June 14, 2010

Breast Cancer Patients with HCV Can Be Treated with Cytotoxic Therapy


By Laura Dean

MedWire News: Patients with breast cancer and chronic hepatitis C virus (HCV) infection can be treated effectively with cytotoxic chemotherapy, US researchers have found.

“Although HCV is the most common blood-borne infection in the United States, little information exists about treatment of breast cancer in the setting of chronic HCV,” note Phuong Khanh Morrow and colleagues from the University of Texas MD Anderson Cancer Center in Houston.

To gain further insight, Morrow and colleagues retrospectively reviewed data for 45 patients (98% women) with invasive breast cancer and HCV who were treated at the MD. Anderson Cancer Center between 2000 and 2008.

In all, 36 (80%) patients received chemotherapy for their breast cancer. The remaining nine patients received either endocrine therapy alone (n=7), or no systemic therapy at all (n=2).

During chemotherapy, nine (25%) patients experienced elevations in aminotransferases and 16 (44%) patients required dose reductions, or had delays in chemotherapy.

“In almost all cases, dose reductions or delays were necessitated by complications of therapy, rather than due to elevations of transaminases,” say Morrow et al.

“However, it is possible that elevations in baseline transaminases could have contributed to the side effects observed, as liver function is a determinant of the metabolism of several of the chemotherapeutic agents utilized,” they add.

There was a high rate (63.9%) of complications that were grade 2 or greater, based on the National Cancer Institute Common Terminology Criteria for Adverse Events. The most common complications were neutropenic fever or infection, non-neutropenic infection, and neuropathy.

In spite of this, the vast majority (92%) of patients were able to complete the number of cycles specified in the initial chemotherapy plan.

“As the majority of these breast cancer patients completed the initial chemotherapy plan, this study indicates that breast cancer patients with HCV can be treated with cytotoxic therapy,” conclude Morrow and co-authors in the Annals of Oncology.

“Comparison with historical controls showed similar rates of hepatic toxicity in the presence (or absence) of HCV, indicating that incidence of transaminitis may not be significantly affected by HCV,” they add.

Ann Oncol 2010; 21: 1233–1236


A New Target for Hepatitis C Virus


by Vincent Racaniello

When infection with hepatitis C virus goes from acute to chronic, severe liver disease may occur which requires organ transplantation. Nearly 200 million people are chronically infected with HCV, necessitating approaches to preventing and treating infections. No HCV vaccine is available, and current antiviral therapy consists of administration of interferon plus ribavirin, a combination that is effective about half the time and is associated with undesirable side effects. New antiviral compounds that target a viral protease and RNA polymerase are currently in clinical trials may eventually reach the market. But our experience with HIV-1 has shown that combinations of three drugs are the most effective for derailing the emergences of drug resistant viruses. The third target for HCV could be NS5A, a viral protein without a known function.

To identify new inhibitors of HCV, a chemical library of one million compounds was screened for the ability to inhibit viral replication in cell culture. The active compound were then subjected to a second screen to eliminate inhibitors of known viral enzymes: the viral protease, RNA polymerase, and helicase. One of the remaining inhibitors was further refined chemically until a very potent derivative was obtained. This molecule, called BMS-790052, has a 50% inhibitory concentration in the picomolar range, and inhibits all the viral genotypes tested. It is the most powerful inhibitor of HCV discovered.

The compound was tested for safety and bioavailability in various animal species. After oral administration, the compound was found in plasma and liver, despite a molecular mass of over 700 daltons. Six different levels of the compound were tested in HCV infected individuals. No adverse effects were reported, and the highest amount administered reduced viral levels in the blood 2,000 fold after one day. These results are promising, but larger trials will now be needed to further confirm the safety and efficacy of the drug.

What is the target of BMS-790052? Two lines of evidence suggest that the compound inhibits the viral protein NS5A. The drug appears to bind NS5A, and viruses resistant to the drug have amino acid changes in this protein. Although NS5A is known to be required for viral replication, its precise function is not known. Because NS5A does not have an easily assayable enzymatic function, it has not previously been a target of drug discovery. The identification of a compound that inhibits NS5A function is an important step forward in HCV drug development. The general approach used to discover BMS-790052 should be useful in identifying inhibitors of other viral proteins that do not have well defined and measurable activities.

I discussed this paper on Futures in Biotech episode #60. If you would like to listen only to the conversation about BMS-790052, download this mp3 file.

Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, Serrano-Wu MH, Langley DR, Sun JH, O’Boyle DR 2nd, Lemm JA, Wang C, Knipe JO, Chien C, Colonno RJ, Grasela DM, Meanwell NA, & Hamann LG (2010). Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature, 465 (7294), 96-100 PMID: 20410884


Sustained Virological Response at 12 Weeks Post-treatment May be as Good as 24 Weeks for Determining Interferon Cure

SUMMARY: People who continue to have undetectable hepatitis C virus (HCV) viral load 12 weeks after completing a course of therapy -- sometimes called SVR-12 -- are as likely to remain free of the virus over the long term as those tested 24 weeks post-treatment, according to a study published in the April 2010 issue of Hepatology. This suggests that clinical trial results 12 weeks after finishing treatment may be an accurate measure of sustained virological response.

By Liz Highleyman

Sustained virological response (SVR) to hepatitis C treatment is usually defined as continued undetectable HCV viral load 24 weeks after completion of therapy. Michelle Martinot-Peignoux and colleagues from France evaluated whether assessment of serum HCV RNA 12 weeks after the end of treatment was as relevant as 24 weeks for determining SVR.

The investigators analyzed sustained treatment outcomes among 573 chronic hepatitis C patients who received pegylated interferon (Pegasys or PegIntron) plus ribavirin and had an end-of-treatment virological response. Viral load was measured using a sensitive TMA assay with a lower limit of 5-10 IU/mL. Viral relapse was defined as reappearance of detectable HCV-RNA between the end of treatment and post-treatment week 24.

  • All 573 participants had undetectable HCV RNA at the end of treatment.
  • At 12 weeks post-treatment, 409 participants still had undetectable viral load.
  • At 24 weeks post-treatment, 408 participants (71%) achieved SVR.
  • Looking back at week 12 results, all but 1 of the patients who were undetectable at week 12 remained so at week 24.
  • Week 12 response had a positive predictive value of 99.7% for predicting Week 24 SVR.
The researchers concluded that assessment of serum HCV RNA 12 weeks after the end of treatment using a highly sensitive TMA assay "is as relevant as after 24 weeks to predict SVR and make decisions on the management of treated patients, suggesting a new definition for SVR.

"Institut National de la Santé et de la Recherche Médicale, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Université Paris VII, Paris, France; Service d'Hépatologie, Hopital Beaujon, Clichy, France.



M Martinot-Peignoux, C Stern, S Maylin, and others. Twelve weeks posttreatment follow-up is as relevant as 24 weeks to determine the sustained virologic response in patients with hepatitis C virus receiving pegylated interferon and ribavirin. Hepatology 51(4):1122-1126 (Abstract). April 2010.


Presidio Pharmaceuticals Selects PPI-1301 as Second Hepatitis C Virus NS5A Inhibitor for Development

SUMMARY: Presidio Pharmaceuticals announced late last month that it has selected a second hepatitis C virus (HCV) NS5A inhibitor -- designated PPI-1301 -- for further testing in clinical trials. The function of the NS, or non-structural, 5A sequence in the HCV genome is not fully understood, but it appears to play a role in viral replication. Combining NS5A inhibitors with HCV protease (NS3/4A) and polymerase (NS5B) inhibitors may increase antiviral potency and slow emergence of drug resistance.

Below is an excerpt from a recent Presidio press release describing the selection of PPI-1301.

Presidio Pharmaceuticals, Inc. Selects SecondClinical Candidate From Hepatitis C Virus NS5A Inhibitor Program

San Francisco, CA -- May 26, 2010 -- Presidio Pharmaceuticals, Inc. announced today that they have selected a second clinical candidate, PPI-1301, from their hepatitis C virus (HCV) NS5A program for advancement into clinical development. Presidio's first NS5A inhibitor, PPI-461, is currently undergoing evaluation in a Phase 1a clinical study.

Inhibitors of the HCV NS5A protein represent an exciting, highly potent class that is distinct from other classes of HCV antivirals that target the viral protease or replicase. With poor response and tolerance issues associated with the current standard of care treatment -- pegylated-IFN [interferon] and ribavirin -- there is clear need for more potent and better tolerated inhibitors that can be administered orally in future combination therapies.

PPI-1301 was derived from a chemical series that is distinct from PPI-461, but similar to PPI-461, exhibits potent and selective activity against all HCV genotypes in HCV replicon assays. PPI-1301 also shows good oral bioavailability and tolerance in animal studies, with elevated liver concentrations relative to serum levels, as well as the potential for once daily dosing in humans. IND-enabling studies for PPI-1301 are currently underway.

"The selection of PPI-1301 underscores Presidio's continued commitment to generating best-in class compounds for treating HCV," commented Richard Colonno, PhD, Chief Scientific Officer, who added, "The advancement of PPI-1301 further demonstrates the breadth and depth of our NS5A program pipeline."

About Presidio Presidio Pharmaceuticals, Inc. is a San Francisco-based specialty pharmaceutical company dedicated to the discovery and development of small-molecule antiviral therapeutics for novel and validated targets. For more information, please visit our website at: http://www.presidiopharma.com/.


SourcePresidio Pharmaceuticals. Presidio Pharmaceuticals, Inc. Selects Second Clinical Candidate From Hepatitis C Virus NS5A Inhibitor Program. Press release. May 26, 2010.


Pharmasset Announces Submission of Abstracts to AASLD Liver Meeting Including an Interim Analysis of

Pharmasset, Inc. announced today that the interim results from the PROPEL study conducted by its partner Roche demonstrate that RG7128 triple combination therapy was safe and well tolerated. In that study, the safety profile of RG7128 (1000mg BID or 500mg BID), when administered for 8 or 12 weeks with Pegasys (peginterferon alfa-2a) and Copegus (ribavirin), the standard of care (SOC), was similar to the safety profile of SOC alone. An interim analysis of the study included all safety data from all 408 patients who had completed the first 12 weeks of the study. The most common adverse events were no different than those frequently noted with SOC alone. There were no findings related to rash, anemia, bone marrow suppression, or nephrotoxicity across any of the arms.

The PROPEL study is evaluating the dose and duration of treatment of RG7128 in combination with SOC in patients with chronic hepatitis C virus (HCV) genotype 1 or genotype 4 who have not been treated previously. The interim analysis also included on-treatment efficacy data demonstrating that >80% of patients had undetectable HCV RNA in all cohorts receiving the 12-week triple regimen compared to <50% for the placebo/SOC cohort. The safety and efficacy results from the interim analysis of the PROPEL Phase 2b study of RG7128 have been submitted by Roche as an abstract to AASLD for the Annual Liver Meeting (October 29 to November 2, 2010).
The title of the abstract is:

"High rates of early viral response, promising safety profile and lack of resistance-related breakthrough in HCV GT 1/4 patients treated with RG7128 plus PegIFN alfa-2a (40KD)/RBV: Planned Week 12 interim analysis from the PROPEL study"

"We are encouraged by the reported efficacy, safety, and resistance data from this interim analysis of the PROPEL study," said M. Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "We believe safety, absence of resistance, as well as antiviral potency will all be important considerations as HCV treatment incorporates direct acting antivirals in combination with interferon, and in potential interferon-free antiviral combination regimens."

No viral rebounds or resistance-related breakthroughs were noted during the first 8 or 12 weeks of triple combination therapy, consistent with the demonstrated high barrier to resistance in earlier RG7128 clinical studies. In clinical reports to date, the S282T mutation associated with RG7128 resistance in vitro has not been detected at baseline in HCV-infected patients enrolling in clinical trials. A separate abstract has been submitted by Roche including details of the resistance analyses that have been conducted during this study, including sequencing of the HCV RNA from all patients at baseline. The abstract is entitled:

"No evidence of drug resistance or baseline S282T resistance mutation among GT1 and GT4 HCV infected patients on nucleoside polymerase inhibitor RG7128 and Peg-IFN/RBV combination treatment for up to 12 weeks: interim analysis from the PROPEL study."

About the Phase 2b PROPEL Study

The Phase 2b study enrolled 408 patients with HCV genotypes 1 or 4, cirrhotic and non-cirrhotic, who have not been treated previously. The primary efficacy endpoint of the study is the proportion of patients who achieve an SVR, defined as HCV below the limit of detection (<15 IU/mL as measured by Roche TaqMan assay) 24 weeks after completion of all treatment. The study is being conducted in North America, Europe, and Australia. Patients were enrolled into one of 5 arms:

-- 24 weeks of total treatment; RG7128 500mg BID in combination with SOC for 12 weeks, followed by 12 weeks of SOC ("12+12", RVR guided)

-- 24 weeks of total treatment; RG7128 1000mg BID in combination with SOC for 12 weeks, followed by 12 weeks of SOC ("12+12", RVR guided)

-- 24 weeks of total treatment; RG7128 1000mg BID in combination with SOC for 8 weeks, followed by a further 16 weeks of SOC ("8+16", RVR guided)

-- 48 weeks of total treatment; RG7128 1000mg BID in combination with SOC for 12 weeks, followed by a further 36 weeks of SOC ("12+36", non-RVR guided")

-- A control arm with SOC for 48 weeks. Patients in the 24-week arms will discontinue all treatment at week 24 if they have achieved RVR, defined as HCV RNA below the limit of detection (<15 IU/mL) at week 4 and maintain these low levels of HCV RNA until week 22, a strategy known as "RVR-guided" treatment. Patients who do not meet these criteria will continue on the standard of care until week 48.

RG7128 is also currently being evaluated in a Phase 2b study in which RG7128 and SOC are given for a total of 24 weeks each ("24+0", RVR guided). The regimen will be assessed in treatment-naive HCV-infected patients with genotypes 1 or 4. Enrollment in this study was completed in early May. In addition, Roche anticipates the initiation of another Phase 2 study in HCV-infected patients with genotypes 2 or 3 by the end of 2010.

About Pharmasset Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis C virus (HCV) and, secondarily, on the development of Racivir(TM) for the treatment of human immunodeficiency virus (HIV). Our research and development efforts focus on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have four clinical-stage product candidates. RG7128, a cytosine analog for chronic HCV infection, is in two Phase 2b clinical studies in combination with Pegasys(R) plus Copegus(R) and is also in the INFORM studies, the first series of studies designed to assess the potential of combinations of small molecules without Pegasys(R) and Copegus(R) to treat chronic HCV.
These clinical studies are being conducted through a strategic collaboration with Roche. Our other clinical stage HCV candidates include PSI-7977, an unpartnered uracil nucleotide analog that has recently completed a Phase 2a study, and PSI-938 an unpartnered guanine nucleotide analog in Phase 1. We also have in our pipeline an additional purine nucleotide analog, PSI-661, an isomer of PSI-879, in advanced preclinical development. Racivir, for the treatment of HIV, has completed a Phase 2 clinical study.

Pegasys® and Copegus® are registered trademarks of Hoffman-La Roche, Inc.

Contact Richard E. T. Smith, Ph.D. VP, Investor Relations and Corporate Communications Office: +1 (609) 613-4181

Forward-Looking Statements

Pharmasset "Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release that are not historical facts are "forward-looking statements," including, without limitation, statements that involve risks, uncertainties, and other important factors, including, without limitation, the risk of cessation or delay of any of the ongoing or planned clinical trials and/or our development of our product candidates, the risk that the results of previously conducted studies involving our product candidates will not be repeated or observed in ongoing or future studies involving our product candidates, the risk that our collaboration with Roche will not continue or will not be successful, and the risk that any one or more of our product candidates will not be successfully developed and commercialized. For a discussion of risks, uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in our Annual Report on Form 10-K for the fiscal year ended September 30, 2009 and our Quarterly Reports on Form 10-Q for the periods ended December 31, 2009 and March 31, 2010 filed with the Securities and Exchange Commission and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission.

Source: Pharmasset, Inc.


Early treatment key to combating hepatitis C virus

Sunday, June 13, 2010

Patients who receive timely treatment for the Hepatitis C virus after infection develop a comprehensive immune response against the virus, according to a new study published in the Journal of Virology.

Therefore, early treatment can restore immune response against Hapatitis C virus and help to eliminate it rapidly. This new discovery of the mechanisms of viral eradication could spur development of new treatments.

About a quarter of infected individuals are known to eradicate the infection spontaneously, sans treatment, according to the study.

Led by Naglaa Shoukry and Julie Bruneau, affiliated to both the UniversitÈ de MontrÈal Hospital Centre and the UniversitÈ de MontrÈal, as well as with other researchers, the study found that early treatment restores a rapid poly-functional immune response, characterized by simultaneous production of multiple antiviral mediators.

HCV is transmitted through infected blood. Although a quarter of infected patients can eradicate the infection spontaneously, the majority develop persistent infection, a major cause of cirrhosis and cancer of the liver.

The only approved treatment for HCV is an anti-viral drug known as pegylated interferon alpha. This drug is successful in only half of cases when administered during chronic infection. Success rates among those treated early after infection are significantly higher or around 90 percent.

In North America alone, most new HCV infections occur among intravenous drug users (IDUs), a vulnerable population that is often undiagnosed and untreated. In the study, researchers followed a group of IDUs at high risk of HCV infection before and immediately after exposure to HCV. Their findings clearly show the importance of early diagnosis and treatment of HCV - particularly in marginalised populations such as IDUs and aboriginal populations.


Success of Hepatitis C Drugs May Depend on Gene Variant

SATURDAY, June 12 (HealthDay News) -- A genetic variant associated with poor response to treatment for hepatitis C infection has been identified by scientists.

The researchers analyzed the DNA of 1,362 hepatitis C patients and pinpointed the variant in those who failed to respond to treatment. The variant occurs in a gene called IL28B, which encodes for the antiviral cytokine (cell-signaling) interferon lambda.

The study was to be presented Saturday at the annual conference of the European Society of Human Genetics.

Current treatment for hepatitis C includes a combination of an interferon and the antiviral medication ribavirin. Side effects are common and can be so serious that some people have to take time off work.

Identifying hepatitis C patients with this genetic variant could spare them from suffering side effects from a treatment that will provide them with little benefit, said the scientists at the University of Lausanne in Switzerland in a news release from the European Society of Human Genetics.

The research may also help in the development of new treatments, they said.

More information

The American Academy of Family Physicians has more about hepatitis C.
-- Robert Preidt
SOURCE: European Society of Human Genetics, news release, June 12, 2010


Trouble for Human Genome's Zalbin

by Meera Venu 14 Jun 10

Human Genome Sciences HGSI announced Monday that it received feedback from the Food and Drug Administration about its application for hepatitis C drug Zalbin. The FDA cast doubt about the risk-benefit profile of the bimonthly dosing regimen. The firm had already withdrawn the drug's application in Europe after the European regulatory authority indicated it would require more data on the risk-benefit profile to approve the drug. Now Human Genome and its partner Novartis NVS need to decide whether to pursue the drug in a monthly dose format, which is currently under development. We previously had doubts about Zalbin and have incorporated pessimistic projections for the drug in our forecasts. At this point, we do not expect to change our fair value estimate, as lowering the U.S. probability of approval to 50% and pushing the potential launch back two years does not significantly alter our valuation. However, we would consider lowering our fair value estimate modestly if the partners decide not to pursue Zalbin


Idenix Pharmaceuticals initiates Phase I/II hepatitis study

Posted on: Mon, 14 Jun 2010 13:10:37 EDT

(Datamonitor via COMTEX) --
Idenix Pharmaceuticals, a biopharmaceutical company, has initiated a Phase I/II, three-day proof-of-concept study of IDX320, a protease inhibitor for the treatment of hepatitis C virus, or HCV, infection, under a clinical trial application.

The study is evaluating IDX320 in treatment-naive hepatitis C genotype 1-infected patients. The proof-of-concept trial in HCV-infected patients is a Phase I/II randomized, parallel-arm, double-blind, placebo-controlled study evaluating the safety and antiviral activity of IDX320 in treatment-naive adult patients infected with chronic hepatitis C.

The study will evaluate four doses of IDX320, ranging from 50 to 400mg once-per-day, administered for three days. Each cohort of the study will evaluate eight patients randomized six to IDX320 and two to placebo.

Jean-Pierre Sommadossi, CEO of Idenix, said: "The potent and multi-genotypic activity demonstrated in vitro, as well as the favorable pharmacokinetics observed in healthy volunteers, suggests a promising profile for further development of IDX320. The landscape for combination development in HCV is evolving quickly. Assuming favorable results from the IDX320 proof-of-concept study, we plan to discuss with regulatory agencies a direct-acting antiviral combination strategy with IDX320 and IDX184, our HCV nucleotide polymerase inhibitor."