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Achillion Announces Nomination of ACH-2684 as Lead Clinical Candidate in Resistance-Focused HCV Program
Compound Demonstrates Excellent Potency Against HCV and Retains Activity Against Resistant Variants
January 28, 2010
NEW HAVEN, Conn., Jan. 28, 2010 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced the nomination of a lead clinical candidate in its third proprietary program against hepatitis C infection. The candidate, ACH-2684, demonstrates excellent potency in the low pico-molar range, as well as good pharmacokinetic and safety profiles in pre-clinical studies.
“The potency and virology profile of ACH-2684 demonstrates that it very effectively suppresses a broad range of natural variants of the hepatitis C virus, and may be effective in prevention and treatment of emerging resistant variants. This compound also retains potent activity against all genotypes. The very high potency of ACH-2684 was achieved by optimizing its interactions against NS3 protease. We have demonstrated in vitro that ACH-2684 can be used in combination with other HCV inhibitors, and that it is synergistic with NS5B nucleoside polymerase inhibitors,” said Milind S. Deshpande, Ph.D., Executive Vice President and Chief Scientific Officer of Achillion. “We have leveraged our expertise in HCV drug discovery and structure-based design to create a set of compounds, including ACH-2684, that are part of a discrete intellectual property estate and to which we currently retain all commercial rights."
Michael D. Kishbauch, Achillion’s President and CEO, stated, “We are quite pleased to announce a clinical candidate from our third proprietary HCV program, further demonstrating our robust drug discovery expertise in this important therapeutic area. The compound, with its potency–resistance profile and preliminary safety characteristics, has the potential to be highly complementary to both our Gilead-partnered NS4A antagonist compounds as well as our ACH-1625 protease inhibitor, which recently achieved strong proof-of-concept results. We expect to move to IND-enabling pre-clinical testing of ACH-2684, and initiate a Phase 1/1b study in 2011.”
The Company will provide additional information on ACH-2684 during its Corporate and Clinical Update conference call and simultaneous webcast on Monday, February 1, 2010 at 4:30 p.m. Eastern time. To participate in the conference call, please dial ( 866 ) 743 – 9944 in the U.S. or ( 720 ) 545 - 0058 for international callers. A live audio webcast of the call will be accessible at www.achillion.com, under the News Center section of the website. Please connect to Achillion's Web site several minutes prior to the start of the broadcast to ensure adequate time for any software download that may be necessary.
About HCV
The hepatitis C virus (HCV) is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80% of individuals become chronically infected following exposure to the virus. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.
About Achillion
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion’s proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease – hepatitis C, resistant bacterial infections and HIV. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-1625, which may not be duplicated in future preclinical studies or in future clinical studies, if any; Achillion's expectations regarding the timing of other preclinical and 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, 2008.
All forward-looking statements reflect Achillion's expectations only as of the date of this release and should not be relied upon as reflecting Achillion's views, expectations or beliefs at any date subsequent to the date of this release. Achillion anticipates that subsequent events and developments may cause these views, expectations and beliefs to change. However, while Achillion may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so. ACHN-G
CONTACT: Achillion Pharmaceuticals, Inc.
Mary Kay Fenton
(203) 624-7000
mfenton@achillion.com
Friday, January 29, 2010
Conatus Pharmaceuticals Initiates Phase II Clinical Trial
Conatus Pharmaceuticals Initiates Phase II Clinical Trial in Combination With Pegylated Interferon and Ribavirin for the Treatment of Hepatitis C Virus (HCV)
SAN DIEGO, Jan. 28 /PRNewswire/ -- Conatus Pharmaceuticals Inc. announced today the initiation of a Phase II clinical trial evaluating CTS-1027 in combination with pegylated interferon (Pegasys®) and ribavirin (Copegus®) in refractory HCV patients. Antiviral activity, safety and tolerability of the triple combination will be assessed after up to 48 weeks of therapy.
"There is a significant unmet medical need in HCV patients who have not responded to pegylated interferon and ribavirin. These patients often progress to cirrhosis, a life-threatening condition. CTS-1027 has the potential to increase the effectiveness of the combination of pegylated interferon and ribavirin in this population," said Dr. Paul J. Pockros, Head, Division of Gastroenterology and Director of the SC Liver Research Consortium and The Scripps Clinic in La Jolla, CA.
CTS-1027 is an oral, small molecule compound that inhibits the activity of key members of a class of protease enzymes, the matrix metalloproteinases or MMPs. CTS-1027's anti-inflammatory and anti-fibrotic effects have been well-established in models of acute hepatitis and liver fibrosis. In addition, CTS-1027 has been shown to reduce and/or block HCV replication in in vitro preclinical models.
This clinical trial is an open-label design testing an optimized dose of CTS-1027 in combination with Pegasys® and Copegus® in HCV-infected patients who were prior null responders to pegylated interferon and ribavirin treatment. Dosing will last for up to 48 weeks. The Company expects approximately 60 patients to be enrolled. The clinical trial will be conducted at up to fifteen medical centers in the U.S. Additional information about the trial can be found at:www.clinicaltrials.gov (Identifier NCT01051921) or www.clinicaltrials.gov/ct2/show/NCT01051921?term=cts1027&rank=2.
"Our studies suggest that CTS-1027 treatment has the potential to amplify the effectiveness of pegylated interferon and ribavirin therapy. We believe that treating the most refractory patients will give us the best indication as to whether CTS-1027 can enhance the activity of existing therapy," said Steven J. Mento, President and CEO of Conatus. "The field is moving towards combinations of small molecules, and CTS-1027 represents a novel approach that we hope will benefit patients infected with HCV."
Conatus Pharmaceuticals Inc. is a privately-held specialty pharmaceutical company engaged in the development of innovative human therapeutics to treat liver disease. Chronic liver disease affects millions of people worldwide and can be caused by many different conditions or "insults" to the liver including Hepatitis C and other viral infections, obesity, chronic alcohol abuse or autoimmune diseases. Conatus was founded by the executive management team of Idun Pharmaceuticals in July 2005 following the successful sale of Idun to Pfizer. For additional information, please visitwww.conatuspharma.com.
Pegasys® and Copegus® are registered trademarks of F. Hoffman-La Roche, Inc.
SOURCE Conatus Pharmaceuticals Inc.
RELATED LINKS
http://www.conatuspharma.com
SAN DIEGO, Jan. 28 /PRNewswire/ -- Conatus Pharmaceuticals Inc. announced today the initiation of a Phase II clinical trial evaluating CTS-1027 in combination with pegylated interferon (Pegasys®) and ribavirin (Copegus®) in refractory HCV patients. Antiviral activity, safety and tolerability of the triple combination will be assessed after up to 48 weeks of therapy.
"There is a significant unmet medical need in HCV patients who have not responded to pegylated interferon and ribavirin. These patients often progress to cirrhosis, a life-threatening condition. CTS-1027 has the potential to increase the effectiveness of the combination of pegylated interferon and ribavirin in this population," said Dr. Paul J. Pockros, Head, Division of Gastroenterology and Director of the SC Liver Research Consortium and The Scripps Clinic in La Jolla, CA.
CTS-1027 is an oral, small molecule compound that inhibits the activity of key members of a class of protease enzymes, the matrix metalloproteinases or MMPs. CTS-1027's anti-inflammatory and anti-fibrotic effects have been well-established in models of acute hepatitis and liver fibrosis. In addition, CTS-1027 has been shown to reduce and/or block HCV replication in in vitro preclinical models.
This clinical trial is an open-label design testing an optimized dose of CTS-1027 in combination with Pegasys® and Copegus® in HCV-infected patients who were prior null responders to pegylated interferon and ribavirin treatment. Dosing will last for up to 48 weeks. The Company expects approximately 60 patients to be enrolled. The clinical trial will be conducted at up to fifteen medical centers in the U.S. Additional information about the trial can be found at:www.clinicaltrials.gov (Identifier NCT01051921) or www.clinicaltrials.gov/ct2/show/NCT01051921?term=cts1027&rank=2.
"Our studies suggest that CTS-1027 treatment has the potential to amplify the effectiveness of pegylated interferon and ribavirin therapy. We believe that treating the most refractory patients will give us the best indication as to whether CTS-1027 can enhance the activity of existing therapy," said Steven J. Mento, President and CEO of Conatus. "The field is moving towards combinations of small molecules, and CTS-1027 represents a novel approach that we hope will benefit patients infected with HCV."
Conatus Pharmaceuticals Inc. is a privately-held specialty pharmaceutical company engaged in the development of innovative human therapeutics to treat liver disease. Chronic liver disease affects millions of people worldwide and can be caused by many different conditions or "insults" to the liver including Hepatitis C and other viral infections, obesity, chronic alcohol abuse or autoimmune diseases. Conatus was founded by the executive management team of Idun Pharmaceuticals in July 2005 following the successful sale of Idun to Pfizer. For additional information, please visitwww.conatuspharma.com.
Pegasys® and Copegus® are registered trademarks of F. Hoffman-La Roche, Inc.
SOURCE Conatus Pharmaceuticals Inc.
RELATED LINKS
http://www.conatuspharma.com
Telaprevir and Peginterferon with or without Ribavirin for Chronic HCV Infection
Telaprevir and Peginterferon with or without Ribavirin for Chronic HCV Infection....A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously (PROVE2)
Download the PDF here
NEJM April 30, 2009
Patients were enrolled at 28 centers in France, Germany, the United Kingdom, and Austria between August 2, 2006, and January 17, 2007. Eligibility criteria included no previous treatment for HCV infection, an age of 18 to 65 years, chronic HCV genotype 1 infection with detectable plasma HCV RNA levels, and no histologic evidence of cirrhosis within 2 years before study day 1. This was a phase 2b, randomized, partially double-blind, placebo-controlled trial.
The rate of sustained virologic response....was....46% (38 of 82) in the PR48 (control) group (P=0.89)......The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia.
Among the 22 patients who had a viral breakthrough during the 12 weeks of telaprevir administration and had a viral RNA level above the limit of detection of the sequencing assay, wild-type virus was found in 1 (5%), variants with low-level resistance in 9 (41%), and variants with high-level resistance in 12 (55%) (Table 3). Among the 42 patients who had a relapse after completion of treatment with telaprevir and had a viral RNA level above the limit of detection of the sequencing assay, wild-type virus was found in 2 (5%), low-level resistant variants in 33 (79%) and high-level resistant variants in 7 (17%). In some patients who did not receive ribavirin, complex changes in sequence were seen during the study.
Pruritus and rash were more frequent in the telaprevir groups than in the control group. Pruritus occurred in 51% of patients (41 of 81) in the T12PR24 group, 63% (52 of 82) in the T12PR12 group, and 59% (46 of 78) in the T12P12 group, as compared with 35% (29 of 82) in the PR48 group. The incidence of rash was 49% (40 of 81 patients) in the T12PR24 group, 44% (36 of 82) in the T12PR12 group, and 47% (37 of 78) in the T12P12 group, as compared with 35% (29 of 82) in the PR48 group. The rashes in patients in the telaprevir-based groups were generally maculopapular and were clinically similar to those observed in drug reactions. The median time to the appearance of a rash of any severity in the telaprevir-based groups was 9 to 12 days. Severe (grade 3) rash was found in 7% of patients (6 of 81) in the T12PR24 group, 6% (5 of 82) in the T12PR12 group, and 3% (2 of 78) in the T12P12 group, but was not seen in the PR48 group (Table 4). There were no grade 4 rashes reported. Twelve of the 163 patients (7%) in the combined T12PR24 and T12PR12 groups discontinued treatment because of rash....
...Telaprevir administration also affected hemoglobin levels during the treatment period. During the first 12 weeks of treatment, the median decrease in the baseline hemoglobin level was 3.0 g per deciliter in the PR48 group, 3.1 g per deciliter in the T12P12 group, and 3.6 and 3.9 g per deciliter in the T12PR24 and T12PR12 groups, respectively."
Christophe HŽzode, M.D., Nicole Forestier, M.D., Geoffrey Dusheiko, M.D., Peter Ferenci, M.D., Stanislas Pol, M.D., Tobias Goeser, M.D., Jean-Pierre Bronowicki, M.D., Marc Bourlire, M.D., Shahin Gharakhanian, M.D., Leif Bengtsson, B.S.C., Lindsay McNair, M.D., M.P.H., Shelley George, M.D., Tara Kieffer, Ph.D., Ann Kwong, Ph.D., Robert S. Kauffman, M.D., Ph.D., John Alam, M.D., Jean-Michel Pawlotsky, M.D., Ph.D., Stefan Zeuzem, M.D., for the PROVE2 Study Team
ABSTRACT
Background- In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment.
Methods- A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 µg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups.
Results- The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia.
Conclusions; In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385 [ClinicalTrials.gov] .)
Hepatitis C virus (HCV) is the most common infectious cause of chronic liver disease in Europe and the United States. Chronic hepatitis C may result in life-threatening complications, including cirrhosis and hepatocellular carcinoma. Antiviral therapy may result in a sustained virologic response, characterized by an undetectable HCV RNA level 24 weeks after the end of therapy, which correlates with a long-term clinical benefit. In patients infected with HCV genotype 1, the most common genotype worldwide, the standard combination of peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of only 40 to 50%.1,2,3
A number of new therapeutic approaches are being assessed.4 The nonstructural 3/4A (NS3/4A) serine protease processes the HCV polyprotein to generate mature viral proteins. Direct protease inhibition emerged as a promising target for therapy when a reduction in viral replication of several log10 units was shown after 2 days of administration of an NS3/4A protease inhibitor.5
Telaprevir is a reversible, selective, orally bioavailable inhibitor of the HCV NS3/4A serine protease.6 Telaprevir monotherapy for 14 days induced a median decline of more than 4.4 log10 units in the plasma HCV RNA level in patients with chronic HCV genotype 1 infection.7 In an early study, all 12 patients with HCV genotype 1 who were receiving telaprevir with peginterferon and ribavirin for 28 days had undetectable HCV RNA levels at the end of the therapy with these three study drugs.8
The Protease Inhibition for Viral Evaluation 2 (PROVE2) trial was a multicenter, randomized, partially double-blind, placebo-controlled phase 2b trial conducted in Europe to assess the efficacy and adverse event profile of various regimens combining telaprevir with peginterferon alfa-2a, with or without ribavirin, as compared with peginterferon alfa-2a and ribavirin alone, in patients infected with HCV genotype 1 who had not been treated previously.
Results
Characteristics of the Patients
Of 388 patients screened, 334 were randomly assigned to a treatment group and 323 received study medication (Figure 1). The characteristics of the treatment groups were similar at baseline (Table 1).
Virologic Responses during the Treatment Period
Table 2 shows the proportion of patients with undetectable HCV RNA (<10 IU per milliliter) at weeks 4, 12, and 24 during the treatment period as well as 24 weeks after completion of planned treatment (the time of assessment for a sustained virologic response) in the four groups. The median time to an undetectable HCV RNA level was 113 days (range, 15 to 337) in the PR48 group, 28 days (range, 8 to 172) in the T12PR24 group, 22 days (range, 4 to 85) in the T12PR12 group, and 29 days (range, 4 to 86) in the T12P12 group. Figure 2 shows the mean change in HCV RNA levels during the first 12 weeks of treatment.
The proportions of patients who had undetectable HCV RNA levels at weeks 4 and 12 were significantly higher in all telaprevir-based groups than in the PR48 group. At week 4, levels were undetectable in 69% of patients in the T12PR24 group, 80% in the T12PR12 group, and 50% in the T12P12 group (vs. 13% in the PR48 group, P<0.001 for each comparison). At week 12, levels were undetectable in 73% of patients in the T12PR24 group (vs. 43% in the PR48 group, P<0.001), 80% in the T12PR12 group (P<0.001), and 62% in the T12P12 group (P=0.02). At the end of treatment Ñ i.e., at week 24 in the T12PR24 group, week 12 in the T12PR12 and T12P12 groups, and week 48 in the PR48 group Ñ the proportions of patients with undetectable HCV RNA levels were higher in both groups receiving all three study drugs (70% in the T12PR24 group and 80% in the T12PR12 group) and in the T12P12 group (62%) than in the PR48 group (55%).
Sustained Virologic Response
A sustained virologic response, defined as an undetectable HCV RNA 24 weeks after completion of therapy, was the primary end point. In the three telaprevir-based groups, 19 patients (14 in the T12P12 group) had detectable HCV RNA at the last study visit before the planned end of treatment and were therefore assigned to complete a total of 48 weeks of peginterferon alfa-2a and ribavirin, according to the protocol. Seven patients (all in the T12P12 group) completed this treatment; three of the seven had a sustained virologic response but were counted as having treatment failure in the analysis of the rate of sustained virologic response.
The rate of sustained virologic response for the PR48 group was 46% (38 of 82 patients). According to the originally planned primary analysis, the rate of sustained virologic response for the combined T12P12 and T12PR12 groups was 48% (77 of 160, P=0.89 for the comparison with the PR48 group).
In the T12PR24 group, a sustained virologic response was achieved in 47 of the 61 patients who completed the assigned treatment and in 9 of the 20 patients who discontinued the study treatment before week 24, for an overall rate of 69% (56 of 81 patients), which was significantly higher than that in the PR48 group (P=0.004). The rate of sustained virologic response was not significantly higher in the T12PR12 group or the T12P12 group than in the PR48 group. In the T12PR12 group, there was a sustained virologic response in 46 of the 72 patients who completed treatment and in 3 of the 10 who discontinued treatment, for an overall rate of 60% (49 of 82 patients, P=0.12 for the comparison with the PR48 group). In the group not receiving ribavirin (the T12P12 group), a sustained virologic response was achieved in 24 of the 70 patients who completed treatment and in 4 of the 8 who discontinued treatment, for an overall rate of 36% (28 of 78 patients, P=0.20 for the comparison with the PR48 group). The difference between the rates in the T12PR12 group and the T12P12 group was significant (P=0.003).
Viral Breakthrough and Relapse
By week 12, a viral breakthrough had been observed in 1 of 82 patients (1%) in the PR48 group, 19 of 78 (24%) in the T12P12 group, 1 of 82 (1%) in the T12PR12 group, and 4 of 81 (5%) in the T12PR24 group. Additional viral breakthroughs occurred in 1 of the 81 patients in the T12PR24 group, after the completion of telaprevir, and in 3 of the 82 patients in the PR48 group between weeks 12 and 48.
Relapse (defined as a detectable HCV RNA level during the 24-week post-treatment period in patients who had undetectable HCV RNA at the end of the treatment period) occurred in 8 of 57 patients (14%) in the T12PR24 group, 19 of 63 (30%) in the T12PR12 group, 22 of 46 (48%) in the T12P12 group, and 10 of 45 (22%) in the PR48 group. In the T12PR24 group, the relapse rate among those who had undetectable HCV RNA at weeks 4 and 12 was 7% (3 of 45 patients).
In the T12PR24, T12PR12, and T12P12 groups, of the 133 patients with a sustained virologic response, 118 returned for follow-up visits through 48 weeks after the completion of treatment. Two of the 133 patients had a late relapse: 1 in the T12PR24 group had discontinued treatment on day 65 and had an HCV RNA level that became detectable 48 weeks after the end of treatment; the other, in the T12P12 group, had discontinued treatment on day 60 and had a detectable HCV RNA level 36 weeks after the end of treatment. In both patients, viral sequence analysis confirmed the recurrence of the original infection.
Analysis of the full-length NS3 protease sequence was carried out in patients with a breakthrough and in those who had a relapse after completion of telaprevir therapy. HCV virus that had low-level resistance to telaprevir was found at baseline in 1% of patients. Among the 22 patients who had a viral breakthrough during the 12 weeks of telaprevir administration and had a viral RNA level above the limit of detection of the sequencing assay, wild-type virus was found in 1 (5%), variants with low-level resistance in 9 (41%), and variants with high-level resistance in 12 (55%) (Table 3). Among the 42 patients who had a relapse after completion of treatment with telaprevir and had a viral RNA level above the limit of detection of the sequencing assay, wild-type virus was found in 2 (5%), low-level resistant variants in 33 (79%) and high-level resistant variants in 7 (17%). In some patients who did not receive ribavirin, complex changes in sequence were seen during the study.
Independent Predictors of Sustained Virologic Response
The association between a sustained virologic response and independent variables was explored with the use of a logistic-regression model. Treatment group and baseline HCV RNA level were the only two variables significantly associated with a sustained virologic response (P<0.001) (Table 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).
Safety
Table 4 lists the principal adverse events reported in each group. Pruritus and rash were more frequent in the telaprevir groups than in the control group. Pruritus occurred in 51% of patients (41 of 81) in the T12PR24 group, 63% (52 of 82) in the T12PR12 group, and 59% (46 of 78) in the T12P12 group, as compared with 35% (29 of 82) in the PR48 group. The incidence of rash was 49% (40 of 81 patients) in the T12PR24 group, 44% (36 of 82) in the T12PR12 group, and 47% (37 of 78) in the T12P12 group, as compared with 35% (29 of 82) in the PR48 group. The rashes in patients in the telaprevir-based groups were generally maculopapular and were clinically similar to those observed in drug reactions. The median time to the appearance of a rash of any severity in the telaprevir-based groups was 9 to 12 days. Severe (grade 3) rash was found in 7% of patients (6 of 81) in the T12PR24 group, 6% (5 of 82) in the T12PR12 group, and 3% (2 of 78) in the T12P12 group, but was not seen in the PR48 group (Table 4). There were no grade 4 rashes reported. Twelve of the 163 patients (7%) in the combined T12PR24 and T12PR12 groups discontinued treatment because of rash.
Telaprevir administration also affected hemoglobin levels during the treatment period. During the first 12 weeks of treatment, the median decrease in the baseline hemoglobin level was 3.0 g per deciliter in the PR48 group, 3.1 g per deciliter in the T12P12 group, and 3.6 and 3.9 g per deciliter in the T12PR24 and T12PR12 groups, respectively.
Other adverse events were similar in type and frequency in the telaprevir-based groups and the control group. Twenty-eight of the 241 patients (12%) in the telaprevir-based groups discontinued the study treatment because of adverse events, including 18 patients who did so before week 12 (i.e., during the period of telaprevir administration), as compared with 6 of 82 patients (7%) in the control group.
Discussion
In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir-containing regimens tested Ñ treatment with telaprevir for 12 weeks and peginterferon alfa-2a and ribavirin for 24 weeks (T12PR24) Ñ resulted in a significantly higher rate, by approximately 20 percentage points, of sustained virologic response than was found with the standard therapy of 48 weeks of peginterferon alfa-2a and ribavirin (PR48). These data, together with those from a similar phase 2 study performed in the United States (PROVE1, described elsewhere in this issue of the Journal),12 support the performance of a larger, phase 3 trial of telaprevir in combination with peginterferon alfa-2a and ribavirin.
However, several questions remain unanswered. Patients with cirrhosis were not evaluated. Durations of triple-combination therapies with peginterferon alfa, ribavirin, and telaprevir that differ from the durations tested in PROVE2 will require further investigation, as will the criteria for extension of peginterferon alfa and ribavirin therapy. Further investigation will shed light on the usefulness of tailoring therapy on the basis of the kinetics of the early viral response.
Our results show the necessity of administering ribavirin in combination with peginterferon alfa and telaprevir. Ribavirin will most likely be required in combination with the use of other specific HCV inhibitors and peginterferon alfa to achieve the high rates of sustained virologic response seen in our study. Among patients receiving telaprevir-based regimens, the addition of ribavirin increased the sustained virologic response rates by preventing relapse and the emergence of both low-level and high-level telaprevir resistance. In spite of its moderate, transient antiviral effect on HCV replication when administered as monotherapy,13 ribavirin has been shown to prevent viral breakthrough during, and relapse after, the treatment period by significantly accelerating the second slope of viral-RNA decrease in patients who have a response to the antiviral effect of peginterferon alfa.14 The modes of action of ribavirin remain under debate.15,16,17,18,19 Our study results are consistent with the notion that ribavirin does not act by directly inhibiting HCV replication, since it cannot be replaced by a potent HCV inhibitor in combination with peginterferon alfa-2a.
Both rash and pruritus were frequently reported in this study, but they did not always occur in combination. Severe rash occurred in approximately 5% of patients treated with telaprevir. Both rash and pruritus regressed after withdrawal of telaprevir and administration of appropriate therapy, including topical treatments for symptoms and corticosteroids (in some cases, systemic corticosteroids). Patients receiving telaprevir should be clinically monitored for dermatologic reactions and treated appropriately. The optimal management of rash and its effect on treatment adherence and efficacy requires further investigation. Decreased hemoglobin levels were also more frequent among the patients receiving telaprevir than among those in the control group, though the condition was not often a cause of treatment discontinuation.
In conclusion, although a significant improvement in sustained virologic response was not shown in association with two of the telaprevir regimens tested, 12 weeks of telaprevir combined with 24 weeks of peginterferon alfa-2a and ribavirin resulted in significantly higher rates of sustained virologic response than 48 weeks of peginterferon and ribavirin alone. This study therefore suggests that the use of telaprevir may improve the rate of sustained virologic response in patients with a chronic HCV genotype 1 infection. A drug-induced rash necessitated that telaprevir be discontinued in some patients. Larger and longer studies are required to assess the efficacy and safety of telaprevir for HCV infection.
Methods
Patients
Patients were enrolled at 28 centers in France, Germany, the United Kingdom, and Austria between August 2, 2006, and January 17, 2007. Eligibility criteria included no previous treatment for HCV infection, an age of 18 to 65 years, chronic HCV genotype 1 infection with detectable plasma HCV RNA levels, and no histologic evidence of cirrhosis within 2 years before study day 1.
The protocol and informed-consent form were approved by appropriate ethics committees at all study centers, in accordance with national procedures. All patients provided written informed consent before participating in the study. The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local laws and regulations.
Study Design
This was a phase 2b, randomized, partially double-blind, placebo-controlled trial. Eligible patients were stratified on the basis of self-reported race or ethnic group (black or other) and baseline weight (>75 kg vs. <75 kg). Patients were randomly assigned to one of four treatment groups: the T12PR24 group, which received telaprevir (VX-950, Vertex Pharmaceuticals), peginterferon alfa-2a (Pegasys, Roche), and ribavirin (Copegus, Roche) for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks; the T12PR12 group, which received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks; the T12P12 group, which received telaprevir and peginterferon alfa-2a, without ribavirin, for 12 weeks; and the PR48 (control) group, which received placebo, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 36 more weeks. Randomization was performed through a central telephone-based system, in a 1:1:1:1 ratio (with randomization blocks of 4). In the PR48 group, as in clinical practice,9 if there was a decline of 2 log10 units in the plasma HCV RNA level at week 12 and the HCV RNA level was undetectable at week 24, treatment was continued; if not, treatment was stopped, since the chance of clearing the infection was extremely low.10,11
Telaprevir was given as a single dose of 1250 mg on study day 1, followed by a dose of 750 mg every 8 hours; peginterferon alfa-2a was given subcutaneously at a dose of 180 µg per week; ribavirin was given orally at a dose of 1000 mg per day (for body weight <75 kg) or 1200 mg per day (for body weight >75 kg). Treatment of the PR48, T12PR12, and T12PR24 groups was double-blinded through week 10. Treatment of the T12P12 group was not blinded, because the absence of ribavirin would result in discernable hematologic effects. Patients in the T12PR24, T12PR12, and T12P12 groups were required to have undetectable HCV RNA levels at the last study visit before the planned end of treatment (i.e., at week 10 for the T12PR12 and T12P12 groups and at week 20 for the T12PR24 group). If patients had detectable HCV RNA levels at this visit, they were to continue to receive peginterferon alfa-2a and ribavirin through treatment week 48. Since the intention was to assess the efficacy of shorter treatment durations, these patients were considered to have treatment failure in the analysis of a sustained virologic response.
The study sponsor and the academic principal investigators were responsible for study design and protocol development. The manuscript was drafted by the principal academic authors with input from the publication committee (consisting of four academic authors). All authors had access to the data and assume responsibility for the accuracy and completeness of the data reported.
Efficacy Assessments
Plasma HCV RNA levels were measured with the use of the COBAS TaqMan HCV assay, version 1.0 (Roche Molecular Systems), with a lower limit of quantification of 30 IU per milliliter and a lower limit of detection of 10 IU per milliliter. HCV RNA assessments were performed at the screening visit, at days 1, 4, and 8, and at weeks 2, 3, 4, 6, 8, 10, and 12; additional assessments occurred at weeks 16, 20, and 24 in the T12PR24 and PR48 groups and at weeks 28, 36, and 48 in the PR48 group. All patients had a follow-up visit 2 weeks after completion of the study treatment. In patients in the three telaprevir-based groups who had completed all treatment (ending at week 12 or week 24), HCV RNA levels were also measured 1, 2, 4, 8, 12, 24, 36, and 48 weeks after completion of the study treatment.
Viral breakthrough during therapy was defined as an increase of more than 1 log10 IU per milliliter from the lowest HCV RNA level or as an HCV RNA level above 100 IU per milliliter in patients with previously undetectable HCV RNA. Relapse was defined as a detectable HCV RNA level during the 24-week post-treatment period in patients who had undetectable HCV RNA at the end of treatment.
Safety Assessments
Safety assessments included physical examinations, recording of adverse events, and serum chemical and hematologic evaluations at all study visits, and electrocardiography at the start and end of the treatment period. The original protocol was amended in January 2007 to add specific evaluations for grade 3 or 4 rashes, including pharmacokinetic analysis and HLA typing of blood samples.
Stepwise temporary reductions or short interruptions of ribavirin or peginterferon alfa-2a therapy were permitted, to manage adverse events or laboratory abnormalities. Dose reduction or interruption of telaprevir was not allowed. The use of granulocyte colony-stimulating factor and erythropoietin was not allowed during the initial 12 weeks of study treatment.
Statistical Analysis
The main efficacy measure was the proportion of patients who had a sustained virologic response: an HCV RNA level that was undetectable (<10 IU per milliliter) 24 weeks after the completion of study treatment. The analysis included all patients who had undergone randomization and had received at least one dose of any study drug. The planned primary analysis was the comparison of the PR48 group with the T12PR12 group and the T12P12 group (which did not receive ribavirin) combined, and the planned secondary analysis was a comparison of each of the three telaprevir-based groups with the PR48 group. Assuming rates of sustained virologic response of 50% in the PR48 group and 70% in the combined T12PR12 and T12P12 groups, we calculated that with 80 patients who could be evaluated in the PR48 group and 160 who could be evaluated in the combined groups, the study would have a statistical power of at least 80% to show a significant difference.
Five planned interim analyses were conducted by the sponsor, Vertex Pharmaceuticals, to monitor safety and assess antiviral efficacy during the treatment period. Each interim analysis included descriptive analyses of safety data (adverse events and laboratory data) and HCV RNA results. There were no stopping rules or a priori plans for changes to the study conduct on the basis of interim analyses.
After the third interim analysis, it became apparent that the T12P12 group did not have a response during the treatment period that was similar to the response of the T12PR12 group, and the statistical-analysis plan was revised by the sponsor to remove the originally planned primary analysis. The original secondary analysis, a comparison of the sustained virologic response in each of the three telaprevir-based groups with the response in the PR48 group, became the primary analysis.
Results of the fourth interim analysis (performed after all patients had reached the end of the treatment period and data on sustained virologic response were available for the T12PR24 group) and fifth interim analysis (conducted when the PR48 group was still undergoing follow-up but data on the post-treatment responses for the three telaprevir groups were available) were made available to the investigators and presented at scientific meetings. Because it is not clear how to adjust the interpretation of the analyses for these unplanned changes and multiple examinations of the data, the results are reported as originally planned.
Treatment assignments were unblinded at week 10 for all patients; therefore, there was no data and safety monitoring board. Safety of the patients was monitored by investigators and three study medical monitors, who reviewed all safety events, and by means of a review of adverse-event data during the interim analyses.
The comparisons between groups were performed with the use of Fisher's exact test. All reported P values are two-sided and have not been adjusted for multiple testing. A prespecified multivariate analysis to evaluate the possible relationship between a sustained virologic response and baseline variables (age, weight and body-mass index, and baseline HCV RNA level) was performed by means of a logistic-regression model with a sustained virologic response as the dependent variable. The following factors were added post hoc and were also explored in the model: sex, HCV genotype 1 subtype (1a vs. 1b), and alanine aminotransferase and fasting glucose levels at baseline. Variables that had a weak association (P>0.20) with a sustained virologic response in the initial logistic-regression model were excluded from the final model.
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NEJM April 30, 2009
Patients were enrolled at 28 centers in France, Germany, the United Kingdom, and Austria between August 2, 2006, and January 17, 2007. Eligibility criteria included no previous treatment for HCV infection, an age of 18 to 65 years, chronic HCV genotype 1 infection with detectable plasma HCV RNA levels, and no histologic evidence of cirrhosis within 2 years before study day 1. This was a phase 2b, randomized, partially double-blind, placebo-controlled trial.
The rate of sustained virologic response....was....46% (38 of 82) in the PR48 (control) group (P=0.89)......The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia.
Among the 22 patients who had a viral breakthrough during the 12 weeks of telaprevir administration and had a viral RNA level above the limit of detection of the sequencing assay, wild-type virus was found in 1 (5%), variants with low-level resistance in 9 (41%), and variants with high-level resistance in 12 (55%) (Table 3). Among the 42 patients who had a relapse after completion of treatment with telaprevir and had a viral RNA level above the limit of detection of the sequencing assay, wild-type virus was found in 2 (5%), low-level resistant variants in 33 (79%) and high-level resistant variants in 7 (17%). In some patients who did not receive ribavirin, complex changes in sequence were seen during the study.
Pruritus and rash were more frequent in the telaprevir groups than in the control group. Pruritus occurred in 51% of patients (41 of 81) in the T12PR24 group, 63% (52 of 82) in the T12PR12 group, and 59% (46 of 78) in the T12P12 group, as compared with 35% (29 of 82) in the PR48 group. The incidence of rash was 49% (40 of 81 patients) in the T12PR24 group, 44% (36 of 82) in the T12PR12 group, and 47% (37 of 78) in the T12P12 group, as compared with 35% (29 of 82) in the PR48 group. The rashes in patients in the telaprevir-based groups were generally maculopapular and were clinically similar to those observed in drug reactions. The median time to the appearance of a rash of any severity in the telaprevir-based groups was 9 to 12 days. Severe (grade 3) rash was found in 7% of patients (6 of 81) in the T12PR24 group, 6% (5 of 82) in the T12PR12 group, and 3% (2 of 78) in the T12P12 group, but was not seen in the PR48 group (Table 4). There were no grade 4 rashes reported. Twelve of the 163 patients (7%) in the combined T12PR24 and T12PR12 groups discontinued treatment because of rash....
...Telaprevir administration also affected hemoglobin levels during the treatment period. During the first 12 weeks of treatment, the median decrease in the baseline hemoglobin level was 3.0 g per deciliter in the PR48 group, 3.1 g per deciliter in the T12P12 group, and 3.6 and 3.9 g per deciliter in the T12PR24 and T12PR12 groups, respectively."
Christophe HŽzode, M.D., Nicole Forestier, M.D., Geoffrey Dusheiko, M.D., Peter Ferenci, M.D., Stanislas Pol, M.D., Tobias Goeser, M.D., Jean-Pierre Bronowicki, M.D., Marc Bourlire, M.D., Shahin Gharakhanian, M.D., Leif Bengtsson, B.S.C., Lindsay McNair, M.D., M.P.H., Shelley George, M.D., Tara Kieffer, Ph.D., Ann Kwong, Ph.D., Robert S. Kauffman, M.D., Ph.D., John Alam, M.D., Jean-Michel Pawlotsky, M.D., Ph.D., Stefan Zeuzem, M.D., for the PROVE2 Study Team
ABSTRACT
Background- In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment.
Methods- A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 µg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups.
Results- The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia.
Conclusions; In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385 [ClinicalTrials.gov] .)
Hepatitis C virus (HCV) is the most common infectious cause of chronic liver disease in Europe and the United States. Chronic hepatitis C may result in life-threatening complications, including cirrhosis and hepatocellular carcinoma. Antiviral therapy may result in a sustained virologic response, characterized by an undetectable HCV RNA level 24 weeks after the end of therapy, which correlates with a long-term clinical benefit. In patients infected with HCV genotype 1, the most common genotype worldwide, the standard combination of peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of only 40 to 50%.1,2,3
A number of new therapeutic approaches are being assessed.4 The nonstructural 3/4A (NS3/4A) serine protease processes the HCV polyprotein to generate mature viral proteins. Direct protease inhibition emerged as a promising target for therapy when a reduction in viral replication of several log10 units was shown after 2 days of administration of an NS3/4A protease inhibitor.5
Telaprevir is a reversible, selective, orally bioavailable inhibitor of the HCV NS3/4A serine protease.6 Telaprevir monotherapy for 14 days induced a median decline of more than 4.4 log10 units in the plasma HCV RNA level in patients with chronic HCV genotype 1 infection.7 In an early study, all 12 patients with HCV genotype 1 who were receiving telaprevir with peginterferon and ribavirin for 28 days had undetectable HCV RNA levels at the end of the therapy with these three study drugs.8
The Protease Inhibition for Viral Evaluation 2 (PROVE2) trial was a multicenter, randomized, partially double-blind, placebo-controlled phase 2b trial conducted in Europe to assess the efficacy and adverse event profile of various regimens combining telaprevir with peginterferon alfa-2a, with or without ribavirin, as compared with peginterferon alfa-2a and ribavirin alone, in patients infected with HCV genotype 1 who had not been treated previously.
Results
Characteristics of the Patients
Of 388 patients screened, 334 were randomly assigned to a treatment group and 323 received study medication (Figure 1). The characteristics of the treatment groups were similar at baseline (Table 1).
Virologic Responses during the Treatment Period
Table 2 shows the proportion of patients with undetectable HCV RNA (<10 IU per milliliter) at weeks 4, 12, and 24 during the treatment period as well as 24 weeks after completion of planned treatment (the time of assessment for a sustained virologic response) in the four groups. The median time to an undetectable HCV RNA level was 113 days (range, 15 to 337) in the PR48 group, 28 days (range, 8 to 172) in the T12PR24 group, 22 days (range, 4 to 85) in the T12PR12 group, and 29 days (range, 4 to 86) in the T12P12 group. Figure 2 shows the mean change in HCV RNA levels during the first 12 weeks of treatment.
The proportions of patients who had undetectable HCV RNA levels at weeks 4 and 12 were significantly higher in all telaprevir-based groups than in the PR48 group. At week 4, levels were undetectable in 69% of patients in the T12PR24 group, 80% in the T12PR12 group, and 50% in the T12P12 group (vs. 13% in the PR48 group, P<0.001 for each comparison). At week 12, levels were undetectable in 73% of patients in the T12PR24 group (vs. 43% in the PR48 group, P<0.001), 80% in the T12PR12 group (P<0.001), and 62% in the T12P12 group (P=0.02). At the end of treatment Ñ i.e., at week 24 in the T12PR24 group, week 12 in the T12PR12 and T12P12 groups, and week 48 in the PR48 group Ñ the proportions of patients with undetectable HCV RNA levels were higher in both groups receiving all three study drugs (70% in the T12PR24 group and 80% in the T12PR12 group) and in the T12P12 group (62%) than in the PR48 group (55%).
Sustained Virologic Response
A sustained virologic response, defined as an undetectable HCV RNA 24 weeks after completion of therapy, was the primary end point. In the three telaprevir-based groups, 19 patients (14 in the T12P12 group) had detectable HCV RNA at the last study visit before the planned end of treatment and were therefore assigned to complete a total of 48 weeks of peginterferon alfa-2a and ribavirin, according to the protocol. Seven patients (all in the T12P12 group) completed this treatment; three of the seven had a sustained virologic response but were counted as having treatment failure in the analysis of the rate of sustained virologic response.
The rate of sustained virologic response for the PR48 group was 46% (38 of 82 patients). According to the originally planned primary analysis, the rate of sustained virologic response for the combined T12P12 and T12PR12 groups was 48% (77 of 160, P=0.89 for the comparison with the PR48 group).
In the T12PR24 group, a sustained virologic response was achieved in 47 of the 61 patients who completed the assigned treatment and in 9 of the 20 patients who discontinued the study treatment before week 24, for an overall rate of 69% (56 of 81 patients), which was significantly higher than that in the PR48 group (P=0.004). The rate of sustained virologic response was not significantly higher in the T12PR12 group or the T12P12 group than in the PR48 group. In the T12PR12 group, there was a sustained virologic response in 46 of the 72 patients who completed treatment and in 3 of the 10 who discontinued treatment, for an overall rate of 60% (49 of 82 patients, P=0.12 for the comparison with the PR48 group). In the group not receiving ribavirin (the T12P12 group), a sustained virologic response was achieved in 24 of the 70 patients who completed treatment and in 4 of the 8 who discontinued treatment, for an overall rate of 36% (28 of 78 patients, P=0.20 for the comparison with the PR48 group). The difference between the rates in the T12PR12 group and the T12P12 group was significant (P=0.003).
Viral Breakthrough and Relapse
By week 12, a viral breakthrough had been observed in 1 of 82 patients (1%) in the PR48 group, 19 of 78 (24%) in the T12P12 group, 1 of 82 (1%) in the T12PR12 group, and 4 of 81 (5%) in the T12PR24 group. Additional viral breakthroughs occurred in 1 of the 81 patients in the T12PR24 group, after the completion of telaprevir, and in 3 of the 82 patients in the PR48 group between weeks 12 and 48.
Relapse (defined as a detectable HCV RNA level during the 24-week post-treatment period in patients who had undetectable HCV RNA at the end of the treatment period) occurred in 8 of 57 patients (14%) in the T12PR24 group, 19 of 63 (30%) in the T12PR12 group, 22 of 46 (48%) in the T12P12 group, and 10 of 45 (22%) in the PR48 group. In the T12PR24 group, the relapse rate among those who had undetectable HCV RNA at weeks 4 and 12 was 7% (3 of 45 patients).
In the T12PR24, T12PR12, and T12P12 groups, of the 133 patients with a sustained virologic response, 118 returned for follow-up visits through 48 weeks after the completion of treatment. Two of the 133 patients had a late relapse: 1 in the T12PR24 group had discontinued treatment on day 65 and had an HCV RNA level that became detectable 48 weeks after the end of treatment; the other, in the T12P12 group, had discontinued treatment on day 60 and had a detectable HCV RNA level 36 weeks after the end of treatment. In both patients, viral sequence analysis confirmed the recurrence of the original infection.
Analysis of the full-length NS3 protease sequence was carried out in patients with a breakthrough and in those who had a relapse after completion of telaprevir therapy. HCV virus that had low-level resistance to telaprevir was found at baseline in 1% of patients. Among the 22 patients who had a viral breakthrough during the 12 weeks of telaprevir administration and had a viral RNA level above the limit of detection of the sequencing assay, wild-type virus was found in 1 (5%), variants with low-level resistance in 9 (41%), and variants with high-level resistance in 12 (55%) (Table 3). Among the 42 patients who had a relapse after completion of treatment with telaprevir and had a viral RNA level above the limit of detection of the sequencing assay, wild-type virus was found in 2 (5%), low-level resistant variants in 33 (79%) and high-level resistant variants in 7 (17%). In some patients who did not receive ribavirin, complex changes in sequence were seen during the study.
Independent Predictors of Sustained Virologic Response
The association between a sustained virologic response and independent variables was explored with the use of a logistic-regression model. Treatment group and baseline HCV RNA level were the only two variables significantly associated with a sustained virologic response (P<0.001) (Table 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).
Safety
Table 4 lists the principal adverse events reported in each group. Pruritus and rash were more frequent in the telaprevir groups than in the control group. Pruritus occurred in 51% of patients (41 of 81) in the T12PR24 group, 63% (52 of 82) in the T12PR12 group, and 59% (46 of 78) in the T12P12 group, as compared with 35% (29 of 82) in the PR48 group. The incidence of rash was 49% (40 of 81 patients) in the T12PR24 group, 44% (36 of 82) in the T12PR12 group, and 47% (37 of 78) in the T12P12 group, as compared with 35% (29 of 82) in the PR48 group. The rashes in patients in the telaprevir-based groups were generally maculopapular and were clinically similar to those observed in drug reactions. The median time to the appearance of a rash of any severity in the telaprevir-based groups was 9 to 12 days. Severe (grade 3) rash was found in 7% of patients (6 of 81) in the T12PR24 group, 6% (5 of 82) in the T12PR12 group, and 3% (2 of 78) in the T12P12 group, but was not seen in the PR48 group (Table 4). There were no grade 4 rashes reported. Twelve of the 163 patients (7%) in the combined T12PR24 and T12PR12 groups discontinued treatment because of rash.
Telaprevir administration also affected hemoglobin levels during the treatment period. During the first 12 weeks of treatment, the median decrease in the baseline hemoglobin level was 3.0 g per deciliter in the PR48 group, 3.1 g per deciliter in the T12P12 group, and 3.6 and 3.9 g per deciliter in the T12PR24 and T12PR12 groups, respectively.
Other adverse events were similar in type and frequency in the telaprevir-based groups and the control group. Twenty-eight of the 241 patients (12%) in the telaprevir-based groups discontinued the study treatment because of adverse events, including 18 patients who did so before week 12 (i.e., during the period of telaprevir administration), as compared with 6 of 82 patients (7%) in the control group.
Discussion
In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir-containing regimens tested Ñ treatment with telaprevir for 12 weeks and peginterferon alfa-2a and ribavirin for 24 weeks (T12PR24) Ñ resulted in a significantly higher rate, by approximately 20 percentage points, of sustained virologic response than was found with the standard therapy of 48 weeks of peginterferon alfa-2a and ribavirin (PR48). These data, together with those from a similar phase 2 study performed in the United States (PROVE1, described elsewhere in this issue of the Journal),12 support the performance of a larger, phase 3 trial of telaprevir in combination with peginterferon alfa-2a and ribavirin.
However, several questions remain unanswered. Patients with cirrhosis were not evaluated. Durations of triple-combination therapies with peginterferon alfa, ribavirin, and telaprevir that differ from the durations tested in PROVE2 will require further investigation, as will the criteria for extension of peginterferon alfa and ribavirin therapy. Further investigation will shed light on the usefulness of tailoring therapy on the basis of the kinetics of the early viral response.
Our results show the necessity of administering ribavirin in combination with peginterferon alfa and telaprevir. Ribavirin will most likely be required in combination with the use of other specific HCV inhibitors and peginterferon alfa to achieve the high rates of sustained virologic response seen in our study. Among patients receiving telaprevir-based regimens, the addition of ribavirin increased the sustained virologic response rates by preventing relapse and the emergence of both low-level and high-level telaprevir resistance. In spite of its moderate, transient antiviral effect on HCV replication when administered as monotherapy,13 ribavirin has been shown to prevent viral breakthrough during, and relapse after, the treatment period by significantly accelerating the second slope of viral-RNA decrease in patients who have a response to the antiviral effect of peginterferon alfa.14 The modes of action of ribavirin remain under debate.15,16,17,18,19 Our study results are consistent with the notion that ribavirin does not act by directly inhibiting HCV replication, since it cannot be replaced by a potent HCV inhibitor in combination with peginterferon alfa-2a.
Both rash and pruritus were frequently reported in this study, but they did not always occur in combination. Severe rash occurred in approximately 5% of patients treated with telaprevir. Both rash and pruritus regressed after withdrawal of telaprevir and administration of appropriate therapy, including topical treatments for symptoms and corticosteroids (in some cases, systemic corticosteroids). Patients receiving telaprevir should be clinically monitored for dermatologic reactions and treated appropriately. The optimal management of rash and its effect on treatment adherence and efficacy requires further investigation. Decreased hemoglobin levels were also more frequent among the patients receiving telaprevir than among those in the control group, though the condition was not often a cause of treatment discontinuation.
In conclusion, although a significant improvement in sustained virologic response was not shown in association with two of the telaprevir regimens tested, 12 weeks of telaprevir combined with 24 weeks of peginterferon alfa-2a and ribavirin resulted in significantly higher rates of sustained virologic response than 48 weeks of peginterferon and ribavirin alone. This study therefore suggests that the use of telaprevir may improve the rate of sustained virologic response in patients with a chronic HCV genotype 1 infection. A drug-induced rash necessitated that telaprevir be discontinued in some patients. Larger and longer studies are required to assess the efficacy and safety of telaprevir for HCV infection.
Methods
Patients
Patients were enrolled at 28 centers in France, Germany, the United Kingdom, and Austria between August 2, 2006, and January 17, 2007. Eligibility criteria included no previous treatment for HCV infection, an age of 18 to 65 years, chronic HCV genotype 1 infection with detectable plasma HCV RNA levels, and no histologic evidence of cirrhosis within 2 years before study day 1.
The protocol and informed-consent form were approved by appropriate ethics committees at all study centers, in accordance with national procedures. All patients provided written informed consent before participating in the study. The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local laws and regulations.
Study Design
This was a phase 2b, randomized, partially double-blind, placebo-controlled trial. Eligible patients were stratified on the basis of self-reported race or ethnic group (black or other) and baseline weight (>75 kg vs. <75 kg). Patients were randomly assigned to one of four treatment groups: the T12PR24 group, which received telaprevir (VX-950, Vertex Pharmaceuticals), peginterferon alfa-2a (Pegasys, Roche), and ribavirin (Copegus, Roche) for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks; the T12PR12 group, which received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks; the T12P12 group, which received telaprevir and peginterferon alfa-2a, without ribavirin, for 12 weeks; and the PR48 (control) group, which received placebo, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 36 more weeks. Randomization was performed through a central telephone-based system, in a 1:1:1:1 ratio (with randomization blocks of 4). In the PR48 group, as in clinical practice,9 if there was a decline of 2 log10 units in the plasma HCV RNA level at week 12 and the HCV RNA level was undetectable at week 24, treatment was continued; if not, treatment was stopped, since the chance of clearing the infection was extremely low.10,11
Telaprevir was given as a single dose of 1250 mg on study day 1, followed by a dose of 750 mg every 8 hours; peginterferon alfa-2a was given subcutaneously at a dose of 180 µg per week; ribavirin was given orally at a dose of 1000 mg per day (for body weight <75 kg) or 1200 mg per day (for body weight >75 kg). Treatment of the PR48, T12PR12, and T12PR24 groups was double-blinded through week 10. Treatment of the T12P12 group was not blinded, because the absence of ribavirin would result in discernable hematologic effects. Patients in the T12PR24, T12PR12, and T12P12 groups were required to have undetectable HCV RNA levels at the last study visit before the planned end of treatment (i.e., at week 10 for the T12PR12 and T12P12 groups and at week 20 for the T12PR24 group). If patients had detectable HCV RNA levels at this visit, they were to continue to receive peginterferon alfa-2a and ribavirin through treatment week 48. Since the intention was to assess the efficacy of shorter treatment durations, these patients were considered to have treatment failure in the analysis of a sustained virologic response.
The study sponsor and the academic principal investigators were responsible for study design and protocol development. The manuscript was drafted by the principal academic authors with input from the publication committee (consisting of four academic authors). All authors had access to the data and assume responsibility for the accuracy and completeness of the data reported.
Efficacy Assessments
Plasma HCV RNA levels were measured with the use of the COBAS TaqMan HCV assay, version 1.0 (Roche Molecular Systems), with a lower limit of quantification of 30 IU per milliliter and a lower limit of detection of 10 IU per milliliter. HCV RNA assessments were performed at the screening visit, at days 1, 4, and 8, and at weeks 2, 3, 4, 6, 8, 10, and 12; additional assessments occurred at weeks 16, 20, and 24 in the T12PR24 and PR48 groups and at weeks 28, 36, and 48 in the PR48 group. All patients had a follow-up visit 2 weeks after completion of the study treatment. In patients in the three telaprevir-based groups who had completed all treatment (ending at week 12 or week 24), HCV RNA levels were also measured 1, 2, 4, 8, 12, 24, 36, and 48 weeks after completion of the study treatment.
Viral breakthrough during therapy was defined as an increase of more than 1 log10 IU per milliliter from the lowest HCV RNA level or as an HCV RNA level above 100 IU per milliliter in patients with previously undetectable HCV RNA. Relapse was defined as a detectable HCV RNA level during the 24-week post-treatment period in patients who had undetectable HCV RNA at the end of treatment.
Safety Assessments
Safety assessments included physical examinations, recording of adverse events, and serum chemical and hematologic evaluations at all study visits, and electrocardiography at the start and end of the treatment period. The original protocol was amended in January 2007 to add specific evaluations for grade 3 or 4 rashes, including pharmacokinetic analysis and HLA typing of blood samples.
Stepwise temporary reductions or short interruptions of ribavirin or peginterferon alfa-2a therapy were permitted, to manage adverse events or laboratory abnormalities. Dose reduction or interruption of telaprevir was not allowed. The use of granulocyte colony-stimulating factor and erythropoietin was not allowed during the initial 12 weeks of study treatment.
Statistical Analysis
The main efficacy measure was the proportion of patients who had a sustained virologic response: an HCV RNA level that was undetectable (<10 IU per milliliter) 24 weeks after the completion of study treatment. The analysis included all patients who had undergone randomization and had received at least one dose of any study drug. The planned primary analysis was the comparison of the PR48 group with the T12PR12 group and the T12P12 group (which did not receive ribavirin) combined, and the planned secondary analysis was a comparison of each of the three telaprevir-based groups with the PR48 group. Assuming rates of sustained virologic response of 50% in the PR48 group and 70% in the combined T12PR12 and T12P12 groups, we calculated that with 80 patients who could be evaluated in the PR48 group and 160 who could be evaluated in the combined groups, the study would have a statistical power of at least 80% to show a significant difference.
Five planned interim analyses were conducted by the sponsor, Vertex Pharmaceuticals, to monitor safety and assess antiviral efficacy during the treatment period. Each interim analysis included descriptive analyses of safety data (adverse events and laboratory data) and HCV RNA results. There were no stopping rules or a priori plans for changes to the study conduct on the basis of interim analyses.
After the third interim analysis, it became apparent that the T12P12 group did not have a response during the treatment period that was similar to the response of the T12PR12 group, and the statistical-analysis plan was revised by the sponsor to remove the originally planned primary analysis. The original secondary analysis, a comparison of the sustained virologic response in each of the three telaprevir-based groups with the response in the PR48 group, became the primary analysis.
Results of the fourth interim analysis (performed after all patients had reached the end of the treatment period and data on sustained virologic response were available for the T12PR24 group) and fifth interim analysis (conducted when the PR48 group was still undergoing follow-up but data on the post-treatment responses for the three telaprevir groups were available) were made available to the investigators and presented at scientific meetings. Because it is not clear how to adjust the interpretation of the analyses for these unplanned changes and multiple examinations of the data, the results are reported as originally planned.
Treatment assignments were unblinded at week 10 for all patients; therefore, there was no data and safety monitoring board. Safety of the patients was monitored by investigators and three study medical monitors, who reviewed all safety events, and by means of a review of adverse-event data during the interim analyses.
The comparisons between groups were performed with the use of Fisher's exact test. All reported P values are two-sided and have not been adjusted for multiple testing. A prespecified multivariate analysis to evaluate the possible relationship between a sustained virologic response and baseline variables (age, weight and body-mass index, and baseline HCV RNA level) was performed by means of a logistic-regression model with a sustained virologic response as the dependent variable. The following factors were added post hoc and were also explored in the model: sex, HCV genotype 1 subtype (1a vs. 1b), and alanine aminotransferase and fasting glucose levels at baseline. Variables that had a weak association (P>0.20) with a sustained virologic response in the initial logistic-regression model were excluded from the final model.
A glimpse of future hepatitis C virus treatment paradigms
A glimpse of future hepatitis C virus treatment paradigms
Hepatology Jan 2010
Norah Terrault, MD MPH, Mandana Khalili, MD, MAS
University of California, San Francisco
Potential conflict of interest: Dr. Terrault received grant support from Vertex Pharmaceuticals and Roche Pharmaceuticals; Dr. Khalili has nothing to disclose.
Editor(s) for this article:
Kris Kowdley 1, Geoffrey McCaughan 2, Christian Trautwein 3
1Seattle, WA
2Newtown, Australia
3Aachen, Germany
Article Text
Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, Bronowicki JP, Bourlière M, Gharakhanian S, Bengtsson L, McNair L, George S, Kieffer T, Kwong A, Kauffman RS, Alam J, Pawlotsky JM, Zeuzem S; PROVE2 Study Team. Collaborators (28) L Benhamou Y, Bourlière M, Bronowicki JP, Couzigou P, Grangé JD, Marcellin P, Mathurin P, Pawlotsky JM, Pol S, Serfaty L, Tran A, Trépo C, Zarski JP, Berg T, Buggisch P, Diepolder H, Erhardt A, Gerken G, Goeser T, Günther R, Rasenack J, Schmidt W, Spengler U, Wedemeyer H, Zeuzem S, Dusheiko G, Mutimer D, Ferenci P. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009 Apr 30;360(18):1839-50. Reprinted with permission.
Abstract
Background: In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment.
METHODS: A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 microg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups.
RESULTS: The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia.
CONCLUSIONS: In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385.) 2009 Massachusetts Medical Society.
McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, Alam J, Muir AJ; PROVE1 Study Team. Collaborators (38): Afdhal N, Arora S, Balan V, Vargas H, Bernstein D, Black M, Brown R, Bzowej N, Davis G, Di Bisceglie A, Dienstag J, Everson G, Faruqui S, Franco J, Fried M, Ghalib R, Gordon SC, Gross J, Jacobson IM, Jensen D, Kugelmas M, Kwo P, Lawitz E, Lee W, Martin P, Nelson D, Northup P, Patel K, Poordad F, Reddy RK, Rodriguez-Torres M, Rustgi V, Schiff E, Sherman K, Shiffman M, Sulkowski M, Szabol G, Younossi Z. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009 Apr 30;360(18):1827-38. Reprinted with permission.
Abstract
Background: Current therapy for chronic hepatitis C virus (HCV) infection is effective in less than 50% of patients infected with HCV genotype 1. Telaprevir, a protease inhibitor specific to the HCV nonstructural 3/4A serine protease, rapidly reduced HCV RNA levels in early studies.
METHODS: We randomly assigned patients infected with HCV genotype 1 to one of three telaprevir groups or to the control group. The control group (called the PR48 group) received peginterferon alfa-2a (180 microg per week) and ribavirin (1000 or 1200 mg per day, according to body weight) for 48 weeks, plus telaprevir-matched placebo for the first 12 weeks (75 patients). The telaprevir groups received telaprevir (1250 mg on day 1 and 750 mg every 8 hours thereafter) for 12 weeks, as well as peginterferon alfa-2a and ribavirin (at the same doses as in the PR48 group) for the same 12 weeks (the T12PR12 group, 17 patients) or for a total of 24 weeks (the T12PR24 group, 79 patients) or 48 weeks (the T12PR48 group, 79 patients). The primary outcome was a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy).
RESULTS: The rate of sustained virologic response was 41% (31 of 75 patients) in the PR48 group, as compared with 61% (48 of 79 patients) in the T12PR24 group (P=0.02), 67% (53 of 79 patients) in the T12PR48 group (P=0.002), and 35% (6 of 17 patients) in the T12PR12 group (this group was exploratory and not compared with the control group). Viral breakthrough occurred in 7% of patients receiving telaprevir. The rate of discontinuation because of adverse events was higher in the three telaprevir-based groups (21%, vs. 11% in the PR48 group), with rash the most common reason for discontinuation.
CONCLUSIONS: Treatment with a telaprevir-based regimen significantly improved sustained virologic response rates in patients with genotype 1 HCV, albeit with higher rates of discontinuation because of adverse events. (ClinicalTrials.gov number, NCT00336479.) 2009 Massachusetts Medical Society
Comments
Chronic HCV infection represents a major public health problem. Eradication of HCV with treatment is the most effective means of preventing liver-related complications. The current standard of care is combined peginterferon (peg-IFN) and ribavirin, which achieves sustained virologic responses (SVR) in only 55% of patients overall,[1][2] but with disappointing response rates in patients with HCV genotype 1.[1][2] HCV genotype 1 infection has been a primary focus of several new drugs that specifically target the virus (STAT-C drugs) including protease inhibitors, nucleoside and non-nucleoside NS5B polymerase inhibitors, and non-nucleoside NS5A inhibitors. The serine protease inhibitors telaprevir and boceprevir are most advanced in clinical study; both have recently completed enrollment of phase-3 studies. NS3/4A is responsible for cleavage of the NS4A/4B, NS4B/5A, and NS5A/B junctions of the large HCV polyprotein that in turn are critical in forming the replicative complex from which viral RNA synthesis occurs.[3] Additionally, NS3 has inhibitory effects on interferon signaling pathways[4] and inhibition of NS3 may help to restore interferon responsiveness. In phase 1 studies, telaprevir produced a 4.4-log10IU/mL reduction in HCV RNA levels over 14 days in subjects infected with HCV genotype 1.[5] Also seen in this early study, was the rapidity with which drug-resistant mutants emerged during treatment with virologic breakthrough evident after only 7-14 days of treatment.[5] Subsequently, it was shown that adding peg-IFN decreased the rate of virologic breakthrough due to drug-resistance and achieved a 5.5-log10IU/mL reduction in HCV RNA with 14 days therapy.[6] Thereafter, peg-IFN became an integral part of evolving treatment algorithms.
The U.S. and European multicenter phase 2b studies of telaprevir in combination with peg-IFN and ribavirin, termed PROVE 1[7] and PROVE 2,[8] respectively, were recently reported. Both studies share certain common aspects of study design, patient populations, and study endpoints. The studies were randomized, double-blind or partially blinded studies of treatment-naïve patients with genotype 1 HCV who were without cirrhosis and predominantly White (over 90% in PROVE 2, and 77% in PROVE 1). The studies differed in the duration and specific drug combinations tested as well as the stopping rules used for suboptimal responders. In PROVE 2, shorter duration therapy was used (12-24 weeks) and telaprevir plus peg-IFN without ribavirin examined. In PROVE 1, all 3 telaprevir-containing regimens utilized triple therapy (telaprevir, peg-IFN, ribavirin) for the initial 12 weeks but the duration of subsequent treatment with peg-IFN and ribavirin differed (0, 12 and 36 weeks). Both PROVE 1 and 2 studies confirmed the benefit of adding telaprevir for 12 weeks to standard combination therapy and concluded that the optimal duration of total therapy appeared to be 24 weeks (i.e., 12 weeks of triple therapy followed by 12 weeks of peg-IFN and ribavirin). This 24-week treatment course increased significantly the SVR rates to 61% and 69% (in PROVE 1 and 2, respectively) compared with 41% and 46% with peg-IFN and ribavirin for 48 weeks.[7][8] Moreover, the PROVE 2 study from Europe clearly showed that the use of ribavirin was critical in achieving superior SVR rates.[8] Thus, the emerging treatment paradigm for telaprevir is one of more intensive therapy (peg-IFN, ribavirin and telaprevir) given for a shorter duration.
The studies utilized different stopping rules. In PROVE 1, patients on telaprevir were continued on their assigned duration of therapy only if they achieved a rapid virologic response with undetectable HCV RNA at 4 weeks.[7] In PROVE 2, patients on telaprevir were continued on their assigned duration of therapy only if they had an undetectable HCV RNA at the end of 10 weeks (in groups treated for total of 12 weeks) or 20 weeks (in group treated for 24 weeks).[8] Patients who did not achieve these virologic responses early in treatment, were continued on peg-IFN and ribavirin alone and considered nonresponders in the ITT analysis. This resulted in early discontinuation of telaprevir in approximately 20% of patients in the PROVE 1.[7] Since most virologic breakthroughs occurred during the first 4 weeks of therapy and about 80% of the breakthroughs occurred before the HCV RNA levels became undetectable, this strategy makes sense to minimize the risk of drug resistance. With this approach, the rate of virologic breakthroughs was low, occurring in 7% (PROVE 1) and 3% (PROVE 2) of patients receiving triple therapy for the first 12 weeks.[7][8] The rate of virologic breakthrough was substantially higher in the telaprevir plus peg-IFN group (24%), highlighting the importance of ribavirin in reducing virologic breakthrough due to drug resistance. There are several unanswered questions regarding strategies to minimize drug resistance. First, while ribavirin is clearly important, it is unknown whether combination therapy with protease inhibitors will require use of standard doses of ribavirin or whether lower doses would yield the desired benefits but with improved tolerability. Second, the appropriate time to stop treatment in suboptimal responders has not been rigorously tested. Rates of virological breakthrough early in treatment were similar in PROVE 1 and 2,[7][8] though different stopping rules were used. Understanding the risks of continued telaprevir exposure in the setting of combination therapy is important as the stopping rules used in these clinical trials may not be as rigorously adhered to when these drugs enter the clinic.
In both studies, high-level resistance was present in the majority of patients experiencing a virologic breakthrough, whereas low-level resistant variants were more frequently seen in those with virologic relapse following discontinuation of therapy. The predominant resistance mutations identified were V36M and R155K in genotype 1a and A156T in genotype 1b, with virologic breakthrough due to resistance emerging more frequently in the genotype 1a patients. Subtype differences in risk of emergent drug-resistance and whether there are sanctuaries that may allow these drug-resistant strains to persist and potentially limit future therapies with drugs of the same class, are questions to be addressed by additional, larger scale studies and by longitudinal examination of drug-exposed patients.
The improved efficacy of telaprevir, peg-IFN and ribavirin comes at a price in terms of tolerability. There were several side effects occurring at a significantly higher frequency in telaprevir-containing treatment arms including pruritus, rash, gastrointestinal symptoms (nausea, vomiting, diarrhea, hemorrhoids) and up to a median of 0.5-1.0 g/dL greater decline in hemoglobin compared to the standard peg-IFN and ribavirin therapy.[7][8] Importantly, the side effects associated with the addition of telaprevir resulted in an approximate doubling of treatment discontinuation rates (21% versus 11% with peg-IFN and ribavirin alone).[7][8] The most common adverse event leading to treatment discontinuation was rash, accounting for one-third of discontinuations. The study's authors comment on the utilization of specific management algorithms for pruritus in subsequent telaprevir studies.[8] Indeed, maximizing tolerance of future telaprevir-based regimens will be of importance to achieve optimal treatment outcomes.
In conclusion, the emerging data on the efficacy of telaprevir combined with peg-IFN and ribavirin are extremely encouraging. The phase 2b studies from McHutchison et al. (PROVE 1) and Hezode et al. (PROVE 2) in HCV genotype 1 patients show that triple therapy of telaprevir, peg-IFN and ribavirin for 12 weeks followed by 12 weeks of peg-IFN and ribavirin yields superior SVR rates with shorter duration of therapy compared to current peg-IFN and ribavirin. However, the improved efficacy comes with additional side effects and a risk of selecting drug-resistant viral variants that may limit subsequent therapeutic options. We can anticipate that the new treatment paradigms will continue to evolve as investigators seek to establish the best balance between benefits and risks. (From Jules: it is important to bear in mind that at AASLD Nov 2009 Vertex reported new data on telaprevir twice daily where the SVR rates were 83% and the rash problems appeared to be less, so by the time telaprevir comes to market management of the rash should be improved and phase 3 studies are ongoing now where we will learn more).
References
1 Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, 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(9286): 958-965. Links
2 Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, Jr., et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975-982. Links
3 Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature 2005; 436(7053): 933-938. Links
4 Foy E, Li K, Wang C, Sumpter R, Jr., Ikeda M, Lemon SM, Gale, M., Jr.. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 2003; 300(5622): 1145-1148. Links
5 Reesink HW, Zeuzem S, Weegink CJ, Forestier N, van Vliet A, van de Wetering de Rooij J, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology 2006; 131: 997-1002. Links
6 Forestier N, Reesink HW, Weegink CJ, McNair L, Kieffer TL, Chu HM, et al. Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C. HEPATOLOGY 2007; 46: 640-648. Links
7 McHutchison J, Everson G, Gordon S, Jacobson I, Sulkowski M, Kauffman R, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360: 1827-1838. Links
8 Hezode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839-1850. Links
Hepatology Jan 2010
Norah Terrault, MD MPH, Mandana Khalili, MD, MAS
University of California, San Francisco
Potential conflict of interest: Dr. Terrault received grant support from Vertex Pharmaceuticals and Roche Pharmaceuticals; Dr. Khalili has nothing to disclose.
Editor(s) for this article:
Kris Kowdley 1, Geoffrey McCaughan 2, Christian Trautwein 3
1Seattle, WA
2Newtown, Australia
3Aachen, Germany
Article Text
Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, Bronowicki JP, Bourlière M, Gharakhanian S, Bengtsson L, McNair L, George S, Kieffer T, Kwong A, Kauffman RS, Alam J, Pawlotsky JM, Zeuzem S; PROVE2 Study Team. Collaborators (28) L Benhamou Y, Bourlière M, Bronowicki JP, Couzigou P, Grangé JD, Marcellin P, Mathurin P, Pawlotsky JM, Pol S, Serfaty L, Tran A, Trépo C, Zarski JP, Berg T, Buggisch P, Diepolder H, Erhardt A, Gerken G, Goeser T, Günther R, Rasenack J, Schmidt W, Spengler U, Wedemeyer H, Zeuzem S, Dusheiko G, Mutimer D, Ferenci P. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009 Apr 30;360(18):1839-50. Reprinted with permission.
Abstract
Background: In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment.
METHODS: A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 microg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups.
RESULTS: The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia.
CONCLUSIONS: In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385.) 2009 Massachusetts Medical Society.
McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, Alam J, Muir AJ; PROVE1 Study Team. Collaborators (38): Afdhal N, Arora S, Balan V, Vargas H, Bernstein D, Black M, Brown R, Bzowej N, Davis G, Di Bisceglie A, Dienstag J, Everson G, Faruqui S, Franco J, Fried M, Ghalib R, Gordon SC, Gross J, Jacobson IM, Jensen D, Kugelmas M, Kwo P, Lawitz E, Lee W, Martin P, Nelson D, Northup P, Patel K, Poordad F, Reddy RK, Rodriguez-Torres M, Rustgi V, Schiff E, Sherman K, Shiffman M, Sulkowski M, Szabol G, Younossi Z. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009 Apr 30;360(18):1827-38. Reprinted with permission.
Abstract
Background: Current therapy for chronic hepatitis C virus (HCV) infection is effective in less than 50% of patients infected with HCV genotype 1. Telaprevir, a protease inhibitor specific to the HCV nonstructural 3/4A serine protease, rapidly reduced HCV RNA levels in early studies.
METHODS: We randomly assigned patients infected with HCV genotype 1 to one of three telaprevir groups or to the control group. The control group (called the PR48 group) received peginterferon alfa-2a (180 microg per week) and ribavirin (1000 or 1200 mg per day, according to body weight) for 48 weeks, plus telaprevir-matched placebo for the first 12 weeks (75 patients). The telaprevir groups received telaprevir (1250 mg on day 1 and 750 mg every 8 hours thereafter) for 12 weeks, as well as peginterferon alfa-2a and ribavirin (at the same doses as in the PR48 group) for the same 12 weeks (the T12PR12 group, 17 patients) or for a total of 24 weeks (the T12PR24 group, 79 patients) or 48 weeks (the T12PR48 group, 79 patients). The primary outcome was a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy).
RESULTS: The rate of sustained virologic response was 41% (31 of 75 patients) in the PR48 group, as compared with 61% (48 of 79 patients) in the T12PR24 group (P=0.02), 67% (53 of 79 patients) in the T12PR48 group (P=0.002), and 35% (6 of 17 patients) in the T12PR12 group (this group was exploratory and not compared with the control group). Viral breakthrough occurred in 7% of patients receiving telaprevir. The rate of discontinuation because of adverse events was higher in the three telaprevir-based groups (21%, vs. 11% in the PR48 group), with rash the most common reason for discontinuation.
CONCLUSIONS: Treatment with a telaprevir-based regimen significantly improved sustained virologic response rates in patients with genotype 1 HCV, albeit with higher rates of discontinuation because of adverse events. (ClinicalTrials.gov number, NCT00336479.) 2009 Massachusetts Medical Society
Comments
Chronic HCV infection represents a major public health problem. Eradication of HCV with treatment is the most effective means of preventing liver-related complications. The current standard of care is combined peginterferon (peg-IFN) and ribavirin, which achieves sustained virologic responses (SVR) in only 55% of patients overall,[1][2] but with disappointing response rates in patients with HCV genotype 1.[1][2] HCV genotype 1 infection has been a primary focus of several new drugs that specifically target the virus (STAT-C drugs) including protease inhibitors, nucleoside and non-nucleoside NS5B polymerase inhibitors, and non-nucleoside NS5A inhibitors. The serine protease inhibitors telaprevir and boceprevir are most advanced in clinical study; both have recently completed enrollment of phase-3 studies. NS3/4A is responsible for cleavage of the NS4A/4B, NS4B/5A, and NS5A/B junctions of the large HCV polyprotein that in turn are critical in forming the replicative complex from which viral RNA synthesis occurs.[3] Additionally, NS3 has inhibitory effects on interferon signaling pathways[4] and inhibition of NS3 may help to restore interferon responsiveness. In phase 1 studies, telaprevir produced a 4.4-log10IU/mL reduction in HCV RNA levels over 14 days in subjects infected with HCV genotype 1.[5] Also seen in this early study, was the rapidity with which drug-resistant mutants emerged during treatment with virologic breakthrough evident after only 7-14 days of treatment.[5] Subsequently, it was shown that adding peg-IFN decreased the rate of virologic breakthrough due to drug-resistance and achieved a 5.5-log10IU/mL reduction in HCV RNA with 14 days therapy.[6] Thereafter, peg-IFN became an integral part of evolving treatment algorithms.
The U.S. and European multicenter phase 2b studies of telaprevir in combination with peg-IFN and ribavirin, termed PROVE 1[7] and PROVE 2,[8] respectively, were recently reported. Both studies share certain common aspects of study design, patient populations, and study endpoints. The studies were randomized, double-blind or partially blinded studies of treatment-naïve patients with genotype 1 HCV who were without cirrhosis and predominantly White (over 90% in PROVE 2, and 77% in PROVE 1). The studies differed in the duration and specific drug combinations tested as well as the stopping rules used for suboptimal responders. In PROVE 2, shorter duration therapy was used (12-24 weeks) and telaprevir plus peg-IFN without ribavirin examined. In PROVE 1, all 3 telaprevir-containing regimens utilized triple therapy (telaprevir, peg-IFN, ribavirin) for the initial 12 weeks but the duration of subsequent treatment with peg-IFN and ribavirin differed (0, 12 and 36 weeks). Both PROVE 1 and 2 studies confirmed the benefit of adding telaprevir for 12 weeks to standard combination therapy and concluded that the optimal duration of total therapy appeared to be 24 weeks (i.e., 12 weeks of triple therapy followed by 12 weeks of peg-IFN and ribavirin). This 24-week treatment course increased significantly the SVR rates to 61% and 69% (in PROVE 1 and 2, respectively) compared with 41% and 46% with peg-IFN and ribavirin for 48 weeks.[7][8] Moreover, the PROVE 2 study from Europe clearly showed that the use of ribavirin was critical in achieving superior SVR rates.[8] Thus, the emerging treatment paradigm for telaprevir is one of more intensive therapy (peg-IFN, ribavirin and telaprevir) given for a shorter duration.
The studies utilized different stopping rules. In PROVE 1, patients on telaprevir were continued on their assigned duration of therapy only if they achieved a rapid virologic response with undetectable HCV RNA at 4 weeks.[7] In PROVE 2, patients on telaprevir were continued on their assigned duration of therapy only if they had an undetectable HCV RNA at the end of 10 weeks (in groups treated for total of 12 weeks) or 20 weeks (in group treated for 24 weeks).[8] Patients who did not achieve these virologic responses early in treatment, were continued on peg-IFN and ribavirin alone and considered nonresponders in the ITT analysis. This resulted in early discontinuation of telaprevir in approximately 20% of patients in the PROVE 1.[7] Since most virologic breakthroughs occurred during the first 4 weeks of therapy and about 80% of the breakthroughs occurred before the HCV RNA levels became undetectable, this strategy makes sense to minimize the risk of drug resistance. With this approach, the rate of virologic breakthroughs was low, occurring in 7% (PROVE 1) and 3% (PROVE 2) of patients receiving triple therapy for the first 12 weeks.[7][8] The rate of virologic breakthrough was substantially higher in the telaprevir plus peg-IFN group (24%), highlighting the importance of ribavirin in reducing virologic breakthrough due to drug resistance. There are several unanswered questions regarding strategies to minimize drug resistance. First, while ribavirin is clearly important, it is unknown whether combination therapy with protease inhibitors will require use of standard doses of ribavirin or whether lower doses would yield the desired benefits but with improved tolerability. Second, the appropriate time to stop treatment in suboptimal responders has not been rigorously tested. Rates of virological breakthrough early in treatment were similar in PROVE 1 and 2,[7][8] though different stopping rules were used. Understanding the risks of continued telaprevir exposure in the setting of combination therapy is important as the stopping rules used in these clinical trials may not be as rigorously adhered to when these drugs enter the clinic.
In both studies, high-level resistance was present in the majority of patients experiencing a virologic breakthrough, whereas low-level resistant variants were more frequently seen in those with virologic relapse following discontinuation of therapy. The predominant resistance mutations identified were V36M and R155K in genotype 1a and A156T in genotype 1b, with virologic breakthrough due to resistance emerging more frequently in the genotype 1a patients. Subtype differences in risk of emergent drug-resistance and whether there are sanctuaries that may allow these drug-resistant strains to persist and potentially limit future therapies with drugs of the same class, are questions to be addressed by additional, larger scale studies and by longitudinal examination of drug-exposed patients.
The improved efficacy of telaprevir, peg-IFN and ribavirin comes at a price in terms of tolerability. There were several side effects occurring at a significantly higher frequency in telaprevir-containing treatment arms including pruritus, rash, gastrointestinal symptoms (nausea, vomiting, diarrhea, hemorrhoids) and up to a median of 0.5-1.0 g/dL greater decline in hemoglobin compared to the standard peg-IFN and ribavirin therapy.[7][8] Importantly, the side effects associated with the addition of telaprevir resulted in an approximate doubling of treatment discontinuation rates (21% versus 11% with peg-IFN and ribavirin alone).[7][8] The most common adverse event leading to treatment discontinuation was rash, accounting for one-third of discontinuations. The study's authors comment on the utilization of specific management algorithms for pruritus in subsequent telaprevir studies.[8] Indeed, maximizing tolerance of future telaprevir-based regimens will be of importance to achieve optimal treatment outcomes.
In conclusion, the emerging data on the efficacy of telaprevir combined with peg-IFN and ribavirin are extremely encouraging. The phase 2b studies from McHutchison et al. (PROVE 1) and Hezode et al. (PROVE 2) in HCV genotype 1 patients show that triple therapy of telaprevir, peg-IFN and ribavirin for 12 weeks followed by 12 weeks of peg-IFN and ribavirin yields superior SVR rates with shorter duration of therapy compared to current peg-IFN and ribavirin. However, the improved efficacy comes with additional side effects and a risk of selecting drug-resistant viral variants that may limit subsequent therapeutic options. We can anticipate that the new treatment paradigms will continue to evolve as investigators seek to establish the best balance between benefits and risks. (From Jules: it is important to bear in mind that at AASLD Nov 2009 Vertex reported new data on telaprevir twice daily where the SVR rates were 83% and the rash problems appeared to be less, so by the time telaprevir comes to market management of the rash should be improved and phase 3 studies are ongoing now where we will learn more).
References
1 Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, 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(9286): 958-965. Links
2 Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, Jr., et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975-982. Links
3 Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature 2005; 436(7053): 933-938. Links
4 Foy E, Li K, Wang C, Sumpter R, Jr., Ikeda M, Lemon SM, Gale, M., Jr.. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 2003; 300(5622): 1145-1148. Links
5 Reesink HW, Zeuzem S, Weegink CJ, Forestier N, van Vliet A, van de Wetering de Rooij J, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology 2006; 131: 997-1002. Links
6 Forestier N, Reesink HW, Weegink CJ, McNair L, Kieffer TL, Chu HM, et al. Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C. HEPATOLOGY 2007; 46: 640-648. Links
7 McHutchison J, Everson G, Gordon S, Jacobson I, Sulkowski M, Kauffman R, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360: 1827-1838. Links
8 Hezode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839-1850. Links
We Can Cure HCV by Jules Levin of, NATAP
We Can Cure HCV by Jules Levin of, NATAP
Last week the Institute of Medicine issued a report putting forth a National Strategy for HCV, the link to the report is immediately below. Just below the link is another link to a report on the consequences of HCV in terms of epidemiology, costs, health, and death. The affect of HCV in African-Americans and marginalized patients populations is unique and has a major impact. It's estimated about 4 million people have HCV in the USA. 3.5% of African-Americans have HCV compared with 1.6% of Caucasians. 1 in 7 Black men between 41-59 yrs old have HCV. The Response rate to the current standard of care therapy, peginterferon+ribavirin is very low for African-Americans. On average for the most difficult-to-treat patients, the SVR or 'cure' rate is about 40-50%, (these are patients with genotype 1 as opposed to genotype 2 where response rates are much higher) but for African-Americans the SVR rates range from 5-25%. There are 2 very relevant reasons for the low response rates: 1- there appears to be a genetic difference between whites & blacks in their innate ability to respond to interferon, which is an immune-based therapy, 2- many of these studies with very low response rates are conducted at urban inner city clinics where patients have a history of illicit drug. There are 20 new anti-viral orally administered drugs in development now which differ from the current therapy in that they do not depend on stimulating the immune system to respond to interferon. Response to these anti-virals is expected to be similar for all. I expect that over the coming 9 years as these drugs roll out and we put together multi-drug combination therapies the 'cure' or SVR rates will be steadily increasing towards 90 or even 100% in the USA for all patient groups. The new drugs will also shorten duration of therapy to 6 months in the future. Of note, HCV is a curable disease so with 6 months of successful therapy the virus is gone and the patient will not have to address HCV again. This presents a unique situation unlike other diseases, we are presented with the opportunity now to cure a disease. Federal support is needed to help accomplish this: funding for programs for testing/screening, linkages to care & education, and support services for patients is needed to accomplish this very reachable goal. 75% of the 4 million people with HCV in the USA are undiagnosed, which is why we need a major testing/screening program to raise awareness to get people tested. Then we need linkages to care to bring people into care. Of he 4 million with HCV in the USA 25% already have cirrhosis, which means we are under a time constraint to get HCV-infected people tested and into care before they start getting liver cancer and dying. Once individuals start getting sick the economic consequences and costs related to HCV start increasing quite signifcantly, so we can avoid many of these consequences if we launch a Federally funded program now.
Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer ...
Link to Millman Report: http://www.vrtx.com/millimanreport.html lso as an FYI - the Milliman site is also up and running now with both a link to the full ...
www.natap.org/2009/HCV/051809_01.htm
From Baby Booming to Hepatitis C
Baby Boomers well past their wild years are now facing the consequences
Quetzalli Castro
http://media.www.chicagoflame.com
Despite affecting 1 percent of the population, hepatitis C remains a disease generally misunderstood by the general public with little in financial commitments from the federal government. The CDC's National Center for HIV/AIDS, Viral Hepatitis, Sexually Transmitted Diseases, and Tuberculosis Prevention had a budget of almost $1 billion for 2008. Only 2 percent of that was allocated to hepatitis B and hepatitis C despite both viruses being five times more prevalent than the rest. According to the CDC Hepatitis C virus (HCV) infection is the most common chronic bloodborne infection in the United States.
Now, a newly-published Institute of Medicine Report on hepatitis B and C underscores how this lack of understanding and attention has played out. Although the risk factors for hepatitis C are widely known and completely preventable, the Institute of Medicine (IOxM) estimates that between 2.7 million and 3.9 million Americans have contracted HCV.
This number in itself is worrying but the most startling statistic about HCV is not its prevalence, but the population it affects. The reports indicate that two-thirds of those infected with the virus are Baby Boomers. For some, Woodstock is a distant memory from their youth where they may have experimented with intravenous drugs. Now they are adults in their 50s or 60s and HCV, which is transferred by contact with infected blood, has a particularly long incubation period, often 20 or 30 years. That means that the side effects of one drug use in the 1970s could start to show up in the next couple of years.
A large part of the problem with curbing HCV's prevalence is that most of these persons are chronically infected and might not be aware of their infection because they are not clinically ill. Infected persons serve as a source of transmission to others and are at risk for chronic liver disease or other HCV-related chronic diseases during the first two or more decades following initial infection. In reality, population-based studies indicate that 40% of chronic liver disease is HCV-related, resulting in an estimated 8,000-10,000 deaths each year (CDC, unpublished data). Furthermore, HCV-associated end-stage liver disease is the most frequent indication for liver transplantation among adults.
The research indicates that right now is a particularly critical point in time for early detection and treatment of hepatitis C, particularly among the Boomer population. The test for HCV can be easily administered, and the CDC and IOM have the risk largely pooled in a specific demographic, why do so many cases go decades undiagnosed? Doctors say it has a lot do with the stigma surrounding liver disease. When someone is diagnosed with cirrhosis of the liver, a person is more likely to be blamed for abusing alcohol among other things before being seen as an HCV infected person. This alone can prevent many from coming forward with their concerns.
At the moment both the IOM and CDC want to change that. The IOM report recommends a comprehensive public education and surveillance campaign, to increase awareness of the disease, following the model of HIV/AIDs public awareness campaigns in the 1990s. All in all, HCV is now a serious challenge for both doctors and public health officials, largely because of its long incubation period and because of this and the stigma that surrounds it, we may be seeing the next biggest campaign for cause since HIV/AIDs.
Last week the Institute of Medicine issued a report putting forth a National Strategy for HCV, the link to the report is immediately below. Just below the link is another link to a report on the consequences of HCV in terms of epidemiology, costs, health, and death. The affect of HCV in African-Americans and marginalized patients populations is unique and has a major impact. It's estimated about 4 million people have HCV in the USA. 3.5% of African-Americans have HCV compared with 1.6% of Caucasians. 1 in 7 Black men between 41-59 yrs old have HCV. The Response rate to the current standard of care therapy, peginterferon+ribavirin is very low for African-Americans. On average for the most difficult-to-treat patients, the SVR or 'cure' rate is about 40-50%, (these are patients with genotype 1 as opposed to genotype 2 where response rates are much higher) but for African-Americans the SVR rates range from 5-25%. There are 2 very relevant reasons for the low response rates: 1- there appears to be a genetic difference between whites & blacks in their innate ability to respond to interferon, which is an immune-based therapy, 2- many of these studies with very low response rates are conducted at urban inner city clinics where patients have a history of illicit drug. There are 20 new anti-viral orally administered drugs in development now which differ from the current therapy in that they do not depend on stimulating the immune system to respond to interferon. Response to these anti-virals is expected to be similar for all. I expect that over the coming 9 years as these drugs roll out and we put together multi-drug combination therapies the 'cure' or SVR rates will be steadily increasing towards 90 or even 100% in the USA for all patient groups. The new drugs will also shorten duration of therapy to 6 months in the future. Of note, HCV is a curable disease so with 6 months of successful therapy the virus is gone and the patient will not have to address HCV again. This presents a unique situation unlike other diseases, we are presented with the opportunity now to cure a disease. Federal support is needed to help accomplish this: funding for programs for testing/screening, linkages to care & education, and support services for patients is needed to accomplish this very reachable goal. 75% of the 4 million people with HCV in the USA are undiagnosed, which is why we need a major testing/screening program to raise awareness to get people tested. Then we need linkages to care to bring people into care. Of he 4 million with HCV in the USA 25% already have cirrhosis, which means we are under a time constraint to get HCV-infected people tested and into care before they start getting liver cancer and dying. Once individuals start getting sick the economic consequences and costs related to HCV start increasing quite signifcantly, so we can avoid many of these consequences if we launch a Federally funded program now.
Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer ...
Link to Millman Report: http://www.vrtx.com/millimanreport.html lso as an FYI - the Milliman site is also up and running now with both a link to the full ...
www.natap.org/2009/HCV/051809_01.htm
From Baby Booming to Hepatitis C
Baby Boomers well past their wild years are now facing the consequences
Quetzalli Castro
http://media.www.chicagoflame.com
Despite affecting 1 percent of the population, hepatitis C remains a disease generally misunderstood by the general public with little in financial commitments from the federal government. The CDC's National Center for HIV/AIDS, Viral Hepatitis, Sexually Transmitted Diseases, and Tuberculosis Prevention had a budget of almost $1 billion for 2008. Only 2 percent of that was allocated to hepatitis B and hepatitis C despite both viruses being five times more prevalent than the rest. According to the CDC Hepatitis C virus (HCV) infection is the most common chronic bloodborne infection in the United States.
Now, a newly-published Institute of Medicine Report on hepatitis B and C underscores how this lack of understanding and attention has played out. Although the risk factors for hepatitis C are widely known and completely preventable, the Institute of Medicine (IOxM) estimates that between 2.7 million and 3.9 million Americans have contracted HCV.
This number in itself is worrying but the most startling statistic about HCV is not its prevalence, but the population it affects. The reports indicate that two-thirds of those infected with the virus are Baby Boomers. For some, Woodstock is a distant memory from their youth where they may have experimented with intravenous drugs. Now they are adults in their 50s or 60s and HCV, which is transferred by contact with infected blood, has a particularly long incubation period, often 20 or 30 years. That means that the side effects of one drug use in the 1970s could start to show up in the next couple of years.
A large part of the problem with curbing HCV's prevalence is that most of these persons are chronically infected and might not be aware of their infection because they are not clinically ill. Infected persons serve as a source of transmission to others and are at risk for chronic liver disease or other HCV-related chronic diseases during the first two or more decades following initial infection. In reality, population-based studies indicate that 40% of chronic liver disease is HCV-related, resulting in an estimated 8,000-10,000 deaths each year (CDC, unpublished data). Furthermore, HCV-associated end-stage liver disease is the most frequent indication for liver transplantation among adults.
The research indicates that right now is a particularly critical point in time for early detection and treatment of hepatitis C, particularly among the Boomer population. The test for HCV can be easily administered, and the CDC and IOM have the risk largely pooled in a specific demographic, why do so many cases go decades undiagnosed? Doctors say it has a lot do with the stigma surrounding liver disease. When someone is diagnosed with cirrhosis of the liver, a person is more likely to be blamed for abusing alcohol among other things before being seen as an HCV infected person. This alone can prevent many from coming forward with their concerns.
At the moment both the IOM and CDC want to change that. The IOM report recommends a comprehensive public education and surveillance campaign, to increase awareness of the disease, following the model of HIV/AIDs public awareness campaigns in the 1990s. All in all, HCV is now a serious challenge for both doctors and public health officials, largely because of its long incubation period and because of this and the stigma that surrounds it, we may be seeing the next biggest campaign for cause since HIV/AIDs.
Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C
Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C - Report from the Institute of Medicine (IOM)
pdf of full report attached
Download the PDF here
"Deaths related to hepatitis C have increased, with the highest number occurring among middle-aged men, non-Hispanic blacks, and American Indians."...."negative perceptions about illicit-drug users, who make up the greatest percentage of those with hepatitis C, can affect the care they receive or their willingness to seek care."....."The committee recommended....improve identification of infected individuals, social and peer support to reduce the stigma of infection, and medical management of those with chronic hepatitis B or C".
"They're the overlooked viruses: Hepatitis B and C together infect three to five times more Americans than the AIDS virus does, and most don't know it. In the next 10 years, these two liver-damaging infections will kill about 150,000 people in the U.S. alone, says a new report Monday from the prestigious Institute of Medicine. 'We have allowed gaps in screening, prevention and treatment to go unchecked,'' said report chairman R. Palmer Beasley of the University of Texas, Houston."
from Jules: "70-90% of people who contracted HIV through injection drug use also have hepatitis C, called HCV/HIV coinfection, this is over 300,000 people. The leading cause of death & hospitalization in HIV in the USA is HCV/HIV coinfection. Current treatment is hard to tolerate but new improved orally administered therapies are in development & promise to make HCV much more treatable with higher 'cure' rates. The Ryan White Care Act contains important HCV language & provides a way to secure funding for HCV/HIV coinfection community-based programs"
-- Ryan White Care Act Hepatitis C & B Language (click here for details)
Released:
January 11, 2010
Up to 5.3 million people-2 percent of the U.S. population-are living with chronic hepatitis B or hepatitis C. These diseases are more common than HIV/AIDS in the U.S. Yet, because hepatitis B and hepatitis C often present no symptoms, most people who have them are unaware until they develop liver cancer or liver disease many years later.
A new IOM study finds that these diseases are not widely recognized as serious public health problems, and as a result, that viral hepatitis prevention, control, and surveillance programs have inadequate resources. The report concludes that the current approach to the prevention and control of chronic hepatitis B and hepatitis C is not working. As a remedy, the IOM recommends increased knowledge and awareness about chronic viral hepatitis among health care providers, social service providers, and the public; improved surveillance for hepatitis B and hepatitis C; and better integration of viral hepatitis services.
Among the key findings by the IOM are that one in fifty Americans has viral hepatitis and the majority of such individuals remain unaware of their disease. While some populations are disproportionately affected, individuals from all segments of society can get the disease. A relative lack of funding for disease surveillance and educational efforts is a major barrier towards eradication of hepatitis B and C.
Summary Brief From IOM: Hepatitis and Liver Cancer-
REPORT BRIEF JANUARY 2010. For more information visit
www.iom.edu/ ...
AASLD Applauds Landmark IOM Study
That Shows the Path to Eradicate Hepatitis B and C
ALEXANDRIA, Va., Jan. 11 /PRNewswire-USNewswire/ -- The American Association for the Study of Liver Disease (AASLD) today reacted favorably to the release by they Institute of Medicine (IOM) of the report of "Hepatitis and Liver Cancer: A National
IOM Press Release
FOR IMMEDIATE RELEASE
IOM REPORT RECOMMENDS STEPS TO REDUCE THREATS POSED BY HEPATITIS B AND C, WHICH DISPROPORTIONATELY AFFECT MINORITIES
Contacts: Christine Stencel, Senior Media Relations Officer Luwam Yeibio, Media Relations Assistant Office of News and Public Information 202-334-2138; e-mail
WASHINGTON -- Stepped-up vaccination requirements, a boost in resources for prevention and treatment, and a public awareness campaign similar to the effort that dispelled the stigma of HIV/AIDS are needed to curb the health threats posed by hepatitis B and hepatitis C, says a new report from the Institute of Medicine.
Chronic hepatitis B and C cause thousands of cases of liver cancer, liver disease, and death each year -- taking the heaviest toll among Asians, Pacific Islanders, and blacks in the U.S. -- and these infections account for nearly half of the liver transplantations that must be performed annually. Resources and efforts to contain the viruses that cause hepatitis B and C lag behind those directed at other infectious diseases of similar impact to public health, noted the committee that wrote the report.
"Although hepatitis B and C are preventable, the rates of infection have not declined over the past several years, underscoring the conclusion that we have allowed gaps in screening, prevention, and treatment to go unchecked," said committee chair R. Palmer Beasley, professor of epidemiology and disease control, University of Texas School of Public Health, Houston. "This report outlines the additional resources and actions needed to reduce the unacceptably high burden of liver disease and cancer associated with these viruses."
An estimated 800,000 to 1.4 million Americans have chronic hepatitis B and between 2.7 million and 3.9 million have chronic hepatitis C. The majority of infected individuals are not aware of their condition until they develop symptoms of liver cancer or liver disease. Few among the populations most at risk -- immigrants from countries where the diseases are endemic, non-Hispanic black men, injection-drug users, and people who had blood transfusions before 1992 -- seek testing or information on how to protect themselves from infection. Moreover, health care and social service providers' knowledge about hepatitis B and C is generally poor, and many fail to follow guidelines for screening patients and providing prevention, treatment, and follow-up services. The report calls for a public awareness initiative along the lines of the effort that succeeded in increasing recognition, prevention, and treatment of HIV/AIDS, which affects three to five times fewer Americans than viral hepatitis. Educational programs and materials that outline risk factors for viral hepatitis and provide information on immunization, prevention, and proper monitoring of infected individuals should be developed and made available to all health professionals and social service providers.
Steps need to be taken to eliminate the stigma associated with viral hepatitis. Negative attitudes about hepatitis B in some cultures may contribute to immigrants' reluctance to seek testing. In China, for example, people with chronic hepatitis B face job and social discrimination. In addition, negative perceptions about illicit-drug users, who make up the greatest percentage of those with hepatitis C, can affect the care they receive or their willingness to seek care.
Although the availability of an effective vaccine against hepatitis B has significantly reduced its spread, some 1,000 infants born to infected mothers develop chronic infections each year, a number that has not declined over the past decade. Moreover, three states -- Alabama, Montana, and South Dakota -- still do not require that children be vaccinated against hepatitis B before entering daycare or school. All full-term newborns whose mothers test positive for hepatitis B should receive the vaccine once they are stable and before leaving the delivery room rather than up to 12 hours after birth as is currently recommended. All states should make hepatitis B vaccination a requirement for school attendance, and health plans need to fully cover the costs associated with the immunization. Particular attention should be given to screening and vaccinating children who were born in countries where hepatitis B circulates widely. Each year, roughly 40,000 to 45,000 people legally emigrate to the United States from countries where hepatitis B is endemic.
Health care and social services related to viral hepatitis are sparse and fragmented among providers and organizations, leading to missed opportunities to prevent the spread of infection and to lessen the impact of chronic infections, the report concludes. The committee recommended several steps to create a more-coordinated approach, including ways to improve identification of infected individuals, social and peer support to reduce the stigma of infection, and medical management of those with chronic hepatitis B or C. These strategies are aimed at not just health professionals in hospitals and doctors' offices, but also individuals and groups that provide services to at-risk populations, including prisons and jails, HIV and STD clinics, shelter-based programs, and mobile health units.
People at greatest risk for hepatitis B include individuals born in East and Southeast Asia, sub-Saharan Africa, and other areas where the virus circulates widely; infants born to women with the disease; and those who have sexual contact or share injection-drug equipment with an infected person. Asians and Pacific Islanders make up 4.5 percent of the U.S. population but account for more than 50 percent of chronic hepatitis B cases. Those at greatest risk for hepatitis C are individuals who received a blood transfusion before 1992 and past or current injection-drug users. The chances of contracting hepatitis C increase with years of drug use and may be as high as 90 percent among long-term users. Deaths related to hepatitis C have increased, with the highest number occurring among middle-aged men, non-Hispanic blacks, and American Indians.
The report was sponsored by the U.S. Centers for Disease Control and Prevention, U.S. Department of Health and Human Services' Office of Minority Health, U.S. Department of Veterans Affairs, and the National Viral Hepatitis Roundtable. Established in 1970 under the charter of the National Academy of Sciences, the Institute of Medicine provides independent, objective, evidence-based advice to policymakers, health professionals, the private sector, and the public. The National Academy of Sciences, National Academy of Engineering, Institute of Medicine, and National Research Council make up the National Academies.
pdf of full report attached
Download the PDF here
"Deaths related to hepatitis C have increased, with the highest number occurring among middle-aged men, non-Hispanic blacks, and American Indians."...."negative perceptions about illicit-drug users, who make up the greatest percentage of those with hepatitis C, can affect the care they receive or their willingness to seek care."....."The committee recommended....improve identification of infected individuals, social and peer support to reduce the stigma of infection, and medical management of those with chronic hepatitis B or C".
"They're the overlooked viruses: Hepatitis B and C together infect three to five times more Americans than the AIDS virus does, and most don't know it. In the next 10 years, these two liver-damaging infections will kill about 150,000 people in the U.S. alone, says a new report Monday from the prestigious Institute of Medicine. 'We have allowed gaps in screening, prevention and treatment to go unchecked,'' said report chairman R. Palmer Beasley of the University of Texas, Houston."
from Jules: "70-90% of people who contracted HIV through injection drug use also have hepatitis C, called HCV/HIV coinfection, this is over 300,000 people. The leading cause of death & hospitalization in HIV in the USA is HCV/HIV coinfection. Current treatment is hard to tolerate but new improved orally administered therapies are in development & promise to make HCV much more treatable with higher 'cure' rates. The Ryan White Care Act contains important HCV language & provides a way to secure funding for HCV/HIV coinfection community-based programs"
-- Ryan White Care Act Hepatitis C & B Language (click here for details)
Released:
January 11, 2010
Up to 5.3 million people-2 percent of the U.S. population-are living with chronic hepatitis B or hepatitis C. These diseases are more common than HIV/AIDS in the U.S. Yet, because hepatitis B and hepatitis C often present no symptoms, most people who have them are unaware until they develop liver cancer or liver disease many years later.
A new IOM study finds that these diseases are not widely recognized as serious public health problems, and as a result, that viral hepatitis prevention, control, and surveillance programs have inadequate resources. The report concludes that the current approach to the prevention and control of chronic hepatitis B and hepatitis C is not working. As a remedy, the IOM recommends increased knowledge and awareness about chronic viral hepatitis among health care providers, social service providers, and the public; improved surveillance for hepatitis B and hepatitis C; and better integration of viral hepatitis services.
Among the key findings by the IOM are that one in fifty Americans has viral hepatitis and the majority of such individuals remain unaware of their disease. While some populations are disproportionately affected, individuals from all segments of society can get the disease. A relative lack of funding for disease surveillance and educational efforts is a major barrier towards eradication of hepatitis B and C.
Summary Brief From IOM: Hepatitis and Liver Cancer-
REPORT BRIEF JANUARY 2010. For more information visit
www.iom.edu/ ...
AASLD Applauds Landmark IOM Study
That Shows the Path to Eradicate Hepatitis B and C
ALEXANDRIA, Va., Jan. 11 /PRNewswire-USNewswire/ -- The American Association for the Study of Liver Disease (AASLD) today reacted favorably to the release by they Institute of Medicine (IOM) of the report of "Hepatitis and Liver Cancer: A National
IOM Press Release
FOR IMMEDIATE RELEASE
IOM REPORT RECOMMENDS STEPS TO REDUCE THREATS POSED BY HEPATITIS B AND C, WHICH DISPROPORTIONATELY AFFECT MINORITIES
Contacts: Christine Stencel, Senior Media Relations Officer Luwam Yeibio, Media Relations Assistant Office of News and Public Information 202-334-2138; e-mail
WASHINGTON -- Stepped-up vaccination requirements, a boost in resources for prevention and treatment, and a public awareness campaign similar to the effort that dispelled the stigma of HIV/AIDS are needed to curb the health threats posed by hepatitis B and hepatitis C, says a new report from the Institute of Medicine.
Chronic hepatitis B and C cause thousands of cases of liver cancer, liver disease, and death each year -- taking the heaviest toll among Asians, Pacific Islanders, and blacks in the U.S. -- and these infections account for nearly half of the liver transplantations that must be performed annually. Resources and efforts to contain the viruses that cause hepatitis B and C lag behind those directed at other infectious diseases of similar impact to public health, noted the committee that wrote the report.
"Although hepatitis B and C are preventable, the rates of infection have not declined over the past several years, underscoring the conclusion that we have allowed gaps in screening, prevention, and treatment to go unchecked," said committee chair R. Palmer Beasley, professor of epidemiology and disease control, University of Texas School of Public Health, Houston. "This report outlines the additional resources and actions needed to reduce the unacceptably high burden of liver disease and cancer associated with these viruses."
An estimated 800,000 to 1.4 million Americans have chronic hepatitis B and between 2.7 million and 3.9 million have chronic hepatitis C. The majority of infected individuals are not aware of their condition until they develop symptoms of liver cancer or liver disease. Few among the populations most at risk -- immigrants from countries where the diseases are endemic, non-Hispanic black men, injection-drug users, and people who had blood transfusions before 1992 -- seek testing or information on how to protect themselves from infection. Moreover, health care and social service providers' knowledge about hepatitis B and C is generally poor, and many fail to follow guidelines for screening patients and providing prevention, treatment, and follow-up services. The report calls for a public awareness initiative along the lines of the effort that succeeded in increasing recognition, prevention, and treatment of HIV/AIDS, which affects three to five times fewer Americans than viral hepatitis. Educational programs and materials that outline risk factors for viral hepatitis and provide information on immunization, prevention, and proper monitoring of infected individuals should be developed and made available to all health professionals and social service providers.
Steps need to be taken to eliminate the stigma associated with viral hepatitis. Negative attitudes about hepatitis B in some cultures may contribute to immigrants' reluctance to seek testing. In China, for example, people with chronic hepatitis B face job and social discrimination. In addition, negative perceptions about illicit-drug users, who make up the greatest percentage of those with hepatitis C, can affect the care they receive or their willingness to seek care.
Although the availability of an effective vaccine against hepatitis B has significantly reduced its spread, some 1,000 infants born to infected mothers develop chronic infections each year, a number that has not declined over the past decade. Moreover, three states -- Alabama, Montana, and South Dakota -- still do not require that children be vaccinated against hepatitis B before entering daycare or school. All full-term newborns whose mothers test positive for hepatitis B should receive the vaccine once they are stable and before leaving the delivery room rather than up to 12 hours after birth as is currently recommended. All states should make hepatitis B vaccination a requirement for school attendance, and health plans need to fully cover the costs associated with the immunization. Particular attention should be given to screening and vaccinating children who were born in countries where hepatitis B circulates widely. Each year, roughly 40,000 to 45,000 people legally emigrate to the United States from countries where hepatitis B is endemic.
Health care and social services related to viral hepatitis are sparse and fragmented among providers and organizations, leading to missed opportunities to prevent the spread of infection and to lessen the impact of chronic infections, the report concludes. The committee recommended several steps to create a more-coordinated approach, including ways to improve identification of infected individuals, social and peer support to reduce the stigma of infection, and medical management of those with chronic hepatitis B or C. These strategies are aimed at not just health professionals in hospitals and doctors' offices, but also individuals and groups that provide services to at-risk populations, including prisons and jails, HIV and STD clinics, shelter-based programs, and mobile health units.
People at greatest risk for hepatitis B include individuals born in East and Southeast Asia, sub-Saharan Africa, and other areas where the virus circulates widely; infants born to women with the disease; and those who have sexual contact or share injection-drug equipment with an infected person. Asians and Pacific Islanders make up 4.5 percent of the U.S. population but account for more than 50 percent of chronic hepatitis B cases. Those at greatest risk for hepatitis C are individuals who received a blood transfusion before 1992 and past or current injection-drug users. The chances of contracting hepatitis C increase with years of drug use and may be as high as 90 percent among long-term users. Deaths related to hepatitis C have increased, with the highest number occurring among middle-aged men, non-Hispanic blacks, and American Indians.
The report was sponsored by the U.S. Centers for Disease Control and Prevention, U.S. Department of Health and Human Services' Office of Minority Health, U.S. Department of Veterans Affairs, and the National Viral Hepatitis Roundtable. Established in 1970 under the charter of the National Academy of Sciences, the Institute of Medicine provides independent, objective, evidence-based advice to policymakers, health professionals, the private sector, and the public. The National Academy of Sciences, National Academy of Engineering, Institute of Medicine, and National Research Council make up the National Academies.
Achillion Pharma At A Glanc
Achillion Pharma At A Glance
Tue, 26 Jan 2010 09:55:00 EST
(RTTNews) - Achillion Pharmaceuticals Inc. ( ACHN | Quote | Chart | News | PowerRating) is scheduled to host a Corporate and Clinical Update conference call on Monday, February 1, highlighting the company's progress in its pipeline of HCV drugs. The company will also provide an update on its partnering efforts related to its antibiotic candidate ACH-702 as well as its HIV product candidate Elvucitabine.
Achillion's product pipeline includes ACH-1625 and ACH-1095 for the treatment of chronic hepatitis C infection; ACH-702 for the treatment of serious, resistant bacterial infections and Elvucitabine for the treatment of HIV.
ACH-1625, a potent HCV inhibitor, is under phase I study. The preliminary results of a phase Ib study of ACH-1625 reported early this month showed that there is a dramatic reduction in viral load after 5 days of monotherapy and continued suppression of viral load after drug discontinuation.
ACH-1095, which targets a viral protein called NS4A, is preparing to enter phase I clinical studies pending FDA consultation. ACH-1095 was developed in collaboration with Gilead Sciences Inc. (GILD) under a license agreement crafted between the two companies on November 24, 2004.
Since Gilead indicated that it does not intend to initiate clinical development of ACH-1095, Achillion and Gilead in May of 2009 agreed in principle to modify their license agreement to allow for advancement of ACH-1095 by Achillion, subject to certain opt-in rights of Gilead.
There continues to be a significant unmet need in the Hepatitis C arena, given the limited efficacy in some population and safety profile of the current standard treatment for HCV, Peginterferon-alfa in combination with Ribavirin. According to Achillion, ACH-1625 has the potential to offer convenient once-daily dosing and an improved safety and tolerability profile compared with other protease inhibitors being studied for the treatment of hepatitis C.
Research firm Decision Resources estimates that the hepatitis C virus drug market will increase from $2.7 billion in 2008 to nearly $7.7 billion in 2013 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan.
Schering-Plough Corp. (SGP), which makes Peg-Intron/Rebetrol and Swiss pharmaceutical giant Roche Holding AG, which makes Pegasys/Copegus are the two well-established players in the hepatitis C market. In 2008, Peg-Intron/Rebetrol generated sales of $1.2 billion for Schering-Plough, while Pegasys/Copegus fetched $1.5 billion in sales for Roche.
ACH-702, a potential treatment for hospital-based bacterial infections, has completed preclinical studies. With a potent broad-spectrum bactericidal activity, the company believes that ACH-702 may play an important role in the fight against drug-resistant bacteria. Drug resistance is resulting in an alarming rise in the incidence of hospital-acquired infections and presents new market opportunities.
Elvucitabine, Achillion's lead HIV product candidate is being evaluated in phase II clinical trials to further explore its safety and efficacy in HIV-infected patients over 48 and 96-weeks of treatment, and the open-label extension of one trial remains ongoing through this year. Achillion is currently seeking to enter a collaboration arrangement for Elvucitabine. Achillion is yet to market a drug and Elvucitabine is its most advanced drug candidate.
Last week, the company priced a firm commitment underwritten public offering of 10.27 million shares of its common stock at public offering price of $2.08 per share. The net proceeds of the offering are expected to be about $19.7 million and will be used for general corporate purposes.
Achillion went public in October 2006, pricing its shares at $11.50 each. Over the last twelve months, ACHN has traded in the range of $1.04-$3.89.
Stay tuned... Michael Kishbauch, Achillion's President and CEO will lead the company's management team in hosting the conference.
Tue, 26 Jan 2010 09:55:00 EST
(RTTNews) - Achillion Pharmaceuticals Inc. ( ACHN | Quote | Chart | News | PowerRating) is scheduled to host a Corporate and Clinical Update conference call on Monday, February 1, highlighting the company's progress in its pipeline of HCV drugs. The company will also provide an update on its partnering efforts related to its antibiotic candidate ACH-702 as well as its HIV product candidate Elvucitabine.
Achillion's product pipeline includes ACH-1625 and ACH-1095 for the treatment of chronic hepatitis C infection; ACH-702 for the treatment of serious, resistant bacterial infections and Elvucitabine for the treatment of HIV.
ACH-1625, a potent HCV inhibitor, is under phase I study. The preliminary results of a phase Ib study of ACH-1625 reported early this month showed that there is a dramatic reduction in viral load after 5 days of monotherapy and continued suppression of viral load after drug discontinuation.
ACH-1095, which targets a viral protein called NS4A, is preparing to enter phase I clinical studies pending FDA consultation. ACH-1095 was developed in collaboration with Gilead Sciences Inc. (GILD) under a license agreement crafted between the two companies on November 24, 2004.
Since Gilead indicated that it does not intend to initiate clinical development of ACH-1095, Achillion and Gilead in May of 2009 agreed in principle to modify their license agreement to allow for advancement of ACH-1095 by Achillion, subject to certain opt-in rights of Gilead.
There continues to be a significant unmet need in the Hepatitis C arena, given the limited efficacy in some population and safety profile of the current standard treatment for HCV, Peginterferon-alfa in combination with Ribavirin. According to Achillion, ACH-1625 has the potential to offer convenient once-daily dosing and an improved safety and tolerability profile compared with other protease inhibitors being studied for the treatment of hepatitis C.
Research firm Decision Resources estimates that the hepatitis C virus drug market will increase from $2.7 billion in 2008 to nearly $7.7 billion in 2013 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan.
Schering-Plough Corp. (SGP), which makes Peg-Intron/Rebetrol and Swiss pharmaceutical giant Roche Holding AG, which makes Pegasys/Copegus are the two well-established players in the hepatitis C market. In 2008, Peg-Intron/Rebetrol generated sales of $1.2 billion for Schering-Plough, while Pegasys/Copegus fetched $1.5 billion in sales for Roche.
ACH-702, a potential treatment for hospital-based bacterial infections, has completed preclinical studies. With a potent broad-spectrum bactericidal activity, the company believes that ACH-702 may play an important role in the fight against drug-resistant bacteria. Drug resistance is resulting in an alarming rise in the incidence of hospital-acquired infections and presents new market opportunities.
Elvucitabine, Achillion's lead HIV product candidate is being evaluated in phase II clinical trials to further explore its safety and efficacy in HIV-infected patients over 48 and 96-weeks of treatment, and the open-label extension of one trial remains ongoing through this year. Achillion is currently seeking to enter a collaboration arrangement for Elvucitabine. Achillion is yet to market a drug and Elvucitabine is its most advanced drug candidate.
Last week, the company priced a firm commitment underwritten public offering of 10.27 million shares of its common stock at public offering price of $2.08 per share. The net proceeds of the offering are expected to be about $19.7 million and will be used for general corporate purposes.
Achillion went public in October 2006, pricing its shares at $11.50 each. Over the last twelve months, ACHN has traded in the range of $1.04-$3.89.
Stay tuned... Michael Kishbauch, Achillion's President and CEO will lead the company's management team in hosting the conference.
HCV Drug Update for Vertex, Roche
HCV Drug Update for Vertex, Roche, Idenix
Vertex: New Drug Application planned for telaprevir in second half of 2010.....Proof-of-concept clinical trials planned for 2010 with novel combination regimens for hepatitis C....Upon completion of ongoing discussions with regulatory authorities, Vertex plans to initiate a combination trial of telaprevir and VX-222 in the first quarter of 2010. This trial is expected to evaluate SVR rates using multiple regimens of telaprevir/VX-222-based therapy in HCV patients.
Intermune/Pharmasset/Roche-Genentech: "The ritonavir-boosted regimen provided a more favorable pharmacokinetic profile than what has been previously observed for 900mg RG7227 administered twice-daily with SOC but without ritonavir. In view of these data, our plan is that the development of RG7227 will be in combination with ritonavir.......the company's plan is that the development of RG7227 will be in combination with low-dose ritonavir. Accordingly, the previously planned 24-week un-boosted part of the on-going Phase 2b triple combination study will now be replaced with a Phase 2b ritonavir-boosted study that is expected to begin in Q3 of 2010"
Idenix: Interim analysis of 50 mg cohort demonstrates potent HCV antiviral activity at 14 days for IDX184, a nucleotide polymerase inhibitor, in combination with PegIFN/Ribavirin. IDX375, a non-nucleoside polymerase inhibitor, exhibited favorable pharmacokinetic properties in a Phase I healthy volunteer study. Clinical Trial Application filed in December 2009 for IDX320, a next-generation protease inhibitor
InterMune Provides Program Update and 2010 Milestones for RG7227 (ITMN-191)
BRISBANE, Calif., Jan 11, 2010 /PRNewswire via COMTEX/ -- InterMune, Inc. (Nasdaq: ITMN) today provided an update (at JP Morgan Healthcare Conf) on its development program for protease inhibitor RG7227 (formerly referred to as ITMN-191) for the treatment of patients chronically infected with the hepatitis C virus (HCV). The company also reported guidance for the 2010 milestones and key events for RG7227.
Dan Welch, Chairman, Chief Executive Officer and President of InterMune, said, "Today we reported preliminary, top-line results from two cohorts of the Phase 1b, 15-day study of low-dose RG7227 co-administered with low-dose ritonavir and standard of care (SOC) in patients with chronic HCV. The majority of patients given ritonavir with 100mg RG7227 twice-daily or 200mg RG7227 once-daily were HCV RNA negative at the end of therapy. The ritonavir-boosted regimen provided a more favorable pharmacokinetic profile than what has been previously observed for 900mg RG7227 administered twice-daily with SOC but without ritonavir. In view of these data, our plan is that the development of RG7227 will be in combination with ritonavir."
Clinical Development Highlights and Recent Events
(RG7227)
- Enrollment began in August 2009 of the company's Phase 2b study of RG7227 in combination with PEGASYS(R) (pegylated interferon alfa-2a) and COPEGUS(R) (ribavirin), one of the options for the current standard of care (SOC) in HCV. The Phase 2b trial was designed to study both twice-daily (600mg and 900mg q12h) and three-times-daily regimens (300mg q8h) and both 12-week and 24-week treatment durations. On November 17, 2009, InterMune announced that three patients in the blinded 900mg q12h dosage cohort experienced an ACTG Grade 4 elevation in ALT levels, one of whom experienced an elevation of total bilirubin while also receiving concomitant allopurinol. After their review of un-blinded data from these patients, the study's independent Data Monitoring Committee (DMC) recommended that the 900mg q12h cohort be discontinued and that all other cohorts of the study continue. The companies accepted the DMC's recommendations. Enrollment of all remaining cohorts was completed in November of 2009.
- The company reported top-line results of a Phase 1 study of ritonavir-boosted RG7227 in healthy volunteers. Ritonavir is an antiviral compound commonly used at low, sub-therapeutic doses to enhance or "boost" the pharmacokinetic (PK) profiles of protease inhibitors. The results of this study demonstrated that the co- administration of low-dose ritonavir increased RG7227 concentration 12 hours post dose by 18 times, with the effect on Cmin being roughly 6 times and 3 times greater than the effect on Cmax and AUC, respectively. These results guided the selection of the substantially lower doses of RG7227 investigated in the Phase 1b MAD study in HCV patients.
- The company reported preliminary, top-line results of a Phase 1b multiple-ascending-dose (MAD) study that was initiated in September 2009 to evaluate low doses of once-daily and twice-daily RG7227 co-administered with low-dose ritonavir in combination with SOC for 15 days in treatment-naive HCV-infected patients. This study is examining the following three dosage regimens of RG7227, each with SOC and 100mg twice-daily ritonavir: o 100mg twice-daily RG7227 o 200mg once-daily RG7227 o 200mg twice-daily RG7227
Preliminary viral kinetic data from the first two cohorts of this study indicate that in the presence of SOC, the majority of patients achieved an undetectable level of HCV RNA after 15 days of treatment. The pharmacokinetic profile of ritonavir-boosted RG7227 was more favorable and less variable than that observed in previously reported studies conducted with much higher doses of un-boosted RG7227. No drug related serious adverse events have been reported to date. The companies hope to present the results from this study at a medical conference in the first half of 2010.
- Based upon these results, the company's plan is that the development of RG7227 will be in combination with low-dose ritonavir. Accordingly, the previously planned 24-week un-boosted part of the on-going Phase 2b triple combination study will now be replaced with a Phase 2b ritonavir-boosted study that is expected to begin in Q3 of 2010. As a result of not conducting Part B of the Phase 2b study, the company will un-blind the Part A 12-week cohorts earlier than originally planned and expects to provide both 4-week RVR data and 12-week EVR data late in the first quarter or early in the second quarter of 2010. In addition, the companies plan to amend the on-going Phase 1b MAD 15-day ritonavir boosting study to evaluate 12 weeks of RG7227 ritonavir-boosted therapy plus SOC.
2010 Key Project Guidance
The company provided the following guidance on the development timelines for RG7227.
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Vertex Reviews 2010 Business Priorities to Support Goal of Becoming Fully-Capable Biopharmaceutical Company
-HCV: New Drug Application planned for telaprevir in second half of 2010, robust commercialization and launch preparedness activities ongoing- -
- Pipeline: Proof-of-concept clinical trials planned for 2010 with novel combination regimens for hepatitis C
- Financial: Vertex enters 2010 with approximately $1.3 billion in cash, cash equivalents & marketable securities and approximately $32 million in outstanding convertible debt-
SAN FRANCISCO, Jan 10, 2010 Today provided an update on key 2010 business priorities in conjunction with the 28th Annual J.P. Morgan Healthcare Conference in San Francisco. The company also discussed recent progress in its lead development programs in hepatitis C virus (HCV) infection and cystic fibrosis (CF) and outlined proof-of-concept clinical trials planned in other serious diseases for 2010.
"2010 will be a defining year for Vertex as we seek to evolve into a fully-capable biopharmaceutical company," said Matthew Emmens, Chairman, President and Chief Executive Officer of Vertex. "With ongoing Phase 3 programs in hepatitis C virus infection and cystic fibrosis, a broad pipeline of other emerging product candidate opportunities and a strong capital structure, we believe Vertex today has a unique opportunity to build a successful company focused on bringing multiple important therapies to patients. In 2010, we look forward to a series of defining events from late-stage and proof-of-concept clinical trials that may support further growth in the years ahead."
Mr. Emmens will deliver a live webcast presentation from the J.P. Morgan Healthcare Conference on Tuesday, January 12 at 2:30 p.m. PT (5:30 p.m. ET) where he will discuss recent clinical progress and provide an overview of Vertex's 2010 priorities. The webcast will be available on Vertex's website, www.vrtx.com.
"Phase 3 data for telaprevir, our lead drug candidate for the treatment of hepatitis C virus infection, will begin to emerge in the spring of 2010 to support the planned submission of a New Drug Application in the second half of this year. Our more than decade-long commitment to improving patient care in HCV is unwavering, and the Phase 3 program for telaprevir will remain our primary focus over the coming year. Importantly, we also recognize the need for continued innovation in the treatment of this disease, and we are preparing to initiate the first clinical trial combining telaprevir with the investigational HCV polymerase inhibitor VX-222 this quarter," stated Mr. Emmens.
"Beyond HCV, Vertex is conducting mid-stage and late-stage development of two novel compounds aimed at addressing, for the first time, the underlying mechanism of the orphan disease of cystic fibrosis. The VX-770 Phase 3 registration program is advancing rapidly, and we expect to obtain Phase 3 data for VX-770 early in 2011. Additionally, we also expect to obtain clinical data from a Phase 2 trial of VX-809 in the coming weeks that could potentially support the evaluation of VX-770 and VX-809 as part of a combination regimen in patients with the most common mutation of this disease.
"Supporting our vision to become a fully-capable biopharmaceutical company, Vertex is also planning multiple proof-of-concept clinical trials in other diseases, such as rheumatoid arthritis and epilepsy, and remains committed to maintaining investment into research to enable future product opportunities," concluded Mr. Emmens.
Phase 3 Registration Program for Telaprevir Nears Completion
Sustained viral response (SVR) data expected from Phase 3 ADVANCE trial in second quarter 2010 and from Phase 3 ILLUMINATE & REALIZE trials in third quarter 2010
- The ADVANCE, ILLUMINATE and REALIZE trials are evaluating telaprevir-based regimens as part of a global Phase 3 registration program in more than 2,200 genotype 1 treatment-naïve and treatment-failure patients with HCV infection.
- Vertex today announced that all patients in the ADVANCE and ILLUMINATE trials, which are evaluating telaprevir in treatment-naïve patients, have completed dosing of all study drugs, including pegylated-interferon (peg-IFN) and ribavirin (RBV), and are now in the post-treatment follow-up period to determine the number of patients who achieve SVR (defined as undetectable HCV RNA 24 weeks after the end of treatment). Vertex expects SVR data to become available from ADVANCE in the second quarter of 2010 and from ILLUMINATE in the third quarter of 2010.
- Vertex today also announced that all patients in the REALIZE trial, which is being conducted by Vertex's collaborator Tibotec and is evaluating telaprevir in patients who did not achieve SVR with a prior pegylated interferon-based treatment, are expected to complete dosing of all study drugs, including pegylated-interferon and ribavirin, by the end of January. Vertex expects SVR data to become available from REALIZE in the third quarter of 2010.
- Vertex plans to submit a New Drug Application (NDA) for telaprevir in the second half of 2010 for both treatment-naïve and treatment-failure patients.
Twice-daily dosing of telaprevir
In November 2009, Vertex announced SVR results from Study C208, an exploratory Phase 2, open-label clinical study of telaprevir. The study was conducted by Tibotec in Europe and evaluated a twice-daily (1125mg q12h) dosing schedule of telaprevir in combination with peg-IFN-alfa-2a (PEGASYS(R)) or peg-IFN-alfa-2b (PEGINTRON(R)) and RBV, as compared to the three-times-daily (750mg q8h) telaprevir dosing schedule used in telaprevir clinical trials to date. The C208 trial enrolled 161 treatment-naïve patients with genotype 1 HCV infection. The C208 data included the first SVR data for telaprevir-based regimens in treatment-naïve patients as part of a response-guided therapy trial design, similar to that being used in the ADVANCE and ILLUMINATE Phase 3 trials of telaprevir.
Vertex has submitted the Study C208 clinical data to the U.S. FDA, and Vertex and Tibotec have initiated discussions with regulatory authorities in the U.S. and E.U. regarding future development plans for telaprevir as part of an every-12-hour (q12h) dosing regimen.
Vertex collaborator completes dosing of telaprevir in Phase 3 trials in Japan
Vertex today announced that its collaborator, Mitsubishi Tanabe Pharma Corporation, has completed the dosing portion for telaprevir in three ongoing Phase 3 trials of telaprevir-based combination therapy in approximately 300 treatment-naïve and treatment-failure HCV patients in Japan.
New capabilities to support potential launch of telaprevir
Vertex continues to build its commercial infrastructure in preparation for the potential launch of telaprevir and has begun to develop and implement internal systems and processes to support the company's commercial operation and the potential future sale of telaprevir.
The company expects to establish key elements of its customer-facing operation in 2010, including the hiring of the sales management team to be charged with the implementation of a fully-functioning commercial sales force in 2011. To inform launch preparedness activities, Vertex continues to conduct extensive HCV market research and is in discussions with key managed markets organizations and specialty pharmacies to generate additional insights on the HCV patient population, HCV patient care and flow, market communication strategies, and reimbursement processes for the HCV market.
Vertex has assembled a global supply chain network to support the potential launch of telaprevir and is currently manufacturing telaprevir at a commercial (metric ton) scale. The company has successfully completed all registration campaigns as well as validation campaigns of the active pharmaceutical ingredient (API) and is prepared to complete drug product validation in advance of the potential launch of telaprevir.
Potential Future Combination Regimens for HCV with Telaprevir and the HCV Polymerase Inhibitor VX-222
Initiation of first clinical trial of telaprevir combined with VX-222 planned for first quarter 2010
Vertex recently completed a multiple-dose Phase 1b viral kinetic study of the investigational oral HCV polymerase inhibitor VX-222. Interim results from the trial are consistent with the findings of a previously-conducted three-day viral kinetic study and support future clinical evaluation of VX-222, including the initiation of the first clinical trial of VX-222 in combination with telaprevir. Additional results from this Phase 1b study of VX-222 are planned for presentation at a medical meeting in 2010.
Upon completion of ongoing discussions with regulatory authorities, Vertex plans to initiate a combination trial of telaprevir and VX-222 in the first quarter of 2010. This trial is expected to evaluate SVR rates using multiple regimens of telaprevir/VX-222-based therapy in HCV patients.
Idenix Pharmaceuticals Highlights Progress in Three HCV Programs
- Interim analysis of 50 mg cohort demonstrates potent HCV antiviral activity at 14 days for IDX184, a nucleotide polymerase inhibitor, in combination with PegIFN/Ribavirin - IDX375, a non-nucleoside polymerase inhibitor, exhibited favorable pharmacokinetic properties in a Phase I healthy volunteer study - Clinical Trial Application filed in December 2009 for IDX320, a next-generation protease inhibitor
CAMBRIDGE, Mass., Jan 11, 2010 /PRNewswire via COMTEX/ -- Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today announced significant progress in three HCV programs. Idenix will provide a business update on these three HCV development programs and on its partnered programs during a presentation by Jean-Pierre Sommadossi, Ph.D., chairman and chief executive officer, to financial analysts and investors at the 28th Annual J.P. Morgan Healthcare Conference in San Francisco on Thursday, January 14 at 8:00 a.m. PST.
IDX184: Nucleotide HCV Polymerase Inhibitor
The phase II clinical trial, initiated in the fourth quarter of 2009, is a randomized, double-blind, placebo-controlled, sequential dose-escalation study evaluating the safety, tolerability, pharmacokinetics and antiviral activity of IDX184 in combination with pegylated interferon and ribavirin in treatment-naive HCV genotype 1-infected patients. Patients will receive a daily dose of IDX184 or placebo plus pegylated interferon and ribavirin for 14 days and then continue on pegylated interferon and ribavirin for an additional 14 days. Antiviral activity will be assessed at the 14-day and 28-day timepoints. Four dosing regimens of IDX184 ranging from 50 to 200 mg per day will be evaluated. In the 100 mg and 200 mg cohorts, QD and BID regimens will be compared. Each cohort includes 20 patients randomized 4:1, IDX184:placebo. This study is being conducted at multiple centers in the United States and Argentina.
Interim analysis of the first 10 patients randomized into the first cohort (50 mg QD):
cohort-2.gif
Median ALT and AST levels, markers of liver injury, improved during treatment. There were no serious adverse events on treatment, no treatment discontinuations and laboratory profiles were comparable to standard PegIFN/Ribavirin treatment. "We are very encouraged by these interim data for IDX184 combined with pegylated interferon and ribavirin and look forward to seeing additional data as the study progresses," said Douglas Mayers, M.D., Idenix's executive vice president and chief medical officer.
IDX375: Non-Nucleoside HCV Polymerase Inhibitor
A Phase I single ascending dose study evaluating the safety, tolerability and pharmacokinetics of IDX375 in healthy volunteers is ongoing. The first five cohorts (25 mg QD, 50 mg QD, 100 mg QD, 200 mg QD and 200 mg BID; 6 active:2 placebo) in this double-blind, placebo-controlled study have been completed. Data suggest favorable plasma exposure of IDX375 with a long elimination half-life of 32-40 hours demonstrating the potential for once- or twice-daily dosing in patients. IDX375 was generally safe and well tolerated. There were no significant lab abnormalities. The most common adverse event was mild diarrhea (3/30 subjects). Additional cohorts with higher single and multiple doses are planned.
IDX320: HCV Protease Inhibitor
A Clinical Trial Application for a new protease inhibitor clinical candidate, IDX320, was filed in December 2009. IDX320 is a non-covalent macrocyclic inhibitor with nanomolar potency, broad genotypic coverage and a favorable preclinical pharmacokinetic profile supporting the potential for once-daily dosing in man.
"We are pleased with these early data from our clinical programs and look forward to their continued advancement throughout the year," said Jean-Pierre Sommadossi, Ph.D., chairman and chief executive officer of Idenix. "In addition, we are excited about our new protease inhibitor clinical candidate, IDX320, and expect to begin a phase I clinical trial soon. With three promising clinical programs that span major HCV drug classes, Idenix is well positioned to play an important role in the transformation of the HCV treatment paradigm."
Vertex: New Drug Application planned for telaprevir in second half of 2010.....Proof-of-concept clinical trials planned for 2010 with novel combination regimens for hepatitis C....Upon completion of ongoing discussions with regulatory authorities, Vertex plans to initiate a combination trial of telaprevir and VX-222 in the first quarter of 2010. This trial is expected to evaluate SVR rates using multiple regimens of telaprevir/VX-222-based therapy in HCV patients.
Intermune/Pharmasset/Roche-Genentech: "The ritonavir-boosted regimen provided a more favorable pharmacokinetic profile than what has been previously observed for 900mg RG7227 administered twice-daily with SOC but without ritonavir. In view of these data, our plan is that the development of RG7227 will be in combination with ritonavir.......the company's plan is that the development of RG7227 will be in combination with low-dose ritonavir. Accordingly, the previously planned 24-week un-boosted part of the on-going Phase 2b triple combination study will now be replaced with a Phase 2b ritonavir-boosted study that is expected to begin in Q3 of 2010"
Idenix: Interim analysis of 50 mg cohort demonstrates potent HCV antiviral activity at 14 days for IDX184, a nucleotide polymerase inhibitor, in combination with PegIFN/Ribavirin. IDX375, a non-nucleoside polymerase inhibitor, exhibited favorable pharmacokinetic properties in a Phase I healthy volunteer study. Clinical Trial Application filed in December 2009 for IDX320, a next-generation protease inhibitor
InterMune Provides Program Update and 2010 Milestones for RG7227 (ITMN-191)
BRISBANE, Calif., Jan 11, 2010 /PRNewswire via COMTEX/ -- InterMune, Inc. (Nasdaq: ITMN) today provided an update (at JP Morgan Healthcare Conf) on its development program for protease inhibitor RG7227 (formerly referred to as ITMN-191) for the treatment of patients chronically infected with the hepatitis C virus (HCV). The company also reported guidance for the 2010 milestones and key events for RG7227.
Dan Welch, Chairman, Chief Executive Officer and President of InterMune, said, "Today we reported preliminary, top-line results from two cohorts of the Phase 1b, 15-day study of low-dose RG7227 co-administered with low-dose ritonavir and standard of care (SOC) in patients with chronic HCV. The majority of patients given ritonavir with 100mg RG7227 twice-daily or 200mg RG7227 once-daily were HCV RNA negative at the end of therapy. The ritonavir-boosted regimen provided a more favorable pharmacokinetic profile than what has been previously observed for 900mg RG7227 administered twice-daily with SOC but without ritonavir. In view of these data, our plan is that the development of RG7227 will be in combination with ritonavir."
Clinical Development Highlights and Recent Events
(RG7227)
- Enrollment began in August 2009 of the company's Phase 2b study of RG7227 in combination with PEGASYS(R) (pegylated interferon alfa-2a) and COPEGUS(R) (ribavirin), one of the options for the current standard of care (SOC) in HCV. The Phase 2b trial was designed to study both twice-daily (600mg and 900mg q12h) and three-times-daily regimens (300mg q8h) and both 12-week and 24-week treatment durations. On November 17, 2009, InterMune announced that three patients in the blinded 900mg q12h dosage cohort experienced an ACTG Grade 4 elevation in ALT levels, one of whom experienced an elevation of total bilirubin while also receiving concomitant allopurinol. After their review of un-blinded data from these patients, the study's independent Data Monitoring Committee (DMC) recommended that the 900mg q12h cohort be discontinued and that all other cohorts of the study continue. The companies accepted the DMC's recommendations. Enrollment of all remaining cohorts was completed in November of 2009.
- The company reported top-line results of a Phase 1 study of ritonavir-boosted RG7227 in healthy volunteers. Ritonavir is an antiviral compound commonly used at low, sub-therapeutic doses to enhance or "boost" the pharmacokinetic (PK) profiles of protease inhibitors. The results of this study demonstrated that the co- administration of low-dose ritonavir increased RG7227 concentration 12 hours post dose by 18 times, with the effect on Cmin being roughly 6 times and 3 times greater than the effect on Cmax and AUC, respectively. These results guided the selection of the substantially lower doses of RG7227 investigated in the Phase 1b MAD study in HCV patients.
- The company reported preliminary, top-line results of a Phase 1b multiple-ascending-dose (MAD) study that was initiated in September 2009 to evaluate low doses of once-daily and twice-daily RG7227 co-administered with low-dose ritonavir in combination with SOC for 15 days in treatment-naive HCV-infected patients. This study is examining the following three dosage regimens of RG7227, each with SOC and 100mg twice-daily ritonavir: o 100mg twice-daily RG7227 o 200mg once-daily RG7227 o 200mg twice-daily RG7227
Preliminary viral kinetic data from the first two cohorts of this study indicate that in the presence of SOC, the majority of patients achieved an undetectable level of HCV RNA after 15 days of treatment. The pharmacokinetic profile of ritonavir-boosted RG7227 was more favorable and less variable than that observed in previously reported studies conducted with much higher doses of un-boosted RG7227. No drug related serious adverse events have been reported to date. The companies hope to present the results from this study at a medical conference in the first half of 2010.
- Based upon these results, the company's plan is that the development of RG7227 will be in combination with low-dose ritonavir. Accordingly, the previously planned 24-week un-boosted part of the on-going Phase 2b triple combination study will now be replaced with a Phase 2b ritonavir-boosted study that is expected to begin in Q3 of 2010. As a result of not conducting Part B of the Phase 2b study, the company will un-blind the Part A 12-week cohorts earlier than originally planned and expects to provide both 4-week RVR data and 12-week EVR data late in the first quarter or early in the second quarter of 2010. In addition, the companies plan to amend the on-going Phase 1b MAD 15-day ritonavir boosting study to evaluate 12 weeks of RG7227 ritonavir-boosted therapy plus SOC.
2010 Key Project Guidance
The company provided the following guidance on the development timelines for RG7227.
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Vertex Reviews 2010 Business Priorities to Support Goal of Becoming Fully-Capable Biopharmaceutical Company
-HCV: New Drug Application planned for telaprevir in second half of 2010, robust commercialization and launch preparedness activities ongoing- -
- Pipeline: Proof-of-concept clinical trials planned for 2010 with novel combination regimens for hepatitis C
- Financial: Vertex enters 2010 with approximately $1.3 billion in cash, cash equivalents & marketable securities and approximately $32 million in outstanding convertible debt-
SAN FRANCISCO, Jan 10, 2010 Today provided an update on key 2010 business priorities in conjunction with the 28th Annual J.P. Morgan Healthcare Conference in San Francisco. The company also discussed recent progress in its lead development programs in hepatitis C virus (HCV) infection and cystic fibrosis (CF) and outlined proof-of-concept clinical trials planned in other serious diseases for 2010.
"2010 will be a defining year for Vertex as we seek to evolve into a fully-capable biopharmaceutical company," said Matthew Emmens, Chairman, President and Chief Executive Officer of Vertex. "With ongoing Phase 3 programs in hepatitis C virus infection and cystic fibrosis, a broad pipeline of other emerging product candidate opportunities and a strong capital structure, we believe Vertex today has a unique opportunity to build a successful company focused on bringing multiple important therapies to patients. In 2010, we look forward to a series of defining events from late-stage and proof-of-concept clinical trials that may support further growth in the years ahead."
Mr. Emmens will deliver a live webcast presentation from the J.P. Morgan Healthcare Conference on Tuesday, January 12 at 2:30 p.m. PT (5:30 p.m. ET) where he will discuss recent clinical progress and provide an overview of Vertex's 2010 priorities. The webcast will be available on Vertex's website, www.vrtx.com.
"Phase 3 data for telaprevir, our lead drug candidate for the treatment of hepatitis C virus infection, will begin to emerge in the spring of 2010 to support the planned submission of a New Drug Application in the second half of this year. Our more than decade-long commitment to improving patient care in HCV is unwavering, and the Phase 3 program for telaprevir will remain our primary focus over the coming year. Importantly, we also recognize the need for continued innovation in the treatment of this disease, and we are preparing to initiate the first clinical trial combining telaprevir with the investigational HCV polymerase inhibitor VX-222 this quarter," stated Mr. Emmens.
"Beyond HCV, Vertex is conducting mid-stage and late-stage development of two novel compounds aimed at addressing, for the first time, the underlying mechanism of the orphan disease of cystic fibrosis. The VX-770 Phase 3 registration program is advancing rapidly, and we expect to obtain Phase 3 data for VX-770 early in 2011. Additionally, we also expect to obtain clinical data from a Phase 2 trial of VX-809 in the coming weeks that could potentially support the evaluation of VX-770 and VX-809 as part of a combination regimen in patients with the most common mutation of this disease.
"Supporting our vision to become a fully-capable biopharmaceutical company, Vertex is also planning multiple proof-of-concept clinical trials in other diseases, such as rheumatoid arthritis and epilepsy, and remains committed to maintaining investment into research to enable future product opportunities," concluded Mr. Emmens.
Phase 3 Registration Program for Telaprevir Nears Completion
Sustained viral response (SVR) data expected from Phase 3 ADVANCE trial in second quarter 2010 and from Phase 3 ILLUMINATE & REALIZE trials in third quarter 2010
- The ADVANCE, ILLUMINATE and REALIZE trials are evaluating telaprevir-based regimens as part of a global Phase 3 registration program in more than 2,200 genotype 1 treatment-naïve and treatment-failure patients with HCV infection.
- Vertex today announced that all patients in the ADVANCE and ILLUMINATE trials, which are evaluating telaprevir in treatment-naïve patients, have completed dosing of all study drugs, including pegylated-interferon (peg-IFN) and ribavirin (RBV), and are now in the post-treatment follow-up period to determine the number of patients who achieve SVR (defined as undetectable HCV RNA 24 weeks after the end of treatment). Vertex expects SVR data to become available from ADVANCE in the second quarter of 2010 and from ILLUMINATE in the third quarter of 2010.
- Vertex today also announced that all patients in the REALIZE trial, which is being conducted by Vertex's collaborator Tibotec and is evaluating telaprevir in patients who did not achieve SVR with a prior pegylated interferon-based treatment, are expected to complete dosing of all study drugs, including pegylated-interferon and ribavirin, by the end of January. Vertex expects SVR data to become available from REALIZE in the third quarter of 2010.
- Vertex plans to submit a New Drug Application (NDA) for telaprevir in the second half of 2010 for both treatment-naïve and treatment-failure patients.
Twice-daily dosing of telaprevir
In November 2009, Vertex announced SVR results from Study C208, an exploratory Phase 2, open-label clinical study of telaprevir. The study was conducted by Tibotec in Europe and evaluated a twice-daily (1125mg q12h) dosing schedule of telaprevir in combination with peg-IFN-alfa-2a (PEGASYS(R)) or peg-IFN-alfa-2b (PEGINTRON(R)) and RBV, as compared to the three-times-daily (750mg q8h) telaprevir dosing schedule used in telaprevir clinical trials to date. The C208 trial enrolled 161 treatment-naïve patients with genotype 1 HCV infection. The C208 data included the first SVR data for telaprevir-based regimens in treatment-naïve patients as part of a response-guided therapy trial design, similar to that being used in the ADVANCE and ILLUMINATE Phase 3 trials of telaprevir.
Vertex has submitted the Study C208 clinical data to the U.S. FDA, and Vertex and Tibotec have initiated discussions with regulatory authorities in the U.S. and E.U. regarding future development plans for telaprevir as part of an every-12-hour (q12h) dosing regimen.
Vertex collaborator completes dosing of telaprevir in Phase 3 trials in Japan
Vertex today announced that its collaborator, Mitsubishi Tanabe Pharma Corporation, has completed the dosing portion for telaprevir in three ongoing Phase 3 trials of telaprevir-based combination therapy in approximately 300 treatment-naïve and treatment-failure HCV patients in Japan.
New capabilities to support potential launch of telaprevir
Vertex continues to build its commercial infrastructure in preparation for the potential launch of telaprevir and has begun to develop and implement internal systems and processes to support the company's commercial operation and the potential future sale of telaprevir.
The company expects to establish key elements of its customer-facing operation in 2010, including the hiring of the sales management team to be charged with the implementation of a fully-functioning commercial sales force in 2011. To inform launch preparedness activities, Vertex continues to conduct extensive HCV market research and is in discussions with key managed markets organizations and specialty pharmacies to generate additional insights on the HCV patient population, HCV patient care and flow, market communication strategies, and reimbursement processes for the HCV market.
Vertex has assembled a global supply chain network to support the potential launch of telaprevir and is currently manufacturing telaprevir at a commercial (metric ton) scale. The company has successfully completed all registration campaigns as well as validation campaigns of the active pharmaceutical ingredient (API) and is prepared to complete drug product validation in advance of the potential launch of telaprevir.
Potential Future Combination Regimens for HCV with Telaprevir and the HCV Polymerase Inhibitor VX-222
Initiation of first clinical trial of telaprevir combined with VX-222 planned for first quarter 2010
Vertex recently completed a multiple-dose Phase 1b viral kinetic study of the investigational oral HCV polymerase inhibitor VX-222. Interim results from the trial are consistent with the findings of a previously-conducted three-day viral kinetic study and support future clinical evaluation of VX-222, including the initiation of the first clinical trial of VX-222 in combination with telaprevir. Additional results from this Phase 1b study of VX-222 are planned for presentation at a medical meeting in 2010.
Upon completion of ongoing discussions with regulatory authorities, Vertex plans to initiate a combination trial of telaprevir and VX-222 in the first quarter of 2010. This trial is expected to evaluate SVR rates using multiple regimens of telaprevir/VX-222-based therapy in HCV patients.
Idenix Pharmaceuticals Highlights Progress in Three HCV Programs
- Interim analysis of 50 mg cohort demonstrates potent HCV antiviral activity at 14 days for IDX184, a nucleotide polymerase inhibitor, in combination with PegIFN/Ribavirin - IDX375, a non-nucleoside polymerase inhibitor, exhibited favorable pharmacokinetic properties in a Phase I healthy volunteer study - Clinical Trial Application filed in December 2009 for IDX320, a next-generation protease inhibitor
CAMBRIDGE, Mass., Jan 11, 2010 /PRNewswire via COMTEX/ -- Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today announced significant progress in three HCV programs. Idenix will provide a business update on these three HCV development programs and on its partnered programs during a presentation by Jean-Pierre Sommadossi, Ph.D., chairman and chief executive officer, to financial analysts and investors at the 28th Annual J.P. Morgan Healthcare Conference in San Francisco on Thursday, January 14 at 8:00 a.m. PST.
IDX184: Nucleotide HCV Polymerase Inhibitor
The phase II clinical trial, initiated in the fourth quarter of 2009, is a randomized, double-blind, placebo-controlled, sequential dose-escalation study evaluating the safety, tolerability, pharmacokinetics and antiviral activity of IDX184 in combination with pegylated interferon and ribavirin in treatment-naive HCV genotype 1-infected patients. Patients will receive a daily dose of IDX184 or placebo plus pegylated interferon and ribavirin for 14 days and then continue on pegylated interferon and ribavirin for an additional 14 days. Antiviral activity will be assessed at the 14-day and 28-day timepoints. Four dosing regimens of IDX184 ranging from 50 to 200 mg per day will be evaluated. In the 100 mg and 200 mg cohorts, QD and BID regimens will be compared. Each cohort includes 20 patients randomized 4:1, IDX184:placebo. This study is being conducted at multiple centers in the United States and Argentina.
Interim analysis of the first 10 patients randomized into the first cohort (50 mg QD):
cohort-2.gif
Median ALT and AST levels, markers of liver injury, improved during treatment. There were no serious adverse events on treatment, no treatment discontinuations and laboratory profiles were comparable to standard PegIFN/Ribavirin treatment. "We are very encouraged by these interim data for IDX184 combined with pegylated interferon and ribavirin and look forward to seeing additional data as the study progresses," said Douglas Mayers, M.D., Idenix's executive vice president and chief medical officer.
IDX375: Non-Nucleoside HCV Polymerase Inhibitor
A Phase I single ascending dose study evaluating the safety, tolerability and pharmacokinetics of IDX375 in healthy volunteers is ongoing. The first five cohorts (25 mg QD, 50 mg QD, 100 mg QD, 200 mg QD and 200 mg BID; 6 active:2 placebo) in this double-blind, placebo-controlled study have been completed. Data suggest favorable plasma exposure of IDX375 with a long elimination half-life of 32-40 hours demonstrating the potential for once- or twice-daily dosing in patients. IDX375 was generally safe and well tolerated. There were no significant lab abnormalities. The most common adverse event was mild diarrhea (3/30 subjects). Additional cohorts with higher single and multiple doses are planned.
IDX320: HCV Protease Inhibitor
A Clinical Trial Application for a new protease inhibitor clinical candidate, IDX320, was filed in December 2009. IDX320 is a non-covalent macrocyclic inhibitor with nanomolar potency, broad genotypic coverage and a favorable preclinical pharmacokinetic profile supporting the potential for once-daily dosing in man.
"We are pleased with these early data from our clinical programs and look forward to their continued advancement throughout the year," said Jean-Pierre Sommadossi, Ph.D., chairman and chief executive officer of Idenix. "In addition, we are excited about our new protease inhibitor clinical candidate, IDX320, and expect to begin a phase I clinical trial soon. With three promising clinical programs that span major HCV drug classes, Idenix is well positioned to play an important role in the transformation of the HCV treatment paradigm."
Dynavax Reports Positive Phase 1b Data for SD-101 in Chronic Hepatitis C Infection
Dynavax Reports Positive Phase 1b Data for SD-101 in Chronic Hepatitis C Infection
In vitro Study Shows SD-101 Induces Both IFN-lambda and IFN-alpha
January 26, 2010
Dynavax Technologies Corporation (NASDAQ: DVAX) announced today data from two studies that differentiate SD-101 from standard-of-care as well as emerging treatments for chronic HCV infection. The findings of a Phase 1b clinical trial and an in vitro study of SD-101's mechanism of action show that the second-generation TLR9 agonist (1) is well tolerated and safe and (2) induces both IFN-lambda and IFN-alpha at concentrations producing antiviral activity. The data will be presented at the 45th Annual Meeting of the European Association for the Study of the Liver in Vienna, Austria in April 2010.
Data from the Phase 1b study of SD-101 in treatment-naïve, genotype 1 HCV patients show:
-- A safety and tolerability profile that compares favorably to that of
IFN-alpha, at all four doses tested;
-- A dose-dependent antiviral response, with 100% of patients at the
highest dose experiencing a greater than one (1) log reduction in viral
load; and
-- The potency of SD-101 as confirmed by biomarker analysis in patients.
The biomarker data point to substantial, dose-related increases in the
expression of key antiviral genes (MX-B and ISG-54k) and genes indicating
enhanced immunity (IP-10 and MCP-1).
The Phase 1b study evaluated four dose levels of SD-101 in 34 chronically infected, treatment-naïve, genotype 1 HCV patients. SD-101 was administered as a monotherapy once weekly, for four weeks, in doses from 0.1 to 5.0 milligrams per week.
The in vitro data from a study of the drug in human blood cells demonstrate that compared to first-generation TLR9 agonists, SD-101 stimulates 20-fold higher levels of both IFN-alpha and IFN-lambda, two classes of IFNs with potent activity against HCV.
According to the Company's Chief Medical Officer, J. Tyler Martin, M.D., "The unique and highly potent pattern of IFN-lambda and IFN-alpha induction by SD-101 represents a novel, differentiated approach for HCV. The safety and antiviral activity demonstrated in this Phase 1b study compares favorably to current treatments, and we believe that further study may support a role for SD-101 as a supplement to current or emerging therapies to treat HCV."
With the completed acquisition of Symphony Dynamo earlier this month, Dynavax has full development and commercialization rights to SD-101. As such, SD-101 has been added to a portfolio of development programs available for partnership from Dynavax.
About HCV
According to the World Health Organization, there are 170 million people worldwide chronically infected with HCV. Over 80% of HCV infections become chronic and can progress over a period of 10 - 40 years. Nearly half of all liver transplants in the U.S. are performed for end-stage hepatitis C. Approved therapies to treat hepatitis C, including pegylated interferon-alpha and ribavirin, represent a market of approximately $3 billion. However, these therapies often cause significant side effects and are effective in treating only about half of all patients infected with HCV.
About Dynavax
Dynavax Technologies Corporation, a clinical-stage biopharmaceutical company, discovers and develops novel products to prevent and treat infectious diseases. The Company's lead product candidate is HEPLISAV, a Phase 3 investigational adult hepatitis B vaccine designed to provide more rapid and increased protection with fewer doses than current licensed vaccines. For more information, visitwww.dynavax.com.
Forward Looking Statements
This press release contains "forward-looking statements" that are subject to a number of risks and uncertainties, including the prospective role of SD-101 in HCV therapy. Actual results may differ materially from those set forth in this press release due to the risks and uncertainties inherent in our business, including whether initial results can be reproduced in future studies, whether successful clinical and regulatory development of SD-101 can occur in a timely manner without significant difficulties or delays in development , the Company's ability to obtain additional financing to support its operations, and other risks detailed in the "Risk Factors" section of our current periodic reports with the SEC. We undertake no obligation to revise or update information herein to reflect events or circumstances in the future, even if new information becomes available.
Contact:
Michael Ostrach
Vice President and Chief Business Officer
510-665-7257
In vitro Study Shows SD-101 Induces Both IFN-lambda and IFN-alpha
January 26, 2010
Dynavax Technologies Corporation (NASDAQ: DVAX) announced today data from two studies that differentiate SD-101 from standard-of-care as well as emerging treatments for chronic HCV infection. The findings of a Phase 1b clinical trial and an in vitro study of SD-101's mechanism of action show that the second-generation TLR9 agonist (1) is well tolerated and safe and (2) induces both IFN-lambda and IFN-alpha at concentrations producing antiviral activity. The data will be presented at the 45th Annual Meeting of the European Association for the Study of the Liver in Vienna, Austria in April 2010.
Data from the Phase 1b study of SD-101 in treatment-naïve, genotype 1 HCV patients show:
-- A safety and tolerability profile that compares favorably to that of
IFN-alpha, at all four doses tested;
-- A dose-dependent antiviral response, with 100% of patients at the
highest dose experiencing a greater than one (1) log reduction in viral
load; and
-- The potency of SD-101 as confirmed by biomarker analysis in patients.
The biomarker data point to substantial, dose-related increases in the
expression of key antiviral genes (MX-B and ISG-54k) and genes indicating
enhanced immunity (IP-10 and MCP-1).
The Phase 1b study evaluated four dose levels of SD-101 in 34 chronically infected, treatment-naïve, genotype 1 HCV patients. SD-101 was administered as a monotherapy once weekly, for four weeks, in doses from 0.1 to 5.0 milligrams per week.
The in vitro data from a study of the drug in human blood cells demonstrate that compared to first-generation TLR9 agonists, SD-101 stimulates 20-fold higher levels of both IFN-alpha and IFN-lambda, two classes of IFNs with potent activity against HCV.
According to the Company's Chief Medical Officer, J. Tyler Martin, M.D., "The unique and highly potent pattern of IFN-lambda and IFN-alpha induction by SD-101 represents a novel, differentiated approach for HCV. The safety and antiviral activity demonstrated in this Phase 1b study compares favorably to current treatments, and we believe that further study may support a role for SD-101 as a supplement to current or emerging therapies to treat HCV."
With the completed acquisition of Symphony Dynamo earlier this month, Dynavax has full development and commercialization rights to SD-101. As such, SD-101 has been added to a portfolio of development programs available for partnership from Dynavax.
About HCV
According to the World Health Organization, there are 170 million people worldwide chronically infected with HCV. Over 80% of HCV infections become chronic and can progress over a period of 10 - 40 years. Nearly half of all liver transplants in the U.S. are performed for end-stage hepatitis C. Approved therapies to treat hepatitis C, including pegylated interferon-alpha and ribavirin, represent a market of approximately $3 billion. However, these therapies often cause significant side effects and are effective in treating only about half of all patients infected with HCV.
About Dynavax
Dynavax Technologies Corporation, a clinical-stage biopharmaceutical company, discovers and develops novel products to prevent and treat infectious diseases. The Company's lead product candidate is HEPLISAV, a Phase 3 investigational adult hepatitis B vaccine designed to provide more rapid and increased protection with fewer doses than current licensed vaccines. For more information, visitwww.dynavax.com.
Forward Looking Statements
This press release contains "forward-looking statements" that are subject to a number of risks and uncertainties, including the prospective role of SD-101 in HCV therapy. Actual results may differ materially from those set forth in this press release due to the risks and uncertainties inherent in our business, including whether initial results can be reproduced in future studies, whether successful clinical and regulatory development of SD-101 can occur in a timely manner without significant difficulties or delays in development , the Company's ability to obtain additional financing to support its operations, and other risks detailed in the "Risk Factors" section of our current periodic reports with the SEC. We undertake no obligation to revise or update information herein to reflect events or circumstances in the future, even if new information becomes available.
Contact:
Michael Ostrach
Vice President and Chief Business Officer
510-665-7257
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