Friday, December 30, 2011

Hepatitis C - Looking Ahead to 2012

As we close out 2011 and usher in 2012, the treatment for hepatitis C remains promising with two new drugs FDA approved, and interferon free regimens in the future, a cure is now finding its way into the world of the difficult to treat patient. Today on the blog we have a few links on these promising therapies, starting with a few recent articles from the scientific journal, Nature.

Updates On The Blog For 2012
New targets for antiviral therapy

Highlights From 2011
These two December 2011 articles published @ Nature discuss the future of HCV Interferon free therapies

*Free registration required to view both articles

New HCV drugs trigger race for more tolerable therapies

Table 1 -
Have no interferon: Interferon-free HCV therapies in mid- and late-stage development.

PhaseCompanyInvestigational drugsDrug action
3PharmassetPSI-7977Polymerase inhibitor
2Abbott LaboratoriesABT-450 plus ABT-333 or ABT-072Protease and polymerase inhibitors

Boehringer-IngelheimBI-201335 and BI-207127Protease and polymerase inhibitors

Bristol-Myers SquibbBMS-650032 and BMS-790052Protease and NS5A inhibitors

Gilead SciencesGS-9451, GS-5885 and GS-9190 (tegobuvir)Protease, polymerase and NS5A inhibitors

InhibitexINX-189Polymerase inhibitor

NovartisDEB025 (alisporivir)Cyclophilin inhibitor

BavituximabPhosphatidylserine-targeted antibody

RocheDanoprevir and RO5024048Protease and polymerase inhibitors

SantarisMiravirsenMicroRNA-122 inhibitor

VertexIncivek (telaprevir) and VX-222Protease and polymerase inhibitors
“There's been real concern that we might never be able to get away from interferon entirely, but now we're starting to get an inkling that that might not be the case,” says Gary Davis, director of the general and transplant hepatology unit at the Baylor University Medical Center in Dallas.
Read more here

Trial watch: An all-oral and interferon-free future for HCV therapy?
December 2011

“An IFN-free (and also ribavirin-free) therapy is the main goal, and given the very promising data from clinical trials, this seems to be realistic...

Read more here

The Race Is On In 2012 For All Oral Regimens To Treat Hepatitis C

Folks, the treatment of hepatitis C is on the verge of so many new therapies that decisions made by you will be influenced by the clinical outcomes of the drugs currently in trials. It has become essential that you keep on top of these new drugs which will enable you along with your physician, to carefully consider an immediate or future treatment plan.

Big Pharma and Collaboration Agreements

In 2011 some of the biggest HCV news came from collaboration agreements between pharmaceutical companies. For instance Alios and Vertex together are conducting a Phase 1 study with ALS-2200 and ALS-2158, we saw Pharmasset and Tibotec hook up to evaluate the combination of PSI-7977 and TMC435, in the following two articles Arpita Dutt and Luke Timmerman discuss those and other collaborations made in 2011.

An update by Adam Feuerstein on the Bristol-Myers Squibb - Inhibitex deal.

** Updated Jan 8 2012

Hep C Takeover Speculation Rains Down on Idenix and Achillion

SAN FRANCISCO (TheStreet) -- Three independent hepatitis C drug developers bought, two more -- Idenix Pharmaceuticals and Achillion Pharmaceuticals-- waiting at the altar.

Bristol-Myers Squibbsnatches up Inhibitex for $2.5 billion in a deal announced Saturday night as the entire biopharmaceutical industry travels here for the start of the J.P. Morgan Healthcare Conference on Monday morning. [Is there any better way to kick off a closely watched investor confab like this than a blockbuster buyout? I think not.]

Gilead Sciences( is expected to close on its $11 billion acquisition of Pharmasset this week or no later than before the end of the month.

It seems teeny by comparison, but let's not forget that Roche bought Anadys Pharmaceuticals for $230 million in October.

All three buyouts were done to achieve the same goal: Develop the next generation of highly potent hepatitis C therapies composed entirely of pills so patients no longer need to endure weekly shots of interferon. The prize for the companies that can cobble together the two or three drugs (perhaps just one) necessary to create this all-oral regimen is about $10 billion or more in expected future hepatitis C revenue.

The pace of hepatitis C deal activity is breathtaking if not unprecedented. Takeover speculation will certainly rain down Monday on Idenix and Achillion given their status as the last two independent Hep C drug developers.
Idenix's lead drug, IDX184, belongs to the same "nucleoside" or "nuc" class of oral Hep C drugs as Pharmasset's PSI-7977 and Inhibitex's INX-189.
The Food and Drug Administration has a partial clinical hold on IDX184 due to liver toxicity that cropped up in a study that combined '184 with another Idenix Hep C drug known as IDX320. Idenix believes this safety signal was caused by '320, and development of that drug was shelved.
To remove '184 from the Hep C safety doghouse and clear it for future combination studies, Idenix is conducting a short phase IIb study with interim data expected imminently, perhaps even this week. If the safety profile of '184 comes back clean, the FDA should be persuaded to lift the partial clinical hold and potential suitors may move quickly to snatch up Idenix.
Idenix executives will be presenting at the J.P. Morgan conference on Wednesday at 5 p.m. EST.

Update Jan 13
IDX184 a weak nuke?

Idenix Seeks Partner for Hepatitis C Combination Drug, CEO Says
By Sasha Damouni
“We are certainly going to combine IDX184 with protease inhibitors, and maybe a NS5A inhibitor,” Renaud said yesterday, describing drugs that attack different checkpoints for the disease as it moved through the human body." 

Achillion expects to release proof-of-concept data from studies of three experimental hepatitis C drugs -- ACH-1625, ACH-2684 and ACH-2928 -- in the first half of the year. ACH-1625 is a once-daily protease inhibitor (the same Hep C drug class as Vertex Pharma's Incivek and Merck's Victrelis) that is being combined with interferon and ribavirin.

Achillion is not scheduled to present at the J.P. Morgan conference this week, but the company's CEO Michael Kishbauch has not been shy about letting investors (and potential suitors) know that his company is for sale.

Update Jan 17 
Jan 17, 2012
- 4:14 -

Additional thoughts and questions on the rapidly evolving (and consolidating) hepatitis C drug landscape:

Who are the potential buyers still out there? Merck, Johnson & Johnson and Abbott are all invested heavily in hepatitis C drug development already, so each could step up as potential acquirers. Merck may have the most to lose because its approved Hep C drugs PEG-Intron and Victrelis are threatened by the push to develop new all-oral therapies.
This is actually the second time that Bristol-Myers has made a hepatitis-related deal in the midst of the J.P. Morgan Healthcare Conference.

In January 2009, Bristol licensed a long-acting interferon from Zymogenetics. In September 2010, Bristol bought Zymogenetics for $885 million. The payoff on this deal now has to be questioned given the drive to do away with long-acting interferons in hepatitis C in favor of developing all-oral regimens.

How many, if any, of these experimental oral Hep C drugs will ultimately fail clinical trials or be shelved due to safety problems? It's hard to believe that all will ultimately be successful, given the typical failure rate seen in drug development.
What happens if either Idenix or Achillion are not acquired? Can these small companies survive on their own? If Hep C turns out to be anything like HIV, the answer is no.

Inhibitex shares have been very volatile recently due to worries about the safety of INX-189. It's not known whether Bristol is protecting itself with an exit clause in its tender offer if INX-189 does run into safety issues.
-- Written by Adam Feuerstein.
Spotlight on Hepatitis-C Market - Analyst Blog
by Arpita Dutt from
Is the hepatitis-C market the next Mecca for the pharma/biotech sector? It seems so if we go by the flurry of activity and heightened interest in this market in the past few quarters. The hepatitis-C virus (HCV) market seems to have caught the eye of several pharma/biotech companies - as evident by the deals being signed for the development of drugs for the treatment of HCV

We are talking about the recent announcements made by big players like Johnson & Johnson, Bristol-Myers Squibb and Gilead Sciences, Inc. All three companies have made it clear they want a piece of the HCV market pie.

Johnson & Johnson's Tibotec Pharmaceuticals and Bristol-Myers Squibb recently announced that they have decided to join forces for the development of Bristol-Myers' daclatasvir (BMS-790052) in combination with Tibotec's TMC435, for the treatment of chronic HCV. What the partners are aiming to do is create an oral once-daily interferon-free cocktail treatment for HCV patients
Bristol-Myers and Johnson & Johnson's announcement comes on the heels of Gilead's announcement regarding its intention to buy Pharmasset, Inc. , a company focused on developing HCV treatments. We think the main attraction for Gilead in this $11 billion deal is Pharmasset's HCV pipeline. Lead candidate PSI-7977 is currently in two phase III studies, with a third phase III study scheduled to commence in the first half of 2012. Successful development could lead to US approval in 2014 thereby making Gilead a front-runner in the oral once-daily interferon-free cocktail treatment HCV market.
We note that both TMC435 and daclatasvir are being evaluated separately in combination with Pharmasset's PSI-7977.

The Allure of the HCV Market
HCV is a hot development area which has come into the limelight with the launch of two new treatments - Vertex Pharmaceuticals' Incivek and Merck's Victrelis. Both drugs gained approval in the US earlier this year. Incivek, which was launched in May 2011, posted a whopping $419.6 million in sales in the first full quarter of its launch.
So, with two new recently launched products in the market, why is the HCV market considered so attractive? Firstly, it is estimated that about 170 million people suffer from HCV infection across the world. However, the treated population is much lower. In major markets like the US, EU, Japan, Australia, Turkey, Canada, etc. only 200,000 HCV patients out of a total of more than 12 million are estimated to receive treatment each year. This means a huge number of HCV patients go untreated, leaving the field open for new treatments.
Secondly, the current standard of care comes with several side effects which make it difficult for patients to remain on treatment. A 48-week course of both peg-interferon (peg-INF - weekly injections) and ribavirin (RBV - oral drug), are the standard treatment for genotype 1 HCV infection. However, this treatment regimen is associated with significant side-effects like fatigue, flu-like symptoms, rash, depression and anemia.
With a large number of HCV patients failing to achieve a sustained viral response (SVR) on the current standard of care, there are several patients who would be open to treatment with new and potentially more effective therapies.
These factors have made the HCV market an attractive commercial opportunity for pharma and biotech companies. Victrelis and Incivek are examples of the changing treatment regimen in the HCV market. Both are protease inhibitors which when added to the standard of care reduce the treatment period and also improve the treatment outcome. However, both need to be administered with peg-IFN and RBV - this leaves the path open for the introduction of treatments with fewer side effects.

Cocktail Therapy - The Next Big Thing in HCV
Companies like Johnson & Johnson and Gilead are trying to develop the next crop of drugs, which are expected to change the treatment paradigm for HCV patients by providing them with all-oral treatment regimens. The aim is to develop a treatment which does not require the administration of interferon, thereby doing away with a whole range of side effects. The treatment duration will also be shorter.
Treatments being developed include HCV polymerase inhibitors and HCV NS5A inhibitors. The future HCV market will most likely consist of cocktail treatment regimens developed by combining different oral treatments.
Vertex Pharma has also recognized the need to continually evolve the HCV treatment pattern and is developing an all-oral combination of VX-222 (a polymerase inhibitor) and Incivek without peg-IFN.

Who Will Win the Race?
With several companies pursuing cocktail therapies for HCV, it will be interesting to see which of these companies will be the first to hit the market with a new treatment option. Currently, it looks like Gilead might be the front-runner assuming the Pharmasset acquisition goes through

The Hepatitis C Market: Biotech’s Version of the Daytona 500
Luke Timmerman

This new report correctly states the ever-changing development in the hepatitis C arena.
Biotech rivalries are sometimes a bit like boxing matches, where you have two lone fighters vying for the prize. But the hepatitis C market is turning into a battle royal that’s more wide open and unpredictable, with all the competitive maneuvering, surprise crashes, and comebacks you might expect from the Daytona 500.

The medical advances in hepatitis C have been dizzying this year, especially in what it means in terms of multi-billion dollar business implications. The safest thing to say is that there’s plenty of good news for patients this year, but that shareholders in the major hepatitis C drug developers had better hold on tight as a new standard of care gets established.

Some commentators figured that Gilead Sciences (NASDAQ: GILD), the world’s biggest maker of HIV drugs, had essentially locked up the dominant position in this new drug class throughits $11 billion acquisition last month of Princeton, NJ-based Pharmasset (NASDAQ: VRUS). But it’s still too soon for anyone to declare victory over the wily and fast-mutating virus that causes hepatitis C. Given the way drug development is going now, it’s possible we could have dueling antiviral drug cocktails that cure almost 100 percent of patients within five years. And before we get there, we’re going to see some fascinating chess moves—and probably a few surprising collaborations—from companies like Vertex Pharmaceuticals, Merck, Roche, Johnson & Johnson, Bristol-Myers Squibb, and Abbott Laboratories, as well as several smaller biotech startups like Alpharetta, GA-based Inhibitex (NASDAQ:INHX).

Xanthopoulos says Gilead was “taken to the cleaners,” and that the hepatitis C market is still up for grabs. “It’s going to take some time before people figure out how it plays out,” he says. The Pharmasset drug “is a powerful player, but you will need other direct-acting antivirals. You want to go to a 100 percent cure rate. I can guarantee the Pharmasset compound isn’t going to do it alone.”

Hepatitis C has never really captured big headlines in the U.S., as it has never benefitted from massive awareness boosting campaigns that have supported research for, say, HIV, or breast cancer. But hepatitis C has clearly emerged as one of the biggest opportunities in pharmaceuticals over the past few years. There are more than 3 million people in the U.S., and an estimated 170 million worldwide, with this liver infection that can lead to cirrhosis and liver cancer. Most people have never bothered to get treated, partly because the infection takes years to fully wreak havoc. The other reason is the standard of care with a combination of drugs—pegylated interferon alpha and ribavirin—causes flu-like symptoms that last for almost a year, and usually cures only 30-40 percent of patients. Essentially, most people figure the treatment is worse than the disease.

Vertex Pharmaceuticals changed the equation back in May. The company won FDA approval for a direct antiviral drug, a protease inhibitor called telaprevir (Incivek), that is added to the usual two-drug combo regimen. By adding the Vertex drug, researchers saw the cure rate boom to almost 80 percent of patients, while cutting the treatment time with the other drugs in half. The Vertex drug also significantly raised the cure rate for patients who failed to respond to prior rounds of therapy.

Vertex looked golden for a while, as its stock soared above $55 a share, sending its market value above $10 billion. Analysts were raving about how Vertex smashed sales expectations in its first few months on the market, and started turning profitable in just its second quarter of selling the drug. Waves of patients were suddenly showing up at doctors’ offices to get treatment for hepatitis C, now that the odds of a cure were so much higher.

But important as the Vertex advance has been, researchers have made it clear that this story isn’t over. The ultimate goal is to get rid of interferon, and its side effects, so that physicians can count on some combination of direct antivirals that can be taken as oral pills. That might include Vertex’s drug in combination with others, or might not.
So that’s why Vertex, and other companies, have feverishly been looking to mix and match various hepatitis C drugs. It’s all part of a quest to come up with the ideal combo that can raise the bar on cure rates, minimize side effects, and maximize convenience.

While people on Wall Street like to embrace a simple storyline with clear winners and losers, the hepatitis C virus is one tricky adversary. Like HIV, it has a tendency to mutate and develop resistance capabilities, whenever scientists throw a new antiviral drug against it. So there isn’t likely to be a single magic bullet. The most likely route to success is with a combination of two, three, or maybe four antiviral drugs that attack the virus from different angles, making it much harder for the bug to mutate and escape one drug.

As Steve Worland, the CEO of San Diego-based Anadys Pharmaceuticals, put itin a guest editorial for Xconomy in September, there are at least four important categories of hepatitis C antivirals. There are protease inhibitors on the market like Vertex’s drug and Merck’s boceprevir (Victrelis). There are nucleotide polymerase inhibitors like Pharmasset’s PSI-7977 and a rival drug called mericitabine from Roche. There are non-nucleotide polymerase inhibitors in the works from Abbott Laboratories, Vertex, and Anadys (which Roche acquired this fall for $230 million.) And Bristol-Myers Squibb is betting on another kind of compound, an NS5A inhibitor. (You could also count microRNA therapies, which Santaris Pharma and Regulus are working on at earlier stages of development.)

Just this year, we’ve seen some fascinating jockeying for position. Drug companies often don’t like to test combinations of experimental drugs together in clinical trials, because when side effects emerge, people often like to point the finger at the other guy’s drug. And who wants to divvy up the profits with some other pharma giant when you have the whole thing yourself?

But with hepatitis C, the market opportunity is so big, and the variety of drugs to attack it is so broad, that pharma companies have set aside those concerns just to get a piece of the action. We’ve already seen Merck and Roche form a partnership to co-market Victrelis against the leading drug on the market from Vertex. Gilead just shelled out the breathtaking sum of $11 billion for Pharmasset, even though the smaller company’s lead compound still has to navigate the third and final phase of clinical trials required for FDA approval. Bristol-Myers Squibb and Johnson & Johnson have teamed up in an interesting new collaboration. Roche, through internal efforts and acquisitions, has sought to put all the pieces of the puzzle together under one roof—a protease inhibitor, a nucleotide polymerase inhibitor, a non-nucleotide polymerase inhibitor.

Nobody knows which compounds will match up best together, which ones will be too toxic in combination, or even how many antivirals will be needed to raise the cure rate. But it’s worth noting that Vertex raised the bar very high, by getting cure rates up to around 80 percent. Doctors are certainly eager to get rid of the nasty interferon part of the regimen, but they will only do that when a new regimen can do at least as well on cure rates. And any of these drugs can be derailed by somewhat mild side effects, since the bar on safety is set quite high already.

It might be relatively safe and simple to declare Gilead/Pharmasset the winners in this market, but this race isn’t even close to over. There are 200 laps in the Daytona 500, and in the hepatitis C race, I’d say we’re at about lap 50. There are going to be some fascinating strategic maneuvers, and maybe even a spectacular crash or two, before somebody zooms in under the checkered flag.

The Pharmasset compound that prompted Gilead to write such a big check, PSI-7977, is “certainly not a panacea, not the lone answer,” says Kleanthis Xanthopoulos, the CEO of San Diego-based Regulus Therapeutics, and the co-founder of another hepatitis C drug developer, Anadys Pharmaceuticals.

Hepatitis C drugs in development

Making The News In 2011

Inhibitex Announces Positive Topline Data in HCV Program
As with other companies in the HCV space, Inhibitex’s goal is to eventually develop an interferon-free regimen, and management provided guidance projecting INX-189 to be on the market in an all-oral treatment regimen around 2016.

J&J, BMS join forces in race to develop interferon-free hep C combos
With analysts projecting the interferon-free combos to become the next frontier of treatment, BMS and Tibotec Pharmaceuticals will put their respective compounds, daclatasvir and TMC435, to the test in a Phase II study in patients with genotype 1 hepatitis C. The study, slated to begin in early 2012, will test the pair of experimental drugs alone, in combination with the antiviral drug ribavirin and with interferon. It will enable the companies to compare the sustained viral response of the three regimens at 12 weeks and 24 weeks, according to the companies' release.

Novartis’ alisporivir may become first interferon-free oral for hepatitis C G2/G3

Novartis reported Phase II data which demonstrated the efficacy of DEB025 (alisporivir) in producing viral elimination in interferon-free regimens (as monotherapy or with ribavirin), in previously untreated patients infected with the hepatitis C virus (HCV) genotypes 2 and 3.
DEB025 belongs to a new class of drugs called cyclophilin inhibitors and offers an effective treatment option across HCV genotypes, with a high barrier to resistance.
The 12-week trial showed that around 49% of the patients on DEB025 plus ribavirin achieved viral clearance (negative HCV RNA) as early as week six.

One third of patients (32%) receiving DEB025 alone also achieved viral clearance after six weeks.
However, 97% of patients with viral clearance who continued to receive interferon-free DEB025 plus ribavirin maintained this viral clearance up to week 12.
Novartis licensed DEB025 from Debiopharm Group, an independent biopharmaceuticals company based in Switzerland.

Pharmasset Announces the Initiation of an Interferon-Free Phase 3 Program with PSI-7977 for HCV
- Three pivotal studies planned to evaluate PSI-7977 400 mg QD plus ribavirin for 12 weeks in patients with HCV

Anticipated US and EU marketing submissions in second half of 2013
PRINCETON, N.J., Nov. 1, 2011 /PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) today announced the initiation of a Phase 3 program with the hepatitis C virus (HCV) nucleotide analog, PSI-7977. This pivotal program will evaluate a 12-week, all-oral, interferon-free regimen of PSI-7977 and ribavirin in patients with HCV, independent of viral genotype or their ability to take interferon therapy.

"After recent discussions with Health Authorities, we are excited to be initiating the first of a series of pivotal studies to explore an interferon-free regimen of PSI-7977 in broad populations of individuals with HCV," said Michael Rogers, Ph.D., Pharmasset's Chief Development Officer.

Twelve Weeks Interferon-Free PSI-7977
Regimen Cures 100 Percent Hep C Genotype 2/3A twelve-week course of Pharmasset’s once-daily experimental nucleotide analog PSI-7977, combined with ribavirin, cured 10 of 10 people living with genotype 2/3 hepatitis C virus (HCV) who used the regimen—without pegylated interferon—in a Phase II clinical trial. The highly encouraging results were reported Sunday, November 6, at the 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco.

Abbott Announces Positive Data from Mid-Stage Trial of Hepatitis C Therapy
In the trials, 44 previously untreated patients with hepatitis C were given ritonavir with Abbott's ABT-450 and one of two Abbott polymerase inhibitors, ABT-333 or ABT-072, and ribavirin for 12 weeks. All patients who remained in the studies achieved an early virologic response at 12 weeks, and of the 10 patients to date who were tested 24 weeks after completing the treatment course, nine had achieved a sustained virologic response, the company said. Abbott plans to present more detailed data on these and other trials of the drug regimen next year.

Vertex and Alios BioPharma Begin Clinical Studies of Nucleotide Drug Candidates ALS-2200 and ALS-2158 for the Treatment of Hepatitis C

“The studies of ALS-2200 and ALS-2158 announced today are designed to generate data that may provide the opportunity to rapidly advance into Phase 2 development where we could evaluate a number of nucleotide-based regimens beginning in the second half of next year, including regimens with INCIVEK or VX-222.” 

Vertex Pharmaceuticals Incorporated and Alios BioPharma, Inc. today announced the initiation of two clinical studies for the nucleotide analogues ALS-2200 and ALS-2158, which are inhibitors of the hepatitis C NS5B polymerase. The studies will evaluate the safety and tolerability of ALS-2200 and ALS-2158 in healthy volunteers followed by a seven-day evaluation to observe the effects on viral kinetics in people with chronic genotype-1 hepatitis C. Data are expected in the second quarter of 2012, which could enable the initiation of studies to evaluate multiple all-oral, interferon-free combination regimens for chronic hepatitis C in the second half of 2012. Vertex has worldwide development and commercialization rights for ALS-2200 and ALS-2158, which were discovered by Alios BioPharma. Alios and Vertex are jointly conducting the Phase 1 studies announced today.

Protease inhibitor BI 201335 and polymerase inhibitor BI 207127

Can We Treat Chronic HCV Infection Without Interferon?

Stefan Zeuzem et al. tested a combination of the HCV polymerase inhibitor BI 207127 and the protease inhibitor BI 201335, each developed by Boehringer Ingelheim, in 31 treatment-naïve patients with chronic HCV, genotype-1 infection. Patients received either 400 mg or 600 mg of BI 207127, 3 times daily, along with 120 mg of BI 201335 and a dose of ribavirin each day for 4 weeks. None of the patients received interferon.

The rate of virologic response (an HCV RNA level below 25 IU/mL) reached 100% by day 22 in the patients given the 600 mg dose of BI 207127, without differences among genotypes—HCV RNA could not even be detected in 71% of the patients by day 29.
One patient in the group given the 400 mg dose of BI 207127 had a virologic breakthrough (a rebound in HCV RNA level) at day 22. The most frequent adverse events were mild gastrointestinal disorders, rash, and photosensitivity, but there were no severe or serious adverse events.
In an editorial that accompanies the article, "Audio-Interferon-Free Regimens for Hepatitis C: Are We There Yet? " Prateek Sharma and Anna Lok agree that an interferon-free regimen of direct-acting antiviral agents and ribavirin can suppress HCV for up to 4 weeks. However, they point out that it is not clear if this response, and lack of adverse events, can be maintained for longer time periods.
In a video abstract, Zeuzem states that these findings are a milestone toward different options to achieve viral eradication. “We are looking toward longer treatment exposure with these direct-acting antivirals … with such a safe and tolerable regimen, we hope that 24 weeks may be sufficient to cure patients, without the need for interferon,” he says.
HCV protease inhibitors such as boceprevir and telaprevir are also effective in treating patients chronic HCV genotype-1 infection. However, these drugs must be given with peginterferon and ribavirin, to prevent the development of drug-resistant variants.

The authors propose that the unique structure of BI 207127 precludes the development of resistant viral variants. The drug interferes with a conformational change required for the HCV NS5B polymerase to initiate RNA synthesis; its binding site is an interface between functional domains that restricts sequence polymorphisms. So, BI 207127 seems to have a higher barrier to resistance than other polymerase inhibitors.

Further studies are needed to to determine the exact role of ribavirin in the antiviral activity of this combination. Zeuzem et al. propose that this drug’s weak direct antiviral activity and ability to induce interferon-sensitive genes contribute to its role in the drug combination.
Sharma and Lok conclude that interferon-free regimens are no longer a dream, and that some regimens will also eventually be ribavirin-free. This is good news for patients who cannot take peginteferon or ribavirin because of their interactions with other medications or tolerability issues. However, caution must be taken in selecting which antiviral agents to combine the appropriate dose and duration of therapy for each HCV genotype and subgenotype.

Novel Interferon-Free Hepatitis C Regimen Promising
The holy grail of hepatitis C antiviral therapy is a virologic cure using a pill
or combination of pills,with no side effects, for as brief a period of time as possible.

Hepatitis C: Impressive Virological Response With Interferon-Free Combination Treatment Plus Ribavirin
On November 7th Boehringer Ingelheim announced results from a pre-specified interim evaluation of a Phase IIb investigation (SOUND-C2). The data demonstrated that the combination of the protease inhibitor BI 201335 and the polymerase inhibitor BI 207127, two oral direct acting hepatitis C virus (HCV) compounds, with and without ribavirin (RBV), resulted in successful virological response rates in previously untreated (treatment-naive) patients with the most difficult to treat genotype-1 (GT1) HCV at week 12.

SVR12 was achieved in 59% of participants in the investigation's shortest treatment period (16weeks). Treatment with interferon was not included in any of the five study groups. On Nov. 7th the results were presented at the American Association for the Study of Liver Diseases (AASLD) 2011 Liver Meeting in San Francisco, USA.


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The Coming of Age of Direct Anti-Viral Agents for HCV

2011 -
Incivek and Victrelis FDA Approved

Boceprevir and Telaprevir A Quick Summary:In 2011 two new drugs were FDA approved for the treatment of hepatitis C. The protease inhibitors: telaprevir (Incivek) and boceprevir (Victrelis), have dramatically shorten treatment duration and have improved cure rates. The triple therapy is used in combination with Peginterferon, and Ribavirin and currently only recommended for patients infected with HCV genotype 1.

*Both boceprevir and telaprevir are not administered as monotherapy

With the approval of both drugs a revision of the prior treatment guidelines became necessary. Click here to view those recommendations approved by the American Association for the Study of Liver Diseases (AASLD).

A Few Keywords and commonly used medical terms during therapy

SVR - Sustained Virologic Response. SVR means that you have no detectable hepatitis C virus in your blood six months after finishing treatment.

Naïve - Patients who have not had any prior treatment for HCV (Naïve)

Relapse - Patients who were HCV RNA negative on a prior course of peginterferon/ribavirin but then relapsed after peginterferon/ribavirin was discontinued (Relapse)-These patients had a viral load so low that it could not be measured at the end of their previous treatment. However, their viral load was higher when it was measured 6 months after treatment

Partial Responder - Patients who had at least 100-fold decrease in HCV RNA after 12 weeks of a prior course of peginterferon/ribavirin (Partial Responder)-These patients' viral loads were greatly reduced after 12 weeks of their previous treatment. However, their viral load was high enough to be measured at the end of treatment

Null Responder - Defined as a person who achieved a less than 2 log10 reduction in HCV RNA at week 12 of a prior course of peginterferon/ribavirin-These patients' viral loads did not go down much during their previous treatment for chronic hepatitis C.


SVR statistics treating with incivek or victrelis

1. Naïve 75%
2. Relapser 80 to 90%
3. Partial Responder 50 to 60%
4. Null Responder 30%


The importance of adherence during triple therapy to prevent resistance is critically important, by following the dosing regimens with the new protease inhibitors resistance is minimized.

A missed or late dose will expose the virus to reduced drug levels, and will promote resistance. The failure to take the protease inhibitors (PIs) with food may also result in less than optimal drug levels. Telaprevir should be dosed with these recommended foods, as for boceprevir the food choice is up to you, although food taken with each dose is still absolutely necessary.

Drug interactions

Other drugs can interact with telaprevir/boceprevir" these interactions can reduce the PI concentrations which will result in less than desirable drug levels.

Dose reductions

Any dose reductions for toxicity, or treatment interruptions for any reason, are not advised as exposure to less than the full dose will promote the emergence of resistance. If therapy must be stopped because of toxicity, the PI must be stopped completely.

Stopping Rules

The stopping rules for both boceprevir- or telaprevir-based regimens should be strictly adhered to. Developing resistance to these drugs can be minimized as long as stopping rules are adhered.

From CCO
*Free registration is required

For all patients treated with boceprevir, the following futility rules should be employed:

If HCV RNA is ≥ 100 IU/mL at Week 12, all 3 medications should be discontinued.

If the patient has confirmed, detectable HCV RNA at Week 24, all 3 medications should be discontinued.

For all patients treated with telaprevir, the following futility rules should be employed:

If HCV RNA is more then 1000 IU/mL at treatment Week 4 or 12, all 3 medications should be discontinued.

If HCV RNA is detectable at Week 24, pegIFN/RBV should be discontinued.

More information on resistance

In the HCV Advocate July newsletter an article "Resisting Resistance" written by Ms. Lucinda K. Porter, RN., discusses viral resistance and the importance of taking the new protease inhibitors as directed.

Related - Patient video; New hepatitis C Drugs and Resistance


*Updated Jan 15 2012
Direct acting antivirals for the treatment of chronic hepatitis C: one pill a day for tomorrow
Second generation DAA are in development. Combinations of antivirals with additive potency that lack cross resistance and with a good safety profile may provide new regimens in the future to make HCV the first chronic viral infection eradicated worldwide with a finite duration of combination DAA therapy without IFN. The aim of this review is to summarize mechanisms of action and results obtained with DAAs.

New targets for antiviral therapy of chronic hepatitis C
Volume 32, Issue Supplement s1, pages 9–16, February 2012
Attributable to its poorly characterized role in HCV RNA replication and the lack of enzymatic activity, NS5A has long been neglected as a primary drug target. However, by using replicon-based screens and subsequent intensive chemical refinements of primary hits, a highly active compound (BMS-790052) characterized by its symmetric structure was identified [34]. This compound has an amazingly high potency with antiviral efficacy in the picomolar range. In fact, it has been calculated that one inhibitor molecule can block 10–100 NS5A molecules, arguing that BMS-790052 might exert a ‘dominant negative’ phenotype. This high potency was well recapitulated in a phase I clinical trial with chronic hepatitis C patients; a single application of 100 mg BMS-790052 reduced viral load around 1000-fold within 24 h after application [34]...
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From CCO- Patient management

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The New Elements of HCV Care: Practical Skills to Optimize Protease Inhibitor–Based TherapyReview the approved indications and proper management of HCV-infected patients with the newly approved protease inhibitors.

CME-Certified Case Vignette:

The New Elements of HCV Care: Practical Skills to Optimize Protease Inhibitor–Based TherapyJoin Graham R. Foster, FRCP, PhD; Paul Y. Kwo, MD; and Fred Poordad, MD, as they discuss optimal management strategies for 8 case scenarios of patients considering or receiving treatment with boceprevir or telaprevir.

Advanced Liver Disease: What Every Hepatitis C Virus Treater Should Know
Identification and treatment of advanced hepatitis C virus (HCV) infection is often challenging. Accurate fibrosis staging can be performed only by liver biopsy. For patients with advanced fibrosis (Metavir score, F3 or F4), progression to decompensated liver disease occurs at a rate of approximately 5% per year and progression to hepatocellular carcinoma occurs at a rate of 1% to 2% per year.

HCV Advocate - A Review Of 2011

HCV Advocate Newsletter
January 2012

2011: Year in Review
Alan Franciscus, Editor-in-Chief


The Year In Hep News
Source: Hep Mag

2011 - Best Book

I just finished "Free from Hepatitis C" written by Lucinda Porter, RN, this helpful book is a must have if you're living with HCV or considering therapy.

Learn more about the author here and here.

The Book Has Been Reviewed At Oh My Aches and Pains

Check out an insightful review written by Selena.

Free from Hepatitis C
by Lucinda Porter, RN

Book Description

For decades, a diagnosis of hepatitis C was the equivalent of serving a life sentence--with a dangerous liver disease. It left patients frightened, confused, and vulnerable, and they took little comfort in knowing that, at best, their condition could be managed but not cured. All of that changed with the discovery that the hepatitis C virus (HCV) could be defeated with new treatments. To shed light on these groundbreaking treatments, Lucinda Porter, a registered nurse, a passionate HCV advocate, and a Hep C patient herself, has written this all-important guide. This comprehensive volume is a must for anyone considering, undergoing, or just wanting to understand HCV treatment.


New Drug Pipeline

New drugs in development for the treatment of hepatitis C

HCV Advocate

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