In the spirit of a recent excellent post on Anadys Pharamceuticals and their experimental hepatitis drug ANA598, I’ve decided to do a little more in depth analysis of the hepatitis C field and share it with my CAPS compatriots. I’m hoping to eventually find the time to describe the hepatitis C programs of about ten developmental biotechs as well as a few competing compounds from large cap companies. But first, a little background.

The hepatitis C virus (HCV) is an RNA virus of the family Flaviviridae. There are six well-established genotypes but only the first three are commonly identified in human infections. Genotype 1 (70% of patients) has a worse prognosis than genotypes 2 and 3, which are essentially equivalent. In the United States, HCV is typically contracted through sharing needles during IV drug use. Chronic infection occurs in 50-80% of infected individuals and will eventually result in cirrhosis and liver failure if untreated.

The hepatitis C virus wasn’t even identified until the mid 1980’s. Alpha interferons, natural inhibitors of viral replication, were approved as treatment of hepatitis C in the 1990’s. A well-established metric for the efficacy of treatment is a sustained virologic response (SVR), which means undetectable hepatitis C RNA six months after termination of treatment. With the original thrice weekly, 48 week course of alpha interferon injections, SVR’s were about 10% for genotype 1 and 30% for genotypes 2 and 3. The next advance came in 1998 with approval of oral ribavarin, a synthetic nucleoside that has minimal activity against hepatitis C alone but significantly augments the efficacy of alpha interferon. The mechanism of ribavarin activity is not well understood. Combination therapy with interferon and ribavirin increased the SVR to 30% for genotype 1 and 60% for genotype 2/3. Another major step forward occurred in 2001 with approval of Schering’s PEG-Intron, which had a substantially longer half-life than prior alpha interferons. This allowed both a reduced frequency of injection and improved efficacy. SVR’s for PEG-Intron combined with ribavirin are 40% for genotype 1 and 82% for genotype 2/3. A year later Roche added Pegasys, using the alpha-2b form rather than the alpha-2a interferon used in PEG-Intron but with similar efficacy.

The current standard of care for chronic hepatitis C infection is different for genotype 1 and genotype 2/3. Genotype 1 requires a 48 week course of treatment with a weekly injection of a PEGylated alpha interferon as well as daily oral ribavirin. For genotype 2/3, 24 weeks of treatment with the same regimen achieves optimal results. In addition, rapid responders (RVR) who are negative for hepatitis C RNA after 4 weeks may stop treatment earlier (24 weeks for genotype 1 and 16 weeks for genotype 2/3).

Developing therapies for hepatitis C include further modifications and upgrades of the existing interferon and nucleoside compounds, as well as completely new weapons such as HCV protease inhibitors (telaprevir, boceprevir, ITMN-191). The HCV NS3/NS4a serine protease catalyzes protein processing that is necessary for viral replication. Vertex’s telaprevir is the most advanced and so far the most successful of the protease inhibitors, so I’ll kick off my hepatitis C series with some information about completed and upcoming trials of telaprevir. In the notes below, TVR is telaprevir and PR is standard of care PEG-IFN + ribavirin. In all the studies TVR is administered together with PR and the numbers indicate weeks of treatment. Therefore TVR12/PR48 indicates 12 weeks of TVR with PR followed by 36 weeks of PR alone.

COMPLETED TRIALS
PROVE 1 – final results were released in 4/08. Phase IIb study of treatment-naïve genotype 1(260 pts). Comparison of TVR12/PR12, TVR12/PR24, TVR12/PR48 with PR48 control. SVR was 35% for TVR12/PR12, 61% for TVR12/PR24 and 67% for TVR12/PR48 vs 41% for PR48. RVR was 79%. RVR’s did not benefit from treatment beyond 24 weeks. 18% discontinuation of TVR due to rash.

PROVE 2 – final results were released in 2008. Phase IIb study of treatment-naïve genotype 1 (323 pts). SVR was 69% for TV12/PR24, 60% for TV12/PR12, 30% for TV12/P12 (no ribavarin), and 46% for PR48. 13% discontinuation due to side effects with TVR vs 10% without.

PROVE 3 - final results were released in 4/09. Phase IIb study of treatment-failure genotype 1. SVR was 51% for TVR12/PR24 and 52% for TVR24/PR48 compared to 14% on PR48. Rash led to discontinuation of treatment in 5% of TVR pts and resolved afterward.

Study C208 – final results 10/09. Comparison of bid and tid dosing of TVR as well as combination with Pegasys or PEG-Intron in treatment-naïve genotype 1 (T12/PR24). RVR’s stopped treatment at 24 wks and non-RVR’s continued PR through week 48. Total follow up was through week 72. Twice daily or thrice daily dosing did not seem to make any difference. RVR was about 80% with Pegasys and 68% with PEG-Intron. SVR was about 82% for all groups.

TRIALS IN PROGRESS
Study 107 – phase II roll-over study of control pts from PROVE trials who did not achieve SVR. Initial protocol was for T12/PR24 which was then switched to T12/PR48 in null responders only. Initial plan to eliminate new null responders at 4 wks was also scrapped. In 10/09 interim analysis of 94/117 pts showed about 56% SVR in prior partial and null responders, 90% SVR in prior relapsers, 75% SVR in prior viral breakthroughs. 23/51 prior null responders were excluded from interim analysis due to their completion of trial prior to protocol amendments. Final results will be released later in 2010.

ADVANCE – phase III telaprevir in treatment-naïve genotype 1 (1050 pts). Three groups of 350 pts: TVR12/PR24, TVR8/PR24, PR48. TVR groups will continue PEG/RBV to week 48 unless they are rapid responders, in which case only follow-up. Follow up continues to week 72. TVR dosing was completed in 2/09 and initial data is expected in Q2 2010.

REALIZE – phase III telaprevir in treatment-failure genotype 1 (650 pts). TVR 12/PR48 with TVR beginning at either week 1 or week 5, as well as a PR48 control group. Initial data is expected in summer 2010.

ILLUMINATE – phase III telaprevir in treatment-naïve genotype 1 (500 pts). TVR12/PR48, with RVR split into two groups at week 24, one with no further treatment and one with PR to week 48. All pts followed through 72 wks. Telaprevir dosing was completed in 5/09 indicating that trial should be finished by 7/10.

Combination trial TVR/VX-222 – initiated 3/10. VX-222 is Vertex’s developmental HCV polymerase inhibitor, acquired by purchasing the private biotech outfit ViroChem last year. Four groups of treatment naïve genotype 1, total 100 pts. 12 weeks of TVR/VX-222 with or without PR, and 100mg or 400mg VX-222. RVR will discontinue at 12 weeks. Non-RVR will continue PR for 24 weeks if no prior PR and at 12 weeks if already receiving PR. Interim data is expected in Q2 2010.

As we can see 2010 is shaping up to be the year that we will see if telaprevir is destined to be the next paradigm shift in the treatment of hepatitis C. To the best of my knowledge Vertex has not released any interim or RVR data from the phase III trials. However, the phase II trials indicate that telaprevir is highly active in HCV and if the phase III data is consistent Vertex’s share price will likely move north of 60. The concern of course is that Vertex already has a market cap over 8B despite an absence of marketed products and a history of dilutive financings. Compare this to Cephalon with a market cap of 5B and quarterly revenues over 500M and Genzyme with a market cap of 15B and quarterly revenues over 1B. Vertex has other promising products in the pipeline as well but any developments threatening the commercialization of telaprevir (such as that nasty rash) could drop the share price more than 50%. Very high stakes.

In my next post on HCV I’ll discuss the competing HCV protease inhibitors in development, including Merck’s boceprevir and Intermune’s ITMN-191, and what threat if any they pose to future profits from telaprevir. I’ll try and get to polymerase inhibitors after that so I can discuss Anadys and ANA598, since Portefeuille’s post was what motivated me to review HCV more comprehensively. I hope that Port and our other high-performing biotech hobbyists will help me correct any inaccuracies and add to our information database on HCV therapies so that we can become a resource for investors around the web.

Part Two : Posted March 8th

Last week, to the great ennui of the CAPS community, I began a new blog series to address the underlying science behind baby biotech. I kicked things off with the fascinating subject of hepatitis C and the protease inhibitor telaprevir, being developed by Vertex. To develop the subject of protease inhibitors further I'll discuss the laggards in the field, Merck’s boceprevir and Intermune’s ITMN-191.

As I described previously, the current standard of care in hepatitis C is PEGylated interferon alpha + ribavirin. This combination treatment yields SVR of 40% for genotype 1 and 82% for genotype 2/3. Phase II data indicates that adding telaprevir to the regimen increases SVR to as much as 70% for genotype 1, and phase III data will be released in a few months.

Merck inherited boceprevir via their merger with Schering-Plough which closed in 11/09. Since the Schering-Plough website is no more and Merck doesn't provide much in the way of clinical trial data on theirs, collecting data on boceprevir is quite work-intensive.

COMPLETED TRIALS

SPRINT-1 - final results 4/09. Phase II boceprevir in 595 treatment-naive genotype 1. Groups received 28 or 44 weeks of boceprevir after 4 weeks of PR (lead-in) or at the beginning of treatment, and a control group received 48 weeks of PR. SVR's were 75% for 44 weeks with lead-in, 56% for 28 weeks with lead-in, 67% for 44weeks without lead-in, 54% for 28 weeks without lead-in, and 38% for PR control. Another treatment arm with low dose ribavirin had poor results. In the lead-in groups, null responders after 4 weeks had a 55% SVR with 44 weeks boceprevir and a 25% SVR after 28 weeks boceprevir. Treatment discontinuation due to side effects was 9-19% in boceprevir arms vs 8% in PR arm.

TRIALS IN PROGRESS

SPRINT-2 - phase III boceprevir in 1099 treament-naive genotype 1. All three groups receive 48 weeks PR (PEG-Intron +ribavirin). One group also receives 28 weeks boceprevir and one group also receives 48 weeks boceprevir. Boceprevir is begun 4 weeks after initiation of PR. Boceprevir patients with RVR by week eight of treatment stop all treatment after 28 weeks. Enrollment completed 1/09. Study completion 6/10 per clinicaltrials.gov.

RESPOND-2 - phase III trial boceprevir in 404 treatment-failure genotype 1. All three groups receive 48 weeks PR. One group also receives 36 weeks boceprevir and one group receives 48 weeks boceprevir. Boceprevir patients with RVR by week eight of treatment stop all treatment after 28 weeks. Enrollment completed 11/08. Study completion 4/10 per clinicaltrials.gov.

While the conventional wisdom is that boceprevir is not as promising as telaprevir, the 75% best SVR for boceprevir compares favorably to the 67-69% SVR seen for telaprevir in the PROVE trials. However, telaprevir definitely has the advantage with respect to data in treatment-failure patients. Only limited data is available for boceprevir, from the null responders in the 4 week lead-in periods in SPRINT-1. But data from the PROVE-3 and ongoing Study 107 trials of telaprevir indicate it has substantial efficacy in patients who have already failed other regimens. Given the potential variability between phase II and phase III data however, boceprevir definitely has the potential to be a significant fly in Vertex's ointment come summer.

And now on to Intermune. The protease inhibitor ITMN-191 has been renamed RG7227 due to a partnership with Roche. The main twist here is that Intermune has been using ritonavir to boost RG7227 levels in trials. Ritonavir is an inhibitor of cytochrome P450-3A4, which degrades protease inhibitors such as the ones being developed for hepatitis C.

COMPLETED TRIALS

Several short phase I trials

INFORM-1 - combination of RG7227 + Pharmasset's polymerase inhibitor RG7128. Highest RG7227 dose cohort had 63% undetectable viral RNA after 2 weeks in treatment-naive and 25% undetectable viral RNA in prior null responders.

TRIALS IN PROGRESS

Phase Ib multiple ascending dose study of RG7227 + ritonavir + PR for 15 days in treatment-naive patients. Initiated in 9/09. Two lowest dose cohorts have been reported, with RVR seen in more than 50%. Trial will continue with higher dose cohorts and likely expansion of treatment to 12 weeks.

Phase IIb study of RG7227 + PR (no ritonavir) for 12 weeks. Initiated in 9/09. Preliminary data is expected in late Q1 or early Q2.

PLANNED TRIALS

Phase IIb of RG7227 + ritonavir + PR for 12 weeks. Expected to begin in Q3 2010.

INFORM-2: RG7227 + ritonavir + RG7128 for 12 weeks. Expected to begin in H2 2010.

Intermune's data is mostly viral kinetics rather than the SVR variety, as they seem to have elected to go with shorter studies to accelerate development. This makes comparisons with telaprevir and boceprevir rather difficult in these early stages. Given that they are far behind in the race, Intermune and Roche are intelligently breaking new ground by combining RG7227 with ritonavir and a polymerase inhibitor, as well as with the standard of care.

If I decide to continue on with this series the next installment will explore the Hepatitis C polymerase inhibitors, such as Pharmasset's RG7128 and Anadys' ANA598.

http://caps.fool.com/Blogs/ViewPost.aspx?bpid=349095&t=01007366137242330765

Hepatitis C: Drugs in the Pipeline
http://egmnblog.wordpress.com
– Sherry Boschert

Feb 15

A rich pipeline of anticipated new drugs to treat hepatitis C is motivating one clinician to delay treatment in select patients who have chronic disease and can safely defer treatment.

According to Dr. Norah Terrault, director of the Viral Hepatitis Center at the University of California, San Francisco, two new protease inhibitors — boceprevir and telaprevir — are expected to be approved as add-on therapy for hepatitis C sometime in the first quarter of 2011, to be used in combination with pegylated interferon and ribavirin.

At a recent conference , Dr. Terrault discussed the pros and cons of treating vs. delaying treatment of hepatitis C in patients co-infected with HIV. The co-infected patients whose hepatitis C she generally treats without delay include any with genotypes 2 or 3 hepatitis C (because all the new drugs are being developed primarily for genotype 1), patients with low levels of hepatitis C RNA regardless of genotype (because they’re the most likely to achieve a sustained viral response to therapy), patients with advanced fibrosis (because “they can’t wait for new treatments”), and patients with acute (not chronic) hepatitis C who are on stable antiretroviral therapy with no opportunistic infections and CD4 counts above 200 cells per cubic millimeter.

For all other co-infected patients, “it’s a matter of weighing the risks and benefits of treating now versus later,” she said. For example, hepatitis C tends to progress faster in the presence of HIV, which could argue for earlier treatment, but the new regimens should offer a better chance of response, if the patient can wait. Toxicity to today’s hepatitis C drugs is a bigger burden for patients with HIV than those without HIV, but the new drug combinations will be even harder to tolerate.

It’s only in the past year that she’s begun deferring treatment for hepatitis C, she said, and the main reasons is that better treatments are “just around the corner.”

Dr. Terrault has received research support from Schering-Plough Corporation (boceprevir) and Vertex Pharmaceuticals Incorporated (telaprevir) as well as numerous other pharmaceutical manufacturers.

Dynavax Reports Promising Early Clinical Trial Data for Experimental Hepatitis C Drug SD-101

http://www.hivandhepatitis.com/hep_c/news/2010/020910_a.html

SUMMARY: Dynavax Technologies Corporation recently announced early findings from laboratory studies and a Phase 1b clinical trial indicating that the investigational hepatitis C drug SD-101, a toll-like receptor 9 (TLR9) agonist, was safe and induced production of higher levels of interferon (IFN) alpha and lambda. Rather than administering manufactured interferon -- the current standard therapy for chronic hepatitis C -- SD-101 is designed to stimulate the immune system to produce more of these naturally occurring cytokines.

Below is a press release from Dynavax describing the study results

Dynavax Reports Positive Phase 1b Data for SD-101
in Chronic Hepatitis C Infection

In vitro Study Shows SD-101 Induces Both IFN-lambda and IFN-alpha

Berkeley, CA -- January 26, 2010 -- Dynavax Technologies Corporation (NASDAQ: DVAX) announced today data from two studies that differentiate SD-101 from standard-of-care as well as emerging treatments for chronic HCV infection. The findings of a Phase 1b clinical trial and an in vitro study of SD-101's mechanism of action show that the second-generation TLR9 agonist (1) is well tolerated and safe and (2) induces both IFN-lambda and IFN-alpha at concentrations producing antiviral activity. The data will be presented at the 45th Annual Meeting of the European Association for the Study of the Liver in Vienna, Austria in April 2010.

Data from the Phase 1b study of SD-101 in treatment-naive, genotype 1 HCV patients show:

	A safety and tolerability profile that compares favorably to that of IFN-alpha, at all four doses tested;
	A dose-dependent antiviral response, with 100% of patients at the highest dose experiencing a greater than one (1) log reduction in viral load; and
	The potency of SD-101 as confirmed by biomarker analysis in patients. The biomarker data point to substantial, dose-related increases in the expression of key antiviral genes (MX-B and ISG-54k) and genes indicating enhanced immunity (IP-10 and MCP-1).

The Phase 1b study evaluated four dose levels of SD-101 in 34 chronically infected, treatment-naive, genotype 1 HCV patients. SD-101 was administered as a monotherapy once weekly, for four weeks, in doses from 0.1 to 5.0 milligrams per week.

The in vitro data from a study of the drug in human blood cells demonstrate that compared to first-generation TLR9 agonists, SD-101 stimulates 20-fold higher levels of both IFN-alpha and IFN-lambda, two classes of IFNs with potent activity against HCV.

According to the company's Chief Medical Officer, J. Tyler Martin, MD, "The unique and highly potent pattern of IFN-lambda and IFN-alpha induction by SD-101 represents a novel, differentiated approach for HCV. The safety and antiviral activity demonstrated in this Phase 1b study compares favorably to current treatments, and we believe that further study may support a role for SD-101 as a supplement to current or emerging therapies to treat HCV."

With the completed acquisition of Symphony Dynamo earlier this month, Dynavax has full development and commercialization rights to SD-101. As such, SD-101 has been added to a portfolio of development programs available for partnership from Dynavax.

About Dynavax

Dynavax Technologies Corporation, a clinical-stage biopharmaceutical company, discovers and develops novel products to prevent and treat infectious diseases. The company's lead product candidate is Heplisav, a Phase 3 investigational adult hepatitis B vaccine designed to provide more rapid and increased protection with fewer doses than current licensed vaccines.

For more information, visit www.dynavax.com.

2/9/10

Source
Dynavax Technologies Corporation. Dynavax Reports Positive Phase 1b Data for SD-101 in Chronic Hepatitis C Infection. Press release. January 26, 2010.

HCV Drug Resistance

Liz Highleyman

A new approach to hepatitis C treatment – specifically targeted antiviral therapy for hepatitis C, or “STAT-C” – promises to improve the likelihood of achieving a cure for hard-to-treat patients. But these new therapies also come with a drawback: HCV can develop drug resistance, making them less effective.

HCV Replication and Mutation
There are two basic approaches to fighting HCV: strengthening the body’s immune response and attacking the virus directly. Interferon-based therapy uses a manufactured version of a natural cytokine to boost immune function. HCV does not develop resistance to interferon over time.

STAT-C drugs block specific steps of the viral lifecycle. For example, HCV protease inhibitors (such as telaprevir and boceprevir) interfere with an enzyme encoded by the NS3/4A gene that processes proteins before they can be assembled into new virions (virus particles). HCV polymerase inhibitors disrupt the action of another enzyme, encoded by the NS5B gene, that copies viral genetic material. (The HCV lifecycle and how drugs work is explained more fully in the December 2009 HCV Advocate.)

Drug resistance can develop when a virus mutates, or changes its genetic code. HCV replicates very rapidly – at an estimated rate of 1012 virions per day – and is prone to errors as it copies its genetic material. The genetic code of mutated HCV is essentially an altered blueprint. Viral proteins consist of a chain of building blocks called amino acids. When the altered blueprint is used to make new proteins and enzymes, the directions call for insertion of a wrong amino acid.

For example, the NS3 protease enzyme produced by mutated HCV might have the usual amino acid valine (V) replaced by alanine (A) at position 107 of the chain – designated V107A. (See chart below for list of amino acids letter codes.)

Amino Acids

Alanine	A
Arginine	R
Asparagine	N
Aspartic Acid	D
Cysteine	C
Glutamic Acid	E
Glutamine	Q
Glycine	G
Histidine	H
Isoleucine	I
Leucine	L
Lysine	K
Methionine	M
Phenylalanine	F
Proline	P
Serine	S
Threonine	T
Tryptophan	W
Tyrosine	Y
Valine	V

In many cases, proteins containing the wrong amino acids do not work properly. This can make mutant HCV less “fit” than wild-type (non-mutated) virus, so it stays at a very low level or dies out. But in other cases, a “wrong” amino acid turns out to be right for the virus, giving it an evolutionary advantage. In fact, this is how viruses manage to survive constant attack by the immune system.

Mechanisms of Resistance
One such advantage is drug resistance – mutations that allow the virus to keep replicating despite the presence of a drug. Amino acid substitutions in the HCV protease or polymerase enzyme can change the protein’s shape and interfere with a drug’s action. For example, a small structural change to the shallow binding pocket of the NS3 protease makes it difficult for a protease inhibitor to fit in and perform its intended function.

HCV polymerase inhibitors are of two types, nucleoside analogs – which act as defective building blocks when the virus tries to copy its genetic material – and non-nucleoside inhibitors, which work by other mechanisms. The HCV NS5B polymerase has at least five sites that are potential drug targets.

Ribavirin, which is used with pegylated interferon to help prevent HCV relapse, is also a nucleoside analog, but it has additional mechanisms of action, and resistance due to viral mutation has not been a concern in hepatitis C treatment.

The emergence of drug resistant mutations sometimes occurs randomly as HCV mutates to evade immune defenses, so an individual who has never been treated may harbor some strains, or quasispecies, that are naturally resistant (known as primary resistance). Most genetic screening studies have detected protease and polymerase resistance mutations at rates of <1% to 5% in previously untreated individuals. These variants are usually only a small minority of the total virus population, and so far they have not been linked to treatment failure – though some research does suggest reduced potency.

More often, resistance is due to continued viral replication and mutation in the presence of a drug. This can happen in two ways. A pre-existing naturally resistant minority variant can become the dominant strain if a drug knocks out the majority wild-type virus. Or, if a drug reduces but does not completely halt viral replication, wild-type HCV can evolve new mutations to evade the drug’s effects. Sometimes a mutation that allows the virus to escape the action of one drug will also make similar agents less effective, a phenomenon known as cross-resistance.

Resistance Studies
Experience treating hepatitis B and HIV led researchers to suspect that using single directly targeted anti-HCV agents – known as monotherapy – would likely promote resistance. As such, resistance testing is part of hepatitis C drug development from the earliest laboratory studies through the final clinical trials.

One or more amino acid substitutions that reduce antiviral potency have been identified for all the HCV protease and polymerase inhibitors currently in development. At the outset, STAT-C agents used as monotherapy may rapidly and dramatically decrease HCV RNA. But before long – days to months, depending on the specific agent – viral load may start to rise again (known as viral breakthrough), indicating that drug-resistant variants are gaining the upper hand.

But drug resistance does not necessarily lead to treatment failure. Even when a mutant virus is less susceptible, a drug still may be potent enough to keep replication under control. Sometimes multiple mutations must coexist to cause a notable decrease in effectiveness. And because HCV treatment is relatively short – typically 24-48 weeks – it does not present the risk of long-term resistance after taking a drug for years (as with hepatitis B) or even for life (as with HIV).

In the November 10, 2009 advance online edition of the Journal of Viral Hepatitis, A.J.V. Thompson and J.G. McHutchison presented an overview of HCV drug resistance, including data from laboratory studies and clinical trials.

Because HCV is difficult to grow in vitro, most laboratory studies use models called replicons that may not respond to drugs exactly like whole virus in the body. Genotypic tests, which examine viral gene sequences for substitutions known to confer resistance, do not always reflect what happens when HCV variants are exposed to drugs in the laboratory (phenotypic testing), which in turn may not predict clinical outcomes in patients.

Nevertheless, some clear patterns have emerged. As noted, the structure of the NS3 protease allows HCV to easily evade protease inhibitors, especially with mutations at positions 155 and 156. For HCV genotype 1, the A156S/T/V and R155K/Q/T substitutions confer resistance to telaprevir, boceprevir, and RG7227 (ITMN-191), especially when additional mutations including V36M and T54A are also present. Other mutations confer resistance primarily to specific drugs, for example V170A for boceprevir and D168V/A for RG7227.

Current polymerase inhibitor candidates produce smaller viral load decreases than protease inhibitors, but they also promote less resistance. Nucleoside analogs such as RG7128 appear to have a particularly high barrier to resistance. Among the non-nucleosides, most agents target only one binding site, and there appears to be no cross-resistance – and perhaps even synergy – between drugs targeting different sites.

To date, no mutations have been found to confer resistance to both protease and polymerase inhibitors, though researchers have produced replicons that simultaneously carry separate protease and polymerase mutations. Fortunately, HCV with protease and/or polymerase resistant mutations appears to remain as responsive as wild-type virus to standard therapy with pegylated interferon plus ribavirin.

Preventing and Overcoming Resistance
The surest way to prevent drug resistance is by completely halting viral replication, or even better, eradicating HCV altogether. With current drugs, however, many people continue to have some level of ongoing viral replication.

Another way to overcome resistance is combination therapy. In order to evade the action of multiple drugs, HCV would have to develop simultaneous mutations, which typically reduces viral fitness in other ways.

Learning from the setbacks of hepatitis B and HIV treatment, researchers understand the benefits of using STAT-C agents in combination regimens from the outset, rather than adding additional drugs after resistance develops. Given how quickly resistance can emerge, the U.S. Food and Drug Administration now limits clinical trials of direct antiviral agents to three days of monotherapy.

Several studies have demonstrated that combining HCV protease inhibitors with pegylated interferon/ribavirin delays the emergence of resistance. In the PROVE trials, however, about 25% of participants who took telaprevir plus pegylated interferon without ribavirin developed resistance. Some trials start with a pegylated interferon/ribavirin “lead-in” period to drive down viral load before adding the direct antiviral agent.

Researchers are exploring combinations of STAT-C agents that work by different mechanisms in the hope of one day eliminating pegylated interferon/ribavirin. In the first such clinical trial (INFORM-1), presented last fall at the 2009 annual meeting of the American Association for the Study of Liver Diseases (AASLD), S. Le Pogam and colleagues showed that over 14 days, the protease inhibitor RG7227 plus the polymerase inhibitor RG7128 produced potent antiviral activity. Viral load declined by as much as 5 logs and no resistant mutations were detected, even in one patient in a low-dose arm who experienced viral breakthrough.

Using another novel approach, L. Delang and colleagues recently demonstrated that adding statin drugs (usually used to manage high cholesterol) to HCV protease and polymerase inhibitors enhanced antiviral activity and reduced emergence of resistant mutations.

In the coming years, hepatitis C therapy is likely to increasingly resemble HIV treatment, using complementary oral drugs that target different steps of the viral lifecycle. As such, it will draw on lessons from that field, such as the importance of good adherence, frequent viral load monitoring, and resistance testing to guide selection of the drugs most likely to be effective.

For more information see:

Selected References
  L. Delang et al. Statins potentiate the in vitro anti-hepatitis C virus activity of selective hepatitis C virus inhibitors and delay or prevent resistance development. Hepatology 50(1): 6-16. July 2009.
  S. Gaudieri et al. Hepatitis C virus drug resistance and immune-driven adaptations: relevance to new antiviral therapy. Hepatology 49(4): 1069-1082. April 2009.
  T. Kuntzen et al. Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naive patients. Hepatology 48(6): 1769-1778. December 2008.
  S. Le Pogam et al. Combination therapy with nucleoside polymerase R7128 and protease R7227/ITMN-191 inhibitors in genotype 1 HCV infected patients: interim resistance analysis of INFORM-1 cohorts A-D. 60th Annual Meeting of the American Association for the Study of Liver Diseases. Boston. October 30-November 1, 2009. Abstract 1585.
  M.F. McCown et al. The hepatitis C virus replicon presents a higher barrier to resistance to nucleoside analogs than to nonnucleoside polymerase or protease inhibitors. Antimicrobial Agents & Chemotherapy 52(5): 1604-1612. May 2008.
  A.J.V. Thompson and J.G. McHutchison. Antiviral resistance and specifically targeted therapy for HCV (STAT-C). Journal of Viral Hepatitis 16(6): 377-387. November 10, 2009 [Epub ahead of print].

http://www.hcvadvocate.org/news/newsLetter/2010/advocate0210.html#3

Vertex, InterMune, and Idenix Present Hepatitis C Drug Development Updates at Investor Conference

http://www.hivandhepatitis.com/hep_c/news/2010/012209_a.html

SUMMARY: At the 28th Annual J.P. Morgan Healthcare Conference, which took place January 11-14 in San Francisco, pharmaceutical and biotechnology companies presented updated information about their clinical development portfolios to potential investors. Among the presenters were 3 companies with directly targeted oral HCV drugs in the pipeline: Vertex Pharmaceuticals (telaprevir, VX-222), InterMune Inc. (RG7227 [formerly known as ITMN-191], RG7128), and Idenix Pharmaceuticals (IDX184, IDX375, IDX320).

Below are edited excerpts from company press releases describing the latest hepatitis C developments. Given that these presentations were aimed at investors, information may be slanted so as to highlight its financial implications.

Clinical trial data for promising agents is expected to be presented by researchers at upcoming medical conferences in the field, including the annual meeting of the European Association for the Study of the Liver (EASL 2010) in April, the Digestive Disease Week (DDW 2010) conference in May, and the American Association for the Study of Liver Diseases' Liver Meeting (AASLD 2010) in late October.

Vertex Plans to Seek Approval of Telaprevir in Second Half of 2010

Matthew Emmens, Chairman, President and Chief Executive Officer of Vertex: "Phase 3 data for telaprevir, our lead drug candidate for the treatment of hepatitis C virus infection, will begin to emerge in the spring of 2010 to support the planned submission of a New Drug Application in the second half of this year. Our more than decade-long commitment to improving patient care in HCV is unwavering, and the Phase 3 program for telaprevir will remain our primary focus over the coming year. Importantly, we also recognize the need for continued innovation in the treatment of this disease, and we are preparing to initiate the first clinical trial combining telaprevir with the investigational HCV polymerase inhibitor VX-222 this quarter."

The hepatitis C program is part of a larger effort to become "a fully-capable biopharmaceutical company," and Vertex is currently working on or planning clinical trials for therapies for cystic fibrosis, rheumatoid arthritis, and epilepsy.

Phase 3 Registration Program for Telaprevir Nears Completion

Sustained viral response (SVR) data expected from Phase 3 ADVANCE trial in second quarter 2010 and from Phase 3 ILLUMINATE & REALIZE trials in third quarter 2010

	The ADVANCE, ILLUMINATE and REALIZE trials are evaluating telaprevir-based regimens as part of a global Phase 3 registration program in more than 2,200 genotype 1 treatment-naive and treatment-failure patients with HCV infection.
	Vertex today announced that all patients in the ADVANCE and ILLUMINATE trials, which are evaluating telaprevir in treatment-naive patients, have completed dosing of all study drugs, including pegylated-interferon (peg-IFN) and ribavirin (RBV), and are now in the post-treatment follow-up period to determine the number of patients who achieve SVR (defined as undetectable HCV RNA 24 weeks after the end of treatment). Vertex expects SVR data to become available from ADVANCE in the second quarter of 2010 and from ILLUMINATE in the third quarter of 2010.
	Vertex today also announced that all patients in the REALIZE trial, which is being conducted by Vertex's collaborator Tibotec and is evaluating telaprevir in patients who did not achieve SVR with a prior pegylated interferon-based treatment, are expected to complete dosing of all study drugs, including pegylated-interferon and ribavirin, by the end of January. Vertex expects SVR data to become available from REALIZE in the third quarter of 2010.
	Vertex plans to submit a New Drug Application (NDA) for telaprevir in the second half of 2010 for both treatment-naive and treatment-failure patients.

Potential Future Combination Regimens for HCV with Telaprevir and the HCV Polymerase Inhibitor VX-222

Vertex recently completed a multiple-dose Phase 1b viral kinetic study of the investigational oral HCV polymerase inhibitor VX-222. Interim results from the trial are consistent with the findings of a previously-conducted three-day viral kinetic study and support future clinical evaluation of VX-222, including the initiation of the first clinical trial of VX-222 in combination with telaprevir. Additional results from this Phase 1b study of VX-222 are planned for presentation at a medical meeting in 2010.

Upon completion of ongoing discussions with regulatory authorities, Vertex plans to initiate a combination trial of telaprevir and VX-222 in the first quarter of 2010. This trial is expected to evaluate SVR rates using multiple regimens of telaprevir/VX-222-based therapy in HCV patients.

The full press release is available online.

For more information about Vertex.

InterMune Provides 2010 Milestones for RG7227 (ITMN-191)

Dan Welch, Chairman, Chief Executive Officer and President of InterMune: "Today we reported preliminary, top-line results from two cohorts of the Phase 1b, 15-day study of low-dose RG7227 co-administered with low-dose ritonavir and standard of care (SOC) in patients with chronic HCV. The majority of patients given ritonavir with 100 mg RG7227 twice-daily or 200 mg RG7227 once-daily were HCV RNA negative at the end of therapy. The ritonavir-boosted regimen provided a more favorable pharmacokinetic profile than what has been previously observed for 900mg RG7227 administered twice-daily with SOC but without ritonavir. In view of these data, our plan is that the development of RG7227 will be in combination with ritonavir."

(RG7227): Clinical Development Highlights and Recent Events

Enrollment began in August 2009 of the company's Phase 2b study of RG7227 in combination with Pegasys) (pegylated interferon alfa-2a) and Copegus (ribavirin), one of the options for the current standard of care (SOC) in HCV. The Phase 2b trial was designed to study both twice-daily (600mg and 900mg q12h) and three-times-daily regimens (300mg q8h) and both 12-week and 24-week treatment durations. On November 17, 2009, InterMune announced that three patients in the blinded 900mg q12h dosage cohort experienced an ACTG Grade 4 elevation in ALT levels, one of whom experienced an elevation of total bilirubin while also receiving concomitant allopurinol. After their review of un-blinded data from these patients, the study's independent Data Monitoring Committee (DMC) recommended that the 900mg q12h cohort be discontinued and that all other cohorts of the study continue. The companies accepted the DMC's recommendations. Enrollment of all remaining cohorts was completed in November of 2009.

The company reported top-line results of a Phase 1 study of ritonavir-boosted RG7227 in healthy volunteers. Ritonavir is an antiviral compound commonly used at low, sub-therapeutic doses to enhance or "boost" the pharmacokinetic (PK) profiles of protease inhibitors. The results of this study demonstrated that the co-administration of low-dose ritonavir increased RG7227 concentration 12 hours post dose by 18 times, with the effect on Cmin being roughly 6 times and 3 times greater than the effect on Cmax and AUC, respectively. These results guided the selection of the substantially lower doses of RG7227 investigated in the Phase 1b MAD study in HCV patients.

The company reported preliminary, top-line results of a Phase 1b multiple-ascending-dose (MAD) study that was initiated in September 2009 to evaluate low doses of once-daily and twice-daily RG7227 co-administered with low-dose ritonavir in combination with SOC for 15 days in treatment-naive HCV-infected patients. This study is examining the following three dosage regimens of RG7227, each with SOC and 100 mg twice-daily ritonavir: 100mg twice-daily RG7227; 200mg once-daily RG7227; 200mg twice-daily RG7227. Preliminary viral kinetic data from the first two cohorts of this study indicate that in the presence of SOC, the majority of patients achieved an undetectable level of HCV RNA after 15 days of treatment. The pharmacokinetic profile of ritonavir-boosted RG7227 was more favorable and less variable than that observed in previously reported studies conducted with much higher doses of un-boosted RG7227. No drug related serious adverse events have been reported to date. The companies hope to present the results from this study at a medical conference in the first half of 2010.

Based upon these results, the company's plan is that the development of RG7227 will be in combination with low-dose ritonavir. Accordingly, the previously planned 24-week un-boosted part of the on-going Phase 2b triple combination study will now be replaced with a Phase 2b ritonavir-boosted study that is expected to begin in Q3 of 2010. As a result of not conducting Part B of the Phase 2b study, the company will un-blind the Part A 12-week cohorts earlier than originally planned and expects to provide both 4-week RVR data and 12-week EVR data late in the first quarter or early in the second quarter of 2010. In addition, the companies plan to amend the on-going Phase 1b MAD 15-day ritonavir boosting study to evaluate 12 weeks of RG7227 ritonavir-boosted therapy plus SOC.

The full press release is available online.

For more information about InterMune, visit http://www.intermune.com.

Idenix Pharmaceuticals Highlights Progress in Three HCV Programs

IDX184: Nucleotide HCV Polymerase Inhibitor

The phase II clinical trial, initiated in the fourth quarter of 2009, is a randomized, double-blind, placebo-controlled, sequential dose-escalation study evaluating the safety, tolerability, pharmacokinetics and antiviral activity of IDX184 in combination with pegylated interferon and ribavirin in treatment-naive HCV genotype 1-infected patients. Patients will receive a daily dose of IDX184 or placebo plus pegylated interferon and ribavirin for 14 days and then continue on pegylated interferon and ribavirin for an additional 14 days. Antiviral activity will be assessed at the 14-day and 28-day timepoints. Four dosing regimens of IDX184 ranging from 50 to 200 mg per day will be evaluated. In the 100 mg and 200 mg cohorts, QD and BID regimens will be compared. Each cohort includes 20 patients randomized 4:1, IDX184:placebo. This study is being conducted at multiple centers in the United States and Argentina.

Interim analysis of the first 10 patients randomized into the first cohort (50 mg QD):
Cohort	Median Change in HCV RNA (log10) at Day 14	Patients with Undetectable Viral Load at Day 14 (<15 IU/mL)
50 mg/day IDX184 + PegIFN/Ribavirin (n=8)	-3.66	2
Placebo + PegIFN/Ribavirin (n=2)	-1.70	0

Median ALT and AST levels, markers of liver injury, improved during treatment. There were no serious adverse events on treatment, no treatment discontinuations and laboratory profiles were comparable to standard PegIFN/Ribavirin treatment.

"We are very encouraged by these interim data for IDX184 combined with pegylated interferon and ribavirin and look forward to seeing additional data as the study progresses," said Douglas Mayers, M.D., Idenix's executive vice president and chief medical officer.

IDX375: Non-Nucleoside HCV Polymerase Inhibitor

A Phase I single ascending dose study evaluating the safety, tolerability and pharmacokinetics of IDX375 in healthy volunteers is ongoing. The first five cohorts (25 mg QD, 50 mg QD, 100 mg QD, 200 mg QD and 200 mg BID; 6 active:2 placebo) in this double-blind, placebo-controlled study have been completed. Data suggest favorable plasma exposure of IDX375 with a long elimination half-life of 32-40 hours demonstrating the potential for once- or twice-daily dosing in patients. IDX375 was generally safe and well tolerated. There were no significant lab abnormalities. The most common adverse event was mild diarrhea (3/30 subjects). Additional cohorts with higher single and multiple doses are planned.

IDX320: HCV Protease Inhibitor

A Clinical Trial Application for a new protease inhibitor clinical candidate, IDX320, was filed in December 2009. IDX320 is a non-covalent macrocyclic inhibitor with nanomolar potency, broad genotypic coverage and a favorable preclinical pharmacokinetic profile supporting the potential for once-daily dosing in man.

"We are pleased with these early data from our clinical programs and look forward to their continued advancement throughout the year," said Jean-Pierre Sommadossi, Ph.D., chairman and chief executive officer of Idenix. "In addition, we are excited about our new protease inhibitor clinical candidate, IDX320, and expect to begin a phase I clinical trial soon. With three promising clinical programs that span major HCV drug classes, Idenix is well positioned to play an important role in the transformation of the HCV treatment paradigm."

The full press release is available online.

For more information about Idenix, see www.idenix.com.

1/22/10

Sources

Vertex. Vertex Reviews 2010 Business Priorities to Support Goal of Becoming Fully-Capable Biopharmaceutical Company. Press release. January 10, 2010.

InterMune. InterMune Provides Program Update and 2010 Milestones for RG7227 (ITMN-191). Press release. January 11, 2010.

Idenix. Idenix Pharmaceuticals Highlights Progress in Three HCV Programs. Press release. January 11, 2010.

Pharmasset Initiates Phase 2a
Trial with PSI-7977, a Chirally Pure Isomer of PSI-7851

PRINCETON, N.J., Jan 21, 2010 /PRNewswire via COMTEX News Network/ -- Pharmasset, Inc. (Nasdaq: VRUS) today announces the initiation of a 28-day Phase 2a study with PSI-7977, a chirally pure isomer form of PSI-7851, a nucleotide analog polymerase inhibitor in development for the treatment of chronic hepatitis C (HCV). The trial will evaluate various doses of PSI-7977 in combination with Pegasys (peginterferon alfa 2a) and Copegus (ribavirin) in patients with HCV genotype 1 who have not been treated previously.

"We recently reported encouraging clinical results with PSI-7851," said Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "We now believe there are a number of advantages in moving forward with a chirally pure isomer of PSI-7851, PSI-7977, including improvements in manufacturing. We look forward to reporting interim data from the Phase 2a trial in the third quarter of 2010, and hope to rapidly progress PSI-7977 into longer-term studies to demonstrate the safety and efficacy of the nucleosides/tides in all HCV genotypes."

About PSI-7977
PSI-7851 is a mixture of two molecules of identical chemical composition, PSI-7976 and PSI-7977, which only differ in the stereo-orientation of one of the atoms. Once inside a liver cell, both molecules are rapidly converted to the same active triphosphate. Given the greater improvements in manufacturing and better in vitro potency, PSI-7977 was selected for further clinical development. A superior formulation in the form of a tablet has been developed and has recently been evaluated in a Phase 1 study in healthy volunteers. The 28 day Phase 2a trial using the improved manufacturing process and tablet formulation has now been initiated and interim results from this study are anticipated in the third quarter of 2010.

About the Phase 2a trial
The Phase 2a trial is expected to enroll about 60 patients with chronic hepatitis C infection who have not been treated previously. The primary goal of the study is to determine the safety and tolerability of PSI-7977 in combination with pegylated interferon and ribavirin. The primary efficacy endpoint of the trial will be the proportion of patients who achieve a rapid virologic response (RVR), defined as undetectable levels of HCV (measured by TaqMan assay) four weeks after the initiation of treatment. Patients will continue to be followed through a Sustained Virologic Response (SVR) endpoint. Patients will be randomized to receive one of four treatments:

- PSI-7977 100mg QD in combination with Pegasys and Copegus for four weeks, followed by 44 weeks of Pegasys and Copegus
- PSI-7977 200mg QD in combination with Pegasys and Copegus for four weeks, followed by 44 weeks of Pegasys and Copegus
- PSI-7977 400mg QD in combination with Pegasys and Copegus for four weeks, followed by 44 weeks of Pegasys and Copegus
- A control arm with Pegasys and Copegus

About Pharmasset
Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis C virus (HCV) and, secondarily, on the development of Racivir(TM) for the treatment of human immunodeficiency virus (HIV). Our research and development efforts focus on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have three clinical-stage product candidates. RG7128, a nucleoside analog for chronic HCV infection, is in a Phase 2b clinical trial in combination with Pegasys(R) plus Copegus(R) and is also in the Phase 1b INFORM studies, the first series of studies designed to assess the potential of combinations of small molecules without Pegasys(R) and Copegus(R) to treat chronic HCV. These clinical studies are being conducted through a strategic collaboration with Roche. Our other clinical stage candidates include PSI-7977, a chirally pure isomer of PSI-7851, an unpartnered, next generation HCV nucleotide analog, that has completed initial Phase 1 clinical studies which provided supportive safety and efficacy data to initiate a Phase 2a trial, and Racivir, for the treatment of HIV, which has completed a Phase 2 clinical trial. We also have two purine nucleotide analogs, PSI-938 and PSI-879, in advanced preclinical development.

Pegasys(R) and Copegus(R) are registered trademarks of Roche.

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

Anadys Pharmaceuticals Provides Progress Update on Phase II Study of ANA598 in Hepatitis C Patients

ANA598 dosing completed in the 200 mg bid cohort

Enrollment completed in the 400 mg bid cohort

SAN DIEGO, Jan. 22 /PRNewswire-FirstCall/ -- Anadys Pharmaceuticals, Inc. (Nasdaq: ANDS) today announced that ANA598 dosing has been completed in the first dose cohort, 200 mg bid, in an ongoing Phase II study of ANA598 in combination with pegylated interferon and ribavirin (SOC) in HCV patients. Anadys expects to receive 12-week safety and antiviral response data for the 200 mg bid cohort in the first quarter of 2010. Anadys also announced that all patients have commenced dosing in the second dose cohort, 400 mg bid. With patient enrollment in this cohort completed, Anadys has accelerated the expected timing to receive 4-week safety and antiviral response at 400 mg bid to the end of the first quarter of 2010 and continues to expect 12-week safety and antiviral response data in the second quarter of 2010.

"We are very pleased with the rapid progress of this study and appreciate the commitment of everyone involved in the trial," said Steve Worland, Ph.D., President and Chief Executive Officer of Anadys. "With continuing positive data, we hope to see ANA598 established as the leading non-nucleoside in HCV, suitable for combination with current standard of care as well as with other direct antivirals currently in development."

Phase II Combination Study

Anadys recently reported positive initial antiviral response and safety results from the 200 mg bid dose cohort based on a planned interim analysis of data at four weeks. In the group receiving ANA598 added to SOC, there was a steady increase in the percentage of patients with undetectable levels of virus from week 1 through week 4, with 56% of patients achieving undetectable levels of virus at week 4 (defined as Rapid Virological Response or RVR), compared to 20% of patients receiving placebo plus SOC achieving an RVR. No patient receiving ANA598 experienced viral rebound (defined as >1 log(10) increase from a prior measurement) through week 4. ANA598 also demonstrated a favorable safety profile through four weeks. There were no serious adverse events reported and the profile of adverse events reported was as expected for patients receiving SOC alone, with comparable rates observed between the ANA598 and placebo arms.

In the ongoing Phase II study, treatment-naive genotype 1 patients are to receive ANA598 or placebo in combination with Pegasys® (peginterferon alfa-2a) and Copegus® (ribavirin, USP) for 12 weeks at dose levels of 200 mg or 400 mg both given twice daily (bid), each with a loading dose of 800 mg bid on day one. After week 12, patients are to continue receiving SOC alone. Patients who achieve undetectable levels of virus at weeks 4 and 12 will be randomized to stop all treatment at week 24 or 48. The primary endpoint of the study is the proportion of patients who achieve undetectable levels of virus at week 12 (defined as complete Early Virological Response, or cEVR). Additional endpoints include safety and tolerability as well as the proportion of patients with undetectable levels of virus at week 4 (defined as Rapid Virological Response, or RVR). Patients will be followed for 24 weeks after stopping therapy to determine the rate of Sustained Virological Response, or SVR. Approximately 90 patients are planned to be enrolled in this study – with approximately 30 patients receiving ANA598 and 15 receiving placebo at each dose level. The study is being managed by the Duke Clinical Research Institute (DCRI) under the leadership of John McHutchison, M.D. and is being conducted at a number of clinical sites in the United States.

About ANA598

ANA598 is a non-nucleoside inhibitor of the HCV RNA polymerase and is wholly owned by Anadys. In a Phase I study in HCV patients, ANA598 demonstrated potent antiviral activity when dosed as monotherapy over three days. Anadys has also completed two long-term chronic toxicology studies of ANA598 (26 weeks duration in rats and 39 weeks duration in monkeys). The No Observed Adverse Effect Level, or NOAEL, is 1000 mg/kg, the highest dose tested, in both the rat and monkey. The completed toxicology studies support the ongoing Phase II clinical study as well as future clinical studies of longer duration.

Anadys has presented in vitro data supporting the use of ANA598 in combination with interferon-alpha as well as with direct antivirals currently in development. In particular, data has shown that ANA598 is synergistic in vitro with interferon-alpha as well as representative HCV protease and polymerase inhibitors. In vitro combination treatment at clinically relevant concentrations of interferon-alpha and ANA598 results in clearance of HCV RNA from cells rather than selection of resistant isolates. Furthermore, ANA598 retains full activity in vitro against mutations conferring resistance to protease inhibitors, nucleoside polymerase inhibitors and non-nucleoside polymerase inhibitors that act at binding sites distinct from that of ANA598, and protease and nucleoside polymerase inhibitors retain full activity in vitro against mutations conferring resistance to ANA598.

ANA598 has received Fast Track Status from the FDA for the treatment of chronic hepatitis C.

Safe Harbor Statement

Statements in this press release that are not strictly historical in nature constitute "forward-looking statements." Such statements include, but are not limited to, references to (i) the expected timing for receiving 12 week data from the 200 mg bid cohort and 4 and 12 week data from the 400 mg bid cohort; (ii) the hope that ANA598 will be established as an important component of future treatment options for patients with hepatitis C; (iii) the ability for patients to achieve EVR and SVR in the ANA598 Phase II study; and (iv) assessments of the safety and tolerability profile of ANA598 based on the interim 4 week analysis from the 200 mg bid cohort. Such forward-looking statements involve known and unknown risks, uncertainties and other factors, which may cause Anadys' actual results to be materially different from historical results or from any results expressed or implied by such forward-looking statements. For example, the results of preclinical and early clinical studies may not be predictive of future results, and Anadys cannot provide any assurances that ANA598 will not have unforeseen safety issues or will continue to have favorable results as the Phase II trial progresses. In addition, Anadys' results may be affected by competition from other biotechnology and pharmaceutical companies, its effectiveness at managing its financial resources, its ability to enter into transactions around its product candidates, its ability to successfully develop and market products, difficulties or delays in its preclinical studies or clinical trials, difficulties or delays in manufacturing its clinical trials materials, the scope and validity of patent protection for its products, regulatory developments and its ability to obtain additional funding to support its operations. Risk factors that may cause actual results to differ are more fully discussed in Anadys' SEC filings, including Anadys' Form 10-K for the year ended December 31, 2008 and Anadys' Form 10-Q for the quarter ended September 30, 2009. All forward-looking statements are qualified in their entirety by this cautionary statement. Anadys is providing this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.

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

SOURCE Anadys Pharmaceuticals, Inc.

RELATED LINKS
http://www.anadyspharma.com

From : hepc.bull -January 2010

DANES SWING A MIGHTY SWORD AGAINST HCV
by Douglas Laird

A recent article published in Science Express
added another drug as a candidate for
treatment against hepatitis C Virus (HCV)
that has shown very exciting possibilities.

Clinical trials demonstrate that it is indeed
well tolerated, which may slightly differentiate
it from protease and polymerase inhibitors
currently in the pipeline as the next addition
to the success of treatment.

Telaprevir and Boceprevir, when combined with standard
therapy, increase the SVR rates in former
non-responders with genotype 1 currently
are producing increased rates of sustained
viral response (SVR) in former nonresponders
with genotype 1, raising SVR
(and chances of a cure) from 15% to around
70%.

There are some issues of drug resistance
that develop when some of these protease
and polymerase inhibitors are used..

Some side effects presently end the treatment
for about 14% of participants. Early reporting
suggests that this may not be so with this
recently announced drug.

The compound in question is called
SPC3649.

The only side effect noted so far is
a cholesterol lowering effect. It has produced
a 350-fold reduction in HCV levels lasting
for two months following 12 weeks of treatment.

There was an additional advantage
discovered, as the drug appears to reset the
immune system in non-responders. Since
there is a genetic disposition involved, some
people have their immune system shut down
rather than fight off the virus when they start
interferon. It appears that this new drug
“actually reset a number of interferon responding
genes… that were deregulated at
the onset of treatment,” according to Santaris
Pharma scientist Henrik Orum. “These genes
are normalized… suggesting that the gene in
non responders could be reset… [to responder
levels].”

These studies show no evidence of viral
escape, indicating that there will be fewer
cases of relapse and non-responders. Viral
“escape” or rebound refers to HCV genetic
mutation, since the virus has a knack of
transforming itself to escape treatment.

Incidentally, this response could be followed
by a jump of ALT during treatment,
which might indicate viral breakthrough.
This happens with interferon treatment and
still happens with the use of the new complementary
drugs nearing development in
10 to 15% of cases.

This is a good reason to check your ALT regularly during treatment.

They may be able to alter approaches at
this point or consider treatment termination.
The target of the SPC3649, microRNA122,
that is required for HCV replication.

All of the six genotypes and over fifty
subtypes of HCV are ‘addicted’ to microRNA122.
The compound likely binds to it
making it unavailable to HCV. Since microRNA122
is universal in many living
organisms it is possible that the drug will
work for everyone. “This paper adds to the
growing body of evidence,” says Orum,
“that the inhibitor platform has the potential
to transform the field of RNA targeted
therapeutics making specific silencing of
RNA targets involved in disease a reality in
human medicine in the longer run.”

Other recent developments with this technology
may have significant impacts on treatments
for HIV, inflammatory disease and even cancer.

It demonstrates a real potential for
HCV treatment in a cocktail with the other
inhibitors without the need for interferon.
In the writer’s view announcements like
this are likely to be counterproductive in BC.
It is the practice for the current government
to limit access to interferon treatment for
arbitrary and contrived reasons.

Present standards for qualifying for treatment require
abnormally high ALT for three months when
we all know that it is possible to die of cirrhosis
without any real change to ALT levels.

A study by Dr Rob Myers in Calgary demonstrated
that forecasts by epidemiologists for
hepatitis mortalities were too low, with four
time increases in hospital related liver visits;
75% of cases are under reported.

Dr Myer's paper came with the potent
metaphor likening the disease to a sleeping
giant awaking. Still it is likely that groggy
policies will continue with the distorted
thinking of BC governance rationalizing that
there are more effective treatments on the
way.

People will continue to fall into the
abyss of brain fog and other costly symptoms
as long as treatment is denied.

Also, the people who suffer increased side effects from
interferon such as anemia will continue to
be denied erythropoietin and subsequently
have their hopes dashed as they are denied
complementary medicine.

After all, if the white blood cell count goes down we know
the treatment is working, right?
Dr Myer’s sleeping giant still lies in a
fitful sleep.

http://www.hepcbc.ca/bulletin/2010/2010-01.pdf

New HCV Drug IDX184 - New Data; Idenix Pharmaceuticals Highlights Progress in Three HCV Programs

Interim analysis of 50 mg cohort demonstrates potent HCV antiviral activity at 14 days for IDX184, a nucleotide polymerase inhibitor, in combination with PegIFN/Ribavirin

- IDX375, a non-nucleoside polymerase inhibitor, exhibited favorable pharmacokinetic properties in a Phase I healthy volunteer study

- Clinical Trial Application filed in December 2009 for IDX320, a next-generation protease inhibitor

CAMBRIDGE, Mass., Jan. 11 /PRNewswire-FirstCall/ -- Idenix Pharmaceuticals, Inc., a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today announced significant progress in three HCV programs. Idenix will provide a business update on these three HCV development programs and on its partnered programs during a presentation by Jean-Pierre Sommadossi, Ph.D., chairman and chief executive officer, to financial analysts and investors at the 28th Annual J.P. Morgan Healthcare Conference in San Francisco on Thursday, January 14 at 8:00 a.m. PST.

IDX184: Nucleotide HCV Polymerase Inhibitor
The phase II clinical trial, initiated in the fourth quarter of 2009, is a randomized, double-blind, placebo-controlled, sequential dose-escalation study evaluating the safety, tolerability, pharmacokinetics and antiviral activity of IDX184 in combination with pegylated interferon and ribavirin in treatment-naive HCV genotype 1-infected patients. Patients will receive a daily dose of IDX184 or placebo plus pegylated interferon and ribavirin for 14 days and then continue on pegylated interferon and ribavirin for an additional 14 days. Antiviral activity will be assessed at the 14-day and 28-day timepoints. Four dosing regimens of IDX184 ranging from 50 to 200 mg per day will be evaluated. In the 100 mg and 200 mg cohorts, QD and BID regimens will be compared. Each cohort includes 20 patients randomized 4:1, IDX184:placebo. This study is being conducted at multiple centers in the United States and Argentina.

Interim analysis of the first 10 patients randomized into the first cohort (50 mg QD):

Median ALT and AST levels, markers of liver injury, improved during treatment. There were no serious adverse events on treatment, no treatment discontinuations and laboratory profiles were comparable to standard PegIFN/Ribavirin treatment.

"We are very encouraged by these interim data for IDX184 combined with pegylated interferon and ribavirin and look forward to seeing additional data as the study progresses," said Douglas Mayers, M.D., Idenix's executive vice president and chief medical officer.

IDX375: Non-Nucleoside HCV Polymerase Inhibitor
A Phase I single ascending dose study evaluating the safety, tolerability and pharmacokinetics of IDX375 in healthy volunteers is ongoing. The first five cohorts (25 mg QD, 50 mg QD, 100 mg QD, 200 mg QD and 200 mg BID; 6 active:2 placebo) in this double-blind, placebo-controlled study have been completed. Data suggest favorable plasma exposure of IDX375 with a long elimination half-life of 32-40 hours demonstrating the potential for once- or twice-daily dosing in patients. IDX375 was generally safe and well tolerated. There were no significant lab abnormalities. The most common adverse event was mild diarrhea (3/30 subjects). Additional cohorts with higher single and multiple doses are planned.

IDX320: HCV Protease Inhibitor
A Clinical Trial Application for a new protease inhibitor clinical candidate, IDX320, was filed in December 2009. IDX320 is a non-covalent macrocyclic inhibitor with nanomolar potency, broad genotypic coverage and a favorable preclinical pharmacokinetic profile supporting the potential for once-daily dosing in man.

"We are pleased with these early data from our clinical programs and look forward to their continued advancement throughout the year," said Jean-Pierre Sommadossi, Ph.D., chairman and chief executive officer of Idenix. "In addition, we are excited about our new protease inhibitor clinical candidate, IDX320, and expect to begin a phase I clinical trial soon. With three promising clinical programs that span major HCV drug classes, Idenix is well positioned to play an important role in the transformation of the HCV treatment paradigm."

2009 Financial Guidance
Idenix today reported that it ended 2009 with approximately $48.1 million of cash, cash equivalents and marketable securities. The company's 2009 financial results have not yet been audited.

About Idenix
Idenix Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts, is a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases. Idenix's current focus is on the treatment of infections caused by hepatitis C virus. For further information about Idenix and to access the webcast of the J.P. Morgan presentation, please refer to www.idenix.com.

Idenix Pharmaceuticals Contact:
Teri Dahlman (617) 995-9905

SOURCE Idenix Pharmaceuticals, Inc.

http://www.natap.org/

Achillion Announces Additional Positive Phase 1b Data With ACH-1625 to Treat Hepatitis C, 5-day monotherapy

Globe Newswire

Second Dosing Cohort Achieves 4.25log10 Viral Load Reduction With Continued Safety and Tolerability

January 11, 2010: 07:00 AM ET

NEW HAVEN, Conn., Jan. 11, 2010 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today reported additional preliminary data from its on-going phase 1b clinical trial of ACH-1625 which demonstrated that the second dosing cohort receiving treatment with ACH-1625 achieved a mean 4.25 log10 reduction in HCV RNA after five-day monotherapy, with continued good safety and tolerability in patients with hepatitis C (HCV). ACH-1625 is an inhibitor of HCV NS3 protease that was discovered and is being developed by Achillion.

Proof-of-Concept Study Results

Today, Achillion announced additional results from a phase 1b clinical study of ACH-1625. HCV-infected subjects in this second dosing cohort (n=9, randomized to 6 active drug, 3 placebo) received doses of 500 mg BID of ACH-1625. Preliminary results showed that a mean reduction in viral load of 4.25 log10 was achieved in the treatment group, as compared to a mean reduction of 0.29 log10 in the placebo group. Safety results from this dosing group were similar to those observed in both the phase 1a segment of the trial and in the first cohort of HCV-infected subjects. Sustained viral suppression was also similar to the first cohort, with patients maintaining a mean reduction of more than 3.0 log10 from baseline through day 12, 7 days after dosing was completed and the last day of viral load measurement in the study.

In December 2009, Achillion announced proof-of-concept data from this phase 1b study. Subjects in the first dosing cohort of HCV-infected patients received doses of 600 mg BID (n=9, randomized to 6 active drug, 3 placebo). Preliminary results showed that a mean reduction in viral load of 3.94 log10 was achieved in the treatment group, as compared to a mean reduction of 0.22 log10 in the placebo group. All subjects in the treatment group had viral load decline between 3.0 and 4.5 log10, and two subjects reached undetectable levels of HCV RNA. Safety results from this dosing group were similar to those observed in the phase 1a segment of the trial. There were no serious adverse events, no clinically significant changes in vital signs, electrocardiograms (ECGs), or laboratory evaluations. All reported adverse events were classified as mild or moderate, were transient and showed no apparent dose relationship. Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of more than 2.0 log10 from baseline through day 12, the last day of viral load measurement in the study.

"We are quite pleased to see that these data corroborate and support the preliminary positive data from the first cohort of the study even at this lower dose. ACH-1625 continues to demonstrate a dramatic reduction in viral load after 5 days of monotherapy, and importantly, showed continued suppression of viral load after drug discontinuation. This is significant as it could be a distinguishing feature and competitive advantage for our compound in comparison to other HCV therapeutics," said Michael D. Kishbauch, Chief Executive Officer of Achillion.

"With continued robust antiviral activity even at this lower dose, we are encouraged now to explore both lower doses and different dosing schedules. We expect to conduct studies of additional doses under this protocol over the next few months and to release additional data thereafter, potentially at the upcoming EASL (European Association for the Study of Liver Disease) meeting in April 2010 in Vienna," added Dr. Elizabeth Olek, Chief Medical Officer of Achillion.

About ACH-1625

ACH-1625 is an HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios demonstrated in preclinical studies, Achillion believes that ACH-1625 has the potential for once daily dosing. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50~1nM.

In phase 1a safety studies with ACH-1625, subjects in the single ascending dose (SAD) segment of the study received single doses ranging from 50 mg to 2000 mg. Subjects in the phase 1a multiple ascending dose (MAD) segment of the study received 5 days of ACH-1625 up to a maximal dose of 2000 mg per day. Preliminary data from the SAD and MAD trial segments demonstrated ACH-1625 was well tolerated at all doses and there were no serious adverse events, no clinically significant changes in vital signs, electrocardiograms (ECGs), or laboratory evaluations. All reported adverse events were classified as mild or moderate, were transient and showed no apparent dose relationship.

About HCV

The hepatitis C virus (HCV) is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80% of individuals become chronically infected following exposure to the virus. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.

About Achillion

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease -hepatitis C, resistant bacterial infections and HIV. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-1625, which may not be duplicated in future cohorts at different doses or in future clinical studies of longer duration; Achillion's expectations regarding timing and duration of other clinical trials, including additional dosing cohorts. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are: uncertainties relating to results of clinical trials, unexpected regulatory actions or delays, and Achillion's ability to obtain additional funding required to conduct its research, development and commercialization activities. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2008.

All forward-looking statements reflect Achillion's expectations only as of the date of this release and should not be relied upon as reflecting Achillion's views, expectations or beliefs at any date subsequent to the date of this release. Achillion anticipates that subsequent events and developments may cause these views, expectations and beliefs to change. However, while Achillion may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so.

CONTACT: Achillion Pharmaceuticals, Inc.
Mary Kay Fenton
(203) 624-7000
mfenton@achillion.com

http://www.natap.org/

Vertex to Ask for Telaprevir OK Later in 2010

Jan 11

Biotechnology company Vertex Pharmaceuticals Inc. said Monday it plans to seek regulatory approval of the experimental hepatitis C drug telaprevir as scheduled during the second half of 2009.

Telaprevir is one of several potential hepatitis C treatments in development. If approved, it could face competition from Schering-Plough Corp.'s experimental hepatitis C drug boceprevir.

Meanwhile, the company will tell investors at a conference it expects a loss of less than $650 million in fiscal 2009, versus a loss of $459.9 million in fiscal 2008, or $397.5 million on an adjusted basis.

Vertex has about $1.3 billion in cash, cash equivalents and marketable securities.

The company will report 2009 financial results and provide a 2010 outlook on Feb. 4.

Shares of Vertex rose $1.28, or 3.2 percent, to $41.95 in midday trading.

Head To Head Study :

Head-to-head studies identify best treatment regimen for hep C

Peginterferon alpha-2a (PegIFNα2a); Commercial name Pegasys) May Yield higher response rate then Peginterferon Alpha-2b (PegIFNα2b); Commercial name Peg Intron.

In patients with chronic hepatitis C, treatment with peginterferon alpha-2a (PegIFNα2a) plus ribavirin (RBV) better suppresses the virus to undetectable levels in the blood than treatment with peginterferon alpha-2b (PegIFNα2b) plus RBV, according to two new head-to-head studies in Gastroenterology, the official journal of the American Gastroenterological Association (AGA) Institute.

Continue Reading......

Also See

Do Differences in Pegylation of Interferon Alfa Matter?, 23 November 2009

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Stefan Zeuzem
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Top Stories of 2009

From HCV Advocate
—Alan Franciscus, Editor-in-Chief

I don’t know about you, but it seems like time is speeding up these days – some say the older you get the faster time flies—personally, I flatly reject that theory! But it does seem like just yesterday that I was sitting on this same chair and writing on this same computer about the top news stories of 2008. At any rate, compiling a list of the top stories has become a tradition here at HCSP/HCV Advocate and I’m always eager to hear about what the staff of HCSP and fellow HCV advocates voice as the most newsworthy items of the year. 2009 provided us all with some amazing news stories and it was difficult to tweak them down to a manageable size; however, we have compiled the following list that we believe contains some of the top news stories—items number one and number two are in what we believe is the order of importance—the remaining items are not in any particular order.

HEALTH CARE REFORM

Back in 2008 I wrote about the possibility of healthcare reform in the United States:

“In 2008 we believe that there will be more movement towards health care reform on a local and state level as we have seen in Massachusetts and San Francisco. We all believe that the time is right for major health care reform in this country and that eventually there will be a national focus on health care reform, but it is going to take many years and much advocacy on the part of all Americans to make health care and services for all Americans a reality.”

– HCV Advocate January 2008

What we all thought would take many years to accomplish is now close to becoming a reality on a national level. We all need to advocate for this important legislation even though it is far from perfect. Hopefully, once a healthcare measure is passed it can be built upon in the future to ensure that every American has access to quality medical care. So even though the issue about health reform is not specifically hepatitis C-related, it touches almost all of us in the HCV community in some way. I can’t even begin to list all of the emails I receive from people who do not have insurance or who have insurance but do not have enough coverage to pay for HCV care and medications.

HCV PIPELINE

HCV Pipeline: It’s not surprising that the most important HCV-related news stories in 2009 involved the medications being developed to treat hepatitis C. The two drugs that are furthest along in development are the HCV protease inhibitors telaprevir and boceprevir tested in studies with the combination of pegylated interferon plus ribavirin. Both drugs will finish their development cycle in 2010 and the phase III data is expected to be sent to the Food and Drug Administration (FDA) for marketing approval in 2010-2011. It is possible that the FDA may approve the drugs by 2011 – that is if there are no glitches in the data and if the FDA doesn’t have any important safety or other concerns that are not addressed in the clinical studies.

• Telaprevir (with pegylated interferon and ribavirin): Seems to be the winner on the basis of clinical results and outcomes. Genotype 1 treatment-naïve: In 2009 data from various clinical trials of telaprevir, pegylated interferon plus ribavirin (phase II) found that 69% of genotype 1 treatment-naïve patients treated for 24 weeks achieved an SVR. Re-treatment of people who did not achieve an SVR with a previous course of pegylated interferon plus ribavirin for 48 weeks resulted in SVR rates between 38% and 76% (depending of type of prior non-SVR). The most prominent side effect was skin rash. Another study evaluated the current dosing schedule of thrice daily (current phase III studies) and compared it to a twice daily dosing schedule (with the same daily drug exposure). The twice-a-day dose was found to be as effective as the thrice daily dose. The implications of the results are not completely clear at this time since all the previous studies and the current phase III studies of telaprevir are using the thrice daily dose.

• Boceprevir (with pegylated interferon and ribavirin): Close on the heels of telaprevir in clinical development. The phase III studies are fully enrolled and they are expected to be completed in 2010. Merck/Schering is expected to apply to the FDA in 2011. Treatment-naïve HCV genotype 1 patients treated for 48 weeks with a combination of boceprevir, pegylated interferon plus ribavirin achieved an SVR of 75%. A small 48 week re-treatment study of boceprevir and pegylated interferon plus ribavirin in people who did not achieve an SVR resulted in an SVR of 55%. The most worrisome side effect of boceprevir is anemia, which is already a problem in ribavirin containing regimes.

• INFORM-1: This study is the first combination HCV therapy of an HCV protease inhibitor (RG7227) and an HCV polymerase inhibitor (RG7128) without interferon and ribavirin. Very early data is quite encouraging with dramatic drops in HCV RNA (viral load). Unfortunately, the 900 mg dose was eliminated from the study due to adverse events so it is unclear what this means for future studies of the combination therapy.

• Albuferon (Zalbin): Human Genome Science’s (HGS) long lasting interferon (dosed every two weeks) tested in combination with ribavirin completed phase III studies and was deemed to be non-inferior to Pegasys (once-a-week dosing) plus ribavirin. Late in 2009, HGS submitted the data to the FDA for marketing approval. Approval is expected in 2010-2011. How this newer long-acting medication will change the landscape of HCV treatment is unclear.

Other important stories this year (no particular order of importance) include:

• Death of a liver cell: It has long been thought that the immune system attacking the hepatitis C virus infecting liver cells was the cause of liver cell death. Researchers from the University of Alberta, Canada, however, have discovered and reported in early 2009 that HCV itself causes some damage to the liver cell and can lead to the death of liver cells.

• Acquisitions: Two big HCV pharmaceutical companies, Roche and Schering, were acquired or merged in 2009. Roche acquired Genentech earlier this year and has already completed a move from Nutley, NJ to South San Francisco, CA. Merck acquired Schering-Plough in early 2009. Merck and Schering will not be fully merged until the beginning of 2010.

• Liver Transplantation: There was much news in 2009 about liver transplantation. Unfortunately, most of the news was about disparities in care and outcomes were negative.

A study that followed 144,507 patients hospitalized in PA with liver-related conditions of whom 4,361 received a liver transplant evaluation and were waitlisted and of these 1,537 received a liver transplant. The authors found that “61 percent of men were evaluated for transplantation compared to 39 percent of women; 73.8 percent of whites were evaluated compared to 8.6 percent of blacks; and 62 percent of patients who had commercial health insurance were evaluated compared to 4.7 percent with Medicare health insurance only.” (www.urbanmecca.net)

A review of records between 1999 and 2008 from 5 transplant centers that included 771 patient records found that there was a 30% higher mortality rate for African Americans compared to whites. The researchers stated that African Americans had more inflammation and severe fibrosis progression compared to whites who were undergoing a liver transplant. (www.medicalnewstoday.com September issue of Liver Transplantation)

In a study of 850 patients who received a liver transplant from March 2002 through December 2007 for HCV-related liver disease, women were found to have worse outcomes following liver transplantation compared to men. (www.AASLD.org )

• Legislation: 2009 was really the year that the HBV and HCV communities bonded. In 2009, “The Viral Hepatitis and Liver Cancer Control Act,” was introduced by Congressman Mike Honda (D-CA) and Congressman Charles Dent (R-PA). This legislation strives to provide $90 million in funding in 2011 to increase the capacity and ability of the Centers for Disease Control to support state efforts in prevention, immunization and surveillance. We should all be focusing our advocacy efforts to support this very important bill that could help to address some of the disparities in care of HBV and HCV.

• Reports: Two important reports were released in 2009: The first, “Silent Epidemic of Viral Hepatitis May Lead to Boom in Serious Liver Disease,” stated that less than 1 in 5 hepatitis C patients (that’s 663,000 out of the 3.9 million who have HCV in US) are receiving HCV treatment. Breaking it down by total new prescriptions filled—126,000 prescriptions of pegylated interferon plus ribavirin in 2002 fell to 83,000 in 2007. The researchers chalked up the decline in prescriptions to lack of diagnosis of HCV and to the fact that fewer than 25% of the patients diagnosed with HCV were referred for HCV antiviral therapy. Another important report released in 2009 was the Consequences of Hepatitis C Virus (HCV): Cost of a Boomer Epidemic of Liver Disease commissioned by Vertex Pharmaceuticals, Inc. and produced by Milliman, Inc. In their detailed report they confirmed previous estimates of the future disease burden of HCV and came to some alarming conclusions:

The annual cost of advanced liver disease will climb to $85 billion in the next two decades

Medicare costs will increase 500%, from $5 billion to $30 billion in the next two decades

These reports will, hopefully, help reinforce the need for immediate passage of the viral hepatitis legislation listed above.

• HIV and Acute HCV: In the last few years there have been numerous reports of sexual transmission of HCV among HIV positive men. In 2009, a study was released that concluded that sexual transmission and not injection drug use was the cause of acute HCV transmission among HIV positive men in New York. It was also reported that, in the HIV positive men who contracted acute HCV, their HCV disease progression was greatly accelerated and recommended immediate treatment with HCV antiviral medications since the majority of people with acute HCV can rid themselves of the virus. Based on the acute outbreaks of HCV in HIV positive men, New York now considers HCV a sexually transmitted disease—at least among HIV positive men. But it is worth mentioning (at least at this time) that the high rate of sexual transmission has only been seen in HIV positive men and the mode of transmission seems to be related to anal receptive sexual practices.

• Metabolic Syndrome and Steatosis: More and more attention is focusing on the universal effects of metabolic syndrome and particularly steatosis. It is expected that steatosis in the next couple of decades will replace HCV as the number one indication for liver transplantation. If you add metabolic syndrome to HCV you have a scary picture of more serious disease progression and lower treatment outcomes. The bad news about steatosis is that currently there are no medications to treat it, but the good news is that it can be successfully treated in most people through healthy diet and exercise. Notice that I said it can be treated and I didn’t say it is easy. But equipped with all the tools needed, eating and maintaining a healthy diet and exercise program is very achievable.

• Treatment Outcome: People with HCV who achieve an SVR will need to receive follow-up medical care over time because some, especially those who were treated and had severe fibrosis or cirrhosis, may have serious disease progression even after achieving an SVR. The take home message on this news is that while the vast majority of people who achieve an SVR will not have any further serious disease progression, some, unfortunately, will continue to have disease progression.

• Unsafe Injections: Exposed thousands to HCV. In early 2009 a report was released which found that there were at least 60,000 people who may have been exposed to hepatitis B and C in the USA alone. (www.newsday.com) Last year it was the Las Vegas outbreak that put 40,000 people at risk. This year is a bit better, but still any exposure is too many—the largest outbreak was at various Veteran medical centers across the U.S. that was estimated to expose 11,000 people to hepatitis B, hepatitis C and HIV from receiving colonoscopies with equipment that was not sterilized. It is amazing that such widespread outbreaks still occur because standard safety practices that have been set up to protect people are not followed.

• Needle Exchange: On a good note, we are on the brink (as of publication) of finally funding needle exchange in this country. The U.S. House of Representatives and the U.S. Senate have passed the legislation and have included funding of needle exchange in the 2010 Federal budget. President Obama is expected to sign the legislation into law. The tide is finally turning regarding the message about needle exchange—that is, it is about preventing disease transmission rather than the falsely perceived notion of encouraging or condoning drug use. Another shift is taking place in the War on Drugs, which has proven to be a failure on almost every level both domestically and internationally. A different approach in this country and around the world could help us reduce the prison population and work within our country to put in place effective measures that would help with possible solutions to drug addiction.

• Growing Liver Cells from Human Skin: The article that was the most interesting to many of us at HCSP was on growing liver cells from human skin! S.A. Duncan and colleagues from The Medical College of Wisconsin in Milwaukee were able to build on previous research led by J. Thomson and colleagues at University of Wisconsin-Madison by manipulating skin cells to form liver cells. The potential of creating liver cells from skin cells will help speed up new tests, drug development, including vaccines, and may even lead to technology that will enable us to completely regenerate a liver. Keep your eyes on this discovery—you will be hearing about this for years to come as a critical point in the science of the liver.

Honorable mention goes to wonderful caffeine where yet another inspiring study has found that drinking coffee may lower the risk of disease progression. The study was part of the HALT-C study. Kidding aside, the study was a self-disclosure study that asked people how much coffee they drank. The actual coffee and caffeine consumption (that is how much caffeine was present in each cup of Joe) was not scientifically evaluated so the take home message on this study: moderate coffee consumption is probably ok for the liver. It would be interesting, though, if a well-designed prospective clinical trial on coffee and caffeine was conducted to determine exactly the benefits and risks, if any, of caffeine consumption.

We would be interested in how you rate the stories, that is, in order of importance. Drop us a line and let us know and include any items you believe that should have been incorporated into our list.

One can only hope that at this time next year (which will be here faster than a speeding bullet) we will be debating about what needs to be improved in the healthcare reform bill that was enacted into law in 2010.

Updates Jan 2010

AASLD 2009 - Part 1 & Part 2
Alan Franciscus, Editor-in-Chief

Part One

The American Association for the Study of Liver Diseases (ASSLD) conference was recently held in Boston, MA. As expected the majority of information about HCV was from studies on the new drugs being developed to treat hepatitis C. That’s the good news about the conference. The not so good news about the conference is that the information about HCV epidemiology, disease progression and disease management was minimal, which is unfortunate (to say the least) because of all the unanswered questions about these important issues. Having said this, the news about all of the new therapies to treat hepatitis C is very exciting and inspiring especially since we are moving closer to the eventual approval of drugs that will improve the treatment response rates. It is, however, important to keep in mind that most of the studies reviewed in this report include only a small number of participants and the period of time the drugs are being taken by people is short. Larger clinical trials with a diverse HCV population using a new drug over a longer period of time will give a much better picture of the safety, tolerability and efficacy of a study drug.

INFORM-1

This is the first clinical trial of the combination of an HCV polymerase inhibitor, RG7128, and an HCV protease inhibitor, RG7227. What is noteworthy is the absence of interferon and ribavirin. The theory behind this clinical trial is that by combining two different types of direct HCV antiviral medications there is a different mechanism of action to attack the virus at different parts of the replication process to help to prevent the virus from becoming resistant to either medication. Also of note is that the drugs are eliminated differently from the body—one from the kidneys and one from the liver. Another compelling reason for hoping this combination will work is that both are oral medications that only have to be taken twice a day—which will make adherence much easier compared to taking a shot of interferon, multiple doses of ribavirin and possibly 3 daily doses of an HCV direct antiviral a day.

All patients in this study were HCV genotype 1 patients who did not have cirrhosis. Treatment relapsers, partial responders and null responders as well as treatment-naïve patients were included in the trial.

Part 1
In April 2009 the results from part 1 of the phase I study were released. In part 1 the combination dosing for 14 days produced a median reduction of HCV RNA of -4.8 to -5.2 log₁₀ IU/ml in the highest doses; all doses of the combination produced HCV RNA reductions (less than 40 IU/mL) in 63% of the trial participants The drugs were well-tolerated over the 14-day dosing period with no serious treatment-related adverse events, dose reductions or discontinuations

Part 2
The objective of the second part of the study was to assess the safety and tolerability of a combination of the two drugs for up to 13 days.

All of the study medications were dosed at BID (twice a day) and in each group two patients received a placebo (sugar pill). A total of 24 patients were randomized to one of three treatment arms; the RNA decline is listed after the dosing regimen below:

8 patients who were treatment failure but NOT null-responders received 1000 mg RG7128 plus 600 mg RG7227

-4.0 log₁₀ IU/ml (range -6.0 to -2.5); HCV RNA < 15 IU/mL = 1 patient

8 patients who were null-responders received 1000 mg RG7128 and 900 mg RG7227.

-4.9 log₁₀ IU/mL (range -5.3 to -3.5); HCV RNA <15 IU/mL = 2 patients

8 patients who were treatment-naïve received 1000 mg RG7128 and 900 mg RG7227.

-5.1 log₁₀ IU/mL (range -5.9 to -3.0); HCV RNA <15 IU/mL – 5 patients

Safety:
Similar to part 1 of the study results released earlier this year, headache was the most common side effect followed by nausea, diarrhea, and rash that were possibly related to the study drugs. There were no treatment discontinuations due to side effects. One person dropped out of the study due to personal reasons.

Resistance:
There was no treatment-emergent resistance identified. One patient in the low dose group had a rebound of HCV RNA viral load, but it was suppressed with treatment of pegylated interferon plus ribavirin.

The authors noted that this is the first interferon-free study to demonstrate that HCV RNA could be suppressed to the same extent as that shown with the use of the combination of HCV protease inhibitors, pegylated interferon and ribavirin over a two week period.

Comments:
The results from this study are remarkable although it is important to remember that the number of people who actually took the drugs was very small and the people were only given the study drugs for a short period of time. The next steps (INFORM-2) are to study the combination of RG7128 and RG7227 with and without pegylated interferon and ribavirin for a longer period of time. The companies expect to start the studies in the first half of 2010.

TELAPREVIR

Telaprevir is currently in phase III studies, but other on-going studies are being conducted and data is being released. Included in this report are results from three different telaprevir studies.

PROVE3 Final
Final SVR results from PROVE3 were released that confirmed that SVR12 data is the same as SVR data—at least in this study. PROVE3 was a study conducted in people who did not achieve an SVR with a previous course of pegylated interferon and ribavirin. The study was composed of 4 treatment arms, but the arm that resulted in the highest response rate and lowest relapse rate was the 48-week treatment arm that included 24 weeks of telaprevir, pegylated interferon, and ribavirin followed by 24 weeks of pegylated interferon plus ribavirin. In this arm the SVR12 results ranged from 53 to 76% depending on the type of prior non-response. This group also had the lowest relapse rate (4%), which is pretty remarkable. The results comparing the SVR12 results to standard SVR (HCV RNA negative 24 weeks after the end of treatment) were the same except that one person was lost to follow-up.

Comments:
This is an important finding since the shorter period of SVR will, hopefully, speed up the future development.

Study C208
Study C208 is an important study because it compared a telaprevir dose taken every 8 hours (current phase III study) to a dose taken every 12 hours.

In the current study there were a total of 161 HCV genotype 1 treatment-naïve patients divided into 4 treatment arms. All patients received the triple combination listed below for 12 weeks followed by an additional 12 weeks with pegylated interferon (Pegasys, PegIntron) plus ribavirin. Listed below are the dosing arms as well as the SVR rates:

Arm A: 40 patients received telaprevir 750 mg every 8 hours plus Pegasys and ribavirin.
      SVR=85%

Arm B: 42 patients received telaprevir 750 mg every 8 hours plus PegIntron plus ribavirin.
      SVR=81%

Arm C: 40 patients received telaprevir 1125 mg every 12 hours with Pegasys and ribavirin.
      SVR= 82.5%

Arm D: 39 patients received telaprevir 1125 mg every 12 hours with PegIntron plus ribavirin.
      SVR=82.1%

*Note: The daily dose or exposure of telaprevir was the same across all treatment arms = 2250 mg

The percentage of people who achieved a rapid virological response (undetectable viral load after 4 weeks) and went on to achieve an SVR was similar across all treatment arms—91 to 93%.

There were 14 people who discontinued treatment due to side effects—7 people due to rash; 2 people due to pruritus (itching). Of note, unlike in previous studies there was a rash management plan that included provider education and recommendations for over-the-counter medications to control the rash; this is believed to have contributed to the lower incidence of rashes in this study.

Comments:
This study is important because it shows that the drug efficacy of the every 12 hours dosing schedule is the same as the every 8 hours dosing schedule. The two drugs that are furthest along in development are telaprevir and boceprevir—both dosing schedules are for taking the protease inhibitor every 8 hours, ribavirin twice a day and pegylated interferon one time a week. Maintaining 100% adherence for many patients will be a struggle with the new triple therapy. Failure to follow a dosing schedule or missing doses of the new direct antivirals will lead to drug resistance and, of course, lower treatment response rates. A regime with drugs taken every day from every 8 to every 12 hours will be a huge step forward in improving adherence and treatment outcomes. But since the phase III studies are using the 3 times a day dose, the immediate implications are unclear.

Study 107
Results from Study 107, an on-going study of people who failed to achieve an SVR with a previous course of pegylated interferon plus ribavirin therapy in prior telaprevir studies (SOC or standard of care arms), were released at AASLD. The interim results were from 94 patients who were rolled over to treatment with telaprevir, pegylated interferon plus ribavirin for 12 weeks followed by either an additional 12 or 36 weeks of pegylated interferon plus ribavirin.

The sustained virological response rates between the two groups (total treatment duration) was not broken down so the results below are listed by type of response:

1. Prior null responders (patients who had a viral load reduction < 1 log₁₀ at week 4 or < 2 log₁₀ at week 12). A total of 28 of whom 16 (57%) achieved an SVR.

2. Prior partial responders (patients who had a viral load reduction > 2 log₁₀ at week 12, but who had detectable HCV RNA at week 24. A total of 29 patients of whom 16 (55%) achieved an SVR.

3. Prior relapsers (patients who had an undetectable viral load during treatment, but had detectable viral load after treatment ended. A total of 29 patients of whom 26 (90%) achieved an SVR.

4. Prior viral breakthrough (patients who had undetectable viral load during treatment, but detectable viral load before the end of treatment. A total of 8 patients of whom 6 (75%) achieved an SVR.

*The SVR rates are combined for both treatment durations by type of non-response, but it was noted that the optimal treatment duration is 48 weeks.

According to a company press release the side effect profile was similar to what has been seen in previous telaprevir studies.

Comments:
This important but small study is encouraging for improving the SVR rates in people who have been previously treated with pegylated interferon plus ribavirin therapy. The larger phase III studies of people who did not achieve an SVR with a previous course of pegylated interferon plus ribavirin will give us a much better picture of the future of retreatment in the HCV population that is in the most need of treatment options.

BOCEPREVIR

The SPRINT-1 was a phase II study of HCV genotype 1 treatment-naïve patients. In the current retrospective study, data from patients from the original study who achieved less than a 1 log₁₀ drop in HCV RNA viral load (called null-responders in this analysis) after 4 weeks of PegIntron plus ribavirin (lead-in phase) was analyzed. All the patients received either 24 or 44 weeks of additional treatment with boceprevir, PegIntron and ribavirin. A total of 206 patient records were analyzed. In both groups of null-responders the SVR rate was 38% (16 out of 50 patients). In the group that was treated for 28 weeks the SVR rate was 25% (7 out of 28 patients) and 55% (12 out of 22 patients) in the group that received 48 weeks of therapy.

Another analysis of the SPRINT-1 clinical trial noted that people who achieved a rapid virological response after treatment with boceprevir, PegIntron and ribavirin were able to achieve an SVR rate of 82% (54 out of 66 patients) in the 28 week treatment arm. In the patients who did not achieve an RVR but who were HCV RNA negative by week 16 and were treated for 48 weeks there was a 79% (15 out of 19 patients) SVR. These results support the rationale for response-guided therapy.

Comments:
While these results are impressive a couple of caveats need to be made: the findings are from an analysis of previous data which can prove to be a slippery slope, and there were small patient numbers as well. The phase III studies of boceprevir will yield much more accurate information about response-guided therapy.

In part 2 of AASLD conference coverage I will discuss the results from more than a dozen studies of the new agents that are being developed to treat hepatitis C.

Part Two/ Jan 2010

In the article “AASLD 2009: Part 1” (above) in last month’s HCV Advocate newsletter, I discussed the top performers in the new class of HCV direct antivirals—telaprevir, boceprevir and the INFORM-1 combination trial. In “AASLD 2009: Part 2” I will discuss some of the many new drugs that are being developed to treat hepatitis C.   The drugs listed below are in very early development (Phase I and Phase II) so the data presented here will be very brief.

HCV PROTEASE INHIBITORS

PHX1766: In a study of healthy volunteers and HCV genotype 1 patients who were given PHX1766 it was found that the average maximal HCV RNA decline after 6 days was -1.2 log10 in the 400mg BID group and -1.8 log10 in the 800mg BID group. PHX1766 was generally well-tolerated. One serious adverse event was reported, but the investigators believed that it was unrelated to the study drug.

MK-7009: Updated information about the ongoing trial was presented. The proportion of subjects who achieved RVR in the MK-7009-containing arms ranged from 69% to 82%, vs. 6% in the placebo group, and the percentage of patients who achieved an EVR ranged from 76 to 89% compared to 60% in the placebo group. No serious adverse events resulted in treatment discontinuation.

TMC435: A study of prior non-responders and treatment-experienced patients found that at day 28, all four patients who completed treatment achieved HCV RNA <25 IU/mL with an overall mean change from baseline of- 5.86 log10 IU/mL. Three of those four patients had HCV RNA below the lower limit of detection (<10 IU/mL) at day 28.

POLYMERASE INHIBITORS

Narlaprevir: Two studies of narlaprevir were presented at AASLD. In the first study, participants were given narlaprevir (twice daily or thrice daily; with and without ritonavir) and PegIntron for 2 weeks followed by PegIntron plus ribavirin for 24 or 48 weeks. A total of 41 (20 treatment-naïve; 21 treatment-experienced) HCV genotype 1 patients were treated. The sustained virological response rates were 81% (13 of 16 patients) in the treatment-naïve group; 17% (1 of 6 patients) in the prior non-responder group; and 50% (5 out of 10 patients) in the group who were prior relapsers. The side effect profile was consistent with side effects seen with pegylated interferon plus ribavirin therapy. The results of this study showing potent antiviral activity of narlaprevir when combined with ritonavir prompted the design of the second study combining a once-a-day dose of narlaprevir with ritonavir.

In the second study, a total of 111 HCV genotype 1 treatment-naïve patients were randomized into 6 groups with different doses of narlaprevir, ritonavir, and PegIntron plus ribavirin.

It was found that the 200 mg/ 400 mg narlaprevir/ritonavir once-a-day groups achieved undetectable HCV-RNA levels at week 4 in 58-87% of patients and at week 12 in 84-87% of patients. Narlaprevir/ritonavir was found to be generally safe and well-tolerated. There was an increased frequency of anemia compared to the group that did not receive narlaprevir/ritonavir. A total of 20 patients discontinued treatment due to side effects—12 to 16% in the narlaprevir arms vs. 39% in the PegIntron plus ribavirin control group.

MK-3281: Twenty-two HCV genotype 1 a/b and genotype 3 male treatment-naïve patients and treatment-experienced patients were treated with MK-3281 monotherapy for 7 days. There was up to a 3.75 log10 (-1.28 to – 3.75) decrease in HCV RNA. The best antiviral response was seen in HCV genotype 1b patients (-3.75 log10). The drug was generally safe and well-tolerated. The most common side effects reported were headache, migraine, dizziness, tiredness, loss of libido, and abdominal pain.

PSI-7851: Results from a multiple dose (50mg, 100mg, 200mg or 400mg) study of 40 treatment-naive HCV genotype 1 patients who were treated with PSI-7851 mono therapy for 3 days were presented. A dose-dependent HCV RNA decline of up to -1.95 log10 IU/mL was observed. The drug was generally well-tolerated for the short period of time it was given. Additional studies of PSI-7851 in combination with pegylated interferon plus ribavirin are being planned.

ABT-333: 41.7% (10 out of 24 patients) who were treated for 28 days with ABT-333 plus pegylated interferon and ribavirin after 28 days of treatment had less than 25 IU/mL HCV RNA (viral load) compared to none out of 6 patients in the placebo, pegylated interferon/ribavirin arm (without ABT-333) for 28 days.

The side effects were reported to be mild in severity (85%) with 63% believed to be from pegylated interferon/ribavirin. There were no serious adverse events or discontinuations due to adverse events.

IDX184: A three-day, phase I proof-of-concept study evaluating the safety and antiviral activity of IDX184 (monotherapy) enrolled 41 treatment-naive HCV genotype 1-infected patients into four dosing groups (25 mg, 50 mg, 75 mg and 100 mg). Mean viral load decreases ranged from 0.47 log10 in the 25 mg group to 0.74 log10 in the 100 mg group after three days of treatment. IDX184 was well-tolerated in this study with no serious adverse events reported and no discontinuations from the study. Idenix announced that it has begun a phase II study of IDX184 in combination with pegylated interferon and ribavirin.

BI 207127: In a small trial of 60 HCV genotype 1 treatment-naïve patients, BI 207127 was found to be a potent inhibitor of viral replication in monotherapy, causing a sharp decline of viral load at 800 mg every 8 hours in the first 24 hours (5/9 patients with > 4 log10 reduction at Day 5, and no viral load breakthroughs). BI 207127 was generally safe and well-tolerated in this study; the only drug-related severe adverse event, a moderate erythema (red skin/rash), was managed effectively. Two other cases of mild transient rash occurred, but it did not require BI 207127 dose reduction or discontinuation. A 4-week combination study with doses of BI 207127 up to 800 mg thrice daily in combination with pegylated interferon and ribavirin will be completed in the 4th quarter of 2009.

THERAPEUTIC VACCINE

GI-5005: There was a report from an ongoing Phase 2b study to compare GI-5005 plus pegylated interferon and ribavirin versus pegylated interferon plus ribavirin alone (without GI-5005) in 140 HCV genotype 1 patients who were either treatment-naïve or prior non-responders produced modest results. On a modified intent-to-treat basis (patients having received at least one dose of combination therapy), treatment-naïve patients receiving GI-5005 plus Peg/ribavirin as a triple therapy had an end-of-treatment complete response rate (HCV RNA < 25 IU/mL by PCR assay at 48 weeks) of 74%, compared with an end-of-treatment response rate of 59% for treatment-naïve patients receiving pegylated interferon/ribavirin (without GI-5005).

http://www.hcvadvocate.org/news/newsLetter/2010/advocate0110.html#1

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