Drug Rash with Eosinophilia and Systemic Symptoms due to Telaprevir.

Interesting case study on Telaprevir rash on BioPortfolio.com, originally published in the journal 'Dermatology' last year.


Summary

We report a case of drug rash with eosinophilia and systemic symptoms (DRESS) due to telaprevir (VX-950), a specific inhibitor of the hepatitis C virus (HCV) serine protease. A 57-year-old woman with chronic hepatitis C was included in a phase 2 rollover study of VX-950. She received VX-950 in combination with pegylated interferon alfa-2a and ribavirin. Six weeks later, she developed a generalized pruritic maculopapular exanthema with malaise, fever, dyspnoea and lymph node swelling. She had an eosinophilia (up to 2.7 x 109 cells/l), large activated lymphocytes and increased concentrations of aminotransferases. Histological examination of a cutaneous biopsy was consistent with a drug rash reaction. The HCV treatment was stopped, and she was treated with topical and oral steroids. Cutaneous and systemic symptoms disappeared within 1 month. Telaprevir was considered the culprit drug. We report to our knowledge the first case of DRESS syndrome due to telaprevir. The safety data of telaprevir is derived mainly from the PROVE1, PROVE2 and PROVE3 studies. They showed a high frequency of cutaneous side effects reported under the imprecise terms of pruritus and rash, leading to an increased rate of treatment discontinuation. Telaprevir, due to its efficacy, is probably on the way to obtaining regulatory approval in the near future. It is therefore important to be aware of the high incidence of cutaneous side effects and better describe them. Our observation suggests that potentially severe hypersensitivity reactions may belong to the spectrum of rashes induced by this drug.
Affiliation

Department of Dermatology, University Hospital of Nice, Nice, France.
Journal Details

Name: Dermatology (Basel, Switzerland)
ISSN: 1421-9832
Pages:
Original article here: http://www.bioportfolio.com/resources/pmarticle/63601/Drug-Rash-With-Eosinophilia-And-Systemic-Symptoms-Due-To-Telaprevir.html

Merck gets FDA and EMEA expedited reviews for Boceprevir....

Merck works it's magic once again, potentially securing first mover advantage for Boceprevir. Probably not what Vertex wanted to hear this morning. - Chris


January 06, 2011 08:00 AM Eastern Time
Boceprevir, Merck’s Investigational Oral Hepatitis C Protease Inhibitor, Receives FDA Priority Review and EMA Accelerated Assessment

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck, known as MSD outside the United States and Canada, announced today that regulatory applications for boceprevir, Merck's investigational oral hepatitis C virus (HCV) protease inhibitor, were submitted in 2010 and have been accepted for expedited review in both the U.S. and the European Union.

“We are pleased that the FDA and EMA have accepted boceprevir for expedited review. Our goal is to be able to bring forward a new treatment option for patients living with chronic hepatitis C, and we are now closer to that goal”

The U.S. Food and Drug Administration (FDA) granted the New Drug Application (NDA) for boceprevir Priority Review status, a designation given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists. FDA's goal for completing a Priority Review is six months.

Additionally, the European Medicines Agency (EMA) accepted the Marketing Authorization Application (MAA) for boceprevir for accelerated assessment. Accelerated assessment is available for products that respond to unmet medical needs or represent a significant improvement over current treatment options within a major public health interest such as treatment of hepatitis C virus infection.

Data in the NDA and MAA have been provided in support of the proposed use of boceprevir for the treatment of chronic HCV genotype 1 infection, in combination with standard therapy, in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy.

"We are pleased that the FDA and EMA have accepted boceprevir for expedited review. Our goal is to be able to bring forward a new treatment option for patients living with chronic hepatitis C, and we are now closer to that goal,” said Dr. Peter S. Kim, Ph.D., president, Merck Research Laboratories.

Merck's global commitment to advancing hepatitis therapy

Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. Extensive research efforts are underway to develop differentiated oral therapies that bring innovation to viral hepatitis care.

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com.

Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2009 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).
Contacts

Merck
Media:
Ian McConnell, 908-423-3046
Robert Consalvo, 908-295-0928
or
Investors:
Joe Romanelli, 908-423-5088

Can elevated IP-10 become a reliable predictive biomarker for response to Pegylated Interferon & Ribavirin?

Move over LabCorp!! Press release regarding a potential diagnostic test to predict response to pegylated interferon/ribavirin from Inserm and Institut Pasteur in collaboration with the Rules Based Medicine, Inc from the US.

Scientists at Inserm and Institut Pasteur have performed biomarker discovery on patients being treated for chronic hepatitis C infection. Their work, published in The Journal of Clinical Investigation, demonstrates that the plasma levels of the protein IP-10 predict, prior to treatment initiation, the efficacy of treatment with pegylated-interferon and ribavirin. Based on these results, the scientists have developed a prognostic test. Commercialization is anticipated in 2011, and will help inform physicians of the chances that patients will respond to standard treatment or if instead they will require new therapeutic cocktails (e.g., inclusion of protease inhibitors).

Importantly, hepatitis C is the leading cause of primary liver cancer (hepatocellular carcinoma) and it remains an important cause of liver failure due to fibrosis and cirrhosis. This infectious disease represents a major public health problem, with greater than 170 million cases worldwide. The World Health Organization estimates 3 to 4 million new cases per year and considers the virus a " viral time bomb" due to the long term sequella of infection.

Currently, there is no approved vaccine available and approximately 80% of individuals infected by the virus develop chronic disease, a risk factor for cirrhosis, liver failure, liver cancer as well as other medical complications (e.g., diabetes).

For the past ten years, treatment has been based on the use of type I interferon given in combination with the anti-viral ribavirin. While effective, it results in a cure for only 50% of patients. Moreover, treatment is long (24 – 48 weeks), and it results in severe side effects (e.g., depression, anemia).

It is in this context that the Inserm and Institut Pasteur sponsored research lab of Dr. Matthew Albert, in close collaboration with the Liver Disease Unit headed by Prof. Stanislas Pol, evaluated plasma biomarkers to define predictors for patients' response to treatment.

With the help of the Centre for Human Immunology at Institut Pasteur, the investigators involved have performed a prospective study. They identified the protein IP-10 as a prognostic biomarker – elevated in those patients for whom treatment was ineffective. This observation was paradoxical as IP-10 is considered a pro-inflammatory molecule, which should have facilitated migration of activated T cells to the liver, the exact cell types responsible for viral immunity. In fact, what was discovered is that the IP-10 had been catabolized and it was a truncated form present in the HCV patients. Strikingly, the short form of IP-10 is an antagonist and inhibits T cell recruitment. Thus, it is suggested that the antagonist form of IP-10 is responsible for the failure to respond to treatment in the 50% of patients who do not benefit from pegylated-interferon / ribavirin treatment.

The investigators worked in close collaboration with an American company, Rules Based Medicine, Inc., who will develop a diagnostic test to distinguish the different forms of IP-10 as a simple blood test. This test will be a significant step towards the improved management of patients with HCV as well as other chronic inflammatory diseases.

###

This scientific work was conducted under the direction of Matthew L. Albert, MD PhD, Mixed Institut Pasteur / Inserm Research Unit; and Stanislas Pol, MD PhD, Univerisity of Paris, Descartes and Institut Cochin. Financial support was provided by the ANRS and promotion of the study was taken by Inserm Medical.

To know more:

Source

Evidence for chemokine antagonisms in human infected chronically with Hepatitis C Virus.
Armanda Casrouge, Jérémie Decalf, Mina Ahloulay, Cyril Lababidi, Hala Mansour, Anaïs Vallet-Pichard, Vincent Mallet, Estelle Mottez, James Mapes, Arnaud Fontanet, Stanislas Pol and Matthew L. Albert.

Journal of Clinical Investigation.

and the related news article

Chemokine antagonism in chronic hepatitis C virus infection.
Edgar D. Charles and Lynn B. Dustin

Journal of Clinical Investigation.

Contact information

Matthew Albert
Unité mixte Institut Pasteur / Inserm
Email : albertm@pasteur.fr
Tel : +33 6 7001 0396

Stanislas Pol
Unité 1016 « Institut Cochin »
Service Hépatologie, Hôpital Cochin
Email : stanislas.pol@cch.aphp.fr

What's Next for Achillion Pharma? Tchoughts from currinBioteh.com contributor Jason Chew...

Interesting article on Achillion HCV pipeline from currinBioteh.com contributor Jason Chew. Read the original article here: http://seekingalpha.com/article/244145-what-s-next-for-achillion-pharma

Achillion stock (ACHN) has been flat all year, underperforming the biotech indices as well as its peers in the Hepatitis C drug development community. The stock began to leap a couple days after the company announced that data from ongoing clinical studies of ACH-1625 has been accepted for presentation at the 21st Annual Conference of the Asian Pacific Association for the Study of the Liver (APASL 2011) to be held February 17-21, 2011. It has since climbed from $2.73 to close at $4.00 Wednesday, a 47% increase since the December 6th announcement.

So why all the excitement? Achillion had been making headlines all year; it promoted two new drugs into the clinic, began Phase II trials for lead candidate ACH-1625, presented at multiple industry conferences, and raised a total of $71.4 million in stock offerings.

The reason, I believe, is a key phrasing in the press release, “data from ongoing clinical studies of ACH-1625” was to be presented at the conference. There is only one ongoing study: A 144 patient Phase IIa randomized, double blinded trial of ACH-1625 in combination with ribavirin and peg-interferon alpha. The trial begins with a dose-ranging 28 day phase that will be evaluated to determine the optimal dose for the final 12 week treatment phase.

The company had initially targeted March 2011 for release of the first set of results. Having the ability to move the release date up to February speaks well for trial enrollment. This data will provide the first look at how Achillion’s lead candidate performs in a larger setting and importantly, in combination with current standard of care. ACH-1625 has already been shown to significantly reduce viral loads in patients by 3 to 4.25 log10 and maintain a sustained viral response even after therapy has stopped. It has also been shown to be safe up to 2000mg/day, a level far above the highest dose tested in this Phase IIa.

Pre-clinical studies show ACH-1625 to be additive-synergistic to ribavirin and peg-interferon alpha; this study will be a first look at how well those studies translate in the clinic. Although 28 days is still short, the multiple active drug doses as well as a placebo control will allow investigators to gauge in detail the effectiveness of ACH-1625 in this combination. In any case, a full profile of the compound and its potential as part of this three-drug regimen will be in known by the end of 2011. There’s a lot riding on this study.

Aside from its lead compound, Achillion also has a lineup of several other HCV antivirals in development. The once promising ACH-1095, an inhibitor of the NS4A protease is in Phase I. It was originally developed in collaboration with Gilead (GILD), but its rights have since been handed back to the company- though Gilead still retains the ability to opt in at a later stage in the compound’s development.

Early this year in January, a second NS3 protease inhibitor, ACH-2684, was nominated to enter clinical development. It's interesting that Achillion is developing additional NS3 inhibitors considering there are so many out there. This one is being positioned as more potent and effective against commonly seen viral mutants. It will enter Phase I trials in 2011.

The NS5A inhibitor, ACH-2928, was nominated in mid-year. It is also set to initiate Phase I testing in 2011. ACH-2928 is one of the few NS5A inhibitors currently in development. The most prominent competitor compound is BMS-790052 from Bristol Myers Squibb (BMY), currently in Phase II and looking pretty good. Both of these compounds have similarly high potencies in vitro.

Achillion also has some work in antibiotics and HBV, but they are not a major focus. The goal now is to push forward with its HCV pipeline. 2011 will be pivotal for the company as data comes in from its lead project. Funds raised during the year will allow it to complete both portions of the Phase II trial and at the same time initiate two separate Phase I studies. It will be interesting to see how the company chooses to proceed from there.

Scripps scientists identify new target to inhibit replication of Hepatitis C virus....

Scientists have discovered a molecular interaction between a structural hepatitis C virus protein (HCV) and a protein critical to viral replication.

This new finding by researchers from the Florida campus of The Scripps Research Institute strongly suggests a novel method of inhibiting the production of the virus and a potential new therapeutic target for hepatitis C drug development.

These new data underline the essential role of the viral protein known as 'core' as a primary organizer of the infectious HCV particle assembly and support a new molecular understanding of the formation of the viral particle itself.

"While our finding that the HCV core interacts with the non-structural helicase protein was not totally unexpected, this had not really been confirmed until this study," said Donny Strosberg, who led the study.

"But the most exciting part is that small molecule inhibitors of dimerization [the joining of two identical subunits] of core actually inhibit interaction between core and helicase, thus possibly preventing production of an infectious viral particle," said Strosberg.

Previously, Strosberg developed a novel quantitative test for monitoring these protein-protein interactions with the specific goal of identifying inhibitors of the core dimerization, which would block virus production.

However, in the new study, Strosberg and colleagues focused on non-structural proteins that provide functions relating to HCV production, in particular NS3 helicase.

The scientists' findings have supported a growing body of evidence that this protein participates in the assembly and production of infectious viral particles.

The interaction of the core protein with this non-structural protein also confirms core as a key organizer of virus assembly and suggests it acts to facilitate the packaging and integration of the newly synthesized viral RNA.

The findings were published in the Journal of General Virology. (ANI)

Janssen Seeks European Marketing Authorization For Investigational Hepatitis C Treatment Telaprevir

It will be interesting to see how Tibotec supports Telaprevir in Europe, with a possible competitor, TMC435 waiting in the wings. Vertex, with it's relatively rich, advanced pipeline in HCV, esp with the relatively drug-interaction free HCV non-nuc VX-222 that would be a nice complementary acquisition for the J&J family. According to outside sources, Merck only expects a 35% marketshare for Boceprevir vs Telaprevir. Given the potential baggage that comes along with Telaprevir with Q8h dosing, highly variable PK at q12h and the potential severity of the rash, esp in people of color, Merck (for once) may be underestimating the market potential of Boceprevir - Chris

Janssen-Cilag International NV announced the submission of a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for telaprevir, an investigational, oral, direct-acting antiviral for the treatment of chronic genotype 1 hepatitis C virus (HCV), the most common form of the virus. Telaprevir is a potent and selective protease inhibitor (PI), which when combined with pegylated-interferon and ribavirin (the current treatment standard), shows activity in patients that are new to treatment and who have been previously treated but were not cured, including partial responders, relapsers and those who have had little or no response (null responders) to the current standard of treatment.

The EMA has accepted telaprevir for accelerated assessment, which is granted to quicken access to innovative, new medicines of major public-health interest. Tibotec BVBA, a global research and development company with specific experience in virology, is developing telaprevir in collaboration with Vertex Pharmaceuticals. Tibotec BVBA is an affiliate company of Janssen.

"The EMA submission for telaprevir is a landmark in the treatment of HCV and demonstrates our dedication to addressing unmet medical needs by developing innovative treatments for infectious diseases," said Johan Van Hoof, Global Therapeutic Area Head Infectious Diseases and Vaccines at Janssen. "Above all, it is an important step towards making telaprevir available to people living with HCV."

It is estimated that 170 million people are living with HCV around the world, including more than five million in Europe. Chronic HCV can result in serious long-term health problems, and an estimated 30 percent of patients will develop progressive liver disease, including cirrhosis (damage and scarring of the liver), which places them at risk for liver insufficiency and liver cancer. HCV is the most common cause of liver transplant in Europe.

The current standard of care for HCV genotype 1 patients, pegylated-interferon and ribavirin, is administered for 48 weeks and only 40 to 50 percent of genotype 1 patients achieve a sustained virologic response (SVR), defined as achieving undetectable levels of the virus in the blood for six months after completion of treatment, and considered an indicator of cure. Re-treatment with pegylated-interferon and ribavirin in patients who have previously failed this treatment shows only limited success. ,

The EMA submission is supported by results from three phase 3 studies, which compared telaprevir in combination with the current standard of treatment to the current standard of treatment alone in HCV genotype 1 patients. Results were very positive:

- Significantly higher SVR rates were observed in treatment-naïve patients treated with telaprevir compared to the current standard treatment of pegylated-interferon and ribavirin (75 percent vs. 44 percent)

- The majority of patients were cured by week 24, which is half the duration of therapy with the current standard of treatment8,

- There was a three-fold increase in cure rates (65 percent vs. 17 percent) across all types of previously treated patients who were given telaprevir compared to the current treatment standard, including prior null responders (31 percent vs. 5 percent) 10

- The most common adverse events in the telaprevir-based treatment groups were fatigue, pruritus, nausea, headache, anemia, rash, influenza-like illness, insomnia, fever and diarrhea. The majority of these adverse events were mild to moderate.8,9,10

"Current treatment for hepatitis is lengthy and only effective for approximately half of treatment-naïve patients, and even fewer patients who failed previous treatment," commented Stefan Zeuzem, Professor of Medicine and Chief, department of medicine, J W Goethe University Hospital, Frankfurt. "If approved, telaprevir would help to significantly improve cure rates and shorten treatment duration for many people living with HCV, compared to current standard treatment."

About the Telaprevir Development Program

To date, more than 2,500 people with HCV genotype 1 have received telaprevir-based therapy (telaprevir combined with the current standard of treatment) as part of Phase 2 studies and the Phase 3 ADVANCE, ILLUMINATE and REALIZE trials.8,9,10 The telaprevir clinical development program is the largest conducted to date for any investigational direct-acting antiviral hepatitis C therapy.

- ADVANCE evaluated telaprevir-based regimens in approximately 1,088 treatment-naïve patients with chronic HCV infection. Data from the ADVANCE trial were presented at the 2010 American Association for the Study of Liver Diseases (AASLD) annual meeting in November 2010.8

- ILLUMINATE evaluated the benefits of extending telaprevir-based therapy in 540 treatment-naïve patients whose HCV was undetectable at weeks 4 and 12 of treatment. 322 of these patients were randomized to receive 24 or 48 weeks of treatment, and it was found that there was no benefit to extending treatment to 48 weeks. Data from the ILLUMINATE meeting were presented at AASLD in November 2010.9

- REALIZE evaluated telaprevir-based regimens in approximately 650 treatment-failure HCV patients. Data from the REALIZE trial will likely be published in 2011.

Telaprevir is being developed by Tibotec BVBA, an affiliate company of Janssen, in collaboration with Vertex Pharmaceuticals and Mitsubishi Tanabe Pharma for the treatment of genotype 1 HCV in combination with pegylated-interferon and ribavirin in both patients who have failed prior treatment and those who have never been treated. Tibotec BVBA has the commercialisation rights for telaprevir in Europe, Latin America, the Middle East, Africa, India, Australia and New Zealand, pending approval by the respective regulatory authorities. Vertex will commercialise telaprevir in the U.S., Canada and Mexico and Mitsubishi Tanabe Pharma has rights to commercialise telaprevir in Japan and certain Far East countries.

About Tibotec BVBA

Tibotec BVBA is a global pharmaceutical and research development company. The Company's main research and development facilities are in Beerse, Belgium with offices in Titusville, NJ and Cork, Ireland. Tibotec is dedicated to the discovery and development of innovative HIV/AIDS and HCV drugs, and anti-infectives for diseases of high unmet medical need.

SciClone drops development of SCV-07 for previous HCV therapy relapsers....

"We are probably going to see more companies drop development programs for HCV therapies as the treatment landscape and probabilities of advancement for competitive compounds continues to increase. At some point, the sponsoring company has to make a decision based on simple cost/benefit ratios and potential for a compound to sustain itself in what will become a crowded market. SciClone will continue its development program for SCV-07 for oral mucositis in patients with head and neck cancer - Chris"


FOSTER CITY, CA -- (MARKET WIRE) -- 12/15/10 -- SciClone Pharmaceuticals, Inc. (NASDAQ: SCLN) today announced topline results from the Company's phase 2b clinical trial of SCV-07 for the treatment of hepatitis C (HCV). The study evaluated the safety and immunomodulatory effects of SCV-07 as a monotherapy and in combination with ribavirin in relapsed HCV patients. Study data demonstrated SCV-07 to be safe and well-tolerated at both administered doses. Topline results showed a clear biological signal from SCV-07 but did not meet the study's primary efficacy endpoint of a 2 log reduction in viral load from baseline level. A secondary measure of efficacy, defined as a reduction in viral load of greater than 0.5 log from baseline level, was seen in 38.5% of the low-dose patients (5/13) and in 44.4% of the high-dose patients (8/18). Additionally, while no patients in the low-dose group achieved greater than a 1 log reduction, 3 of the high-dose patients achieved greater than a 1 log reduction in viral load. This proof of concept study was designed to provide an estimate of SCV-07's treatment effect in relapsed HCV patients and guide further studies of SCV-07 in addressing this chronic infection.

"Although the data showed an interesting biological signal, due to the rapidly changing landscape of effective treatments which increase the complexity and risks of developing drugs in chronic HCV, we have decided not to continue development in this indication. On another front, we continue to be excited about the potential for SCV-07 in the prevention of oral mucositis in patients with head and neck cancer and the initiation of our phase 2b study, which should begin by early 2011," stated Friedhelm Blobel, Ph.D., President and Chief Executive Officer of SciClone. "Our primary focus remains on rapidly growing our commercially successful specialty pharmaceutical business in China and other key emerging markets to increase profitability and generate cash for our shareholders."

Study Design
The phase 2b multicenter, multi-dose, open-label study was designed to evaluate the safety and immunomodulatory effects of SCV-07 as a monotherapy or in combination with ribavirin in non-cirrhotic patients with genotype 1 chronic HCV who have relapsed after at least 44 weeks of treatment with pegylated interferon and ribavirin. The study, which also monitored biomarkers of immune activation and HCV viral load dynamics, included two treatment cohorts of 20 patients each who received SCV-07 at a dose of either 0.1 mg/kg or 1.0 mg/kg. The eight week treatment period included four weeks of SCV-07 monotherapy followed by four weeks of SCV-07 in combination with ribavirin. The trial also included three follow-up visits within seven weeks after the completion of treatment.

About SCV-07
SCV-07 (gamma-D-glutamyl-L-tryptophan) is a small molecule which appears to stimulate the immune system through inhibition of STAT3 signaling and the resulting effects on T-helper 1 cells. SCV-07 has been shown to be efficacious in animal models of immune-sensitive diseases, including prevention of oral mucositis, treatment of cancer, viral infections, and enhancement of response to vaccines.

Additionally, SciClone is currently planning to initiate a phase 2b study of SCV-07 for the prevention of oral mucositis by early 2011. As compared to the company's recently completed phase 2a trial, the phase 2b study design is expected to include higher doses of SCV-07 and be adequately powered to demonstrate statistical significance. Additionally, researchers expect to continue to investigate the role of specific genetic profiles on patient response to SCV-07, as well as the potential link between cytokine activity and SCV-07's sub-cellular mechanism of action.

SCV-07 is protected by composition of matter patents as well as multiple method of treatment patents. SciClone has exclusive worldwide rights to SCV-07 outside of Russia, where the molecule has recently been approved for stimulation of depressed immune systems.

About SciClone
SciClone Pharmaceuticals (NASDAQ: SCLN) is a revenue-generating, China-centric, specialty pharmaceutical company with a substantial international business and a product portfolio of novel therapies for cancer and infectious diseases. The Company is focused on continuing sales growth and executing a clinical development strategy with prudently managed costs. ZADAXIN® (thymalfasin) is approved in over 30 countries for the treatment of hepatitis B (HBV) and hepatitis C (HCV), certain cancers, and as a vaccine adjuvant. In addition to further studying thymalfasin's use as a vaccine enhancer, SciClone is planning to evaluate SCV-07 in a phase 2b trial to modify the course of oral mucositis in patients with head and neck cancer; and recently completed a phase 2b trial of SCV-07 for the treatment of HCV. The Company also has exclusive commercialization and distribution rights in China to a novel treatment for advanced liver cancer, DC Bead®, currently under review by regulatory agencies in that country. Additionally, SciClone owns exclusive commercialization and distribution rights to the anti-nausea drug ondansetron RapidFilm® in China, including Hong Kong and Macau, and Vietnam. The Company intends to seek regulatory approval for the product, commonly used to treat and prevent nausea and vomiting caused by chemotherapy, radiotherapy, and surgery, in these markets. For additional information, please visit www.sciclone.com.

Forward-looking statements
The information in this press release contains forward-looking statements, including our expectations and beliefs regarding the timing and results of our clinical trials. You are urged to consider statements that include the words "may," "will," "would," "could," "should," "might," "believes," "estimates," "projects," "potential," "expects," "plans," "anticipates," "intends," "continues," "forecast," "designed," "goal," or the negative of those words or other comparable words to be uncertain and forward-looking. These statements are subject to risks and uncertainties that are difficult to predict and actual outcomes may differ materially. These risks and uncertainties include our forward-looking statements regarding our commercial and development objectives because of uncertainties, including future sales, product pricing, the timing of clinical trial events such as patient enrollment, requirements of, and future actions of, the U.S. Food and Drug Administration, the fact that experimental data, and clinical results derived from studies with animals or a limited group of patients, as well as comparisons with other clinical trials, may not be predictive of the results of larger studies and, therefore, such experimental or clinical data are not necessarily predictive indicative of the efficacy or safety or the results of larger studies and clinical trials. Please also refer to the other risks and uncertainties described in SciClone's filings with the Securities and Exchange Commission. All forward-looking statements are based on information currently available to SciClone, and SciClone assumes no obligation to update any such forward-looking statements.

DC Bead is a registered trademark of Biocompatibles UK Limited.

RapidFilm is a registered trademark of Labtec Gesellschaft für technologische Forschung und Entwicklung mbH.

Source: SciClone Pharmaceuticals, Inc.

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Pharmasset exploring interferon-sparing Phase II trial for it's nucelotide analog PSI-7977 for Genotype 2/3 HCV...

Possible great niche for PSI-7977 in Genotype 2/3 subjects, possibly cutting the duration of therapy in half for these patients and possibly taking the interferon component out of the equation. -Chris

Pharmasset Initiates Exploratory Interferon Sparing Clinical Trial of PSI-7977 for Chronic Hepatitis C


Exploratory phase 2 trial in patients with HCV genotype 2 or 3 to receive PSI-7977 400mg QD and ribavirin, with 0-12 weeks of pegylated interferon

Interim data expected in first half of 2011

PRINCETON, N.J., Dec. 14, 2010 /PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today that dosing has begun in an exploratory study of PSI-7977, a nucleotide analog polymerase inhibitor, for the treatment of chronic hepatitis C (HCV). The trial will evaluate PSI-7977 400mg QD in combination with ribavirin (RBV), with 0, 4, 8, or 12 weeks of pegylated interferon alfa 2a (Peg-IFN) in treatment-naive patients infected with HCV genotype 2 or 3.
"Based on the encouraging efficacy, safety and resistance data from the Phase 2a trial with PSI-7977 in combination with pegylated interferon and ribavirin, we initiated a study to explore shorter durations of interferon, including an interferon-free regimen in treatment naïve patients with HCV genotype 2 or 3," stated Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "An important limitation to the current treatment of HCV patients is the use of interferon with its associated side effect profile. We believe that PSI-7977's high barrier to resistance and the lack of a significant effect of IL28B genotype in the Phase 2a trial provide us an opportunity with PSI-7977 to explore shorter durations of interferon, and potentially even removing it from the treatment regimen altogether."

About the Trial
The trial is anticipated to enroll approximately 40 patients infected with HCV genotype 2 or 3 who have not previously been treated. The primary endpoint of the trial will be the assessment of safety and tolerability of PSI-7977 400mg QD and RBV for 12 weeks, administered with or without pegylated interferon (Peg-IFN) in treatment naïve patients with HCV genotypes 2 or 3. The trial will be conducted in New Zealand. Patients will be randomized into one of 4 arms:

-- PSI-7977 400mg QD in combination with RBV for 12 weeks (no interferon);
-- PSI-7977 400mg QD in combination with RBV for 12 weeks, with only 4 weeks of Peg-IFN;
-- PSI-7977 400mg QD in combination with RBV for 12 weeks, with only 8 weeks of Peg-IFN;
-- PSI-7977 400mg QD in combination with Peg-IFN and RBV for 12 weeks.

Patients will be stratified by HCV genotype and IL28B status to ensure balance across cohorts.
Pharmasset anticipates reporting interim data from this trial in the first half of 2011.

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). 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 four clinical-stage product candidates. RG7128, a cytosine nucleoside analog for chronic HCV infection, is in two Phase 2b clinical studies in combination with Pegasys(R) plus Copegus(R) and is also in the 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 HCV candidates include PSI-7977, an unpartnered uracil nucleotide analog that has recently initiated dosing in a Phase 2b study in patients with HCV genotypes 1, 2, or 3, and PSI-938, an unpartnered guanosine nucleotide analog which recently completed a 7-day monotherapy study. We also have in our pipeline an additional purine nucleotide analog, PSI-661, in advanced preclinical development.

Bruce Bacon, MD on Boceprevir RESPOND-2 study....

Research Fuels Hope for Hard-To-Treat Hepatitis C Patients
Released: 12/6/2010 12:00 PM EST
Source: Saint Louis University Medical Center

Newswise — The outlook for patients with hepatitis C continues to improve as results from a clinical trial led by a Saint Louis University researcher found that the drug boceprevir helped cure hard-to-treat patients. The findings were reported at the 61st annual meeting of the American Association for the Study of Liver Disease’s earlier in November.

Bruce R. Bacon, M.D., professor of internal medicine at Saint Louis University School of Medicine and co-principal investigator of the HCV RESPOND-2 study, studied the protease inhibitor, boceprevir, and found that it significantly increased the number of patients whose blood had undetectable levels of the virus.

“These findings are especially significant for patients who don’t respond to initial treatment,” said Bacon. “When the hepatitis C virus is not eliminated, debilitating fatigue and more serious problems can follow.”

Hepatitis C is caused by a virus that is transmitted by contact with blood. The infection may initially be asymptomatic, but for patients who develop chronic hepatitis C infection, inflammation of the liver may develop, leading to fibrosis and cirrhosis (scarring of the liver), as well as other complications including liver cancer and death.

The prognosis varies for patients with chronic hepatitis C. With the current standard therapy, about half fully recover after an initial course of peginterferon and ribavirin anti-viral therapy that may last from six months to a year.

The remaining patients, known as non-responders, may improve with initial treatment but the virus is not eliminated, or may not respond to treatment at all.

For this group, the only current option is to retreat patients with the same or similar drugs, which increases the likelihood of severe treatment side-effects. In addition, researchers have found that the success of treatment depends on the major strain, or genotype, of hepatitis C that a patient has.

The HCV RESPOND-2 study looked at 403 patients with chronic hepatitis C infections with genotype one, the most difficult strain of the virus to treat, who still had significant levels of the virus after being treated with peginterferon and ribavirin, the standard hepatitis C treatment.

"These results are very exciting," Bacon said. “In this study, boceprevir helped cure significantly more patients in 24 weeks of therapy than did treatment with peginterferon and ribavirin alone."

A second study, HCV SPRINT-2, examined patients with hepatitis C with genotype one who had not yet been treated with the standard treatment. They, too, responded well to the drug.

Bacon calls the progress made in treating hepatitis C remarkable.

“We’ve gone from the discovery of the virus in 1989 to where we are now, 22 years later, when we have the ability to cure a large majority of those with hepatitis C,” Bacon said. “It’s a true success story.”

“Drugs like boceprevir are going to revolutionize care of those with hepatitis C.”

The clinical trial was funded by Merck, which expects to begin seeking FDA approval this year.

Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.

Achillion To Present Data From Studies Of ACH-1625 In Hepatitis C At Asian Pacific Liver Conference

Achillion To Present Data From Studies Of ACH-1625 In Hepatitis C At Asian Pacific Liver Conference
GlobeNewswire
12/06/10 - 07:00 AM EST

NEW HAVEN, Conn., Dec. 6, 2010 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced that data from the Company's ongoing clinical studies of ACH-1625 has been accepted for presentation at the 21st Annual Conference of the Asian Pacific Association for the Study of the Liver (APASL 2011) to be held February 17-21, 2011 in Bangkok, Thailand.

ACH-1625 is an inhibitor of HCV NS3 protease that was discovered and is being developed by Achillion.

The presentation, entitled "Viral Kinetics Modeling of Short-term Monotherapy Data of ACH-1625, an HCV Protease Inhibitor," will be presented by Dr. Atul Agarwal, Senior Director of Computational Chemistry of Achillion. (Abstract A-315-0024-00792.) The presentation describes a mathematical analysis of HCV RNA data collected after oral administration of ACH-1625 in HCV genotype 1 infected subjects. This analysis shows rapid and near complete hepatitis C virus clearance following ACH-1625 administration at all dose levels tested. In addition, mathematical modeling of HCV viral kinetics provided information that allowed for subsequent dose selection for Phase II clinical development of ACH-1625.

"These data support and further demonstrate ACH-1625's robust antiviral activity," said Dr. Agarwal. "With clinical data that demonstrated reductions in viral RNA between 3-4.25 log10, these mathematical data quantitatively show the percentage of total virus cleared after five days of ACH-1625 monotherapy. This data also identifies specific patient population characteristics."

"We are pleased to continue to put forward a large body of scientific and clinical data on ACH-1625," commented Michael D. Kishbauch, Chief Executive Officer of Achillion. "We look forward to completing the current Phase II clinical trial of ACH-1625 to further support its profile as a potential best-in-class protease inhibitor for the treatment of HCV."

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 clinical studies, HCV-infected patients receiving doses ranging from 200 to 600 mg twice daily, and 400 to 600 mg once daily, showed mean maximal reductions in viral load ranging from of 3.07 log10 to 4.25 log10. 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 1log10 from baseline through day 12, the last day of viral load measurement in the study.

Pharmasset Initiates Dosing in a Combination Study of PSI-7977 and PSI-938 for Chronic Hepatitis C...

First study to look at a combination of of a purine and a pyrimidine nucleotide analog (PSI-938 and PSI-7977 respectively). Pharmasset believes the combination of two 'nucs' has a potential higher barrier to resistance, making it attractive to use in combo with other STAT-C/DAA drugs. The company plans a Phase II trail looking at the combination without interferon mid-2011 - Chris

- Phase 1 combination study of a pyrimidine (PSI-7977) and purine (PSI-938) nucleotide analog in patients with chronic hepatitis C

- Interim data expected in first quarter of 2011

PRINCETON, N.J., Nov. 30, 2010 /PRNewswire-FirstCall/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today that dosing has begun in Part 2 of a Phase 1 study. This is the first clinical study combining a purine (PSI-938) and a pyrimidine (PSI-7977) nucleotide analog for HCV, and is designed to evaluate once daily doses of PSI-7977 and PSI-938 in patients with HCV who have not been treated previously.

"We are excited to be initiating this combination study with two proprietary nucleotide analogs for HCV," stated Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "Based on our in vitro data, we believe the combination of two nucleotide analogs could provide potent antiviral activity across multiple HCV genotypes and could also have a higher barrier to resistance compared to other DAA combinations. We believe nucleotide analogs have a number of key attributes that may make them ideal partners for other DAA combinations, in addition to a 'nuc-nuc' combination."

About the Phase 1 Trial

In Part 1 of the Phase 1 multiple ascending dose study of PSI-938, suppression of HCV RNA below the limit of detection (LOD, <15 IU/mL) was observed in over half of the patients who received PSI-938 at daily doses of 200 mg or 300 mg for seven days. Part 2 of the study is designed to evaluate the combination of PSI-938 and PSI-7977. The primary objective is to assess the safety, tolerability and pharmacokinetics of PSI-938 administered alone for 14 days, and in combination with PSI-7977 for 7 to 14 days. The secondary objective is to evaluate viral kinetics of HCV RNA during monotherapy and combination nucleotide dosing. Approximately forty patients are expected to be enrolled into four cohorts as follows:

* PSI-938 QD administered as monotherapy for 14 days, followed by;
* PSI-938 QD for 7 days followed by PSI-938 plus PSI-7977 QD for 7 days and
* PSI-7977 QD for 7 days followed by PSI-938 plus PSI-7977 QD for 7 days, followed by;
* PSI-938 plus PSI-7977 QD for 14 days


We expect to report preliminary results from Part 2 of this Phase 1 study during the first quarter of calendar year 2011. We also expect to initiate a Phase 2 study of PSI-938 in combination with PSI-7977 during mid-2011. This Phase 2 study proposes to explore durations of PSI-938 and PSI-7977 in interferon-free combinations with an SVR endpoint.

Avilla Therapeutics publishes paper on a new class of highly selective, irreversible HCV protease inhibitors

Publication in Nature Chemical Biology demonstrates that irreversible covalent inhibition can increase selectivity, potency and duration of action, broadens applications for targeted covalent drugs to the protease gene family

WALTHAM, MA – November 28, 2010 – Avila Therapeutics™, Inc., a biotechnology company developing novel targeted covalent drugs, has published research in Nature Chemical Biology demonstrating the first-ever selective irreversible inhibition of a viral protease using a targeted covalent drug. In the paper titled "Selective Irreversible Inhibition of a Protease by Targeting a Non-Catalytic Cysteine", Avila used its proprietary Avilomics™ platform to design covalent irreversible protease inhibitors that are highly selective, potent and with superior duration of action as compared to conventional protease inhibitors.

Importantly, the published research demonstrates that covalent drugs can be designed and targeted to irreversibly and covalently bond to molecular domains specific to proteases. This is the first report of the irreversible covalent approach being successfully extended to proteases, a very broad class of proteins that includes many important potential drug targets.

"This research elevates covalent drug design to a fundamentally new level," said Simon Campbell, PhD, CBE, FMedSci, FRS, a renowned scientist and former Senior Vice President for Worldwide Drug Discovery and Medicinal R&D Europe of Pfizer. "By creating extremely selective protease inhibitors with their platform, Avila is showing the remarkable therapeutic potential of irreversible covalent drugs to address a broad spectrum of drug targets."

"This publication showcases the creation of a whole new class of small molecule drugs," said Juswinder Singh, PhD, Chief Scientific Officer of Avila and a co-author of the paper. "This approach can make a difference to patients living with HCV infection, and we expect to make an impact in other important areas such as cancer and inflammatory disease."

In order to maximize selectivity and minimize off-target effects, the irreversible covalent inhibitors of HCV protease were designed to covalently target a unique structure in the HCV protease not found in human proteases. Key findings include:

* A representative irreversible covalent inhibitor designed, by Avila, was shown to inhibit the HCV protease (also known as "NS3") in cells at a concentration of 6 nM .
* Specific covalent bond formation between the drug and target protease was demonstrated through use of mass spectrometry and also x-ray crystallography.
* Very high selectivity of the Avila compounds was demonstrated by showing no notable inhibition of a panel of human proteases in biochemical assays with additional specificity demonstrated in cellular assays; this was contrasted experimentally with Telaprevir, an HCV protease inhibitor in late-stage clinical testing which demonstrated off-target biochemical activity against several human targets.

Avila has subsequently optimized additional drug candidates, yielding current development candidates, AVL-181 and AVL-192, which have excellent pharmacokinetics and bind potently to wild- type HCV protease as well as multiple genotypes and mutant forms of HCV protease.

###

About Avila Therapeutics™, Inc.

Avila focuses on design and development of targeted covalent drugs to achieve best-in class outcomes that cannot be achieved through traditional chemistries. This approach is called "protein silencing". The company's product pipeline has been built using its proprietary Avilomics™ platform and is currently focused on viral infection, cancer and autoimmune disease. Avila is funded by leading venture capital firms: Abingworth, Advent Venture Partners, Atlas Venture, Novartis Option Fund, and Polaris Venture Partners. For additional information, please visit http://www.avilatx.com

Unmet needs spur innovative drug development for Hepatitis C...

Article I authored for TrendSlate blog.

Large, unmet needs in medicine have always spurred innovation in novel drug development. A textbook case of this can be found in the effort to fight Hepatitis C (HCV) infection. Hepatitis C is a blood borne virus that primarily affects the liver. The virus triggers an immune response – one that the virus almost always successfully evades– causing liver inflammation and scarring. Slowly, over a period of 20-30 years in most cases, the scarring can progress to decompensated cirrhosis, liver cancer and eventually liver failure. Lack of general knowledge regarding the disease in both the patient and healthcare provider population has created an environment of chronic underscreening, underdiagnosis and lack of proper treatment.

By the most conservative of estimates, researchers have put the worldwide number of HCV infected at 180 million, with 3 to 5 million here in the United States. With large portion of the infections occurring before the early 90’s when an effective technology came out to screen the blood donor pool, most of the burden of the disease sits squarely on the shoulders of those born between 1946 and 1964 – the baby boomer generation. Given that the progression of disease from infection to liver damage is roughly 20 years, there has been a correlating recent uptick in the worldwide incidence of liver disease. Without an effective therapy, experts expect a four fold increase in the incidence of Hepatitis C-related liver disease in the next 20 years. Inextricably linked are healthcare costs… a highly regarded 2009 forecast from the Milliman Consulting Group pegs an increase in healthcare costs from the current $30 billion to over $85 billion in 2027. Most of that burden is forecasted to fall in the lap of already-cash strapped government payors. That is one financial tidal wave to be avoided.

The current treatment for Hepatitis C is arduous for both patient and provider, costly and comes with a largely insufficient cure rate, especially genotype 1, the most common genotype found in the United States. With a 50% cure rate at best (called ‘SVR’ or ‘Sustained Viral Response’), the current treatment of pegylated interferon and nucleoside analog ribavirin is also fraught with side events and tolerability issues that make it not unlike a 48 week endurance contest. Pegylated interferon works by stimulating the host immune response and ribavirin is thought to work by preventing relapse, although it’s exact mechanism of action is unknown. Using the two together means 48 weeks of flu-like symptoms, depression and fatigue. With 50% of patients not responding and/or tolerating this regimen, there is certainly a lot of room for improvement. This fact, coupled with a refocused FDA prioritizing reviews with an eye out for compounds that meet unmet disease states, make HCV an attractive target for intrepid drug developers.

From the scrappiest of the little Biopharma startups to the biggest of behemoth Big Pharma companies, there is plenty of innovation going in developing drugs to effectively treat HCV. As I’m typing this, there are currently over 120 compounds in all stages of development with new ones being added as others undoubtedly falter. Most of these new compounds fall under the umbrella of “STAT-C Drugs” or “Specifically Targeted Antiviral Therapy for Hepatitis C”, Unlike the non-specific method of action of pegylated interferon and ribavirin, STAT-C drugs are a new class of compounds that customized to target specific areas integral to the life cycle of Hepatitis C virus. The goal is to terminate that life cycle, thereby preventing viral replication.

Nearest to market are Vertex Pharmaceuticals and Merck with HCV protease inhibitors Telaprevir and Boceprevir respectively, due to hit the market at about the same time in 2011. Some experts even predict a dual FDA review which will surely test the mettle of both companies. It is fitting, however, that Vertex is amongst the leaders in STAT-C development. They fired the first shot in the equivalent of a drug development revolution when Vertex scientists first published the structure of the HCV protease in 1996 and then used computer-generated modeling to design molecules to bind to the protease. Unlike the HIV protease, HCV didn’t present a nice, big pocket to fit a molecule in. The binding site of the HCV protease was described as more of a “dent in a dinner plate”, making the design more difficult. That program created the Telaprevir molecule. Vertex did it again in 1998, identifying the 3D structure of the NS3 HCV Helicase. This, however, has been a less successful target than the protease. No doubt that both discoveries lead to a industry-wide gold rush in HCV drug development. The forecasted revenue for these two novel drugs? Between 2-3 billion by 2014 for Vertex’s Telaprevir alone, according to some market oracles.

In terms of competition, it looks as if both Vertex and Merck look to have the STAT-C market to themselves for two or three years. Both companies have additional STAT-C compounds in in the pipeline. Looming closely behind are companies like Roche, Bristol Meyers Squibb, Gilead, Boehringer Ingelheim and Tibotec with their own compounds and no shortage of capital to get them to market. Yet despite the leaps in drug development innovation for HCV, a big, yet unanswered question remains. All the trials with both Telaprevir and Boceprevir were done in combination with the current standard of care, pegylated interferon and ribavirin. The addition of either compound provided an average increase in SVR of around 20% and cut the duration of therapy by 50% compared to pegylated interferon and ribavirin alone. Both compounds added additional leverage in boosting the SVRs of patients that had been previously treated but were not cured as well as making significant inroads in populations that have significant genetic barriers to treatment success such as Hispanics and African Americans. A 20% increase in SVR in half the time is remarkable achievement. The fact remains however, that even 12-16 weeks of treatment may be rough to get through given the side effect baggage of pegylated interferon and ribavirin combined with the additional side effects of the new compounds. If a combination of better-tolerated STAT-C drugs can be robust enough to prevent viral resistance and breakthrough without the non-virus specific immune modulating effects of peyglated interferon and ribavirin, even more patients could be treated.

Don’t think drug developers haven’t dreamed of ditching pegylated interferon and ribavirin. Many of the aforementioned companies are doing trials using their STAT-C regimens in combination both with and without pegylated interferon and ribavirin to explore the possibilities. Is it reasonable to think a virus that mutates so rapidly as to create every single possible mutation of itself every day be outwitted by drugs that target multiple points of the virus life cycle? The jury is still out. Vertex recently discontinued an arm in their trial pairing Telaprevir with a low dose of their non-nucleoside polymerase inhibitor VX-222 without pegylated interferon and ribavirin because some patients experienced viral breakthrough. In the higher dose arms, they paired Telaprevir plus VX-222 as well as pegylated interferon and ribavirin and at the time of the press release, those patients remained undetectable. Other trials with different combinations of drugs are currently progressing, so that particular question remains without a definitive answer.

Whatever the ultimate outcome for the STAT-C drugs, it’s clear that a significant milestone has been achieved in terms of drug development. Science and innovation are addressing a clear unmet need. We have an upcoming armory of novel compounds aimed at turning the $85 billion dollar tidal wave into a mere ripple by cutting the down the duration of therapy, increasing SVR and ultimately saving lives. Drugs will continue to improve as developers work to reduce adverse events, increase efficacy and make dosing more convenient. We’ll also witness dramatic shifts in the marketplace due to cost – how will the evolving managed care environment embrace the STAT-C drugs? What effects will STAT-C drugs have on utilization and provider reimbursement? How will patient assistance programs be designed? What role will support groups, community advocates and politics play in educating the masses on the disease and it’s treatment? What are the barriers to access to care? What about drug interactions and resistance profiles? What does HCV viral resistance mean? It is indeed a very exciting time for drug development, but definitely not for the faint of heart

Zobair M. Younossi, MD discusses "A New Era of Hepatitis C Therapy"

Zobair M. Younossi, MD, the Executive Director of the Center for Liver Diseases and Vice President of Research at the Inova Health System in Falls Church, Virginia discusses the STAT-C drugs and other novel therapies for Hepatitis C from AASLD 2010. Features a video and transcript. Watch and read here.

New Journal article: Forthcoming challenges in the management of STAT-C therapy

New article "Forthcoming challenges in the management of STAT-C therapy" published online in Digestive and Liver Diseases(full article available in PDF format as well). This is the first article I've seen addressing the importance pharmacokinetics in STAT-C therapy and applies some of what we've learned from HIV antiretroviral therapy. Definitely worth a read - Cmin/IC50 ratios DO matter!!

Forthcoming challenges in the management of STAT-C therapy

Raffaele Bruno, Serena Cima, Laura Maiocchi, Paolo Sacchi

Received 22 July 2010; accepted 9 September 2010. published online 27 October 2010.
Corrected Proof

Abstract

Agents that specifically target the replication cycle of the virus [specifically targeted antiviral therapies for hepatitis C (STAT-Cs)] by directly inhibiting the NS3/4A serine protease, the NS5B polymerase and NS5A are currently in clinical development. The need to achieve serum drug concentrations able to suppress viral replication is a key factor for a successful antiviral therapy and the prevention of resistance. Thus pharmacokinetics parameters became important issues for drugs used in the therapy of hepatitis C. The ratio of Cmin/IC50 (inhibitory quotient or IQ) can provide a surrogate measure of a drug's ability to suppress HCV replication, by taking into account the relationship between plasma drug levels and viral susceptibility to the drug. Ritonavir boosting may be a useful strategy to improve pharmacokinetic parameters. Characterising resistance to STAT-Cs in clinical trials is essential for the management of a drug regimen to reduce the development of resistance and thereby maximise SVR rate. The lesson of HIV therapy, provide a compelling case for the exploration of combinations of direct-acting antiviral agents.

Rash scare & potential crowded marketplace keeps ANA598 partnerless...

BioWorld Today - Oct. 18, 2010

Financings Roundup

Having yet to sign a partnership for hepatitis C drug ANA598, Anadys Pharmaceuticals Inc. is pulling in $25 million in a public offering to support an upcoming Phase IIb study of the non-nucleoside polymerase inhibitor.

The San Diego-based firm priced the offering of about 13.9 million shares at $1.80 apiece, marking a 13.5 percent discount to Thursday's closing price.

That discount, plus the added dilution to the company's stock, sent shares (NASDAQ:ANDS) tumbling 33 cents, or 15.9 percent, to close Friday at $1.75.

In May, Anadys raised $12.5 million in a registered direct offering and hired Lazard Freres & Co. LLC to help pursue strategic alternatives such as sale of the company or out-licensing assets.

That includes ANA598, which, despite promising early efficacy data, has been dinged by reports of rash in a Phase Ib trial, followed by a higher-than-expected placebo effect that diminished 12-week virological response data in a Phase II study. (See BioWorld Today, April 24, 2009, and Feb. 26, 2010.)

Add to that the increasing competition in the HCV space, and it's no surprise that prospective partners might be skeptical.

Leerink Swann analyst Howard Liang noted last month that recent Phase III data on HCV protease inhibitors, especially Vertex Pharmaceuticals Inc.'s telaprevir "set a high efficacy bar" while early data for NS5A inhibitor BMS-790052 from Bristol-Myers Squibb Co. and nucleoside polymerase inhibitors for Roche AG (RG7128) and Pharmasset Inc. (PSI-7977) also have been impressive.

"In comparison, ANA598's early data do not look compelling," Liang wrote in a Sept. 27 research report.

Anadys is hoping that further Phase II data and results from the Phase IIb study slated to start early next year might prove tempting enough to snag a partner to help with the costly Phase III program.

The ongoing Phase II study is testing ANA598 in combination with the standard-of-care regimen pegylated interferon and ribavirin in treatment-naive HCV patients with genotype 1 disease.

Anadys has data for three of the six patients in the 200-mg twice-daily group, treated for 24 weeks and then had HCV levels measured 24 weeks after all treatment stopped. All three of those patients achieved sustained viral response.

The planned 48-week Phase IIb trial will test ANA598, again in combination with pegylated interferon and ribavirin, in about 200 patients, including both treatment-naive and treatment-experienced subjects.

Anadys is working to finalize the design with the FDA.

Elsewhere in its pipeline, the company has ANA773, an HCV drug designed to induce endogenous interferon that acts via the Toll-like receptor 7 pathway.

Work on that program was suspended in 2009 to concentrate resources on ANA598, but data from a monotherapy trial, plus recent developments suggesting that interferon-based treatment might continue to have a place in the HCV landscape, prompted the firm to restart ANA773. A 28-day combination study of the drug plus ribavirin is expected to begin dosing in the second quarter of 2011 . (See BioWorld Today, June 5, 2009.)

Proceeds from the latest financing, which will add to the $22. 1 million Anadys had in the bank as of June 30, also will be used for general corporate purposes, including working capital.

The firm could pull in an additional $3.7 million if underwriter Lazard Capital Markets LLC exercises its full overallotment option of about 2. 1 million shares.

Prior to the offering, Anadys had about 46.2 million shares outstanding.

Excerpts from a "Hepatology" commentary on the future of Taribavirn - by Paul Kwo, MD and Rakesh Vinayek MD.... (Thank you NATAP.org)

The Next Step for Taribavirin - Commentary        Hepatology Sept 24 2010   Paul Y Kwo and Rakesh Vinayek   Excerpts:   In this issue of Hepatology, Poordad and colleagues report the SVR rates of weight-based TBV compared to weight-based RBV in naïve genotype I HCV-infected patients. In this US Phase 2b randomized open-label controlled parallel group study, 278 naïve genotype I subjects were randomized to TBV 20, 25, or 30 mg/kg/day or RBV 800-1400 mg, pegIFN alfa-2b for 48 weeks. An early virologic response (EVR) defined as undetectable HCV RNA (< 39 I.U. at Week 12) or a 2 log reduction in baseline HCV RNA, the primary endpoint of the study, was comparable across all treatment arms. The SVR rate was also preserved across all treatment arms, ranging between 27 and 28%. The overall response rates in this trial were low though the high percentage of African Americans (20%) and those with advanced fibrosis may explain the lower SVR rates. It would be interesting to know the IL-28 composition of the treatment population as there may have been a high prevalence of unfavorable Il-28 CT or TT genotype patients present which could also explain in part the low SVR rates.   While SVR rates were not different between treatment arms, a lower relapse rate was seen with an incremental increase in the dose of TBV, similar to that observed with RBV. In addition, the per protocol SVR rates were substantially higher again demonstrating the importance of adherence to therapy to provide optimal SVR rates in the genotype I population. Lower anemia rates (defined as hemoglobin < 10 grams/dL) were seen in the TBV arms throughout the entire 48 weeks, with cumulative anemia rates being significantly lower across the two lower TBV arms (20 mg and 25 mg/kg) compared to weight-based RBV. However, as the dose of TBV was increased to 30 mg/kg, the anemia rate was numerically lower than with RBV but was not significant, other than at week 4, suggesting that higher doses TBV may lead to similar rates of anemia and other side effects observed with RBV. The pharmacokinetic analysis showed that this effect correlated with RBV plasma exposure. Furthermore, within the first 12 weeks of treatment when maintaining the dose of RBV has been shown to be most critical, significantly lower rates of anemia were observed with TBV compared with RBV (7-15% vs 24%, respectively) within the first 12 weeks of treatment although this translated clinically into comparable, not superior SVR rates in the TBV arms. Even though, fewer patients treated with TBV required dose reduction (13-28%) compared to 32% patients treated with RBV, it should also be noted that dropout rates for anemia were not different amongst the TBV arms compared to the RBV arms in this study, though this may be due to relatively small sample size. There does appear to be an increased rate of diarrhea in the TBV arms compared to RBV. This may be significant as some DAA agents are also associated with increased GI side effects and, as we enter an era where DAA agents and other drugs are combined, side effects could limit the efficacy of multi-drug combinations. Finally, while not statistically significant, insomnia was numerically higher in the TBV arms and should be a side effect of some concern in future trials. Thus, as significantly fewer dose reductions were noted only in the TBV 20 mg/kg arm as compared to the higher doses of TBV and RBV with similar SVR rates, the dose of 20 mg/kg may also require study in the future with DAA agents  So what does the future hold for taribavirin? Phase 2 and ongoing Phase 3 trials strongly suggest that DAA agents will be added to pegIFN and RBV to obtain higher SVR rates, albeit at the expense of higher rates of anemia and other side effects. Currently, the role of ESAs in the treatment of HCV with DAA agents is not yet precisely defined, though we await the results of ongoing trials. The inclusion of TBV into the HCV armamentarium may serve as an opportunity to combine with pegIFN and DAA agents to reduce the rates of anemia and avoid RBV dose reduction or introduction of ESAs. As RBV reduction or removal of RBV is associated with increased rates of breakthrough and development of resistance to DAA agents, TBV may have a role in populations particularly sensitive to ribavirin-related anemia , including those with advanced liver disease, older patients, patients who have undergone liver transplantation, HIV/HCV coinfected individuals, patients with hemoglobulinopathies and chronic renal failure 20. However, with the commencement of several trials comprising of multiple combinations of DAA agents with and without pegIFN/RBV, and the development of newer protease inhibitors with potentially lower rates of anemia, the role of TBV remains less precisely defined and could potentially have a finite life cycle. Studies with combinations of DAA agents with PEGIFN/RBV have been initiated and these studies will multiply. Whether or not RBV (and TBV) can be eliminated altogether remains to be determined.  Particularly in those patients with unfavorable treatment characteristics, RBV may remain a part of our therapeutic armamentarium for years to come; and, if so, TBV could be an option which has the potential to limit toxicity and potentially reduce costs. The ideal study may be to combine TBV with a DAA agent and pegIFN and compare it to RBV, to see if SVR rates can be preserved or improved by minimizing dose reductions and reducing the emergence of resistance. Given the long wait between the approval of pegIFN and RBV and yet unapproved DAA agents, one should not discount the potential contribution of TBV. Many promising agents have already been stopped in development due to lack of efficacy or toxicity 21-22. Thus, if TBV can be shown to preserve or improve efficacy rates in combination with DAAs and Peg IFN, with lower rates of anemia, the use of TBV in these clinical settings would be a welcome addition to the HCV armamentarium as we begin to expand the HCV populations that we treat.

FDA issues draft guidelines for STAT-C/DAA development ...

The FDA has just issued a draft of potential guidelines for companies developing STAT-C / DAA drugs for Hepatitis C.  This is for comment only, the FDA will issue their final guidelines toward the end of the year.  The draft can be viewed on the FDA website.

Idenix compounds put on 'clinical hold' after three serious adverse events...

CAMBRIDGE, Mass., Sept. 7 /PRNewswire-FirstCall/ -- Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today announced that the company received verbal notice on Friday, September 3, 2010 from the U.S. Food and Drug Administration (FDA) that the IDX184 and IDX320 programs have been placed on clinical hold. A clinical hold is an order issued by the FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. This decision was made after Idenix notified the FDA of three serious adverse events that occurred during a drug-drug interaction study of the combination of IDX184 and IDX320 in healthy volunteers. These observed serious adverse events were elevated liver function tests detected in three subjects during post exposure safety visits. The liver function tests have returned to nearly normal levels in all three subjects during follow-up. All planned studies of IDX184 and IDX320 to date have been completed and there are currently no healthy volunteers or patients receiving IDX184 or IDX320. Idenix will submit full data to the FDA from recently completed preclinical and clinical studies, including 3-month chronic toxicology studies of IDX184, a 14-day study of IDX184 in combination with pegylated interferon/ribavirin (PegIFN/RBV), a 3-day proof-of-concept study of IDX320 in hepatitis C (HCV) infected patients, and the IDX184 and IDX320 drug-drug interaction study in healthy volunteers in order to assess next steps in the development of both compounds.

"We have not yet received a formal letter from the FDA, nor has the Agency had an opportunity to review the safety and efficacy data from recently completed clinical trials with IDX184 and IDX320. Based upon our discussions with the Agency, we are primarily focused on three cases of elevated liver function tests observed during our drug-drug interaction study of the combination of IDX184 and IDX320 in healthy volunteers," said Jean-Pierre Sommadossi, Ph.D., Idenix Chairman and Chief Executive Officer. "Based upon the safety and antiviral activity we observed in the IDX184 14-day study and the IDX320 3-day proof-of-concept study, both in HCV-infected patients, we remain committed to the future potential of these drug candidates. We will work closely with independent experts and our external safety committee to better understand the cause of these serious adverse events in the combination study of IDX184 and IDX320 and to provide the FDA with more information in order to expedite their review and resolve this matter as quickly as possible."
Full data presentations of IDX184, IDX320 and IDX375 studies will be presented at the annual meeting of the American Association for the Study of Liver Diseases (AASLD), which will be held at the end of October in Boston.

Phase I: IDX184/IDX320 Combination
Idenix completed a two-week Phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and pharmacokinetic drug-drug interaction between IDX320 and IDX184 in healthy volunteers. Two cohorts were evaluated in the study with 10 subjects in each cohort randomized eight to active drug and two to placebo. Subjects in the first cohort received 400 mg once-daily of IDX320 for the first week, subsequently adding 100 mg once-daily of IDX184 for the second week. Subjects in the second cohort received 100 mg once-daily of IDX184 plus placebo for the first week, subsequently adding 400 mg once-daily of IDX320 for the second week. The combination of IDX184 and IDX320 was generally safe and well tolerated during the 14 days of treatment. Liver function abnormalities deemed to be serious adverse events were detected in three subjects during the post exposure safety visits. Liver function tests in these subjects have returned to nearly normal during follow-up. Pharmacokinetic drug-drug interactions between IDX184 and IDX320 were not considered to be clinically significant. Neither the plasma exposure of IDX184 and its metabolite, 2'-methylguanosine, nor IDX320 plasma exposure explain these three serious adverse events.

Phase IIa: IDX184, a liver-targeted HCV nucleotide prodrug
This 14-day, Phase IIa clinical trial evaluated 50 to 200 mg doses of IDX184 in combination with PegIFN/RBV in treatment-naive HCV genotype 1-infected patients. At Day 14, mean (+/- standard deviation) viral load reductions were 1.5 (+/- 1.3) logs for placebo (n=16), 2.7 (+/- 1.3) logs for 50 mg IDX184 QD (n=16), 4.0 (+/- 1.7) logs for 50 mg IDX184 BID (n=8), 4.2 (+/- 1.9) logs for 100 mg QD (n=8), 4.1 (+/- 1.2), for 150 mg QD (n=15), 4.1 (+/-1.4) logs for 100 mg BID (n=8) and 3.7 (+/- 1.2) logs for 200 mg QD (n=8). In the cohorts of 100 mg, 150 mg, and 200 mg daily doses in combination with PegIFN/RBV, 50%, 40% and 25%, respectively, of patients achieved undetectable virus levels (<15 IU/mL) by Day 14. Liver injury parameters (ALT and AST) improved with all doses of IDX184. The side effect profile of the three drug combination was consistent with the known side effect profile of PegIFN/RBV alone. The most common adverse events reported were fatigue, myalgia, headache and nausea.
Phase I/II: IDX 320, an HCV protease inhibitor

This randomized, parallel-arm, double-blind, placebo-controlled proof-of-concept trial evaluated the safety, tolerability, antiviral activity and pharmacokinetics of IDX320 in treatment-naive HCV genotype 1-infected patients. Thirty patients were randomized equally and received placebo, 50, 100, 200 or 400 mg of IDX320 orally once-a-day for three days. One cohort of eight patients was randomized to receive 200 mg IDX320 BID or placebo. At Day 3, mean (+/- standard deviation) viral load reductions were 0.1 (+/- 0.15) logs for placebo (n=5), 2.6 (+/-0.49) logs for 50 mg IDX320 QD (n=5), 3.1 (+/- 0.29) logs for 100 mg QD (n=6), 3.1 (+/- 0.41) logs for 200 mg QD (n=6) and 3.3 (+/- 0.28) logs for 400 mg QD (n=7). At daily doses of placebo, 50, 100, 200, and 400 mg, 0%, 20%, 67%, 67% and 86%, respectively, of patients achieved greater than or equal to 3 log reduction in HCV RNA at the end of treatment. In the 200 mg IDX 320 BID cohort at Day 3, mean (+/- standard deviation) viral load reductions were 3.8 (+/- 0.52) logs and all patients (100%) achieved greater than or equal to 3 log reduction in HCV RNA. In the 3-day proof-of-concept study, IDX320 was generally safe, well tolerated, and demonstrated potent, dose-related HCV antiviral activity.

Phase I: IDX375, an HCV non-nucleoside polymerase inhibitor
Idenix has an ongoing Phase I clinical trial in healthy volunteers evaluating single doses of the free acid form of IDX375 ranging from 200 to 1200 mg per day. Overall, IDX375 achieved pharmacologically relevant drug exposure and was well tolerated for doses up to 1200 mg for one day in healthy subjects. In the fourth quarter of 2010, Idenix plans to initiate a 3-day proof-of-concept trial in treatment-naive genotype 1 HCV-infected patients.

Conference Call Information
Idenix will hold a conference call today at 8:30 a.m. ET. To access the call please dial (800) 471-3635 U.S./Canada or (706) 758-9475 International and enter passcode 99538089. A replay of the conference call and webcast will be available until September 21, 2010. To access the replay, please dial (800) 642-1687 U.S./Canada or (706) 645-9291 International and enter the passcode 99538089.
About HCV

Inhibitex completes phase 1a trial of nucleotide polymerase inhibitor INX-189

Proof-of-Concept Trial in Patients with Chronic Hepatitis C Planned for Q4 2010

ATLANTA--(BUSINESS WIRE)--Sep 1, 2010 - Inhibitex, Inc. (Nasdaq: INHX), announced today that it has successfully completed a Phase1a, first-in-man, single ascending dose trial of INX-189, its nucleotide polymerase inhibitor in development for the treatment of chronic hepatitis C (HCV) infections. In this trial, 42 healthy volunteers received either a single oral dose of INX-189, ranging from 3 mg to 100 mg, or placebo. The Company plans to present detailed results from this trial during a future scientific meeting. Preliminary data from the trial are as follows:

• INX-189 was generally well tolerated at all dose levels;
• No drug-related serious adverse events;
• No dose-related trends in frequency or type of adverse events; adverse events occurring in more than one subject were headache and nasal congestion;
• No grade II or higher laboratory abnormality adverse events or clinically significant changes in ECGs; and
• Pharmacokinetic data supports INX-189's potential for once daily (QD) dosing.

“We are encouraged with the initial safety and pharmacokinetic profile of INX-189 in this first-in-man trial,” stated Dr. Joseph Patti, Senior Vice President and Chief Scientific Officer of Inhibitex, Inc. “Based upon the pharmacokinetics observed in this study, we continue to believe that INX-189 has the potential to demonstrate antiviral activity with a low once-daily dose, and we look forward to assessing its ability to reduce HCV RNA viral loads in patients with chronic hepatitis C in a Phase 1b multiple ascending dose trial we plan to start in the fourth quarter.”

About Inhibitex

Inhibitex, Inc., headquartered in Alpharetta, Georgia, is a biopharmaceutical company focused on developing products to prevent and treat serious infectious diseases. The Company's pipeline includes FV-100, which is in Phase II clinical development for the treatment of shingles, and INX-189, a nucleotide polymerase inhibitor in development for the treatment of chronic hepatitis C infections. The Company also has additional HCV nucleotide polymerase inhibitors in preclinical development and has licensed the use of its proprietary MSCRAMM^® protein platform to Pfizer for the development of staphylococcal vaccines. For additional information about the Company, please visit www.inhibitex.com.