| Experimental
HIV Maturation Inhibitor Bevirimat Demonstrates Good Antiviral Activity and Favorable
Safety Profile By
Liz Highleyman Different
classes of antiretroviral drugs
attack HIV at different stages of its lifecycle. The currently approved classes
target HIV entry into cells (fusion and CCR5 inhibitors), integration of the viral
genome (integrase inhibitors), copying of viral genetic material from RNA to DNA
(reverse transcriptase inhibitors), and processing of viral proteins (protease
inhibitors). The
investigational drug bevirimat
(formerly PA-457) is a maturation inhibitor that interferes with the assembly
and budding of functional new viral particles that can infect additional CD4 cells.
Specifically, it targets the HIV Gag capsid SP-1 cleavage site. Phase 2 bevirimat
data were presented last week at the 48th International
Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008) in Washington,
DC A prior 10-day
study showed that 200 mg once-daily bevirimat monotherapy produced a 1 log reduction
in HIV viral load. A separate retrospective analysis showed that patients without
key baseline Gag polymorphisms (mutations) at positions Q369, V370, or T371 were
more likely to respond to bevirimat. Database screening indicated that about one-third
of treatment-experienced HIV patients in North American and European carry at
least 1 of the Gag polymorphisms associated with bevirimat resistance. In
the Phase 2 double-blind, randomized, dose-escalation study described at ICAAC
(Study 203), 59 treatment-experienced patients with at least 1 primary resistance
mutation received 14 days of bevirimat (n = 46) or placebo (n = 13) as functional
monotherapy added to a failing background regimen. All had a viral load > 2000
copies/mL at baseline. Participants
initially received a 400 mg bevirimat tablet or placebo. After it was determined
that the original tablet formulation had trouble delivering an adequate concentration
of the drug, the study was modified and patients received liquid bevirimat at
doses of 250, 300, 350, or 400 mg once-daily, or else placebo. In
a second stage of the study with an amended study design, 29 treatment-experienced
and treatment-naive patients were prospectively screened for the key Gag mutations
linked to bevirimat resistance, which were present in about half. All were treated
with a 300 mg dose of liquid bevirimat or placebo for 14 days. Most
study participants (95%) were men, the mean age was 47 years, the baseline viral
load was about 4.25 log10 copies/mL, and the baseline CD4 count was 319 cells/mm3
in the bevirimat arms and 393 cells/mm3 in the placebo arms. Results
•
In the initial stage of the study, log10
viral load reductions at week 2 were as follows:
•
Bevirimat 400 mg tablets: 0.36 log;
•
Bevirimat 250 mg liquid: 0.63 log;
•
Bevirimat 300 mg liquid: 1.02 log;
•
Bevirimat 350 mg liquid: 0.62 log;
•
Bevirimat 400 mg liquid: 44 log;
•
Placebo: 0.1 log.
•
The mean CD4 cell increase was 20 cells/mm3
in the combined bevirimat arms and 6 cells/mm3 in the placebo arm.
•
All patients who received at least 250
mg of liquid bevirimat achieved trough levels (lowest level between doses) greater
than 20 mcg/mL.
•
In the second stage, among patients treated
with 300 mg liquid bevirimat, average viral load reduction were as follows:
•
8 treatment-experienced patients with
the key Gag polymorphisms: 0.65 log;
•
10 treatment-experienced patients without
key mutations: 1.10 log;
•
9 treatment-naive patients: 1.04 log.
•
About 90% of patients with bevirimat trough
levels of at least 20 mcg/mL and without the key Gag mutations had viral load
reductions of at least 0.5 log, including about 75% with > 1.0 log reduction
(group mean 1.18 log).
•
Overall, 65% of patients receiving bevirimat
and 89% receiving placebo experienced at least 1 adverse event (AE).
•
For patients in the bevirimat and placebo
arms, respectively, the most common AEs were diarrhea (20% vs 38%), nausea (17%
vs 15%), and headache (9% vs 23%); all were rated as mild.
•
More patients taking bevirimat had elevated
glucose (8% vs 0%), but more in the placebo arm had elevated triglycerides (7%
vs 23%).
•
7% of patients taking bevirimat had abnormal
dreams and 3% experienced dizziness, compared with none in the placebo group.
These
findings led the study investigators to conclude, "Through 2 weeks bevirimat
and placebo were similarly well tolerated, and responder patients with bevirimat
troughs > 20 mcg/mL had a high magnitude viral load reduction." In
a related 14-day pharmacokinetics/pharmacodynamics study, researchers found that
bevirimat exhibited predictable and linear pharmacokinetics. They determined that
the maximum antiviral effect of was observed at doses < 400 mg/day.
Based on these
results Panacos Pharmaceuticals is planning Phase 3 clinical trials, most likely
using a new lower-dose tablet formulation that appears to have better bioavailability,
to confirm the utility of bevirimat in treatment-experienced HIV patients. In
addition, Panacos last week announced data from another trial (Study 204) in which
participants received 200 mg or 300 mg twice-daily bevirimat using a 50 mg tablet.
An excerpt from the company's recent press release is reprinted below: Panacos
Announces Preliminary Results
of Bevirimat Study 204 Results
confirm bevirimat tablet formulation dosed twice daily achieves target plasma
levels Watertown,
Mass. -- October 27, 2008 -- Panacos Pharmaceuticals, Inc. (NASDAQ: PANC) announced
today the bevirimat Study 204 achieved its primary objective by demonstrating
bevirimat plasma levels in HIV-positive patients to be in a target range for virologic
reduction. Bevirimat is a novel HIV-1 Gag maturation inhibitor in Phase 2b testing,
and the data from the successful completion of this study will be used to optimize
the bevirimat tablet dose for future Phase 2 as well as Phase 3 registration trials. After
14 days of bevirimat treatment given twice daily [BID] at doses of 200 mg or 300
mg (using the 50 mg tablet), 100% of 32 treatment-naive and treatment-experienced
patients in Study 204 had bevirimat plasma concentrations well above the previously
identified minimum target of 20 mcg/mL. In addition, bevirimat's safety profile
was comparable to earlier studies where it had been indistinguishable from placebo. Taken
in combination with the recent bioavailability data from Study 114, which utilized
the newly developed 100 mg tablets, these findings from Study 204 indicate that
upcoming Phase 2 and Phase 3 registration trials will utilize a convenient patient-friendly
bevirimat formulation that consistently attains plasma levels in a desirable range. "Study
204 was an important clinical milestone for Panacos and validated that twice daily
dosing with a tablet formulation is a viable option to bring our patients to plasma
levels well above the previously established target concentration required to
have a treatment response. In addition, the short-term safety profile remains
very encouraging and is similar to earlier studies, comparable to placebo. All
of the data generated to date consistently point to the value of bevirimat as
a useful component of antiviral drug regimens for people living with HIV,"
stated Alan W. Dunton, MD, President and Chief Executive of Panacos. "We
plan to initiate Study 205, our extended-duration trial of bevirimat in 100 mg
tablets, in the first half of 2009." Study
204 was a 14-day trial in 32 HIV patients (26 treatment-naive and 6 treatment-experienced)
conducted in Australia. Patients received bevirimat 50 mg tablet doses of either
200 mg or 300 mg given twice a day for 14 days. Patients were not screened for
inclusion based on the presence or absence of Gag polymorphisms, although this
data was collected. The primary endpoint of the study was pharmacokinetics (i.e.,
Cmin, the level of bevirimat measured at Day 14 in blood plasma). Viral load also
was measured. Patients who wished to continue treatment after Day 14 and include
bevirimat in their optimized regimen were given that option, if they had achieved
a 0.5 log10 viral load reduction after 2 weeks of bevirimat monotherapy. As
noted, bevirimat was well-tolerated with the rate and type of adverse events similar
to earlier studies. There were no serious adverse events and no adverse event-related
discontinuations. Bevirimat
was well absorbed; all 32 patients exceeded the minimum target plasma concentration
of 20 mcg/mL. Patients receiving 200 mg BID had a mean Cmin of 47 mcg/mL, and
patients receiving 300 mg BID had a mean Cmin of 74 mcg/mL. In
the 26 treatment-naive patients, the mean viral load reduction was -0.74 log10
copies/mL, with individual responses up to -2.05 log10 copies/mL. In the treatment-naive
patients who were free of Gag polymorphisms at positions 369, 370 or 371 (which
the company has determined to be the predictors of response to bevirimat), the
mean viral load reduction was -0.93 log10 copies/mL. In the treatment-naive patients
with Gag polymorphisms at one or more of these three positions, the mean viral
load reduction was -0.60 log10 copies/mL. These results continue to support the
use of Gag polymorphisms to determine response to bevirimat, and the company plans
to refine this genotyping approach further. In
the six treatment-experienced patients, the virologic data are not being included
in the overall analysis because they stopped their prior treatment regimen just
three days before beginning bevirimat monotherapy treatment, which resulted in
highly variable viral load dynamics. Their data are being used for safety and
pharmacokinetic analysis. Based
on a review of three independent North American and European patient data sets
comprising 1,034 HIV-positive patients, 62% of patients are free of baseline Gag
polymorphisms at codons 369, 370 or 371. While only 14 of the 32 patients in Study
204 from four clinics in Sydney, Australia, were free of these same polymorphisms,
this does not significantly impact the growing database being used to assess the
prevalence of Gag polymorphisms worldwide. 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 15 clinical studies with bevirimat in nearly 650 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 studies.
The company previously determined the optimal dose range of bevirimat and identified
patient response predictors to bevirimat, which now have been confirmed in multiple
laboratory analyses and the prospective study. Panacos has recently developed
a tablet formulation of bevirimat that demonstrates bioavailability and pharmacokinetics
comparable to that of the previous solution formulation (Study 114). The company
completed its Phase 2b study of bevirimat (Study 204) that confirmed an optimal
dose can be achieved with a twice daily dose of bevirimat tablets. Efficacy and
additional safety obtained from Study 204 support the 100 mg bevirimat tablet
formulation should be studied further in HIV patients. In
addition to bevirimat, the Company has a second-generation program in HIV maturation
inhibition that includes compounds with activity against HIV containing Gag polymorphisms.
Panacos has also selected a lead compound, PA-161, for preclinical development
in its oral HIV fusion inhibitor program. For
more information, visit www.panacos.com |
11/04/08 References J
Lalezari; S McCallister, M Gigliotti, and others. A Phase 2 Safety and Efficacy
Study of Bevirimat (BVM) in Heavily Treatment Experienced HIV+ Patients Identifies
the Target Phase 3 Study Profile. 48th International Conference on Antimicrobial
Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract
H-891. DE Martin,
l Wang-Smith, EP Acosta, and others. Pharmacokinetics/ Pharmacodynamics of Bevirimat
(BVM) in a 14-Day Functional Monotherapy Trial in HIV-Infected Patients. Abstract
A-954. Other
source
Panacos Pharmaceuticals. Panacos Announces Preliminary Results of
Bevirimat Study 204. Press release. October 27, 2008. |
