Maturation Inhibitor
Bevirimat (PA-457) Demonstrates Good Anti-HIV Activity in Phase 2b Study
Panos
Pharmaceutical’s bevirimat
(formerly PA-457) is the sole HIV maturation inhibitor in the development
pipeline. On June 20, the company announced
promising results from a Phase 2b study of the drug.
Below is an excerpt from the
announcement:
Panacos Announces Substantial
Antiviral Response in Bevirimat 250 mg Cohort, Data Support Further Dose Escalation
in Phase 2b Study
WATERTOWN,
Mass. -- (BUSINESS WIRE) -- June 20, 2007 -- Panacos Pharmaceuticals, Inc. (NASDAQ:
PANC), a biotechnology company dedicated
to developing the next generation of antiviral therapeutic products, today announced
preliminary results from the 250 mg cohort of a Phase 2b study of bevirimat (PA-457)
in patients failing HIV therapy due to drug resistance.
Bevirimat
plasma concentrations and antiviral effect were approximately double those seen
in the first Phase 2b cohort that had used a suboptimal tablet formulation. No
safety or tolerability issues with bevirimat arose in this cohort, consistent
with previous clinical experience. The results of the 250 mg cohort support further
dose escalation as planned in order to fully explore the dose-response relationship
of bevirimat.
Following
dosing with 250 mg of bevirimat solution administered on top of patients' failing
background regimens, the mean trough plasma concentration of bevirimat at steady
state was 38.3 micrograms/ml compared
to 19.9 micrograms/ml at steady state in the 400 mg tablet cohort. These plasma
concentrations were also higher than the steady state concentration of 33.8 micrograms/ml
seen in the top dose of the earlier Phase 2a monotherapy study, and were in line
with expectations based on previous clinical studies of the oral solution formulation.
A
mean viral load reduction of 0.68 log10 was seen in bevirimat treated
patients on day 15, the primary endpoint of the study. This compared
to placebo patients who had a mean increase in viral load of 0.18 log10
and to bevirimat patients in the 400 mg tablet cohort, who had a mean reduction
in viral load of 0.36 log10. At the 250 mg dose, 71% of patients had
a confirmed viral load reduction of at least 0.50 log10 during the
course of the study. The antiviral effect in the 250 mg cohort was comparable to the 200 mg cohort in the Phase 2a study
at day 11, the primary endpoint of the Phase 2a study. The mean viral load reduction
in the 250 mg cohort in the current study of highly treatment-experienced patients
was 0.79 log10, compared to 0.90 log10 in the 200 mg cohort
in the Phase 2a study of mostly treatment-naive patients.
"We
were pleased to have these data supporting bevirimat's efficacy in patients failing
therapy due to resistance -- the initial target population for our first planned
NDA submission," said Alan W. Dunton, MD, Panacos' Chief Executive Officer.
"This confirms our belief that the lower than expected plasma concentrations
observed in the earlier 400 mg tablet cohort were caused by the prototype tablet
formulation, and not by bevirimat itself. In the 250 mg cohort, we saw potent
antiviral activity that was consistent with bevirimat plasma levels, which supports
going to higher doses to achieve greater responses. We anticipate completing
a 300 mg dose cohort in the third quarter, continuing to escalate towards the
peak of the dose-response curve thereafter."
About
the Phase 2b Bevirimat Study
The
objectives of the Phase 2b study of bevirimat are to examine the antiviral efficacy,
pharmacokinetics, and safety of bevirimat in combination
with other HIV drugs. The first cohort in this study, which used a tablet dose
of 400 mg, was completed in December
2006. The results of this cohort confirmed the antiviral activity of bevirimat
shown in previous studies and extended it to HIV patients failing therapy due
to antiretroviral resistance. However, the prototype tablet formulation used in
that cohort resulted in bevirimat plasma concentrations that were lower than anticipated.
A
revised Phase 2b trial design was announced in March 2007. The new design tests
the tolerability and efficacy of bevirimat in treatment-experienced patients failing
current therapy at increasing doses using the oral liquid formulation which was
utilized in the bevirimat Phase 2a trial. Phase 2b dose escalation with the liquid
formulation involves 14-day "functional monotherapy," where patients
are dosed with either placebo or bevirimat in combination
with their failing antiretroviral therapy. This design is similar to the first
Phase 2b cohort, except that patients do not continue on to extended dosing, which
was a feature of the tablet cohort. The primary endpoints of the trial are safety,
pharmacokinetics, and viral load reduction on day 15. Panacos plans to continue
escalating the dose in subsequent cohorts by 50 mg per cohort following a review
by the Company, FDA, and outside clinical experts of the safety and antiviral
response from each preceding cohort, releasing data from each cohort as analysis
is completed.
About
Panacos
Panacos
is developing the next generation of anti-infective products through discovery
and development of small molecule oral drugs for the treatment of HIV and other
major human viral diseases. HIV infects approximately 1.7 million people in North
America and Western Europe and approximately 40 million people worldwide.
Approximately 650,000 patients are treated annually for HIV in the United States and Western
Europe. Resistance to currently available drugs is one of the most
pressing problems in HIV therapy and the leading cause of treatment failure. Panacos'
proprietary discovery technologies are designed to combat resistance by focusing on novel targets in the
virus life cycle, including virus maturation and virus fusion.
Panacos'
lead candidate, bevirimat (PA-457), is the first in a new class of oral HIV therapeutics
under development called maturation inhibitors, discovered by Panacos scientists
and their academic collaborators. Based on its novel mechanism of action, bevirimat
is designed to have potent activity against a broad range of HIV strains, including
those that are resistant to existing classes of drugs. The Company has completed
seven clinical studies of bevirimat in over 300 subjects, showing significant
reductions in viral load in HIV-infected subjects and a promising safety profile,
and is currently in Phase 2b clinical trials. The Company also has a second-generation
program in HIV maturation inhibition in clinical testing and a research program
to develop oral HIV fusion inhibitors.
Except
for the historical information contained herein, statements made herein, including
those relating to bevirimat's clinical development, the potential results of treatment
with bevirimat and future clinical trials and clinical practice are forward-looking
statements made pursuant to the safe harbor provisions of the Private Securities
Litigation Reform Act of 1995. These statements involve risks as set forth in
the Company's filings with the Securities and Exchange Commission, including,
but not limited to, the Company's Annual Report on Form 10-K for the fiscal year
ended December 31, 2006. These risks and uncertainties could cause actual results
to differ materially from any forward-looking statements made herein. The Company
undertakes no obligation to publicly update forward-looking statements, whether
because of new information, future events or otherwise, except as required by
applicable law.
Resistance
to Bevirimat
In related news, Panacos announced in late May that
HIV strains that have developed resistance to protease inhibitors appear to have
reduced potential to develop resistance to bevirimat.
Below is an excerpt from the announcement:
Preclinical Study Finds Protease Inhibitor-Resistant
HIV May Have Reduced Potential to Develop Resistance to Panacos' Bevirimat
WATERTOWN,
Mass. -- (BUSINESS WIRE) -- May 29, 2007 -- Panacos Pharmaceuticals, Inc. (NASDAQ:PANC),
a biotechnology company dedicated to developing the next generation of antiviral
therapeutic products, today announced the results of a new study indicating that
HIV resistant to Protease Inhibitors (PI) may have reduced potential for the development
of resistance to the HIV maturation inhibitor bevirimat in laboratory assays.
The study, carried out by scientists in Dr. Eric Freed's group at the HIV Drug
Resistance Program at the National Cancer Institute, Frederick, MD, in collaboration
with Panacos, was presented at the Cold Spring Harbor Laboratory's (CSHL) Retrovirus
Conference held May 22-27, 2007 in Cold Spring Harbor, NY.
While
resistance to bevirimat has not yet been reported in clinical studies, bevirimat-resistant
HIV can be generated in the laboratory, as is the case with other HIV drugs. In
previous studies where HIV was grown for several weeks in cell culture in the
presence of bevirimat at suboptimal concentrations, mutations conferring resistance
to bevirimat were found exclusively at or near bevirimat's target, the capsid-SP1
cleavage site in the HIV Gag protein. Cleavage of capsid from SP1, the final step
in viral maturation, is mediated by the viral protease enzyme. Bevirimat inhibits
this cleavage step by interacting with the capsid-SP1 junction in Gag, suggesting
that pre-existing PI resistance mutations may have an impact on the development
of bevirimat resistance.
In
the new study, wild-type HIV, as well as HIV bearing major mutations conferring
PI resistance, were grown in cell culture in the presence of bevirimat at suboptimal
concentrations. Bevirimat resistance developed after several weeks in both wild-type
and PI-resistant HIV, but took more than twice as long to develop in the PI-resistant
virus. The bevirimat resistance mutation that appeared in PI-resistant virus was
located at the CA-SP1 junction and has been observed previously in bevirimat resistance
generation studies. The CSHL conference presentation concluded that bevirimat
resistance may be less likely to arise in PI-resistant HIV strains.
Dr.
Graham P. Allaway, Panacos' President and Chief Operating Officer commented, "Clinical
studies to date suggest resistance to bevirimat does not develop rapidly, in contrast
to some currently marketed HIV drugs, possibly because there is selective pressure
to maintain the integrity of the capsid-SP1 cleavage site sequence, which is highly
conserved among HIV strains. While resistance tends to develop eventually to all
HIV inhibitors, the new study suggests there may be a greater hurdle to bevirimat
resistance development in patients with PI-resistant virus. These patients represent
one of the major groups who could potentially benefit from novel-mechanism HIV
drugs such as bevirimat."
06/22/07
Sources
Panacos
Pharmaceuticals. Panacos Announces Substantial Antiviral Response in Bevirimat
250 mg Cohort, Data Support Further Dose Escalation in Phase 2b Study. Press
release. May 29, 2007.
Panacos Pharmaceuticals. Preclinical Study Finds
Protease Inhibitor-Resistant HIV May Have Reduced Potential to Develop Resistance
to Panacos' Bevirimat. Press release. June 20, 2007.
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