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.

Phase	Company	Investigational drugs	Drug action
3	Pharmasset	PSI-7977	Polymerase inhibitor
2	Abbott Laboratories	ABT-450 plus ABT-333 or ABT-072	Protease and polymerase inhibitors
	Boehringer-Ingelheim	BI-201335 and BI-207127	Protease and polymerase inhibitors
	Bristol-Myers Squibb	BMS-650032 and BMS-790052	Protease and NS5A inhibitors
	Gilead Sciences	GS-9451, GS-5885 and GS-9190 (tegobuvir)	Protease, polymerase and NS5A inhibitors
	Inhibitex	INX-189	Polymerase inhibitor
	Novartis	DEB025 (alisporivir)	Cyclophilin inhibitor
	Peregrine Pharmaceuticals	Bavituximab	Phosphatidylserine-targeted antibody
	Roche	Danoprevir and RO5024048	Protease and polymerase inhibitors
	Santaris	Miravirsen	MicroRNA-122 inhibitor
	Vertex	Incivek (telaprevir) and VX-222	Protease and polymerase inhibitors

• Tables index

“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

Related:
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 -

Video-ACH-1625-Achillion CFO Mary Kay Fenton on the benefits of the company’s new hepatitis C drug.

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 Zacks.com

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.

Audio/Video
Audio

Interferon-Free Regimens for Hepatitis C: Are We There Yet?

Download PDF

Video

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.

The STATS

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%

Resistance

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


Links

*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

*Free registration required

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.

Audio-Perspective
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.
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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

Looking Back, Focusing Forward: The Year in Hep News

________________________________


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

Free from Hepatitis C: Your Complete Guide to Healing Hepatitis C

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.

Links

New Drug Pipeline

New drugs in development for the treatment of hepatitis C

HCV Advocate

Hepatitis C Treatments in Current Clinical Development

Metformin Hikes B12 Deficiency in Type 2 Diabetes

OTC supplements fail to correct B12 deficiencies in type 2 diabetes, regardless of metformin therapy

THURSDAY, Dec. 29 (HealthDay News) --

The use of metformin therapy in adults with type 2 diabetes is linked to a biochemical B12 deficiency greater than that found in other adults with type 2 diabetes and adults without diabetes, and current over-the-counter supplements are not sufficient to correct the deficiency in either of these type 2 diabetes groups, according to research published online Dec. 16 in Diabetes Care.

Lael Reinstatler, M.P.H., of the Rollins School of Public Health at Emory University in Atlanta, and colleagues analyzed data from the National Health and Nutrition Examination Survey to determine the prevalence of biochemical B12 deficiency in adults aged 50 years and older with type 2 diabetes taking metformin, compared with those not taking metformin and those without diabetes. They also sought to determine whether this relationship could be modified by vitamin B12 supplementation.

The researchers found biochemical B12 deficiency present in 5.8 percent of 575 adults aged 50 and older with type 2 diabetes who used metformin, compared to 2.4 percent of 1,046 adults not using the therapy. The deficiency was also found in 3.3 percent of 6,867 adults without diabetes. Taking supplements containing vitamin B12 was not associated with reducing biochemical deficiencies among the study group with diabetes. However, for those without diabetes, consumption of any vitamin supplements containing B12 resulted in reducing deficiencies by two-thirds.

"Our results have public health and clinical implications by suggesting that neither 2.4 µg, the current Institute of Medicine recommendation for daily B12 intake, nor 6 µg, the amount found in most multivitamins, is sufficient for those with type 2 diabetes taking metformin," the authors write.

Abstract
Full Text (subscription or payment may be required)

Last Updated: December 29, 2011

HCV News Ticker-Cirrhosis Tied to Increased Risk of Liver Cancer in Diabetics

New On The Blog

Bavituximab-Peregrine Provides Update on hepatitis C Clinical Program

Optimization of Comorbidity Therapy to Achieve Sustained Viral Response in HCV Patients

Recent Trends of Japanese Hepatocellular Carcinoma due to HCV

Tailor-Made Therapy for Viral Hepatitis

Hospital sued for improper sterilization of equipment; Fear of disease claimed

Tattoos and Piercings: A Review for the Emergency Physician

Natural Variation in Drug Susceptibility to HCV Polymerase Inhibitors in Treatment-naïve HCV Patient Isolates

Management of Hepatitis C Infection



Cirrhosis Tied to Increased Risk of Liver Cancer in Diabetics

By David Douglas

NEW YORK (Reuters Health) Dec 26 - Cirrhosis and hepatitis are associated with the occurrence of hepatocellular carcinoma (HCC) in patients with diabetes, and hepatitis C is of particular importance, Taiwanese researchers report in a November 15 online paper in The American Journal of Gastroenterology.

As Dr. Shih-Wei Lai told Reuters Health by email, "In our study, diabetic patients comorbid with liver cirrhosis, hepatitis B, and hepatitis C were at significantly increased risk of developing hepatocellular carcinoma, and the risk associated with hepatitis C was stronger than that with hepatitis B."

Dr. Lai of China Medical University, Taichung and colleagues note that there is accumulating evidence that patients with diabetes mellitus are more prone to cancer in general and liver cancer in particular. An American study indicated that the risk of HCC in diabetic patients was more than twice that in non-diabetics, and there have been some similar findings in Taiwan.

To clarify the effect of diabetes on HCC risk, the team examined a health insurance database covering the years 2000 to 2005 and used the information to compare 19,349 newly diagnosed diabetes patients with 77,396 matched controls. Where possible, they were followed until the end of 2008.

The HCC incidence was doubled in diabetics compared with controls (21.0 versus 10.4 per 10,000 person-years), which translated to an adjusted hazard ratio of 1.73, the team found. Hazard ratios were also significantly and independently increased by being male (2.32), and having cirrhosis (8.65), hepatitis B (2.52), and hepatitis C (5.61).

Stratified analyses showed that subjects with diabetes and cirrhosis along with hepatitis C had the greatest elevation in risk (hazard ratio, 72.4).

The researchers then went on to examine the association between HCC and anti-diabetic medication. After adjustment, metformin use was associated with significant protection (hazard ratio, 0.49). This was also true of thiazolidinediones (hazard ratio, 0.56). Taking insulin, sulfonylureas, and other agents also reduced the risk, but not significantly.

Overall, given the influence of the studied comorbidities, concluded Dr. Lai, "These observations suggest that patients with these disorders may be the high-risk group that deserves to be closely monitored. The importance of hepatitis C should not be overlooked."

SOURCE: http://bit.ly/vHt1Dv

Am J Gastroenterol 2011.

Risk Factors for Hepatocellular Carcinoma in a Cohort Infected With Hepatitis B or C

Scott R Walter; Hla-Hla Thein; Heather F Gidding; Janaki Amin; Matthew G Law; Jacob George; Gregory J Dore

Posted: 12/28/2011; J Gastroenterol Hepatol. 2011;26(12):1757-1764. © 2011 Blackwell Publishing

Discussion Only

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This study identifies sociodemographic and health factors predictive of developing HCC among a cohort of people with chronic HBV or HCV infection in NSW. The incidence of HCC increased with age and comorbidity score, and was higher among males, metropolitan residents, and those with ALD, and particularly cirrhosis. Older age, being male, and having a high comorbidity score were significantly and independently associated with the risk of HCC. Co-infection with HBV and HCV was associated with increased HCC risk in the HCV cohort, and of all risk factors considered, cirrhosis conferred the greatest additional risk, regardless of infection type.

The risk of HCC was observed to increase significantly with age for both HBV- and HCV-infected groups. Such an increase in risk with age has been widely observed,^[32] but in some countries, age-specific incidence peaks in the 60s, rather than late 70 s or beyond, possibly due to variation in the prevalence of certain risk factors between regions.^[17,21]

Being male is another well-known risk factor for HCC, although there is considerable regional variation in the relative risk compared to females.^[21] While relative risks of males compared to females for HCC among the general population range from close to one to almost nine, in most regions in the world, males have two to four times the risk of females,^[21] consistent with our results.

A clear increase in the risk of HCC with comorbidity score was observed for both infection groups. Few studies have assessed the association between comorbidity score and HCC risk, as it is often more informative to examine individual health conditions. Each comorbid condition influences the risk of HCC by varying degrees, and multiple conditions might interact in complex ways. However, in terms of identifying high-risk individuals, the comorbidity score quantifies the combined effect of multiple conditions, without the need to interpret risks associated with multiple factors and their interactions.

A number of papers have reported a twofold to threefold increase in HCC risk due to diabetes,^[14–16,26] some of which also found an interaction between viral hepatitis and diabetes.^[14,16] While including diabetes in the models suggested an increase in the risk of comparable magnitude, the difference was not sufficiently significant to remain in the final model, suggesting that in our cohort, this is a low-risk condition relative to other factors considered.

Alcohol consumption has been identified as a key risk factor for HCC, interacting synergistically with chronic viral hepatitis infection,^[16,33] but relatively few studies have examined the risk associated with ALD.^[34] We observed significant risk associated with hospitalization with this condition, possibly through the combined effects of alcohol-related and hepatitis-related liver injury. The observed increased risk of HCC among those with HBV/HCV co-infection is consistent with other studies, which found that the combined effect of the two infections is more than additive, but less than multiplicative.^{[17,18,20,35]}

Cirrhosis is well known as the precursor for the vast majority of chronic viral hepatitis-related HCC cases.^[19,36,37] Not surprisingly, our study identified cirrhosis as the strongest predictor of HCC for both HBV and HCV cohorts. Two studies based in Taiwan found a 12-fold and 50-fold increase in risk due to cirrhosis among a HBV-infected cohort.^[25,38] Sherman reports a more than 20-fold increase in HCC incidence in people with HCV and cirrhosis, compared to those with HCV alone.^[36] The magnitude of these estimates approximately agrees with the very high risk identified in our study. The combined effects of cirrhosis and ALD indicated further amplified risk of HCC, particularly among those with HCV. Having a hospital record for both conditions likely indicates advanced or rapidly-progressing liver disease.

A limitation of this study was the incompleteness of country of birth information in the viral hepatitis notification data, which inhibited analysis of the differential risk of developing HCC between people born in different regions. This is particularly pertinent, given that more than half of the HBV-infected group have immigrated from HBV-endemic countries, such as China and Vietnam,^[39,40] while the majority of those with HCV are Australian born.^[41] Region of birth might also confound the association between remoteness and HCC, since there are much higher proportions of Asian born people in metropolitan areas than non-metropolitan areas.^[42] This is particularly likely to be a factor among the HBV-infected cohort. More limited access to specific HCC diagnostic services in non-metropolitan areas might also be a factor in producing an apparently lower incidence of HCC.

A further limitation was the availability of cirrhosis data only through hospitalization codes, particularly as liver biopsy and hepatic elastography diagnosis are generally undertaken through outpatient services. Also, linked treatment data were not available for this study, which eliminated the possibility of examining the extent to which antiviral therapy reduces HCC risk; however, this might form the basis of future studies when additional data permit.

HCC screening and surveillance among at-risk groups have only relatively recently been shown to improve survival.^[43,44] Cases only presenting when symptomatic often have a poorer prognosis and fewer treatment options than those detected in the asymptomatic stage of disease.^[24,45] In light of its ability to detect tumors early and improve treatment eligibility and survival, screening and surveillance play a key role in reducing the burden of HCC. However, it is only practiced by some groups in NSW, with less than 20% of HCC cases being identified via surveillance.^[45,46] Identifying and quantifying risk factors specific to a population, as we have done, forms an integral part of targeting cost-effective surveillance and provides motivation for more widespread screening of high-risk groups.

Antiviral therapy has been shown to limit the progression of liver disease, and in some HBV cases, can reverse decompensated cirrhosis, considerably reducing the risk of HCC.^[37,47] Thus, antiviral therapy of chronic viral hepatitis represents a pivotal pathway for reducing the burden of HCC. This also bolsters the case for increasing treatment uptake in general among those with chronic viral hepatitis infection, given that currently, approximately 5% of HBV-infected people^[48] and 1–2% of HCV-infected people^[41] receive antiviral therapy. A combination of surveillance and treatment has been shown to be a more cost-effective way to reduce the burden of liver cancer than surveillance alone.^[46]

In summary, this study has identified and quantified important risk factors for HCC within a high-risk, population-based cohort. Several key factors emerged as independent and significant risks for HCC. Although some previously-reported risk factors were not significant in our analysis, those that were identified were largely consistent with studies conducted in other regions of the world. The association with older age highlights the potential impact of HBV and HCV screening of at-risk groups and early clinical assessment. Antiviral therapy for chronic viral hepatitis is an important strategy for preventing HCC, and further research is required to quantify its mitigation of HCC risk at a population level in the Australian context.

If you carry a donor card people like me can have a transplant

A cancer sufferer who has been placed on the transplant waiting list wants her story to raise awareness of the importance of carrying a donor card.

Rhiannon Jeans, 43, from Scunthorpe, has suffered from Primary Billiary Cirrhosis, an incurable liver disease, for ten years and has since been diagnosed with liver cancer.

This has made the need for Rhiannon's surgery more urgent and she has since been placed on the waiting list for a liver transplant.

She said: "My condition is a chronic liver disease that usually affects women. It is quite rare and people don't often know that they have got it.

"I always knew that the cure was a transplant as it is an incurable disease but it depends on how the disease progresses.

"But when I found out I had liver cancer this made the need for a transplant more urgent.".. Continue reading..

HIV/HCV

Early guidance on use of hepatitis C protease inhibitors in HIV-co-infected patientsMichael Carter

Published: 29 December 2011

Doctors in the US state of Maryland have issued preliminary guidance for the use of hepatitis C protease inhibitors by patients co-infected with HIV. Published in the online edition of Clinical Infectious Diseases, the provisional recommendations support use of the protease inhibitors in selected groups of co-infected patients.

“The benefits of including these medications will outweigh the risks for some individuals,” comment the authors.

In May 2011 the protease inhibitors boceprevir and telaprevir were approved in the US for the treatment of chronic hepatitis C genotype 1 infection. In clinical trials, involving hepatitis C-mono-infected individuals, the use of these drugs in combination with pegylated interferon and ribavirin improved rates of sustained virological response by between 25% and 31%.

Clinical trials into the safety and efficacy of these hepatitis C protease inhibitors are currently underway involving patients co-infected with HIV....Continue reading..

Top 10 HIV and hepatitis stories of 2011

HIV prevention garnered the most headlines, with studies showing that antiretroviral therapy prevents transmission and pre-exposure prophylaxis works. On the hepatitis C front, the first new direct-acting antiviral drugs were approved, ushering in a new era of more effective treatment.

In our last issue for 2011, HIVandHepatitis.com reviews some the year's major news highlights. HIV prevention garnered the most headlines, with studies showing that antiretroviral therapy (ART) prevents transmission and pre-exposure prophylaxis (PrEP) works -- at least for some people some of the time. On the hepatitis C front, the first new direct-acting antiviral drugs were approved, ushering in a new era of more effective treatment.

1. AIDS at 30

An overarching theme of the year was the 30th anniversary of AIDS, an opportunity to take stock of the remarkable progress over the past 3 decades as well as work yet to be done.

The anniversary is dated from the first medical report about the epidemic. The June 5, 1981, issue of Morbidity and Mortality Weekly Report (MMWR) included an article about a strange cluster of Pneumocystis pneumonia (PCP) cases among previously healthy gay men in Los Angeles. The July 4 issue described 2 dozen cases of PCP and a rare cancer, Kaposi sarcoma, in California and New York. The first 2 MMWR reports of AIDS are included in The Body's comprehensive archive of articles on the history of the HIV/AIDS epidemic.

2. Treatment is Prevention

The biggest HIV news of 2011 involved findings that were widely anticipated and already informing clinical practice and personal decisions, but data from a large randomized controlled trial removed any doubt: HIV treatment isHIV prevention....Continue reading..

Clinical Trials

Drug Trials Not Representative, Researchers Charge

By Emily P. Walker, Washington Correspondent, MedPage Today
Published: December 27, 2011

Few major randomized, controlled clinical trials examine the effects of a drug in patients who have multiple chronic conditions, even though more than one-quarter of all Americans are living with at least two chronic health conditions, researchers reported.

The proportion is even greater for older individuals, two out of three of whom are likely to have at least two chronic health conditions, according to Alejandro Jadad, MD, and colleagues from the Centre for Health, Wellness and Cancer Survivorship at the University Health Network in Toronto.

That means that most trials on which the FDA bases its approval of new drugs are not generalizable to the U.S. population, they wrote in a research letter published in the Dec. 28 issue of the Journal of the American Medical Association.

Jadad and his colleagues examined all randomized controlled studies that dealt with an intervention for a long-lasting or chronic disease or condition that were published from January-March in 1995, 2000, 2005, and 2010 in five major peer-reviewed medical journals -- BMJ, CMAJ, JAMA, The Lancet, and the New England Journal of Medicine -- as well as six journals that focus on the most prevalent chronic conditions, including Circulation and Annals of General Psychiatry.

Only six of the 284 published trials analyzed (2.1%) explicitly included patients with multiple chronic conditions, and that percentage didn't change much from 1995 to 2010. In 179 of the randomized controlled trials, patients with multiple medical conditions were explicitly excluded from the trial.

Patients with multiple conditions were mentioned often in trial reports, although not actually included in the trial. About 70% of the published trial reports mentioned multiple coexisting diseases; with general medical journals describing them more often than specialized journals (72% versus 69%; P=0.02).

The letter authors concluded that few randomized controlled clinical trials published in the last 15 years have included patients with multiple chronic conditions.

Although the study was small, the authors said the finding "invites reflection about the risk of unintended harm from inappropriate generalization of trial results conducted in populations with a single disease."

"Given the possible drug-to-drug, drug-to-disease, and disease-to-disease interactions that remain unexamined, most of the evidence gathered to date by [randomized controlled clinical trials] is of limited value to guide decisions," they wrote.

The study authors said it may be useful for the FDA to have drug companies include subgroups of patients with the most common combinations of diseases in their drug development process; to observe safety outcomes of adding a new drug to patients who are already medicated for other conditions; and to have post-marketing studies that include the risk stratification to allow for meta-analyses across populations, such as those with multiple conditions.

Off Topic

Most intriguing ‘Medical Mysteries’ of 2011

Highlights from our series of tough-to-diagnose medical problems.
Click here to view slideshow

Bavituximab-Peregrine Provides Update on hepatitis C Clinical Program

Preliminary Data From Phase II Study Shows Antiviral Activity and Positive Safety Profile at Both Bavituximab Doses Evaluated; Supporting Further Dosing and Combination Studies; Company to Seek Collaboration to Advance HCV Program While Continuing to Focus on Its Lead Bavituximab Clinical Program in Multiple Solid Tumor Indications Including Lung Cancer

TUSTIN, CA--(Marketwire - Dec 29, 2011) - Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM), a clinical-stage biopharmaceutical company developing first-in-class monoclonal antibodies for the treatment of cancer and viral infections, today provided an update from its randomized Phase II bavituximab study in patients infected with genotype-1 chronic hepatitis C virus (HCV). Patients were randomized in the three-arm study to receive one of two doses of bavituximab (0.3mg/kg or 3mg/kg) or pegylated interferon alpha-2a, in combination with ribavirin. The goals of the study were to determine if bavituximab plus ribavirin has a better safety profile as compared to interferon plus ribavirin, to confirm that the combination of bavituximab and ribavirin has antiviral activity defined as 12 week early virologic response (EVR)¹ and to compare antiviral activity of peg-interferon plus ribavirin versus bavituximab plus ribavirin.

A preliminary data analysis indicates that the combination of bavituximab and ribavirin appeared safe and well tolerated with patients reporting fewer side effects than in the interferon-containing arm. Initial data from the study also indicated that both dose levels of bavituximab with ribavirin demonstrated antiviral activity, however the antiviral effects in patients receiving the 0.3 mg/kg dosing level were more pronounced. A comparison of the viral data indicated that the kinetics of antiviral activity were different between the interferon and bavituximab treatment groups with a high percentage of those patients achieving EVR in the interferon arm of the study doing so between week 4 and 8 and the majority of patients achieving EVR in the bavituximab groups doing so at the week 12 end of study timepoint. More patients had achieved EVR in the interferon-containing group by the end of the study, however based on the nature of late EVR development in the bavituximab containing arms at the very end of the 12 week trial, a longer-term evaluation is needed to adequately compare the effectiveness of bavituximab and interferon. The company plans to present full results from the study at a medical conference in 2012.

"We are pleased with the initial results we have seen from this clinical study evaluating the combination of bavituximab with an established antiviral drug in HCV patients. We see good evidence that the combination of bavituximab with ribavirin has a better safety profile than an interferon containing regimen which was one of the primary objectives of the study," said Joseph S. Shan, vice president of clinical and regulatory affairs at Peregrine Pharmaceuticals. "In addition, we also see that while both dose levels of bavituximab were active, the lower dose level appears more active in HCV patients than the high dose level. Taken together, these early results are very important in validating that the combination of bavituximab with its immunological mechanism of action with an active antiviral agent has a good safety profile and promising antiviral activity. These results suggest that future studies evaluating longer bavituximab treatment durations at or around the lower dose level in combination with ribavirin and potentially direct acting antivirals in certain patient populations may hold promise as interferon-free HCV therapeutic regimens."

"The early data from this trial are promising and suggest that continued development of bavituximab in HCV patients is warranted to explore the full immune-modulating potential of the compound in combination with antiviral agents," said Steven W. King, president and chief executive officer of Peregrine. "With this data in hand, we plan to actively seek development partners interested in working with us to move the PS-targeting antiviral program forward while we continue to focus our resources on the advancement of our bavituximab oncology clinical program in multiple solid tumor indications including non-small cell lung cancer (NSCLC) and pancreatic cancers as well as other indications with high unmet medical need. With as many as six data points coming over the next six months or so from our ongoing phase II trials in front and second line NSCLC and the additional possible data points coming from five additional oncology trials, this is a good time to seek partners for the antiviral program which has shown promise in this study. We look forward to sharing full data from the HCV trial in 2012 and to moving the program forward in the future."

1. EVR is defined as equal or greater than a 2 log reduction in HCV RNA from baseline.

About the Phase II HCV Trial
In this multicenter Phase II randomized trial, 66 patients with previously untreated genotype-1 chronic HCV infection were randomly assigned to one of three treatment arms. Patients received daily oral ribavirin (1000 mg) with either weekly bavituximab (0.3 mg/kg or 3 mg/kg) or pegylated interferon alpha-2a (180 µg) for up to 12 weeks and were tested for safety parameters and antiviral activity.

About Bavituximab's Antiviral Approach
Bavituximab is the first in a new class of patented antibody therapeutics that target and bind to phosphatidylserine (PS), a specific phospholipid component of cell membranes. Bavituximab helps reactivate and direct the body's immune system to destroy infected cells and virus particles that exhibit this specific phospholipid on their surface. Since their target is host-derived rather than pathogen-derived, PS-targeting antibodies have the potential for broad-spectrum antiviral activity and are also expected to be much less susceptible to the viral mutations that often lead to drug resistance.

About Peregrine Pharmaceuticals
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative monoclonal antibodies in clinical trials for the treatment of cancer and serious viral infections. The company is pursuing multiple clinical programs in cancer and hepatitis C virus infection with its lead product candidate bavituximab and novel brain cancer agent Cotara®. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. (www.avidbio.com), which provides development and biomanufacturing services for both Peregrine and outside customers. Additional information about Peregrine can be found at www.peregrineinc.com.

Safe Harbor Statement: Statements in this press release which are not purely historical, including statements regarding Peregrine Pharmaceuticals' intentions, hopes, beliefs, expectations, representations, projections, plans or predictions of the future are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The forward-looking statements involve risks and uncertainties including, but not limited to, the risk that results from the randomized Phase II trial will not be consistent with results experienced in the earlier single-arm Phase I studies, the risk that results from the randomized Phase II trial may not support registration filings with the U.S. Food and Drug Administration, the risk that Peregrine may not have or raise adequate financial resources to complete the planned clinical programs, and the risk that Peregrine will not find a development partner interested in the antiviral applications of its PS-targeting technology. Factors that could cause actual results to differ materially or otherwise adversely impact the company's ability to obtain regulatory approval for its product candidates include, but are not limited to, uncertainties associated with completing preclinical and clinical trials for our technologies; the early stage of product development; the significant costs to develop our products as all of our products are currently in development, preclinical studies or clinical trials; obtaining additional financing to support our operations and the development of our products; obtaining regulatory approval for our technologies; anticipated timing of regulatory filings and the potential success in gaining regulatory approval and complying with governmental regulations applicable to our business. Our business could be affected by a number of other factors, including the risk factors listed from time to time in the company's SEC reports including, but not limited to, the annual report on Form 10-K for the year ended April 30, 2011 and quarterly report on Form 10-Q for the quarter ended October 31, 2011. The company cautions investors not to place undue reliance on the forward-looking statements contained in this press release. Peregrine Pharmaceuticals, Inc. disclaims any obligation, and does not undertake to update or revise any forward-looking statements in this press release.

Peregrine Pharmaceuticals Inc - PPHM - provided an update from its randomized Phase II bavituximab study in patients infected with genotype-1 chronic hepatitis C virus. According to the company, Preliminary Data From Phase II Study Shows Antiviral Activity and Positive Safety Profile at Both Bavituximab Doses Evaluated