered. Clinically,
bevirimat's adverse event profile in the prospective study was unchanged from
earlier studies, where it was indistinguishable from placebo.
"In
a very short period of time, we have discovered and prospectively confirmed the
patient response predictors of bevirimat," said Dr. Alan W. Dunton, Panacos'
President and CEO. "We can target the specific patients who will respond
well to bevirimat in advance of treatment with a simple and rapid genotype assay,
the type of HIV resistance test most frequently ordered by HIV-treating clinicians.
In the population with the response predictors, we have seen a significant response
to bevirimat treatment. Bevirimat's safety profile and predictable potent response
also suggest its potential utility in earlier treatment lines. I am pleased with
the significant progress our team has made since our March
2008 announcement of the retrospective observation of response predictors
to bevirimat."
The predictors of response to bevirimat are located
at three codon positions on the 500-amino acid HIV-1 Gag protein. Bevirimat specifically
blocks a late step in processing of Gag, leading to the production of virus particles
that are structurally defective and are incapable of spreading infection around
the body. Patients who have virus with the most commonly occurring amino acids
at positions 369, 370 or 371 on Gag (i.e., who lack polymorphisms at these positions)
are much more likely to respond to bevirimat treatment. In contrast, those patients
whose virus has polymorphisms (variants) at these positions are less likely to
respond to the drug.
The prospective study, an extension of Study 203,
was a 14-day trial in 27 treatment-experienced and treatment-naive patients and
was conducted at multiple sites in the U.S. One dose was tested in all participants:
300 mg of bevirimat liquid given once a day. Patients were screened at baseline
for any Gag polymorphism at positions 369, 370 or 371 and divided into 3 cohorts
-- 9 treatment-naive patients, 10 treatment-experienced patients without polymorphisms,
and 8 treatment-experienced patients with polymorphisms. All treatment-related
adverse events observed were of mild intensity. The primary endpoint was viral
load reduction at day 15.
Table:
Prospective Study Week 2 Viral Load Reduction (VLR) data | Patients
with Response Predictors (No Polymorphisms at Gag codons 369, 370, or 371) | Patients
without Response Predictors (Any Polymorphism at Gag codons 369, 370, or 371 | | N | 18 | 9 | | Mean
Viral Load Reduction (log copies/mL) | -1.13 | -0.59
P<0.04 |
The
frequency of Gag polymorphisms is variable, depending on the population tested.
In one survey of an academic patient database in North America, no polymorphisms
at Gag positions 369, 370, or 371 were observed in 60.2% of 567 treatment-naive
patients nor in 59.7% of 114 treatment-experienced patients. A 2007 publication
from multiple HIV clinics in France demonstrated approximately 68.3% of samples
from 82 protease inhibitor-experienced patients were free of these same Gag polymorphisms
(Malet, et al, AIDS 2007: 21(7): 871-873). Pending regulatory concurrence, [Panacos]
believes that patients without these Gag polymorphisms should be ideal candidates
for a Phase 3 bevirimat clinical study, as they would be expected to have an optimal
treatment response.
Panacos' Development Programs
Panacos'
lead compound, bevirimat (PA-457), is the first in the new class of HIV drugs
under development called maturation inhibitors, discovered by company scientists
and their academic collaborators. Bevirimat is designed to have potent activity
against a broad range of HIV strains, and studies have shown bevirimat is a potent
inhibitor of HIV isolates that are resistant to currently approved drugs. Panacos
has completed 12 clinical studies with bevirimat in over 500 patients and healthy
volunteers, showing significant reductions in viral load in HIV-infected patients
and a promising safety profile. It is currently in Phase 2b clinical trials. The
company has completed a Phase 2b dose escalation study of bevirimat (Study 203)
and determined the optimal dose range. The retrospective clinical data from Study
203 resulted in the discovery of the patient response predictors to bevirimat,
which now has been confirmed in multiple laboratory analyses and the prospective
study.
In addition to bevirimat, the company has a second-generation program
in HIV maturation inhibition and has selected a lead compound for preclinical
development in its oral HIV fusion inhibitor program. The new understanding of
the role of Gag polymorphisms in maturation inhibitor activity is unique to Panacos
and the company is building a strong intellectual property position around its
important discovery.
For more information about Panacos, visit www.panacos.com. |
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