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PA-457
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Overview
The Company's lead compound, bevirimat (PA-457), is the first in the new class of HIV drugs called Maturation Inhibitors that specifically block a late step in processing of the HIV Gag protein. Following bevirimat treatment, virus particles released from HIV-infected cells are non-infectious and virus replication is terminated. This antiviral target is unique to Panacos and the Company is building a strong intellectual property position around its ground-breaking discovery.
Studies have shown that bevirimat is a potent inhibitor of HIV isolates that are resistant to currently approved drugs. Furthermore, bevirimat exhibits potent antiviral activity in an animal model of HIV infection, the SCID mouse model. Following oral administration of bevirimat to HIV-infected SCID mice, the level of HIV replication was reduced by more than 90%. Bevirimat also potently inhibited replication of an HIV strain resistant to the approved drug AZT in this animal model.
Bevirimat has several other positive characteristics supporting its further development. These include data from several studies demonstrating that the compound should not be subject to metabolic interactions with currently approved HIV drugs, reducing the chance of drug-drug interactions when used in combination therapy. Indeed, bevirimat is synergistic in antiviral activity when tested in mixtures with approved drugs.
In addition to its utility as a new therapy for patients failing current treatments due to drug resistance, Panacos believes bevirimat may also be suitable for first-line therapy of HIV infection. In either case, it is likely that peak annual sales of bevirimat could grow well in excess of $500 million per year and approach $1 billion if it is successfully brought to market.
Mechanism of Action
Bevirimat is the first in a new class of HIV drugs called Maturation Inhibitors. Bevirimat blocks HIV maturation by inhibiting the final step in the processing of the HIV Gag protein. The resulting virus particles are structurally defective and are incapable of spreading infection around the body. The mechanism of action of bevirimat is described in a November 2003 publication in the journal Proceedings of the National Academy of Sciences of the USA (Li et al., Proc. Natl. Acad. Sci. USA, 100, 13555-13560 (2003)).
Panacos Presents Data on Lack of Clinical Resistance Development to Bevirimat (PA-457) at International HIV Drug Resistance Conference
WATERTOWN, Mass.--(BUSINESS WIRE)--June 14, 2006--Panacos Pharmaceuticals, Inc. (Nasdaq:PANC), a biotechnology company dedicated to developing the next generation of antiviral therapeutic products, today presented data demonstrating lack of rapid emergence of resistance to bevirimat in single and multiple dose monotherapy studies in HIV infected patients. The study, presented at the XV International HIV Drug Resistance Workshop in Sitges, Spain, was the result of a collaboration between Panacos and Dr. Eric Freed's group in the HIV Drug Resistance Program at the National Cancer Institute, Frederick, MD, USA.
In the new report, HIV was isolated from patients prior to, and following, monotherapy with bevirimat in single dose Phase 1/2 and multiple dose Phase 2a clinical studies. The amino acid sequence of the bevirimat target, the capsid-SP1 region of the HIV-1 Gag protein, from these viruses was determined by an approach called population sequencing which determines whether a significant proportion of virus within a patient exhibits resistance. No resistance mutations previously identified in laboratory cell culture assays were seen in patient isolates from these studies, nor was there any evidence of "viral rebound," or resurgence in viral load, during the period of bevirimat treatment. These results suggest that resistance to bevirimat does not emerge rapidly in patients, in contrast to some approved drugs where clinical resistance may be seen in the first 14 days of monotherapy. The results are noteworthy because bevirimat has a relatively long half-life of around 2.5 to 3 days. As a result, patients in the Phase 2a study were exposed to sub-optimal concentrations of bevirimat as monotherapy for up to three weeks following completion of the ten day treatment period, potentially an ideal situation for resistance development. Sequencing of the protease and reverse transcriptase genes did not reveal any new resistance mutations appearing during the study, nor did any pre-existing mutations affect the bevirimat treatment response.
Dr. Graham P. Allaway, Panacos' Chief Operating Officer commented, "We know the capsid-SP1 region is highly conserved among patient HIV isolates. While not definitive, these new data support the hypothesis of a genetic barrier to clinically significant bevirimat resistance in patients. We expect that resistance will be further suppressed when patients are treated with bevirimat in combination with other HIV drugs, as is expected to occur in future clinical trials and in clinical practice."
Clinical Trials
Phase 1a Clinical Trial
The safety and pharmacokinetics of this compound were examined in uninfected, healthy male volunteers following a single oral dose of 25 to 250 mg. bevirimat was well tolerated and exhibited good oral bioavailability and favorable pharmacokinetics. All doses produced mean circulating plasma levels which exceeded the target therapeutic concentration. At doses of 50 mg or above, bevirimat levels continued to exceed the target concentration even at 24 hours after administration. These results suggest that bevirimat will be suitable for once daily oral dosing, the gold standard for HIV drugs. This study was the subject of a presentation at the XV International AIDS Conference in Bangkok, Thailand (July 2004).
Phase 1b Clinical trial
Based on the promising results of the first clinical study, bevirimat was advanced into a multiple dose Phase 1 trial to examine the safety and pharmacokinetics of the compound in uninfected, healthy volunteers. In this study, bevirimat was administered once daily for 10 days. Plasma concentrations at all dose levels were well above the level predicted to provide therapeutic benefit in HIV-infected patients. The drug was well tolerated. The results of this study were presented at the Twelfth Annual Conference on Retroviruses and Opportunistic Infections in Boston in February 2005.
Phase 1/2 Trial
Based on the Phase 1 results, a Phase 1/2 study was carried out in HIV-infected patients to analyze pharmacokinetics and to determine the antiviral effect of a single oral dose of bevirimat in patients not on other therapy. Positive preliminary results were announced in November 2004 from this proof-of-concept study. A significant reduction in the level of virus in the plasma, known as viral load, of up to approximately 0.7 log10 was seen in patients receiving the highest dose levels, including patients with HIV strains resistant to existing classes of anitiretroviral drugs. Mean viral load decreased in the two highest dose groups and was significantly different from placebo at multiple time points following dosing. These findings are similar to results obtained in single dose clinical trials of other potent HIV drugs including the approved drug tenofovir* provide proof of concept for the antiviral activity of bevirimat.
*(Barditch-Crovo, P., et al. (2001). Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob. Agents. Chemother., 45, 2733-2739.)
Phase 2a Trial
A multi-dose Phase 2a study was performed in HIV-infected patients at several sites in the U.S. and was designed to demonstrate the antiviral potency of bevirimat following its once-daily oral dosing for 10 days in HIV-infected patients who were not on other antiretroviral therapy.
Phase 2b Trial
Panacos announced the commencement of a multicenter Phase 2b trial studying the effects of combination therapy in HIV-infected patients on June 12, 2006.
Panacos Drug Candidate PA-457 Shows Potent Antiviral Activity in HIV-infected Patients
Viral Load Reduction Meets Primary Endpoint of Phase 2a Study
Watertown, MA (August 22, 2005) - Panacos Pharmaceuticals, Inc. (Nasdaq: PANC) ("Panacos" or "the Company"), a biotechnology company dedicated to developing the next generation of antiviral therapeutic products, today announced the successful completion of a Phase 2a clinical study of its lead HIV drug candidate, PA-457, and provided preliminary analysis of the results. The study met its primary endpoint by demonstrating a statistically significant reduction in the level of HIV in the blood, known as viral load, compared to placebo. The median reduction in viral load in the trial was greater than 1 log10, or a 90% decrease, at the highest dose. PA-457 is the first in a new class of HIV drugs called Maturation Inhibitors, with broad activity against HIV, including strains resistant to currently approved drugs, the most common cause of HIV treatment failure.
In this randomized double-blind Phase 2a study, performed at leading academic centers in the US, PA-457 at one of four doses (25, 50, 100 or 200mg; 6 patients per group) or placebo (8 patients), was administered orally once daily for 10 days to HIV-infected subjects not on other antiretroviral therapy. The primary endpoint was viral load reduction on Day 11. Other endpoints included safety, tolerability and pharmacokinetics of the drug.
At the 100 and 200 mg doses, PA-457 treatment for 10 days resulted in statistically significant reductions in viral load compared to placebo, with individual decreases of up to 1.7 log10. At the 200mg dose level, the median viral load change at Day 11 was -1.03 log10. Median Day 11 values at the other dose levels were: Placebo: +0.03 log10; 25mg: +0.05 log10; 50mg: -0.17 log10; 100mg: -0.48 log10. In patients with baseline viral loads under 100,000 copies/ml the median Day 11 reduction was -1.52 log10 at the 200mg dose level (three of six patients) and -0.56 log10 at the 100mg dose level (five of six patients).
Genetic analysis of HIV in patients pre- and post- treatment, available now for 21 out of 33 patients in the study, showed no evidence of the development of resistance to PA-457, the same result as seen previously in a single dose study with PA-457. All doses were observed to be generally safe and well tolerated with no Grade 3 or 4 laboratory abnormalities. All adverse experiences were mild or moderate and no dose-limiting toxicity was identified. One moderate adverse event was classified as possibly related to drug and was categorized as serious based on the subject's hospitalization for diagnostic tests. It involved a patient with a 5-year history of poorly controlled hypertension who exhibited transient findings of a possible lacunar cerebrovascular accident, a known complication of hypertension.
Graham P. Allaway Ph.D., Chief Operating Officer of Panacos, said: "This study indicates that PA-457 has potent anti-HIV activity, providing further clinical proof of principle for this new class of antiretroviral drugs. The overall viral load reduction at the 200mg dose of over 1 log10 strongly supports further development of PA-457. The 1.5 log10 viral load reduction seen in patients at the 200mg dose with less than 100,000 viral copies/ml may potentially reflect the potency of the drug when used in combination therapy in normal clinical practice." Panacos is submitting the results of this study as a late breaker abstract to the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), to be held in New Orleans, LA September 21-24, 2005. If accepted, a detailed description of the study will be provided at that conference.
"We are extremely pleased with the results of this important Phase 2a study," commented Samuel K. Ackerman, MD, Chairman and CEO of Panacos. "We believe that PA-457 is a potential breakthrough drug which could play a role throughout the HIV treatment spectrum, including both naive and treatment-experienced patients, based on once-a-day oral dosing, potent activity observed against drug resistant virus and a promising safety profile. We now plan to move forward aggressively to initiate a Phase 2b study of the drug in the first half of 2006."
About PA-457
PA-457 is a small molecule, oral HIV drug candidate. It works by a mechanism different from that of approved drugs or other drugs in development, by blocking a key step in the processing of a viral core protein called capsid. This novel mechanism of action, called maturation inhibition, was discovered by Panacos scientists and their collaborators. Preclinical studies have shown that PA-457 retains full activity against drug-resistant virus, is effective in an animal model of HIV infection and should be suitable for use in combination therapy with other drugs. A previous clinical study indicated that a single oral dose of PA-457 has antiviral activity in HIV-infected patients, including individuals infected with drug resistant strains. Clinical results to date will need to be confirmed and extended in longer term trials with larger patient numbers prior to approval.
The US Food and Drug Administration (FDA) has granted Fast Track designation to PA-457. Fast Track is a process designed to expedite development and approval of new drugs that may have the potential to improve treatment for serious or life-threatening diseases. Developers of Fast Tracked products have greater access to FDA resources as well as eligibility for rolling NDA submissions. In addition, Fast Track designation may enable priority FDA review and accelerated approval.
Panacos Announces Initiation of Phase 2b Clinical Trial of First-In-Class HIV Maturation Inhibitor, Bevirimat (PA-457)
WATERTOWN, Mass., Jun 12, 2006 (BUSINESS WIRE) -- Panacos Pharmaceuticals, Inc. (Nasdaq:PANC), a biotechnology company dedicated to developing the next generation of antiviral therapeutic products, today announced the initiation of a Phase 2b clinical trial of bevirimat (previously designated PA-457), the Company's lead drug candidate for the treatment of HIV. Institutional Review Board (IRB) and other approvals have been received at initial study sites and the study is now open for enrollment.
"Initiation of the Phase 2b study of bevirimat represents a key milestone for Panacos," said Dr. Samuel K. Ackerman, Panacos' President and CEO. "With the benefit of the results of our Phase 2a study, we have been able to focus on a dose range that we believe will provide maximum antiviral benefit to patients. In the Phase 2b trial, we plan to test these doses of bevirimat in combination with approved HIV drugs as part of an optimized regimen in patients failing treatment due to drug resistance. The goal of this study is to select the most appropriate dose to take into pivotal Phase 3 testing."
Study Design
In the Phase 2b study, HIV-infected patients failing their current antiretroviral therapy will receive oral bevirimat or placebo once daily for three months in combination with background antiretroviral therapy. Initially, twelve patients per dose plus four placebo patients will be enrolled in each of three bevirimat dosage groups (400mg, 500mg and 600mg) in a dose-escalation fashion. For the first two weeks of treatment, patients will receive bevirimat or placebo in addition to their previous background therapy ("functional monotherapy"), following which each patient's background will be optimized and treatment continued for a total of three months. Groups receiving doses higher than 600mg may be enrolled following review of functional monotherapy data from the first three groups by the Company and FDA. Following evaluation of data, the Company also plans to submit a protocol amendment to expand patient numbers to a total of approximately 36 patients receiving bevirimat at each of the selected doses.
Efficacy endpoints of the study will include reduction in viral load after 14 days of functional monotherapy and after three months of dosing. If doses up to 600mg are evaluated and all three dosage groups are expanded, the total number of patients in the trial would be approximately 144, including 108 patients receiving bevirimat and 36 patients receiving placebo. Patients completing three months of therapy would be eligible for a rollover protocol to continue long-term dosing.
Panacos Presents Data at 13th Conference on Retroviruses and Opportunistic Infections
WATERTOWN, Mass., Feb 09, 2006 (BUSINESS WIRE) -- Panacos Pharmaceuticals, Inc. (Nasdaq:PANC), a biotechnology company dedicated to developing the next generation of antiviral therapeutic products, today announced that its lead product candidate, the HIV maturation inhibitor PA-457, was the subject of three presentations at the 13th Conference on Retroviruses and Opportunistic Infections (CROI) held this week in Denver, Colorado.
The first presentation was a more detailed analysis of PA-457's Phase 2a data, which were initially announced by Panacos on August 22, 2005. The new analysis was presented by Dr. Patrick F. Smith of the University at Buffalo in an oral presentation titled: "Pharmacokinetics/Pharmacodynamics of PA-457 in a 10-day Multiple Dose Monotherapy Trial in HIV-infected Patients." The presentation was co-authored by the investigators on the Phase 2a trial as well as Panacos scientists. The Phase 2a study demonstrated that PA-457 had potent anti-HIV activity following 10 days of once-daily dosing in HIV-infected patients, meeting its primary endpoint with a statistically significant median reduction in viral load of greater than 1 log10 at 200 mg, the highest dose level in the study. In his presentation, Dr. Smith described the use of a mathematical model to analyze the relationship between PA-457's pharmacokinetics and the drug's antiviral effect. The model explained 84% of the antiviral response to PA-457 that was observed in the Phase 2a trial, with PA-457 plasma concentration accounting for most (88%) of the modeled variability in antiviral responses among patients. Dr. Smith's analysis also suggested that doses higher than 200mg may lead to greater antiviral activity, which Panacos intends to explore in future clinical trials.
In another oral presentation at CROI, Dr. Catherine Adamson of Dr. Eric Freed's laboratory at the National Cancer Institute presented a study completed in collaboration with Panacos, titled: "Viral resistance to PA-457, a novel inhibitor of HIV-1 maturation." This study extended previous work by analyzing PA-457-resistant HIV variants that were generated in vitro by serial HIV passage at sub-optimum drug concentrations. Amino acid changes conferring PA-457-resistance were found exclusively near the junction of two HIV proteins, called capsid and SP1, adding to the evidence that this junction is PA-457's molecular target. PA-457 blocks HIV maturation by preventing the separation of capsid from SP1, so that following PA-457 treatment the HIV virus particles released from infected cells are immature and non-infectious. Several of the resistant mutant virus strains in this study exhibited reduced fitness for replication. The study also analyzed virus from patients in the Phase 2a clinical study and found that no resistance mutations were detected during or following treatment with PA-457. The study concluded that there may be a high genetic barrier to resistance development against PA-457.
A third study entitled: "The first in class maturation inhibitor, PA-457, is a potent inhibitor of HIV drug-resistant isolates and acts synergistically with approved HIV drugs in vitro," was presented by Nicole Kilgore of Panacos. In this study, PA-457's anti-HIV activity was tested against a number of commonly occurring HIV strains resistant to approved drugs including nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs, protease inhibitors, and fusion inhibitors. The study indicated that PA-457 had potent anti-HIV activity in vitro against all resistant strains tested. These results are consistent with PA-457 having a distinct mechanism of action and no cross-resistance with currently approved drugs. Drug resistance is the most pressing problem in HIV therapy and the leading cause of treatment failure.
This presentation also included study results indicating that PA-457's in vitro anti-HIV activity is in most cases synergistic in combination with approved drugs, with no antagonism observed in any combination. These results support the potential for increased activity of PA-457 when used in combination therapy.
"We believe that these data on the Phase 2a study, resistance profile, and synergistic activity of PA-457 continue to be encouraging indicators for future development," said Dr. Samuel Ackerman, President and CEO of Panacos. "Of particular interest are the pharmacodynamic modeling results, which support our plan to go higher in dose in an upcoming Phase 2b study of PA-457, with the likelihood of achieving an even greater antiviral response than we saw in Phase 2a."
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