Seeking Alpha - Achillion Pharmaceuticals: Hope, Hype, And Hep C

An article appearing 3/27/12 by Stephen Simpson on Seeking Alpha.com - one of the more level-headed articles appearing on that particular site in recent months, IMO (admittedly, coming from me, that might not mean much!). It's very hard to be prescient in regards to Achillion's future in HCV, but with a wholly-owned, advancing pipeline diversified among viral targets, it has to be considered at least somewhat of a target of companies like Merck, J&J and Vertex that need to fill holes in their pipeline or need compounds with synergistic activity. Mr. Simpson also gives a quick rundown of what's happening in the HCV drug development marketplace as well as some apocryphal statistics on HCV infection within South America that could feasibly boost the value of the HCV market considerably by 2016 over current thinking, in his estimation.   


Achillion Pharmaceuticals: Hope, Hype, And Hep C

By Stephen Simpson - Seeking Alpha

I've followed biotech for a long time now, and I have a hard time thinking of an example of another addressable market like hepatitis C (HCV) where investor interest has just exploded in the space of about a year. Like antisense, monoclonal antibodies, RNAi, genomics, stem cells and every other hot property in biotech, there has been no end of hope, hype, and hucksterism. Although HCV is likely to grow into a very financially significant drug target in the coming years, it's worth wondering just how much of the frenzy today can be justified in long-term valuations.

In particular, I'm curious about Achillion Pharmaceuticals (ACHN) these days. I've watched this stock for a while now and came close to buying on multiple times in the pre-2010 pre-$2 level. I underestimated just how fast this market would heat up, though, and had to re-learn a painful lesson - sometimes, you snooze and you lose.

Achillion jumps out as the only serious HCV play I'm aware of with a market cap below $1 billion (while Idenix (IDIX) is hardly a giant at $1.1 billion). Not only is it relatively small, but it also may be one of the relatively few players with its own home-grown effective combination therapy.

Of course everything Achillion is working on in HCV is still in the clinic and as Gilead (GILD) showed so clearly recently, "surprising" clinical results are not always positive surprises. The end result, then, is that this may be the next Pharmasset or just another biotech destined to flame out.

The Good - Interesting Compounds All Their Own

Achillion has at least two HCV antivirals well worth watching - ACH-1625 and ACH-3102.

ACH-1625 is a potentially pangenotypical NS3 protease inhibitor (PI) that has shown both solid efficacy and encouraging safety in early studies. Showing both strong efficacy and safety thus far, it could perhaps be the backbone for future combination therapies. That said, pangenotypical efficacy is not yet established and the compound still has not gone through a pivotal Phase 3 study.

The good news with antivirals is that, unlikely oncology and anti-inflammatory drugs, efficacy signals in early pilot studies often hold up through pivotal studies. What's more, these studies are relatively easy to enroll and can be completed expeditiously. What that all means for investors is that ACH-1625 could have a relatively quick path to market.

Achillion is also developing ACH-3102, a NS5a inhibitor, and expects to put it in human studies soon. This drug looks like it should be less subject to resistance and the company (as well as bulls) seem more excited about this drug than the more advanced ACH-2928 (also a NS5a inhibitor). Coupled with ACH-1625, this could be a very interesting combo therapy, but it's worth mentioning that almost every drug is interesting to bulls going into Phase 2 studies.

These aren't the only drugs in Achillion's HCV pipeline, and the company does have identified experimental compounds targeting bacterial infections and HIV. It should be noted too that Achillion's HCV pipeline is wholly-owned.

The Bad - Competition, And Expectations, Left Right And Center

Achillion is very definitely not going to be the first company to market with new HCV drugs, and there is apt to be extensive competition in the market. That is not only going to place a premium on the SVR efficacy data and safety profile, but also potentially on the marketing muscle of the company in question.

Since its acquisition of Pharmasset, Gilead was put in the pole position in the race to develop blockbuster HCV drugs. That is, until the company reported Phase 2 data on the superstar-to-be '7977 that showed it is not 100% perfect. Specifically, this Phase 2 study indicated that '7977 may not be effective in null responders (patients who have failed to respond to earlier treatments), and may give new hope to alternate approaches that include a NS5a inhibitor or NS3 protease inhibitor.

That said, a little perspective is in order. Maybe '7977 isn't flawless, but SVR-12 rates of 91% in genotype 1 and 100% in genotypes 2 and 3 in a thus far safe drug is still pretty impressive. Moreover, Gilead is looking at a variety of combination possibilities and while the company would certainly love to have "the one antiviral to rule them all", being a part of a blockbuster combination therapy is not a bad consolation prize.

Along Gilead and Achillion is a host of companies developing therapies and a sea of drugs known more by number than by name.

Bristol-Myers Squibb (BMY) has its NS5a inhibitor daclatasvir well along in studies, a PI ('032), and the NS5b inhibitor it acquired with the Inhibitex deal, as well as other earlier stage compounds. The NS5a inhibitor has shown solid efficacy, and its PI/NS5 combo showed 100% SVR without PEG-interferon or ribavarin.

Of course there are many more. Abbott (ABT) has its own all-oral combination (NS5a and PI), as does Roche (RHHBY.PK), although the efficacy in the Roche compounds has not been as encouraging. Johnson & Johnson (JNJ) has its TMC435 PI that it in-licensed from Medivir, and Boeringher Ingelheim has its PI as well. Indenix has a nucleotide inhibitor and NS5a inhibitor in trials and a non-nuc in preclinical development.

Last and not least are Vertex (VRTX) and Merck (MRK). These companies have brought the two newest HCV drugs to market (Incivek and Victrelis, respectively). Vertex has a PI in trials and two nucleotide inhibitors licensed in from Alios, while Merck's PI has seen a significant setback tied to safety issues.

A Quick Rundown On The Market, Prospects, And Deals

The oft-repeated statistic on HCV says that there are between 130 million and 170 million infected persons around the world. Approximately 4 million of those are in the U.S., with another 5 million the EU. By way of comparison, Brazil is thought to have at least 7 million HCV patients, India at least 10 million, and China 43 million.

Untreated HCV offer leads to severe chronic liver disease (including cirrhosis), but the long-used PEG-interferon and ribavirin therapy (dominated by Roche and Merck) has had success rates of below 50% in long-term usage.

That efficacy underlies a lot of the market expectation on HCV drugs. While the pre-Incivek/Victrelis HCV market was estimated to be about $3 billion (with $2.5 billion of that going to PEG-inteferon), analysts believe better efficacy could drive that figure close to $10 billion in 2016.

Admittedly, that's a large number. It may not be completely out of line, though, if these 90%+ SVR rates hold up in pivotal studies. Offer people with a serious lifelong illness a safer, more effective drug that is also easier to take and you can almost always charge a premium for it. Also, think about it this way - the U.S. and European insurance/payer systems are willing to pay several tens of thousands of dollars for cancer therapies that offer a few extra months of median survival benefit, so there's clearly a willingness to pay for better clinical outcomes.

What's this all mean for Achillion?

I could see ACH-1625 garnering perhaps up to a billion in sales if the early results hold all the way through studies. Moreover, there's the potential to be had from the combo therapy; whether that's in combination with another Achillion drug or a rival compound (like, say, Gilead's '7977). If Achillion could garner $1 billion in sales, that would translate into a fair value of $13 to $18 per share today based upon your forward multiple estimate (6x or 8x).

I'm sure $1 billion in sales will sound too small to Achillion bulls. Fair enough; if the early results hold up, maybe it's an even bigger blockbuster, but it looks like there are going to be a lot of competing therapies on the market and good marketing is going to deliver sales even in inferior compounds.

It may well be the case, though, that Achillion never makes it to the point where its sales matter. I would be quite surprised to see Achillion partner its drugs, but I think a buyout could well happen. Certainly there have been plenty of chatter on that subject, what with Gilead and Bristol-Myers paying up for HCV compounds (and Roche also making some deals of its own).

So how does the M&A scene break out? I don't think Bristol-Myers would need Achillion, and I don't think Gilead would go that route either unless a '7977/ACH-1625 really showed something special. Johnson & Johnson may think it needs non-PI partner compounds and may not want to pay for the overlap between their PI programs.

That said, I think there are a lot of names left that could be interested. Merck arguably needs a better protease inhibitor, and likewise Roche, Abbott, and Vertex may find that they need better compounds than they presently have. Companies like Sanofi (SNY) and GlaxoSmithKline (GSK) aren't doing much here today, but could find Achillion to be a ready-made HCV platform. Odds are, though, that Achillion holds out a bit for a desperate buyer - not because there's anything wrong with its pipeline, but because a desperate Merck or Roche may pony up a better deal if they feel pressure.

The Bottom Line

Taking a midpoint of that earlier $13-$18 range, I'd say Achillion may be worth about $15.50 a share today. Annoyingly, that's almost spot on with the current consensus number. I do believe there could be more upside as its pipeline matures and rivals run into problems, but I usually want more than 50% undervaluation before buying into a new biotech story.

Disclosure: I am long RHHBY.PK

British Columbia expands HCV coverage to include Victrelis...

Article posted on 3/26/12 via Vancouver 24 hours. Looks like Victrelis is now available in British Columbia via PharmaCare for patients with genotype 1 infection. 

B.C. expands coverage for hep C

By ERICA BULMAN, 24 HOURS

PharmaCare coverage for eligible patients with chronic hepatitis C (genotype 1) is being expanded to include the drug boceprevir, approved by Health Canada in July 2011.

New hep C patients who haven’t been treated, those who have relapsed after treatment or responded only partially to another treatment, will be eligible.

Boceprevir is taken in combination with two other drugs — peginterferon and ribavirin — over 24 to 44 weeks.

“The rapid approval of boceprevir is a major step forward towards the potential future elimination of hepatitis C infections in British Columbians,” said Dr. Mel Krajdenof the BC Centre for Disease Control. “Viral cure is known to reduce mortality, improve quality of life and prevent progression of liver disease.”

Without PharmaCare or private drug plan coverage, boceprevir would cost patients about $1,050 per week, the province estimated.

In clinical trials, patients who’d never received treatment and took the boceprevir combination had a 25% higher cure rate over those who didn’t.

In patients unsuccessful in other therapies, the boceprevir cure rate was 38% higher than those who received peginterferon and ribavirin alone.

There are about 64,000 British Columbians currently diagnosed with hep C, 25% of whom have cleared their infection without treatment, according to the province.

Untreated the disease can result in liver failure and death.

Hepatitis C virus induces oxidative stress, DNA damage and modulates the DNA repair enzyme NEIL1...

Article below posted 3/25/12 on Someone Somewhere.com - interesting article appearing in 'Journal of Gastroenterology and Hepatology'  on how HCV may induce oxidative stress which could compromise the repair of damaged DNA, leading to liver cirrhosis and hepatocellular carcinoma. 

Hepatitis C virus induces oxidative stress, DNA damage and modulates the DNA repair enzyme NEIL1
— 03/25/2012
   
Hepatitis C virus (HCV)-induced chronic inflammation may induce oxidative stress which could compromise the repair of damaged DNA, rendering cells more susceptible to spontaneous or mutagen-induced alterations, the underlying cause of liver cirrhosis and hepatocellular carcinoma. In the current study we examined the induction of reactive oxygen species (ROS) resulting from HCV infection and evaluated its effect on the host DNA damage and repair machinery.

Methods:  HCV infected human hepatoma cells were analyzed to determine (i) ROS, (ii) 8-oxoG and (iii) DNA glycosylases NEIL1, NEIL2, OGG1. Liver biopsies were analyzed for NEIL1.

Results:  Human hepatoma cells infected with HCV JFH-1 showed 30–60-fold increases in ROS levels compared to uninfected cells. Levels of the oxidatively modified guanosine base 8-oxoguanine (8-oxoG) were significantly increased sixfold in the HCV-infected cells. Because DNA glycosylases are the enzymes that remove oxidized nucleotides, their expression in HCV-infected cells was analyzed. NEIL1 but not OGG1 or NEIL2 gene expression was impaired in HCV-infected cells. In accordance, we found reduced glycosylase (NEIL1-specific) activity in HCV-infected cells. The antioxidant N-acetyl cystein (NAC) efficiently reversed the NEIL1 repression by inhibiting ROS induction by HCV. NEIL1 expression was also partly restored when virus-infected cells were treated with interferon (IFN). HCV core and to a lesser extent NS3-4a and NS5A induced ROS, and downregulated NEIL1 expression. Liver biopsy specimens showed significant impairment of NEIL1 levels in HCV-infected patients with advanced liver disease compared to patients with no disease.

Conclusion:  Collectively, the data indicate that HCV induction of ROS and perturbation of NEIL1 expression may be mechanistically involved in progression of liver disease and suggest that antioxidant and antiviral therapies can reverse these deleterious effects of HCV in part by restoring function of the DNA repair enzyme/s

Source: Journal of Gastroenterology and Hepatology

Medgenics gets OK to start Phase IIa trial of their EPODURE biopump...

Article posted 3/23/12 on Proactive Investors.com. Israel-based Medgenics gets Israeli Ministry of Health OK to being a Phase IIa trial of it's EPODURE biopump to treat HCV, anemia & haemophilia. The technology will allow patients to continuously produce and maintain their own proteins without dangerous variations in PK.   


Medgenics gets approval to begin Phase IIa clinical study on EPODURE biopump

Fri 11:17 am by Giles Gwinnett

Medgenics has received the green light to begin a Phase IIa clinical study on its EPODURE which is used to treat anaemia.

The company has received clearance from the Israeli Ministry of Health to begin the study, it said.

The firm's biopump system sees a tiny sliver of the patient's tissue taken and modified to carry the gene to enable it to continuously produce the required protein to treat the condition.

It is is developing three applications of the technology - to treat anaemia, hepatitis-C and haemophilia.

The study, announced today, will involve 20 patients and will asess EPODURE's ability to replace months of routine injections for anaemic patients who have end-stage renal failure - or kidney disease.

Each patient will receive an individually targeted initial dose of EPODURE biopumps designed to produce levels of the protein that would replace the routine injections over a period of 4-12 months.

President and CEO of the firm Andrew Pearlman said he expected the phase IIa study to build on the positive clinical results from the earlier Phase I/II study of EPODURE to treat pre-dialysis patients with chronic kidney disease.

"This is the first clinical study that will permit adjustment of the EPODURE dose based on patients' needs as is currently done in standard EPO (erythropoietin) treatment, and will be standard in future EPODURE use.

"This represents a significant change from the fixed-dose study we previously conducted in pre-dialysis patients," he said.

Dr Pearlman added that the company's EPODURE Biopump technology offered potential advantages over current therapy because it enabled patients to continuously produce and deliver their own proteins.

"Sustained delivery of EPO is expected to help keep hemoglobin within the target range to reduce the risks of hemoglobin variability, while avoiding the possible risks posed by EPO concentrations many times the normal physiological range, as observed with EPO administrations.

"EPODURE could potentially be a safer anemia management tool. Additionally, the cost benefits for the management of anemia could be highly significant," he said.

EASL abstracts to be available online April 4, 2012...

Posted on 3/22/12 on The Street.com. EASL will now allow full access to clinical data abstracts online on April 4, 2012. 

EASL Backs Down, Will Publicly Disclose Key Hep C Data
By Adam Feuerstein    03/22/12

BOSTON (TheStreet) -- The European Association for the Study of the Liver, better known as EASL, has backed down and will no longer unfairly and selectively disclose potentially stock-moving hepatitis C clinical data ahead of its important and closely followed conference next month.

In a total reverse of its previous policy, EASL said Thursday that research abstracts for its International Liver Congress, taking place April 18-22 in Barcelona, would be made publicly available online on April 4. Clinical data in the abstracts will not be under embargo, meaning journalists will be allowed to report on them.

"EASL is making these changes in light of recent criticism of its proposed policy, which suggests 'selective distribution' of officially accepted clinical data in advance of the Congress would make our proposed embargo policy untenable," EASL said in a statement issued Thursday.

The EASL meeting is where Gilead Sciences, Bristol-Myers Squibb, Abbott, Idenix Pharmaceuticals, Vertex Pharmaceuticals and Merck are among the companies expected to present new clinical data on experimental hepatitis C therapies. Therefore, the meeting is as vitally important to hepatitis C doctors and patients as it is to investors.

Yet under its old policy, EASL wanted to provide an advance look at potentially market-moving hepatitis C drug data to the medical society's members or registered attendees of the EASL meeting -- a group which includes hedge fund/mutual fund portfolio managers and sell-side analysts, all of whom can pay for early access.

EASL had planned to selectively distribute hepatitis C drug research abstracts to these folks today. The same documents were not going to be made available to the public, which meant that a select group of investors would have had access to potentially stock-moving clinical data while a majority of investors were to be kept in the dark.

In columns published Tuesday and Wednesday, I criticized EASL's abstract distribution policy as being misguided, unfair and quite frankly unworkable. Smarter medical and scientific groups like the American Society of Clinical Oncology (ASCO) realized years ago that trying to compartmentalize research abstracts was futile. Information cannot be selectivity disclosed and expected not to leak, especially information that will weigh on the market valuations of biotech and drug firms involved in new hepatitis C drug research.

EASL, to its credit, has now admitted the unfairness of its policy and took the necessary corrective steps.

In its statement Thursday, EASL said it "accepts that we must address this issue, and we acknowledge the efforts of several individuals to draw this to our attention."

--Written by Adam Feuerstein in Boston.

The Street.com: EASL Gives Wall Street's Privileged Investors Sneaky Preview to Key Hep C Data

Article posted on The Street.com on 3/20/12. Spring is in the air, and that means that one of the most important meetings in HCV drug development - EASL - is right around the corner.  The Street author Adam Feuerstein is none too pleased on EASL's rather elitist approach to disseminating important data ahead of time to only a chosen, privileged few. He's right - and he's also right that EASL's attempt at keeping this data embargoed until the actual start of the conference is pert near impossible.  The time has come for reform and revolution. I'd be right there on the front lines, but there's too much good stuff on TV. 

EASL Gives Wall Street's Privileged Investors Sneaky Preview to Key Hep C Data

By Adam Feuerstein    03/20/12 - 10:45 AM

Update: After this column was published, EASL announced a delay in the release of research abstracts for the International Liver Congress to Tues. March 27.

BARCELONA (TheStreet) -- Investing in hepatitis C drug stocks is a suckers bet this week because the European Association for the Study of the Liver, better known as EASL, has rigged the game so that Wall Street's privileged investors get a sneak peek at new clinical data ahead of an important and closely followed conference next month.

EASL's International Liver Congress, taking place April 18-22 in Barcelona, is the must-follow medical meeting of the spring. Gilead Sciences, Bristol-Myers Squibb, Abbott, Idenix Pharmaceuticals, Vertex Pharmaceuticals and Merck are among the companies rolling out new clinical data on experimental hepatitis C therapies.

But if you want an advance look at potentially market-moving hepatitis C drug data, you'll have to be an EASL member or a registered attendee of the EASL meeting -- a group which includes hedge fund and mutual fund portfolio managers and sell-side analysts, all of whom can pay for early access.

EASL plans to selectively distribute hepatitis C drug research abstracts to these folks on Thursday. The same documents will not be made available to the public. That means a select group of investors will have access to potentially stock-moving clinical data while a majority of investors will be kept in the dark.

Journalists registered to cover the EASL meeting will also be granted early access to hepatitis C research abstracts but they are barred by EASL's restrictive embargo rules from writing about any new data until the start of the April meeting.

EASL's abstract distribution policy is misguided, unfair and quite frankly unworkable. Smarter medical and scientific groups like the American Society of Clinical Oncology (ASCO) realized years ago that trying to compartmentalize research abstracts was futile. Information cannot be selectivity disclosed and expected not to leak, especially information that will weigh on the market valuations of biotech and drug firms involved in new hepatitis C drug research.

That's why most medical and scientific groups made research abstracts freely available to everyone in advance of major conferences.

Jacqui Sisto, an EASL spokesperson, explained via email that selective disclosure of research abstracts "ensures the integrity of the International Liver Congress." Really? EASL appears to be corrupting its most important meeting, not making it more honest.

The Motley Fool takes on universal testing for HCV...

Article posted on 3/16/12 on Motley Fool.com. The Motley Fool's Brian Orelli, Ph.D on the economics of universal testing for HCV. He makes the case that drug companies should leverage public policy to uncover as many potential patients as possible. What Dr. Orelli missed is that every HCV drug development company with skin in the game is already doing that through the Viral Hepatitis Action Coalition. A good read anyway.

Hep C Drugmakers' Best Outcome


By Brian Orelli, PhD

March 16, 2012

Treating hepatitis C is a losing proposition. Unlike treatments for chronic diseases -- high blood pressure or diabetes, for instance -- if a hepatitis C drug does its job, the patient is cured. It's a one-and-done treatment. Since the hepatitis C epidemic peaked many years ago, hepatitis C drugmakers need to find a new source of patients.

A report published in Clinical Infectious Diseases might have the solution: people who are already infected, but don't know it yet.

Current guidelines recommend testing only people who have identified risk factors such as drug use, blood transfusions before blood-bank testing began in 1992, or unexplained liver-function abnormalities, for example -- but that misses a substantial number of infected individuals. Estimates vary, but somewhere between 50% and 75% of people infected with hepatitis C don't know it.

Most probably have the risk factors, but they're unwilling to admit to the drug use, especially if it was years ago, or have forgotten about the blood infusion. Or the doctors aren't asking the right questions to identify the risk factors -- it's a touchy subject, you know.

The solution: Test everyone. You'll get a lot of negative results -- less than 2% of the population is infected -- but you'll catch those who might not have been diagnosed before they progress to serious liver problems.

The researchers plugged everything from costs to cure rates to likelihood of progression of liver disease and a lot of additional parameters into one giant formula and concluded that it would be cost-effective to screen everyone between the age of 20 and 69. Hepatitis C leads to liver cancer and other complications, and eliminating the cost of a liver transplant -- a quarter-of-a-million-dollar procedure -- can make up for a lot of $20 tests.

Sounds good, in theory

One journal article isn't going to change public policy; that will require a recommendation from the Centers for Disease Control and Prevention, which is a slow and methodical process.

If the CDC does institute universal testing for adults, hepatitis C test makers would certainly benefit. Just keep in mind that there's substantial competition out there: Abbott Labs (NYSE: ABT ) , Roche, Siemens, and OraSure Technologies (Nasdaq: OSUR ) all sell hepatitis C tests. They don't disclose margins on individual tests, but considering the number of players involved, I'd have to guess they aren't great.

Drugmakers developing hepatitis C treatments will be the real beneficiaries if more people are diagnosed. With the cost of treatment in the $80,000 range, each new patient is quite valuable.

That is, if they're treated
As the authors of the paper point out, screening is cost-effective -- and makes drugmakers money -- only if the patients who test positive are actually treated. Hepatitis C is a chronic infection that takes years to do any real damage in patients. Unlike cancer, where there's an immediate need for treatment, hepatitis C patients can take their time.

That could mean patients are lost to follow-up. It could also mean patients wait until drugs go off patent and there are cheap generics available before taking the drugs.

Identifying more patients is good, but they're not going to be moneymakers without the help of doctors.

Something companies can control
The cure rate of hepatitis C drugs is one of the factors that determine whether testing is worth the effort. If there were no way to treat patients, identifying infected patients would be only marginally useful.

As it is, Vertex Pharmaceuticals' (Nasdaq: VRTX ) Incivek has increased the standard of care substantially. Roche's Pegasys and Merck's (NYSE: MRK ) Pegintron cure about half of the patients, while adding Incivek increases that to around 70%.

As Gilead Sciences (Nasdaq: GILD ) , Abbott, and others develop better drugs, and we get closer to 100% cure rates, the benefit of testing will increase. It would be nice to have the patients waiting when the second-round of oral medications are approved, but drugmakers might have to get the drugs approved first and then show that identifying additional patients is beneficial.

UCSD chemists uncover target for new class of HCV Direct Acting Antivirals...

Article posted 3/19/12 on Science Daily.com. UCSD scientists, using X-ray crystallography, uncover a new drug target for the class of drugs called 'benzimidazoles' whose MOA is to act directly on the HCV virus' RNA.

Discovery Provides Blueprint for New Drugs That Can Inhibit Hepatitis C Virus


ScienceDaily (Mar. 19, 2012) — Chemists at the University of California, San Diego have produced the first high resolution structure of a molecule that when attached to the genetic material of the hepatitis C virus prevents it from reproducing.

Hepatitis C is a chronic infectious disease that affects some 170 million people worldwide and causes chronic liver disease and liver cancer. According to the Centers for Disease Control and Prevention, hepatitis C now kills more Americans each year than HIV.

The structure of the molecule, which was published in a paper in this week's early online edition of the journal Proceedings of the National Academy of Sciences, provides a detailed blueprint for the design of drugs that can inhibit the replication of the hepatitis C virus, which proliferates by hijacking the cellular machinery in humans to manufacture duplicate viral particles.

Finding a way to stop that process could effectively treat viral infections of hepatitis C, for which no vaccine is currently available. But until now scientists have identified few inhibiting compounds that directly act on the virus's ribonucleic acid (RNA) genome -- the organism's full complement of genetic material.

"This lack of detailed information on how inhibitors lock onto the viral genome target has hampered the development of better drugs," said Thomas Hermann, an associate professor of chemistry and biochemistry at UC San Diego who headed the research team, which also included scientists from San Diego State University. The team detailed the structure of a molecule that induces the viral RNA to open up a portion of its hinge-like structure and encapsulate the inhibitor like a perfectly fit glove, blocking the ability of the hepatitis C virus to replicate.

The molecule is from a class of compounds called benzimidazoles, known to stop the production of viral proteins in infected human cells. Its three-dimensional atomic structure was determined by X-ray crystallography, a method of mapping the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread. The angles and intensities of the light beams allowed the scientists to calculate the structure of the viral RNA-inhibitor complex.

"This structure will guide approaches to rationally design better drug candidates and improve the known benzimidazole inhibitors," said Hermann. "Also, the crystal structure demonstrates that the binding pocket for the inhibitors in the hepatitis C virus RNA resembles drug-binding pockets in proteins. This is important to help overcome the notion that RNA targets are so unlike traditional protein targets that drug discovery approaches with small molecule inhibitors are difficult to achieve for RNA."

The study was supported by the National Institutes of Health and National Science Foundation.

Okairos AG begins mid-stage trial of preventative vaccine for HCV...

Posted 3/14/12 via Bloomberg.com .  Swiss company Okairos AG begins mid-stage trial looking a what it hopes to be the first preventative vaccine for the Hepatitis C virus. 

Former Merck Unit Works on First Vaccine for Hepatitis C
By Makiko Kitamura - Mar 14, 2012 1:00 AM PT

Okairos AG, a biotechnology business that Merck & Co. (MRK) sold to venture capital funds in 2007, is seeking to produce the first preventive vaccine for hepatitis C, challenging makers of treatments for the disease.

Okairos has begun a mid-stage study, funded by the U.S. National Institutes of Health, of a gene-based vaccine designed to stimulate the body’s immune system to prevent hepatitis C from taking hold, Chief Operating Officer Tom Woiwode said in a phone interview from the company’s Basel, Switzerland, headquarters.

No vaccine exists for hepatitis C, which affects as many as 170 million people globally, putting them at risk of developing liver cancer, according to the World Health Organization. The growing population of patients infected with the virus spurred Gilead Sciences Inc. (GILD)’s decision in November to buy experimental hepatitis C-treatment maker Pharmasset Inc. for $10.8 billion and Bristol-Myers Squibb Co. (BMY)’s acquisition in February of Inhibitex Inc. for $2.5 billion.

“This could change the landscape quite a bit,” said Les Funtleyder, a health-care strategist and portfolio manager at Miller Tabak & Co. in New York. “In theory, if you could vaccinate everyone, you’d need a lot less drug.” Funtleyder said he isn’t aware of any other preventive vaccines in development.
Disease Transmission

Okairos’s vaccine would target those who may be at risk of infection. The disease is most commonly transmitted through contaminated blood transfusions, organ transplants, contaminated syringes and needle-injected drug use, according to the WHO.

Most preventive vaccines stimulate the production of antibodies, molecules produced by the immune system as part of the body’s defenses. Development of Okarios’s vaccine was triggered by studies of patients with early-stage hepatitis C, of whom about 20 percent spontaneously clear the virus and avoid advancing to the chronic phase, Woiwode said.

Researchers have found those patients tend to have a strong response in the blood’s T cells, Woiwode said. Armed with that knowledge, Okairos developed technology that delivers genetic material to stimulate T cells, the white blood cells that help the body fight diseases.

This approach contrasts with most other vaccines, which stimulate an antibody response, Woiwode said.

“We’ve opened up a new path that will allow us to address a number of diseases, hepatitis C being the first one,” he said in the interview yesterday.

Even if a vaccine is approved, medicines are needed to treat patients already infected, Miller Tabak’s Funtleyder said.

Industry Projects
Merck and Vertex Pharmaceuticals Inc. (VRTX) won approval last year for the first new therapies for hepatitis C in almost a decade. Johnson & Johnson (JNJ), a partner in the Vertex drug, is also cooperating with Swedish drugmaker Medivir AB (MVIRB) on a hepatitis treatment. Basel-based Roche Holding AG (ROG) agreed in October to buy Anadys Pharmaceuticals Inc., another maker of experimental medicines for hepatitis C, for about $230 million.

Profectus Biosciences Inc., a Baltimore-based vaccine manufacturer, is also developing a drug that prevents patients with early-stage hepatitis C from advancing to the chronic stage. The company plans clinical trials of the product in 2013.

Investors in Okairos, which is also developing malaria, cancer and flu vaccines, include Boehringer Ingelheim Venture Fund, Life Sciences Partners, Novartis Venture Funds and Versant Ventures. The Swiss company has also received grants from the European Union and the Bill and Melinda Gates Foundation.

The company is in discussions with potential partners for marketing the vaccine, Woiwode said.

“I have no doubt that if this Phase 2 study is successful, there will be no shortage of interest to work with us to bring this to the market globally,” he said.
To contact the reporter on this story: Makiko Kitamura in London at mkitamura1@bloomberg.net

To contact the editor responsible for this story: Phil Serafino at pserafino@bloomberg.net

TMC435 going head-to-head with Telaprevir in Phase III study...

Press release posted 3/13/12 on Medivir.com. Viral Matters editor comments: Medivir is feeling pretty confident in it's HCV protease inhibitor TMC435, so confident that the company has commenced in screening patients for a head-to-head Phase III 744 patient genotype 1 null and partial responder trial vs Telaprevir + P/R. This trial should give everyone a clearer picture on TMC435's efficacy in this difficult-to-treat population vs the new Standard of Care. Pretty gutsy. I like it. 

Medivir announces new studies in phase III program for TMC435

13-Mar-12
· Study in previous non-responder Hepatitis C genotype-1 infected patients
· Study in Hepatitis C genotype-4 infected patients

Huddinge, Sweden – MedivirAB (OMX: MVIR) a research based specialty pharmaceutical company focused on infectious diseases announces that its oral, once daily investigational protease inhibitor TMC435, developed by Janssen Pharmaceuticals for the treatment of Hepatitis C virus (HCV), has commenced patient dosing and started screening in two new phase III clinical trials, HPC3001 and HPC3011, respectively.

HPC3001
HPC3001 is a phase III efficacy, safety and tolerability study comparing TMC435 versus telaprevir, each in combination with Pegylated Interferon α-2a (PegINF) and ribavirin (RBV), in hepatitis C genotype-1 infected patients who were null or partial responders to prior PegINF/RBV therapy. The study which is a randomized, double-blind, double-dummy, two-arm study is targeted to enroll 744 patients.

The aim of the study is to demonstrate the efficacy of TMC435 based therapy compared to the approved telaprevir regimen in this difficult to treat population.

Patients will receive TMC435 150 mg once daily or telaprevir 750 mg administered every eight hours (q8h) in combination with PegINF/RBV for 12 weeks followed by 36 weeks of PegIFN/RBV alone. The primary endpoint of the study is sustained virological response at 12 weeks (SVR12).

HPC3011
HPC3011 is an open label, single arm phase III trial to explore the efficacy, safety and tolerability of TMC435 150 mg once daily, in combination with PegIFN/RBV in 100 treatment naïve or treatment experienced, Hepatitis C genotype-4 infected patients.

Current standard of care treatment for chronic HCV genotype-4 infection consists of 48 weeks of PegIFN/RBV with a large proportion of patients do not achieve SVR with this treatment regimen.

All subjects will receive 12 weeks triple therapy of TMC435 150 mg once daily and PegIFN/RBV, followed by PegIFN/RBV alone. The duration of total treatment is response guided in treatment naïve and prior relapser subjects and patients are eligible to stop all treatment at week 24 if predefined response-guided criteria are met. Subjects with cirrhosis will receive 48 weeks of therapy, irrespective of on-treatment virologic response and treatment history. The primary endpoint in the study is SVR12.

TMC435 - Ongoing global phase III program in brief:

· TMC435-C208 or QUEST-1 in 375 treatment-naïve genotype-1 patients
· TMC435-C216 or QUEST-2 in 375 treatment-naïve genotype-1 patients
· TMC435-C3007 or PROMISE in 375 genotype-1 patients who have relapsed after prior interferon-based treatment
· Phase III program in Japan, includes 417 genotype-1 treatment naïve and treatment experienced patients

Charlotte Edenius, Executive VP Research and Development, of Medivir commented,
"We are extremely pleased to expand the phase III program with these two new trials as we continue development of TMC435 for broad patient populations. The 744 patient HPC3001 study is aimed at further confirming the positive findings of the ASPIRE phase IIb trial in genotype-1 non-responder patient populations and in the HPC3011 study, the genotype-4 activity of TMC435 is being investigated.”

For more information about Medivir, please contact:
Medivir Mobil: +46 708 537 292
Rein Piir, EVP Corporate Affairs & IR
M:Communications Medivir@mcomgroup.com
Europe: Mary-Jane Elliott, Amber Bielecka, Hollie Vile +44(0)20 7920 2330

About TMC435
TMC435 is an investigational HCV protease inhibitor in late phase III clinical development. It is an efficacious, safe and well-tolerated once-daily  (q.d.) drug jointly developed by Janssen Pharmaceuticals to treat chronic hepatitis C virus infections.

TMC435 is in phase III clinical development in combination with PegIFN/RBV but is also being evaluated with Direct-acting Antiviral (DAA) agents in interferon-free combinations both with and without ribavirin (RBV).

For additional information please visit www.medivir.com and www.clinicaltrials.gov

About Hepatitis C
Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The WHO estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.

About Medivir
Medivir is an emerging research-based specialty pharmaceutical company focused on the development of high-value treatments for infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is TMC435, a novel protease inhibitor in phase III clinical development for hepatitis C that is being developed in collaboration with Janssen Pharmaceuticals.

In June 2011, Medivir acquired the specialty pharmaceutical company BioPhausia to ensure timely commercialisation of TMC435 in the Nordic markets, once approved.

Medivir’s first product, the unique cold sore product Xerese®/Xerclear®, was launched on the US market in 2011. Xerese®/Xerclear®, which has been approved in both the US and Europe, is being launched in collaboration with GlaxoSmithKline to be sold OTC in Europe, Japan and Russia. Rights in North America, Canada and Mexico were sold to Meda AB in June 2011. Medivir has retained the Rx rights for Xerclear® in Sweden and Finland.

For more information about Medivir, please visit the Company’s website: www.medivir.com

Seeking Alpha.com: Will Medgenics Become The Next Hepatitis C Take Over Candidate?

Posted on 3/12/12 on Seeking Alpha.com. The following comments by the Viral Matters editor: Seeking Alpha contributor Ray Dirks speculates that Medgenics - with it's proprietary EPODURE (for anemia) and INFRADURE (for interferon) biopump devices - would be an attractive candidate for take over. EPODURE might be a go, but the market for INFRADUR could be severely limited to disease states outside of HCV if 'interferon free' therapy becomes a reality.  As it is only in preclinical trials, INFRADUR has plenty of time to see where the 2nd and 3rd generation of anti-HCV Direct Acting Antivirals take us

Will Medgenics Become The Next Hepatitis-C Take Over Candidate?

By Ray Dirks - Seeking Alpha

Interest in the hepatitis-C space has been hot since the euphoria of Big Pharma's acquisition of Inhibitex (INHX) and others began to spread further in early January. Smaller biotechs are being snapped up by larger pharmaceutical companies driven by the need to pump up their product pipelines.

Last November, Gilead Sciences (GILD) bought Princeton, NJ-based Pharmasset for $11 billion for the next generation of hepatitis-C treatments. Vertex Pharmaceuticals, working with Merck, is offering a pill for hepatitis-C, but it has to be taken three times a day though stands the chance to make $2 billion in a couple of years, when approved.

Then there was the Bristol-Myers Squibb (BMY) acquisition of Inhibitex for $2.5 billion and Roche's (RHHBY.PK) purchase of Anadys Pharmaceuticals for $230 million. Let's not forget that Novartis (NVS) and Enanta Pharmaceuticals are in collaboration to develop and sell a brand-new hepatitis-C inhibitor for nearly $500 million.

When one looks at Medgenics (MDGN), at a market cap of only $46 million, we have have to wonder how a company with an innovative approach to treating hepatitis-C would not be of interest to a bigger pharmaceutical partner or buyer. The firm has a very unique way to treat the disease which may not have been recognized by investors yet, but we're betting that will soon change.

Last month when shares were trading at around the $3.50 level, we made a case for the disruptive technology being developed by Medgenics, focusing on the value it has for the $90 billion protein therapy market that is projected to grow to over $130 million over the next several years. Shares nearly doubled after that report and have since seen a healthy pull back.

We've looked specifically at Medgenic's EPODURE product, a proprietary biopump that produces erythropoietin within the patient's own body, now in Phase I/II clinical trials to treat anemia in chronic kidney disease. The anemia market is dominated by Amgen's Epogen that carries with it a high price tag and serious side effects.

Now we'd like to draw attention to another of Medgenic's products in development, using its biopump technology - INFRADURE, that produces interferon-alpha and is currently in the preclinical stage for the treatment of hepatitis-C. In the U.S., hepatitis-C ranks second only to alcoholism as a cause of liver disease and is the leading reason for liver transplants. The Center for Disease Control and Prevention estimates that 3.2 million people in the U.S. have chronic hepatitis-C (far out-passing HIV) and costs due to treating the disease now exceed $600 million each year, with a projection of growing to $11 billion in 2019.

Interferon, or the more popular form, peginterferon-alpha, is usually used in combination with ribavirin, another antiviral medication. Treatment is expensive, around $20,000 per year for a 48-week injected dose, which puts it out of reach in developing countries where it is badly needed. Further, only 50% of patients benefit. There is clearly a medical call for a cheaper and more effective drug.

Medgenic's INFRADURE provides an answer. Like EPODURE and other products under development, INFRADURE uses Medgenic's biopump platform technology where the patient's own tissue, taken during a biopsy, is processed then inserted into the biopump to continuously produce and deliver interferon-alpha, a natural protein produced by the body. Also like EPODURE, this approach would eliminate weekly and expensive injections, particularly since Hepatitis-C progresses very slowly.

Two drugs are on the market to treat hepatitis-C: Pegasys, made by Genentech and PEG-Intron, made by Schering-Plough. Both are meant for weekly injections. Both are very similar and meant to be used in combination with ribavirin. Side effects for this combination are startling, the most reported ones being mental illness, thoughts of hurting or killing yourself or others, unusual thoughts or behaviors, the compulsion to use street drugs if they had been used in the past, alcohol abuse, and aggressiveness. Heart disease and autoimmune disorders are also common. Pegasys and PEG-Intron used with ribavirin causes birth defects or death in an unborn baby.

For example,the FDA's review of Schering Plough's application for PEG-Intron included a number of patients that either committed or attempted suicide, murdered others, relapsed to drug or alcohol addiction, and underwent severe depression. As we mentioned, heart attacks and heart valve disease also appeared, as well as lupus, extremely low red blood cell count, kidney failure, partial blindness, and hearing loss.

INFRADURE will go into human clinical trials in the first half of this year. Based on laboratory and animal data that reported up to six months of consistent delivery of interferon-alpha, Phase I clinical trial results should show efficacy based on results seen with EPODURE.

We draw your attention to the value of Medgenic's platform technology. Besides anemia and hepatitis-C, Medgenic's product is being designed for use in hemophilia, multiple sclerosis, arthritis, obesity and diabetes.

We advise our readers to watch this company going forward as we continue to expect even more bullish developments and positive news flow going forward.

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.

New Hep C meds may override watchful waiting for patients with no symptoms

Article posted on 3/11/12 on MedCityNews.com - Viral Matters editor comments following: Contrarians exist everywhere, some good at pointing out where mainstream thinking has gone awry, and some just embracing the opposite point of view for reasons beyond the scope for this blog. Here is an article authored by Michael Kirsch, MD a community physician and frequent writing contributor to various on-line medical-related blogs and websites.  His opinion is to watch, wait and observe. I'm sure that this is a valid approach with some patients, but it's helpful to keep in mind that liver disease progression is non-linear and cannot be predicted.  Aside from the reasons that Dr. Kirsch lists below to treat, there are others as well that come with active replicating Hepatitis C virus - lymphoma, neurological impairment and osteoporosis. The decision to treat or not to treat should be an active dialog between patient and provider, nevertheless both parties should be fully informed when it comes to treating or not treating Hepatitis C.  

New Hep C meds may override watchful waiting for patients with no symptoms

I seemany patients with hepatitis C (HCV). None of them are under treatment and they all feel quite well. Why don’t I treat them? After all, potential consequences of HCV include:

* Cirrhosis
* Hepatocellular carcinoma. or liver cancer
* End stage liver disease with all the trimmings
* Liver transplantation
* Death

One would think that a portentous list like this would justify any treatment, even hazardous therapies. But, I’ve never seen it this way, and my hepatitis C patients are all doing well under periodic observation.

Yes, I know that the disease can be serious. I recall one patient with advanced disease whom I referred for consideration of a liver transplant many years ago. There may have been one or two others along the way who received treatment for the disease also.

The vast majority of hepatitis C patients I see in my community practice feel entirely well and the diagnosis was discovered by accident. In other words, these patients did not exhibit symptoms or abnormal findings on the physical examination that led a physician to suspect a liver condition, which then led to testing for hepatitis C. Some of them were picked up by the blood bank when their gift of life was declined. Sometimes, a life insurance company makes the diagnosis during their health assessment as they try to cull out from their enrollees those destined to ascend skyward prematurely. In most cases, patients are diagnosed with hepatitis C when physicians like me order diagnostic HCV blood test to evaluate abnormal liver blood tests. Nearly all of these patients have no symptoms of liver disease and the abnormal liver blood tests may not be a HCV manifestation.

What should we advise patients with HCV who feel perfectly well? Of course, patients should make the call after they have been informed of the risks and benefits of treatment. In my experience, after this discussion, none of these patients wants to proceed. Hopefully, I am meeting my obligation to present the issues to them fairly. I am certainly aware of my bias, and do my best to compartmentalize it.

I think that there has been a rush to treatment with these patients. Academic centers tend to be more enthusiastic about racing for the HCV cure with toxic medicines, although in fairness, their HCV population is very different from mine. Their patients are much more ill, so the risk/benefit analysis of treatmentmay calculate out differently. Nevertheless, academicians in writing and on the speaking circuit tend to extol the virtue of treatment, which they regard as the default response. Watchful waiting just doesn’t have the red meat appeal for liver gurus. They argue that eradicating the virus will prevent the dire consequences I listed at the top of this post. However, when there was only treatment available 20 years ago -injectable interferon - academics were gaga over this it, which had a full page of side effects and was effective in less than 20% of patients treated. I’m amazed that interferon slid by the FDA. Now,HCV can be cured in a majority of patients, according to data from two drugs approved in 2011 to treat the disease, although there remains substantial toxicity from the medications.

Even experts acknowledge that only a minority of HCV patients will develop serious complications. I’m not persuaded that we have a reliable method to determine who will progress and who won’t. And if we did, how firm is the evidence that treating a patient who is destined for cirrhosis will avert this outcome? Those who believe in HCV treatment will find data to support their view and practice. And those of who are skeptics will do the same. That’s the beauty of medicine. There’s always conflicting studies to choose from to support any view.

What would Newton say?
Many of my HCV patientscan date with some precision whenthey contracted the virus. The event may have been a blood transfusion decades ago or from intravenous drug use during a youthful period of hard times and bad judgement.Many of these patients, therefore, have had the virus for decades and are not suffering any illeffects. While I cannot guarantee a sanguine outcome, I view this in Newtonian terms.

An HCV virus that is asleep tends to remain asleep.

Other physicians don’t share my approach and may be dismissive of my nihilism. I wonder how many of them would accept a treatment with enormous toxicity and cost for themselves as readily as they prescribe it to others? This question applies to all physicians, including me, who prescibe medicine and advise patients. Remember, we physicians discuss the risks of all treatments with patients in advance. But, we don’t suffer the complications.

HCV patients, get informed. Make sure the treatment won’t be worse than the disease.

Original article: The REAL drug to beat in Hepatitis C treatment: Ribavirin

An article I authored and recently published online thanks to the great folks at GastroHep.tv, a multi-media, cutting edge online resource for the Gastroenterology and Hepatology community. 



The REAL Drug to Beat in Treating Hepatitis C: Ribavirin

by Chris Barnes

By now, most of us are aware – some of us painfully so – that the Hepatitis C drug development market is red hot. Investors and developers alike need a scorecard to keep track of who is buying who and for what potential blockbuster drug in the race to make it big in treating Hepatitis C.  All of this hullabaloo is for good reason – the CDC estimates there are over 170 million people infected with Hepatitis C worldwide[1], a vast majority of them don’t know that they have it.  That is paradoxically both an enormous and lucrative problem. This means there are a lot of potential patients for pharmaceutical companies to treat with blockbuster anti-HCV drugs.

The names of the compounds in development are like alphabet soup – GS-7977, VX-222, BMS-790052, BI-201335, TMC 435, BL-8020… protease inhibitors, polymerase inhibitors, cyclophilin inhibitors… the list goes on and on. This is a good thing for both drug makers and patients. Drugs to treat Hepatitis C are becoming more potent and more tolerable.  And the race for the next blockbuster drug means there is no shortage of drugs and drug classes to choose from.  Drug developers may even realize the holy grail of Hepatitis C treatment – an all oral, interferon-free regimen consisting of 2-4 pills a day. That’s right, no shots, no interferon. This would potentially make treatment for Hepatitis C infinitely more tolerable for patients.

So the HCV drug development biz is booming… but the hottest drug to beat in Hepatitis C?  Ribavirin.  A cheap, generic anti-viral. It turns out that even with all the advances drug makers are realizing in interferon-free drug combinations, ribavirin is critical to the success in curing patients of Hepatitis C.   The trouble is that no one is really sure how ribavirin works. All we know is that treatment response rates are infinitely higher when it is part of a Hepatitis C antiviral regimen.[2][3][4]

Researchers are busy trying to find out just what makes ribavirin tick, but let’s look at a few of the current theories on how the drug works:

Ribavirin may cause something called ‘error catastrophe’ in the lifecycle of the HCV virus.[5]Ribavirin is a nucleoside analog – this means that ribavirin can fool the virus into thinking that it’s one of the building blocks needed for the virus to replicate. So when the virus tries to replicate itself, it picks ribavirin as a building block instead of the real thing. This mucks up the replication process leading to ‘error catastrophe’ – in other words, the virus is no longer able to make copies of itself.
Inosine monophosphate dehydrogenase (IMPDH). That’s a tongue-twister to be sure, but it’s also a cellular enzyme the human body makes and the HCV virus needs. Ribavirin may inhibit this enzyme, which consequently shuts down the energy supply the Hepatitis C virus requires to survive and replicate.[1]
The Hepatitis C virus is sneaky. It has a peculiar knack for evading the body’s immune system[2], so anything that might disrupt that ability would be very valuable to an anti-HCV regimen. It turns out that ribavirin may have this unique ability by helping the body mount a specific anti-viral response to the Hepatitis C virus, which is essential in fully clearing the virus. [3]
While ribavirin’s exact mechanism of action remains a mystery, there is one thing we do know for certain – we need ribavirin to fight Hepatitis C. Paring ribavirin with the above new antiviral compounds currently in development – called Direct Acting Antivirals  or DAAs -  that target and disrupt numerous points in the lifecycle of the virus, lead to significantly better cure rates then just using the DAAs alone. While interferon may go the way of the buffalo, it appears that the lowly, unsexy ribavirin is here to stay.  This makes ribavirin the REAL drug to beat in the Hepatitis C drug development marketplace.

References

[1] Perz JF, et al. The contribution of hepatits B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006; 45: 529-38

[2] Vertex Pharmaceuticals, Inc. (2010)  Vertex adds ribavirin in additional treatment arm in ongoing phase II VX-222 & Telaprevir combo trial. [Press Release] Retrieved from http://viralmatters.blogspot.com/2010/11/vertex-adds-ribavirin-in-additional.html

[3] Hezode, Christopher, et al. (2009) Telaprevir and Peginterferon with or without Ribavirin for chronic HCV Infection. Retrieved from http://www.nejm.org/doi/full/10.1056/NEJMoa0807650

[4] Smith, M. (2012). New Combo KOs HCV Without Interferon, Ribavirin  [Online article] Retrieved from: http://www.medpagetoday.com/InfectiousDisease/Hepatitis/30739

[5] Maag D, et al. RNA virus error catastrophe: direct molecular test by using ribavirin. Proc. Natl. Acad. Sck. 2001; 98: 6895-900

Merck's hepatitis C drug wins UK cost endorsement...

Posted on 3/8/12 via Reuters.

Merck's hepatitis C drug wins UK cost endorsement

LONDON, March 9 | Fri Mar 9, 2012 12:01am GMT

(Reuters) - U.S. drugmaker Merck & Co's new hepatitis C drug Victrelis was recommended for use within Britain's state health service on Friday, despite its hefty price tag.

The National Institute for Health and Clinical Excellence, which often spurns expensive new medicines on cost grounds, said significant improvements seen with Victrelis made it a cost-effective option.

The drug, also known as boceprevir, is designed for use in combination with peginterferon alfa and ribavirin for patients with liver disease due to genotype 1 chronic hepatitis C, the most common form.

Encouraging Phase II Telaprevir HIV/HCV coinfection treatment data presented at CROI...

Posted on March 6 on Vertex Pharmaceuticals.com: Data presented at CROI from the Phase II Telaprevir trial looking at the safety and effectiveness of Telaprevir + P/R in the HIV/HCV co-infected patient (all on Atripla and Reyataz as their antiretroviral regimen).  While this is SVR12 data and not the 'true' SVR of 24 weeks past End of Treatment (EOT), this data looks encouraging with 74% (28/38) patients undetectable at SVR12.  Given the huge potential of drug-drug-interactions with Telaprevir and antiretroviral regimens, it looks as if the Atripla + Reyataz regimen in combination with TVR + P/R is the one to go with - VERY encouraging in that there have been no HIV breakthroughs while on TVR + P/R + Reyataz + Atripla. The coinfected patient is a critical patients - coinfected individuals have have markedly increased disease progression far and above that of the monoinfected patient.  Considering that Boceprevir cannot be used in the HIV/HCV coinfected patient, Vertex has this niche all to itself until the 2nd gen compounds prove themselves.  I'm sure these interim results come to the relief of many providers who treat this patient population. 

Data from Phase 2 Study of an INCIVEK® Combination Regimen Showed 74% of People Co-Infected with Hepatitis C and HIV Had Undetectable Hepatitis C Virus 12 Weeks After Treatment Ended (SVR12)

- INCIVEK was well tolerated with commonly used Atripla- and Reyataz-based HIV treatment regimens, and no patients experienced HIV breakthrough -

- Enrollment is ongoing in Phase 3 study evaluating 24- and 48-week treatment durations in people who are co-infected -

SEATTLE--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced interim results from an ongoing Phase 2 study designed to evaluate the safety and tolerability of INCIVEK® (telaprevir) tablets in combination with pegylated-interferon and ribavirin in people who are co-infected with genotype 1 hepatitis C virus and human immunodeficiency virus (HIV). Data showed 74 percent (28/38) of patients who were treated with INCIVEK (in-SEE-veck) combination therapy had undetectable hepatitis C virus (HCV RNA) 12 weeks after the end of all study treatment (SVR12) compared to 45 percent (10/22) who were treated with pegylated-interferon and ribavirin alone. INCIVEK was well tolerated with commonly used Atripla®- and Reyataz®-based HIV treatment regimens. Changes in CD4 counts were similar between the treatment groups and no HIV viral load breakthroughs were observed in either treatment group during the study. The most common adverse events in the INCIVEK arms of the study were fatigue, pruritis (itching), headache, nausea and rash. No cases of severe rash were reported and there were no discontinuations due to rash. Interim results from this study are being presented at the Conference on Retroviruses and Opportunistic Infections (CROI), March 5 to 8, 2012 in Seattle.

"Hepatitis C generally progresses faster, leads to more long-term liver complications and has been harder to cure among people who also have HIV," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer at Vertex. "These new INCIVEK data are important as we work toward our goal of helping cure more people with hepatitis C. We're actively enrolling co-infected patients in a Phase 3 study and expect that data from this study will be included in a submission for a supplemental approval of INCIVEK."

The Phase 2 study includes two parts: Part A is evaluating people who are not currently being treated with antiretroviral therapy (ART) for HIV infection and Part B is evaluating those who are taking an Atripla- or Reyataz-based regimen for HIV. This study enrolled patients who were new to hepatitis C treatment (treatment naïve). Patients who were randomized to receive INCIVEK were treated with 12 weeks of INCIVEK, pegylated-interferon and ribavirin, followed by 36 weeks of pegylated-interferon and ribavirin alone. Interim data also showed that 68 percent (26/38) of patients treated with INCIVEK combination therapy in this study had a rapid viral response (RVR, undetectable hepatitis C virus at week 4 of treatment) compared to none (0/22) of the patients who received pegylated-interferon and ribavirin alone.

"There is a great need for treatments that are well tolerated and offer co-infected patients a better chance at a cure for hepatitis C while maintaining suppression of their HIV," said Douglas Dieterich, M.D., Professor of Medicine in the Division of Liver Diseases, Mount Sinai School of Medicine, New York City. "It's very encouraging that nearly three out of four people had undetectable hepatitis C virus 12 weeks after stopping INCIVEK combination therapy and that their HIV medicines continued to work during treatment."

Interim Study Results

Sixty-two people 18 and older were enrolled in this Phase 2 study and 60 received at least one dose of study drug. This analysis was conducted 12 weeks after patients completed all treatment. The ART regimens evaluated in this study were selected based on current HIV treatment guidelines from the U.S. Department of Health and Human Services, International AIDS Society and drug-drug interaction studies of INCIVEK with commonly used ART medicines.

Interim Intent To Treat Analysis of Study #110

Part A (No ART)

Part B Atripla®-based regimen

Part B Reyataz®-based regimen

Total

INCIVEK- based Arm+

Control Arm++

INCIVEK- based Arm+

Control Arm++

INCIVEK- based Arm+

Control Arm++

INCIVEK- based Arm+

Control Arm++

RVR*

71% (5/7)

0% (0/6)

75% (12/16)

0% (0/8)

60% (9/15)

0% (0/8)

68% (26/38)

0% (0/22)

eRVR**

57% (4/7)

0% (0/6)

75% (12/16)

0% (0/8)

47% (7/15)

0% (0/8)

61% (23/38)

0% (0/22)

SVR12

71% (5/7)

33% (2/6)

69% (11/16)

50% (4/8)

80% (12/15)

50% (4/8)

74% (28/38)

45% (10/22)

Atripla-based regimen (efavirenz, tenofovir disoproxil fumarate and emtricitabine): INCIVEK was dosed at 1,125 mg, every 8 hours (q8h).

Reyataz-based regimen (ritonavir-boosted atazanavir, tenofovir disoproxil fumarate and emtricitabine or lamivudine): INCIVEK was dosed at 750 mg, every 8 hours (q8h).

*RVR: Rapid Viral Response; undetectable HCV RNA at week 4.

**eRVR: extended Rapid Viral Response; undetectable HCV RNA at weeks 4 and 12.

+12 weeks of INCIVEK, Pegasys® (PEG, pegylated-interferon alfa-2a) and Copegus® (RBV, ribavirin) followed by 36 weeks of only PEG and RBV.

++48 weeks of PEG and RBV only for hepatitis C treatment.

             
Atripla-based regimen (efavirenz, tenofovir disoproxil fumarate and emtricitabine): INCIVEK was dosed at 1,125 mg, every 8 hours (q8h).

Reyataz-based regimen (ritonavir-boosted atazanavir, tenofovir disoproxil fumarate and emtricitabine or lamivudine): INCIVEK was dosed at 750 mg, every 8 hours (q8h).

*RVR: Rapid Viral Response; undetectable HCV RNA at week 4.
**eRVR: extended Rapid Viral Response; undetectable HCV RNA at weeks 4 and 12.

+12 weeks of INCIVEK, Pegasys® (PEG, pegylated-interferon alfa-2a) and Copegus® (RBV, ribavirin) followed by 36 weeks of only PEG and RBV.
++48 weeks of PEG and RBV only for hepatitis C treatment.

The majority of adverse events in this study were mild or moderate. Adverse events that occurred more frequently in the INCIVEK arms compared to placebo (≥10 percent difference) were pruritis (itching), headache, nausea, rash, fever, and depression. Three patients, all in Arm B, discontinued all study treatment due to adverse events (one each due to gall stones, hemolytic anemia and nausea/vomiting).

About this Phase 2 Study

Vertex and its collaborator Janssen conducted extensive drug-drug interaction studies with INCIVEK and commonly used HIV medicines prior to initiating a development program in people co-infected with hepatitis C (HCV) and HIV. This Phase 2 study is a two-part (A and B), randomized, double-blind, placebo-controlled, parallel group, multi-center study in people chronically infected with both HCV and HIV who were new to HCV treatment. The primary endpoint of the study is to evaluate the safety and tolerability of INCIVEK combination therapy in people co-infected with HCV and HIV. A secondary endpoint is to evaluate rates of sustained viral response (SVR) 12 and 24 weeks after the end of treatment. The study is being conducted by Vertex in collaboration with Janssen.

Phase 3 Study Actively Enrolling

Enrollment is ongoing in a Phase 3 study evaluating 24- and 48-week response-guided regimens of INCIVEK combination therapy in people co-infected with HCV and HIV. Patients who are either new to treatment for HCV, or who had relapsed after at least one prior course of therapy with pegylated-interferon and ribavirin alone, will receive 24 or 48 weeks of INCIVEK combination treatment, based on their antiviral response. Patients who had not responded to a prior course of treatment (partial responders and nulls) will receive 48 weeks of INCIVEK combination treatment. A similar study is also being initiated by Janssen in its territories.

Data from In Vitro Evaluation of INCIVEK and HIV Protease Inhibitors

Also being presented at CROI this week are data from an in vitro evaluation of the anti-HIV activity of four HIV protease inhibitors (amprenavir, darunavir, lopinavir and atazanavir) in combination with INCIVEK. In the study, no antagonistic effects on the antiviral activity were observed when INCIVEK was used in combination with amprenavir, darunavir, and lopinavir, and slight antagonistic effects were observed on the antiviral activity of atazanavir.

About INCIVEK

INCIVEK ® (telaprevir) tablets is an oral medicine that acts directly on the hepatitis C virus protease, an enzyme essential for viral replication. INCIVEK is the most prescribed direct-acting antiviral for the treatment of adults with genotype 1 chronic hepatitis C and has been used to treat more than 30,000 people in the United States.

INCIVEK was approved by the U.S. Food and Drug Administration (FDA) in May 2011 and by Health Canada in August 2011 for use in combination with pegylated-interferon and ribavirin for 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). INCIVEK is approved for people who are new to treatment, and for people who were treated previously with interferon-based treatment but who did not achieve a sustained viral response, or viral cure (relapsers, partial responders and null responders).

Vertex developed telaprevir in collaboration with Janssen and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America where it is being marketed under the brand name INCIVEK (in-SEE-veck). Janssen has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. In September 2011, telaprevir was approved in the European Union and Switzerland. Telaprevir is known as INCIVO® in Europe. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries. In September 2011, telaprevir was approved in Japan and is known as Telavic®.

INCIVEK® is a registered trademark of Vertex Pharmaceuticals Incorporated.

PEGASYS® and COPEGUS® are registered trademarks of Hoffmann-La Roche.

Reyataz® is a registered trademark of Bristol-Myers Squibb.

Atripla® is a registered trademark of Bristol-Myers Squibb and Gilead Sciences, LLC.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.1 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.1 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.1

Unlike HIV and hepatitis B virus, chronic hepatitis C can be cured.2 However, approximately 60 percent of people do not achieve SVR,3,4,5 or viral cure,6 after treatment with 48 weeks of pegylated-interferon and ribavirin alone. If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.7,8

More than 170 million people worldwide are chronically infected with hepatitis C.6 In the United States, nearly 4 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.9 Hepatitis C is four times more prevalent in the United States compared to HIV.9 The majority of people with hepatitis C in the United States were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.10 Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 4,600 to 12,000 deaths annually.11,12 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.9

About Hepatitis C and HIV Co-Infection

There are 1 million people living with HIV in the United States, and an estimated 300,000 people living with HIV/AIDS in the United States are also infected with hepatitis C. 13 There have been dramatic improvements in the treatment of HIV and the prognosis for people living with HIV. However, liver disease progresses more rapidly in people co-infected with hepatitis C and HIV, with an increased rate of progression to cirrhosis, decompensated liver disease, hepatocellular carcinoma and death. 14, 15, 16, 17 The hepatitis C cure rate with a 48-week treatment of pegylated-interferon and ribavirin, the current standard of care for people with co-infection, is approximately 29 percent.18

About Vertex

Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives.

Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis, epilepsy and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada. Today, Vertex has more than 2,000 employees around the world, and Science magazine named Vertex number one on its 2011 list of Top Employers in the life sciences.

Vertex's press releases are available at www.vrtx.com.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including Dr. Kauffman's statements in the second paragraph of this press release and statements regarding ongoing and planned Phase 3 studies of INCIVEK combination therapy in people co-infected with HCV and HIV. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the outcomes from future clinical trials of INCIVEK combination therapy in co-infected patients may not be favorable and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

IMPORTANT SAFETY INFORMATION

Indication

INCIVEK® (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment. It is not known if INCIVEK is safe and effective in children under 18 years of age.

Important Safety Information

INCIVEK should always be taken in combination with peginterferon alfa and ribavirin. Ribavirin may cause birth defects or death of an unborn baby. Therefore, a patient should not take INCIVEK combination treatment if she is pregnant or may become pregnant, or if he is a man with a sexual partner who is pregnant. Patients must use two forms of effective birth control during treatment and for the 6 months after treatment with these medicines. Hormonal forms of birth control, including birth control pills, vaginal rings, implants or injections, may not work during treatment with INCIVEK.

INCIVEK and other medicines can affect each other and can also cause side effects that can be serious or life threatening. There are certain medicines patients cannot take with INCIVEK combination treatment. Patients should tell their healthcare providers about all the medicines they take, including prescription and non-prescription medicines, vitamins and herbal supplements.

INCIVEK can cause serious side effects including skin reactions, rash and anemia that can be severe. The most common side effects of INCIVEK include itching, nausea, diarrhea, vomiting, anal or rectal problems, taste changes and tiredness. There are other possible side effects of INCIVEK, and side effects associated with peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. Patients should tell their healthcare providers about any side effect that bothers them or doesn't go away.

Please see full Prescribing Information for INCIVEK including the Medication Guide, available at www.INCIVEK.com.

(VRTX-GEN)

References:

1 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed February 22, 2012.

2 Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900.

3 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.

4 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

5 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.

6 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.

7 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).

8 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.

9 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed February 22, 2012.

10 Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. Available at: http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed February 22, 2012. This report was commissioned by Vertex Pharmaceuticals, Inc.

11 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.

12 Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.

13 HIV Advocate. HIV/HCV Coinfection. Available at: http://www.hcvadvocate.org/hepatitis/factsheets_pdf/HIV_HCV20coinfecton_10.pdf. Accessed February 28, 2012.

14 Martin-Carbonero L, Benhamou Y, Puoti M, Berenguer J, Mallolas J, Quereda C, et al. Incidence and predictors of severe liver fibrosis in human immunodeficiency virus-infected patients with chronic hepatitis C: a European collaborative study. CID 2004;38:128-33.

15 Martinez-Sierra C, Arizcorreta A, Diaz F, Roldan R, Martin-Herrera M, Perez- Guzman E, et al. Progression of chronic hepatitis C to liver fibrosis and cirrhosis in patients coinfected with hepatitis C virus and human immunodeficiency virus. CID 2003;36:491-8.

16 Matthews GV, Dore GJ. HIV and hepatitis C coinfection. JGH. 2008; 23: 1000-1008.

17 Bruno R, Sacchi P, Puoti M, Soriano V, Filice G. HCV chronic hepatitis in patients with HIV: clinical management issues Am J Gastroenterol 2001; 97:1598—1606.

18 Levin, J. Pegasys/RBV in APRICOT Study- Adherence Improves SVR 300% in genotype 1. Available at: http://www.natap.org/2005/ICAAC/icaac_31.htm Accessed February 28, 2012.



Vertex Pharmaceuticals Incorporated

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