RxPG News : Antivirals

Phase Ib Trial Is Evaluating Bavituximab Administered With Common Chemotherapy Regimens

Fri, 17 Nov 2006 22:31:37 PST

( from http://www.rxpgnews.com ) Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM), a clinical stage biopharmaceutical company developing targeted therapeutics for the treatment of cancer and hepatitis C virus (HCV) infection, today announced initiation of patient treatment in its Phase lb clinical trial to evaluate its lead anti-phospholipid immunotherapy agent bavituximab given in combination with common cancer chemotherapy agents. The trial is expected to enroll up to 12 patients at three clinical sites in India.

"We are very pleased that patient dosing is underway in this clinical study of bavituximab in combination with commonly-used chemotherapy drugs because preclinical studies support the concept that chemotherapy and bavituximab should have synergistic anti-tumor effects," said Steven W. King, president and CEO of Peregrine. "We are encouraged that the regulatory and logistical requirements for initiating this trial have proceeded so smoothly and we look forward to working with our clinical sites to complete patient enrollment in this study over the next few months. We believe the results from this study, in combination with data from our ongoing U.S. cancer trial, will help support advancing bavituximab into Phase II combination therapy cancer trials in 2007."

The Phase Ib trial is designed to test the safety and tolerability of bavituximab over an 8-week administration period when given with standard chemotherapy regimens including docetaxel, gemcitabine and carboplatin/paclitaxel. These regimens are commonly used for treating major cancer types, including breast, lung and pancreatic cancer, and patients with these various types of cancer are potentially eligible for the trial. Study endpoints include safety and drug pharmacokinetics. Patients will also be evaluated for tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, although this assessment is not a formal endpoint of the study. Patients will be followed for an additional four weeks after their last dose of bavituximab and may continue with chemotherapy according to standard-of-care guidelines. The trial is being conducted according to International Conference on Harmonization (ICH) and Good Clinical Practices (GCP) guidelines.

Preclinical studies have confirmed that bavituximab acts synergistically when administered in combination with chemotherapy in major tumor types. Preclinical studies presented at the AACR annual meeting showed the potential of a bavituximab equivalent plus chemotherapy or radiation to increase survival in resistant breast and brain cancer, a very positive result in these models of advanced disease. A study published in the International Journal of Cancer demonstrated that a bavituximab equivalent given in combination with gemcitabine showed encouraging efficacy in animal models of pancreatic cancer, including reductions in metastatic disease, and an article in Cancer Research reported that a bavituximab equivalent plus docetaxel inhibited tumor growth by 93% in a model of advanced breast cancer.

Bavituximab is currently in clinical trials in the U.S. for the treatment of solid tumors and chronic hepatitis C infection. Clinical data to date has shown that bavituximab is generally safe and well tolerated.

Complete Inhibition of Viral Replication in H5N1 In Vivo Model by Bavituximab

Thu, 25 May 2006 13:08:37 PST

( from http://www.rxpgnews.com ) Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM), a biopharmaceutical company with a portfolio of innovative, clinical stage product candidates for the treatment of hepatitis C virus (HCV) infection and cancer, today announced that its lead anti-viral compound bavituximab (formerly Tarvacin) completely inhibited replication of a laboratory strain of the H5N1 virus, commonly known as avian flu, in fertilized chicken eggs, an in vivo model for influenza anti- viral activity. These preliminary findings will be reported today at the 106th general meeting of The American Society for Microbiology (ASM) in Orlando, Florida by Dr. Philip Thorpe, a member of the Peregrine Scientific Resource Board and professor of pharmacology at the University of Texas Southwestern Medical Center at Dallas. Bavituximab, a monoclonal antibody with unique anti-viral and anti-cancer properties, has already demonstrated good tolerability in a Phase l trial in patients with HCV infection.

"This first set of results showing that bavituximab appears to have inhibited H5N1 viral replication in the fertilized egg model and the supportive data confirming that bavituximab binds to H5N1 viral particles are encouraging," said Dr. Thorpe. "These early data support the view that bavituximab may be active against H5N1 and other common strains of influenza."

The H5N1 studies reported by Dr. Thorpe were conducted at a number of independent research laboratories. Peregrine has also been collaborating with other researchers to evaluate the potential of bavituximab delivered by different routes of administration to treat infections caused by influenza A, the viral family that includes the H5N1 strain. Peregrine has ongoing studies to evaluate various delivery methods and treatment regimens to treat influenza in a number of in vivo models, including well-established mouse and ferret models. These studies include assessments of bavituximab delivered by nasal inhalation, a form of delivery expected to be more effective than systemic delivery alone for respiratory viruses that lodge deep in the lungs.

"These early experimental data suggesting that bavituximab may have activity against the avian flu, along with preliminary data recently generated showing signs of activity in a ferret model of influenza A infection, give us momentum and direction as we pursue a variety of preclinical initiatives to assess the anti-viral potential of bavituximab," said Steven W. King, president and CEO of Peregrine. "With a repeat dose safety study in HCV patients expected to begin next month, we should be well-positioned to initiate clinical trials for bavituximab in additional indications once we have sufficient preclinical data in hand."

Bavituximab is an antibody that attaches to specific cellular components called phospholipids found on the surface of virus particles, including influenza and certain other virus strains, as well as on the outer surface of human host cells only when they are infected with these viruses. Bavituximab helps stimulate the body's natural immune defenses to destroy both the virus particles and the infected cells, without affecting healthy cells. Bavituximab is in Phase 1 clinical trials for hepatitis C virus infections and for solid tumor cancers. A Phase 1b repeat dose study in HCV patients is expected to start in June.

FDA Gives Tentative Approval to Abacavir

Sat, 20 May 2006 03:00:37 PST

( from http://www.rxpgnews.com ) The Food and Drug Administration (FDA) today announced the tentative approval of generic abacavir (a-BAK-a-veer) sulfate tablets manufactured by Aurobindo Pharma LTD. of Hyderabad, India. Abacavir sulfate tablets are the first generic version of the already approved Ziagen Tablets, an anti-HIV medication manufactured by GlaxoSmithKline. This product will now be available for consideration for purchase under the President's Emergency Plan for AIDS Relief.

"FDA's action adds yet another anti-HIV product to those available for purchase under the President's Plan and demonstrates our continuing commitment to ensuring that safe, effective, and quality manufactured medications are available for purchase under the President's Plan," said Murray M. Lumpkin, M.D., Deputy Commissioner for International and Special Programs.

The President's Emergency Plan for AIDS Relief, which President Bush first announced in his 2003 State of the Union Address, is currently providing $15 billion to fight the HIV/AIDS pandemic over five years, with a special focus on 15 of the hardest hit countries. The President's plan is designed to prevent seven million new HIV infections, treat at least two million HIV-infected people, and care for ten million HIV-affected individuals, AIDS orphans and vulnerable children. It targets three specific areas related to HIV/AIDS:

* Prevention of HIV transmission;
* Treatment of AIDS and associated conditions;
* Care, including palliative care for HIV infected-individuals, and care for orphans and vulnerable children.

Abacavir is one of the non-nucleoside reverse transcriptase inhibitors (NRTIs), a class of drugs that helps keep the AIDS virus from reproducing. It is used in combination with other antiretroviral agents for the treatment of HIV-1 infection.

The agency's tentative approval of this product means that Aurobindo's product meets all of FDA's manufacturing quality and clinical safety and efficacy standards. Although existing patents and/or exclusivity prevent its marketing in the United States, the product can be marketed abroad and used under the PEPFAR plan.

Telbivudine emerging as a potent new treatment option for Hepatitis B

Fri, 29 Jul 2005 22:24:38 PST

( from http://www.rxpgnews.com ) Novartis Pharma AG and Idenix Pharmaceuticals, Inc. announced today that the phase III GLOBE registration trial for telbivudine successfully reached its primary, composite efficacy endpoint of therapeutic response at one year in chronic hepatitis B patients. This endpoint, which was designed to assess if telbivudine was at least as effective as lamivudine, evaluated the combination of viral suppression (serum HBV DNA suppression below 100,000 copies/mL) coupled with either improved liver function (ALT normalization) or loss of detectable hepatitis B e-antigen (HBeAg).

The largest hepatitis B registration trial to date, GLOBE enrolled more than 1,350 patients in over 130 centers worldwide. The ongoing trial is evaluating the safety and efficacy of telbivudine compared to lamivudine in patients with HBeAg-positive and HBeAg-negative compensated chronic hepatitis B for two years of treatment in two daily treatment regimens: telbivudine 600 mg or lamivudine 100 mg.

The one-year analysis of this trial will be the primary data used for preparing the marketing registration applications. Novartis and Idenix plan to file with the U.S. Food and Drug Administration (FDA) by the end of 2005 for marketing approval of telbivudine for the treatment of chronic HBV. Worldwide marketing filings, including the filing that will be submitted to the European Medicines Agency (EMEA), are expected in the first quarter of 2006. Novartis and Idenix are co-developing telbivudine.

The World Health Organization (WHO) has estimated that approximately 350 million people, or 5% of the world's population, are chronically infected with hepatitis B virus or HBV. Current treatment options are often associated with limited efficacy, poor tolerability or resistance concerns, and new therapeutic options are needed to respond to the significant unmet need in treating chronic HBV.

"We believe that telbivudine is emerging as an important, potent new treatment option for hepatitis B, providing rapid and profound viral suppression," said Joerg Reinhardt, Global Head of Development, Novartis Pharma AG. "Through our ongoing development programs and our collaboration with Idenix, we will continue to advance new hepatitis therapies to address the significant unmet medical needs that exist in this area."

The companies anticipate that complete data from the GLOBE study will be submitted for presentation to the American Association for the Study of Liver Disease (AASLD) meeting in San Francisco, California, November 11-15, 2005.

More About Telbivudine

Telbivudine is a specific and selective, oral, once-daily nucleoside that is unique in its preferential inhibition of 2nd strand HBV DNA synthesis. This distinct mechanism of action may be responsible for the rapid and profound viral suppression associated with telbivudine treatment.

The GLOBE study results continue to support a favorable overall safety profile for telbivudine with no substantial safety issues being identified to date through the combined two years of treatment in the phase IIb clinical trial and in the phase III clinical program to date.

An additional phase III trial (NV-02B-011) is evaluating the safety and efficacy of telbivudine compared to lamivudine in HBeAg-positive and HBeAg-negative patients with decompensated chronic hepatitis B. This ongoing trial has enrolled 87 patients to date.

About Hepatitis B

Chronic Hepatitis B is caused by a virus that attacks the liver. The virus, which is called hepatitis B virus (HBV), can cause lifelong infection, cirrhosis (scarring) of the liver, liver cancer, liver failure, and death. The WHO estimates that annually over 50 million people become infected with HBV and that more than one million individuals die from HBV-related chronic liver disease.

New Saquinavir Formulation Simplifies Dosing Regimen for HIV Patients

Mon, 30 May 2005 20:47:38 PST

( from http://www.rxpgnews.com ) Roche announced the European marketing approval for its new 500 mg formulation of Invirase (saquinavir mesylate), an effective and well tolerated protease inhibitor used in the treatment of HIV infection. The new 500 mg tablet will simplify the dosing regimen for patients by reducing the daily tablet count by more than half, from five tablets twice-daily to two tablets twice-daily.

Antiretroviral therapies have become more and more effective and have transformed HIV infection into more of a chronic disease with patients living much longer than before1. As such it is particularly important to offer effective therapies to patients that are both well tolerated and convenient.

The new Invirase 500 mg formulation will meet the needs of patients by offering a simpler and more convenient treatment option with excellent efficacy and a well established tolerability profile. Patients can easily switch from the current 200 mg capsule to the new 500 mg tablets, continuing to benefit from Invirase's high antiviral efficacy but with far more convenience.

The launch of the 500 mg tablet is a further example of Roche's continuing commitment not only to the treatment of HIV but also to the development of medicines that more closely meet the needs of patients said William M. Burns, CEO of Roche's Pharmaceutical Division.

The reduced pill burden offered by the new Invirase 500 mg tablet will make boosted Invirase a much more attractive treatment option for patients and will encourage its use in early as well as advanced stages of HIV disease, said Dr Anton Pozniak, Consultant Physician and Senior Lecturer at Chelsea and Westminster Hospital, London UK.

Invirase is approved for use in combination with a low dose of another protease inhibitor ( PI ), ritonavir in combination with other antiretroviral drugs. Boosted Invirase has been shown in numerous clinical trials2, 3 to be highly potent with an excellent tolerability profile and limited toxicity. Invirase is recommended as a first line boosted PI in the International AIDS Society ( IAS ) guidelines which gave it the highest possible clinical evidence based rating4. Invirase 500 mg received FDA approval in the USA after priority review on December 18, 2004.

About Boosted Invirase

Invirase, originally approved by the FDA in 1995, was the first HIV protease inhibitor on the market. Its introduction represented a major milestone in the treatment of HIV/AIDS. In December 2003, the FDA approved Invirase for use in boosted dosing regimens with ritonavir ( 1000 mg Invirase/100 mg ritonavir bid ). Co-administering Invirase with ritonavir enhances therapeutic blood levels of the drug and enables simplified dosing.

Data from the Staccato clinical study show reductions in patients' HIV RNA recorded in the first 24 weeks on therapy that are the best ever seen in a large cohort of patients given HAART. Some 96% of patients achieved viral load reductions to <400 hiv rna copies ml and 89/<50 hiv rna copies ml/

CPG 10101 Shows Significant Antiviral Activity in Chronic Hepatitis C Patients

Mon, 23 May 2005 11:20:38 PST

( from http://www.rxpgnews.com ) Coley Pharmaceutical Group, Inc today announced at the Digestive Disease Week conference that Actilon(TM) (CPG 10101) was relatively well tolerated and showed antiviral activity in the company's Phase Ib clinical study in chronic Hepatitis C patients.

In this Phase Ib study forty-two adult patients with chronic Hepatitis C virus, or HCV, were enrolled. These patients had previously failed to achieve a sustained viral response after 24-48 weeks of standard therapy with interferon-alpha plus ribavirin or were intolerant of interferon-alpha and all but two were virus genotype 1. Patients receiving 20 mg of Actilon subcutaneously twice weekly achieved a maximum 1.4 mean log decrease ( 96% ) of virus within 4 weeks. Five of the six patients receiving the 20 mg dose of Actilon achieved at least a one log ( 90% ) reduction of virus while on therapy.

Actilon showed good safety and tolerability, pharmacodynamic immune responses consistent with the drug's mechanism of action, and dose-related blood pharmacokinetics when given to HCV patients, as had been previously shown in Coley's Phase Ia clinical trial in normal volunteers. Initial antiviral activity was observed in this double-blind trial after only 1 mg of Actilon given twice weekly, and dosing has been increased to 20 mg with acceptable tolerability.

Measurements of biomarker responses in blood indicated that Actilon stimulates the innate immune system and immune activation induced by Actilon correlates with partial clearance of virus. Decreases in HCV RNA levels began to be observed after a single dose and were observed to be dose dependent.

"We are very encouraged by the results of this Phase Ib study showing antiviral effects with Actilon given to patients with relapsed or treatment resistant genotype 1 Hepatitis C," said John Whisnant, M.D., Senior Vice President, Drug Development of Coley Pharmaceutical Group. "Actilon's observed ability to direct the immune system therapeutically is consistent with its mechanism and with our experience with other Coley TLR Therapeutics in clinical development."

Data from the Phase Ib study were presented by Dr. Bruce Bacon, Professor of Internal Medicine at Saint Louis University School of Medicine in an oral presentation entitled "Safety and Pharmacodynamic ( PD ) and Pharmacokinetic ( PK ) Profiles of CPG 10101 ( Actilon( TM ) ), a Novel TLR9 Agonist: Comparison in Normal Volunteers and HCV-Infected Individuals". Interim results from this study were presented previously at The American Association of Liver Disease ( AASLD ) meeting in November 2004.

About the Study

The Phase Ib double-blind study was designed to assess antiviral responses, safety and tolerability of Actilon over an 80-fold dose range. Forty-two adult subjects with chronic Hepatitis C virus were enrolled; virtually all were virus genotype 1 patients who had previously failed to achieve a sustained viral response after 24-48 weeks of standard therapy with interferon-alpha plus ribavirin. Patients were randomized to receive placebo or Actilon in sequentially higher dose cohorts ( 0.25, 1, 4, 10 and 20 mg ) by twice weekly subcutaneous injections for four weeks.

Researchers observed responses in immune system markers including drug- related increases in interferon-alpha plasma levels and other markers indicative of antiviral activity. Actilon was relatively well tolerated at all doses in most patients, including 20 mg, the highest dose cohort completed, with no dose limiting toxicities. Mild to moderate injection site reactions and mild flu-like symptoms were consistent with the expected pharmacological mode of action of Actilon.

About Actilon( TM )

Actilon is a member of a new class of investigational medicines known as TLR Therapeutics( TM ) being developed by Coley and its partners for the treatment of major medical conditions including cancers, infectious diseases, allergy and asthma.

TLR Therapeutics target Toll-like receptors ( TLRs ) which act as immune system sentinels that recognize the distinct molecular patterns characteristic of foreign pathogens. Coley is focusing its efforts initially on the discovery and development of TLR Therapeutics which target and stimulate Toll-like receptor 9 ( TLR9 ), which is found in a subset of dendritic and B cells.

Coley believes that Actilon stimulates TLR9, targeting dendritic cells and B cells, to induce both early and long term immune responses. The short-term innate immune response is thought to drive rapid reductions in viral load in the blood. Longer term, Actilon is thought to promote virus-specific adaptive immunity, including strong T cell responses, to provide sustained anti-viral effects.

About Hepatitis C Virus

Hepatitis C virus, which infects the liver and certain immune cells, leads to serious liver diseases such as cirrhosis and liver cancer more frequently than any other form of hepatitis. HCV is an RNA virus known to undergo a high rate of mutation that may help it both to avoid control by the immune system and to develop resistance to direct antiviral medications. According to the World Health Organization, HCV infects approximately 170 million people worldwide, including at least 2.7 million in the United States, and 10-20 percent of those chronically infected with HCV will ultimately develop liver cirrhosis, making HCV the leading cause of liver transplants in the United States. The Hepatitis Foundation International estimates that between 8,000 and 10,000 people die annually from HCV-related cirrhosis or liver cancer. Coley believes, there is an unmet need for therapies with better side effect profiles and equivalent or superior efficacy, especially in the difficult-to-treat population of genotype 1 patients, who have failed to achieve a sustained virologic response following interferon-alpha and ribavirin therapy.

Further Studies Needed for Tipranavir

Fri, 20 May 2005 08:26:38 PST

( from http://www.rxpgnews.com ) Boehringer Ingelheim's Aptivus should be approved for treatment resistant HIV patients, but further studies are needed to guide use of the drug, FDA's Antiviral Drugs Advisory Committee recommended May 19.

"We as a committee have agreed that we feel that there is efficacy demonstrated, but the exact usefulness needs to be monitored in the future," committee chair Janet Englund (University of Washington) said.

The panel voted 11 to 3 in favor of recommending accelerated approval for Aptivus (tipranavir).

Committee members emphasized that further data are necessary to understand how to appropriately use the agent.

The committee needs "guidance both from the company's future studies and from the FDA to be able to use the drug in the best possible way," Englund said.

Further information is needed on how to monitor and manage adverse events, as well as greater clarity on which patients are most likely to respond to tipranavir, committee members said.

Studying long-term liver toxicity should be a priority, committee members said. In pivotal trials, 6% of tipranavir patients exhibited grade 3/4 elevations in ALT/ALS liver enzymes, compared to 2% of patients receiving active control.

"I clearly would urge the pharmaceutical sponsor, since we know that there is this persistent elevation in liver function studies, to generate data that lets us know the baggage with elevation over time," committee member Lauren Wood (Uniformed Services University of Health Sciences) said.

Genotype data on patients likely to respond to Aptivus would also be useful, committee members said. An eight-week "�escape clause" in the Phase III trials made it difficult to isolate which patients responded to therapy.

BI is currently conducting an extended follow-up of the two pivotal trials, as well as trials in treatment-na've HIV patients and pediatric patients.

Comparator Arm Suboptimal in Tipranavir Trial

Thu, 19 May 2005 08:47:38 PST

( from http://www.rxpgnews.com ) Patient resistance to comparator protease inhibitors used in Boehringer Ingelheim's Aptivus (tipranavir) pivotal trials will likely be a central issue in the Antiviral Drugs Advisory Committee's review of the HIV agent.

"In both RESIST trials combined, 87% of the subjects were possibly/definitely resistant to the assigned comparator protease inhibitor," FDA's briefing document for the May 19 meeting states.

The open-label trials were designed to evaluate tipranavir boosted with ritonavir plus an optimized background regimen versus a comparator PI/r plus an optimized background regimen.

However, "in actuality, the results should be interpreted more as tipranavir/r versus a partially active control with both arms utilizing a large variety of optimized background regimen (n = 161 different drug combinations as per FDA statistical analysis)," the document states.

Boehringer Ingelheim "had difficulty enrolling the RESIST trials as designed to compare tipranavir/r to an active CPI/r, so they amended the protocol to allow subjects with no available sensitive PI, as per their genotype, to enroll," FDA explained.

While the amendment allowed for complete enrollment of RESIST 1 and 2, "most of the [comparator] patients entered the trial already genotypically resistant to their assigned PI. Therefore, the [comparator] arm is not truly an active control arm, but a suboptimal control arm."

As a result "the studies must be evaluated for superiority," FDA said. BI is seeking accelerated approval in heavily pre-treated patients.

Despite finding a lower 24-week response rate in both trials than that reported by the company, FDA's analysis continued to show a statistically significant result for the Aptivus regimen in RESIST 1 and 2.

In RESIST 1, the company found that 41.5% of tipranavir patients had a confirmed 1 log drop in HIV RNA vs. 22.3% for the comparator. RESIST 2 results were similar, with a 41% response rate for tipranavir vs. 14.9% for the comparator (p less than 0.0001 for both trials).

The agency's analysis lowers the response rates to 36% for tipranavir vs. 16% in RESIST 1 and 32% vs. 13% in RESIST 2 (p less than 0.001 for both).

"We believe that the FDA analysis differs from the applicant's results primarily due to [a] group of subjects who had initial lack of virologic response during [the] first 8 weeks," FDA said, referencing an "escape clause" in the studies that counted discontinuations as treatment failures at week 24.

The design issues cited by the agency could apply to future development of HIV agents for heavily pretreated groups. FDA is asking the committee to discuss lessons learned from tipranavir's development with regard to the "use of escape clauses resulting in a diminishing comparator arm."

The agency will also ask the committee to discuss several safety concerns, including tipranavir/ritonavir drug-drug interactions, "monitoring and management of hepatotoxicity," and further investigation and characterization of a "safety signal of rash in females."

Hepatotoxicity has been a safety concern throughout the tipranavir development program, FDA noted. "At this time, FDA exploratory analyses examining the possible baseline risk factors' are ongoing."

Aptivus has also been associated with gastrointestinal adverse events and elevated triglycerides.

Aptivus would be the second non-peptidic protease inhibitor; Pfizer's Viracept (nelfinavir) was approved in 1997.

Telbivudine Demonstrates Advantages Over Lamivudine in HBeAg-positive Chronic Hepatitis B

Tue, 17 May 2005 08:52:38 PST

( from http://www.rxpgnews.com ) Idenix Pharmaceuticals, Inc. today announced the presentation of interim two-year results from an extended-treatment phase IIb clinical trial for telbivudine demonstrating continuing advantages compared to lamivudine across key efficacy endpoints through two years of treatment in HBeAg-positive chronic hepatitis B patients.

Further analyses of the two-year data indicate that the link between early and profound viral suppression and markers of improved clinical outcomes that were demonstrated at one year extends through two years of treatment. These data were presented today at the 2005 Digestive Disease Week meeting in Chicago, Illinois by Ching-Lung Lai, M.D., lead investigator and Professor of Medicine and Hepatology, Department of Medicine, University of Hong Kong.

The ongoing phase IIb clinical trial compares telbivudine monotherapy and a combination of telbivudine and lamivudine, with lamivudine monotherapy in 104 treatment-naive patients with HBeAg-positive chronic hepatitis B.

Patients receiving telbivudine monotherapy achieved a 1.5 log10, or 30-fold, greater mean viral load reduction compared to patients receiving lamivudine monotherapy at two years. At two years, the percent of patients receiving telbivudine monotherapy in whom levels of serum HBV DNA became undetectable by a sensitive PCR-based assay was 71 percent, more than double that of the 32 percent of patients receiving lamivudine monotherapy (p less than 0.05). Serum ALT normalization, a marker of reduced liver inflammation, was significantly greater in patients treated with telbivudine monotherapy (81 percent) compared to lamivudine monotherapy patients (47 percent) through two years (p less than 0.05). In addition, substantially more patients receiving telbivudine monotherapy (38 percent) achieved HBeAg seroconversion compared to patients in the lamivudine monotherapy group (22 percent).

The rate of treatment failure for patients receiving telbivudine monotherapy (4.5 percent) was significantly lower than the rate of treatment failure in the lamivudine monotherapy group (21 percent) (p less than 0.05). The study results also continue to support a favorable overall safety profile for telbivudine with no substantial safety issues being identified through two years of treatment.

"Analysis of the study data across treatment groups suggest that two-year efficacy outcomes, such as persistent control of HBV replication, serum ALT normalization, and HBeAg seroconversion, are associated with achieving rapid viral suppression early in treatment," said Professor Lai. "Forty-one percent of patients with profound viral suppression after 24 weeks of treatment achieved seroconversion at two years, compared to only 15 percent of patients who did not achieve similar rapid viral response. This correlation between early reduction of viral load levels and longer-term efficacy outcomes suggests that maximizing viral load suppression early in the course of treatment is an important therapeutic goal."

Additional scientific analyses utilized combined two-year data from all patients regardless of treatment group and evaluated two-year efficacy outcomes according to serum HBV DNA level at week 24 of treatment. The results indicated that patients who had HBV DNA levels below 1000 copies/mL by week 24 of treatment had a much higher likelihood of achieving HBeAg seroconversion (41 percent vs. 15 percent), serum ALT normalization (85 percent vs. 51 percent) and undetectable levels of HBV DNA (86 percent vs. 23 percent) after two years of treatment compared to patients whose HBV DNA level was greater than 1000 copies/mL at week 24.

These analyses also demonstrate that patients with viral load levels below 1000 copies/mL were less likely to experience treatment failure than patients with HBV DNA levels above 1000 copies/mL (2 percent vs. 17 percent). Nearly 70 percent of patients receiving telbivudine monotherapy achieved rapid and profound suppression of HBV DNA (to levels below 1000 copies/mL) within the first 24 weeks of treatment, compared to 33 percent of lamivudine monotherapy patients.

"These two-year treatment results for telbivudine demonstrate that, across key measures of virologic and clinical outcomes in hepatitis B patients, the efficacy advantages for telbivudine treatment seen after one year were maintained through two years of treatment," said Nathaniel Brown, M.D., Idenix's executive vice president clinical development and chief medical officer. "We are encouraged by these longer-term phase IIb data and look forward to the results of the comprehensive telbivudine phase III GLOBE study, evaluating more than 1370 hepatitis B patients worldwide, which we expect to be available in the fall of this year."

Study Design

The telbivudine phase IIb program is comparing the safety and antiviral effectiveness of telbivudine, and telbivudine in combination with lamivudine, with a control arm of lamivudine monotherapy in two sequential, linked trials. The first clinical trial enrolled 104 treatment naive HBeAg-positive adults with chronic hepatitis B for one year of treatment in one of five daily treatment regimens: telbivudine 400 mg, telbivudine 600 mg, telbivudine 400 mg + lamivudine 100 mg, telbivudine 600 mg + lamivudine 100 mg or standard lamivudine therapy (100 mg per day).

The telbivudine phase IIb extended treatment clinical trial is a two-year extension of the initial one-year phase IIb clinical trial, to obtain comparative data for telbivudine and lamivudine for a total of three years. The two patient groups treated with telbivudine monotherapy in the initial one-year clinical trial are receiving 600 mg/day of telbivudine in the extension trial. The patient groups that received telbivudine combined with lamivudine in the initial one-year clinical trial are receiving telbivudine 600 mg/day combined with lamivudine 100 mg/day in the extension trial. The patients who received lamivudine 100 mg/day in the initial one-year trial continue to receive such treatment in the extension trial. The two-year phase IIb analysis includes combined data from the completed one-year plus one year of the extended treatment trial.

Results from the initial one-year phase IIb clinical trial were presented by Professor Lai at the American Association for the Study of Liver Diseases (AASLD) in October 2003. After one year of treatment, telbivudine monotherapy demonstrated significantly greater viral suppression, viral clearance by PCR assay, and serum ALT normalization, and a proportionally higher HBeAg seroconversion rate, compared to lamivudine monotherapy.

About Telbivudine

Telbivudine is a specific and selective, oral, once-daily nucleoside being developed for the treatment of chronic hepatitis B. To date, preclinical and clinical data demonstrate a favorable safety profile and marked antiviral activity against HBV.

Telbivudine is currently being evaluated in a two-year international phase III clinical trial comparing telbivudine to lamivudine, referred to as the GLOBE study. The phase III clinical trial is fully enrolled with more than 1370 patients, HBeAg+ or HBeAg-, with compensated liver disease. This trial is ongoing at over 100 clinical sites located in 20 countries in Europe, North America and Asia. Idenix, working jointly with Novartis, currently expects to commence the submission of worldwide marketing applications for telbivudine, beginning with a U.S. New Drug Application filing in late 2005.

The development of telbivudine and the telbivudine/valtorcitabine combination for the treatment of chronic hepatitis B demonstrates the commitment of Idenix and Novartis Pharma AG to develop and introduce new, improved treatment options in this area of significant unmet medical need.

About Hepatitis B

Despite the presence of global immunization programs for hepatitis B virus, the World Health Organization (WHO) has estimated that approximately 350 million people, or 5% of the world's population, are chronically infected with hepatitis B virus. Chronic hepatitis B can lead to cirrhosis, liver failure and hepatocellular carcinoma (liver cancer). The WHO also estimates that annually over 50 million people become infected with hepatitis B virus and that more than one million individuals die from HBV-related chronic liver disease demonstrating the urgent need for new treatment.

VX-950 : An Oral Hepatitis C virus Protease Inhibitor Shows Potent Antiviral Activity

Tue, 10 May 2005 20:05:38 PST

( from http://www.rxpgnews.com ) Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced interim results that indicate that the investigational oral hepatitis C virus (HCV) protease inhibitor VX-950 was well-tolerated and demonstrated potent antiviral activity in a Phase Ib clinical trial.

The study enrolled 34 patients with chronic genotype 1 HCV infection who were treated for 14 days with placebo or one of three dose regimens of VX-950. Patients receiving 750 mg of VX-950 every eight hours achieved a median reduction in HCV-RNA of greater than 4 log10, equivalent to a more than 10,000-fold decrease in viral levels, at the end of 14 days of treatment.

A median reduction in HCV-RNA of greater than 2 log10 was seen in each of the other two VX-950 dose groups at the end of 14 days of treatment. Every patient receiving VX-950 achieved greater than a 2 log10 reduction in HCV-RNA within the first three days of treatment. Genotype 1 HCV infection is the most difficult strain of HCV to treat and the most prevalent strain in the United States, Western Europe and Japan. Results from the study will be presented by a clinical investigator on May 17, 2005 at Digestive Disease Week(R) (DDW), a medical conference to be held in Chicago, Illinois.

In accordance with the embargo policy of the meeting, the specific data from the trial beyond what is described in this press release will not be disclosed until the DDW presentation.

"Vertex is committed to developing innovative compounds for the treatment of chronic HCV infection. VX-950, one of the most advanced agents in a promising new class of direct antivirals, underscores that commitment," said Joshua Boger, Ph.D., Chairman and Chief Executive Officer of Vertex. "The demonstration of antiviral activity in this early clinical study is highly encouraging, and we look forward to sharing these data in greater detail at DDW next week."

Based on the results of the Phase Ib clinical study, the Company plans to explore the development of VX-950 as monotherapy and in combination with other HCV treatments. Vertex plans to consult with the U.S. FDA and European regulatory authorities on the Company's development plans. Vertex expects to file an investigational new drug (IND) application in the second half of 2005 to support Phase II clinical development of VX-950 in the United States. In collaboration with Vertex, Mitsubishi Pharma Corporation is developing VX-950 in Japan and certain Far East countries.

Trial Design

The Phase Ib clinical trial was a double-blind, randomized placebo- controlled study designed to evaluate the tolerability, pharmacokinetics and effect on viral kinetics of three doses of VX-950 -- 450 mg every 8 hours, 1250 mg every 12 hours, or 750 mg every 8 hours -- over a period of 14 days, with additional post-treatment follow-up. A key goal of the study was to assess different dosing levels and frequencies for VX-950 to provide insight into dose selection for future monotherapy and combination therapy studies. Thirty-four patients with chronic genotype 1 hepatitis C virus infection were enrolled in the study; six patients received placebo and 28 patients received VX-950. The study was conducted at three centers in Europe. The trial included treatment-experienced and treatment-naive HCV-infected patients.

VX-950 Demonstrates Antiviral Activity

Interim Phase Ib clinical trial results indicate that VX-950 was well- tolerated across all three dose groups with no serious adverse events reported, and no treatment discontinuations. Treatment with VX-950 also resulted in significant reductions in plasma HCV-RNA. Within three days of treatment, the median reduction in HCV-RNA was greater than 3 log10 in all three VX-950 dose groups. In the dose group receiving 750 mg of VX-950 every 8 hours, there was a further reduction in viral levels between days 3 and 14 of treatment, with mean and median HCV-RNA reductions of greater than 4 log10 at day 14. Trough plasma concentrations of VX-950 were highest in the 750 mg every 8 hour dose group. In the 450 mg q8h and 1250 mg q12h dose groups, maximal effects were seen between days 3 and 7 of treatment. Subsequently, there was an increase of approximately 1 log10 in median HCV-RNA between days 7 and 14 evident in both groups. Full analysis of the study, including a detailed pharmacokinetic and viral sequencing evaluation, is underway.

Baraclude (Entecavir) For Treatment Of Chronic Hepatitis B approved by FDA

Thu, 31 Mar 2005 21:25:38 PST

( from http://www.rxpgnews.com ) Bristol-Myers Squibb Company (NYSE: BMY) announced today that the U.S. Food and Drug Administration (FDA) approved Baraclude (entecavir).

Baraclude is indicated for the treatment of chronic hepatitis B infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. Baraclude is an oral antiviral therapy specifically designed to block the replication of hepatitis B virus (HBV) in the body by interfering with the virus's ability to infect cells. The drug will be available in the United States as early as April 8, 2005.

"With the approval of Baraclude, Bristol-Myers Squibb will now be able to address another area of significant unmet medical need, building on our growing presence in fighting cancer, HIV/AIDS, schizophrenia and other diseases," said Peter R. Dolan, chairman and chief executive officer. "Baraclude represents the company's fourth new pharmaceutical approved in less than two and a half years, and has the potential to help many adult patients with chronic hepatitis B infection. Developed in our own laboratories, Baraclude is an important step forward for patients and our company, as we seek to realize our mission of extending and enhancing human life by focusing on discovering, developing and providing innovative treatments for serious diseases."

"In clinical trials, Baraclude demonstrated greater levels of viral suppression compared to lamivudine after 48 weeks of treatment," said Robert Gish, M.D., medical director of the California Pacific Medical Center's Liver Transplant Program. "With today's FDA approval of Baraclude, physicians have an important new medication to treat chronic hepatitis B."

Chronic hepatitis B infection is a potentially life-threatening disease. More than half a million people worldwide die each year from primary liver cancer, and up to 80 percent of primary liver cancers are caused by chronic hepatitis B. In the United States, more than one million people have developed chronic hepatitis B infection and more than 5,000 Americans die from hepatitis B and hepatitis B-related liver complications each year.

"Despite these alarming statistics, it is estimated that only a small percent of diagnosed chronic hepatitis B patients in the U.S. are currently receiving treatment for their disease," said Timothy Block, Ph.D., president, Hepatitis B Foundation and professor, Drexel Medical College. "The availability of Baraclude (entecavir) is an important development that provides a new option for therapy."

Baraclude is a nucleoside analogue with a recommended dosage of a single 0.5-milligram tablet once-daily for chronic hepatitis B patients beginning treatment for the first time (nucleoside-naïve patients), and a single 1-milligram tablet once-daily for patients experiencing resistance to lamivudine (lamivudine-refractory patients).

The Baraclude clinical trial program was the largest-ever conducted in chronic hepatitis B, and the first to compare two antivirals, Baraclude versus lamivudine (the most commonly used oral antiviral therapy for the treatment of chronic hepatitis B worldwide). In these studies after 48 weeks, Baraclude demonstrated statistically significant improvements compared to lamivudine in liver histology, HBV viral load reductions to undetectable levels (defined as less than 300 copies/mL) and normalization of alanine aminotransferase (ALT) levels (less than or equal to 1 times the upper limit of normal), a measure used to determine the degree of liver damage.

In these studies, Baraclude demonstrated comparable safety to lamivudine with a favorable resistance profile. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including Baraclude and lamivudine. The most common side effects of Baraclude in clinical studies were headache, tiredness, dizziness, and nausea. Cross resistance has been observed among HBV nucleoside analogues. Lamivudine-resistant patients may not respond as well as nucleoside-naïve patients to Baraclude therapy.