Friday, February 10, 2012

HCV Friday Round Up:When Will We Have Interferon-Free Treatment for Hepatitis C?

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In The News

From Medscape Gastroenterology > Ask the Experts

When Will We Have Interferon-Free Treatment for Hepatitis C?
William F. Balistreri, MD
Posted: 02/09/2012

Is it true that we are close to treatment of patients with chronic hepatitis C virus (HCV) infection with an interferon-free regimen?

Response from William F. Balistreri, MD

Professor of Medicine, University of Cincinnati College of Medicine; Staff Physician, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 

A New Era of Therapy
Combination therapy with pegylated interferon (PEG-IFN) and ribavirin long stood as the standard of care for chronic hepatitis C virus (HCV) infection. Although effective in achieving high rates of sustained virologic response (SVR), this combination regimen was associated with troublesome side effects.[1] Therefore, the development of 2 effective protease inhibitors -- telaprevir and boceprevir -- was hailed as a new era of therapy for patients with HCV genotype 1 infection.[2] These direct-acting antiviral agents act at specific steps in the viral lifecycle and allow more effective treatment with a shorter duration.

Telaprevir and boceprevir, linear inhibitors of the HCV nonstructural protein 3/4A (NS3/4A) serine protease, were approved by the US Food and Drug Administration for HCV treatment in May 2011. However, the recent American Association for the Study of Liver Diseases (AASLD) recommendations indicate that these direct-acting antiviral agents must be used in combination with PEG-IFN and ribavirin.[1] This is far from the ideal regimen; because of poor tolerability, many treatment candidates will decide not to pursue treatment or to defer treatment until an IFN-free regimen is available. 

An Ideal Strategy for HCV
It is true that an IFN-free regimen is "no longer a dream."[3] It is now viewed as part of a larger goal: the development and validation of an ideal strategy to treat HCV infection. The long sought-after therapeutic objective is to define a strategy that would be highly effective against allHCV genotypes, simple (oral drugs only, low pill burden, and short duration), and safe and tolerable, with low rates of resistance emergence. The recommended strategy would also assess each potential treatment candidate for interleukin 28B genotype, which is a robust pretreatment predictor of SVR to therapy in patients with genotype 1 chronic HCV infection.[1]

How close are we? Various compounds, encompassing at least 5 distinct drug classes, are currently under development for the treatment of chronic HCV infection, and the results of trials of several investigational agents were recently published.[3-5] Many other drug trials were presented at The Liver Meeting 2011: The AASLD 62nd Annual Meeting. These drugs bring us one step closer to the long sought-after ideal: the ability to delete noisome IFN injections from treatment strategies. 

Promising Preliminary Results
Let me illustrate by focusing on phase 2 studies presented by 2 groups who reported exciting preliminary results of an investigational agent (PSI-7977) even in the absence of IFN coadministration.[6,7] PSI-7977, a uridine nucleotide analog polymerase inhibitor, is administered orally once daily and has strong antiviral activity against HCV genotype 1 when used in combination with PEG-IFN and ribavirin. A double-blind placebo-controlled dose-ranging study of PSI-7977 in patients with HCV genotype 1 documented a rapid virologic response (RVR) in 98% of patients, with an end-of-treatment response at 24 weeks in 91%.[6] The RVR in the placebo group was 19%, and the end-of-treatment response was 50%. Of specific note, all patients with the difficult-to-treat interleukin 28B single-nucleotide polymorphism T/T mutation had an RVR -- all became HCV-negative by week 3, and 100% went on to achieve an SVR.

In another phase 2 study, this investigational compound allowed all patients to achieve an RVR. More than 80% of the treatment group had nondetectable HCV RNA at 2 weeks, and all patients had undetectable levels at 3 weeks.[7] All patients achieved normalization of serum alanine aminotransferase levels. No serious adverse events were attributable to PSI-7977, and as expected, safety and tolerability were greatest in the IFN-free treatment group.

Thus, PSI-7977 exhibits high-potency antiviral activity against a broad range of HCV genotypes, has a high barrier to resistance, and has a reassuring safety profile. This drug also allowed a shorter duration of therapy for viral clearance. These studies support the continued exploration of this drug and related compounds -- alone, with other direct-acting antiviral agents, or with shorter duration of IFN therapy in patients with all HCV genotypes. Further studies will hopefully confirm the initial excitement and optimism and, of note, will document the spectrum of potential adverse effects. 

Getting to IFN-Free Regimens
Within the next 5 years, IFN-free regimens may be a reality and available in the clinic. As Sharma and Lok[3] stated, "[I]t is possible that some of these regimens will also be ribavirin free. This will be good news for patients who wish to be treated but have to defer treatment because of contraindications to use of PEG-IFN or ribavirin, or out of concerns about their ability to tolerate these medications." The ideal strategy is on the horizon.

  1. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:1433-1444. Abstract
  2. Jensen DM. A new era of hepatitis C therapy begins. N Engl J Med. 2011;364:1272-1274. Abstract
  3. Sharma P, Lok AS. Interferon-free treatment regimens for hepatitis C: are we there yet? Gastroenterology. 2011;141:1963-1967.
  4. Gane EJ, Roberts SK, Stedman CA, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2010;376:1467-1475. Abstract
  5. Zuezem S, Asselah T, Angus P, et al. Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection. Gastroenterology. 2011;141:2047-2055. Abstract
  6. Lawitz E, Lalezar JP, Hassanein T, et al. Once-daily PSI-7977 plus PEG/RBV in treatment-naive patients with HCV GT1: robust end of treatment response rates are sustained post-treatment. Program and abstracts of The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting; November 9-13, 2011; Boston, Massachusetts. Abstract 225.
  7. Gane EJ, Stedman CA, Hyland RH, et al. Once daily PSI-7977 plus RBV: pegylated interferon-alfa not required for complete rapid viral response in treatment-naive patients with HCV GT2 or GT3. Program and abstracts of The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting; November 9-13, 2011; Boston, Massachusetts. Abstract 34. 

Chronic Liver Disease Foundation Issues Statement in Support of Birth-Cohort Screening for Hepatitis C
Recommendations Include Expanded Testing with Rapid Point-of-Care HCV TestCLARK, N.J., Feb. 9, 2012 (GLOBE NEWSWIRE) -- The Chronic Liver Disease Foundation (CLDF), a leading educational organization dedicated to increasing awareness of the effect of chronic liver disease (CLD) in the United States, issued today a position paper in support of expanding screening for hepatitis C (HCV) in the United States.

The position paper, "Endorsement of Birth-Cohort Approach to Expand Screening for Hepatitis C," outlines the CLDF's recommendations for a more effective strategy to identify patients with HCV infection and link such patients to expert care and treatment.
HCV is the most common blood-borne chronic viral infection in the U.S., with more than four million Americans currently infected with the HCV virus. Of these, up to 75 percent are unaware of their infection. Individuals born between the years of 1945 and 1965 have an HCV prevalence level four times higher than those born outside the birth cohort.

While the CDC currently recommends HCV screening only for individuals found to be at risk for the HCV infection, it is currently evaluating the potential benefits of using a birth-cohort based approach to HCV screening to help increase identification of HCV-positive patients.
The CLDF issued the following recommendations in support of the expansion of HCV screening efforts:
  • Routine screening for HCV among persons born between 1945 and 1965
  • Use of the OraQuick HCV rapid point-of-care test to expand testing opportunities and facilitate immediate care
  • Educational programs aimed at primary care providers to increase awareness of HCV risk factors
  • Testing for HCV in primary care setting with established linkages to HCV
  • Creative ways to increase access to HCV testing and care for injection-drug users and other underserved populations.
"Today, more than 4 million Americans are infected with hepatitis C and the vast majority does not know it," said Dr. Willis C. Maddrey, President of the Chronic Liver Disease Foundation. "Hepatitis C is a leading cause of chronic liver disease, cirrhosis and liver cancer. However, new therapies are now available that can effectively treat a high percentage of people with HCV infection, making expanded and accessible testing for HCV – particularly among those born between 1945 and 1965 – a critical step in fighting this epidemic."

About the Chronic Liver Disease Foundation
Established in 2001, the Chronic Liver Disease Foundation is a nonprofit 501(c)(3) educational organization dedicated to providing hepatology related continuing medical education, news and information to healthcare professionals across the US. The CLDF is led by a Board of Trustees comprised of nationally renowned liver disease specialists. Furthermore, the CLDF believes that educational programs should be developed by the specialists who are actively involved in the research, treatment and management of a disease. As such, the CLDF has developed a network of 75 Centers of Educational Expertise and multiple Advisory Boards who are actively involved in program creation related to specific disease topics which include: hemochromatosis, hepatic encephalopathy, hepatitis B, hepatitis C, hepatocellular carcinoma, HIV co-infection, liver transplantation and NASH/NAFLD. The CLDF's educational opportunities are offered in a variety of formats including an interactive web site, live meetings, teleconferences, print pieces, webcasts and other electronic mediums.  For more information, please visit


GI & Hepatology News is the official newspaper of the AGA Institute and provides the gastroenterologist with timely and relevant news and commentary about clinical developments and about the impact of health-care policy. The newspaper is led by an internationally renowned board of editors.GI & Hepatology News is published monthly

Big Pharma

BOSTON (MarketWatch) — 
That’s a nagging question for investors, who have watched Vertex’s once-bright star fade as the shares of rival hepatitis C-drug developers supernovae. But Vertex shares could get a good stoking by mid-year, when the results of three key drug studies are due out.
Vertex’s stock had a banner 2011, its shares propelled to new heights by enthusiasm for its drug Incivek, a treatment for the hepatitis C virus, or HCV, a potentially deadly disease that attacks the liver. The drug belongs to a class of medications known as protease inhibitors that also includes Merck & Co.’ss new HCV drug Victrelis. 

In recent months, however, investor faith in Incivek’s long-term marketability has been deeply shaken by positive news about rival HCV drugs in development, particularly those in a class of drugs known as nucleotides, or “nukes.” 

As a result, shares of Vertex swung from a 52-week peak of $58.87 in mid-May 2011, to a low of $26.50 by late November, when Gilead Sciences Inc. announced it was buying nuke-drug developer Pharmasset Inc. for $11 billion, a move that further underscored the perceived value of nuke drugs. 

Over the past couple of months, the stock has managed to climb back into the upper $30s, due largely to anticipation ahead of the expected approval of the company’s drug Kalydeco. A novel treatment for the genetic disease cystic fibrosis, or CF, Kalydeco won approval earlier this month.
What’s still haunting the stock, say analysts, is concern about how well Incivek sales will hold up when the first nuke drugs hit the market and how well Vertex will be able to build-out its HCV and CF franchises. 

With key clinical data for both drug programs looming on the horizon, many analysts have taken a wait-and-see approach to the stock. According to FactSet, the average analyst rating currently for Vertex is overweight, with a price target of just over $46 a share.
Two upcoming events, however, could give the shares a needed jolt. 

The first is the expected release of early clinical data for two HCV nuke drugs that Vertex is co-developing with Alios BioPharma. The data is expected in the second quarter.
“Vertex’s HCV franchise is quickly becoming obsolete; to stay in the race, Vertex has to develop all oral, pan-genotypic combinations as quickly as possible, and the Alios nukes are the key to such hope,” wrote William Blair analyst Katherine Xu in a recent note, about the significance of the data.
Xu recently lowered her price target for Vertex to $44 from $45, citing slower than expected sales of Incivek, but maintained her buy rating on the stock. 

The second set of data, which involves the company’s CF drugs, could be the real market mover, however.
“Positive results in CF could get the stock moving again,” said Needham & Co. analyst Alan Carr, who also has a hold rating on the stock. 

The CF data will be from a Phase II trial that is testing Kalydeco, which is only approved for use in about CF patients with a rare gene mutation called G551D, or about 4% of CF patients, with another experimental CF drug dubbed VX-809. 

Vertex is banking that the Kalydeco/VX-809 combo can successfully treat patients with the F508del gene mutation, which is carried by up to 90% of all CF patients. The data is expected mid-year.
Kalydeco, by the way, isn’t cheap. At nearly $300,000 a year, it ranks as one of the most expensive drugs on the market. It’s high price is due in part to its regulatory status as an “ultra-orphan” drug. The regulatory designation is designed to encourage the development of drugs for life-threatening and extremely rare conditions by offering certain financial incentives, such as market exclusivity.
Carr said that even with its current narrow prescribing indication, Kalydeco could reach peak sales of $1 billion a year. Even if Vertex were forced to lower the price of the product, which would like happen if it were approved for a much larger patient population, sales could still be in the billions.
“According to our probability-adjusted net present value model, for every 10% increase in the probability of success for the combo, Vertex’s stock will have $4-$5 per share in upside, representing a powerful lever,” wrote Xu, of the CF drugs. 

“We believe there is a good chance for the Phase II combo data to be successful, which may compensate for the decline of the HCV franchise and lead to the next leg of growth for Vertex,” Xu added. 

That said, the Kalydeco data may also prove to be a bust. Data from an earlier segment of the Phase II trial showed the combination to be only modestly effective. Vertex is hoping that data from a second segment of the trial, which is administering VX-809 in higher doses over a longer period of time, yields more impressive results.
“People are getting pretty excited, but I’m just not there yet,” said JMP Securities analyst Liisa Bayko in a recent interview. Bayko currently has a hold rating on the stock.

FDA sets draft rules for biotech drug copies
Thu Feb 9, 2012 4:46pm EST
By Deena Beasley
(Reuters) - The Food and Drug Administration's long-awaited guidelines for the sale of lower-cost versions of biotechnology drugs leave open the possibility that some products might not need to be tested in humans.

(China Daily, February 3, 2012)
"Analysis by Medicins sans Frontieres, an international health organization, suggests India now makes one-fifth of the world's generic drugs, with about 50 percent shipped abroad and sold (often illegally) at a fraction of the cost…To tackle the problem of illegally imported drugs, the State Council last year launched a special health campaign. 'It mainly aimed at Internet scams in which profiteers promoted and sold fake drugs or those sourced through illegal channels,' said Bian Zhenjia, deputy director of the State Food and Drug Administration, who added that medication designed for long-term use, such as treatments for impotence, diabetes, hypertension and cancer, are major targets for criminals…Jia Ping [a Beijing lawyer who specializes in public health cases] said he fears that the drugs market is not currently a priority for authorities in China…Although there is no legal barrier to such a system in China, 'no domestic pharmaceutical company has so far applied for compulsory licensing of a foreign patent drug,' he said, adding that Chinese manufacturers had a 'relatively poor understanding about World Trade Organization treaties and public health.'"

Healthy You

Fallout From Fatigue Syndrome Retraction Is Wide
(The New York Times, February 6, 2012) 
"When scientists reported in 2009 that a little-known mouse retrovirus was present in a large number of people with chronic fatigue syndrome, suggesting a possible cause of the condition, the news made international headlines. For patients desperate for answers, many of them severely disabled for years, the finding…seemed a godsend…In hopes of treating their condition, some patients even began taking antiretroviral drugs used to treat H.I.V., a retrovirus related to the murine leukemia viruses suddenly suspected of involvement in chronic fatigue syndrome. More recently, however, the hopes of these patients have suffered an extraordinary battering. In a scientific reversal as dramatic and strange as any in recent memory, the finding has been officially discredited; a string of subsequent studies failed to confirm it, and most scientists have attributed the initial results to laboratory contamination. In late December, the original paper, published in the journal Science, and one other study that appeared to support it were retracted within days of each other. As the published evidence for the hypothesis fell apart, a legal melodrama erupted, dismaying and demoralizing patients and many members of the scientific community."

Diet & Chronic Disease Prevention
(The Washington Post, February 8, 2012)"The amount of trans fat in the American bloodstream fell by more than half after the Food and Drug Administration [FDA] required food manufacturers to label how much of the unhealthful ingredient is in their products, according to a new study. Blood levels of trans fat declined 58 percent from 2000 to 2008. FDA began requiring trans-fat labeling in 2003. During the same period several parts of the country -- New York most famously -- passed laws limiting trans fats in restaurant food and cooking. The makers of processed food also voluntarily replaced trans fats with less harmful oils. The decline, unusually big and abrupt, strongly suggests government regulation was effective in altering a risk factor for heart disease for a broad swath of the population. Researchers at the Centers for Disease Control and Prevention discovered the decline by analyzing blood drawn as part of the National Health and Nutrition Examination Survey, which interviews and examines a sample of Americans at least once a decade. The trend was seen in white adults; researchers are looking to see if it occurred in other ethnic and racial groups, too. Trans fats, which are used for deep-frying and as an ingredient in baked goods and spreads, increase the risk of heart disease.

Processed Foods

Here’s an interesting video from Stefani Bardin, a TEDxManhattan 2011 fellow, and Braden Kuo, MD, a gastroenterology instructor at Harvard. According to their description, the video uses “the M2A and SmartPill devices to look at how the human body responds to processed versus whole foods.” While I’m by no means an expert on this subject, the video makes for some interesting watching.
Via Devour


(The Economist, London, February 4, 2012)
"More than 2,700 researchers from around the world have so far signed an online pledge…promising not to submit their work to Elsevier’s journals, or to referee or edit papers appearing in…[they agree with Cambridge University mathematician Timothy Gowers] First, that Elsevier charges too much for its products. Second, that its practice of 'bundling' journals forces libraries which wish to subscribe to a particular publication to buy it as part of a set that includes several others they may not want. And third, that it supports legislation…that would forbid the government requiring that free access be given to taxpayer-funded research. Elsevier insists it is being misrepresented…[the] petition, though, is symptomatic of a wider conflict between academics and their publishers -- a conflict that is being thrown into sharp relief by the rise of online publishing…This situation has been simmering for years…And there have indeed been attempts to create alternatives to commercial publishing…But despite the enthusiasm…there are reasons for the continued dominance of traditional publishers…Commercial publishers have begun to experiment with open-access ideas, such as charging authors for publication rather than readers for reading. But...things could become more urgent. After all, publishers need academics more than academics need publishers."

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