EASL: Interim Phase 2 Data Showed Rapid Viral Response to VX-222 in Combination with Telaprevir, Pegylated-Interferon and Ribavirin Among People With Hepatitis C

First study to evaluate four-drug, 12-week treatment duration for hepatitis C

BERLIN--(press release March 31 2011) Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced interim results from an ongoing Phase 2 study (ZENITH) designed to assess the safety and tolerability of 12-week response-guided treatment regimens with its polymerase inhibitor, VX-222, and its protease inhibitor, telaprevir, in combination with pegylated-interferon and ribavirin in people with genotype 1 chronic hepatitis C who were new to treatment. The study enrolled 106 people into one of four treatment groups. Among those who received VX-222 (400 mg) in combination with telaprevir, pegylated-interferon and ribavirin, interim data showed that 90 percent (27/30) of them had undetectable hepatitis C virus at week 12. Half (15/30) of those in the VX-222 (400 mg) treatment group were eligible to stop all treatment at week 12. People in this same treatment group who were not eligible to stop all treatment at 12 weeks were assigned to receive 24 total weeks of treatment: 12 weeks of the four-drug regimen followed by 12 weeks of pegylated-interferon and ribavirin alone. Preliminary safety results showed that the most frequently reported adverse events were mild gastrointestinal symptoms and mild fatigue. At the time of this analysis, there were no discontinuations due to gastrointestinal symptoms. Data from this study are being presented today at The International Liver Congress 2011, the 46th annual meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany.

"Telaprevir triple therapy demonstrated significant improvements in viral cure rates and an ability to halve treatment time to 24 weeks for many people in late-stage studies," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. "Reducing treatment time in half again to 12 weeks would be another important advance and the early data from this study provide new information about the potential to do this with a four-drug VX-222 regimen."

Using an intent-to-treat analysis, 57 percent (17/30) of people treated with VX-222 (400 mg) in combination with telaprevir, pegylated-interferon and ribavirin had undetectable hepatitis C virus by week two. Among people who were treated with VX-222 (100 mg) in combination with telaprevir, pegylated-interferon and ribavirin, 38 percent (11/29) had undetectable hepatitis C virus by week two. To determine if patients were eligible to stop all treatment at 12 weeks in ZENITH, they had to have undetectable hepatitis C virus at weeks two and eight. Using the eligibility criteria for a 12-week total treatment duration, half (15/30) of the patients in the high-dose VX-222 combination group and 38 percent (11/29) in the low-dose combination group were eligible to stop all treatment at 12 weeks. Ninety percent (27/30) of patients in the high-dose VX-222 group had undetectable hepatitis C virus by week 12 as did 83 percent (24/29) in the low-dose VX-222 group. No viral breakthrough was observed through week 12 among patients receiving the four-drug combinations.

"The early data from this study are encouraging because they showed patients had a very rapid decline in hepatitis C virus as early as the second week of treatment," said Adrian Di Bisceglie, M.D., Chief of Hepatology at Saint Louis University School of Medicine. "Hepatitis C virus was undetectable at week 12 of treatment in 90 percent of patients who received the higher dose of VX-222, and half of those in this treatment group were eligible to stop all treatment at that time."

ZENITH is an ongoing Phase 2 study that enrolled 106 people and began with four treatment arms evaluating two-drug and four-drug combination regimens. The primary endpoint is safety and tolerability and the secondary endpoint is on-treatment antiviral activity and the proportion of people in each treatment arm who achieve a sustained viral response (SVR, defined as undetectable hepatitis C virus 24 weeks after the end of treatment). The study is designed to evaluate various combinations of VX-222, telaprevir, pegylated-interferon and ribavirin for the treatment of genotype 1 chronic hepatitis C. In this study, VX-222, telaprevir and ribavirin are given twice daily. Arms A (n=18) and B (n=29) were designed to evaluate the all-oral, two-drug combination regimens of VX-222 (400 mg or 100 mg) and telaprevir (1,125 mg). Both of these study arms were discontinued due to a pre-defined stopping rule related to viral breakthrough. Arms C (n=29) and D (n=30) are ongoing and designed to evaluate the four-drug combination regimens of VX-222 (400 mg and 100 mg), telaprevir (1,125 mg), pegylated-interferon and ribavirin. An additional treatment arm has been added to the study to evaluate an all-oral, three-drug regimen of VX-222, telaprevir and ribavirin in people with genotype 1b chronic hepatitis C. This study arm is now open for enrollment. A sixth and final arm may be added to the trial per protocol based on data from the study.

HCV RNA was evaluated using the TaqMan assay version 2.0.

*As part of a response-guided regimen, people who have undetectable hepatitis C virus at weeks 2 and 8 are eligible to stop all treatment at week 12.

+ VX-222 (100 mg, BID), telaprevir (1,125 mg, BID), Pegasys(R) (pegylated-interferon alfa-2a) and Copegus(R) (ribavirin).

++ VX-222 (400 mg, BID), telaprevir (1,125 mg, BID), Pegasys(R) (pegylated-interferon alfa-2a) and Copegus(R) (ribavirin).

--------------------------------------

Preliminary Safety and Tolerability

The 12-week safety and tolerability results are preliminary and include data on all patients enrolled in the study: those enrolled in the two-drug (n=47) and four-drug (n=59) treatment arms. The most frequent adverse events observed in this study were mild gastrointestinal symptoms (including diarrhea, nausea and vomiting) and mild fatigue. No patients discontinued due to gastrointestinal symptoms.

Preliminary safety data indicate that there were six discontinuations due to adverse events among the four treatment arms through week 12. There were two serious adverse events considered by the investigator to be potentially related to study medication: acute renal failure (Arm B), which resolved after study medications were discontinued and anemia (Arm C). There was one additional severe adverse event reported of pneumonia, septic shock and renal failure; this severe adverse event was considered by the investigator to be unrelated to study medication. The three additional discontinuations included rash (n=2) and a motor vehicle accident with facial fractures (n=1).

About Telaprevir and VX-222

Vertex has two oral medicines in development for the treatment of genotype 1 chronic hepatitis C: telaprevir and VX-222. Telaprevir is an investigational, oral inhibitor that acts directly on the HCV protease, an enzyme essential for viral replication. To date, more than 2,500 people with genotype 1 chronic hepatitis C have received telaprevir in Phase 2 and Phase 3 studies. Vertex has been granted Priority Review for its applications for the approval of telaprevir by the U.S. Food and Drug Administration (FDA) and Health Canada. The FDA has scheduled its Antiviral Drugs Advisory Committee to discuss the New Drug Application for telaprevir on April 28, 2011. A target response date of May 23, 2011 is set under the Prescription Drug User Fee Act (PDUFA).

Vertex is developing telaprevir in collaboration with Tibotec BVBA and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America. Through its affiliate, Janssen, Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.

VX-222 is an investigational, oral, non-nucleoside inhibitor of HCV NS5B polymerase. VX-222 is currently being evaluated in combination with telaprevir, pegylated-interferon and ribavirin in a Phase 2 study. Vertex has worldwide commercial rights for VX-222.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.1 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.1 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.1 Approximately 60 percent of people who undergo treatment of an initial 48-week regimen of pegylated-interferon and ribavirin, the currently approved medicines for genotype 1 hepatitis C, do not achieve SVR,2,3,4 or viral cure.5 If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.6,7

More than 170 million people worldwide are chronically infected with hepatitis C.5 In the United States, nearly 4 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.8 The majority of people with hepatitis C in the United States were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.9 Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 4,600 to 12,000 deaths annually.10,11 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.9

PEGASYS® and COPEGUS® are registered trademarks of Hoffmann-La Roche.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including statements regarding (i) the potential importance of reducing treatment time to 12 weeks and early data from this study providing new information about the potential to do this with a four-drug VX-222 regimen; (ii) the early data being encouraging because the data showed patients had a very rapid decline in hepatitis C virus as early as the second week of treatment; (iii) the possibility that a sixth treatment arm may be added to the trial; (iv) the date of the scheduled meeting of the FDA's Antiviral Advisory Committee and (v) the FDA's target response date for the telaprevir NDA. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that Vertex could experience unforeseen delays in obtaining approval to market telaprevir; that the interim on-treatment data presented in this press release may not be predictive of the final outcomes from this clinical trial, outcomes from any future clinical trials of telaprevir/VX-222 may not be favorable; that future scientific, clinical, competitive or other market factors may adversely affect the potential for telaprevir/VX-222-based therapy and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at http://www.vrtx.com/. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

About Vertex

Vertex creates new possibilities in medicine. Our team aims to discover, develop and commercialize innovative therapies so people with serious diseases can lead better lives.

Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, epilepsy and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada.

For more information and to view Vertex's press releases, please visit http://www.vrtx.com/.

(VRTX - GEN)

1 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed March 21, 2011.

2 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.

3 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

4 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.

5 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.

6 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).

7 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.

8 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed March 21, 2011.

9 Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. Available at: http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed March 21, 2011. This report was commissioned by Vertex Pharmaceuticals, Inc.

10 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.

11 Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.

Vertex Pharmaceuticals Incorporated

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Dawn Kalmar, 617-444-6992
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Zachry Barber, 617-444-6992

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EASL: OctoPlus' licensee Biolex presents final Phase IIb results at EASL highlighting tolerability advantages of Locteron in treatment of HCV

SOURCE: OctoPlus N.V.

Mar 31, 2011 03:22 ET

LEIDEN, NETHERLANDS--(Marketwire - March 31, 2011) -

Presentation highlights strong antiviral activity and SVR rates, significant reductions in flu-like adverse events and reduced rates of depression

Significant tolerability advantages and a 50% reduction in dosing frequency support Locteron's attractiveness for use in new triple- and quad- combination regimens

OctoPlus N.V. ("OctoPlus" or the "Company") (Euronext: OCTO) announces that its licensee Biolex Therapeutics will present today final results from the Locteron® Phase IIb clinical study at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. These data highlight important tolerability advantages of Locteron versus current HCV treatments. Jan Egberts, CEO of OctoPlus, comments: "These positive final results from the Phase IIb clinical study with Locteron further confirm the long term benefits of Locteron's controlled release mechanism. Our PolyActive technology has enabled the development of an interferon alpha with a significantly improved side effect profile, achieving both a 50% reduction in flu-like adverse events and substantially lower rates of depression compared to conventional interferon treatments. In combination with its reduced injection frequency, these benefits clearly position Locteron as the interferon of choice for future hepatitis C treatments." The following information was taken directly from Biolex' press release (see www.biolex.com).

Biolex announces that final 72-week results from its SELECT-2 Phase 2b trial of Locteron® for the treatment of hepatitis C are being presented today at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. Data presented today show that Locteron achieved the SELECT-2 study objectives by demonstrating viral kinetics and response rates that were comparable with or exceeded the PEG-Intron® control while also achieving a statistically significant reduction in flu-like adverse events, reduced rates of depression, lower use of concomitant medications and a reduced rate of discontinuation due to adverse events. Locteron, the only controlled- release interferon alpha, is designed to offer key tolerability and dosing advantages over currently marketed interferons and serve as a core component of new combination therapies as the treatment of hepatitis C evolves to triple- and quad-drug regimens.

Locteron dosing convenience and efficacy

Locteron is administered once every other week and requires half as many injections as the currently marketed interferons, each of which are injected once per week. In SELECT-2, the sustained virologic response rate (SVR) for each of the three Locteron doses studied was comparable with or exceeded the response rate for the PEG-Intron control as outlined in the table below. Click on the link below for the press release including tables.

Click here for the press release in PDF format: http://hugin.info/137076/R/1501932/437140.pdf

This announcement is distributed by Thomson Reuters on behalf of Thomson Reuters clients. The owner of this announcement warrants that:

(i) the releases contained herein are protected by copyright and other applicable laws; and

(ii) they are solely responsible for the content, accuracy and originality of the information contained therein.

Source: OctoPlus N.V. via Thomson Reuters ONE

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New Drugs for Hepatitis C on the Horizon

With the promise of two new drugs to fortify the current treatment protocol, doctors see promise of a better-tailored cocktail, similar to HIV treatments, to beat back this common and often debilitating infection

By Katherine Harmon
March 30, 2011

Some 3.2 million Americans have chronic hepatitis C, an infection that can linger in the body for years before producing symptoms. It can eventually lead to serious liver scarring and cancer. And most infections in the U.S. are the disease's particularly tough breed, known as genotype 1, which has a cure rate of less than 40 percent with the best current treatment.

Two new drugs for this type, however, are now racing toward approval by the U.S. Food and Drug Administration, which could come as soon as late May. Both compounds are protease inhibitors and are expected to hit the market at about the same time.

Hepatitis C is spread through contact with blood and occasionally other bodily fluids, and 65 to 70 percent of people infected with the disease are unaware that they have it, according to John Ward, director of the Division of Viral Hepatitis at the U.S. Centers for Disease Control and Prevention. In the U.S. about one in 30 baby boomers has hepatitis C, and one in four people with HIV has the infection, he noted at a 2010 talk. The disease is responsible for some $33.3 billion in medical costs each year.

"We've been waiting for these drugs for a long time," says Darryn Potosky, a hepatologist at the University of Maryland Medical Center, who often has to tell patients they face steep odds of beating the disease.

If the new drugs come to market, patients would take one or the other in addition to the current two-drug treatment regimen. "It seems hepatitis C therapy is moving in the direction of HIV therapy, with multiple drug cocktails," Potosky says. And with that come "hopes that we can tailor treatments to patients."

Two new studies of one of the drugs, boceprevir, will be published in the March 31 issue of the New England Journal of Medicine. Both phase III trials were funded by Schering-Plough (now part of Merck), which makes the drug. There have not yet been any studies comparing boceprevir and the other new protease inhibitor, telaprevir (made by Vertex), but given the drugs' similarity, experts say they both seem promising.

In the new boceprevir trials, adding the drug to the current standard treatment (of interferon and ribavirin) effectively doubled the percentage of patients who were able to suppress the virus—an effect called sustained viral response, which is a mark of being effectively "cured."

"Patients with hepatitis C genotype 1 infection can anticipate a significant therapeutic advance," says Donald Jensen, a professor of medicine at the University of Chicago Medical Center, who wrote an editorial on the new research for the same issue of NEJM. But because these new drugs will each need to be used in combination with the existing two-drug regimes, they "will be associated with more side effects and more complexity."

Long road to safety

Doctors have long hoped for a safe and effective drug to beat hepatitis C (HCV) genotype 1—which, among strains of the disease, is "the most common and the hardest to treat at the same time," Potosky says. Some 70 to 80 percent of people infected with hepatitis C in the U.S. have this type.

With excitement building for these new drugs to arrive in the market, those who have been working on the problem have not forgotten that getting to this point "has been painstakingly slow," says Stuart Gordon of Henry Ford Hospital in Detroit, who coauthored one of the new studies.

Just finding the right compounds was challenging, he notes. An early protease-inhibitor contender, made by Boehringer Ingelheim, was found to be too toxic, and "many of the HCV polymerase inhibitors had to stop their development because of unacceptable side effects," Gordon notes.

And because the new treatment regime must be shown to be better than the current standard of care, which is a 48-week course, "the sheer time involved in conducting these large trials" made for slow going. But a payoff might be near.

One new trial, of 1,097 patients with hepatitis C genotype 1 who had never been treated, found that after 24 or 44 weeks of adding boceprevir to their drug regimen some two-thirds of non-black patients showed they were effectively suppressing the virus. The drug combo was not as effective for black patients, who are less likely to have a gene alteration that is linked to responsiveness to one of the drugs. But adding boceprevir still boosted response rates in these patients from 23 percent to more than half in the 44-week treatment group.

In the other trial, 403 patients with the disease who had not responded to traditional treatment—either showing no improvement or relapsing—were studied. Adding boceprevir to the standard treatment for 32 or 44 weeks resulted in sustained viral response rates in 59 and 66 percent of patients, respectively, compared with 38 percent in the control group.

The studies were both somewhat unusual in that they started patients out with a month-long lead-in period in which patients received the two drugs already available—before boceprevir was introduced to some groups. This "allowed some prediction capability of both subsequent response as well as risk of developing resistant variants," Jensen explains.

Early studies showed that although a protease inhibitor given on its own was very effective initially, it often led to resistant strains of the virus in a matter of days, Gordon says. Even with interferon and ribavirin, resistance "remains a concern," he says. To keep it to a minimum, "clinicians must follow such patients very closely during therapy because if the viral level starts to rise after initially declining, then the protease inhibitor must be stopped to prevent the development of even more resistant strains."

Potosky notes that the extent of resistance will only become clear with time—and as more people take the new drugs. And just as they monitor HIV patients for telltale resistance patterns, doctors should be able to detect early signs of resistance in people being treated for hepatitis C as well.

Adding boceprevir also increased the amount of side effects patients experienced. More than 40 percent of subjects taking this third drug required treatment for anemia in one of the studies, and in the other, severe anemia led doctors to decrease dosage in some 20 percent of subjects. Even though some of these cases were serious, few patients dropped out of treatment.

With boceprevir and telaprevir likely in the home stretch to reach potentially millions of hepatitis C patients in the U.S., doctors and researchers are now turning their focus to the many challenges that remain.

Aside from keeping resistance low and dialing down side effects, the next steps are to try to simplify the treatment regimen. "Everyone wants to get rid of interferon and ribavirin because both have toxicity that make them often difficult to tolerate," Gordon notes. Interferon also currently is usually administered via injection, so moving to an all-oral, once-a-day dosing would make treatment better and more consistent.

Gordon also looks forward to finding ways to help special populations of patients, including those who have HIV, end-stage liver disease or renal disease, as well as children, "who are currently not eligible for our current therapies."

Source

Boceprevir for Previously Treated Chronic HCV Genotype 1 Infection

Bruce R. Bacon, M.D., Stuart C. Gordon, M.D., Eric Lawitz, M.D., Patrick Marcellin, M.D., John M. Vierling, M.D., Stefan Zeuzem, M.D., Fred Poordad, M.D., Zachary D. Goodman, M.D., Ph.D., Heather L. Sings, Ph.D., Navdeep Boparai, M.S., Margaret Burroughs, M.D., Clifford A. Brass, M.D., Ph.D., Janice K. Albrecht, Ph.D., and Rafael Esteban, M.D. for the HCV RESPOND-2 Investigators

N Engl J Med 2011; 364:1207-1217 March 31, 2011

Background

In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment.

Methods

To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks.

Results

A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log10 IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls.

Conclusions

The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.)

Results

Baseline Characteristics

A total of 640 patients were evaluated for enrollment in the study; 403 were enrolled and underwent randomization and treatment (Figure S1 in the Supplementary Appendix). The baseline demographic characteristics were balanced among the three treatment groups (Table 1Table 1Baseline Characteristics of the Patients, According to Treatment Group.), with the exception of high viral load (group 2 vs. group 1, P=0.04). The mean age was 52.7 years, 12% of patients were black, and the mean body weight was 84.9 kg. Approximately 88% of patients had a high viral load (an HCV RNA level >800,000 IU per milliliter) at baseline. The prevalence of infection with HCV genotypes 1a and 1b was similar (47% and 44%, respectively). A total of 19% of patients had a Metavir fibrosis score of 3 or 4. The majority of patients (64%) had had a relapse after previous HCV therapy.

Efficacy

In the primary-analysis population, rates of sustained virologic response were significantly higher among patients receiving boceprevir than among those treated with peginterferon-ribavirin alone (Figure 2Figure 2Patients with a Sustained Virologic Response, According to Treatment Group and Analysis.), with overall rates of sustained virologic response of 21%, 59%, and 66% in groups 1, 2, and 3, respectively (P<0.001). This increase seen with boceprevir was due largely to end-of-treatment rates of response (i.e., an undetectable HCV RNA level) that were greater in group 2 (70%) and group 3 (77%) than in group 1 (31%), as well as a decreased rate of relapse in group 2 (in 17 of 111 patients [15%]) and group 3 (in 14 of 121 patients [12%]) as compared with group 1 (in 8 of 25 patients [32%]). Viral breakthrough and incomplete virologic response were infrequent during the treatment period (with either occurring in 1 of 80 patients [1%] in group 1, in 9 of 162 patients [6%] in group 2, and in 7 of 161 patients [4%] in group 3).

The rates of sustained virologic response among patients with prior relapse were 29% in group 1, versus 69% and 75% in group 2 and group 3, respectively; among patients with prior nonresponse, the corresponding rates were 7% versus 40% and 52%. A total of 102 patients (15%, 28%, and 27% in groups 1, 2, and 3, respectively) had a poor response to interferon, defined as a decrease in the HCV RNA level of less than 1 log10 IU per milliliter after the 4-week lead-in period (Figure 2). In this subgroup, a sustained virologic response was achieved in none of the patients in group 1 and in 33% and 34% in groups 2 and 3, respectively. Among patients who had a good response to interferon (a decrease in HCV RNA level of 1 log10 IU per milliliter or more at treatment week 4), the rates of sustained virologic response were 25%, 73%, and 79% in group 1, group 2, and group 3, respectively.

An assessment for amino acid variants associated with reduced susceptibility to boceprevir was performed for 114 patients in group 2 or group 3 in whom a sustained virologic response did not occur. Postbaseline data were available for 98 of the 114 patients (86%), with variants detected in 43 of these 98 patients (44%). The rate of amino acid variants associated with reduced susceptibility to boceprevir was higher among patients with a poor response to interferon (13 of 46 [28%] in group 2 and 15 of 44 [34%] in group 3) than among patients with a good response to interferon (10 of 110 [9%] in group 2 and 7 of 112 [6%] in group 3).

In group 2, the duration of total therapy was based on a prespecified decision at treatment week 8, at which time patients with an undetectable HCV RNA level were eligible for a shorter period of therapy. The proportion of patients with an undetectable HCV RNA level at week 8 in the boceprevir groups (74 of 162 patients [46%] in group 2 and 84 of 161 patients [52%] in group 3) was approximately six times the proportion in group 1 (7 of 80 [9%]). Early response (i.e., an undetectable HCV RNA level at week 8) was associated with high rate of sustained virologic response in all three groups (7 of 7 patients [100%] in group 1; 64 of 74 patients [86%] in group 2; and 74 of 84 patients [88%] in group 3).

An evaluation of treatment effect according to subgroups of baseline characteristics showed that the numerical odds of a sustained virologic response was greater, across all subgroups, with either response-guided triple therapy (group 2) or 44-week triple therapy (group 3) than with the standard of care (group 1) (Figure 3Figure 3Odds Ratios for a Sustained Virologic Response in Group 2 versus Group 1 and Group 3 versus Group 1, According to Subgroup.).

Although there was a sustained virologic response in 12 more patients in group 3 than in group 2, the rates in each group did not differ significantly (odds ratio of a sustained virologic response in group 3 vs. group 2, 1.4; 95% confidence interval, 0.9 to 2.2). A similarly small difference was seen between these two groups during the period in which the therapy was identical (week 0 through treatment week 36), with 9 to 14 more patients having an undetectable HCV RNA level during treatment weeks 8 to 36 in group 3 than in group 2 (Figure S2 in the Supplementary Appendix). In post hoc exploratory analyses, we observed that this difference appeared to be driven by patients with cirrhosis at baseline: the percentage of patients with cirrhosis who had an undetectable HCV RNA level at week 8 was 18% (3 of 17 patients) in group 2, versus 73% (16 of 22 patients) in group 3, despite identical treatment through this time point (Figure S2 in the Supplementary Appendix). This suggests an underlying difference in responsiveness that is not fully accounted for by treatment-group randomization. In contrast, among patients without cirrhosis at baseline, the percentage with an undetectable HCV RNA level at week 8 was 50% (66 of 132 patients) in group 2 and 49% (63 of 128) in group 3. The odds of a sustained virologic response were similar between group 3 and group 2 for most baseline factors except for body weight under 75 kg, elevated alanine aminotransferase level, and cirrhosis, for which there was a greater odds of a sustained virologic response in group 3 (Figure S3 in the Supplementary Appendix). In contrast, the odds of a sustained virologic response were not different for those with advanced fibrosis (a Metavir fibrosis score of 3 or 4), which is often preferentially used owing to the variability of biopsy readings.

Multivariable stepwise logistic-regression analysis served to identify five baseline factors that were significantly associated with achievement of a sustained virologic response: assignment to either boceprevir group rather than the control group (odds ratios for group 2 and group 3 vs. group 1, 7.3 and 10.7, respectively; P<0.001 for both comparisons), previous relapse (odds ratio vs. previous nonresponse, 3.1; P<0.001), low viral load at baseline (odds ratio vs. high load, 2.5; P=0.02), and absence of cirrhosis (odds ratio vs. presence, 2.1; P=0.04) (Table S1 in the Supplementary Appendix). When the decline in viral load (i.e., decrease from baseline in the HCV RNA level of ≥1.0 log10 IU per milliliter vs. <1.0 log10 IU per milliliter) at week 4 (was added to the model, the week 4 response was a stronger predictor of sustained virologic response than historical response (odds ratio, 5.2; P<0.001).

Safety

The study included a stopping rule whereby patients in whom an undetectable HCV RNA level was not achieved by treatment week 12 discontinued all therapy. The low rate of an undetectable HCV RNA level by treatment week 12 in group 1 resulted in 61% of patients discontinuing treatment for this reason, as compared with 22% and 18% of patients in group 2 and group 3, respectively (Figure S1 in the Supplementary Appendix). Thus, the median duration of treatment was 2.4 to 3.2 times longer in the boceprevir groups than in the control group (Table 2Table 2Adverse Events, According to Treatment Group.).

In the boceprevir groups as compared with the control group, a greater proportion of patients reported serious adverse events and there were more discontinuations and dose modifications owing to adverse events. There was a higher incidence of anemia in the groups receiving boceprevir (43 to 46%) than in the control group (20%). Consistent with the increased incidence of anemia, the proportion of patients with hemoglobin levels of 6.5 to less than 9.5 g per deciliter was higher in groups 2 and 3 than in group 1; however, discontinuation owing to anemia was infrequent (occurring in 0% of patients group 1 and group 2 and in 3% [5 of 161 patients] in group 3). Erythropoietin was administered to 21%, 41%, and 46% of patients in groups 1, 2, and 3, respectively. Of the 403 patients, 17 received a transfusion for the management of anemia; 16 of these patients also received erythropoietin. Adverse events, dose modifications, and study-drug discontinuation in the 49 patients with cirrhosis are summarized in Table S3 in the Supplementary Appendix.

The most common adverse events observed in all treatment groups were flulike symptoms that are typically reported in association with peginterferon-ribavirin therapy (Table S5 in the Supplementary Appendix). Dysgeusia, rash, and dry skin were reported more commonly in the boceprevir groups than in the control group.

Discussion

Our data show that the addition of boceprevir to peginterferon-ribavirin therapy leads to high rates of sustained virologic response among patients in whom prior treatment had failed. Furthermore, patients who had previously had a relapse after receiving the standard of care had rates of sustained virologic response of up to 75%, with rates of 40 to 52% in the subgroup of patients with a previous nonresponse. Patients with undetectable HCV RNA levels at treatment week 8 were shown to have a rate of sustained virologic response that was similar whether boceprevir was taken for 32 weeks or 44 weeks; thus, an early response identified patients who could benefit from shorter treatment. There were no identified groups of patients with a previous treatment failure for whom the standard of care was more efficacious than was triple therapy. We observed high rates of a sustained virologic response among black patients and patients with advanced liver disease, who usually have a poor response,17,18 representing a clinically significant improvement over the standard of care.19

Rates of anemia were higher among patients receiving boceprevir-containing regimens than among those receiving control therapy, and many patients required erythropoietin treatment. Discontinuation for anemia was infrequent (affecting 3% of patients in group 3 only). Consistent with the increased incidence of anemia, a higher proportion of boceprevir recipients, as compared with controls, had a neutrophil count of 500 to less than 750 per cubic millimeter or underwent a red-cell transfusion.

This study included a 4-week lead-in period during which peginterferon-ribavirin was administered, which allowed for the assessment of the patient's interferon responsiveness immediately before the addition of boceprevir. We have previously shown that a decline in viral load of less than 1 log10 IU per milliliter after 4 weeks of peginterferon-ribavirin therapy is significantly correlated to a decline of less than 2 log10 IU per milliliter after 12 weeks of treatment.20 We identified 102 patients with a poor response to interferon, defined as a decrease in the HCV RNA level of less than 1 log10 IU per milliliter at week 4. This is an important recognition of the changes that can evolve over time in patients who had previously been treated and are awaiting retreatment. Possible explanations for such changes include an increase in body weight, development of glucose intolerance, an increase in hepatic steatosis, and progression of fibrosis, all of which could have resulted in diminished responsiveness to peginterferon-ribavirin. Notably, a sustained virologic response was achieved, after boceprevir was added to the standard of care, in 33 to 34% of the patients with a poor response to interferon, as compared with 0% in the patients retreated with peginterferon-ribavirin alone.

In summary, the results of our phase 3 trial show that boceprevir, when added to peginterferon alfa-2b and ribavirin, leads to high rates of sustained virologic response in difficult-to-treat patients.

The opinions expressed in this report represent the consensus of the authors and do not necessarily reflect the formal position of Merck or other institutions listed as authors' affiliations.

Sponsored by Schering-Plough (now part of Merck).

Methods

Study Oversight

The study protocol is available with the full text of this article at NEJM.org. The trial (HCV RESPOND-2 [Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2]) was funded by Schering-Plough (now part of Merck) and was designed, managed, and analyzed by Merck in conjunction with the external academic investigators and members of the external data and safety monitoring board. The academic authors had agreements with the sponsor concerning the confidentiality of the data. The academic authors collected the data, which was then analyzed by the sponsor. The sponsor held the data and made them available to the academic authors. The first draft of the manuscript was written by one academic author and three industry authors. All authors were involved in the collection, analysis, or interpretation of the data; revision of the manuscript; and the decision to submit the manuscript for publication. All authors vouch for the completeness and accuracy of the data and analyses as well as the fidelity of the study to the protocol.

Study Patients

From August through November 2008, we screened 640 patients with HCV genotype 1 infection at 80 sites in North America and Europe. Eligibility criteria included demonstrated responsiveness to interferon (minimum duration of therapy, 12 weeks). We defined patients as having either nonresponse (i.e., a decrease in the HCV RNA level of at least 2 log10 IU per milliliter by week 12 but with a detectable HCV RNA level during the therapy period) or relapse (i.e., an undetectable HCV RNA level at the end of treatment, without subsequent attainment of a sustained virologic response [i.e., with a detectable HCV RNA level during the follow-up period]).

Exclusion criteria included hepatitis B or infection with the human immunodeficiency virus, any other cause of clinically significant liver disease, decompensated liver disease, uncontrolled diabetes mellitus, a severe psychiatric disorder, and active substance abuse. Liver-biopsy specimens were assessed for Metavir fibrosis scores and steatosis scores by a single academic author who is a pathologist and was unaware of the assignment of boceprevir or placebo. Possible Metavir fibrosis scores are as follows: a score of 0 indicates no fibrosis, 1 indicates portal fibrosis without septa, 2 indicates portal fibrosis with few septa, 3 indicates numerous septa without cirrhosis, and 4 indicates cirrhosis.

Study Design

The primary objective was to compare two treatment regimens containing boceprevir in combination with open-label peginterferon alfa-2b and ribavirin (PegIntron and Rebetol, respectively; Merck) to treatment with peginterferon-ribavirin plus placebo in previously treated adults with chronic HCV genotype 1 infection. Our study was conducted in accordance with the principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies. All patients provided written informed consent before randomization.

Patients were randomly assigned, in a 1:2:2 ratio with the use of an interactive voice-response system, to one of three treatment groups, with stratification according to previous response to therapy (nonresponse or relapse) and HCV subgenotype (1a or 1b) as determined by means of sequencing of the HCV 5' noncoding region (Trugene).13 Patients with HCV genotype 1 infection whose HCV subtype could not be classified were randomly assigned to one of the treatment groups. The HCV genotype 1 subtype was also determined by means of sequencing of the nonstructural 5B (NS5B) region (Virco).

The study design is illustrated in Figure 1Figure 1Study Design.. For purposes of the study doses, peginterferon alfa-2b was administered subcutaneously at a dose of 1.5 μg per kilogram of body weight once weekly, and ribavirin was administered at a divided daily dose of 600 to 1400 mg per day on the basis of body weight. Treatment with boceprevir consisted of oral administration at a dose of 800 mg three times daily (to be taken with food and with an interval of 7 to 9 hours between doses) in four capsules of 200 mg each. Placebo was matched to boceprevir. The study was double-blinded regarding the administration of boceprevir.

During the 4-week lead-in period, all patients received peginterferon plus ribavirin. Subsequent treatment varied according to group. Group 1 (the control group) received peginterferon-ribavirin plus boceprevir-matched placebo for 44 weeks. Group 2 received a response-guided therapy regimen consisting of boceprevir plus peginterferon-ribavirin, for 32 weeks; according to the week 12 stopping rule, patients with an undetectable HCV RNA level at weeks 8 and 12 completed therapy at week 36, whereas those with a detectable HCV RNA level at week 8 (but an undetectable level at week 12) received peginterferon-ribavirin plus placebo for an additional 12 weeks. Group 3 received boceprevir and peginterferon-ribavirin for 44 weeks.

The stopping rule applied in all groups was that failure to achieve an undetectable HCV RNA level at week 12 resulted in discontinuation of all treatment and advancement to follow-up.

Plasma HCV RNA levels were measured with the use of the TaqMan 2.0 assay (Roche Diagnostics), which has lower limits of quantification and detection of 25 and 9.3 IU per milliliter, respectively; the lower limit of detection was used for decision making at various points throughout the study.13 Measurement was performed at the screening visit, at baseline, every 2 weeks through week 12, and then at weeks 16, 20, 24, 30, 36, 42, and 48, as well as at weeks 4, 12, and 24 of the follow-up period.

Safety

Adverse events were graded by investigators according to a modified World Health Organization grading system. Non-life-threatening adverse events were managed by means of dose reduction. The recommended guidelines for a two-step dose reduction of peginterferon and for a three-step dose reduction of ribavirin were similar to those previously described (as is summarized in the Supplementary Appendix, available at NEJM.org).7,14-16

Viral breakthrough was defined as achievement of an undetectable HCV RNA level and subsequent occurrence of an HCV RNA level greater than 1000 IU per milliliter. Incomplete virologic response and rebound was defined as an increase of 1 log10 IU per milliliter in the HCV RNA level from the nadir, with an HCV RNA level greater than 1000 IU per milliliter (if both samples being compared were collected the same number of days after the last peginterferon injection). In cases in which the timing between the peginterferon injection and the HCV RNA sample collection was different for the two samples, an increase of 2 log10 IU per milliliter was required to meet this criterion. If a patient had virologic breakthrough or an incomplete virologic response and rebound while receiving therapy, boceprevir treatment could be discontinued, but peginterferon-ribavirin could be continued for up to 48 weeks with appropriate clinical follow-up.

Statistical Analysis

Analyses regarding the primary objective included data from all patients who received at least one dose of any study medication. The key secondary objective was to compare the two boceprevir regimens with the peginterferon-ribavirin regimen in patients who completed the lead-in period and received at least one dose of placebo or boceprevir. Specifically, comparisons for the primary and key secondary objectives were made between group 3 and group 1 and between group 2 and group 1.

The primary efficacy end point was a sustained virologic response, defined as an undetectable plasma HCV RNA level at week 24 of the follow-up period. Secondary and other efficacy analyses were performed to calculate the proportion of patients with an early response (i.e., an undetectable HCV RNA level at week 8) in whom a sustained virologic response was achieved, as well as the proportion of patients with a relapse.

The primary statistical comparison was carried out with the use of a two-sided Cochran-Mantel-Haenszel chi-square test with adjustment for the baseline stratification factors. The study had a statistical power of 90% to detect an absolute improvement in the rate of sustained virologic response by 21 percentage points over the rate in group 1 (assuming response rates of 22% in the control group and 43% in the boceprevir groups) with the use of a two-sided chi-square test and an alpha value of 0.05.

To control for type I error in the primary analysis, a step-down approach was used. Group 3 was first compared against group 1. If the P value for the comparison was less than 0.05, the next comparison - of group 2 and group 1 - was carried out. A similar step-down approach was prespecified to control for the type I error regarding the key secondary objective. To account for multiplicity between the primary and key secondary analyses, the key secondary analyses were conducted only if the significance of the primary comparisons was established. P values calculated for sustained virologic response are provided for only the two prespecified primary and key secondary comparisons.

Summary statistics are reported for each of the three treatment regimens for subgroups of patients defined according to prespecified baseline characteristics. Multivariable logistic-regression analyses involving treatment regimen and prespecified baseline characteristics were performed to evaluate sustained virologic responses. A stepwise procedure was used to identify independent predictors of sustained virologic response (with P=0.05 as the threshold level for variables to be entered into the model and retained in the final model). In addition, we fit a stepwise logistic-regression model of the response (decrease from baseline in the HCV RNA level of ≥1.0 log10 IU per milliliter vs. <1.0 log10 IU per milliliter) at treatment week 4 and baseline characteristics.

Source

Boceprevir for Untreated Chronic HCV Genotype 1 Infection

Fred Poordad, M.D., Jonathan McCone, Jr., M.D., Bruce R. Bacon, M.D., Savino Bruno, M.D., Michael P. Manns, M.D., Mark S. Sulkowski, M.D., Ira M. Jacobson, M.D., K. Rajender Reddy, M.D., Zachary D. Goodman, M.D., Ph.D., Navdeep Boparai, M.S., Mark J. DiNubile, M.D., Vilma Sniukiene, M.D., Clifford A. Brass, M.D., Ph.D., Janice K. Albrecht, Ph.D., and Jean-Pierre Bronowicki, M.D., Ph.D. for the SPRINT-2 Investigators

N Engl J Med 2011; 364:1195-1206 March 31, 2011

Background

Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.

Methods

We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.

Results

A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.

Conclusions

The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.)

The opinions expressed in this report represent the consensus of the coauthors and do not necessarily reflect the formal position of Merck or the other institutions listed as authors' affiliations.

Supported by Schering-Plough (now Merck).

Chronic infection with the hepatitis C virus (HCV) affects more than 170 million people worldwide.1,2 Rates of sustained virologic response associated with peginterferon-ribavirin therapy remain below 50% and are often less than 30% among patients who have HCV genotype 1 infection and certain baseline characteristics, such as advanced fibrosis, diabetes, coinfection with the human immunodeficiency virus (HIV), or African heritage.3-9 Recent efforts to improve the rate of sustained virologic response have focused on oral direct-acting antiviral agents.10-13

Boceprevir is a linear peptidomimetic ketoamide serine protease inhibitor that binds reversibly to the HCV nonstructural 3 (NS3) active site.14 Like other protease inhibitors, boceprevir must be given with peginterferon-ribavirin to minimize the emergence of viral resistance. 15,16 In the SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial, we examined whether the addition of boceprevir to standard therapy could improve the rates of sustained virologic response in previously untreated patients infected with HCV genotype 1.

Results

Study Patients

A total of 1246 and 226 patients were screened for the nonblack cohort and the black cohort, respectively, of whom 940 nonblack patients and 159 black patients were randomly assigned to a treatment group from August 2008 through January 2009 (Figure S1 in the Supplementary Appendix). Two patients in the nonblack cohort did not receive any study drug and were not included in the analyses. All the other randomly assigned patients received at least 1 dose of study medication. Baseline characteristics are shown in Table 1Table 1Selected Baseline Characteristics of Patients Who Received at Least One Dose of Study Medication, According to Cohort and Treatment Group.

A total of 49 patients discontinued the peginterferon-ribavirin therapy during the lead-in period and did not receive boceprevir or placebo. Discontinuation for reasons of futility at week 24 occurred in 84 of 311 patients (27%), 24 of 316 patients (8%), and 28 of 311 patients (9%) in the nonblack cohort and in 24 of 52 patients (46%), 9 of 52 patients (17%), and 8 of 55 patients (15%) in the black cohort in groups 1, 2, and 3, respectively.

Efficacy

Response rates were significantly higher among patients receiving a boceprevir-containing regimen than among controls (Table 2Table 2Rates of Virologic Responses among Patients Who Received at Least One Dose of Any Study Medication, According to Cohort and Treatment Group.). Among nonblacks, the rate of a sustained virologic response was 40% with the standard of care and was significantly higher (P<0.001) in both boceprevir groups - 67% in group 2 and 68% in group 3 - for relative increases of 68% and 70%, respectively, over control rates. Among blacks, the rate of a sustained virologic response was 23% in group 1, 42% in group 2 (P=0.04, vs. group 1), and 53% in group 3 (P=0.004, vs. group 1). In a modified intention-to-treat analysis that included all nonblacks receiving at least one dose of boceprevir or placebo, the respective rates of sustained virologic response in groups 1, 2, and 3 were 42%, 70% (P<0.001, vs. group 1), and 71% (P<0.001, vs. group 1), the corresponding rates among blacks were 26%, 47% (P=0.04, vs. group 1), and 53% (P=0.01, vs. group 1). In the nonblack cohort, viral breakthrough occurred in 1 to 2% of patients in each treatment group, whereas rates of relapse were lower in the two boceprevir groups than in the standard-therapy group. The numbers of events in the smaller black cohort were too few to permit comparison between treatment groups.

The 4-week lead-in period of peginterferon-ribavirin treatment allowed for the assessment of interferon responsiveness and its relationship to sustained virologic response. At week 4, 23% of nonblacks and 38% of blacks had a decrease of less than 1 log10 IU per milliliter in the HCV RNA level from baseline, which was associated with lower rates of sustained virologic response (Table 2) and higher rates of boceprevir-resistance-associated variants (genotypic mutations of the protease conferring reduced sensitivity to boceprevir) (Table 3Table 3Common Clinical Adverse Events, Resistance-Associated HCV Variants, and Hematologic Abnormalities, According to Treatment Group.) than was a decrease of 1 log10 IU per milliliter or more in the HCV RNA level, regardless of the treatment group. However, whether the decrease in the HCV RNA level at week 4 was more or less than 1 log10 IU per milliliter, rates of sustained virologic response were consistently higher in the boceprevir groups than in the control group.

The percentages of patients with undetectable HCV RNA levels at week 8 who had a sustained virologic response were high, irrespective of the treatment regimen, but this response at week 8 occurred approximately three times as often in the boceprevir groups as in the control group. At this time point, the patients had received boceprevir or placebo for 4 weeks and peginterferon-ribavirin for 8 weeks.

The rates of sustained virologic response among nonblacks were similar in group 2 (67%) and in group 3 (68%), whereas among blacks they were 42% and 53%, respectively. Among nonblack boceprevir recipients whose HCV RNA levels became undetectable by week 8 (60%) and those with undetectable HCV RNA levels through week 24 (47%), the rate of sustained virologic response was 97% in group 2 (which had received 24 weeks of boceprevir and a total of 28 weeks of therapy) and 96% in group 3 (which had received 44 weeks of boceprevir and a total of 48 weeks of therapy) (Table 2).

In group 2, a total of 22% of the patients with a detectable HCV RNA level between week 8 and week 24 received therapy for more than 28 weeks. Among patients in whom HCV RNA levels were still detectable at week 8, rates of sustained virologic response were 74% in group 2 (after receiving 24 weeks of boceprevir) as well as in group 3 (after receiving 44 weeks of boceprevir).

Predictors of sustained virologic response were identical in models for each cohort. Rates of sustained virologic response in patients with advanced fibrosis were lower than in those with mild fibrosis, although the numbers of patients with a Metavir fibrosis score of 3 or 4 (indicating bridging fibrosis or cirrhosis) were small, particularly in the black cohort (Table 4Table 4Odds Ratios for a Sustained Virologic Response, According to Predictor Variables.). In an expanded model that included virologic responses during the treatment period, a decrease in the HCV RNA level by 1 log10 IU per milliliter or more at the end of the 4-week lead-in period was strongly predictive of a sustained virologic response (odds ratio vs. a decrease of <1 log10 IU per milliliter, 9.0; 95% confidence interval, 6.3 to 12.8; P<0.001). In general, subgroup analyses across a range of baseline factors favored group 2 and group 3 over group 1, with no consistent differences between groups 2 and 3 (Figure S2 in the Supplementary Appendix). For groups 1, 2, and 3 in the nonblack cohort, rates of sustained virologic response were 33%, 64%, and 59%, respectively, among patients with a hemoglobin level of 10 g per deciliter or higher during the treatment period, as compared with 60%, 72%, and 79%, respectively, among patients with a nadir hemoglobin level of less than 10 g per deciliter during the treatment period.

Safety

Adverse events occurred in more than 98% of the study patients, with serious adverse events in 9%, 11%, and 12% of patients in groups 1, 2, and 3, respectively (Table S2 in the Supplementary Appendix). There were six deaths during the study: four patients in the control group died, as did two patients in the boceprevir groups. Two suicides (one in group 1 and one in group 2) were judged to have possibly been related to peginterferon. No other deaths were considered to be drug-related.

Fatigue, headache, and nausea were the most common clinical adverse events in all treatment groups (Table 3). Dysgeusia occurred more than twice as often in boceprevir recipients than in controls. Anemia was reported as an adverse event in 29% of controls and 49% of boceprevir recipients. Anemia was classified as grade 1 in 36% of controls, grade 2 in 17%, grade 3 in 2%, and grade 4 in 0%; the respective percentages among boceprevir recipients were 43%, 31%, 3%, and 1%. Four patients in group 1 discontinued the study owing to anemia, as compared with six patients in group 2 and seven patients in group 3. Overall, 13% of controls and 21% of boceprevir recipients required dose reductions because of anemia. Erythropoietin was administered in 24% of controls and 43% of boceprevir recipients. A total of 85% and 86% of patients in group 2 and group 3, respectively, had neutropenia of grade 1 to 4, as compared with 77% of those in the control group; 28% and 33% of patients in groups 1 and 2, respectively, had grade 1 to 4 thrombocytopenia, as compared with 13% of controls.

Discussion

SPRINT-2 compared two regimens of boceprevir added to peginterferon alfa-2b-ribavirin therapy (the standard of care) and the standard of care alone. Two distinct cohorts were enrolled on the basis of self-identified race (nonblack patients and black patients) to allow for an independent estimate of rates of response among black patients, a group historically underrepresented in HCV-treatment trials.

As compared with peginterferon alfa-2b-ribavirin therapy alone, the addition of boceprevir significantly increased the rate of a sustained virologic response among previously untreated black and nonblack patients infected with HCV genotype 1, including those with a decrease of less than 1 log10 IU per milliliter in the HCV RNA level at week 4. Among nonblack patients, the combination therapy with boceprevir was associated with a relative increase of approximately 70% in the rates of sustained virologic response over standard therapy. Although lower among black patients than among nonblack patients, the rates of sustained virologic response with the boceprevir regimens were nearly double those with the standard of care. Patients with an undetectable HCV RNA level at week 8 had a higher rate of sustained virologic response than patients with a detectable level at week 8, irrespective of treatment regimen. Given the relatively small numbers of patients with cirrhosis in the trial, further study is warranted to define optimal therapy in this population.

Our study evaluated a response-guided treatment strategy with individualized treatment duration on the basis of the HCV RNA level between weeks 8 and 24. Patients in whom the HCV RNA level became undetectable by week 8 and remained so up to week 24 were given boceprevir plus peginterferon-ribavirin for 24 weeks. The rates of sustained virologic response among both black and nonblack patients were significantly higher with response-guided therapy than with standard treatment. Regardless of the virologic response at week 4 or week 8, response-guided therapy that included 24 weeks of boceprevir administration resulted in overall rates of sustained virologic response that were similar to those after 44 weeks of triple therapy. Patients who had undetectable HCV RNA levels by week 8 had very high rates of sustained virologic response as compared with patients who had detectable levels between weeks 8 and 24. There were too few black patients in whom the HCV RNA level was detectable between weeks 8 and 24 to conclusively define the optimal treatment for this population.

This trial featured the use of peginterferon-ribavirin for 4 weeks (the lead-in period) before boceprevir was added. Theoretically, a lead-in phase would serve to lower HCV RNA levels before exposure to a protease inhibitor, thereby reducing the risk of viral breakthrough or resistance to the direct-acting antiviral agent, as noted in a phase 2 study in which boceprevir with lead-in therapy was compared with boceprevir without lead-in therapy.10 However, lead-in therapy has other benefits, such as allowing for assessment of the relationship between interferon responsiveness and subsequent sustained virologic response in patients receiving boceprevir. Patients with a poor response to interferon, defined as a reduction in the HCV RNA level of less than 1 log10 IU per milliliter after 4 weeks of peginterferon-ribavirin therapy, had sufficiently high rates of sustained virologic response, as compared with the control group, to dispel concern that the addition of a protease inhibitor to the treatment regimen would be equivalent to functional monotherapy. However, these patients were less likely than patients with a robust response to interferon to have a sustained virologic response after boceprevir was added.17-19 Thus, patients who have a poor response to interferon may need to be monitored closely to determine who may benefit from better therapies, once they are available. Conversely, in patients with undetectable HCV RNA levels after the lead-in period, boceprevir administration may not result in a higher rate of sustained virologic response than that achieved with the use of peginterferon and ribavirin alone. The lead-in period can further serve to test both compliance and tolerability before exposure to a class of drugs to which resistance can develop.15,16

The regimens that included boceprevir were associated with increased rates of anemia, and nearly twice as many boceprevir recipients as controls had a hemoglobin level of less than 9.5 g per deciliter or received erythropoietin (43% vs. 24%). Among patients receiving erythropoietin, the average duration of use was shortest in group 2. Neither the incidence of serious adverse events nor the frequency of discontinuation owing to an adverse event differed significantly between patients receiving boceprevir and those receiving standard therapy. The rate of a sustained virologic response was significantly greater with boceprevir plus peginterferon-ribavirin than with peginterferon-ribavirin alone among both black and nonblack patients.

The opinions expressed in this report represent the consensus of the coauthors and do not necessarily reflect the formal position of Merck or the other institutions listed as authors' affiliations.

Supported by Schering-Plough (now Merck).

Methods

Study Design

A detailed description of the study methods is provided in the Supplementary Appendix (available with the full text of this article at NEJM.org). We conducted a phase 3, international, randomized, placebo-controlled study comparing the safety and efficacy of standard therapy with peginterferon alfa-2b and ribavirin (PegIntron and Rebetol, respectively; Merck) with the safety and efficacy of two treatment regimens in which boceprevir was added after a lead-in period of treatment with peginterferon-ribavirin alone (Figure 1Figure 1Study Design.). Because of the marked difference in rates of sustained virologic response between blacks and nonblacks,7 self-identified blacks and nonblacks were enrolled separately into two cohorts.

The sponsor, patients, and study personnel were unaware of the assignment to the boceprevir or placebo group; the use of peginterferon and ribavirin was open label. The trial was conducted in accordance with the principles of Good Clinical Practice and the study protocol (including the data analysis plan; available at NEJM.org); the study design was approved by the appropriate institutional review boards and regulatory agencies. Each participant provided written informed consent before undergoing any study-related procedure. The trial was designed, managed, and analyzed by the industry authors in conjunction with the academic authors under the oversight of an independent data review advisory board. The academic authors had full access to all the data. The core writing team consisted of the principal academic author and all the industry authors, who were also responsible for the decision to submit the manuscript for publication, before which the sponsor reviewed a draft. Each author vouches for the fidelity of the trial conduct to the protocol and the completeness and accuracy of the results and data analyses.

Enrolled patients in each cohort were randomly assigned, in a 1:1:1 ratio and by means of an interactive voice-response system, to one of the three treatment groups, after stratification on the basis of the baseline HCV RNA level (≤400,000 vs. >400,000 IU per milliliter) and HCV genotype 1 subtype (1a vs. 1b). Patients in whom HCV could not be subtyped were randomly assigned to a treatment group within their HCV RNA stratum.

Selection of Patients

Eligibility criteria were a history of no previous treatment for HCV infection, age of 18 years or older, weight of 40 to 125 kg, chronic infection with HCV genotype 1, and plasma HCV RNA level of 10,000 IU per milliliter or greater. Exclusion criteria were liver disease of other cause, decompensated cirrhosis, renal insufficiency, HIV or hepatitis B infection, pregnancy or current breast-feeding, and active cancer. Liver-biopsy specimens were assigned Metavir fibrosis scores and steatosis scores by a single academic author who is a pathologist and was unaware of the assignment to the boceprevir or placebo group. The HCV genotype 1 subtype was determined with the use of the Trugene assay (Bayer Diagnostics) for purposes of randomization and by sequencing of the nonstructural 5B (NS5B) region (Virco) for subsequent analyses.

Study Regimens

Peginterferon alfa-2b was administered subcutaneously at a dose of 1.5 μg per kilogram of body weight once weekly; and weight-based oral ribavirin was administered at a total dose of 600 to 1400 mg per day in divided doses, given in the morning and evening. Treatment with boceprevir consisted of oral administration at a dose of 800 mg three times daily (to be taken with food and at an interval of 7 to 9 hours between doses) in four capsules of 200 mg each. Placebo was matched to boceprevir.

All patients received peginterferon-ribavirin during the 4-week lead-in period (Figure 1). Patients randomly assigned to group 1 (the standard of care) received peginterferon-ribavirin treatment for 44 weeks after the lead-in period, as well as thrice-daily placebo beginning at week 5. Patients randomly assigned to group 2 (response-guided therapy) received peginterferon-ribavirin plus boceprevir for a total of 24 weeks after the lead-in period; if HCV RNA levels were undetectable from week 8 through week 24, treatment was considered complete, but if HCV RNA levels were detectable at any visit from week 8 up to but not including week 24, peginterferon-ribavirin was continued, and placebo was administered, at week 28 through week 48. Patients randomly assigned to group 3 (fixed-duration therapy) received peginterferon-ribavirin plus oral boceprevir for 44 weeks after the lead-in period.

In all three groups, the study treatment was discontinued for all patients with a detectable HCV RNA level at week 24, according to a standard futility rule. Boceprevir was given for 24 weeks in group 2 and 44 weeks in group 3. All patients were followed through week 72.

Viral breakthrough was defined as achievement of an undetectable HCV RNA level and subsequent occurrence of an HCV RNA level greater than 1000 IU per milliliter. Incomplete virologic response and rebound was defined as an increase of 1 log10 IU per milliliter in the HCV RNA level from the nadir, with an HCV RNA level greater than 1000 IU per milliliter (if both samples being compared were collected the same number of days after the last peginterferon injection). In cases in which the timing between the peginterferon injection and the HCV RNA sample collection was different for the two samples, an increase of 2 log10 IU per milliliter was required to meet this criterion. If a patient had virologic breakthrough or an incomplete virologic response and rebound while receiving therapy, boceprevir treatment could be discontinued, but peginterferon-ribavirin could be continued for up to 48 weeks with appropriate clinical follow-up.

Efficacy Assessment

Plasma HCV RNA levels were measured with the use of the TaqMan 2.0 assay (Roche Diagnostics), which has lower limits of quantification and detection of 25 and 9.3 IU per milliliter, respectively; the lower limit of detection was used for decision making at various points throughout the study. HCV RNA testing was performed at the screening visit, at baseline, every 2 weeks through week 12, and at weeks 16, 20, 24, 28, 34, 40, 48, 52, 60, and 72 (depending on the treatment duration). Patients in whom study therapy was stopped because of futility were considered to have had treatment failure.

Safety Assessment

Adverse events were graded by investigators according to a modified World Health Organization grading system. Non-life-threatening hematologic adverse events were managed by means of dose reduction or administration of hematopoietic growth factors (or both). Reduction of the ribavirin dose or administration of erythropoietin was recommended when the hemoglobin level dropped to less than 10 g per deciliter, but these decisions were made at the discretion of the investigators; erythropoietin was to be stopped if the hemoglobin level rebounded to 12 g per deciliter or greater.

Statistical Analysis

The trial was designed as a superiority study to detect differences in the rates of sustained virologic response with either of the two boceprevir regimens (group 2 or group 3) as compared with standard therapy alone (group 1). The primary analyses involved all patients who had received at least one dose of any study medication; key secondary efficacy analyses were conducted for the modified intention-to-treat population, consisting of patients who completed the lead-in period of treatment and received at least one dose of boceprevir or placebo. Rates of response were determined separately (per protocol) for the nonblack cohort and the black cohort.

The protocol-specified primary efficacy end point was a sustained virologic response, defined as undetectable HCV RNA levels for 24 weeks after the completion of therapy. If HCV RNA measurements for this time point or later were missing, the 12-week post-treatment measurement was used. Relapse was defined as the occurrence of an undetectable HCV RNA level at the end of treatment but a detectable HCV RNA level at some point during the follow-up period.

Within-cohort comparisons were performed with the use of the two-sided Cochran-Mantel-Haenszel chi-square test (after adjustment for baseline stratification factors). A step-down approach was applied to hypothesis testing. Group 3 was first compared with group 1. If the resultant P value was 0.05 or less, the superiority of fixed-duration therapy including boceprevir over standard therapy would be supported, and group 2 would then be compared with group 1. If this P value was also 0.05 or less, the superiority of response-guided therapy including boceprevir over standard therapy would likewise be established.

Secondary analyses were to be conducted only if the primary comparisons showed significant differences. Formal hypothesis testing comparing the two boceprevir groups was not specified in the protocol. A multivariate logistic-regression model that included baseline characteristics and treatment group was used to identify predictors of sustained virologic response. A stepwise procedure was used to identify independent covariates, with an alpha level of 0.05 as the threshold level for variables to be entered into, and retained in, the model.

Assuming a rate of sustained virologic response of 45% in group 1 of the nonblack cohort, we calculated that 310 subjects per group would need to be enrolled for the study to have a statistical power of 90% to detect an absolute increase of 13 percentage points in the rate of sustained virologic response in group 3 as compared with group 1, with the use of a two-sided chi-square test and an alpha level of 0.05. Assuming a rate of sustained virologic response of 50% in the black cohort overall, 50 patients per group, and the use of a two-sided 95% confidence interval, we estimated that the true rate of a sustained virologic response in the black population could be estimated, within ±14%, for each of the three treatment groups.

Safety analyses included all patients who had been randomly assigned to a study group and had received at least one dose of any study medication.

Source

Could HIV-infected organs save lives?

Public release date: 30-Mar-2011

Contact: Stephanie Desmon
sdesmon1@jhmi.edu
410-955-8665
Johns Hopkins Medical Institutions

Johns Hopkins researchers argue for reversing ban on transplanting infected organs and making them available to HIV-infected patients

If Congress reversed its ban on allowing people with HIV to be organ donors after their death, roughly 500 HIV-positive patients with kidney or liver failure each year could get transplants within months, rather than the years they currently wait on the list, new Johns Hopkins research suggests.

"If this legal ban were lifted, we could potentially provide organ transplants to every single HIV-infected transplant candidate on the waiting list," says Dorry L. Segev, M.D., Ph.D., an associate professor of surgery at the Johns Hopkins University School of Medicine and the study's senior author. "Instead of discarding the otherwise healthy organs of HIV-infected people when they die, those organs could be available for HIV-positive candidates."

Not only would HIV-positive transplant candidates get organs sooner if such transplants were legalized, Segev says, but by transplanting those patients and moving them off the waiting list, the time to transplant would be shorter for non-HIV-infected patients.

The ban on organ donation by HIV-positive patients is a relic of the 1980s, when it was still unclear what caused AIDS, at the time a devastating new epidemic sweeping the United States. Congress put the ban into the National Organ Transplant Act of 1984 and it has never been updated, despite the fact that HIV is no longer an immediate death sentence but a chronic disease managed with medication.

The number of HIV-positive patients receiving kidney or liver transplants — with non-HIV-infected organs — is on the rise as doctors become more comfortable with the idea, and patients are having good outcomes, Segev says. In 2009, more than 100 HIV-positive patients got new kidneys and 29 got new livers. HIV-infected patients may encounter accelerated rates of liver and kidney disease due in part to the toxic effects of antiretroviral therapy, the medications that keep HIV at bay.

Segev and his colleagues set out in their study, published early online in the American Journal of Transplantation, to estimate the number of people who die each year in the United States who are good potential organ donors except for that they are HIV-positive. They culled data from two main sources — the Nationwide Inpatient Study, which has information on in-hospital deaths of HIV-infected patients, and the HIV Research Network, a nationally representative registry of people with HIV. The team determined that the number of annual deaths with what are believed to be organs suitable for transplantation was approximately the same as estimated by each data source — an average of 534 each year between 2005 and 2008 in the Nationwide Inpatient Study and an average of 494 each year between 2000 and 2008 in the HIV Research Network.

While no transplants of HIV-infected organs into HIV-infected patients have been done in the United States because of the ban, Segev says doctors in South Africa have started doing this type of transplant with excellent results.

Segev suggests that, in transitioning to a system where HIV-infected donor organs can be transplanted into HIV-infected patients, doctors can call on the lessons and experience of transplanting hepatitis C patients with organs from people with the same disease. This practice, which has not always been the standard, has substantially shortened the waiting list for these recipients without significantly compromising patient or graft survival. The decision of whether or not to use these organs is not a legal one, but one made by the clinician.

Using HIV-infected organs is not without concerns. There are medical and safety issues that need to be addressed. Doctors need to make sure that the harvested organs are healthy enough for transplant and that there is minimal risk of infecting the recipient with a more aggressive strain of the virus. There is also a fear that an HIV-infected organ could accidentally be transplanted into an HIV-negative recipient. Segev says that hepatitis C-infected organs are clearly marked as such and similar protocols can be developed with HIV-infected organs.

"The same processes that are in place to protect people from getting an organ with hepatitis C accidentally could be put in place for HIV-infected organs," Segev says. "When you consider the alternative — a high risk of dying on the waiting list — then these small challenges are overshadowed by the large potential benefit."

Segev says eliminating the prohibition on HIV-infected organ donation would have immediate results. At first, he predicts, there would be more HIV-infected organs than people on the waiting list. Then, as doctors realized that their HIV-infected patients would no longer have to wait five-to-seven years for a transplant, Segev says he thinks more and more HIV-infected patients would sign up for the shortened list for an HIV-infected organ.

"The whole equation for seeking a transplant for someone with HIV and kidney or liver failure would change if this source of organs became available," he says. "We want the decisions taken out of the hands of Congress and put into the hands of clinicians."

###

This research was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases.

Other Johns Hopkins researchers contributing to this study include Brian J. Boyarsky, B.A.; Erin C. Hall, M.D., M.P.H.; Andrew L. Singer, M.D., Ph.D.; Robert A. Montgomery, M.D., D.Phil.; and Kelly A. Gebo, M.D., M.P.H.

For more information: http://www.hopkinsmedicine.org/transplant/About/Segev.html

Source

OraQuick HCV Rapid Test Now Approved for Use With Fingerstick Whole Blood Samples

Infectious Disease Special Edition
ISSUE: MARCH 2011 VOLUME: 1

OraSure Technologies, Inc. has received FDA approval for its OraQuick HCV Rapid Antibody Test, which detects HCV antibodies with a fingerstick whole blood sample.

The fingerstick whole blood claim is the second application to be approved by the FDA for the OraQuick HCV test. The first product, approved in June 2010, required venous whole blood specimens.

The OraQuick HCV Rapid Antibody Test is the first FDA-approved rapid, point-of-care test to detect antibodies to hepatitis C virus. This test eliminates the need to draw blood and provides results in 20 minutes, which may allow healthcare providers to identify more individuals infected with hepatitis C.

OraSure is partnering with Merck & Co., through its predecessor Schering Plough Corp., to collaborate on the development and promotion of the OraQuick HCV test.

For more information, visit http://www.orasure.com/.

—Based on a press release from OraSure Technologies, Inc.

Source

Pharmasset Initiates Phase 2b ATOMIC Trial of PSI-7977 for Multiple HCV Genotypes

PRINCETON, N.J., March 30, 2011 /PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today that screening has begun in a Phase 2b study of PSI-7977, a nucleotide analog polymerase inhibitor for the treatment of chronic hepatitis C (HCV). The trial will evaluate PSI-7977 400mg QD with pegylated interferon and ribavirin in patients with HCV genotype 1, 4, 5 or 6 who have not been treated previously.

"We are encouraged by the early efficacy and safety data being generated with our nucleotide analogs, PSI-7977 and PSI-938," stated Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "The ATOMIC trial is designed to explore 12 and 24 week durations of PSI-7977. The potency, high barrier to resistance, and consistent antiviral activity across genotypes provided the data to support an interferon free dosing period in this trial, as well as enabling us to enroll multiple genotypes in this trial."

About the Phase 2b ATOMIC Trial

This Phase 2b trial is planned to enroll approximately 300 patients with chronic HCV genotype 1 who have not been treated previously. The primary endpoint of the trial will be the safety and tolerability of PSI-7977 in combination with peginterferon and ribavirin over 12 or 24 weeks. The trial will be conducted in the U.S. Patients will be randomized (1:2:3) into the following arms:

* PSI-7977 400mg QD with peginterferon and ribavirin for 12 weeks;

* PSI-7977 400mg QD with peginterferon and ribavirin for 24 weeks;

* PSI-7977 400mg QD with peginterferon and ribavirin for 12 weeks, followed by either PSI-7977 400mg QD monotherapy for 12 weeks or PSI-7977 400mg QD plus ribavirin for 12 weeks.

HCV GT1 patients will be stratified by IL28B status and baseline HCV RNA to ensure balance across cohorts. An additional 25 treatment-naïve patients with HCV genotype 4, 5, 6 or indeterminate genotype, will receive PSI-7977 400mg QD with peginterferon and ribavirin for 24 weeks.

Additional details on this and all Pharmasset trials can be found at http://www.clinicaltrials.gov/

About Pharmasset

Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis C virus (HCV). Our research and development efforts focus on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have three clinical-stage product candidates. Mericitabine (RG7128, MCB), a cytosine nucleoside analog for chronic HCV infection, is in two Phase 2b clinical studies in combination with Pegasys® plus Copegus® and is also in the INFORM studies, the first series of studies designed to assess the potential of combinations of small molecules without Pegasys® and Copegus®, all conducted through a strategic collaboration with Roche. PSI-7977 is our unpartnered uracil nucleotide analog currently dosing in three Phase 2 studies in patients with HCV genotypes 1 through 6, including studies with abbreviated duration or no interferon. PSI-938 is our unpartnered guanosine nucleotide analog which recently completed a 14-day monotherapy and combination study with PSI-7977. We also have in our pipeline an additional purine nucleotide analog, PSI-661, in advanced preclinical development.

Pegasys® and Copegus® are registered trademarks of Roche.

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

Forward-Looking Statements

Pharmasset "Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release that are not historical facts are "forward-looking statements," that involve risks, uncertainties, and other important factors, including, without limitation, the risk of cessation or delay of any of the ongoing or planned clinical trials and/or our development of our product candidates, the risk that the results of previously conducted studies involving our product candidates will not be repeated or observed in ongoing or future studies involving our product candidates, the risk that our collaboration with Roche will not continue or will not be successful, and the risk that any one or more of our product candidates will not be successfully developed and commercialized. For a discussion of risks, uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in our Annual Report on Form 10-K for the fiscal year ended September 30, 2010 and our Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commission and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission.

SOURCE Pharmasset, Inc.

Source

Presidio Pharmaceuticals, Inc. Announces Positive Results in a Phase 1b Clinical Trial of PPI-461, a Novel, Potent Broadly-Active Hepatitis C Virus (HCV) Inhibitor

SAN FRANCISCO----Presidio Pharmaceuticals, Inc. announced today positive preliminary results from a Phase 1b clinical trial of PPI-461, a novel HCV NS5A inhibitor for the treatment of patients with chronic hepatitis C. "These positive clinical data for PPI-461 in hepatitis C patients further support the inclusion of NS5A inhibitors in clinical development of novel combination therapies. Such future combination therapies are expected to substantially improve patient outcomes and should help stem the rising incidence of HCV-associated severe liver disease and premature mortality"

The PPI-461 phase 1b clinical trial reported here is a multiple ascending dose, randomized, blinded, placebo-controlled study in treatment-naïve adult hepatitis C patients with HCV genotype-1 infection; this trial is presently ongoing in the U.K., Denmark, and the United States. The study objectives are to assess the safety, tolerability, pharmacokinetics, and initial antiviral effects of PPI-461 during once-daily (QD) dosing at three dosing levels (50, 100, and 200 mg/day) for three days. Each dosing cohort of 8 patients is randomized 6 (PPI-461):2 (placebo). Two dosing groups have completed study treatment to date; the third (200 mg) dosing group is ongoing.

The interim Phase 1b trial results indicate that PPI-461 has been well-tolerated, with no serious or severe adverse events and no modifications or premature discontinuations of study treatment. Among PPI-461 recipients there have been only transient clinical adverse events, of non-specific types commonly seen in clinical trials, with no dose-related or treatment-related patterns of specific adverse events or laboratory abnormalities.

Pharmacokinetic (PK) analyses of patients' PPI-461 blood levels indicate that substantial blood levels of PPI-461 have been achieved rapidly and are dose proportional. Importantly, blood levels that are inhibitory for HCV replication have been maintained throughout the 24-hr inter-dose periods in the study patients.

Virologic data from the first two dosing groups indicate rapid and marked reductions in patients' serum viral loads (HCV RNA levels), in both dosing groups, in the first two days of treatment. The 50 mg dosing group achieved a mean maximal HCV RNA reduction of 3.1 log10 IU/mL (5 of 6 patients), while the 100 mg group achieved a mean maximal HCV RNA reduction of 3.7 log10 IU/mL (6 of 6 patients). The mean maximal HCV RNA reduction for 4 Placebo treated patients was 0.3 log10 IU/mL. One patient in the 50 mg cohort had a negligible response to PPI-461(0.4 log10 IU/mL HCV RNA reduction). This patient entered the study with highly resistant virus, as evidenced by NS5A resistance substitutions (L31M, Y93N, L28F, R30N) detected at high levels in pre-treatment sera. Such a patient would be expected to have minimal efficacy with any NS5A inhibitor, since these agents share common key resistance mutations, as will be reported in a Presidio presentation at the 2011 annual meeting of the European Association for the Study of Liver Disease (EASL) in Berlin on April 2nd (R. Colonno et al., poster #1199).

Efficacy data for individual patients receiving active PPI-461 treatment in the first two dosing cohorts in the Phase 1b trial are presented in Table 1:

"These positive clinical data for PPI-461 in hepatitis C patients further support the inclusion of NS5A inhibitors in clinical development of novel combination therapies. Such future combination therapies are expected to substantially improve patient outcomes and should help stem the rising incidence of HCV-associated severe liver disease and premature mortality," said Nathaniel A. Brown, M.D., Presidio's Chief Medical Officer.

The final results of the completed Phase 1b trial of PPI-461 will be submitted for presentation at a scientific meeting later this year.

About Presidio's HCV NS5A Inhibitors

Inhibitors of the HCV NS5A protein represent an exciting, highly potent class that is mechanistically distinct from other classes of direct-acting HCV antivirals that target the viral protease or replicase (polymerase).

PPI-461 is the first in a series of novel and selective HCV NS5A inhibitors discovered by Presidio Pharmaceuticals. Presidio's NS5A candidates are selected from numerous internal discovery leads, based on their potent activity against all major HCV genotypes and their potential for once-daily dosing with good tolerance. A Presidio presentation at the 2011 annual meeting of EASL in Berlin on April 2nd (R. Colonno et al., Poster #1200) will highlight the preclinical profile of three other novel NS5A inhibitors in development by Presidio, which derive from distinct chemical series.

About Presidio

Presidio Pharmaceuticals, Inc. is a San Francisco-based clinical stage specialty pharmaceutical company dedicated to the discovery and development of small-molecule antiviral therapeutics for novel and validated targets. For more information, please visit our website at: http://www.presidiopharma.com/.

Contacts
Presidio Pharmaceuticals, Inc.
Omar K. Haffar, PhD,
415-655-7561
omar@presidiopharma.com

Source

Achillion Announces Positive RVR Results With ACH-1625 to Treat Chronic Hepatitis C

Once-Daily Dose Achieves 75 - 81% RVR in a Well Tolerated Combination Regimen

NEW HAVEN, Conn., March 30, 2011 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced top-line results from its on-going Phase 2a clinical trial of ACH-1625 dosed once daily (QD) in combination with Pegasys® (peginterferon alfa-2a) and Copegus® (ribavirin), a current standard of care (SOC) in patients with chronic hepatitis C (HCV) infection. The analysis demonstrated that 75-81% of patients receiving ACH-1625 achieved rapid virologic response (RVR) with a promising safety and tolerability profile. ACH-1625 is an inhibitor of HCV NS3 protease that was discovered by and is being developed by Achillion.

Study Design

In this first of a two segment Phase 2a trial, a total of 64 patients were enrolled and randomized across three doses of ACH-1625 given once daily (200mg, 400mg or 800mg) or placebo with peginterferon alfa-2a and ribavirin, and were dosed for 4 weeks of therapy. Patients then continue on SOC for up to an additional 44 weeks. Subjects were randomized and stratified by HCV genotype and IL28B genotype.

Top-line Results

The majority of the 64 patients enrolled were HCV genotype 1a (73%), with a smaller percentage of HCV genotype 1b patients (25%). A total of 75% of the patients enrolled were genotype CT/TT, a marker of the patient's diminished response to interferon, and 25% were genotype CC. All patients receiving 4 weeks of treatment with ACH-1625 demonstrated continuous and substantial declines in HCV RNA with no viral breakthrough during therapy at any of the doses. Preliminary results for the 64 patients enrolled demonstrate RVR percent and viral load reduction as follows:

Mean maximum HCV RNA

decline through Week 4 (log10) 4.90 4.63 4.96 2.25 Safety results from a planned safety analysis included 56 patients from this segment of the trial and indicated that adverse events (AEs) were similar to those observed in the previously reported Phase 1a and 1b trials of ACH-1625. Over 4 weeks of co-administration of ACH-1625 with SOC, there were no discontinuations due to adverse events and there were no serious adverse events (SAEs) reported. Most reported AEs in patients receiving ACH-1625 were classified as mild to moderate and were transient. The most common AEs were consistent with peginterferon alfa-2a and ribavirin.

"These data reflect a positive outcome with high RVR, irrespective of IL28B status, which places ACH-1625 among the most potent protease inhibitors in development," commented Elizabeth A. Olek, M.D., Vice President and Chief Medical Officer of Achillion. "We look forward to selecting two of these doses and beginning the second segment of the trial, dosing ACH-1625 with SOC over 12 weeks, and anticipate reporting cEVR data by the end of this year." "We are quite pleased with the continued robust efficacy results and good safety profile with once-daily doses of ACH-1625," said Michael D. Kishbauch, Achillion's President and Chief Executive Officer. "ACH-1625 continues to demonstrate best-in-class features, including once-daily dosing, robust antiviral activity, coupled with safety and tolerability for patients. These attributes distinguish our drug and suggest it could offer improvements over other next-generation protease inhibitors that will reach the market mid-decade."

The preliminary safety profile of ACH-1625 continues to support future plans to combine this protease inhibitor with other directly acting antiviral agents. Achillion expects to initiate during 2012 a clinical trial evaluating ACH-1625 in combination with ACH-2928, an internally discovered and developed NS5A inhibitor.

About ACH-1625

ACH-1625 is a HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. ACH-1625 has rapid and extensive partitioning to the liver, as well as high liver/plasma ratios. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50 of approximately 1nM. In Phase 1a clinical studies, subjects receiving both single and multiple ascending doses ranging from 50 mg to 2000 mg per day for periods up to 5 days demonstrated that ACH-1625 was well tolerated at all doses and there were no SAEs, and no clinically significant changes in vital signs, electrocardiograms or laboratory evaluations. In Phase 1b clinical studies, HCV-infected patients receiving doses ranging from 200 to 600 mg twice daily, and 400 to 600 mg once daily, showed mean maximal reductions in viral load ranging from of 3.63 log10 to 4.25 log10. Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of at least 1log10 from baseline through day 12, the last day of viral load measurement in the study.

About HCV

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

About Achillion Pharmaceuticals

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

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-1625, which may not be duplicated in future cohorts at different doses or in future clinical studies of longer duration; Achillion's expectations regarding timing and duration of other clinical trials. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are: uncertainties relating to results of clinical trials, unexpected regulatory actions or delays, and Achillion's ability to obtain additional funding required to conduct its research, development and commercialization activities. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2010.

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

ACHN-G

CONTACT: Company Contact:
Glenn Schulman
Achillion Pharmaceuticals, Inc.
Tel. (203) 624-7000
gschulman@achillion.com

Source

Tibotec Advances Global Clinical Research Program for TMC435 in HCV; Will Present Four Abstracts Evaluating Safety and Efficacy at EASL

-Company Recently Launched Phase III Studies of TMC435 in Treatment-Naive HCV Patients in 12 Countries-

CORK, Ireland, March 29, 2011 /PRNewswire/ -- Tibotec Pharmaceuticals announced today that four abstracts reporting research findings with TMC435, the company's investigational hepatitis C protease inhibitor, have been accepted for presentation at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany, March 30 to April 3, 2011.

The four abstracts for TMC435 support Tibotec's continued efforts to advance its research and development program for the treatment of HCV. TMC435 highlights at the meeting include one oral presentation and one late-breaker poster presentation:

* Analysis of the predictive nature of IL28B genotype and pretreatment serum IP-10 in treatment-naive HCV patients from phase IIb PILLAR study on TMC435 administered with pegIFN/ribavirin

* Results from interim 24 week data of the international phase IIb randomized, double-blind, placebo-controlled ASPIRE study on efficacy, tolerability, safety, and pharmacokinetics of TMC435 administered with pegIFN/ribavirin in treatment-experienced HCV patients

"Tibotec is committed to developing innovative new treatment options that may offer better treatment outcomes and that may decrease the duration of treatment for patients with chronic hepatitis C infection," said Brian Woodfall M.D., Vice President of Global Clinical Development at Tibotec. "The company's presence at this year's EASL meeting and the recent launch of the phase 3 clinical trial program for TMC435 reinforce the value of this investigational agent in our growing HCV pipeline."

The titles of the abstracts and times for Tibotec's presentations on TMC435 appear below - full abstracts can also be accessed at http://www.easl.eu/.

Oral Presentation:

* "Impact of IL28B genotype and pretreatment serum IP-10 in treatment-naive genotype-1 HCV patients treated with TMC435 in combination with peginterferon alpha-2a and ribavirin in PILLAR study" - Thursday, March 31, 2011 from 17:00 to 19:00

Poster Presentations:

* Late-breaker "The ASPIRE trial: TMC435 in treatment-experienced patients with genotype-1 HCV infection who have failed previous PEG/RBV treatment" - Thursday, March 31, 2011 to Saturday, April 2, 2011

* "Pharmacokinetics of TMC435 in subjects with moderate hepatic impairment" - Thursday, March 31, 2011 from 09:00 to 18:00

* "Treatment outcome and resistance analysis in HCV genotype-1 patients previously exposed to TMC435 monotherapy and re-treated with TMC435 in combination with pegIFNalpha-2a/ribavirin" - Saturday, April 2, 2011 from 09:00 to 18:00

About HCV

HCV is a blood-borne infectious disease that affects the liver. With an estimated 170 million people infected worldwide and three to four million people newly infected each year, 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 worldwide. The current standard of care for HCV, pegylated interferon combined with ribavirin, causes serious side effects and only cures 40 to 50 percent of genotype 1 patients. The development of new therapies, particularly direct antivirals with different modes of action, may allow HCV patients to undergo a shorter and more effective treatment regimen.

About Tibotec Pharmaceuticals

Tibotec Pharmaceuticals is a global pharmaceutical and research development company and one of the companies that compose the Janssen Pharmaceutical Companies of Johnson & Johnson. 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.

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