Obesity Plus Drinking Worst Combo for Liver

By Michael Smith, North American Correspondent, MedPage Today

Published: April 26, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM – Obesity and heavy drinking are each known risk factors for liver disease, but together they appear to be even worse, researchers said here.

Analysis of a large population-based cohort of women in England showed that the risk of liver cirrhosis and decompensation was markedly increased if participants were either obese or heavy drinkers, according to researchers led by William Rosenberg, MBBS, DPhil, of the University College London.

But the combination of the two was "super-additive," Rosenberg told MedPage Today during the meeting of the European Association for the Study of the Liver, more than doubling the risk seen with either of the other risk factors (P<0.001).

"At first glance, (the study finding) doesn't seem very surprising," he said.

But the analysis of 108,000 women ages 50 to 75 taking part in a cancer screening trial is the largest to look at the incidence of advanced liver disease in the context of overweight and alcohol use.

And it did find one surprise, Rosenberg said: that being overweight and being obese have different effects when combined with alcohol use.

In women who were overweight and drank, the two risks simply added up, but in those who were obese – usually defined as a body mass index (BMI) of 30 or higher – the risks were synergistic.

"If you're obese, the damage you can do to yourself (by drinking heavily) is much greater than if you're just overweight," Rosenberg said.

Among the 108,000 women in the analysis, there were 616 events of advanced liver disease over a median follow-up of 9.4 years, the researchers found.

Women with a low body mass index who also had low alcohol intake were at the lowest risk, with a cumulative hazard of less than 0.001. Those who had a high BMI but drank lightly had a similar but slightly higher hazard, they found.

Slimmer women who drank heavily had about double the hazard of those who were low in both categories, but heavy drinkers with a high BMI had a cumulative hazard of greater than 0.004.

"The public health message is enormously important," Rosenberg said. "People are not aware that they are putting themselves at this risk."

The study should be viewed in the context of common heavy drinking in Europe and a 10-fold increase in death from cirrhosis among middle-age women in England from 1970 to 2000, commented Daniele Prati, MD, of the Ospedale Alessandro Manzoni in Lecco, Italy, who was not involved in the study but who moderated a press conference at which some details were discussed.

Prati told MedPage Today that the findings are not surprising, but it's important to see that they've been established in a large population.

Now, it's up to governments to "sensitize the population about risk," he said.

The UKCTOCS study has support from the MRC, Cancer Research UK and National Health Service. Trembling and Rosenberg did not report any additional support or make any disclosures.

Prati reported financial links with Roche, BMS, Novartis, and AbbVie.

Primary source: European Association for the Study of the Liver
Source reference:
Trembling PM, et al "Influence of BMI and alcohol on liver-related morbidity and mortality in a cohort of 108,000 women from the general population from UKCTOCS" EASL 2013; Abstract 115.

Source

Liver Imaging Tests Vie to Replace Biopsy

By John Gever, Deputy Managing Editor, MedPage Today

Published: April 26, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM -- Although biopsy remains the gold standard for diagnosing liver fibrosis, imaging tests increasingly appear to be a viable way to garner equivalent information with less patient discomfort and risk, researchers said here.

In presentations at the meeting of the European Association for the Study of the Liver, scientists from across Europe reported on the strengths and weaknesses of various imaging modalities as tools for routine clinical practice.

There was no clear winner among transient elastography, magnetic resonance elastography (MRE), real-time shear wave elastography (RTSWE), and acoustic radiation force impulse (ARFI) imaging, but all appeared to be nearly as accurate as liver biopsy in quantitative assessment of fibrosis and for predicting outcomes such as death and cirrhotic decompensation.

The role of liver imaging for these purposes in the U.S. has recently come to the fore with the FDA's clearance last week of the Fibroscan transient elastography device. Fibroscan is the established leader in noninvasive fibrosis imaging and, according to its French manufacturer, Echosens, the U.S. is the last major market to approve its device.

All these forms of elastography work by setting up shear waves in the liver. Patterns of propagation of these waves correspond to the degree of liver stiffness, which in turn correlates with the level of fibrosis. All but MRE use ultrasound to generate the waves.

Studies presented here evaluated one or more of these technologies against another, with or without liver biopsy as a reference standard, and in a variety of patient populations.

Transient Elastography Versus Biopsy

Perhaps the most direct assessment was reported by Juan Macias, MD, of Hospital Universitario de Valme in Seville, Spain. He reported a retrospective analysis of 297 patients coinfected with HIV and hepatitis C virus (HCV) who had been tested with liver biopsy as well as transient elastography, with these tests performed within a year of each other. The study period covered 2005 to 2011.

Findings indicated that fibrosis stage as established from biopsies and liver stiffness measurements from transient elastography were equally accurate in predicting overall mortality and decompensation of cirrhosis.

Kaplan-Meier curves for patients with stage F4 fibrosis (overt cirrhosis) and for those with elastography measurements in the highest quintile (21 kPa and above) were nearly identical through up to 6 years of follow-up, for both all-cause death and for decompensation of cirrhosis, Macias reported.

Point estimates of the increased risk for these outcomes were somewhat higher in models based on biopsy findings than in the elastography-based analyses, but the error bars in the latter were markedly smaller.

For example, the risk of decompensation doubled with each increase in fibrosis stage (hazard ratio 2.00, 95% CI 1.32 to 3.00), whereas each 5-kPa increase in liver stiffness corresponded to a hazard ratio of 1.42 (95% CI 1.31 to 1.55).

"The noninvasive nature of [transient elastography] should favor its use instead of liver biopsy when the only issue is predicting the clinical outcome of liver disease in HIV-HCV coinfection," Macias told attendees.

ARFI Versus Transient Elastography

Acoustic radiation force impulse imaging is another up-and-coming imaging method for liver disease. Like transient elastography, it uses ultrasound to generate mechanical waves within the liver, but the nature of the waves and the interpretation of the resultant patterns differs.

Derek Bardou of CHU Angers in Angers, France, noted that the two technologies have been compared head-to-head in previous studies, with pooled data suggesting that ARFI is less accurate.

But transient elastography has a significant drawback -- it doesn't work on obese patients. Bardou pointed out that the previous analyses were all conducted on a per-protocol basis, such that patients for whom the transient elastography attempt failed to yield usable results were excluded.

He argued that a more stringent "intent-to-diagnose" analysis would be a better reflection of the utility of the two methods in routine practice.

From 2009 to early 2013, he and his colleagues used both methods on a total of 267 patients with chronic, noncancerous liver disease (patients with cirrhotic complications or sepsis were excluded) who also underwent liver biopsies. Areas under the receiver-operating characteristic (AUROC) curves for classifying patients' liver disease stage were calculated for both test types, with biopsy results serving as the reference standard.

The researchers found that, on a per-protocol basis, AUROC values with ARFI were indeed lower -- indicating poorer accuracy -- than those seen with transient elastography. In this analysis, Bardou and colleagues excluded 6.7% of patients in whom transient elastography could not be performed. ARFI failed in fewer than 1%.

But in the intent-to-diagnosis analysis involving all 267 patients, there was no significant difference in AUROC values for the two methods.

Bardou added that whole-liver results with ARFI were more accurate than findings only in the right lobe, the "classical" way to perform ARFI, he explained.

RTSWE Versus Transient Elastography Versus Biopsy

Another study reported here sought to validate real-time shear wave elastography as an alternative -- not necessarily superior -- to liver biopsy.

Giovanna Ferraioli, MD, of Italy's University of Pavia, presented findings from 88 patients with chronic liver disease of varied origin and 33 healthy controls.

Patients underwent both RTSWE (using the ElastPQ system) and transient elastography as well as biopsy. The controls had only the noninvasive testing.

RTSWE, in this study, involved a fixed "sample box" located a maximum of 70 mm below the Glisson's capsule within the liver. Patients held their breath for 2 to 4 seconds and 10 images were collected, with the median stiffness value in kPa used as the final result. As the name suggests, and unlike transient elastography, RTSWE delivers readings almost immediately. In some studies, it has appeared to be more accurate as well.

Both imaging methods showed stiffness values that progressed upward with the degree of fibrosis ascertained with the biopsies. RTSWE yielded somewhat more detail, in that the median values for each patient group stratified according to fibrosis stage (F0/1 to F4) tracked steadily higher. Transient elastography results for patients with F2 fibrosis, on the other hand, were nearly identical to those with F0/1 disease (5.45 versus 5.5 kPa).

Ferraioli and colleagues found that, as expected, RTSWE values in the healthy controls were lower than in patients with liver disease (median 3.3 kPa, interquartile range 3.7 to 4.0).

Transient elastography readings tended to be higher (median 3.8 kPa, interquartile range 4.5 to 5.0) and overlapped in the controls with those from patients with liver disease (median in F2 patients 5.45, interquartile range 4.3 to 8.0).

RTSWE "compares favorably" with transient elastography, Ferraioli concluded.

MR Elastography Versus Biopsy

Use of MRI equipment to analyze liver stiffness is an even newer approach. It, too, can be used to generate vibrations that propagate through the liver. Rocio Gallego-Duran, also of the Hospital Universio de Valme, reported on a validation study in which artificial neural networks were used to generate elastography values from MRI scans.

Her study involved 63 patients with biopsy-confirmed non-alcoholic fatty liver disease, including 32 with non-alcoholic steatohepatitis (NASH) and 25 with significant fibrosis.

The first 22 of these patients were used as a "training cohort" for fine-tuning the software settings to match biopsy results as closely as possible. The resulting model was then tested in the remaining 41 patients, serving as a validation cohort.

For diagnosing NASH, the model showed sensitivity of 77% and specificity of 90%, Gallego-Duran reported. Positive and negative predictive values were 89% and 79%, respectively.

The model was not quite as good at diagnosing fibrosis. With the best-performing cutoff values, sensitivity was 87% but specificity was only 63%. As a result, the positive predictive value was just 59%, although the negative predictive value was a respectable 89%.

Gallego-Duran told attendees that the MRI-based technique holds some potential advantages over the ultrasound-based methods. Because it produces high-resolution images of the entire liver, it may provide a fuller picture of liver disease and can also reveal other types of liver injury. Patients' body fat also is not an issue for image quality, as it is for transient elastography, she said.

None of the studies had commercial funding.

All of the presenters declared that they had no relevant financial interests.

Primary source: European Association for the Study of the Liver
Source reference:
Macias J, et al "Performance of liver stiffness compared with liver biopsy to predict survival and decompensations of cirrhosis among HIV/HCV-coinfected patients" EASL 2013; Abstract 20.

Additional source: European Association for the Study of the Liver
Source reference:
Bardou D, et al "First intention-to-diagnose comparison of ARFI and Fibroscan in chronic liver diseases" EASL 2013; Abstract 15.

Additional source: European Association for the Study of the Liver
Source reference:
Ferraioli G, et al "Performance of ELASTPQ^® shear wave elastography technique for assessing fibrosis in chronic viral hepatitis" EASL 2013; Abstract 16.

Source

Anemia Top Side Effect of HCV Antivirals

By John Gever, Deputy Managing Editor, MedPage Today

Published: April 26, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM -- Two years after direct-acting antiviral drugs for hepatitis C virus (HCV) infection hit the U.S. market, anemia has been far and away their most significant adverse effect, researchers said here.

Outcomes in more than 1,400 U.S. patients taking a HCV protease inhibitor in routine practice for chronic infection indicated that more than half had experienced anemia, whether they received boceprevir (Victrelis) or telaprevir (Incivek), according to Michael W. Fried, MD, of the University of North Carolina in Chapel Hill.

Triple therapy with one of these drugs plus ribavirin and pegylated interferon is now the standard of care for HCV genotype 1.

Although severe skin rashes have been telaprevir's most talked-about side effect, prompting the FDA to add a boxed warning to the drug's label, severe anemia was much more common. Of the 1,082 patients in the study taking telaprevir, 27 showed severe anemia, compared with five patients developing severe rash, Fried and colleagues found.

Among 344 patients on boceprevir, six developed severe anemia.

These data were collected by a consortium of 44 academic centers and 59 community-based clinics in the U.S., which have sought to enroll all patients receiving these drugs. The only exclusion criteria were consent refusal or participation in another study of HCV therapies.

Beyond that, clinicians were free to prescribe dosing regimens and manage adverse effects according to their own judgment.

Anemia in most patients was treated mainly by reducing ribavirin dosages, for patients with cirrhosis as well as those without (65% and 54%, respectively).

Clinicians resorted to erythropoietin-type drugs in 13% of cirrhotic patients and 19% of those with no cirrhosis. Transfusions were given to 17% and 8% of cirrhotic and noncirrhotic patients, respectively.

Baseline cirrhosis was a significant risk factor for severe anemia and premature discontinuation of treatment. Fried and colleagues found odds ratios of 1.5 to 2.2 (all P<0.05) for risk of these outcomes as well as for any serious adverse event and for early discontinuation attributed to adverse effects.

Some 11% of the 550 patients with cirrhosis developed decompensation on treatment, compared with 1% of noncirrhotic patients.

Fried and colleagues also found virologic response rates in their patients to be similar to, if not better than, those seen during the drugs' clinical trials.

Patients taking telaprevir had HCV viral loads below the limits of detection or quantitation at rates of 91% to 96% at treatment week 12, depending on prior treatment history.

Corresponding data for boceprevir patients ranged from 63% to 87%.

About one-quarter of patients in the study stopped all therapy prematurely. Lack of efficacy and adverse events accounted for 35% and 40% of discontinuations, respectively.

At a press briefing, Laurent Castera, MD, of Centre Hospitalier Universitaire de Bordeaux in France, who was not involved with the study, said it was noteworthy in representing a real-world patient population, as opposed to the carefully selected samples enrolled in clinical trials.

Despite the broader mix of patients seen in the post-marketing study, Castera said the efficacy results were "comparable" to those seen in the two drugs' registration trials. Rates of anemia and other adverse events also tracked closely with previous trial results, in which some degree of anemia occurred with both drugs in half of patients.

The study was funded by Vertex, Merck, Kadmon, and Genentech.

Fried reported relationships with Genentech, Merck, Vertex, Gilead, Bristol-Myers Squibb, and Abbott.

Castera reported relationships with Bristol-Myers Squibb, Merck, Gilead, and Echosens.

Primary source: European Association for the Study of the Liver
Source reference:
Fried M, et al "HCV-TARGET: a longitudinal, observational study of North American patients with chronic hepatitis C (HCV) treated with boceprevir or telaprevir" EASL 2013; Abstract 818.

Source

The race toward an interferon free world: The current field of Hepatitis C Virus treatment research, including recent financial deals

PRESS RELEASE

April 26, 2013, 4:39 p.m. EDT

Gilead Sciences Leads the Way in Delivering the First All Oral Treatment for HCV

NEW YORK, April 26, 2013 /PRNewswire via COMTEX/ -- Citeline�, an Informa business unit, and the world's leading research authority on pharmaceutical clinical trials has just published an exclusive whitepaper examining the current progress towards a remarkable improvement in the medical treatment for HCV.

With news of the impending breakthrough in HCV treatment, Citeline reviews the current landscape of clinical trials and drugs in this competitive space as well as the recent history of HCV-related financial deals. In addition the whitepaper takes a look at the timing of current Phase III trials evaluating all oral regimens to determine how long Gilead may be the sole player in this space.

Based on information in Citeline's clinical trial intelligence tool, Trialtrove�, 83% of the 200 planned and ongoing Phase I-III clinical trials for pipeline HCV drugs (excluding vaccines) are being conducted by 10 companies; these 10 companies, including Bristol-Myers Squibb, Gilead, Merck and AbbVie, among others, are the focus of this report. Gilead leads in the number of Phase II trials and is conducting over twice as many as the next most active Phase II sponsor, Bristol-Myers Squibb.

According to Doro Shin, MPH, Citeline's Senior Analyst, Infectious & Genitourinary Diseases, "Gilead's lead in direct acting antiviral (DAA) agents for the treatment of HCV could lead to a shorter, oral, and interferon free treatment of the disease, with a dramatic reduction in unwanted side effects. This is truly a new era in HCV treatment. "

Moreover, in reviewing deals over the last five years we discovered between March 2008 and March 2013, there were a total of 18 HCV specific industry partnerships. In both years partnerships comprised of research and discovery and commercialization agreements occurred most frequently; however, three partnerships in 2012 also included licensing agreements. The complete report provides details of these partnership and M&A details including deal values.

"DAAs are clearly dominating in the HCV treatment field as evidenced by the clinical trial landscape and recent financial dealings," remarks Ms. Shin. "With these DAAs, the race is on toward the first interferon free HCV treatment regimen, but the contenders have entered themselves into different events to ensure that they get the gold."

To read this exclusive whitepaper - The race toward an interferon free world: The current field of HCV treatment research, including recent financial deals go to www.citeline.com/resource-center/whitepapers

About Citeline Citeline, Inc., an Informa company. Citeline is the world's most comprehensive source of real-time R&D and commercial intelligence featuring an unmatched data collection of global clinical trials, clinical trial investigator profiles, drug development pipelines and commercial intelligence.

Contact for Further InformationSean McIntoshDirector of MarketingCiteline Inc.52 Vanderbilt Ave7th FloorNew York, NY 10017212-520-2741sean.mcintosh@citeline.com www.citeline.com

SOURCE Citeline

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Stiff Spleen Predicts Decompensation in Cirrhotic Patients

Medscape Medical News > Conference News

Daniel M. Keller, PhD

Apr 26, 2013

Amsterdam, the Netherlands — In a multivariate analysis of compensated cirrhotic patients infected with hepatitis C virus, spleen stiffness and model for end-stage liver disease (MELD) score emerged as independent predictors of decompensation, leading investigators to develop a predictive model.

"In compensated hepatitis C–related cirrhotic patients, the proposed model…could replace hepatic venous pressure gradient for predicting portal-hypertension-related clinical decompensation," senior author Davide Festi, MD, from the University of Bologna in Italy, told delegates here at the International Liver Congress 2013.

Dr. Festi explained that the prognosis of compensated cirrhotic patients is strongly associated with the development of portal hypertension, and the gold standard for evaluating portal hypertension is the hepatic venous pressure gradient. However, it is an invasive technique that should be performed only by highly experienced operators. Potential complications include bleeding and supraventricular arrhythmias.

Noninvasive tests to predict portal hypertension include serum markers, ultrasonography, elastosonography, magnetic resonance elastography, and transient elastography (FibroScan). Elastography measurements correlate well with hepatic venous pressure gradient.

For their study, Dr. Festi and colleagues examined 85 patients with compensated hepatitis C–related cirrhosis and a normal body mass index. Median age was 59 years, just over half of patients had esophageal varices, and 66% were men.

After study participants were screened with transient elastography for liver and spleen stiffness, esophagogastroduodenoscopy, biochemical tests, abdominal ultrasonography, and hepatic venous pressure gradient, the investigators conducted clinical, biochemical, and ultrasound assessments every 6 months. If patients had a low risk for varices at baseline, they underwent esophagogastroduodenoscopy every 12 months. At follow-up, ascites, variceal bleeding, or hepatic encephalopathy were considered evidence of clinical decompensation.

At baseline, median aspartate aminotransferase and alanine aminotransferase values were each 56 U/L, platelet count was 109.5 × 10³/L, median MELD score was 9, liver stiffness was 23 kPa, spleen stiffness was 56 kPa, and hepatic venous pressure gradient was 13 mm Hg. Median follow-up was 730 days. Five patients were lost to follow-up at 2 years, leaving 80 evaluable patients.

At 2 years, 26 of the 80 patients (32%) experienced clinical decompensation, and 11 (14%) experienced other events without decompensation (development of hepatocellular carcinoma, enlargement of varices, or spleen enlargement).

Model Predicts Chance of Decompensation at 2 Years

On multivariate analysis, independent predictors of clinical decompensation were spleen stiffness (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.04 - 1.13; P < .001) and MELD score (HR, 1.43; 95% CI, 1.07 - 1.91; P = .016). The investigators incorporated these 2 elements into an equation that predicted clinical decompensation at 2 years.

With an upper predicted-risk cutoff of 0.78, the model had a positive predictive value of 88% that a clinical decompensation event would occur within 2 years; with a lower cutoff of 0.2, the model had a negative predictive value of 97% that no event would occur within 2 years.

The investigators developed a decision algorithm for predicting decompensation. If spleen stiffness is less than 53.4 kPa, the patient has a 97% chance that no decompensation-defining event will occur within 2 years. If spleen stiffness is above 53.4 kPa, the equation they developed predicts decompensation with 88% accuracy.

After Dr. Festi's presentation, 2 audience members debated whether spleen stiffness results from congestion or fibrosis. In the end, there was no definitive resolution of the issue. However, regardless of the cause, the model stands.

The association between splenomegaly and portal hypertension has been known for years. "What is new is the idea of measuring spleen stiffness. So far what we have been measuring is spleen enlargement, which, along with platelet count, is usually a good sign of portal hypertension," session chair Laurent Castera, MD, from Hôpital Beaujon and the University of Paris in Clichy, France, told Medscape Medical News.

He explained that liver stiffness not only helps in the staging of liver fibrosis and the diagnosis of cirrhosis; it also helps determine prognosis. Recent studies have suggested that spleen stiffness correlates well with portal hypertension, "maybe even better than liver stiffness alone," he said. This model and algorithm "could be clinically useful because, although hepatic venous pressure gradient is a reference method for portal hypertension, it's only available in very few centers. For instance, in France, there are fewer than 5 centers.... So there's really a role for noninvasive methods to better diagnose and stage portal hypertension," Dr. Castera noted.

However, he advises caution when trying to draw conclusions from the study because of the limited number of patients involved and the short follow-up. Furthermore, from a technical standpoint, measuring spleen stiffness has its limitations "because, when using transient elastography, you cannot choose the region of interest. It's blind," he explained. "Also, it was not initially designed to measure spleen stiffness, but liver stiffness."

In addition, a limitation to measuring liver or spleen stiffness is obesity, which affects "around 20% of patients, at least in Europe, and possibly more in the United States," he said.

Dr. Castera cautions that at this point, the concept of using spleen stiffness is based on a single study. To establish relevant cutoffs and to validate the concept will require larger groups of patients and several independent studies.

With the increasing prevalence of compensated cirrhosis, especially from hepatitis C virus infection, but without signs of portal hypertension, such as varices, "what you want is an exam that is able to rule out very confidently the presence of varices," he noted. "The use of noninvasive methods may be useful because you would spare an invasive endoscopy exam."

Dr. Festi and Dr. Castera have disclosed no relevant financial relationships.

International Liver Congress 2013: 48th Annual Meeting of the European Association for the Study of the Liver (EASL). Abstract 22. Presented April 25, 2013.

Source

Gilead Sciences, Inc. (GILD) Leading the Charge in Hepatitis C Space with Shorter-Duration Drugs

April 26, 2013

Gilead Sciences, Inc. (GILD) is set to take more market share of the hepatitis C space as the company develops HCV drugs with a duration of just under a year, and the potential to go even lower, providing a significant opportunity for GILD that could bring high rewards to investors, says David Ferreiro, Executive Director and Senior Analyst at Oppenheimer & Co. Inc.

“The company that I have the most conviction in within the biotech space is still Gilead (GILD), and they have a lot going on in their pipeline. The investor interests over the past year or more around the hepatitis C space, or HCV space, has been tremendous. And certainly Gilead has been leading that charge since they acquired Pharmasset early last year,” Ferreiro said.

FOR MORE INFORMATION ABOUT THIS INTERVIEW CLICK HERE.

There is considerable market opportunity in HCV due to a significant unmet medical need, large reservoir of patients and a lack of care standards, Ferreiro says. GILD is set to take more market share as it addresses the need to bring forth drugs that are more tolerable, have a shorter duration and are more efficacious, Ferreiro adds.

“Gilead has few drugs in development that seem to work in a range of genotypes…the duration has moved down from just under a year, which is at the current standard of care to 12 to 24 weeks right now with the potential to go lower, so I’d say that’s probably the biggest opportunity out there for Gilead. We already understand this to be a huge opportunity, but there are ways that it can be bigger. For example, we are all still relatively conservative about how well new therapies can penetrate that market. I think that’s the unknown, and could bring much higher reward to the investor,” Ferreiro said.

Source

Ligand Presents Preclinical Data on HepDirect™ Liver-Targeting Technology Platform at 2013 International Liver Congress (EASL) Annual Meeting

SAN DIEGO--(BUSINESS WIRE)-- Ligand Pharmaceuticals Incorporated (NASDAQ: LGND) announced that data from preclinical studies evaluating Ligand’s HepDirect™ liver-targeting technology platform will be featured in a poster presentation at the 48^th Annual International Liver Congress hosted by the European Association for the Study of the Liver (EASL) in Amsterdam. The data show highly targeted liver delivery of a clinically active NS5B polymerase inhibitor utilizing the HepDirect technology platform, and demonstrated that HepDirect liver targeting of active nucleosides may be an effective method to improve efficacy while reducing systemic side effects in HCV treatment.

In preclinical studies, Ligand evaluated the pharmacokinetics and liver targeting of LGD-7501, a HepDirect prodrug designed for increased liver targeting compared to other phosphoramidate prodrugs of the same active nucleoside. The compound using HepDirect technology efficiently targeted the liver with greatly reduced systemic distribution in preclinical models, providing further proof-of-concept of the value and utility of the HepDirect technology platform.

“Our HepDirect technology is an important example of Ligand’s diverse portfolio of internal and un-partnered assets and technologies, and has applicability for liver-targeting for a wide range of therapeutic areas, including HCV,” commented Matthew W. Foehr, Chief Operating Officer of Ligand Pharmaceuticals. “These positive findings represent the first preclinical example of HepDirect’s delivery efficiency when directly compared to other prodrugs of the same active nucleoside that have been previously tested clinically.”

About Ligand’s HepDirect HCV Inhibitor Program

HepDirect is a pro-drug technology that targets delivery of certain drugs to the liver by using a proprietary chemical modification that renders a drug biologically inactive until cleaved by a liver-specific enzyme. Antiviral therapies for the treatment of HCV often have significant undesired side effects related to systemic exposure of the compounds. The HepDirect technology may improve the efficacy and/or safety of certain drugs and can be applied to marketed or new drug products.

About Ligand Pharmaceuticals

Ligand is a biopharmaceutical company that develops and acquires assets it believes will generate royalty revenues and, under its lean corporate cost structure, produce sustainable profitability. Ligand has a diverse asset portfolio addressing the unmet medical needs of patients for a broad spectrum of diseases including thrombocytopenia, multiple myeloma, diabetes, hepatitis, muscle wasting, dyslipidemia, anemia and osteoporosis. Ligand’s Captisol platform technology is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. Ligand has established multiple alliances with the world's leading pharmaceutical companies including GlaxoSmithKline, Onyx Pharmaceuticals, Merck, Pfizer, Baxter International, Bristol-Myers Squibb, Celgene, Lundbeck Inc., Eli Lilly & Co., Spectrum Pharmaceuticals and The Medicines Company. Please visit www.captisol.com for more information on Captisol or www.ligand.com for more information on Ligand.

Follow Ligand on Twitter @Ligand_LGND.

Forward-Looking Statements

This news release contains certain forward-looking statements by Ligand that involve risks and uncertainties and reflect Ligand's judgment as of the date of this release. These statements include those related to the level of targeting, the utility, importance and value of LGD-7501, the HepDirect technology, Ligand’s assets and the HCV Inhibitor program. Actual events or results may differ from our expectations. For example, there can be no assurance that LGD-7501 or other HepDirect or HCV Inhibitor drug candidates will progress through clinical development or receive required regulatory approvals within the expected timelines or at all, that further clinical trials will confirm any safety or other characteristics or profile described in this press release, that there will be a market of any size for such drug candidates or that such drug candidates will be beneficial to patients or successfully marketed. The failure to meet expectations with respect to any of the foregoing matters may have a negative effect on Ligand's stock price. Additional information concerning these and other risk factors affecting Ligand's business can be found in prior press releases available via www.ligand.com as well as in Ligand's public periodic filings with the Securities and Exchange Commission at www.sec.gov. Ligand disclaims any intent or obligation to update these forward-looking statements beyond the date of this release. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

Source: Ligand Pharmaceuticals Incorporated

Ligand Pharmaceuticals Incorporated
John Higgins, President and CEO
Jennifer Capuzelo, Investor Relations
858-550-7584
jcapuzelo@ligand.com
or
LHA
Don Markley, 310-691-7100
dmarkley@lhai.com

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INCIVO® Receives Positive Opinion from the Committee for Medicinal Products for Human Use (CHMP) for the Treatment of Genotype-1 Hepatitis C Virus (HCV)

July 22, 2011

-Expanding new treatment class for patients with HCV-

Beerse, Belgium, 22 July, 2011 - Tibotec Virco-Virology BVBA, one of the Janssen Pharmaceutical Companies, announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending the approval of INCIVO (telaprevir), a direct acting antiviral (DAA) for the treatment of chronic genotype-1 hepatitis C virus (HCV), in combination with pegylated-interferon and ribavirin, the previously accepted standard of care.

The CHMP positive opinion is based on results from three phase III clinical trials, ADVANCE¹, REALIZE² and ILLUMINATE³ which evaluated the efficacy and safety of telaprevir in combination with pegylated-interferon and ribavirin in more than 2,290 treatment-naïve and previously-treated genotype 1 HCV patients.^1,2,3 Data from ADVANCE and REALIZE were published in the 23^rd June edition of the New England Journal of Medicine. Data from the ILLUMINATE study were presented at the 61^st annual meeting of the American Association for the Study of Liver Diseases in 2010.

The CHMP positive opinion is a critical step in the approval process and will be considered by the European Commission, which has authority to approve medicines for use throughout the European Union. Telaprevir was approved by the U.S. Food and Drug Administration (FDA) in May 2011 and is marketed by Vertex Pharmaceuticals under the brand name INCIVEK^™. Following marketing authorization approvals, telaprevir will be marketed in the EU and certain other global territories under the brand name INCIVO by the Janssen Companies.

"We are encouraged by this positive decision from the CHMP and will continue to work closely with other regulatory authorities to make telaprevir available for people with HCV. If approved by the European Commission, the addition of telaprevir will offer patients an improved treatment option compared to the previously accepted standard of care, which only cures 40-50 percent of genotype 1 patients" said Ramon Polo, INCIVO Compound Development Team Leader. "Telaprevir is part of Janssen's expanding infectious disease portfolio, which is comprised of innovative therapies in HIV/AIDS, tuberculosis and now HCV that are helping to redefine and improve treatment outcomes. Janssen remains dedicated to improving the lives of patients and supporting healthcare professionals around the world."

About INCIVO
INCIVO is being developed by Tibotec, one of the Janssen Pharmaceutical Companies, in collaboration with Vertex Pharmaceuticals and Mitsubishi Tanabe Pharma. The Janssen Companies have the right to commercialize telaprevir in Europe, Latin America, the Middle East, Africa, India, Australia and New Zealand under the commercial name INCIVO^®; Vertex has the right to commercialize telaprevir in North America under the name INCIVEK^™; Mitsubishi Tanabe Pharma has the right to commercialize telaprevir in Japan and certain Far Eastern countries.

On May 23^rd 2011, US FDA approved telaprevir for the treatment of people with chronic genotype 1 hepatitis C with compensated liver disease.

About HCV
HCV is a blood-borne infectious disease that affects the liver.⁴ With an estimated 170 million people infected worldwide, and three to four million people newly infected each year,⁵ HCV puts a significant burden on patients and society. Chronic infection with HCV can lead to liver cancer and other serious and fatal liver diseases, and is the most common cause of liver transplant in Europe.⁶ The previously accepted standard of treatment for HCV is pegylated-interferon combined with ribavirin,⁷ however this only cures 40-50 percent of genotype 1 patients.⁸

About Tibotec
Tibotec Virco-Virology BVBA, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, 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 hepatitis C drugs, and anti-infectives for diseases of high unmet medical need.

About Janssen
The Janssen Pharmaceutical Companies of Johnson & Johnson are dedicated to addressing and solving the most important unmet medical needs of our time, including oncology , immunology, neuroscience, infectious disease, and cardiovascular and metabolic diseases.

Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world.

More information can be found at www.janssen-emea.com

This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Tibotec Virco-Virology BVBA, any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to, general industry conditions and competition; economic factors, such as interest rate and currency exchange rate fluctuations; technological advances and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; domestic and foreign health care reforms and governmental laws and regulations; trends toward health care cost containment; and increased scrutiny of the healthcare industry by government agencies. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 2, 2011. Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. The Janssen Pharmaceutical Companies and Johnson & Johnson do not undertake to update any forward-looking statements as a result of new information or future events or developments.

References:

1. John G et al. Telaprevir in Combination with Peginterferon and Ribavirin in Genotype 1 HCV Treatment-Naïve Patients: Final Results of Phase 3 ADVANCE study. Paper presented at: The Liver Meeting of the American Association for the Study of Liver Diseases (AASLD); 2010.
2. Zeuzem S, Andreone P, Pol S et al. REALIZE trial final results: telaprevir-based regimen for genotype 1 hepatitis C virus infection in patients with prior null response, partial response or relapse to peginterferon/ribavirin. Paper presented at: 46th annual meeting of the European Association for the Study of the Liver (EASL); 2011.
3. Sherman KE et al. Telaprevir in Combination with Peginterferon Alfa2a and Ribavirin for 24 or 48 weeks in Treatment-Naive Genotype 1 HCV Patients who Achieved an Extended Rapid Viral Response: Final Results of Phase 3 ILLUMINATE Study. Paper presented at: The Liver Meeting of the American Association for the Study of Liver Diseases (AASLD); 2010.
4. Centres for Disease Control and Prevention. Hepatitis C FAQs. [cited 2009 Dec 17] Available from: http://www.cdc.gov/hepatitis/C/cFAQ.htm#transmission.
5. World Health Organization. Hepatitis C. Weekly Epidemiological Record. 1997;72:65-69.
6. The Hepatitis C Trust. Treatments: Potential New Drugs. [cited 2010 Feb 20] Available from: http://www.hepctrust.org.uk/treatment/potential-new-drugs/Drugs+that+target+the+virus.
7. McHutchison J. et al. Peginterferon Alfa-2b or Alfa-2a with Ribavirin for Treatment of Hepatitis C Infection. N Engl J Med. 2009; 361: 580-93.
8. Simin M et al. Cochrane systematic review: pegylated interferon plus ribavirin vs. interferon plus ribavirin for chronic hepatitis C. Alimentary Pharmacology & Therapeutics. 2007; 25(10):1153-62.

Source

Probiotics Found to Reduce Hepatic Encephalopathy in Cirrhotic Patients

Virtual Press Office

Amsterdam, 25 April 2013

Amsterdam, The Netherlands, Thursday 25 April 2013: Probiotics could emerge as a treatment plan to manage hepatic encephalopathy (HE) therapy after a new study[1] announced at the International Liver Congress™ 2013 found they significantly reduced development of the notoriously difficult-to-treat disease.

The study analysed the efficacy of probiotics in preventing the development of HE in 160 cirrhotic patients over a period of approximately nine months and found significant improvements in reducing patients’ arterial ammonia levels after three months of treatment with probiotics.

Ammonia, produced by gut bacteria, is thought to be one of the main mediators of cerebral dysfunction in HE. Probiotics work by enriching the gut flora with a non-urease producing microorganisms, which decrease ammonia production.[2] Probiotics are live microorganisms (mostly bacteria) that produce a health benefit on the host when administered in adequate amounts.[3]

Twice as many patients taking a placebo developed overt HE (the study’s primary endpoint) compared to patients taking probiotics in the form of a capsule.

EASL’s Treasurer, Prof. Mauro Bernardi welcomed the findings and said they would provide a positive impact for cirrhotic patients at risk of developing HE for whom the prognosis is typically very poor.

Prof. Bernardi said: “Hepatic encephalopathy is an insidious disease that’s caused by an accumulation of toxins in the blood that are normally removed by the liver. Treatment normally involves the use of antibiotics or laxatives to suppress the production of toxic substances in the intestine but there is still a great deal of room for improvement so it will be exciting to see the results of further studies to determine if clinicians have a new form of treatment on the cards.”

Hepatic encephalopathy is a spectrum of neuropsychiatric abnormalities including personality changes, intellectual impairment and reduced levels of consciousness in patients with liver failure, after exclusion of other known brain disease.

- Ends -

Disclaimer: the data referenced in this release is based on the submitted abstract. More recent data may be presented at the International Liver Congress™ 2013.

Notes to Editors

About EASL

EASL is the leading European scientific society involved in promoting research and education in hepatology. EASL attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

EASL’s main focus on education and research is delivered through numerous events and initiatives, including:

• The International Liver CongressTM which is the main scientific and professional event in hepatology worldwide
• Meetings including Monothematic and Special conferences, Post Graduate courses and other endorsed meetings that take place throughout the year
• Clinical and Basic Schools of Hepatology, a series of events covering different aspects in the field of hepatology
• Journal of Hepatology published monthly
• Participation in a number of policy initiatives at European level

About The International Liver Congress^TM 2013

The International Liver Congress™ 2013, the 48th annual meeting of the European Association for the study of the Liver, is being held at the RAI Convention Centre in Amsterdam from April 24 – 28, 2013. The congress annually attracts in excess of 9,000 clinicians and scientists from around the world and provides an opportunity to hear the latest research, perspectives and treatments of liver disease from principal experts in the field.

For further information on the studies, or to request an interview, please do not hesitate to contact the EASL Press Office on:

Email: easlpressoffice@cohnwolfe.com

Dimple Natali +44 7900 138 904

Courtney Lock +44 7894 386 422

References

[1] M.K Lunia, AN OPEN LABEL RANDOMISED CONTROLLED TRIAL OF PROBIOTICS FOR PRIMARY PROPHYLAXIS OF HEPATIC ENCEPHALOPATHY IN PATIENTS WITH CIRRHOSIS. Presented at the International Liver CongressTM 2013.

[2] A. Agrawal, Secondary Prophylaxis of Hepatic Encephalopathy in Cirrhosis, An Open-Label, Randomized Controlled Trial of Lactulose, Probiotics, and No Therapy. Available
http://www.medscape.com/viewarticle/767674_3 [Accessed 9/4/13].

[3] World Health Organization and Food and Agriculture Organizationof the United Nations. Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria. Avahttp://www.who.int/foodsafety/publications/fs_management/en/probiotics.pdf [Accessed 9/4/13].

Source

ILC 2013: HEPATITIS C - NEW DAA's READY FOR PRIME TIME (Video)

Provided by ILC Press

Also See: Studies show encouraging data in a wide range of HCV patient populations

ILC 2013: HEPATITIS C - EXISTING TREATMENTS (Video)

Provided by ILC Press 

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Therapy Free of Side Effects of Other HCV Drugs

By Michael Smith, North American Correspondent, MedPage Today

Published: April 25, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

AMSTERDAM – An investigational protease inhibitor (PI) led to viral cures in about four out of five hepatitis C virus (HCV) patients, a researcher reported here.

In a phase III study, either of two doses of faldaprevir combined with pegylated interferon and ribavirin significantly outperformed placebo, according to Peter Ferenci, MD, of the Medical University of Vienna.

But importantly, Ferenci told MedPage Today during the meeting of the European Association for the Study of the Liver, they did so without the side effects associated with earlier drugs in the class.

The efficacy results are "indeed very good," commented Mark Thursz, MD, of St. Mary's Hospital in London, who was not involved in the study but who moderated a press conference at which some details were discussed.

But the most important aspect of the results, Thursz said, is the safety profile of the drug. "This will be far better tolerated by our patients in the clinic than the earlier PIs," he told reporters.

Two protease inhibitors – telaprevir (Incivek) and boceprevir (Victrelis) – have been approved for patients with the difficult-to-treat HCV genotype 1, but they have been associated with serious and sometimes dangerous adverse events.

Both, for instance, cause significant anemia, and telaprevir has been associated with life-threatening rash that in at least two cases led to death.

But they are the only drugs so far approved that directly target HCV; the companion medications, pegylated interferon and ribavirin, are respectively an immune booster and a viral replication inhibitor.

That was the context when the industry-sponsored trial was designed, Ferenci told MedPage Today – the earlier protease inhibitors were regarded as the competitors, with interferon (given intravenously) and ribavirin alone as the standard of care.

Since then, he said, there has been a "revolution" in HCV, with a host of oral direct-acting agents under investigation and clinicians hoping that interferon and perhaps ribavirin can be banished from the clinic.

Indeed, Ferenci noted, research is underway to see if faldaprevir, in combination with other oral direct-acting HCV drugs, can be effective in the absence of interferon and possibly without interferon or ribavirin.

In the current study, investigators enrolled 652 patients with genotype 1 HCV and randomly assigned them for 24 weeks to get placebo or either 120 or 240 milligrams of faldaprevir daily. All patients also got then-standard therapy with interferon and ribavirin.

Patients with what the investigators called "early treatment success" – defined as low levels of HCV at week 4 and undetectable levels at week 8 – were eligible to stop treatment at week 24, while others got another 24 weeks of interferon and ribavirin.

In the placebo arm, 22% of patients had early treatment success, Ferenci reported, compared with 87% in the low-dose faldaprevir arm and 89% in the high-dose arm, and stopped treatment at 24 weeks.

The primary endpoint of the study was 12-week sustained virologic response (SVR₁₂) – no detectable HCV RNA 12 weeks after the end of treatment.

The investigators found that 52% of patients in the placebo arm reached that endpoint, similar to historical results. In the low-dose faldaprevir arm, the SVR12 rate was 79%, compared with 80% in the high-dose arm (P<0.0001 for both).

The only adverse event clearly caused by the drug, Ferenci said, was an elevation in bilirubin, but that was not associated with elevated liver enzymes and had "no clinical significance."

Some patients reported rash but did not need medical attention for it, he added.

Indeed, he said, the rates of most observed adverse events, including those regarded as serious, were similar among the arms, with little difference in discontinuations owing to adverse events.

The study was supported by Boehringer Ingelheim. Ferenci reported financial links with the company and with Roche, Merck, Vertex, Idenix, Achelion, Rottapharm-Madaus, and BMS.

Thursz reported financial links with Abbott and Gilead.

Primary source: European Association for the Study of the Liver
Source reference:
Ferenci P, et al "Faldaprevir plus pegylated interferon alfa-2A and ribavirin in chronic HCV genotype-1 treatment-naïve patients: final results from STARTVERSO1, a randomised, double-blind, placebo controlled phase III trial" EASL 2013; Abstract 1416

Source

Once-Daily HCV Drug Stars in Phase III Trials

By John Gever, Deputy Managing Editor, MedPage Today

Published: April 25, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM -- Treatment-naive patients with hepatitis C virus (HCV) infection showed high viral cure rates when treated with simeprevir, an investigational once-daily oral drug, along with standard therapy, researchers said here.

Sustained 12-week virologic responses (SVR12), defined as viral loads too low to be measured, occurred in eight out of 10 patients with HCV genotype 1 receiving simeprevir in two identical, placebo-controlled phase III trials conducted in the U.S. and Europe, according to presentations at the annual meeting of the European Association for the Study of the Liver.

All patients in these trials also received standard anti-HCV treatment with pegylated interferon and ribavirin for 24 or 48 weeks. SVR12 rates in the trials' placebo groups were 50% in both cases (P<0.001 versus the simeprevir groups).

Simeprevir is an orally active, second-generation inhibitor of the HCV NS3/4A protease. Two first-generation products, boceprevir (Victrelis) and telaprevir (Incivek), were approved in 2011. Both have significant disadvantages: they must be taken three times a day, and telaprevir has been linked to life-threatening skin rashes while boceprevir can cause serious anemia.

As a result, drug firms have been working to develop HCV protease inhibitors with better safety profiles and that can be given just once a day.

Each of the phase III simeprevir studies randomized approximately 400 treatment-naive HCV patients in a 2:1 ratio to 150 mg of the drug or placebo in addition to peginterferon and ribavirin.

Both trials were designed to use "response-guided therapy," under which patients achieving viral loads of less than 25 IU/mL at week four and and below detection limits at week 12 had the peginterferon and ribavirin stopped at week 24. Those showing responses short of these standards continued on treatment through week 48.

Patients with poor responses (less than a two-log reduction in HCV viral loads by week 12 or confirmed loads of at least 25 IU/mL at weeks 24 or 36) were taken off the study.

Results of the U.S. trial, called QUEST-1, were reported by Ira Jacobson, MD, of Weill Cornell Medical College in New York City, and colleagues. Not only did simeprevir meet the study's primary endpoint of superiority over placebo in SVR12 rates, but it also was highly effective against the hard-to-treat genotype 1a form of the virus.

Additionally, it was better than placebo in patients with all three IL28B genotypes, although response rates were especially high with the drug in patients with the TT and CT forms of the gene. Responses to simeprevir were also equally good irrespective of METAVIR score, which measured liver fibrosis and inflammation.

The only subgroup for whom simeprevir was not more effective than placebo was patients with genotype 1a and the so-called Q80K polymorphism, Jacobson and colleagues indicated.

Results were closely similar in the European QUEST-2 trial, according to data reported at a press conference prior to the study's formal presentation later this week.

Adverse events in both trials were similar in number in the active-drug and placebo groups. In QUEST-2, rates of skin rash and photosensitivity were somewhat higher with simeprevir versus placebo, but those events were not increased with the drug in QUEST-1.

Conversely, anemia, neutropenia, and elevated bilirubin appeared more common with simeprevir in QUEST-1, but not in QUEST-2.

Other efficacy data from QUEST-1 were as follows:

• Patients taken off study for poor virologic response: 7% simeprevir, 66% placebo
• Simeprevir patients qualifying for shortened peginterferon/ribavirin treatment: 85%
• Patients with undetectable virus at week four: 80% simeprevir, 12% placebo

Jacobson and colleagues also reported that SVR12 rates were nearly as great in patients with HCV genotype 1a as in those with the more responsive 1b genotype. However, most of the responses in the 1a patients occurred in those without the Q80K polymorphism, for whom the SVR12 rate was the same with simeprevir as with placebo.

Relatively poor simeprevir responses were also seen in patients with emergent mutations in the Ns3 protease at position 155 in genotype 1a and at position 168 in genotype 1b.

Press briefing co-moderator Mark Thursz, MD, of St. Mary's Hospital in London, commented that the data suggest that simeprevir and other second-generation products have succeeded in surpassing boceprevir and telaprevir.

"With the new protease inhibitors, [the side effect profile] seems to be better, more patients get shorter periods of treatment, and more patients get cured," he said.

A third trial of simeprevir in HCV patients previously treated with other drugs is ongoing, Jacobson and colleagues indicated.

The drug's manufacturer, the Janssen unit of Johnson & Johnson, applied last month for U.S. marketing approval of simeprevir to be given with peginterferon and ribavirin. It also has applications in the works in Japan and the European Union.

Both studies were funded by Johnson & Johnson's Janssen unit.

Study authors declared that they had relationships with unspecified commercial entities that could be perceived as having a connection to the studies. Both included investigators who were Janssen employees.

Primary source: European Association for the Study of the Liver
Source reference:
Jacobson I, et al "Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-1, a phase III trial" EASL 2013; Abstract 1425.

Additional source: European Association for the Study of the Liver
Source reference:
Manns M, et al "Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-2, a phase III trial" EASL 2013; Abstract 1413.

Source

Oral Regimen Sustains Hepatitis C Viral Response to 24 Weeks

Medscape Medical News > Conference News

Daniel M. Keller, PhD

Apr 25, 2013

AMSTERDAM, the Netherlands — A regimen of 3 direct-acting antiviral drugs plus ritonavir and ribavirin produced sustained virologic response rates in more than 90% of a broad range of patients infected with hepatitis C 24 weeks after therapy, results from a new clinical trial show.

Kris Kowdley, MD, from the Liver Center of Excellence in the Digestive Disease Institute at Virginia Mason Medical Center in Seattle, Washington, presented the results here at the International Liver Congress 2013.

The randomized, open-label, multicenter phase 2b trial, known as Aviator, shows that the sustained virologic responses seen at 12 weeks with an all-oral interferon-free regimen, presented last year at the annual meeting of the American Association for the Study of the Liver Diseases by Dr. Kowdley, are sustainable.

In the Aviator trial, noncirrhotic patients with genotype 1 hepatitis C virus who were treatment-naïve or had not responded to peginterferon and ribavirin were treated with combinations of direct-acting antiviral drugs with or without ribavirin for 8, 12, or 24 weeks.

The direct-acting antiviral drugs were once-daily ABT-450r (an NS3/4A protease inhibitor boosted with ritonavir), once-daily ABT-267 (an NS5A inhibitor), and twice-daily ABT-333 (a non-nucleoside NS5B inhibitor).

The 571 patients were predominantly white, and the mean age was 48 to 53 years. The majority, 59% to 71%, had hepatitis C genotype 1a, and mean baseline viral load was 6.6 log₁₀ hepatitis C RNA. Overall, 27% to 34% of treatment-naive patients had genotype IL28B CC, whereas only 2% to 4% of the null responders did.

Patients coinfected with HIV or hepatitis B were excluded from the study.

For the 79 treatment-naive patients who received the regimen consisting of 3 direct-acting antiviral drugs plus ribavirin for 12 weeks, 96% achieved sustained virologic response rates at 24 weeks (99% achieved this at 12 weeks).

High Response Rates

Response rates were no higher with 24 weeks of treatment than with 12 weeks of treatment. Even with only 8 weeks of treatment, 88% of patients achieved sustained virologic response rates at 24 weeks and 89% achieved this at 12 weeks.

For the null responders who received the triple-drug plus ribavirin regimen, 93% of the 45 patients who received 12 weeks of treatment achieved sustained virologic response, as did 95% of the 43 patients who received 24 weeks of treatment.

With the triple-drug plus ribavirin regimen, the achievement of sustained virologic response was similar in the treatment-naive and null-responder patients, regardless of sex, genotype (1a or 1b), host IL28B genotype, severity of liver fibrosis, or baseline RNA level.

Of the 247 patients who received the triple-drug plus ribavirin regimen for 12 or 24 weeks, 4 (1.6%) discontinued the study because of drug-related adverse effects.

Of 4 serious adverse effects noted in the analysis, 1 arthralgia was possibly related to therapy. More common adverse effects, reported in more than 10% of patients, were headache, fatigue, nausea, insomnia, and diarrhea. Of the patients with grade 3/4 laboratory abnormalities, 6 had elevated total bilirubin and 1 had elevated alanine aminotransferase, which resolved with continuation of the drugs.

Dr. Kowdley told Medscape Medical News that results from the Aviator trial highlight 2 key points. "First, prolonging the therapy for another 12 weeks does not appear to improve the sustained virologic response. Second, greater treatment exposure does not seem to increase the risk of resistance; we're not seeing a drop off or more breakthroughs, because the number of breakthroughs has remained at 0. That's a really important point."

With the triple-drug plus ribavirin regimen, which is the optimal regimen, "sustained virologic response at 24 weeks remains very durable, compared with sustained virologic response at 12 weeks. That is true in both the null responders and treatment-naive patients.... So for those patients who do end up, for whatever reason, being on 24 weeks, we can feel, I think, reasonably confident that the resistance risk is not increased," Dr. Kowdley said.

A concern all along has been the high pill burden of this all-oral regimen. Dr. Kowdley said he expects that, for upcoming trials, reformulations will combine the once-daily ABT-267, ABT-450, and ritonavir into 1 pill, while keeping the twice-daily ABT-333 and the ribavirin separate. "I would say that in the phase 3 program and going forward, the pill burden should be lower," he predicted.

The sustained virologic response for treatment-naive patients is "extremely impressive," said Mark Thursz, MD, from Imperial College in London, the United Kingdom, and secretary general of the European Association for the Study of the Liver. Similarly, for null responders, Dr. Thursz, who was not involved in the study, said he is "quite excited" by the "really high sustained virologic responses."

He remarked that, in general, the protease inhibitors in development to treat hepatitis C virus have "much cleaner profiles than the current ones that we're using," but he added that "it's not quite time to bury the interferon yet."

However, "the vital signs are not looking good for either boceprevir or telaprevir." In light of the drugs now in trials, "it's time to move on," Dr. Thursz said.

The study was supported by AbbVie. Dr. Kowdley reports receiving research support from AbbVie, Beckman Boehringer Ingelheim, Bristol-Myers Squibb, Gilead/Pharmasset, Ikaria, Intercept, Janssen, Merck, Mochida, Vertex, Scientific Consulting, and Novartis; and being on advisory boards for AbbVie, Gilead, Merck, and Vertex. Dr. Thursz has disclosed no relevant financial relationships.

International Liver Congress 2013: 48th Annual Meeting of the European Association for the Study of the Liver (EASL). Abstract 3. Presented April 25, 2013.

Source

Unsafe injection practices fuelling Hepatitis in India

Hetal Vyas, TNN | Apr 25, 2013, 07.55 PM IST

BANGALORE: Though little alarm has been sounded about it, Hepatitis is increasing at a worrying rate in India. Recent World Health Organization (WHO) data puts Hepatitis B cases in India at approximately 1.1 million, with 240,000 annual deaths due to complications associated with it. Similarly for Hepatitis C, the figure for India is put at 400,000 cases, with about 96,000 deaths annually of causes related to the hepatitis C infection. A large percentage of these cases are due to unsafe injection practices.

The WHO also says that unsafe practices and the overuse of injections across the globe can cause an estimated 33% of Hepatitis B virus, 42% of Hepatitis C virus and 2% of all new HIV(human immunodeficiency virus) infections every single year.

Experts said that this is definitely alarming for Indian situation where injections are administered for common symptoms like diarrhea, fever and even cough. In a year a person is given 2.9 injections on an average as per INCLEN study published in WHO's SEARO bulletin recently.

Overall, three billion injections are estimated to be administered annually in India; of which 1.89 billion were unsafe. Moreover, injections administered for curative purpose constituted 82.5% and a majority of these are unnecessary.

According to Dr. Santanu Chattopadhyay, Gastroenterologist, Founder and CEO, NationWide Primary Healthcare Services.: "Hepatitis B & C can both be contracted through the sharing of needles during drug use; via reuse of infected syringes; through blood transfusion, if the blood was not properly screened; and during a tattoo or piercing done with infected tools. In rare cases, an infected pregnant woman could spread the virus to her baby at birth. Even sharing of razors or tooth brushes with an infected person can spread the disease."

In this case, prevention is definitely better than cure. Says Dr Praveen Kumar, Medical Gastroenterologist, and Professor in Gastroenterology, Vydehi Medical College and Vydehi Mallya Hospital: "Treatment for Hepatitis is very expensive. Therefore awareness and stringent enforcement is essential to save the population. In India unsafe injection practices and the reuse of needles is a major cause of concern, so it is imperative to spread awareness among medical practitioners, patients and the public at large," he said.

The INCLEN study has found that of all the injections administered in India, 62% were found to be unsafe. They were administered incorrectly or were a threat for transmitting blood borne viruses.

Source

Risk of HCV transmission very low in monogamous heterosexual couples

^{Courtesy U.S. Dept of Veterans Affairs}

Hepatitis C is rarely transmitted between long-term monogamous heterosexual partners, said Dr. Norah Terrault.

By: MICHELE G. SULLIVAN, Ob.Gyn. News Digital Network

04/25/13

The risk of sexually transmitting a chronic hepatitis C infection to a long-term monogamous heterosexual partner is very low, averaging just about 1% per year.

That risk level works out to a transmission rate of about one in every 190,000 sexual contacts, Dr. Norah Terrault and her colleagues reported in the April issue of Hepatology (2013;57:881-9).

The cross-sectional study also found that no one sexual practice – including anal intercourse or intercourse during menses – significantly increased the risk of transmission, wrote Dr. Terrault of the University of California, San Francisco. The findings can be used to provide "unambiguous and reassuring counseling messages," she and her coinvestigators noted.

The study included 500 subjects with chronic HCV infections, and their sexual partners. All couples reported longtime, monogamous relationships (median duration, 15 years); however, the relationship duration varied widely, spanning 2-52 years.

Each of the partners was interviewed separately about their sexual contacts and practices. At the time of interview, the index subjects were a median of 49 years old and the partners, a median of 48 years.

The HCV-positive subjects reported the highest incidence of past risk factors, including blood transfusions before 1992 (32%), injected illegal drugs (54%), and being stuck by a bloody sharp item in a hospital (4%). Nearly half (46%) reported having had at least 20 lifetime sexual partners, with 21% having had 50 or more.

However, partners also reported some risk factors: 11% had an early transfusion, 2% used illegal drugs, and 2% had a hospital sharps incident. Many (27%) also reported having had at least 20 sexual partners.

Among the 500 couples, 20 partners (4%) were coinfected with HCV. Of these, nine were concordantly infected, eight discordantly, and three were indeterminate.

Six of the concordant couples underwent phylogenetic typing. Three were infected with the same HCV isolate and three with different strains. The investigators estimated the time of transmission and any additional risk factor among the three couples with concordant strains.

For the first couple, with an 18-year relationship, transmission probably occurred after about 6.5 years. The female partner had a history of injected drug use, while the male had no identifiable risk factors.

The second couple had a 28-year relationship; transmission probably occurred at around 15 years, the investigators said. "The female partner had a history of injectable drug use and both partners reported more than 20 prior sexual partners, a history of sexual transmitted diseases, and a history of snorting of drugs."

For the third couple, who had been together for 10 years, transmission probably occurred at around year 6. "The male partner had a history of injectable drug use, of being stuck by a sharp bloody object while working in a hospital, and more than 20 prior sexual partners; both partners reported snorting drugs and sharing snorting equipment."

The investigators determined that these infections were probably sexually transmitted between the partners – a prevalence of about 1%. "The estimated risk per sexual contact ranged from 1/380,000 to 1/190, 000," they said.

However, they were unable to identify any behaviors that significantly increased the risk of transmission. Compared with couples without coinfection, coinfected couples were more likely to have vaginal intercourse during menses (100% vs. 66%), more likely to have anal intercourse (67% vs. 30%), and less likely to use condoms (0% vs. 30%), but none of these differences was statistically significant.

"HCV transmission by sex from chronically infected persons to their heterosexual partners in a long-term monogamous relationship likely occurs, but is a rare event," the authors concluded. "Our results provide a basis for specific counseling messages that clinicians can use with their patients... [that] support the current national recommendations that couples not change their sexual practices if they are in a monogamous heterosexual relationship."

None of the study authors reported any financial conflicts.

msullivan@frontlinemedcom.com

Source

Bristol-Myers gains FDA's 'breakthrough' track in race for hep C drug approval

April 25, 2013 | By John Carroll

Bristol-Myers Squibb ($BMY) just gained an inside regulatory track in the frantic race to get new interferon-free hepatitis C drugs to the FDA. The big biotech reported in its quarterly statement that the agency has provided the coveted "breakthrough" status for a combination of daclatasvir with two other direct-acting antivirals, asunaprevir, an NS3 protease inhibitor and BMS-791325, an NS5B non-nucleoside polymerase inhibitor.

The combo approach is designed to stop the virus from replicating. Just days ago the company reported that the drug worked in 15 of 16 patients during a 24-week trial. Now investigators plan to settle on an ideal dose and launch a late-stage study later this year.

BMS is the latest in a long line-up of high-profile biopharma companies to land a breakthrough designation. In theory, the agency is committed to working with these companies now to expedite a path through the FDA and on to the market--possibly granting an accelerated approval ahead of a traditional pivotal study. In practice, there's still not much of a track record to demonstrate exactly what kind of advantage, if any, will be provided.

One thing, though, is certain. The roster of companies to win breakthrough status also includes Merck ($MRK), Novartis ($NVS), Johnson & Johnson ($JNJ), Vertex ($VRTX) and others--all well-established companies with a very long track record in R&D. So far, no small biotechs have made it to the list, indicating that at least initially regulators are staying in their comfort zone when it comes to who they want to work with.

The breakthrough designation also reflects a certain kind of vindication for BMS, which saw its newly acquired hep C drug 094 blow up in the clinic, killing one patient and injuring others. The company is behind Gilead ($GILD) and AbbVie ($ABBV) in this race--but it is gaining ground.

BMS has also achieved a fast-track designation for nivolumab, its PD-1 cancer drug in late-stage development. That therapy remains the company's most exciting therapy in late-stage development, according to a number of analysts who track Bristol-Myers.

- here's the release on the Q1 numbers

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SCYNEXIS Presents SCY-635 Data on HCV at International Liver Congress

April 25, 2013 11:11 AM Eastern Daylight Time

-- SCY-635 Shows Potential to Augment Current Treatments --

AMSTERDAM--(BUSINESS WIRE)--Drug discovery and development company SCYNEXIS, Inc. presented 2 studies indicating that oral treatment SCY-635 induces the production of interferon in HCV infected patients at the 48^th annual meeting of the European Association for the Study of the Liver.

In an oral presentation, Dr. Koichi Watashi, Department of Virology II, National Institute of Infectious Diseases, Japan, reported results of the study, Potentiate Interferon Signaling Through Diminished PKR Phosphorylation in HCV-Infected Cells, at the Translational Research in HCV session on Thursday, April 25 from 4 to 6 p.m.

The study examined the effect of cyclophilin inhibitors on the interferon (IFN) signaling pathway using an HCV-infected cell culture system. Results of this study suggest that cyclophilin inhibitors release the negative regulation of interferon stimulated genes (ISG) and allow their translation in HCV-infected cells. This mechanism contributes to the anti-HCV activity of cyclophilin inhibitors, in addition to the direct suppression of HCV replication.

The poster presentation, entitled The Cyclophilin Inhibitor SCY-635 Restores the Innate Recognition of HCV by Peripheral Blood Mononuclear Cells (PBMC) from HCV-Infected Subjects, was presented by Peter Probst, SCYNEXIS, in the session on Hepatitis research and will be displayed from 9 a.m. to 5 p.m on Saturday, April 27.

The study evaluated the ability of SCY-635 to modulate the innate immune response to HCV of peripheral blood mononuclear cells (PBMC) from study subjects with HCV. The data suggest that SCY-635 induces production of interferon by PBMC in a portion of HCV study subjects but has no stimulatory effect on PBMC from healthy controls. It also suggests that SCY-635 may induce and maintain an adaptive anti-HCV immune response by inhibiting the HCV-induced impairment of dendritic cells.

The full abstract for the oral presentation can be found here and the abstract for the poster presentation can be viewed here.

About HCV and Therapeutic Need

The World Health Organization estimates that about 3% of the world’s population is infected with HCV and that there are more than 170 million chronic carriers who are at risk of developing liver cirrhosis and/or liver cancer. While the majority of antiviral research remains focused on viral targets such as protease and polymerase enzymes, therapies such as SCY-635 that are based on immunomodulation to counteract viral immune evasion could be of great therapeutic value.

About SCY-635

SCY-635 is a novel oral cyclophilin inhibitor in Phase 2 studies for the treatment of Hepatitis C (HCV) and in preclinical studies for the treatment of Hepatitis B (HBV). Studies to date have demonstrated that SCY-635 is unique in that it plays a dual role as a synergistic Direct Acting Antiviral (DAA) and a stimulator of the host immune system (Immune Acting Antiviral or IAA). The addition of SCY-635 to the repertoire of currently approved HCV therapies could breathe new life into the future of the immunotherapeutic options for treating HCV.

About SCYNEXIS

SCYNEXIS delivers innovative solutions to solve the toughest problems in drug discovery and development for our pharmaceutical, global health, animal health and life science partners. Our contract research services include Integrated Pharmaceutical Solutions, Discovery Research and Integrated Parasitology. We have successfully delivered preclinical and clinical drug candidates to our customers across all major therapeutic indications and have developed our own proprietary cyclophilin inhibitor programs for the treatment of a broad range of diseases, including HCV, HBV and inflammation. Founded in 2000, SCYNEXIS is located in Research Triangle Park, North Carolina. Visit www.scynexis.com.

Contacts

SCYNEXIS Media Contacts:
SCYNEXIS
Alissa Maupin, + 1-919-206-7246
Alissa.Maupin@scynexis.com
or
Media Contact:
MacDougall Biomedical Communications
Cory Tromblee, +1 781-235-3060
ctromblee@macbiocom.com

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Sofosbuvir: the final nail in the coffin for hepatitis C? Commentary

Download the PDF here

The Lancet Infectious Diseases May 2013

Michael P Manns a, Markus Cornberg a

In The Lancet Infectious Diseases, Eric Lawitz and colleagues1 report results from their randomised phase 2 trial, in which they showed a more than 90% cure rate of hepatitis C in patients given a combination of pegylated interferon alfa-2a (peginterferon), ribavirin, and sofosbuvir, a novel nucleoside inhibitor of the hepatitis C virus (HCV) NS5B polymerase. Among the 60 or so drugs under development for HCV, nucleoside inhibitors seem to be the most promising of the three classes of direct-acting antivirals currently in phase 3 trials (figure): NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors, which can be subdivided into nucleoside inhibitors or non-nucleoside inhibitors. Nucleoside inhibitors, namely sofosbuvir, seem to be best in terms of resistance profile, activity against all virus genotypes, adverse events, and antiviral potency. And as such, the emergence of sofosbuvir is an important milestone in the fight against hepatitis C.

The first such milestone was the approval of interferon alfa in the early 1990s.2 The addition of ribavirin to interferon alfa in 1998 doubled response rates;3 and once weekly peginterferon was introduced in combination with ribavirin in 2001.4 In 2003, the protease inhibitor BILN 2061 (Boehringer Ingelheim, Ingelheim, Germany) provided the first proof of concept for direct-acting antivirals against HCV.5 8 years later, the protease inhibitors boceprevir and telaprevir were approved for treatment of HCV genotype-1.6, 7 Boceprevir and telaprevir improved sustained viral response rates (SVR) from about 40-44% to 68-75% in treatment-naive patients with genotype-1.6, 7

SVR means patients are cured and has been associated with prevention of hepatocellular carcinoma and even improvements in overall mortality.8 However, these protease inhibitors have several limitations: activity against genotype-1 only, dosing every 8 h, and many potentially serious drug interactions. Both protease inhibitors have to be given in combination with peginterferon plus ribavirin because monotherapy results in rapid emergence of drug-resistant variants, which explains why previous null-responders to peginterferon plus ribavirin had SVRs of only 30-40% when given triple therapy with peginterferon, ribavirin, and a NS3/4A protease inhibitor.9 Boceprevir and telaprevir add to the adverse event profile of peginterferon plus ribavirin, especially in patients with cirrhosis-namely, a doubling of anaemia.10, 11

A need for new drugs clearly exists. Ideally, novel direct-acting antivirals should fulfil the following requirements: oral administration once daily, few side-effects and drug interactions, short treatment duration, high barrier to resistance, and effectiveness against all major HCV genotypes. New drugs should also help in the development of an oral interferon-sparing regimen.12

Lawitz and colleagues' trial forms the basis for the phase 3 testing of sofosbuvir. The investigators not only showed high SVR with sofosbuvir but also the activity against HCV genotypes 1-3. No drug-resistant variants were seen with 400 mg daily sofosbuvir, and only two patients had viral relapse.1 Therefore, a daily dose of 400 mg sofosbuvir was chosen as the dose for further trials, including phase 3 trials. Sofosbuvir was safe and did not add notably to the adverse event profile of peginterferon and ribavirin. Limitations of the study were that only treatment-naive, non-cirrhotic patients were included.

Lawitz and colleagues showed that response-guided treatment for 24-48 weeks is not necessary,1 and the findings of another phase 2 study (the ATOMIC study) suggested that a treatment duration of 12 weeks' sofosbuvir in combination with peginterferon plus ribavirin is sufficient, irrespective of baseline factors such as patients' IL28B status or viral load.13 The ATOMIC trial enrolled more than 300 treatment-naive, non-cirrhotic patients with genotypes 1, 4, or 6, showing 87-89% SVR after 12 weeks or 24 weeks of sofosbuvir in combination with peginterferon plus ribavirin. Additionally, sofosbuvir has already been shown to be highly effective in protocols that do not include interferon alfa.14 12 weeks of sofosbuvir plus ribavirin resulted in 84-100% SVR in treatment-naive patients with HCV genotypes 1-3.14 However, nine of ten patients with genotype-1 who had previously not responded to peginterferon plus ribavirin had a relapse without detection of drug-resistant variants. Thus, sofosbuvir plus ribavirin might be sufficient for easy-to-treat patients but more difficult-to-treat patients might need sofosbuvir in combination with peginterferon plus ribavirin or other direct-acting antivirals. In another trial,15 sofosbuvir together with the experimental NS5A inhibitor daclatasvir (Bristol-Myers Squibb, NY, USA) showed excellent (>90%) SVR in patients with HCV genotypes 1-3.15 Sofosbuvir is now being further developed in combination with ledipasvir (formerly known as GS-5885), Gilead Science's own NS5A inhibitor-both drugs are designed as a fixed-dose combination in one tablet. Thus, sofosbuvir seems to fulfil all the aforementioned requirements for new direct-acting antivirals. The key question is, therefore, does one pill fit all?

Certainly there are some important questions to be answered before we can call sofosbuvir the final nail in the coffin for hepatitis C. How effective and safe is the drug in patients with advanced liver disease, including those with decompensated cirrhosis? Does it prevent and treat HCV recurrence after liver transplantation? How effective is it in the treatment of difficult-to-treat HCV genotypes such as genotype 3?

In February this year, Gilead Sciences announced that patients with HCV genotype-3 are more difficult to treat than previously thought.16 However, these data give hope for patients with chronic HCV infection, and, barring any unforeseen surprises, sofosbuvir should be approved by early 2014.

MPM has received financial compensation for consultancy or lecture activities from Achillion, Idenix, Vertex, Roche, Bristol-Myers Squibb, Gilead Sciences, Boehringer Ingelheim, Novartis, Merck, Janssen Pharmaceuticals, and GlaxoSmithKline, and research grants from Roche, Gilead Sciences, Novartis, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, and Janssen Pharmaceuticals. MC has received financial compensation for consultancy or lecture activities from Roche, Bristol-Myers Squibb, Gilead Sciences, Novartis, Merck, and Janssen Pharmaceuticals, and research grants from Roche, Gilead Sciences, and Merck.

GILEAD'S SOFOSBUVIR FOR HEPATITIS C MEETS PRIMARY ENDPOINT IN FOURTH PIVOTAL PHASE 3 STUDY
http://www.natap.org/2013/HCV/022013_07.htm

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