Vertex licenses early-stage polymerase inhibitors...

Interesting licensing deal between Vertex and Alios BioPharma for two preclinical HCV polymerase inhibitors. With so many promising HCV compounds in the later stages of development and only so many of the lucrative insured baby boomer Tx naive population to go around, you have to wonder about this deal... Unless Vertex is laying down the foundation for an HCV resistance arms race similar to what we've experienced in the HIV therapeutic category. Could Vertex ultimately cash in on a problem they helped create with Telaprevir resistance? i

Vertex licenses Hep C candidates in milestone-heavy deal

Vertex Pharmaceuticals Inc. of Cambridge and Alios BioPharma Inc. of South San Francisco, Calif., have announced a deal under which Vertex will license two Alios compounds designed to be inhibitors of the hepatitis C virus polymerase enzyme.

With the deal, Vertex said it has multiple opportunities to develop new, all-oral combination regimens for chronic hepatitis C. Vertex expects the nucleotide drug candidates, ALS-2200 and ALS-2158, wto enter clinical development later this year.

In return for Vertex gaining worldwide rights to the hepatitis C drug candidates, Alios gets a $60 million upfront payment and research and development costs of ALS-2200 and ALS-2158 covered by Vertex. The Cambridge pharmaceutical firm could pay up to $715 million in R&D milestone payments if both drugs are approved, and up to $750 million more if both drug candidates then meet sales milestones.

The announcement came just weeks after Vertex won approval from the U.S. Food and Drug Administration for its hepatitis C drug, Incivek.

“The recent approval of Incivek was a milestone in hepatitis C care, and today’s announcement underscores our long-term commitment to further improving the treatment of this disease with new combinations of medicines,” said Peter Mueller, Ph.D., chief scientific officer and executive vice resident of global research and development at Vertex in a press release. “Alios has discovered anti-HCV nucleotides that have the potential to be leading agents in hepatitis C. Based on impressive in vitro data, we look forward to evaluating ALS-2200 and ALS-2158 together and in combination with our approved and investigational hepatitis C medicines with the goal of creating a highly potent all-oral regimen in the years ahead.”

Approval of Incivek also spurred Vertex to sign a lease for a new headquarters in Boston’s waterfront innovation district.

 

Diana Sylvestre article on the possibilities of HCV resistance in underserved populations with the new DAA agents....

A sobering article on the very real possibility of HCV resistance developing in underserved population in the June 9, 2011 issue of NATURE by O.A.S.I.S. Executive Director, Diana Sylvestre. On a personal note, I had the great honor of calling on her while I worked at Vertex. Truly one of the most remarkably compassionate human beings I have ever met. Don't let that fool you, because I also had the experience of being with her when she stared down a former patient wielding a golf club. This is one tough lady.

Published online 08 June 2011

The hepatitis C virus is endemic among injection drug users, who could harbour treatment-resistant viruses. We need to adapt to this reality, says Diana Sylvestre

Diana Sylvestre informs her patient that the hepatitis C virus has re-emerged six months after treatment.

The first antiviral agents that act directly on the hepatitis C virus (HCV) are about to hit the market. Healthcare workers have been awaiting the release of these new medications for some time, in the hope that treatment response rates would improve, even in populations of patients who are challenging to treat. But underneath the glow of anticipation lies a concern about poorly characterized risks, including the emergence of drug-resistant viral strains. The real-world impact of this risk is unclear as most of those who contract the virus do so through injection drug use and are disregarded from clinical trails.

The new protease inhibitors can elicit resistance even in patients who follow dosing regimens. But when corners are cut, risk rises. Shortening treatment, as new regimens promise to do, might reduce the burden of side effects. But the day-to-day misery will be worse with triple regimens than with the standard dual treatment, and it is important to appreciate the human tendency to reduce or skip doses of medications that make us feel ill.

Injection drug users are more complex patients: many have an unstable housing situation, unreliable transport or subject to prescription refill delays owing to insurance company bungling, which they are poorly equipped to deal with. They might be arrested and jailed during treatment. So, even though studies have shown that injection drug users have similar medication compliance rates to non-drug users4, 5, 6, external circumstances may prevent the medication fidelity that is expected and needed.

So far, modestly reduced adherence to the interferon-α and ribavirin therapy has not led to viral resistance. Taking only 80% of the prescribed interferon and ribavirin dosages for 80% of the projected duration of treatment is sufficient to achieve optimal response rates. This allows those who treat injection drug users (including me) enough latitude to be successful. We have been able to reduce the burden of HCV in those who are most at risk of transmitting it.

Unfortunately, there is no such information on new treatment regimens. It is unclear at what point reduced adherence may become a problem. The virus rapidly mutates, so the antiviral 'pressure' exerted by the medication needs to be maintained so mutant viruses are constantly destroyed. Such protease-inhibitor-resistant strains can persist for at least three years after the withdrawal of medication1, 2, 3. And the conformational changes that underpin resistance to one protease inhibitor may also confer resistance to other inhibitors of that protease — a phenomenon called class resistance. And worse: if active injection drug users become reservoirs of protease inhibitor resistance, these viral strains could predominate, requiring the kind of therapeutic arms race that we see in other infections such as HIV and Staphylococcus aureus.

Regulators should require that clinical trials consider current or former injection drug users. This is not currently being done. The US Food and Drug Administration (FDA) Guidance for Industry document encourages trial sponsors to initiate trials early in drug development for “special populations” with unmet needs: transplant patients, people co-infected with HIV and HCV, and those with decompensated, or severe, cirrhosis. The document fails to mention injection drug users. It is as though they don't exist. If diabetics or out-of-care asthmatics were at risk, the approach would be different. Instead, the FDA has turned its back on the majority population with HCV and is approving new drugs despite having almost no understanding of their potential to cause long-term harm.

Because HCV affects those on the fringes of society, large-scale treatment studies have not been representative of the face of the disease. Their doctors are not invited to enroll them in trials. Therefore, little is known about which patients are good candidates for treatment, the importance of adherence to the treatment regimen and the outcomes in the real world — this ignorance leaves addicted HCV patients subject to the vagaries of a medical system that might not welcome them. This is unacceptable from both a humanist and a public-health standpoint.

It is time that regulators, pharmaceutical companies and healthcare workers come to terms with the fact that many patients with HCV are injection drug users. These patients must be included in safety, tolerability and efficacy trials; regulatory studies should include clinics where HCV-infected drug users are seen. And study investigators should be more representative of the kinds of doctors that usually care for these patients.

The new therapies raise the possibility of eradicating hepatitis C. But that won't happen unless the key parties in this medical drama develop a more realistic approach to understanding and treating this disease.

Pharmasset Announces the Expansion of the ELECTRON Trial in Chronic Hepatitis C

Pharmasset adding arms to it's genotype 2/3 ELECTRON trial looking at shorter durations of therapy in addition to inteferon-free monotherapy for it's PSI-7977 nucleotide analog. Nucs traditionally have a very high barrier to resistance in comparison to non-nucs, but with a virus capable of making every possibly mutation of itself in the course of a day, is nuc monotherapy without an immune system modulator or another viral life cycle-specific inhibitor enough, even in the relatively easy-to-treat G2 and 3 virus? If it's not, what are the odds of a PSI-7977 resistant quasispecies developing and the corresponding fitness level compared to wild type of those variants? Guess we'll find out soon enough. If anyone can shed further enlightenment, please do.

PRINCETON, N.J., June 8, 2011 /PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today the addition of three treatment cohorts to the ELECTRON trial of PSI-7977, a nucleotide analog polymerase inhibitor, for the treatment of chronic hepatitis C (HCV). The rapid and consistent antiviral effects and high barrier to resistance demonstrated with PSI-7977 to date provide the rationale for additional exploratory regimens in this setting. This amendment will add one arm exploring 12 weeks of PSI-7977 monotherapy (without peginterferon and ribavirin) and two arms of interferon-sparing therapy: one for 8 weeks of PSI-7977 plus peginterferon and ribavirin (Peg-IFN/RBV) in patients with HCV genotype 2 (GT2) or 3 (GT3) and one for 12 weeks of PSI-7977 plus Peg-IFN/RBV in patients with HCV genotype 1 (GT1) prior null responses.

"The combination data reported at EASL demonstrated that SVRs were achievable with two oral DAAs in the absence of peginterferon and ribavirin," stated Bill Symonds, PharmD, Pharmasset's Senior Vice President of Clinical Pharmacology and Translational Medicine, "We continue to explore the potential for removing peginterferon and ribavirin from the HCV treatment regimen. Given the encouraging data we are seeing in ELECTRON, we have decided to expand the study to investigate PSI-7977 monotherapy, as well as shorter treatment regimens based on the promising data we reported at EASL from PROTON."

Pharmasset anticipates reporting results from the first four arms of the trial (n=40) during the second half of 2011. We have submitted a number of abstracts to the 2011 American Association for the Study of Liver Diseases (AASLD) meeting, including data from the ELECTRON and PROTON trials.

About the Trial

The ELECTRON trial is an exploratory study of PSI-7977 for the treatment of chronic HCV infection. Part 1 of the trial is evaluating 12-week regimens of PSI-7977 400mg QD in combination with ribavirin (RBV) only, and in separate arms with abbreviated durations of Peg-IFN for 4, 8, or 12 weeks in treatment-naive patients with HCV GT2 or GT3. The primary endpoint of the trial is the safety and tolerability of PSI-7977 400mg QD and RBV for 12 weeks, administered with or without Peg-IFN. On May 11, 2011, Pharmasset announced the completed enrollment of Part 1 of ELECTRON in patients with HCV GT 2 or GT 3:

* PSI-7977 400mg with RBV for 12 weeks (no peginterferon);
* PSI-7977 400mg with RBV for 12 weeks; Peg-IFN weeks 1-4 only;
* PSI-7977 400mg with RBV for 12 weeks, Peg-IFN weeks 1-8 only;
* PSI-7977 400mg with Peg-IFN and RBV for 12 weeks.


In Part 2 of ELECTRON, Pharmasset will enroll an additional 30 patients into exploratory regimens of monotherapy and abbreviated durations of total therapy. Following on the first four Cohorts of ELECTRON a 5th cohort will be added to explore 7977 400mg monotherapy in treatment-naive patients with HCV GT2 or GT3:

* PSI-7977 400mg monotherapy for 12 weeks.


With the previously reported 100% SVR12 in naive GT2/3 subjects in PROTON, a 6th and 7th cohort will be added to ELECTRON to explore shorter treatment durations in both GT2/3 naive subjects and HCV GT1 subjects who have documented null responses (less than 2 log(10) IU/mL reduction in HCV RNA after 12 weeks of Peg-IFN/RBV):

* PSI-7977 400mg with Peg-IFN/RBV for 8 weeks
* PSI-7977 400mg QD with Peg-IFN/RBV for 12 weeks.


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 the development of oral therapeutics for the treatment of hepatitis C virus (HCV) infection. Our research and development efforts are focused on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have three clinical-stage product candidates advancing in trials in various populations. Our pyrimidine, PSI-7977, an unpartnered uracil nucleotide analog, is currently under study in three Phase 2b trials in patients with HCV genotypes 1 through 6, including abbreviated duration interferon and interferon-free regimens. Our purine, PSI-938, an unpartnered guanosine nucleotide analog, recently reported safety and efficacy data from 14 days of monotherapy as well as 14 days in combination with the pyrimidine, PSI-7977. An SVR-endpoint study of the purine-pyrimidine combination is anticipated to begin in the third quarter of 2011. Mericitabine (RG7128) continues in two Phase 2b trials and one interferon-free trial being conducted through a strategic collaboration with Roche.

Contact
Richard E. T. Smith, Ph.D.
VP, Investor Relations and Corporate Communications
Office: +1 (609) 865-0693

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," 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, 2010 and our Quarterly Reports on Form 10-Q 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.

Heavy Coffee Consumption Linked to Better Hep C Treatment Response...

The growing amount of evidence seems to support that a good ol' cup o' joe is good for your liver, even better if you happen to be on antiviral therapy for HCV. A synopsis of a study published in the June issue of 'Gastroenterology' below.

Heavy Coffee Consumption Linked to Better Hep C Treatment Response

By: MARY ANN MOON, Internal Medicine News Digital Network

06/01/11

|
Patients with advanced hepatitis C virus–related liver disease who drank three or more cups of coffee per day were three times more likely to respond to therapy with peginterferon alfa-2a plus ribavirin at four time points than were patients who didn’t drink coffee, Neal David Freedman, Ph.D., and his colleagues reported in the June issue of Gastroenterology.

The reason for this benefit is not yet known, but it appears that coffee drinkers’ improved response was independent of other factors known to influence hepatitis C virus (HCV) virologic response to therapy, such as the patient’s race, serum HCV RNA level, the presence or absence of cirrhosis, and the AST/ALT (aspartate aminotransferase/alanine aminotransferase) ratio, said Dr. Freedman of the National Cancer Institute and his associates.


In this study of patients with advanced liver disease related to hepatitis C, 61% of the heavy coffee drinkers tolerated the full dose of peginterferon alfa-2a plus ribavirin, while only 50% of the non–coffee drinkers did so.

In previous studies of hepatic disease, coffee drinking has been associated with lower levels of liver enzymes, a reduced progression of chronic liver disease, and a decreased incidence of hepatocellular carcinoma. But coffee’s effect in chronic HCV infection has not been studied until now.

The investigators examined coffee intake and virologic response to treatment using data from the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial, which involved patients with chronic hepatitis C who had fibrosis or cirrhosis at baseline, showed no sign of hepatic decompensation or hepatocellular carcinoma, and had failed to respond to interferon therapy.

For this study, Dr. Freedman and his colleagues assessed 885 subjects who completed a food frequency questionnaire at the beginning of the study. This included a measure of the portion size and frequency of coffee and tea intake, but did not distinguish between caffeinated and decaffeinated drinks and did not differentiate black tea from green tea.

A total of 85% of the subjects were coffee drinkers, and 15% of subjects drank three or more cups per day, which was defined as heavy coffee consumption.

The data showed that 61% of the heavy coffee drinkers tolerated the full dose of peginterferon alfa-2a plus ribavirin, while only 50% of the non–coffee drinkers did so (P = .0015). Heavy coffee drinkers also were less likely to require a dose reduction because of either a low neutrophil count or a low platelet count.

The decline in serum HCV RNA levels during treatment was greater with higher coffee intake. In addition, the absolute levels of HCV RNA were lower in heavy coffee drinkers than in nondrinkers at weeks 12, 20, and 24 of treatment. These benefits were seen even though higher coffee consumption had been associated with higher initial HCV RNA levels at baseline, the researchers noted.

In addition, heavy coffee drinkers were more likely than nondrinkers to show a virologic response early in the course of treatment (73% vs. 46%), to show no detectable serum HCV RNA at week 20 (52% vs. 26%), to show no detectable serum HCV RNA at week 48 (49% vs. 22%), and to have a sustained virologic response (26% vs. 11%).

Adjustment of the data to account for potential confounding factors such as age, sex, race, alcohol use, the presence of cirrhosis, the AST/ALT ratio, the baseline HCV RNA level, and the HCV genotype attenuated the associations with coffee somewhat, but the correlations remained significant at each virologic response end point.

The association between heavy coffee drinking and improved virologic response persisted in a subgroup analysis of only white patients, and it was actually stronger in patients with an unfavorable genotype (positive for the IL28B SNP rs12979860) than in those with a favorable genotype (negative for that SNP).

In contrast to these findings for coffee, there were no associations between tea drinking and treatment response.

Coffee contains more than 1,000 compounds, "any one of which could be involved in the virologic response." This study could not differentiate any possible role for caffeine, a major constituent of coffee.

However, "it is unlikely that coffee or its constituents have a direct antiviral effect. If so, HCV RNA levels at baseline would have been expected to be lower with greater coffee consumption," when in fact they were higher. It is more likely that coffee facilitates the response to peginterferon and ribavirin by some mechanism that is not yet understood, perhaps related to its association with cholesterol or with insulin resistance.

"As in all observational studies, we cannot exclude unmeasured or residual confounding as an explanation for our results. Observed associations could also simply be due to chance," Dr. Freedman and his associates said.

For that reason, further studies are needed to replicate these results in other populations, they added.

This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, the National Center for Research Resources, and Hoffman–La Roche. One of Dr. Freedman’s associates reported ties to Hoffmann–La Roche (now Genentech) and Tibotec.

Analysts speculate on PSI-7977 possibly receiving earlier than anticipated FDA approval...

From Forbes.com

Associated Press
Ahead of the Bell: Pharmasset shares rise
Associated Press, 06.03.11, 09:02 AM EDT

NEW YORK -- A Citi Investment Research analyst said Friday that Pharmasset Inc.'s leading hepatitis C drug candidate could be approved sooner than expected, and he nearly tripled his price target on Pharmasset shares.

Shares of the Princeton, N.J., company rose $3.33, or 3.3 percent, to $104.20 in pre-market trading.

Analyst Yaron Werber said the drug candidate, which is designated PSI-7977, could be approved as soon as mid-2014 to treat two relatively rare types of hepatitis C.

Werber previously thought PSI-7977 wouldn't reach the market until late 2015, and he raised his target on Pharmasset ( VRUS - news - people ) to $200 per share from $71 to reflect the chances of an earlier approval, which would boost sales of the drug.

Werber said PSI-7977 could get to the market sooner if it is approved to treat hepatitis C genotypes 2 and 3, which make up a minority of cases. In late May, Pharmasset started a mid-stage clinical trial of PSI-7977 as a treatment for hepatitis C genotypes 1, 2, and 3. Genotype 1 makes up about 70 percent of hepatitis C diagnoses. Werber said he thinks the drug "will have solid data and will be one of the dominant drugs in hepatitis C."

The analyst said Pharmasset should present study data in November and should start late-stage studies in early 2012. He thinks the company will be profitable in 2016.

Ever wonder who came up with the brand name "Incivek"?

I have an insatiable interest in the business side of drug development paralleled only by my equally insatiable interest in nearly useless drug development trivia. So thank the Gods for self-congratulatory PR statements from brand consulting companies to feed the need. If you ever wondered who came up with the brand name for Telaprevir, look no further.

Addison Whitney Develops Name for Newly Approved Hepatitis C Treatment

Global branding firm names newly approved INCIVEK.

(PRWEB) June 03, 2011

Addison Whitney is pleased to announce the FDA approval of INCIVEK™ (telaprevir) from Vertex Pharmaceuticals Incorporated. INCIVEK is a prescription medication used with peginterferon alfa and ribavirin. The new drug will treat chronic hepatitis C genotype 1 infection in adults with stable liver problems who have not been treated before or who have failed previous treatment.

After developing the name INCIVEK, Addison Whitney streamlined the approval process by conducting safety validation research and providing Vertex with supporting documentation for the FDA review. “This was a true collaboration with our clients at Vertex that required a time sensitive approach to all aspects of the naming process,” said Daniel Plaisance, Vice President.

INCIVEK is expected to become a leading treatment for hepatitis C. FDA panelists said it appeared to raise the cure rate for hepatitis C to about 80 percent, compared with 40 percent with current therapies. The FDA has approved INCIVEK tablets for a broad group of people with genotype 1 chronic hepatitis C with compensated liver disease (some level of damage to the liver but the liver still functions), including cirrhosis (scarring of the liver).

“This is a very exciting time for Addison Whitney Health,” said Senior Vice President Vince Budd. “Not only is it great to see another one of our brands approved for a potential blockbuster product, but it showcases our high success rate of getting names approved by the global health authorities. Our clients have already received a number of approvals for names our company created, screened, tested and supported this year; and I look forward to seeing many more over the coming months.”

About Addison Whitney:
Addison Whitney is a global, full-service brand consulting firm. Founded in 1991, the firm offers branding expertise in the areas of verbal branding, visual branding, brand strategy, and research and analysis. Clients come to Addison Whitney from industries including: consumer, technology, business to business, financial, hospitality and other market segments. Addison Whitney health, a specialized healthcare division of Addison Whitney, serves the branding needs of pharmaceutical, biotechnology, life science, and medical specialties. For more information, visit http://www.addisonwhitney.com.

For more information please contact Sara Abadi at 704-697-4039 or sara.abadi(at)addisonwhitney(dot)com.

New trials looking at treating HCV genotypes 1,2,3,4 and 5 with Pharmasett's PSI-7997

New studies that popped up in Clinical Trials.gov looking at Pharmasett's PSI-7977 with and without Peg in Genotypes 1, 2, 3, 4 and 5. Many thanks to the good people over at NATAP.org for the heads' up on these trials.


PSI-7977 With Pegylated Interferon and Ribavirin Hepatitis C Virus (HCV) Genotypes 1,4,5,6 (ATOMIC)


Open-Labeled Study of PSI-7977 and RBV With and Without PEG-IFN in Treatment-Naïve Patients With HCV GT2 or GT3