I know the Pharmasset folks are bullish about a interferon-free drug combo to treat HCV - actually, we ALL are, but until we have SVR data from that particular combination and others like it in development, interferon is here to stay. Biolex (who features ex-Vertex CCO Kurt Graves as it's Executive Chairman of the Board) is the entity here in the States that is developing Locteron. The deal with Locteron is that it's a Peg-less PegIntron with a sexy new controlled release technology that allows it to be dosed every other week. Added benefits are a nice reduction in flu-like side-effects and interferon-related depression. Results of it's Phase IIb study, SELECT-2, comparing it to Pegintron look pretty good. Locteron maintains and/or beats it's pegylated cousin in the SVR department (SVR 41% (640 μg); 34% (480 μg); 36% (320 μg); 33% (Pegintron))while chopping the number of shots in half and reducing AE's. The big problem at this point isn't the threat of an interferon-free HCV drug combo, but lack of data with a DAA. I'm not schooled in Biolex, but I'm sure that's the company's hope going forward. Or it may just file with a DAA-less indication if the Phase III data and competitive environment look promising enough. Either way, the thought of a more user-friendly interferon is pretty enticing. Hopefully, investors will feel the same way.
OctoPlus N.V. ("OctoPlus" or the "Company") (Euronext: OCTO) announces that its licensee Biolex Therapeutics will present today final results from the Locteron® Phase IIb clinical study at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. These data highlight important tolerability advantages of Locteron versus current HCV treatments.
Jan Egberts, CEO of OctoPlus, comments: "These positive final results from the Phase IIb clinical study with Locteron further confirm the long term benefits of Locteron's controlled release mechanism. Our PolyActive technology has enabled the development of an interferon alpha with a significantly improved side effect profile, achieving both a 50% reduction in flu-like adverse events and substantially lower rates of depression compared to conventional interferon treatments. In combination with its reduced injection frequency, these benefits clearly position Locteron as the interferon of choice for future hepatitis C treatments."
The following information was taken directly from Biolex' press release (see www.biolex.com).
Biolex announces that final 72-week results from its SELECT-2 Phase 2b trial of Locteron® for the treatment of hepatitis C are being presented today at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. Data presented today show that Locteron achieved the SELECT-2 study objectives by demonstrating viral kinetics and response rates that were comparable with or exceeded the PEG-Intron® control while also achieving a statistically significant reduction in flu-like adverse events, reduced rates of depression, lower use of concomitant medications and a reduced rate of discontinuation due to adverse events. Locteron, the only controlled-release interferon alpha, is designed to offer key tolerability and dosing advantages over currently marketed interferons and serve as a core component of new combination therapies as the treatment of hepatitis C evolves to triple- and quad-drug regimens.
Locteron dosing convenience and efficacy
Locteron is administered once every other week and requires half as many injections as the currently marketed interferons, each of which are injected once per week. In SELECT-2, the sustained virologic response rate (SVR) for each of the three Locteron doses studied was comparable with or exceeded the response rate for the PEG-Intron control as outlined in the table below.
Click on the link for the press release including tables.
Thursday, March 31, 2011
Wednesday, March 30, 2011
Boceprevir in Treatment Naive Genotype 1 published in the New England Journal of Medicine??
Boceprevir trial in Genotype 1 treatment-naive patients gets published in NEJM. Merck must have the inside line to the Gods, I don't know how they do it. Thanks to the great NATAP for the info.
Fred Poordad, M.D., Jonathan McCone, Jr., M.D., Bruce R. Bacon, M.D., Savino Bruno, M.D., Michael P. Manns, M.D., Mark S. Sulkowski, M.D., Ira M. Jacobson, M.D., K. Rajender Reddy, M.D., Zachary D. Goodman, M.D., Ph.D., Navdeep Boparai, M.S., Mark J. DiNubile, M.D., Vilma Sniukiene, M.D., Clifford A. Brass, M.D., Ph.D., Janice K. Albrecht, Ph.D., and Jean-Pierre Bronowicki, M.D., Ph.D. for the SPRINT-2 Investigators
N Engl J Med 2011; 364:1195-1206March 31, 2011
Background
Peginterferon–ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.
Methods
We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon–ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon–ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon–ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon–ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.
Results
A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon–ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. Conclusions The addition of boceprevir to standard therapy with peginterferon–ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.) The opinions expressed in this report represent the consensus of the coauthors and do not necessarily reflect the formal position of Merck or the other institutions listed as authors' affiliations. Supported by Schering-Plough (now Merck). Chronic infection with the hepatitis C virus (HCV) affects more than 170 million people worldwide.1,2 Rates of sustained virologic response associated with peginterferon–ribavirin therapy remain below 50% and are often less than 30% among patients who have HCV genotype 1 infection and certain baseline characteristics, such as advanced fibrosis, diabetes, coinfection with the human immunodeficiency virus (HIV), or African heritage.3-9 Recent efforts to improve the rate of sustained virologic response have focused on oral direct-acting antiviral agents.10-13 Boceprevir is a linear peptidomimetic ketoamide serine protease inhibitor that binds reversibly to the HCV nonstructural 3 (NS3) active site.14 Like other protease inhibitors, boceprevir must be given with peginterferon–ribavirin to minimize the emergence of viral resistance. 15,16 In the SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial, we examined whether the addition of boceprevir to standard therapy could improve the rates of sustained virologic response in previously untreated patients infected with HCV genotype 1. Results Study Patients A total of 1246 and 226 patients were screened for the nonblack cohort and the black cohort, respectively, of whom 940 nonblack patients and 159 black patients were randomly assigned to a treatment group from August 2008 through January 2009 (Figure S1 in the Supplementary Appendix). Two patients in the nonblack cohort did not receive any study drug and were not included in the analyses. All the other randomly assigned patients received at least 1 dose of study medication. Baseline characteristics are shown in Table 1Table 1Selected Baseline Characteristics of Patients Who Received at Least One Dose of Study Medication, According to Cohort and Treatment Group.. A total of 49 patients discontinued the peginterferon–ribavirin therapy during the lead-in period and did not receive boceprevir or placebo. Discontinuation for reasons of futility at week 24 occurred in 84 of 311 patients (27%), 24 of 316 patients (8%), and 28 of 311 patients (9%) in the nonblack cohort and in 24 of 52 patients (46%), 9 of 52 patients (17%), and 8 of 55 patients (15%) in the black cohort in groups 1, 2, and 3, respectively. Efficacy Response rates were significantly higher among patients receiving a boceprevir-containing regimen than among controls (Table 2Table 2Rates of Virologic Responses among Patients Who Received at Least One Dose of Any Study Medication, According to Cohort and Treatment Group.). Among nonblacks, the rate of a sustained virologic response was 40% with the standard of care and was significantly higher (P<0.001) in both boceprevir groups — 67% in group 2 and 68% in group 3 — for relative increases of 68% and 70%, respectively, over control rates. Among blacks, the rate of a sustained virologic response was 23% in group 1, 42% in group 2 (P=0.04, vs. group 1), and 53% in group 3 (P=0.004, vs. group 1). In a modified intention-to-treat analysis that included all nonblacks receiving at least one dose of boceprevir or placebo, the respective rates of sustained virologic response in groups 1, 2, and 3 were 42%, 70% (P<0.001, vs. group 1), and 71% (P<0.001, vs. group 1), the corresponding rates among blacks were 26%, 47% (P=0.04, vs. group 1), and 53% (P=0.01, vs. group 1). In the nonblack cohort, viral breakthrough occurred in 1 to 2% of patients in each treatment group, whereas rates of relapse were lower in the two boceprevir groups than in the standard-therapy group. The numbers of events in the smaller black cohort were too few to permit comparison between treatment groups. The 4-week lead-in period of peginterferon–ribavirin treatment allowed for the assessment of interferon responsiveness and its relationship to sustained virologic response. At week 4, 23% of nonblacks and 38% of blacks had a decrease of less than 1 log10 IU per milliliter in the HCV RNA level from baseline, which was associated with lower rates of sustained virologic response (Table 2) and higher rates of boceprevir-resistance–associated variants (genotypic mutations of the protease conferring reduced sensitivity to boceprevir) (Table 3Table 3Common Clinical Adverse Events, Resistance-Associated HCV Variants, and Hematologic Abnormalities, According to Treatment Group.) than was a decrease of 1 log10 IU per milliliter or more in the HCV RNA level, regardless of the treatment group. However, whether the decrease in the HCV RNA level at week 4 was more or less than 1 log10 IU per milliliter, rates of sustained virologic response were consistently higher in the boceprevir groups than in the control group. The percentages of patients with undetectable HCV RNA levels at week 8 who had a sustained virologic response were high, irrespective of the treatment regimen, but this response at week 8 occurred approximately three times as often in the boceprevir groups as in the control group. At this time point, the patients had received boceprevir or placebo for 4 weeks and peginterferon–ribavirin for 8 weeks. The rates of sustained virologic response among nonblacks were similar in group 2 (67%) and in group 3 (68%), whereas among blacks they were 42% and 53%, respectively. Among nonblack boceprevir recipients whose HCV RNA levels became undetectable by week 8 (60%) and those with undetectable HCV RNA levels through week 24 (47%), the rate of sustained virologic response was 97% in group 2 (which had received 24 weeks of boceprevir and a total of 28 weeks of therapy) and 96% in group 3 (which had received 44 weeks of boceprevir and a total of 48 weeks of therapy) (Table 2). In group 2, a total of 22% of the patients with a detectable HCV RNA level between week 8 and week 24 received therapy for more than 28 weeks. Among patients in whom HCV RNA levels were still detectable at week 8, rates of sustained virologic response were 74% in group 2 (after receiving 24 weeks of boceprevir) as well as in group 3 (after receiving 44 weeks of boceprevir). Predictors of sustained virologic response were identical in models for each cohort. Rates of sustained virologic response in patients with advanced fibrosis were lower than in those with mild fibrosis, although the numbers of patients with a Metavir fibrosis score of 3 or 4 (indicating bridging fibrosis or cirrhosis) were small, particularly in the black cohort (Table 4Table 4Odds Ratios for a Sustained Virologic Response, According to Predictor Variables.). In an expanded model that included virologic responses during the treatment period, a decrease in the HCV RNA level by 1 log10 IU per milliliter or more at the end of the 4-week lead-in period was strongly predictive of a sustained virologic response (odds ratio vs. a decrease of <1 log10 IU per milliliter, 9.0; 95% confidence interval, 6.3 to 12.8; P<0.001). In general, subgroup analyses across a range of baseline factors favored group 2 and group 3 over group 1, with no consistent differences between groups 2 and 3 (Figure S2 in the Supplementary Appendix). For groups 1, 2, and 3 in the nonblack cohort, rates of sustained virologic response were 33%, 64%, and 59%, respectively, among patients with a hemoglobin level of 10 g per deciliter or higher during the treatment period, as compared with 60%, 72%, and 79%, respectively, among patients with a nadir hemoglobin level of less than 10 g per deciliter during the treatment period. Safety Adverse events occurred in more than 98% of the study patients, with serious adverse events in 9%, 11%, and 12% of patients in groups 1, 2, and 3, respectively (Table S2 in the Supplementary Appendix). There were six deaths during the study: four patients in the control group died, as did two patients in the boceprevir groups. Two suicides (one in group 1 and one in group 2) were judged to have possibly been related to peginterferon. No other deaths were considered to be drug-related. Fatigue, headache, and nausea were the most common clinical adverse events in all treatment groups (Table 3). Dysgeusia occurred more than twice as often in boceprevir recipients than in controls. Anemia was reported as an adverse event in 29% of controls and 49% of boceprevir recipients. Anemia was classified as grade 1 in 36% of controls, grade 2 in 17%, grade 3 in 2%, and grade 4 in 0%; the respective percentages among boceprevir recipients were 43%, 31%, 3%, and 1%. Four patients in group 1 discontinued the study owing to anemia, as compared with six patients in group 2 and seven patients in group 3. Overall, 13% of controls and 21% of boceprevir recipients required dose reductions because of anemia. Erythropoietin was administered in 24% of controls and 43% of boceprevir recipients. A total of 85% and 86% of patients in group 2 and group 3, respectively, had neutropenia of grade 1 to 4, as compared with 77% of those in the control group; 28% and 33% of patients in groups 1 and 2, respectively, had grade 1 to 4 thrombocytopenia, as compared with 13% of controls. Discussion SPRINT-2 compared two regimens of boceprevir added to peginterferon alfa-2b–ribavirin therapy (the standard of care) and the standard of care alone. Two distinct cohorts were enrolled on the basis of self-identified race (nonblack patients and black patients) to allow for an independent estimate of rates of response among black patients, a group historically underrepresented in HCV-treatment trials. As compared with peginterferon alfa-2b–ribavirin therapy alone, the addition of boceprevir significantly increased the rate of a sustained virologic response among previously untreated black and nonblack patients infected with HCV genotype 1, including those with a decrease of less than 1 log10 IU per milliliter in the HCV RNA level at week 4. Among nonblack patients, the combination therapy with boceprevir was associated with a relative increase of approximately 70% in the rates of sustained virologic response over standard therapy. Although lower among black patients than among nonblack patients, the rates of sustained virologic response with the boceprevir regimens were nearly double those with the standard of care. Patients with an undetectable HCV RNA level at week 8 had a higher rate of sustained virologic response than patients with a detectable level at week 8, irrespective of treatment regimen. Given the relatively small numbers of patients with cirrhosis in the trial, further study is warranted to define optimal therapy in this population. Our study evaluated a response-guided treatment strategy with individualized treatment duration on the basis of the HCV RNA level between weeks 8 and 24. Patients in whom the HCV RNA level became undetectable by week 8 and remained so up to week 24 were given boceprevir plus peginterferon–ribavirin for 24 weeks. The rates of sustained virologic response among both black and nonblack patients were significantly higher with response-guided therapy than with standard treatment. Regardless of the virologic response at week 4 or week 8, response-guided therapy that included 24 weeks of boceprevir administration resulted in overall rates of sustained virologic response that were similar to those after 44 weeks of triple therapy. Patients who had undetectable HCV RNA levels by week 8 had very high rates of sustained virologic response as compared with patients who had detectable levels between weeks 8 and 24. There were too few black patients in whom the HCV RNA level was detectable between weeks 8 and 24 to conclusively define the optimal treatment for this population. This trial featured the use of peginterferon–ribavirin for 4 weeks (the lead-in period) before boceprevir was added. Theoretically, a lead-in phase would serve to lower HCV RNA levels before exposure to a protease inhibitor, thereby reducing the risk of viral breakthrough or resistance to the direct-acting antiviral agent, as noted in a phase 2 study in which boceprevir with lead-in therapy was compared with boceprevir without lead-in therapy.10 However, lead-in therapy has other benefits, such as allowing for assessment of the relationship between interferon responsiveness and subsequent sustained virologic response in patients receiving boceprevir. Patients with a poor response to interferon, defined as a reduction in the HCV RNA level of less than 1 log10 IU per milliliter after 4 weeks of peginterferon–ribavirin therapy, had sufficiently high rates of sustained virologic response, as compared with the control group, to dispel concern that the addition of a protease inhibitor to the treatment regimen would be equivalent to functional monotherapy. However, these patients were less likely than patients with a robust response to interferon to have a sustained virologic response after boceprevir was added.17-19 Thus, patients who have a poor response to interferon may need to be monitored closely to determine who may benefit from better therapies, once they are available. Conversely, in patients with undetectable HCV RNA levels after the lead-in period, boceprevir administration may not result in a higher rate of sustained virologic response than that achieved with the use of peginterferon and ribavirin alone. The lead-in period can further serve to test both compliance and tolerability before exposure to a class of drugs to which resistance can develop.15,16 The regimens that included boceprevir were associated with increased rates of anemia, and nearly twice as many boceprevir recipients as controls had a hemoglobin level of less than 9.5 g per deciliter or received erythropoietin (43% vs. 24%). Among patients receiving erythropoietin, the average duration of use was shortest in group 2. Neither the incidence of serious adverse events nor the frequency of discontinuation owing to an adverse event differed significantly between patients receiving boceprevir and those receiving standard therapy. The rate of a sustained virologic response was significantly greater with boceprevir plus peginterferon–ribavirin than with peginterferon–ribavirin alone among both black and nonblack patients. The opinions expressed in this report represent the consensus of the coauthors and do not necessarily reflect the formal position of Merck or the other institutions listed as authors' affiliations. Supported by Schering-Plough (now Merck). Methods Study Design A detailed description of the study methods is provided in the Supplementary Appendix (available with the full text of this article at NEJM.org). We conducted a phase 3, international, randomized, placebo-controlled study comparing the safety and efficacy of standard therapy with peginterferon alfa-2b and ribavirin (PegIntron and Rebetol, respectively; Merck) with the safety and efficacy of two treatment regimens in which boceprevir was added after a lead-in period of treatment with peginterferon–ribavirin alone (Figure 1Figure 1Study Design.). Because of the marked difference in rates of sustained virologic response between blacks and nonblacks,7 self-identified blacks and nonblacks were enrolled separately into two cohorts. The sponsor, patients, and study personnel were unaware of the assignment to the boceprevir or placebo group; the use of peginterferon and ribavirin was open label. The trial was conducted in accordance with the principles of Good Clinical Practice and the study protocol (including the data analysis plan; available at NEJM.org); the study design was approved by the appropriate institutional review boards and regulatory agencies. Each participant provided written informed consent before undergoing any study-related procedure. The trial was designed, managed, and analyzed by the industry authors in conjunction with the academic authors under the oversight of an independent data review advisory board. The academic authors had full access to all the data. The core writing team consisted of the principal academic author and all the industry authors, who were also responsible for the decision to submit the manuscript for publication, before which the sponsor reviewed a draft. Each author vouches for the fidelity of the trial conduct to the protocol and the completeness and accuracy of the results and data analyses. Enrolled patients in each cohort were randomly assigned, in a 1:1:1 ratio and by means of an interactive voice-response system, to one of the three treatment groups, after stratification on the basis of the baseline HCV RNA level (≤400,000 vs. >400,000 IU per milliliter) and HCV genotype 1 subtype (1a vs. 1b). Patients in whom HCV could not be subtyped were randomly assigned to a treatment group within their HCV RNA stratum.
Selection of Patients
Eligibility criteria were a history of no previous treatment for HCV infection, age of 18 years or older, weight of 40 to 125 kg, chronic infection with HCV genotype 1, and plasma HCV RNA level of 10,000 IU per milliliter or greater. Exclusion criteria were liver disease of other cause, decompensated cirrhosis, renal insufficiency, HIV or hepatitis B infection, pregnancy or current breast-feeding, and active cancer. Liver-biopsy specimens were assigned Metavir fibrosis scores and steatosis scores by a single academic author who is a pathologist and was unaware of the assignment to the boceprevir or placebo group. The HCV genotype 1 subtype was determined with the use of the Trugene assay (Bayer Diagnostics) for purposes of randomization and by sequencing of the nonstructural 5B (NS5B) region (Virco) for subsequent analyses.
Study Regimens
Peginterferon alfa-2b was administered subcutaneously at a dose of 1.5 μg per kilogram of body weight once weekly; and weight-based oral ribavirin was administered at a total dose of 600 to 1400 mg per day in divided doses, given in the morning and evening. Treatment with boceprevir consisted of oral administration at a dose of 800 mg three times daily (to be taken with food and at an interval of 7 to 9 hours between doses) in four capsules of 200 mg each. Placebo was matched to boceprevir.
All patients received peginterferon–ribavirin during the 4-week lead-in period (Figure 1). Patients randomly assigned to group 1 (the standard of care) received peginterferon–ribavirin treatment for 44 weeks after the lead-in period, as well as thrice-daily placebo beginning at week 5. Patients randomly assigned to group 2 (response-guided therapy) received peginterferon–ribavirin plus boceprevir for a total of 24 weeks after the lead-in period; if HCV RNA levels were undetectable from week 8 through week 24, treatment was considered complete, but if HCV RNA levels were detectable at any visit from week 8 up to but not including week 24, peginterferon–ribavirin was continued, and placebo was administered, at week 28 through week 48. Patients randomly assigned to group 3 (fixed-duration therapy) received peginterferon–ribavirin plus oral boceprevir for 44 weeks after the lead-in period.
In all three groups, the study treatment was discontinued for all patients with a detectable HCV RNA level at week 24, according to a standard futility rule. Boceprevir was given for 24 weeks in group 2 and 44 weeks in group 3. All patients were followed through week 72.
Viral breakthrough was defined as achievement of an undetectable HCV RNA level and subsequent occurrence of an HCV RNA level greater than 1000 IU per milliliter. Incomplete virologic response and rebound was defined as an increase of 1 log10 IU per milliliter in the HCV RNA level from the nadir, with an HCV RNA level greater than 1000 IU per milliliter (if both samples being compared were collected the same number of days after the last peginterferon injection). In cases in which the timing between the peginterferon injection and the HCV RNA sample collection was different for the two samples, an increase of 2 log10 IU per milliliter was required to meet this criterion. If a patient had virologic breakthrough or an incomplete virologic response and rebound while receiving therapy, boceprevir treatment could be discontinued, but peginterferon–ribavirin could be continued for up to 48 weeks with appropriate clinical follow-up.
Efficacy Assessment
Plasma HCV RNA levels were measured with the use of the TaqMan 2.0 assay (Roche Diagnostics), which has lower limits of quantification and detection of 25 and 9.3 IU per milliliter, respectively; the lower limit of detection was used for decision making at various points throughout the study. HCV RNA testing was performed at the screening visit, at baseline, every 2 weeks through week 12, and at weeks 16, 20, 24, 28, 34, 40, 48, 52, 60, and 72 (depending on the treatment duration). Patients in whom study therapy was stopped because of futility were considered to have had treatment failure.
Safety Assessment
Adverse events were graded by investigators according to a modified World Health Organization grading system. Non–life-threatening hematologic adverse events were managed by means of dose reduction or administration of hematopoietic growth factors (or both). Reduction of the ribavirin dose or administration of erythropoietin was recommended when the hemoglobin level dropped to less than 10 g per deciliter, but these decisions were made at the discretion of the investigators; erythropoietin was to be stopped if the hemoglobin level rebounded to 12 g per deciliter or greater.
Statistical Analysis
The trial was designed as a superiority study to detect differences in the rates of sustained virologic response with either of the two boceprevir regimens (group 2 or group 3) as compared with standard therapy alone (group 1). The primary analyses involved all patients who had received at least one dose of any study medication; key secondary efficacy analyses were conducted for the modified intention-to-treat population, consisting of patients who completed the lead-in period of treatment and received at least one dose of boceprevir or placebo. Rates of response were determined separately (per protocol) for the nonblack cohort and the black cohort.
The protocol-specified primary efficacy end point was a sustained virologic response, defined as undetectable HCV RNA levels for 24 weeks after the completion of therapy. If HCV RNA measurements for this time point or later were missing, the 12-week post-treatment measurement was used. Relapse was defined as the occurrence of an undetectable HCV RNA level at the end of treatment but a detectable HCV RNA level at some point during the follow-up period.
Within-cohort comparisons were performed with the use of the two-sided Cochran–Mantel–Haenszel chi-square test (after adjustment for baseline stratification factors). A step-down approach was applied to hypothesis testing. Group 3 was first compared with group 1. If the resultant P value was 0.05 or less, the superiority of fixed-duration therapy including boceprevir over standard therapy would be supported, and group 2 would then be compared with group 1. If this P value was also 0.05 or less, the superiority of response-guided therapy including boceprevir over standard therapy would likewise be established.
Secondary analyses were to be conducted only if the primary comparisons showed significant differences. Formal hypothesis testing comparing the two boceprevir groups was not specified in the protocol. A multivariate logistic-regression model that included baseline characteristics and treatment group was used to identify predictors of sustained virologic response. A stepwise procedure was used to identify independent covariates, with an alpha level of 0.05 as the threshold level for variables to be entered into, and retained in, the model.
Assuming a rate of sustained virologic response of 45% in group 1 of the nonblack cohort, we calculated that 310 subjects per group would need to be enrolled for the study to have a statistical power of 90% to detect an absolute increase of 13 percentage points in the rate of sustained virologic response in group 3 as compared with group 1, with the use of a two-sided chi-square test and an alpha level of 0.05. Assuming a rate of sustained virologic response of 50% in the black cohort overall, 50 patients per group, and the use of a two-sided 95% confidence interval, we estimated that the true rate of a sustained virologic response in the black population could be estimated, within ±14%, for each of the three treatment groups.
Safety analyses included all patients who had been randomly assigned to a study group and had received at least one dose of any study medication.
Fred Poordad, M.D., Jonathan McCone, Jr., M.D., Bruce R. Bacon, M.D., Savino Bruno, M.D., Michael P. Manns, M.D., Mark S. Sulkowski, M.D., Ira M. Jacobson, M.D., K. Rajender Reddy, M.D., Zachary D. Goodman, M.D., Ph.D., Navdeep Boparai, M.S., Mark J. DiNubile, M.D., Vilma Sniukiene, M.D., Clifford A. Brass, M.D., Ph.D., Janice K. Albrecht, Ph.D., and Jean-Pierre Bronowicki, M.D., Ph.D. for the SPRINT-2 Investigators
N Engl J Med 2011; 364:1195-1206March 31, 2011
Background
Peginterferon–ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.
Methods
We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon–ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon–ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon–ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon–ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.
Results
A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon–ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. Conclusions The addition of boceprevir to standard therapy with peginterferon–ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.) The opinions expressed in this report represent the consensus of the coauthors and do not necessarily reflect the formal position of Merck or the other institutions listed as authors' affiliations. Supported by Schering-Plough (now Merck). Chronic infection with the hepatitis C virus (HCV) affects more than 170 million people worldwide.1,2 Rates of sustained virologic response associated with peginterferon–ribavirin therapy remain below 50% and are often less than 30% among patients who have HCV genotype 1 infection and certain baseline characteristics, such as advanced fibrosis, diabetes, coinfection with the human immunodeficiency virus (HIV), or African heritage.3-9 Recent efforts to improve the rate of sustained virologic response have focused on oral direct-acting antiviral agents.10-13 Boceprevir is a linear peptidomimetic ketoamide serine protease inhibitor that binds reversibly to the HCV nonstructural 3 (NS3) active site.14 Like other protease inhibitors, boceprevir must be given with peginterferon–ribavirin to minimize the emergence of viral resistance. 15,16 In the SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial, we examined whether the addition of boceprevir to standard therapy could improve the rates of sustained virologic response in previously untreated patients infected with HCV genotype 1. Results Study Patients A total of 1246 and 226 patients were screened for the nonblack cohort and the black cohort, respectively, of whom 940 nonblack patients and 159 black patients were randomly assigned to a treatment group from August 2008 through January 2009 (Figure S1 in the Supplementary Appendix). Two patients in the nonblack cohort did not receive any study drug and were not included in the analyses. All the other randomly assigned patients received at least 1 dose of study medication. Baseline characteristics are shown in Table 1Table 1Selected Baseline Characteristics of Patients Who Received at Least One Dose of Study Medication, According to Cohort and Treatment Group.. A total of 49 patients discontinued the peginterferon–ribavirin therapy during the lead-in period and did not receive boceprevir or placebo. Discontinuation for reasons of futility at week 24 occurred in 84 of 311 patients (27%), 24 of 316 patients (8%), and 28 of 311 patients (9%) in the nonblack cohort and in 24 of 52 patients (46%), 9 of 52 patients (17%), and 8 of 55 patients (15%) in the black cohort in groups 1, 2, and 3, respectively. Efficacy Response rates were significantly higher among patients receiving a boceprevir-containing regimen than among controls (Table 2Table 2Rates of Virologic Responses among Patients Who Received at Least One Dose of Any Study Medication, According to Cohort and Treatment Group.). Among nonblacks, the rate of a sustained virologic response was 40% with the standard of care and was significantly higher (P<0.001) in both boceprevir groups — 67% in group 2 and 68% in group 3 — for relative increases of 68% and 70%, respectively, over control rates. Among blacks, the rate of a sustained virologic response was 23% in group 1, 42% in group 2 (P=0.04, vs. group 1), and 53% in group 3 (P=0.004, vs. group 1). In a modified intention-to-treat analysis that included all nonblacks receiving at least one dose of boceprevir or placebo, the respective rates of sustained virologic response in groups 1, 2, and 3 were 42%, 70% (P<0.001, vs. group 1), and 71% (P<0.001, vs. group 1), the corresponding rates among blacks were 26%, 47% (P=0.04, vs. group 1), and 53% (P=0.01, vs. group 1). In the nonblack cohort, viral breakthrough occurred in 1 to 2% of patients in each treatment group, whereas rates of relapse were lower in the two boceprevir groups than in the standard-therapy group. The numbers of events in the smaller black cohort were too few to permit comparison between treatment groups. The 4-week lead-in period of peginterferon–ribavirin treatment allowed for the assessment of interferon responsiveness and its relationship to sustained virologic response. At week 4, 23% of nonblacks and 38% of blacks had a decrease of less than 1 log10 IU per milliliter in the HCV RNA level from baseline, which was associated with lower rates of sustained virologic response (Table 2) and higher rates of boceprevir-resistance–associated variants (genotypic mutations of the protease conferring reduced sensitivity to boceprevir) (Table 3Table 3Common Clinical Adverse Events, Resistance-Associated HCV Variants, and Hematologic Abnormalities, According to Treatment Group.) than was a decrease of 1 log10 IU per milliliter or more in the HCV RNA level, regardless of the treatment group. However, whether the decrease in the HCV RNA level at week 4 was more or less than 1 log10 IU per milliliter, rates of sustained virologic response were consistently higher in the boceprevir groups than in the control group. The percentages of patients with undetectable HCV RNA levels at week 8 who had a sustained virologic response were high, irrespective of the treatment regimen, but this response at week 8 occurred approximately three times as often in the boceprevir groups as in the control group. At this time point, the patients had received boceprevir or placebo for 4 weeks and peginterferon–ribavirin for 8 weeks. The rates of sustained virologic response among nonblacks were similar in group 2 (67%) and in group 3 (68%), whereas among blacks they were 42% and 53%, respectively. Among nonblack boceprevir recipients whose HCV RNA levels became undetectable by week 8 (60%) and those with undetectable HCV RNA levels through week 24 (47%), the rate of sustained virologic response was 97% in group 2 (which had received 24 weeks of boceprevir and a total of 28 weeks of therapy) and 96% in group 3 (which had received 44 weeks of boceprevir and a total of 48 weeks of therapy) (Table 2). In group 2, a total of 22% of the patients with a detectable HCV RNA level between week 8 and week 24 received therapy for more than 28 weeks. Among patients in whom HCV RNA levels were still detectable at week 8, rates of sustained virologic response were 74% in group 2 (after receiving 24 weeks of boceprevir) as well as in group 3 (after receiving 44 weeks of boceprevir). Predictors of sustained virologic response were identical in models for each cohort. Rates of sustained virologic response in patients with advanced fibrosis were lower than in those with mild fibrosis, although the numbers of patients with a Metavir fibrosis score of 3 or 4 (indicating bridging fibrosis or cirrhosis) were small, particularly in the black cohort (Table 4Table 4Odds Ratios for a Sustained Virologic Response, According to Predictor Variables.). In an expanded model that included virologic responses during the treatment period, a decrease in the HCV RNA level by 1 log10 IU per milliliter or more at the end of the 4-week lead-in period was strongly predictive of a sustained virologic response (odds ratio vs. a decrease of <1 log10 IU per milliliter, 9.0; 95% confidence interval, 6.3 to 12.8; P<0.001). In general, subgroup analyses across a range of baseline factors favored group 2 and group 3 over group 1, with no consistent differences between groups 2 and 3 (Figure S2 in the Supplementary Appendix). For groups 1, 2, and 3 in the nonblack cohort, rates of sustained virologic response were 33%, 64%, and 59%, respectively, among patients with a hemoglobin level of 10 g per deciliter or higher during the treatment period, as compared with 60%, 72%, and 79%, respectively, among patients with a nadir hemoglobin level of less than 10 g per deciliter during the treatment period. Safety Adverse events occurred in more than 98% of the study patients, with serious adverse events in 9%, 11%, and 12% of patients in groups 1, 2, and 3, respectively (Table S2 in the Supplementary Appendix). There were six deaths during the study: four patients in the control group died, as did two patients in the boceprevir groups. Two suicides (one in group 1 and one in group 2) were judged to have possibly been related to peginterferon. No other deaths were considered to be drug-related. Fatigue, headache, and nausea were the most common clinical adverse events in all treatment groups (Table 3). Dysgeusia occurred more than twice as often in boceprevir recipients than in controls. Anemia was reported as an adverse event in 29% of controls and 49% of boceprevir recipients. Anemia was classified as grade 1 in 36% of controls, grade 2 in 17%, grade 3 in 2%, and grade 4 in 0%; the respective percentages among boceprevir recipients were 43%, 31%, 3%, and 1%. Four patients in group 1 discontinued the study owing to anemia, as compared with six patients in group 2 and seven patients in group 3. Overall, 13% of controls and 21% of boceprevir recipients required dose reductions because of anemia. Erythropoietin was administered in 24% of controls and 43% of boceprevir recipients. A total of 85% and 86% of patients in group 2 and group 3, respectively, had neutropenia of grade 1 to 4, as compared with 77% of those in the control group; 28% and 33% of patients in groups 1 and 2, respectively, had grade 1 to 4 thrombocytopenia, as compared with 13% of controls. Discussion SPRINT-2 compared two regimens of boceprevir added to peginterferon alfa-2b–ribavirin therapy (the standard of care) and the standard of care alone. Two distinct cohorts were enrolled on the basis of self-identified race (nonblack patients and black patients) to allow for an independent estimate of rates of response among black patients, a group historically underrepresented in HCV-treatment trials. As compared with peginterferon alfa-2b–ribavirin therapy alone, the addition of boceprevir significantly increased the rate of a sustained virologic response among previously untreated black and nonblack patients infected with HCV genotype 1, including those with a decrease of less than 1 log10 IU per milliliter in the HCV RNA level at week 4. Among nonblack patients, the combination therapy with boceprevir was associated with a relative increase of approximately 70% in the rates of sustained virologic response over standard therapy. Although lower among black patients than among nonblack patients, the rates of sustained virologic response with the boceprevir regimens were nearly double those with the standard of care. Patients with an undetectable HCV RNA level at week 8 had a higher rate of sustained virologic response than patients with a detectable level at week 8, irrespective of treatment regimen. Given the relatively small numbers of patients with cirrhosis in the trial, further study is warranted to define optimal therapy in this population. Our study evaluated a response-guided treatment strategy with individualized treatment duration on the basis of the HCV RNA level between weeks 8 and 24. Patients in whom the HCV RNA level became undetectable by week 8 and remained so up to week 24 were given boceprevir plus peginterferon–ribavirin for 24 weeks. The rates of sustained virologic response among both black and nonblack patients were significantly higher with response-guided therapy than with standard treatment. Regardless of the virologic response at week 4 or week 8, response-guided therapy that included 24 weeks of boceprevir administration resulted in overall rates of sustained virologic response that were similar to those after 44 weeks of triple therapy. Patients who had undetectable HCV RNA levels by week 8 had very high rates of sustained virologic response as compared with patients who had detectable levels between weeks 8 and 24. There were too few black patients in whom the HCV RNA level was detectable between weeks 8 and 24 to conclusively define the optimal treatment for this population. This trial featured the use of peginterferon–ribavirin for 4 weeks (the lead-in period) before boceprevir was added. Theoretically, a lead-in phase would serve to lower HCV RNA levels before exposure to a protease inhibitor, thereby reducing the risk of viral breakthrough or resistance to the direct-acting antiviral agent, as noted in a phase 2 study in which boceprevir with lead-in therapy was compared with boceprevir without lead-in therapy.10 However, lead-in therapy has other benefits, such as allowing for assessment of the relationship between interferon responsiveness and subsequent sustained virologic response in patients receiving boceprevir. Patients with a poor response to interferon, defined as a reduction in the HCV RNA level of less than 1 log10 IU per milliliter after 4 weeks of peginterferon–ribavirin therapy, had sufficiently high rates of sustained virologic response, as compared with the control group, to dispel concern that the addition of a protease inhibitor to the treatment regimen would be equivalent to functional monotherapy. However, these patients were less likely than patients with a robust response to interferon to have a sustained virologic response after boceprevir was added.17-19 Thus, patients who have a poor response to interferon may need to be monitored closely to determine who may benefit from better therapies, once they are available. Conversely, in patients with undetectable HCV RNA levels after the lead-in period, boceprevir administration may not result in a higher rate of sustained virologic response than that achieved with the use of peginterferon and ribavirin alone. The lead-in period can further serve to test both compliance and tolerability before exposure to a class of drugs to which resistance can develop.15,16 The regimens that included boceprevir were associated with increased rates of anemia, and nearly twice as many boceprevir recipients as controls had a hemoglobin level of less than 9.5 g per deciliter or received erythropoietin (43% vs. 24%). Among patients receiving erythropoietin, the average duration of use was shortest in group 2. Neither the incidence of serious adverse events nor the frequency of discontinuation owing to an adverse event differed significantly between patients receiving boceprevir and those receiving standard therapy. The rate of a sustained virologic response was significantly greater with boceprevir plus peginterferon–ribavirin than with peginterferon–ribavirin alone among both black and nonblack patients. The opinions expressed in this report represent the consensus of the coauthors and do not necessarily reflect the formal position of Merck or the other institutions listed as authors' affiliations. Supported by Schering-Plough (now Merck). Methods Study Design A detailed description of the study methods is provided in the Supplementary Appendix (available with the full text of this article at NEJM.org). We conducted a phase 3, international, randomized, placebo-controlled study comparing the safety and efficacy of standard therapy with peginterferon alfa-2b and ribavirin (PegIntron and Rebetol, respectively; Merck) with the safety and efficacy of two treatment regimens in which boceprevir was added after a lead-in period of treatment with peginterferon–ribavirin alone (Figure 1Figure 1Study Design.). Because of the marked difference in rates of sustained virologic response between blacks and nonblacks,7 self-identified blacks and nonblacks were enrolled separately into two cohorts. The sponsor, patients, and study personnel were unaware of the assignment to the boceprevir or placebo group; the use of peginterferon and ribavirin was open label. The trial was conducted in accordance with the principles of Good Clinical Practice and the study protocol (including the data analysis plan; available at NEJM.org); the study design was approved by the appropriate institutional review boards and regulatory agencies. Each participant provided written informed consent before undergoing any study-related procedure. The trial was designed, managed, and analyzed by the industry authors in conjunction with the academic authors under the oversight of an independent data review advisory board. The academic authors had full access to all the data. The core writing team consisted of the principal academic author and all the industry authors, who were also responsible for the decision to submit the manuscript for publication, before which the sponsor reviewed a draft. Each author vouches for the fidelity of the trial conduct to the protocol and the completeness and accuracy of the results and data analyses. Enrolled patients in each cohort were randomly assigned, in a 1:1:1 ratio and by means of an interactive voice-response system, to one of the three treatment groups, after stratification on the basis of the baseline HCV RNA level (≤400,000 vs. >400,000 IU per milliliter) and HCV genotype 1 subtype (1a vs. 1b). Patients in whom HCV could not be subtyped were randomly assigned to a treatment group within their HCV RNA stratum.
Selection of Patients
Eligibility criteria were a history of no previous treatment for HCV infection, age of 18 years or older, weight of 40 to 125 kg, chronic infection with HCV genotype 1, and plasma HCV RNA level of 10,000 IU per milliliter or greater. Exclusion criteria were liver disease of other cause, decompensated cirrhosis, renal insufficiency, HIV or hepatitis B infection, pregnancy or current breast-feeding, and active cancer. Liver-biopsy specimens were assigned Metavir fibrosis scores and steatosis scores by a single academic author who is a pathologist and was unaware of the assignment to the boceprevir or placebo group. The HCV genotype 1 subtype was determined with the use of the Trugene assay (Bayer Diagnostics) for purposes of randomization and by sequencing of the nonstructural 5B (NS5B) region (Virco) for subsequent analyses.
Study Regimens
Peginterferon alfa-2b was administered subcutaneously at a dose of 1.5 μg per kilogram of body weight once weekly; and weight-based oral ribavirin was administered at a total dose of 600 to 1400 mg per day in divided doses, given in the morning and evening. Treatment with boceprevir consisted of oral administration at a dose of 800 mg three times daily (to be taken with food and at an interval of 7 to 9 hours between doses) in four capsules of 200 mg each. Placebo was matched to boceprevir.
All patients received peginterferon–ribavirin during the 4-week lead-in period (Figure 1). Patients randomly assigned to group 1 (the standard of care) received peginterferon–ribavirin treatment for 44 weeks after the lead-in period, as well as thrice-daily placebo beginning at week 5. Patients randomly assigned to group 2 (response-guided therapy) received peginterferon–ribavirin plus boceprevir for a total of 24 weeks after the lead-in period; if HCV RNA levels were undetectable from week 8 through week 24, treatment was considered complete, but if HCV RNA levels were detectable at any visit from week 8 up to but not including week 24, peginterferon–ribavirin was continued, and placebo was administered, at week 28 through week 48. Patients randomly assigned to group 3 (fixed-duration therapy) received peginterferon–ribavirin plus oral boceprevir for 44 weeks after the lead-in period.
In all three groups, the study treatment was discontinued for all patients with a detectable HCV RNA level at week 24, according to a standard futility rule. Boceprevir was given for 24 weeks in group 2 and 44 weeks in group 3. All patients were followed through week 72.
Viral breakthrough was defined as achievement of an undetectable HCV RNA level and subsequent occurrence of an HCV RNA level greater than 1000 IU per milliliter. Incomplete virologic response and rebound was defined as an increase of 1 log10 IU per milliliter in the HCV RNA level from the nadir, with an HCV RNA level greater than 1000 IU per milliliter (if both samples being compared were collected the same number of days after the last peginterferon injection). In cases in which the timing between the peginterferon injection and the HCV RNA sample collection was different for the two samples, an increase of 2 log10 IU per milliliter was required to meet this criterion. If a patient had virologic breakthrough or an incomplete virologic response and rebound while receiving therapy, boceprevir treatment could be discontinued, but peginterferon–ribavirin could be continued for up to 48 weeks with appropriate clinical follow-up.
Efficacy Assessment
Plasma HCV RNA levels were measured with the use of the TaqMan 2.0 assay (Roche Diagnostics), which has lower limits of quantification and detection of 25 and 9.3 IU per milliliter, respectively; the lower limit of detection was used for decision making at various points throughout the study. HCV RNA testing was performed at the screening visit, at baseline, every 2 weeks through week 12, and at weeks 16, 20, 24, 28, 34, 40, 48, 52, 60, and 72 (depending on the treatment duration). Patients in whom study therapy was stopped because of futility were considered to have had treatment failure.
Safety Assessment
Adverse events were graded by investigators according to a modified World Health Organization grading system. Non–life-threatening hematologic adverse events were managed by means of dose reduction or administration of hematopoietic growth factors (or both). Reduction of the ribavirin dose or administration of erythropoietin was recommended when the hemoglobin level dropped to less than 10 g per deciliter, but these decisions were made at the discretion of the investigators; erythropoietin was to be stopped if the hemoglobin level rebounded to 12 g per deciliter or greater.
Statistical Analysis
The trial was designed as a superiority study to detect differences in the rates of sustained virologic response with either of the two boceprevir regimens (group 2 or group 3) as compared with standard therapy alone (group 1). The primary analyses involved all patients who had received at least one dose of any study medication; key secondary efficacy analyses were conducted for the modified intention-to-treat population, consisting of patients who completed the lead-in period of treatment and received at least one dose of boceprevir or placebo. Rates of response were determined separately (per protocol) for the nonblack cohort and the black cohort.
The protocol-specified primary efficacy end point was a sustained virologic response, defined as undetectable HCV RNA levels for 24 weeks after the completion of therapy. If HCV RNA measurements for this time point or later were missing, the 12-week post-treatment measurement was used. Relapse was defined as the occurrence of an undetectable HCV RNA level at the end of treatment but a detectable HCV RNA level at some point during the follow-up period.
Within-cohort comparisons were performed with the use of the two-sided Cochran–Mantel–Haenszel chi-square test (after adjustment for baseline stratification factors). A step-down approach was applied to hypothesis testing. Group 3 was first compared with group 1. If the resultant P value was 0.05 or less, the superiority of fixed-duration therapy including boceprevir over standard therapy would be supported, and group 2 would then be compared with group 1. If this P value was also 0.05 or less, the superiority of response-guided therapy including boceprevir over standard therapy would likewise be established.
Secondary analyses were to be conducted only if the primary comparisons showed significant differences. Formal hypothesis testing comparing the two boceprevir groups was not specified in the protocol. A multivariate logistic-regression model that included baseline characteristics and treatment group was used to identify predictors of sustained virologic response. A stepwise procedure was used to identify independent covariates, with an alpha level of 0.05 as the threshold level for variables to be entered into, and retained in, the model.
Assuming a rate of sustained virologic response of 45% in group 1 of the nonblack cohort, we calculated that 310 subjects per group would need to be enrolled for the study to have a statistical power of 90% to detect an absolute increase of 13 percentage points in the rate of sustained virologic response in group 3 as compared with group 1, with the use of a two-sided chi-square test and an alpha level of 0.05. Assuming a rate of sustained virologic response of 50% in the black cohort overall, 50 patients per group, and the use of a two-sided 95% confidence interval, we estimated that the true rate of a sustained virologic response in the black population could be estimated, within ±14%, for each of the three treatment groups.
Safety analyses included all patients who had been randomly assigned to a study group and had received at least one dose of any study medication.
Interim results for phase 1b trial on Presidio Pharmaceuticals' PPI-461HCV NS5A Inhibitor
Data from EASL will be coming in fast and hard in the coming days. Here, San Fran-based Presidio Pharmaceuticals talks about interim Phase 1b results from PPI-461, one of the promising compounds from it's novel NS5A inhibitor program. Usually, interim data on a Phase 1b trial doesn't mean a whole lot, but PPI-461 has a unique mechanism of action, not much to report in terms of adverse events, and is active against seven genotypes. One more thing - the fact that one Tx-naive patient had baseline resistance to PPI-461 is concerning, however, and probably deserves further investigation on it's own.
Mar. 30, 2011 (Business Wire) -- Presidio Pharmaceuticals, Inc. announced today positive preliminary results from a Phase 1b clinical trial of PPI-461, a novel HCV NS5A inhibitor for the treatment of patients with chronic hepatitis C.
The PPI-461 phase 1b clinical trial reported here is a multiple ascending dose, randomized, blinded, placebo-controlled study in treatment-naïve adult hepatitis C patients with HCV genotype-1 infection; this trial is presently ongoing in the U.K., Denmark, and the United States. The study objectives are to assess the safety, tolerability, pharmacokinetics, and initial antiviral effects of PPI-461 during once-daily (QD) dosing at three dosing levels (50, 100, and 200 mg/day) for three days. Each dosing cohort of 8 patients is randomized 6 (PPI-461):2 (placebo). Two dosing groups have completed study treatment to date; the third (200 mg) dosing group is ongoing.
The interim Phase 1b trial results indicate that PPI-461 has been well-tolerated, with no serious or severe adverse events and no modifications or premature discontinuations of study treatment. Among PPI-461 recipients there have been only transient clinical adverse events, of non-specific types commonly seen in clinical trials, with no dose-related or treatment-related patterns of specific adverse events or laboratory abnormalities.
Pharmacokinetic (PK) analyses of patients’ PPI-461 blood levels indicate that substantial blood levels of PPI-461 have been achieved rapidly and are dose proportional. Importantly, blood levels that are inhibitory for HCV replication have been maintained throughout the 24-hr inter-dose periods in the study patients.
Virologic data from the first two dosing groups indicate rapid and marked reductions in patients’ serum viral loads (HCV RNA levels), in both dosing groups, in the first two days of treatment. The 50 mg dosing group achieved a mean maximal HCV RNA reduction of 3.1 log10 IU/mL (5 of 6 patients), while the 100 mg group achieved a mean maximal HCV RNA reduction of 3.7 log10 IU/mL (6 of 6 patients). The mean maximal HCV RNA reduction for 4 Placebo treated patients was 0.3 log10 IU/mL. One patient in the 50 mg cohort had a negligible response to PPI-461(0.4 log10 IU/mL HCV RNA reduction). This patient entered the study with highly resistant virus, as evidenced by NS5A resistance substitutions (L31M, Y93N, L28F, R30N) detected at high levels in pre-treatment sera. Such a patient would be expected to have minimal efficacy with any NS5A inhibitor, since these agents share common key resistance mutations, as will be reported in a Presidio presentation at the 2011 annual meeting of the European Association for the Study of Liver Disease (EASL) in Berlin on April 2nd (R. Colonno et al., poster #1199).
“These positive clinical data for PPI-461 in hepatitis C patients further support the inclusion of NS5A inhibitors in clinical development of novel combination therapies. Such future combination therapies are expected to substantially improve patient outcomes and should help stem the rising incidence of HCV-associated severe liver disease and premature mortality,” said Nathaniel A. Brown, M.D., Presidio’s Chief Medical Officer.
The final results of the completed Phase 1b trial of PPI-461 will be submitted for presentation at a scientific meeting later this year.
About Presidio’s HCV NS5A Inhibitors
Inhibitors of the HCV NS5A protein represent an exciting, highly potent class that is mechanistically distinct from other classes of direct-acting HCV antivirals that target the viral protease or replicase (polymerase).
PPI-461 is the first in a series of novel and selective HCV NS5A inhibitors discovered by Presidio Pharmaceuticals. Presidio’s NS5A candidates are selected from numerous internal discovery leads, based on their potent activity against all major HCV genotypes and their potential for once-daily dosing with good tolerance. A Presidio presentation at the 2011 annual meeting of EASL in Berlin on April 2nd (R. Colonno et al., Poster #1200) will highlight the preclinical profile of three other novel NS5A inhibitors in development by Presidio, which derive from distinct chemical series.
About Presidio
Presidio Pharmaceuticals, Inc. is a San Francisco-based clinical stage specialty pharmaceutical company dedicated to the discovery and development of small-molecule antiviral therapeutics for novel and validated targets. For more information, please visit our website at: www.presidiopharma.com.
Presidio Pharmaceuticals, Inc.
Omar K. Haffar, PhD, 415-655-7561
omar@presidiopharma.com
Mar. 30, 2011 (Business Wire) -- Presidio Pharmaceuticals, Inc. announced today positive preliminary results from a Phase 1b clinical trial of PPI-461, a novel HCV NS5A inhibitor for the treatment of patients with chronic hepatitis C.
The PPI-461 phase 1b clinical trial reported here is a multiple ascending dose, randomized, blinded, placebo-controlled study in treatment-naïve adult hepatitis C patients with HCV genotype-1 infection; this trial is presently ongoing in the U.K., Denmark, and the United States. The study objectives are to assess the safety, tolerability, pharmacokinetics, and initial antiviral effects of PPI-461 during once-daily (QD) dosing at three dosing levels (50, 100, and 200 mg/day) for three days. Each dosing cohort of 8 patients is randomized 6 (PPI-461):2 (placebo). Two dosing groups have completed study treatment to date; the third (200 mg) dosing group is ongoing.
The interim Phase 1b trial results indicate that PPI-461 has been well-tolerated, with no serious or severe adverse events and no modifications or premature discontinuations of study treatment. Among PPI-461 recipients there have been only transient clinical adverse events, of non-specific types commonly seen in clinical trials, with no dose-related or treatment-related patterns of specific adverse events or laboratory abnormalities.
Pharmacokinetic (PK) analyses of patients’ PPI-461 blood levels indicate that substantial blood levels of PPI-461 have been achieved rapidly and are dose proportional. Importantly, blood levels that are inhibitory for HCV replication have been maintained throughout the 24-hr inter-dose periods in the study patients.
Virologic data from the first two dosing groups indicate rapid and marked reductions in patients’ serum viral loads (HCV RNA levels), in both dosing groups, in the first two days of treatment. The 50 mg dosing group achieved a mean maximal HCV RNA reduction of 3.1 log10 IU/mL (5 of 6 patients), while the 100 mg group achieved a mean maximal HCV RNA reduction of 3.7 log10 IU/mL (6 of 6 patients). The mean maximal HCV RNA reduction for 4 Placebo treated patients was 0.3 log10 IU/mL. One patient in the 50 mg cohort had a negligible response to PPI-461(0.4 log10 IU/mL HCV RNA reduction). This patient entered the study with highly resistant virus, as evidenced by NS5A resistance substitutions (L31M, Y93N, L28F, R30N) detected at high levels in pre-treatment sera. Such a patient would be expected to have minimal efficacy with any NS5A inhibitor, since these agents share common key resistance mutations, as will be reported in a Presidio presentation at the 2011 annual meeting of the European Association for the Study of Liver Disease (EASL) in Berlin on April 2nd (R. Colonno et al., poster #1199).
“These positive clinical data for PPI-461 in hepatitis C patients further support the inclusion of NS5A inhibitors in clinical development of novel combination therapies. Such future combination therapies are expected to substantially improve patient outcomes and should help stem the rising incidence of HCV-associated severe liver disease and premature mortality,” said Nathaniel A. Brown, M.D., Presidio’s Chief Medical Officer.
The final results of the completed Phase 1b trial of PPI-461 will be submitted for presentation at a scientific meeting later this year.
About Presidio’s HCV NS5A Inhibitors
Inhibitors of the HCV NS5A protein represent an exciting, highly potent class that is mechanistically distinct from other classes of direct-acting HCV antivirals that target the viral protease or replicase (polymerase).
PPI-461 is the first in a series of novel and selective HCV NS5A inhibitors discovered by Presidio Pharmaceuticals. Presidio’s NS5A candidates are selected from numerous internal discovery leads, based on their potent activity against all major HCV genotypes and their potential for once-daily dosing with good tolerance. A Presidio presentation at the 2011 annual meeting of EASL in Berlin on April 2nd (R. Colonno et al., Poster #1200) will highlight the preclinical profile of three other novel NS5A inhibitors in development by Presidio, which derive from distinct chemical series.
About Presidio
Presidio Pharmaceuticals, Inc. is a San Francisco-based clinical stage specialty pharmaceutical company dedicated to the discovery and development of small-molecule antiviral therapeutics for novel and validated targets. For more information, please visit our website at: www.presidiopharma.com.
Presidio Pharmaceuticals, Inc.
Omar K. Haffar, PhD, 415-655-7561
omar@presidiopharma.com
Tuesday, March 29, 2011
C-Pharma - new company focused on development of Hepatitis C products
Cyplasin Biomedical Ltd Announces Name Change And Creation of a Subsidiary C-Pharma Inc.
EDMONTON, March 29 /CNW/ - Cyplasin Biomedical is a product-oriented, specialty pharmaceutical company focused on developing products for multi-billion dollar markets. The Company is pleased to announce that in order to better reflect multiple new product development opportunities and to continue its current product development programs for Hepatitis C; will effective immediately, change its name to Compass Biotechnologies Inc., and will continue to be traded on the OTC Link exchange under a new trading symbol "COBI".
Compass Biotechnologies Inc., plans on developing several new technologies and revenue generating products and through its wholly owned subsidiary C-Pharma, continue to finance and develop the previously announced Hepatitis C products.
Compass CEO Garth Likes commented, "The creation of C-Pharma to focus solely on the current and future Hepatitis franchise creates a dedicated focus AND VALUE for our shareholders. Compass Biotechnologies will in parallel be able to take advantage of several new and complementary technologies and products that will further add increased value. The new product opportunities within Compass will be announced in the near future as the various components of the project are finalized."
Shareholders of the previously named company "Cyplasin" will be able to physically exchange their share certificates for "Compass" certificates by contacting the Company's transfer agent Pacific Stock Transfer. Detailed exchange instructions will be posted on our website www.c-pharma.net in the next few days.
ABOUT Compass Biotechnology Inc and its wholly owned subsidiary C-Pharma Inc : http://www.c-pharma.net/
Compass Biotechnologies Inc., is a publically-traded specialty pharmaceutical company (OTCQB:COBI) with headquarters in Edmonton, Alberta.
C-PHARMA Inc has amassed a portfolio of key products for the treatment and prevention of HCV infection, which affects over 4 million people in the U.S. and several hundred million people worldwide.
C-Pharma's technology encompasses the use of recombinant DNA technology to manufacture recombinant cytokines and virus like particles (VLPs). VLPs can be engineered to incorporate various viral and non-viral antigens for use as vaccines against many different types of targets such as hepatitis C. C-Pharma is using the technology to develop a hepatitis C vaccine ( C- Vaxin) to prevent hepatitis C viral infection. The Company is also pursuing a revenue generation strategy by commercializing highly profitable therapeutic drugs (C-Virin & C-Pegferon) for use in the hepatitis C market.
EDMONTON, March 29 /CNW/ - Cyplasin Biomedical is a product-oriented, specialty pharmaceutical company focused on developing products for multi-billion dollar markets. The Company is pleased to announce that in order to better reflect multiple new product development opportunities and to continue its current product development programs for Hepatitis C; will effective immediately, change its name to Compass Biotechnologies Inc., and will continue to be traded on the OTC Link exchange under a new trading symbol "COBI".
Compass Biotechnologies Inc., plans on developing several new technologies and revenue generating products and through its wholly owned subsidiary C-Pharma, continue to finance and develop the previously announced Hepatitis C products.
Compass CEO Garth Likes commented, "The creation of C-Pharma to focus solely on the current and future Hepatitis franchise creates a dedicated focus AND VALUE for our shareholders. Compass Biotechnologies will in parallel be able to take advantage of several new and complementary technologies and products that will further add increased value. The new product opportunities within Compass will be announced in the near future as the various components of the project are finalized."
Shareholders of the previously named company "Cyplasin" will be able to physically exchange their share certificates for "Compass" certificates by contacting the Company's transfer agent Pacific Stock Transfer. Detailed exchange instructions will be posted on our website www.c-pharma.net in the next few days.
ABOUT Compass Biotechnology Inc and its wholly owned subsidiary C-Pharma Inc : http://www.c-pharma.net/
Compass Biotechnologies Inc., is a publically-traded specialty pharmaceutical company (OTCQB:COBI) with headquarters in Edmonton, Alberta.
C-PHARMA Inc has amassed a portfolio of key products for the treatment and prevention of HCV infection, which affects over 4 million people in the U.S. and several hundred million people worldwide.
C-Pharma's technology encompasses the use of recombinant DNA technology to manufacture recombinant cytokines and virus like particles (VLPs). VLPs can be engineered to incorporate various viral and non-viral antigens for use as vaccines against many different types of targets such as hepatitis C. C-Pharma is using the technology to develop a hepatitis C vaccine ( C- Vaxin) to prevent hepatitis C viral infection. The Company is also pursuing a revenue generation strategy by commercializing highly profitable therapeutic drugs (C-Virin & C-Pegferon) for use in the hepatitis C market.
Friday, March 25, 2011
OraSure Technologies seeks to expand laboratory access to OraQuick(R) HCV Rapid Test
BETHLEHEM, Pa., March 23, 2011 (GLOBE NEWSWIRE) -- OraSure Technologies, Inc. (Nasdaq:OSUR) announced today that it has submitted to the U.S. Food and Drug Administration ("FDA") an application for a waiver under the Clinical Laboratory Improvement Amendments of 1988 ("CLIA") for its OraQuick® HCV Rapid Antibody Test for use with venous whole blood and fingerstick whole blood specimens.
The OraQuick® HCV Rapid Antibody Test is the first and only FDA-approved rapid test for the detection of antibodies to the hepatitis C virus and is currently classified as a moderately complex test which can be used by approximately 40,000 laboratories certified as meeting certain quality and training requirements under CLIA. According to the Centers for Medicaid and Medicare Services, if the CLIA waiver application is approved, the OraQuick® HCV test could then be available for use by more than 180,000 sites nationwide, including those that can perform CLIA-waived tests such as outreach clinics, community-based organizations and physician offices.
"If approved, a CLIA waiver would enable greater access to a test that could play a vital role in identifying HCV infection in the United States," said Douglas A. Michels, President and Chief Executive Officer of OraSure Technologies. "Most importantly, the CLIA waiver will enable healthcare providers, those on the front lines of fighting this disease, to identify more individuals infected with hepatitis C and connect them to care and treatment."
About OraSure Technologies
OraSure Technologies develops, manufactures and markets oral fluid specimen collection devices using proprietary oral fluid technologies, diagnostic products including immunoassays and other in vitro diagnostic tests, and other medical devices. These products are sold in the United States as well as internationally to various clinical laboratories, hospitals, clinics, community-based organizations and other public health organizations, distributors, government agencies, physicians' offices, and commercial and industrial entities.
The OraQuick® HCV Rapid Antibody Test is the first and only FDA-approved rapid test for the detection of antibodies to the hepatitis C virus and is currently classified as a moderately complex test which can be used by approximately 40,000 laboratories certified as meeting certain quality and training requirements under CLIA. According to the Centers for Medicaid and Medicare Services, if the CLIA waiver application is approved, the OraQuick® HCV test could then be available for use by more than 180,000 sites nationwide, including those that can perform CLIA-waived tests such as outreach clinics, community-based organizations and physician offices.
"If approved, a CLIA waiver would enable greater access to a test that could play a vital role in identifying HCV infection in the United States," said Douglas A. Michels, President and Chief Executive Officer of OraSure Technologies. "Most importantly, the CLIA waiver will enable healthcare providers, those on the front lines of fighting this disease, to identify more individuals infected with hepatitis C and connect them to care and treatment."
About OraSure Technologies
OraSure Technologies develops, manufactures and markets oral fluid specimen collection devices using proprietary oral fluid technologies, diagnostic products including immunoassays and other in vitro diagnostic tests, and other medical devices. These products are sold in the United States as well as internationally to various clinical laboratories, hospitals, clinics, community-based organizations and other public health organizations, distributors, government agencies, physicians' offices, and commercial and industrial entities.
Tuesday, March 22, 2011
Jurgen Rockstroh comments HCV/HIV coinfection in the era of Direct Acting Antivirals...
Jurgen K. Rockstroh M.D., Professor of Medicine University of Bonn, Germany, gives us a synopsis of what the new DAAs for Hepatitis C will mean for patients with HIV/HCV coinfection. I highly recommend a full read through, Dr. Rockstroh walks through the latest efficacy, resistance and drug -drug interaction data on Boceprevir and Telaprevir as well as current epidemiological patterns in the disease state . We'll need SVR data from both drugs to make a full assessment, but from the interim 12 week data, it appears Telaprevir is very effective at reducing HCV viral load in the coinfected patient, although there are some serious drug-drug interactions to look out for as well as a higher incidence of adverse events. Read the entire article here
Sunday, March 20, 2011
Conatus Pharmaceuticals - Phase II data on Hepatitis C MMP inhibitor CTS-1027 to be presented at EASL
Privately-held Conatus Pharmaceuticals will have two posters on the Phase II trial of it's inhibitor of matrix metalloprotease (MMP) activity, CTS-1027 - the only MMP inhibitor currently in development for HCV at this time.
Conatus Pharmaceuticals Inc. today announced the acceptance of two poster presentations of Phase 2 clinical trial data of CTS-1027 for the treatment of hepatitis C virus-infected patients at the 46th annual meeting of the European Association for the Study of the Liver (EASL) to be held in Berlin, Germany, on March 30 to April 3, 2011.
Specifically, abstract 562 entitled: 24-WEEK TREATMENT WITH CTS-1027 IN COMBINATION WITH RIBAVIRIN REDUCES HCV-RNA IN TREATMENT NAIVE GENOTYPE-1 PATIENTS will be presented.
In addition, abstract 549 entitled: UNIQUE PATTERN OF VIROLOGIC RESPONSE IN PATIENTS WITH GENOTYPE-1 HCV: A PHASE II STUDY OF CTS-1027 IN COMBINATION WITH PEGINTEFERON/RIBAVIRIN (SOC) IN NULL RESPONDERS will also be presented.
"This will be the first public disclosure of these exciting clinical results and represents a significant step forward to raise awareness of CTS-1027 for the treatment of HCV," said Alfred P. Spada, Ph.D., Senior Vice President, Research and Development at Conatus.
"CTS-1027 is a first-in-class oral, small molecule inhibitor of host matrix metalloprotease (MMP) activity. There are no other drugs under development for HCV that operate by the same mechanism of action. Most other approaches to treat HCV infection are direct-acting anti-viral drugs whose activity is directed against virus proteins or enzymes with the objective of reducing the production of virus in infected cells. CTS-1027 by comparison is distinctly different in that its activity is hypothesized to facilitate the immune clearance of virus-infected cells and decrease the frequency of new infections, both of which are of key importance in curing HCV infections," said Steven J. Mento, Ph.D, President and CEO of Conatus.
Conatus Pharmaceuticals Inc. is a privately-held biopharmaceutical company engaged in the development of innovative human therapeutics to treat liver disease and oncology. Conatus' lead drug candidate, CTS-1027 is in multiple Phase 2 clinical trials for the treatment of hepatitis C virus (HCV). Conatus was founded by the executive management team of Idun Pharmaceuticals in July 2005 following the sale of Idun to Pfizer.
SOURCE Conatus Pharmaceuticals Inc.
Conatus Pharmaceuticals Inc. today announced the acceptance of two poster presentations of Phase 2 clinical trial data of CTS-1027 for the treatment of hepatitis C virus-infected patients at the 46th annual meeting of the European Association for the Study of the Liver (EASL) to be held in Berlin, Germany, on March 30 to April 3, 2011.
Specifically, abstract 562 entitled: 24-WEEK TREATMENT WITH CTS-1027 IN COMBINATION WITH RIBAVIRIN REDUCES HCV-RNA IN TREATMENT NAIVE GENOTYPE-1 PATIENTS will be presented.
In addition, abstract 549 entitled: UNIQUE PATTERN OF VIROLOGIC RESPONSE IN PATIENTS WITH GENOTYPE-1 HCV: A PHASE II STUDY OF CTS-1027 IN COMBINATION WITH PEGINTEFERON/RIBAVIRIN (SOC) IN NULL RESPONDERS will also be presented.
"This will be the first public disclosure of these exciting clinical results and represents a significant step forward to raise awareness of CTS-1027 for the treatment of HCV," said Alfred P. Spada, Ph.D., Senior Vice President, Research and Development at Conatus.
"CTS-1027 is a first-in-class oral, small molecule inhibitor of host matrix metalloprotease (MMP) activity. There are no other drugs under development for HCV that operate by the same mechanism of action. Most other approaches to treat HCV infection are direct-acting anti-viral drugs whose activity is directed against virus proteins or enzymes with the objective of reducing the production of virus in infected cells. CTS-1027 by comparison is distinctly different in that its activity is hypothesized to facilitate the immune clearance of virus-infected cells and decrease the frequency of new infections, both of which are of key importance in curing HCV infections," said Steven J. Mento, Ph.D, President and CEO of Conatus.
Conatus Pharmaceuticals Inc. is a privately-held biopharmaceutical company engaged in the development of innovative human therapeutics to treat liver disease and oncology. Conatus' lead drug candidate, CTS-1027 is in multiple Phase 2 clinical trials for the treatment of hepatitis C virus (HCV). Conatus was founded by the executive management team of Idun Pharmaceuticals in July 2005 following the sale of Idun to Pfizer.
SOURCE Conatus Pharmaceuticals Inc.
Thursday, March 17, 2011
Boehringer Ingelheim to show final Phase IIb data for it's BI 20133 protease inhibitor...
New data from the Boehringer Ingelheim hepatitis C virus (HCV) portfolio will be presented in oral scientific sessions at the International Liver CongressTM 2011, the 46th Annual Meeting of the European Association for the Study of the Liver (EASL), taking place 30 March-3 April in Berlin, Germany. The data will include final results from SILEN-C1 and SILEN-C2, two Phase IIb studies evaluating one of Boehringer Ingelheim’s investigational compounds for Hepatitis C treatment, the once-daily, oral protease inhibitor BI 201335 in combination with the current standard-of-care (pegylated-interferon and ribavirin).
Oral presentations (Friday, 1 April, 2011; Parallel Session: HCV Drug Development, Hall 1)
SILEN-C1: Sustained Virologic Response (SVR) and safety of BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in treatment-naïve patients with chronic genotype 1 HCV infection
(Abstract 60. M. Sulkowski, et al. 16:00h - 16:15h)
SILEN-C2: Sustained Virologic Response (SVR) and safety of BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in chronic HCV genotype-1 patients with non-response to P/R
(Abstract 66. M. Sulkowski, et al. 17:30h - 17:45h)
Boehringer Ingelheim is continuing its long heritage in virology and is dedicated to developing new medicines to improve treatment for HCV patients. BI 201335 is part of a growing HCV portfolio that is being investigated with the aim of identifying a simpler HCV cure, overcoming the challenges of current treatments.
Additional HCV studies to be presented at EASL
SVR and Pharmacokinetics of the HCV protease inhibitor BI201335 with PegIFN/RBV in HCV genotype-1 patients with compensated liver cirrhosis and non-response to previous PegIFN/RBV
(Poster 1231. S. Pol, et al.; Saturday, 2 April, 2011, 09:00h - 18:00h)
Mechanisms of isolated unconjugated hyperbilirubinemia induced by the HCV NS3/4A protease inhibitor BI201335 (Poster 1236. R. Sane, et al.;Saturday, 2 April, 2011, 09:00h - 18:00h)
BI201335 Pharmacokinetics and early effect on viral load in HCV genotype-1 patients
(Poster 1249. C. Yong, et al.;Saturday, April 2, 2011, 09:00h - 18:00h)
Preclinical Characterization of the hepatitis C virus NS5B polymerase non-nucleoside inhibitor BILB 1941 (Poster 1215. G. Kukolj et. al.; Friday, 30 March, 2011, 09:00h - 18:00h)
The abstracts can be accessed through the EASL website, www.easl.eu.
For more information on BI’s hepatitis portfolio, please visit www.boehringer-ingelheim.com and follow us on Twitter. www.twitter.com/boehringer.
Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates in 50 countries and more than 41,500 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.
Within the company’s global research network, Virology is one of the seven R&D areas with focus on Hepatitis C.
In 2009, Boehringer Ingelheim posted net sales of 12.7 billion euro (US $17.7 billion) while spending 21% of net sales in its largest business segment, Prescription Medicines, on research and development.
Oral presentations (Friday, 1 April, 2011; Parallel Session: HCV Drug Development, Hall 1)
SILEN-C1: Sustained Virologic Response (SVR) and safety of BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in treatment-naïve patients with chronic genotype 1 HCV infection
(Abstract 60. M. Sulkowski, et al. 16:00h - 16:15h)
SILEN-C2: Sustained Virologic Response (SVR) and safety of BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in chronic HCV genotype-1 patients with non-response to P/R
(Abstract 66. M. Sulkowski, et al. 17:30h - 17:45h)
Boehringer Ingelheim is continuing its long heritage in virology and is dedicated to developing new medicines to improve treatment for HCV patients. BI 201335 is part of a growing HCV portfolio that is being investigated with the aim of identifying a simpler HCV cure, overcoming the challenges of current treatments.
Additional HCV studies to be presented at EASL
SVR and Pharmacokinetics of the HCV protease inhibitor BI201335 with PegIFN/RBV in HCV genotype-1 patients with compensated liver cirrhosis and non-response to previous PegIFN/RBV
(Poster 1231. S. Pol, et al.; Saturday, 2 April, 2011, 09:00h - 18:00h)
Mechanisms of isolated unconjugated hyperbilirubinemia induced by the HCV NS3/4A protease inhibitor BI201335 (Poster 1236. R. Sane, et al.;Saturday, 2 April, 2011, 09:00h - 18:00h)
BI201335 Pharmacokinetics and early effect on viral load in HCV genotype-1 patients
(Poster 1249. C. Yong, et al.;Saturday, April 2, 2011, 09:00h - 18:00h)
Preclinical Characterization of the hepatitis C virus NS5B polymerase non-nucleoside inhibitor BILB 1941 (Poster 1215. G. Kukolj et. al.; Friday, 30 March, 2011, 09:00h - 18:00h)
The abstracts can be accessed through the EASL website, www.easl.eu.
For more information on BI’s hepatitis portfolio, please visit www.boehringer-ingelheim.com and follow us on Twitter. www.twitter.com/boehringer.
Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates in 50 countries and more than 41,500 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.
Within the company’s global research network, Virology is one of the seven R&D areas with focus on Hepatitis C.
In 2009, Boehringer Ingelheim posted net sales of 12.7 billion euro (US $17.7 billion) while spending 21% of net sales in its largest business segment, Prescription Medicines, on research and development.
Inovio Pharmaceutical partner ChronTech starts Phase II trial of Hepatitis C vaccine
ChronTech Pharma AB is using Inovio's new cellular delivery system as a foundation for it's HCV vaccine, ChronVac-C. The phase 1 trial using ChronVac-C was encouraging, with 5 of 6 subjects achieving an SVR from the initial 7 in the trial. They are starting a Phase IIb trial in Sweden, 20 patients will be given the vaccine plus SOC, another group of 12 will be given SOC alone.
BLUE BELL, PA – March 14, 2011 -- Inovio Pharmaceuticals, Inc. (NYSE Amex: INO), a leader in the development of therapeutic and preventive vaccines against cancers and infectious diseases, announced today that its partner, ChronTech Pharma AB (formerly Tripep AB), has initiated a Phase IIb clinical study of its ChronVac-C® DNA vaccine for hepatitis C virus (HCV), delivered by Inovio’s proprietary electroporation DNA vaccine delivery technology, in combination with standard of care.
In a Phase I clinical trial of ChronVac-C using Inovio’s MedPulser® electroporation device the therapy resulted in a robust increase in T-cell immune responses against HCV and was safe and well-tolerated. Post-study observation of subjects who completed the protocol and then entered into standard of care (SOC) treatment using interferon and ribavirin showed a complete and rapid viral response (four weeks) in 70% of those participants (5 of 7 patients). More significantly, 83% of the participants (5 of 6 patients) who were monitored for an extended period of time, continued to be free of the virus six months after they completed SOC. SOC treatment alone usually results in about 40-50% of patients reaching undetectable virus levels after six months of treatment.
This Phase II follow-on trial is an open-label, single-dose, randomized trial of 32 patients to further explore the effect of the ChronVac-C® DNA vaccine administered by Inovio’s MedPulser® electroporation delivery device. The therapy will be given two times, with four weeks in between, followed by SOC treatment after the final vaccine dose in treatment-naïve chronic HCV infected genotype-1 subjects. This trial will assess the level of immune responses, levels of HCV viral load, and further assess the response to the delivery technology. Twenty patients will receive ChronVac-C® vaccine delivered with Inovio’s electroporation device; the 12-patient comparison group will receive standard-of-care treatment alone. The study has received approval from the Swedish Medical Products Agency and local ethical committee.
“If we can repeat the Phase I results in this phase IIb study there is certainly a possibility that vaccination with ChronVac-C® before drug therapy could become a part of the standard of care therapy for patients with chronic hepatitis C-virus infection. In particular, we hope that vaccination with this novel therapy will result in a considerable shortening of the duration of interferon and ribavirin treatment,” said Anders Vahlne, CEO of ChronTech Pharma AB.
Dr. J. Joseph Kim, Inovio’s president and CEO, said: “We are encouraged by the phase I results showing the improved cure rate in patients who received the HCV vaccine followed by a SOC drug therapy. Any improvement to the HCV standard of care response rates would be well-received by HCV patients and practitioners. We are pleased to collaborate in this advancement of ChronVac-C®, using Inovio’s innovative delivery technology, into Phase II.”
About Hepatitis C Virus
Hepatitis C virus (HCV) infection is the most common chronic blood borne infection in the United States, where approximately 3.5 million persons have been chronically infected. Worldwide, about 300 million people have been infected with HCV. Based on current statistics for hepatitis C, it is estimated that 8,000 to 10,000 people die each year from chronic liver disease caused by this condition. Chronic HCV infection is the leading indication for liver transplants in the United States. Total health costs associated with hepatitis C virus in the U.S. are estimated at more than $15 billion per year. No vaccine for HCV is currently available.
About Inovio’s Electroporation-Based Delivery Technology
Inovio's electroporation-based DNA delivery systems can increase the cellular uptake of an agent by 1,000 times or more. When used to deliver DNA vaccines, Inovio's systems can increase levels of gene expression (i.e. production of the coded protein) and immune responses by 100 times or more compared to plasmid DNA delivered without other delivery enhancements. Inovio has recently reported best-in-class immune responses with DNA vaccines for cervical dysplasias/cancers and HIV. Inovio has also shown the safety and tolerability of its electroporation devices in many hundreds of patients and continues to advance device innovations to further enhance the utility of these devices for mass vaccinations.
BLUE BELL, PA – March 14, 2011 -- Inovio Pharmaceuticals, Inc. (NYSE Amex: INO), a leader in the development of therapeutic and preventive vaccines against cancers and infectious diseases, announced today that its partner, ChronTech Pharma AB (formerly Tripep AB), has initiated a Phase IIb clinical study of its ChronVac-C® DNA vaccine for hepatitis C virus (HCV), delivered by Inovio’s proprietary electroporation DNA vaccine delivery technology, in combination with standard of care.
In a Phase I clinical trial of ChronVac-C using Inovio’s MedPulser® electroporation device the therapy resulted in a robust increase in T-cell immune responses against HCV and was safe and well-tolerated. Post-study observation of subjects who completed the protocol and then entered into standard of care (SOC) treatment using interferon and ribavirin showed a complete and rapid viral response (four weeks) in 70% of those participants (5 of 7 patients). More significantly, 83% of the participants (5 of 6 patients) who were monitored for an extended period of time, continued to be free of the virus six months after they completed SOC. SOC treatment alone usually results in about 40-50% of patients reaching undetectable virus levels after six months of treatment.
This Phase II follow-on trial is an open-label, single-dose, randomized trial of 32 patients to further explore the effect of the ChronVac-C® DNA vaccine administered by Inovio’s MedPulser® electroporation delivery device. The therapy will be given two times, with four weeks in between, followed by SOC treatment after the final vaccine dose in treatment-naïve chronic HCV infected genotype-1 subjects. This trial will assess the level of immune responses, levels of HCV viral load, and further assess the response to the delivery technology. Twenty patients will receive ChronVac-C® vaccine delivered with Inovio’s electroporation device; the 12-patient comparison group will receive standard-of-care treatment alone. The study has received approval from the Swedish Medical Products Agency and local ethical committee.
“If we can repeat the Phase I results in this phase IIb study there is certainly a possibility that vaccination with ChronVac-C® before drug therapy could become a part of the standard of care therapy for patients with chronic hepatitis C-virus infection. In particular, we hope that vaccination with this novel therapy will result in a considerable shortening of the duration of interferon and ribavirin treatment,” said Anders Vahlne, CEO of ChronTech Pharma AB.
Dr. J. Joseph Kim, Inovio’s president and CEO, said: “We are encouraged by the phase I results showing the improved cure rate in patients who received the HCV vaccine followed by a SOC drug therapy. Any improvement to the HCV standard of care response rates would be well-received by HCV patients and practitioners. We are pleased to collaborate in this advancement of ChronVac-C®, using Inovio’s innovative delivery technology, into Phase II.”
About Hepatitis C Virus
Hepatitis C virus (HCV) infection is the most common chronic blood borne infection in the United States, where approximately 3.5 million persons have been chronically infected. Worldwide, about 300 million people have been infected with HCV. Based on current statistics for hepatitis C, it is estimated that 8,000 to 10,000 people die each year from chronic liver disease caused by this condition. Chronic HCV infection is the leading indication for liver transplants in the United States. Total health costs associated with hepatitis C virus in the U.S. are estimated at more than $15 billion per year. No vaccine for HCV is currently available.
About Inovio’s Electroporation-Based Delivery Technology
Inovio's electroporation-based DNA delivery systems can increase the cellular uptake of an agent by 1,000 times or more. When used to deliver DNA vaccines, Inovio's systems can increase levels of gene expression (i.e. production of the coded protein) and immune responses by 100 times or more compared to plasmid DNA delivered without other delivery enhancements. Inovio has recently reported best-in-class immune responses with DNA vaccines for cervical dysplasias/cancers and HIV. Inovio has also shown the safety and tolerability of its electroporation devices in many hundreds of patients and continues to advance device innovations to further enhance the utility of these devices for mass vaccinations.
Tuesday, March 15, 2011
New CCO Interactive and Downloadable Slide Set Available: Future Generations: Understanding the Similarities and Differences Among Direct-Acting Antivirals for Hepatitis C
For those that like to geek-out to quality slide decks (the hallmark of the folks at CCO) there is both an interactive presentation (with Stefan Zeuzem, MD) and a downloadable slide deck entitled "Future Generations: Understanding the Similarities and Differences Among Direct-Acting Antivirals for Hepatitis C". This happens to come at a perfect time for the DAA layperson, right before the impending launch of the first generation DAAs, Telaprevir and Boceprevir. You can watch and/or download the presentation right here
iTherX Initiates Phase 1b Study of First-in-Class Hepatitis C Virus Entry Inhibitor ITX-5061...
Holy Jeebus!! There is a ton of data on new Direct Acting Antivirals that is going to be presented at EASL judging by the amount of press releases jamming my inbox. Keep in mind 80% will never make it to market as drugs are sidelined due to toxicities or limited potential given the relative potential of all the other drugs in development. Still, these are exciting times indeed for people living with HCV. Science continues to develop more tolerable and efficacious therapies to eradicate the HCV virus, even in the difficult-to-treat post-transplant patient population where the use of pioneering drugs like Telaprevir and Boceprevir will be limited.
-- Preclinical Studies Show that ITX-5061 Prevents Hepatitis C from Invading Liver Cells --
SAN DIEGO, March 15, 2011 /PRNewswire/ -- iTherX, a pharmaceutical company dedicated to discovering and developing a new class of therapies for hepatitis C, today announced that it has commenced patient recruitment in an open-label, proof-of-concept Phase 1b study of its lead compound ITX-5061 in liver transplant patients with hepatitis C virus infection (HCV). ITX-5061 represents a first-in-class compound that inhibits entry of the hepatitis C virus into liver cells.
"ITX-5061 possesses a unique mechanism of action that prevents the hepatitis C virus from entering liver cells and has demonstrated potent preclinical antiviral activity against all HCV genotypes.In addition, it has already demonstrated safety in more than 280 subjects," said Jeffrey McKelvy, PhD, MD, President and Chief Executive Officer of iTherX. "We hope ITX-5061 will significantly improve long-term transplant outcomes."
The primary objective of the Phase 1b clinical trial will be to assess the safety and tolerability of ITX-5061 in liver transplant patients. The study will also assess HCV viral load for three months after liver transplantation to determine if ITX-5061 has any immediate and/or sustained impact on viral kinetics in treated patients. Approximately 20 patients will be enrolled into one of two cohorts: one group will receive supportive care only, while the second cohort will also receive ITX-5061 at a150 mg daily dose for seven days. The trial is being conducted at the University of Birmingham, UK under the direction of David Mutimer, MBBS, MD, FRACP, FRCP, Reader in Hepatology at Birmingham University and Consultant Hepatologist to the Birmingham QE Hospital Liver and Hepatobiliary Unit.
Preclinical studies have shown ITX-5061 to be a potent and selective inhibitor of HCV entry into hepatocytes, capable of preventing virus binding/fusion and cell to cell spread, suggesting ITX-5061 may reduce re-infection rates following liver transplant.
"Recurrence of HCV infection among liver transplant patients is universal and immediate. Clinicians have long sought ways to prevent re-infection by HCV, improve transplant patient outcomes and extend survival," said Dr. Mutimer. "The potential of ITX-5061 to prevent or reduce viral infection of the new liver by halting viral-entry into healthy cells represents an extraordinarily novel approach, and we are excited to advance the clinical development of this promising antiviral compound."
The Phase 1b trial of ITX-5061 in liver transplant recipients is funded through an educational grant from iTherX with the National Institute of Health Research Biomedical Research Unit (NIH-BRU Birmingham).
This is a second clinical study for ITX-5061 in hepatitis C. The first study, a single agent placebo-controlled dose response study commenced in August 2010, is being conducted in treatment naïve chronic HCV patients by the AIDS Clinical Trial Group of the National Institute of Allergy and Infectious Diseases.
About Hepatitis C
Hepatitis C virus (HCV) infection, a disease that attacks the liver, affects 170 million people worldwide. The majority of individuals develop chronic infection and up to 20 percent of infected individuals will develop cirrhosis with the attendant risks of liver failure and liver cell cancer. The current standard of care is combination antiviral treatment with pegylated interferon-alpha and ribavirin, which results in a cure for approximately half of all patients. Unfortunately, many patients present with clinically silent infection or advanced disease, at which time antiviral treatment is generally ineffective. For these patients, liver transplantation may be the only option. End-stage liver disease due to chronic HCV infection has become the leading indication for liver transplantation in the United States. Recurrence of hepatitis C virus after liver transplantation is inevitable and disease progression is rapid when compared with disease in the non-transplanted liver.
About iTherX
iTherX is a pharmaceutical company focused on the discovery and development of a novel class of antiviral therapeutics that act by blocking entry of the hepatitis C virus into liver cells to halt the spread of infection. The company's lead program, ITX-5061, is currently in Phase 1b clinical studies intended to evaluate antiviral activity and safety in patients with HCV infection. In addition to ITX-5061, iTherX is leveraging its proprietary expertise in molecular virology and medicinal chemistry to establish a pipeline of viral entry inhibitors, with additional candidates currently undergoing preclinical testing.
-- Preclinical Studies Show that ITX-5061 Prevents Hepatitis C from Invading Liver Cells --
SAN DIEGO, March 15, 2011 /PRNewswire/ -- iTherX, a pharmaceutical company dedicated to discovering and developing a new class of therapies for hepatitis C, today announced that it has commenced patient recruitment in an open-label, proof-of-concept Phase 1b study of its lead compound ITX-5061 in liver transplant patients with hepatitis C virus infection (HCV). ITX-5061 represents a first-in-class compound that inhibits entry of the hepatitis C virus into liver cells.
"ITX-5061 possesses a unique mechanism of action that prevents the hepatitis C virus from entering liver cells and has demonstrated potent preclinical antiviral activity against all HCV genotypes.In addition, it has already demonstrated safety in more than 280 subjects," said Jeffrey McKelvy, PhD, MD, President and Chief Executive Officer of iTherX. "We hope ITX-5061 will significantly improve long-term transplant outcomes."
The primary objective of the Phase 1b clinical trial will be to assess the safety and tolerability of ITX-5061 in liver transplant patients. The study will also assess HCV viral load for three months after liver transplantation to determine if ITX-5061 has any immediate and/or sustained impact on viral kinetics in treated patients. Approximately 20 patients will be enrolled into one of two cohorts: one group will receive supportive care only, while the second cohort will also receive ITX-5061 at a150 mg daily dose for seven days. The trial is being conducted at the University of Birmingham, UK under the direction of David Mutimer, MBBS, MD, FRACP, FRCP, Reader in Hepatology at Birmingham University and Consultant Hepatologist to the Birmingham QE Hospital Liver and Hepatobiliary Unit.
Preclinical studies have shown ITX-5061 to be a potent and selective inhibitor of HCV entry into hepatocytes, capable of preventing virus binding/fusion and cell to cell spread, suggesting ITX-5061 may reduce re-infection rates following liver transplant.
"Recurrence of HCV infection among liver transplant patients is universal and immediate. Clinicians have long sought ways to prevent re-infection by HCV, improve transplant patient outcomes and extend survival," said Dr. Mutimer. "The potential of ITX-5061 to prevent or reduce viral infection of the new liver by halting viral-entry into healthy cells represents an extraordinarily novel approach, and we are excited to advance the clinical development of this promising antiviral compound."
The Phase 1b trial of ITX-5061 in liver transplant recipients is funded through an educational grant from iTherX with the National Institute of Health Research Biomedical Research Unit (NIH-BRU Birmingham).
This is a second clinical study for ITX-5061 in hepatitis C. The first study, a single agent placebo-controlled dose response study commenced in August 2010, is being conducted in treatment naïve chronic HCV patients by the AIDS Clinical Trial Group of the National Institute of Allergy and Infectious Diseases.
About Hepatitis C
Hepatitis C virus (HCV) infection, a disease that attacks the liver, affects 170 million people worldwide. The majority of individuals develop chronic infection and up to 20 percent of infected individuals will develop cirrhosis with the attendant risks of liver failure and liver cell cancer. The current standard of care is combination antiviral treatment with pegylated interferon-alpha and ribavirin, which results in a cure for approximately half of all patients. Unfortunately, many patients present with clinically silent infection or advanced disease, at which time antiviral treatment is generally ineffective. For these patients, liver transplantation may be the only option. End-stage liver disease due to chronic HCV infection has become the leading indication for liver transplantation in the United States. Recurrence of hepatitis C virus after liver transplantation is inevitable and disease progression is rapid when compared with disease in the non-transplanted liver.
About iTherX
iTherX is a pharmaceutical company focused on the discovery and development of a novel class of antiviral therapeutics that act by blocking entry of the hepatitis C virus into liver cells to halt the spread of infection. The company's lead program, ITX-5061, is currently in Phase 1b clinical studies intended to evaluate antiviral activity and safety in patients with HCV infection. In addition to ITX-5061, iTherX is leveraging its proprietary expertise in molecular virology and medicinal chemistry to establish a pipeline of viral entry inhibitors, with additional candidates currently undergoing preclinical testing.
FDA Advisory Panel to review Boceprevir & Telaprevir on April 27th & 28th...
FDA Panel To Review Merck, Vertex Hepatitis Drugs In Late April
First Published Monday, 14 March 2011 05:08 pm - © 2011 Dow Jones
By Thomas Gryta
Of DOW JONES NEWSWIRES
NEW YORK -(Dow Jones)- A U.S. Food and Drug Administration panel will review two hepatitis C drugs in development from Vertex Pharmaceuticals Inc. (VRTX) and Merck & Co. Inc. (MRK) in late April, as the companies race to compete against each other in a potentially lucrative market.
The agency's Antiviral Drugs Advisory Committee will review Merck's boceprevir on April 27 and Vertex's telaprevir on April 28. The widely expected reviews will have outside experts recommend whether the agency should allow the drugs on the market.
Both drugs have shown success in increasing the cure rates of the liver disease when added to current treatments.
They are expected to come to the market at similar times and be widely used, creating a market share battle. Merck said in early January that it was granted a six-month review; Vertex is getting a similar review and expects a decision by May 23.
Many on Wall Street believe that clinical trials show Vertex's telaprevir is the preferable drug, although Merck's Chief Executive Kenneth Frazier has repeatedly stated his confidence in boceprevir's prospects.
Wells Fargo recently projected $1.4 billion in U.S. sales next year for telaprevir. Vertex owns the North American rights to the drug and would get a royalty on overseas sales from partner Johnson & Johnson (JNJ).
Hepatitis C is a blood-transmitted virus that causes liver inflammation and can lead to cirrhosis, cancer and liver failure.
Both the Merck and Vertex drugs are known as protease inhibitors, which are designed to block an enzyme that helps the hepatitis C virus replicate. Standard treatment is a combination of the drug pegylated interferon and ribavirin, but adding the new drugs may improve cure rates and shorten the duration of treatment.
-By Thomas Gryta, Dow Jones Newswires; 212-416-2169;
First Published Monday, 14 March 2011 05:08 pm - © 2011 Dow Jones
By Thomas Gryta
Of DOW JONES NEWSWIRES
NEW YORK -(Dow Jones)- A U.S. Food and Drug Administration panel will review two hepatitis C drugs in development from Vertex Pharmaceuticals Inc. (VRTX) and Merck & Co. Inc. (MRK) in late April, as the companies race to compete against each other in a potentially lucrative market.
The agency's Antiviral Drugs Advisory Committee will review Merck's boceprevir on April 27 and Vertex's telaprevir on April 28. The widely expected reviews will have outside experts recommend whether the agency should allow the drugs on the market.
Both drugs have shown success in increasing the cure rates of the liver disease when added to current treatments.
They are expected to come to the market at similar times and be widely used, creating a market share battle. Merck said in early January that it was granted a six-month review; Vertex is getting a similar review and expects a decision by May 23.
Many on Wall Street believe that clinical trials show Vertex's telaprevir is the preferable drug, although Merck's Chief Executive Kenneth Frazier has repeatedly stated his confidence in boceprevir's prospects.
Wells Fargo recently projected $1.4 billion in U.S. sales next year for telaprevir. Vertex owns the North American rights to the drug and would get a royalty on overseas sales from partner Johnson & Johnson (JNJ).
Hepatitis C is a blood-transmitted virus that causes liver inflammation and can lead to cirrhosis, cancer and liver failure.
Both the Merck and Vertex drugs are known as protease inhibitors, which are designed to block an enzyme that helps the hepatitis C virus replicate. Standard treatment is a combination of the drug pegylated interferon and ribavirin, but adding the new drugs may improve cure rates and shorten the duration of treatment.
-By Thomas Gryta, Dow Jones Newswires; 212-416-2169;
Sunday, March 13, 2011
Gilead 's GS-9256 + GS-9190 + P/R looking good going into EASL...
This about as vague a press release I've read, but Gilead must be somewhat confident given that they've paid big bucks to acquire John McHutchison as their Senior Vice President, Liver Disease Therapeutics. More to come as everyone gets a closer look at the data at EASL.
Gilead's hepatitis C therapy called successful
Kristen Hallam, Bloomberg News
Wednesday, March 9, 2011
Gilead Sciences Inc.'s four-drug combination eliminated hepatitis C virus in patients in an early-stage study, RBC Capital Markets LLC analysts said.
The findings support an ongoing midstage study of the combination, the analysts, led by Michael Yee in San Francisco, wrote Monday in a note to investors, citing an abstract of the trial. The analysts said they expect data next year from a midstage study by the Foster City company.
The early-stage study examined a combination of Gilead's GS-9256 and GS-9190 with two older drugs that are the standard of care, ribavirin and Peg-interferon, according to the note.
The data will be presented at the annual meeting of the European Association for the Study of the Liver starting March 30 in Berlin.
Market data provided by Bloomberg News
Gilead's hepatitis C therapy called successful
Kristen Hallam, Bloomberg News
Wednesday, March 9, 2011
Gilead Sciences Inc.'s four-drug combination eliminated hepatitis C virus in patients in an early-stage study, RBC Capital Markets LLC analysts said.
The findings support an ongoing midstage study of the combination, the analysts, led by Michael Yee in San Francisco, wrote Monday in a note to investors, citing an abstract of the trial. The analysts said they expect data next year from a midstage study by the Foster City company.
The early-stage study examined a combination of Gilead's GS-9256 and GS-9190 with two older drugs that are the standard of care, ribavirin and Peg-interferon, according to the note.
The data will be presented at the annual meeting of the European Association for the Study of the Liver starting March 30 in Berlin.
Market data provided by Bloomberg News
Friday, March 11, 2011
Seeking Alpha's Robert Weinstein on Pharmasset's nuc-nuc press release...
Good read. Weinstein is my new 'don't believe the hype' role model... http://seekingalpha.com/article/257743-pharmasset-the-real-numbers-behind-the-hype
NATAP posts CROI coverage....
Always great coverage from the NATAP folks is just a click away... http://www.natap.org/2011/CROI/CROI.htm
Thursday, March 10, 2011
EASL: Telaprevir in combination with Peg-INF2a and RBV increased SVR rates in treatment-naive patients regardless of race or ethnicity
Some impressive Telaprevir TVR) treatment naive pooled analysis data to be presented at the upcoming EASL meeting in Berlin, looking at SVR rate differences between race and ethnicity in the ADVANCE and ILLUMINATE trials. Specifically, differences between the TVR arms and Peg-inf2a/Ribavirin (PR). Most impressive were the differences in SVR, relapse and viral failure in Black/African American subjects. In the TVR + PR for 12 weeks, then PR for another 12 or 36 weeks depending on viral response, total SVR was 61%, relapse was 13% and viral failure was 9%. Compare this to the 48 week PR control arm, which showed 25% SVR, 36% relapse and 46% viral failure. Total TVR-related SVR was still lower than non-Black/African Americans (61% vs 75%, respectively) but the improvement from the current standard of care (48 weeks of PR) is significant and encouraging. See the full poster abstract here: http://www1.easl.eu/easl2011/program/Posters/Abstract222.htm
TELAPREVIR IN COMBINATION WITH PEGINTERFERON ALFA-2A AND RIBAVIRIN INCREASED SUSTAINED VIROLOGIC RESPONSE RATES IN TREATMENT-NAïVE PATIENTS REGARDLESS OF RACE OR ETHNICITY
G.M. Dusheiko1*, M.W. Fried2, R. Reddy3, D.R. Nelson4, N. Bzowej5, N. Adda6, C.I. Wright6, L. Bengtsson6, S. George6, S.L. Flamm7
1Royal Free and University College, London, UK, 2University of North Carolina at Chapel Hill, Chapel Hill, NC, 3University of Pennsylvania School of Medicine, Philadelphia, PA, 4University of Florida, Gainesville, FL, 5California Pacific Medical Center, San Francisco, CA, 6Vertex Pharmaceuticals Incorporated, Cambridge, MA, 7Northwestern University, Chicago, IL, USA. *g.dusheiko@medsch.ucl.ac.uk
Background and aims: ADVANCE and ILLUMINATE were Phase 3 randomized studies that evaluated the safety and efficacy of telaprevir (T) in combination with peginterferon alfa-2a (P) and ribavirin (R) in treatment-naïve genotype 1 HCV patients. In this pooled analysis, we evaluated the effect of race or ethnicity on the response to treatment with telaprevir-based therapy.
Methods: Patients who received 12 weeks of response-guided telaprevir-based therapy for a total treatment duration of 24 or 48 weeks (ADVANCE N=903 and ILLUMINATE N=540) were compared to ADVANCE patients who received 48 weeks of PR alone (N=361). Race and ethnicity were self-reported and were not mutually exclusive. Ethnicity was not reported in 13 patients as the question was not allowed per local regulations.
Results: Efficacy outcomes are presented in the Table. The most common ( ≥ 25% in any subgroup) adverse events in patients who received telaprevir-based therapy were: fatigue, pruritus, nausea, headache, anemia, rash, influenza-like illness, insomnia, neutropenia, and diarrhea. Discontinuations of all drugs during telaprevir phase were: due to adverse events (7% in T12PR and 4% in PR), rash events (1% in T12PR and 0% in PR) and anemia events (1% in T12PR and < 1% in PR).
View table here: http://www1.easl.eu/easl2011/program/Posters/Abstract222.htm
Conclusions: Telaprevir-based therapy provided a substantial improvement in SVR rates in Black/African American and Hispanic/Latino patient populations known to achieve lower SVR rates when treated with PR alone. Low rates of discontinuations of all drugs due to adverse events, rash and anemia events were observed across all subgroups during the telaprevir phase.
TELAPREVIR IN COMBINATION WITH PEGINTERFERON ALFA-2A AND RIBAVIRIN INCREASED SUSTAINED VIROLOGIC RESPONSE RATES IN TREATMENT-NAïVE PATIENTS REGARDLESS OF RACE OR ETHNICITY
G.M. Dusheiko1*, M.W. Fried2, R. Reddy3, D.R. Nelson4, N. Bzowej5, N. Adda6, C.I. Wright6, L. Bengtsson6, S. George6, S.L. Flamm7
1Royal Free and University College, London, UK, 2University of North Carolina at Chapel Hill, Chapel Hill, NC, 3University of Pennsylvania School of Medicine, Philadelphia, PA, 4University of Florida, Gainesville, FL, 5California Pacific Medical Center, San Francisco, CA, 6Vertex Pharmaceuticals Incorporated, Cambridge, MA, 7Northwestern University, Chicago, IL, USA. *g.dusheiko@medsch.ucl.ac.uk
Background and aims: ADVANCE and ILLUMINATE were Phase 3 randomized studies that evaluated the safety and efficacy of telaprevir (T) in combination with peginterferon alfa-2a (P) and ribavirin (R) in treatment-naïve genotype 1 HCV patients. In this pooled analysis, we evaluated the effect of race or ethnicity on the response to treatment with telaprevir-based therapy.
Methods: Patients who received 12 weeks of response-guided telaprevir-based therapy for a total treatment duration of 24 or 48 weeks (ADVANCE N=903 and ILLUMINATE N=540) were compared to ADVANCE patients who received 48 weeks of PR alone (N=361). Race and ethnicity were self-reported and were not mutually exclusive. Ethnicity was not reported in 13 patients as the question was not allowed per local regulations.
Results: Efficacy outcomes are presented in the Table. The most common ( ≥ 25% in any subgroup) adverse events in patients who received telaprevir-based therapy were: fatigue, pruritus, nausea, headache, anemia, rash, influenza-like illness, insomnia, neutropenia, and diarrhea. Discontinuations of all drugs during telaprevir phase were: due to adverse events (7% in T12PR and 4% in PR), rash events (1% in T12PR and 0% in PR) and anemia events (1% in T12PR and < 1% in PR).
View table here: http://www1.easl.eu/easl2011/program/Posters/Abstract222.htm
Conclusions: Telaprevir-based therapy provided a substantial improvement in SVR rates in Black/African American and Hispanic/Latino patient populations known to achieve lower SVR rates when treated with PR alone. Low rates of discontinuations of all drugs due to adverse events, rash and anemia events were observed across all subgroups during the telaprevir phase.
Tuesday, March 8, 2011
Could an all-oral agent to treat HCV be on the way?
Two week interim data for Pharmasset's Interferon/Ribavirin-free nuc-nuc combo is a long way from an SVR, but so far the company has earned bragging rights by having 15/16 subjects in this early phase trial go undetectable after two weeks. This is seemingly a pretty potent combo in comparison to Vertex's data with it's nuc VX-222 + Telaprevir + Peg Interferon + Ribavirin. Depending on the arm, that data topped out at 38-57% undetectability after 14 days in comparison to 94% with PSI-938 and PSI-7977. Pharmasset’s new landmark was enough for investors to spin like tops and goose the stock to new heights. Keep in mind that investors don’t always act rationally and It’s difficult to predict outcomes as all we know regarding viral kinetics and positive/negative predictive values comes from regimens that contain peg-inf plus ribavirin as its therapeutic backbone. If PSI-938 and PSI-7977 can retain 94% undetectable at four weeks, I’ll be proportionally reassured regarding this combo’s future. It will be interesting how the company defines when it’s time to stop therapy given that there isn’t an immunomodulator aboard. At what time points will the company declare EOT and SVR? An all oral combo would be an amazing paradigm shift for this disease state and will set the bar extremely high for drug developers looking to get into the HCV therapeutic category, but there’s a long road ahead.
Pharmasset Hep C Data Wows Investors
Adam Feuerstein
03/08/11 - 11:46 AM EST
PRINCETON, N.J. (TheStreet) -- Pharmasset(VRUS) shares are soaring on the release of new but very preliminary data that hints at a breakthrough, all-oral cure for hepatitis C.
Treatment with two oral drugs developed by Pharmasset resulted in 15 of 16, or 94%, of patients reporting undetectable levels of the hepatitis C virus after 14 days, according to interim results from a study released Monday.
These early data on the two Pharmasset drugs -- PSI-938 and PSI-7977 are the best reported to date by any company seeking to develop a new, all-oral therapy for hepatitis C. This Pharmasset effort is drawing even more attention because it potentially eliminates the need for patients to be treated with long-acting interferon, one of two drugs currently used to treat hepatitis C but which is difficult for patients to tolerate and causes many side effects.
Pharmasset shares rose 24% on Monday and were up another 8% to $66.92 on Tuesday.
The PSI-938 and PSI-7977 combination data were released Monday in a research abstract released online by the European Association for the Study of the Liver (EASL), which holds its annual meeting March 30 through April 3.
EASL makes research abstracts for its annual meeting freely available to the public but prohibits journalists from writing about the data contained in the research abstracts until they are presented at the annual meeting. TheStreet refuses to adhere to EASL's media embargo since these hepatitis C data are freely available online now and are impacting the stock prices of publicly traded companies developing hepatitis C drugs.
While investors are displaying great enthusiasm for the Pharmasset all-oral drug combination, the data from the study are very early. One particular risk seen in other, similar studies that omit long-acting interferon is the development of mutated hepatitis C virus that can quickly become resistant to drug treatment.
None of the patients treated in the Pharmasset study have reported rebounding levels of hepatitis C virus, according to the research abstract, but so-called viral rebound may emerge as patients are treated longer, or when treatment is stopped and these patients are followed long-term to determine if they are truly cured.
Pharmasset owns full rights to both PSI-938 and PSI-7977. The company is developing another hepatitis C drug, RG7128, in partnership with Roche.
"We believe the full data of a 14-day combination of PSI-7977 / PSI-938 to be presented at the upcoming EASL could show proof of principle for a nuc-nuc combination and position Pharmasset as one of the front runners in the race to develop an interferon-free regimen, which is considered a Holy Grail in hepatitis C treatment," said Leerink Swann analyst Howard Liang in a note to clients Tuesday.
The EASL meeting at the end of the month will also feature data from other companies seeking to develop various combination treatments for hepatitis C.
Vertex Pharmaceuticals(VRTX) is studying a "quad" regimen consisting of two experimental drugs, VX-222 and telaprevir, combined with the current standard of care, long-acting interferon and ribavirin. An EASL research abstract released Monday reported treatment with Vertex's "quad" therapy resulted in 38-57% of patients with undetectable virus after two weeks and 86-87% undetectable after four weeks.
One potential competitive disadvantage to the Vertex quad is that patients still need to be treated with long-acting interferon, which requires weekly injections. Vertex previously reported disappointing results from an all-oral Hep C drug regimen that eliminated interferon.
Telaprevir is currently under review by regulators in the U.S. and Europe. The U.S. Food and Drug Administration is expected to make an approval decision on or before May 23.
Gilead Sciences(GILD) and Bristol-Myers Squibb(BMY) will also be presenting new data from Hep C combination drug studies at the EASL meeting later this month.
--Written by Adam Feuerstein in Boston.
Pharmasset Hep C Data Wows Investors
Adam Feuerstein
03/08/11 - 11:46 AM EST
PRINCETON, N.J. (TheStreet) -- Pharmasset(VRUS) shares are soaring on the release of new but very preliminary data that hints at a breakthrough, all-oral cure for hepatitis C.
Treatment with two oral drugs developed by Pharmasset resulted in 15 of 16, or 94%, of patients reporting undetectable levels of the hepatitis C virus after 14 days, according to interim results from a study released Monday.
These early data on the two Pharmasset drugs -- PSI-938 and PSI-7977 are the best reported to date by any company seeking to develop a new, all-oral therapy for hepatitis C. This Pharmasset effort is drawing even more attention because it potentially eliminates the need for patients to be treated with long-acting interferon, one of two drugs currently used to treat hepatitis C but which is difficult for patients to tolerate and causes many side effects.
Pharmasset shares rose 24% on Monday and were up another 8% to $66.92 on Tuesday.
The PSI-938 and PSI-7977 combination data were released Monday in a research abstract released online by the European Association for the Study of the Liver (EASL), which holds its annual meeting March 30 through April 3.
EASL makes research abstracts for its annual meeting freely available to the public but prohibits journalists from writing about the data contained in the research abstracts until they are presented at the annual meeting. TheStreet refuses to adhere to EASL's media embargo since these hepatitis C data are freely available online now and are impacting the stock prices of publicly traded companies developing hepatitis C drugs.
While investors are displaying great enthusiasm for the Pharmasset all-oral drug combination, the data from the study are very early. One particular risk seen in other, similar studies that omit long-acting interferon is the development of mutated hepatitis C virus that can quickly become resistant to drug treatment.
None of the patients treated in the Pharmasset study have reported rebounding levels of hepatitis C virus, according to the research abstract, but so-called viral rebound may emerge as patients are treated longer, or when treatment is stopped and these patients are followed long-term to determine if they are truly cured.
Pharmasset owns full rights to both PSI-938 and PSI-7977. The company is developing another hepatitis C drug, RG7128, in partnership with Roche.
"We believe the full data of a 14-day combination of PSI-7977 / PSI-938 to be presented at the upcoming EASL could show proof of principle for a nuc-nuc combination and position Pharmasset as one of the front runners in the race to develop an interferon-free regimen, which is considered a Holy Grail in hepatitis C treatment," said Leerink Swann analyst Howard Liang in a note to clients Tuesday.
The EASL meeting at the end of the month will also feature data from other companies seeking to develop various combination treatments for hepatitis C.
Vertex Pharmaceuticals(VRTX) is studying a "quad" regimen consisting of two experimental drugs, VX-222 and telaprevir, combined with the current standard of care, long-acting interferon and ribavirin. An EASL research abstract released Monday reported treatment with Vertex's "quad" therapy resulted in 38-57% of patients with undetectable virus after two weeks and 86-87% undetectable after four weeks.
One potential competitive disadvantage to the Vertex quad is that patients still need to be treated with long-acting interferon, which requires weekly injections. Vertex previously reported disappointing results from an all-oral Hep C drug regimen that eliminated interferon.
Telaprevir is currently under review by regulators in the U.S. and Europe. The U.S. Food and Drug Administration is expected to make an approval decision on or before May 23.
Gilead Sciences(GILD) and Bristol-Myers Squibb(BMY) will also be presenting new data from Hep C combination drug studies at the EASL meeting later this month.
--Written by Adam Feuerstein in Boston.
Thursday, March 3, 2011
Pharmacokinetic Interactions Between Antiretroviral Agents and the Investigational HCV Protease Inhibitor Telaprevir in Healthy Volunteers
Jules Levin reports on the DDIs between Telaprevir (TVR) and some of the current drugs to treat HIV. As you have probably read, the RVR rates for Telaprevir in co-infected patients ranged from 70 to 75% in a sample size of 60 randomized to patients not on treatment as well as patients currently on Viread or an Atazanavir regimen. No info was available on whether patients HIV was controlled during that four week period. Based on the data on DDIs between Telaprevir and ARTs presented by R van Heeswijk,et al, Telaprevir is both an inducer and inhibitor of CYP3A, which means it is likely to interact with most ARTs on the market. Indeed, they did see reduced exposure to Telaprevir and variable effects on HIV protease inhibitors and tenofovir.
Telaprevir AUC using the 750mg Q8h dose with Lopinavir, Durnavir, Atazanavir (ATV) and Fosamprenavir saw 54%, 20%, 35% and 32% reductions respectively. Looking at the HIV PI concentrations, Ritonavir boosted Lopinavir, Durnavir, Atazanavir and Fosamprenavir saw no change, 40% less, 17% increase and 47% decrease with Telaprevir 750mg q8h respectively.
These interactions prompted Vertex to choose regimens with the least effect on exposure for their co-infected trial. ATV/r 300/100mg qd + TVR 750mg q8h/P+r and Efavirenz 600mg qd + TVR 1125 q8h/P+r.
Despite the author conclusions below, there is cause for concern in regards to DDIs with common ARVs and TVR. The PK concentrations of drugs are highly variable in individuals due to a variety of reasons. Add DDIs to the mix and even the slightest change in drug concentrations can case a Cmin to dip below the IC50 of the virus, with potential to cause either HIV and/or HCVresistance. Because of this, we might see resurgence of Therapeutic Drug Monitoring (TDM)in an effort to prevent resistance - Chris
AUTHOR CONCLUSIONS
RTV-boosted HIV PIs + TVR 750 mg q8h
–(Mutual) drug interactions were observed
•Reduced exposure to TVR, variable effects on HIV PIs
–Protein displacement may play a role in reduction of total concentrations (in-vitro evaluation ongoing)
–Appropriate doses have not been established
–
EFV and Tenofovir + TVR 1125 mg q8h
–Small changes in TVR, EFV and tenofovir exposure
–Higher TVR dose (1125 mg q8h) partly offset interaction with EFV
–
Based on these results, a pilot study of TVR in HIV/HCV co-infection was initiated with ATV/r 300/100 mg qd + TVR 750 mg q8h or EFV 600 mg qd + TVR 1125 mg q8h (plus Peg-IFN and ribavirin)
Telaprevir AUC using the 750mg Q8h dose with Lopinavir, Durnavir, Atazanavir (ATV) and Fosamprenavir saw 54%, 20%, 35% and 32% reductions respectively. Looking at the HIV PI concentrations, Ritonavir boosted Lopinavir, Durnavir, Atazanavir and Fosamprenavir saw no change, 40% less, 17% increase and 47% decrease with Telaprevir 750mg q8h respectively.
These interactions prompted Vertex to choose regimens with the least effect on exposure for their co-infected trial. ATV/r 300/100mg qd + TVR 750mg q8h/P+r and Efavirenz 600mg qd + TVR 1125 q8h/P+r.
Despite the author conclusions below, there is cause for concern in regards to DDIs with common ARVs and TVR. The PK concentrations of drugs are highly variable in individuals due to a variety of reasons. Add DDIs to the mix and even the slightest change in drug concentrations can case a Cmin to dip below the IC50 of the virus, with potential to cause either HIV and/or HCVresistance. Because of this, we might see resurgence of Therapeutic Drug Monitoring (TDM)in an effort to prevent resistance - Chris
AUTHOR CONCLUSIONS
RTV-boosted HIV PIs + TVR 750 mg q8h
–(Mutual) drug interactions were observed
•Reduced exposure to TVR, variable effects on HIV PIs
–Protein displacement may play a role in reduction of total concentrations (in-vitro evaluation ongoing)
–Appropriate doses have not been established
–
EFV and Tenofovir + TVR 1125 mg q8h
–Small changes in TVR, EFV and tenofovir exposure
–Higher TVR dose (1125 mg q8h) partly offset interaction with EFV
–
Based on these results, a pilot study of TVR in HIV/HCV co-infection was initiated with ATV/r 300/100 mg qd + TVR 750 mg q8h or EFV 600 mg qd + TVR 1125 mg q8h (plus Peg-IFN and ribavirin)
Wednesday, March 2, 2011
Vertex shows Telaprevir RVR data in HIV/HCV co-infected subjects...
Press release from Vertex regarding RVR rate in treatment naive co-infected subjects. Good RVR rates in subjects on both Atripla and boosted Atazanavir (and ? backbone. 'N' is small and of course you'd never treat HCV in someone that wasn't already stable on HIV therapy, but looks promising in those that haven't any resistance to Atripla components and Atazanavir plus whatever backbone regimen was used.
UPDATE 1-Vertex drug promising in hep C patients with HIV
1:06pm EST
* RVR rate 70 pct with telaprevir combination therapy
* RVR rate 5 pct on standard hepatitis C drugs alone
* Vertex expects final cure rate data in 2012
By Bill Berkrot
NEW YORK, March 2 (Reuters) - Vertex Pharmaceuticals Inc's (VRTX.O: Quote, Profile, Research, Stock Buzz) hepatitis C drug telaprevir helped eliminate the virus in 70 percent of patients who were also infected with HIV, according to interim analysis from a small midstage clinical trial, the company said.
Telaprevir is awaiting a U.S. approval decision after demonstrating an ability to greatly improve hepatitis cure rates when combined with current standard of care medicines compared with those drugs alone.
Patients in the co-infection study, which was presented at a medical meeting on Wednesday, had not yet received other treatment for hepatitis. Telaprevir was tested in one group of patients who were not receiving antiretroviral therapy for HIV and another group who were.
The interim analysis looked for a rapid viral response (RVR), meaning the hepatitis C virus was undetectable in the blood after four weeks of treatment.
At four weeks, 70 percent of those in the 60-patient study who received combination therapy with telaprevir had achieved RVR compared with 5 percent who received only the standard drugs of pegylated interferon and ribavirin, according to data presented at the Conference on Retroviruses and Opportunistic Infections in Boston.
Undetectable virus must be maintained for a far longer period of time in order to achieve sustained viral response (SVR), which is tantamount to a cure. But RVR can be an early indicator of eventual success rates.
SVR rates from the study are expected to be available next year, Vertex said.
In patients who were not also receiving HIV antiretroviral therapy, 71 percent of those treated with telaprevir achieved RVR compared with none on the standard drugs.
For co-infected patients taking Gilead Sciences Inc's Atripla for HIV, 75 percent on telaprevir combination therapy hit RVR versus one patient, or 13 percent, in the control arm.
For HIV patients being treated by Bristol-Myers Squibb's Reyataz, 64 percent on telaprevir hit RVR versus no one in the eight-patient control arm.
Vertex shares were up $1.12, or 2.4 percent, at $47.17 in afternoon trade on Nasdaq. (Reporting by Bill Berkrot, editing by Dave Zimmerman)
UPDATE 1-Vertex drug promising in hep C patients with HIV
1:06pm EST
* RVR rate 70 pct with telaprevir combination therapy
* RVR rate 5 pct on standard hepatitis C drugs alone
* Vertex expects final cure rate data in 2012
By Bill Berkrot
NEW YORK, March 2 (Reuters) - Vertex Pharmaceuticals Inc's (VRTX.O: Quote, Profile, Research, Stock Buzz) hepatitis C drug telaprevir helped eliminate the virus in 70 percent of patients who were also infected with HIV, according to interim analysis from a small midstage clinical trial, the company said.
Telaprevir is awaiting a U.S. approval decision after demonstrating an ability to greatly improve hepatitis cure rates when combined with current standard of care medicines compared with those drugs alone.
Patients in the co-infection study, which was presented at a medical meeting on Wednesday, had not yet received other treatment for hepatitis. Telaprevir was tested in one group of patients who were not receiving antiretroviral therapy for HIV and another group who were.
The interim analysis looked for a rapid viral response (RVR), meaning the hepatitis C virus was undetectable in the blood after four weeks of treatment.
At four weeks, 70 percent of those in the 60-patient study who received combination therapy with telaprevir had achieved RVR compared with 5 percent who received only the standard drugs of pegylated interferon and ribavirin, according to data presented at the Conference on Retroviruses and Opportunistic Infections in Boston.
Undetectable virus must be maintained for a far longer period of time in order to achieve sustained viral response (SVR), which is tantamount to a cure. But RVR can be an early indicator of eventual success rates.
SVR rates from the study are expected to be available next year, Vertex said.
In patients who were not also receiving HIV antiretroviral therapy, 71 percent of those treated with telaprevir achieved RVR compared with none on the standard drugs.
For co-infected patients taking Gilead Sciences Inc's Atripla for HIV, 75 percent on telaprevir combination therapy hit RVR versus one patient, or 13 percent, in the control arm.
For HIV patients being treated by Bristol-Myers Squibb's Reyataz, 64 percent on telaprevir hit RVR versus no one in the eight-patient control arm.
Vertex shares were up $1.12, or 2.4 percent, at $47.17 in afternoon trade on Nasdaq. (Reporting by Bill Berkrot, editing by Dave Zimmerman)
Tuesday, March 1, 2011
From CROI: Clinical Pharmacology of Boceprevir: Metabolism, Excretion, and Drug-Drug Interactions
(Jules Levin of NATAP.org reports on a session at CROI looking at Boceprevir drug interactions. Fortunately, with the notable exception of Efavirenz, it looks like BOC is a pretty clean drug in terms of DDI's)
Clinical Pharmacology of Boceprevir: Metabolism, Excretion, and Drug-Drug Interactions - see attached full slide report
Reported by Jules Levin
CROI – March 1, 2011
Boston, MA
C Kasserra, E Hughes, M Treitel,
S Gupta, and E O'Mara
AUTHOR CONCLUSIONS
•Radiolabeled data support a primarily hepatic-mediated clearance of BOC
•CYP3A4 probes
–Marked ↑ in midazolam exposure in the presence of BOC indicates that BOC is a strong, reversible inhibitor of CYP3A4
–↑ exposure to BOC with ketoconazole suggests involvement of another non–CYP3A4-mediated pathway
•Metabolic inhibitors (even in combination) did not alter BOC PK profile substantially to change BOC’s dose or schedule
–Diflunisal (AKR inhibitor) did not alter BOC exposure
–Ritonavir (CYP 3A4 inhibitor) did not substantively affect exposure to BOC
–Clarithromycin (CYP3A4, P-gp inhibitor) did not affect exposure to BOC
•No dosage adjustment is needed for the coadministration of BOC with tenofovir or peginterferon
•Clinical implications of a ↓ mean BOC trough concentration when coadministered with efavirenz will be clearer as data from coinfected populations are obtained
•Boceprevir did not affect the exposure to drospirenone/ ethinylestradiol in a manner that would be anticipated to reduce contraceptive efficacy
Clinical Pharmacology of Boceprevir: Metabolism, Excretion, and Drug-Drug Interactions - see attached full slide report
Reported by Jules Levin
CROI – March 1, 2011
Boston, MA
C Kasserra, E Hughes, M Treitel,
S Gupta, and E O'Mara
AUTHOR CONCLUSIONS
•Radiolabeled data support a primarily hepatic-mediated clearance of BOC
•CYP3A4 probes
–Marked ↑ in midazolam exposure in the presence of BOC indicates that BOC is a strong, reversible inhibitor of CYP3A4
–↑ exposure to BOC with ketoconazole suggests involvement of another non–CYP3A4-mediated pathway
•Metabolic inhibitors (even in combination) did not alter BOC PK profile substantially to change BOC’s dose or schedule
–Diflunisal (AKR inhibitor) did not alter BOC exposure
–Ritonavir (CYP 3A4 inhibitor) did not substantively affect exposure to BOC
–Clarithromycin (CYP3A4, P-gp inhibitor) did not affect exposure to BOC
•No dosage adjustment is needed for the coadministration of BOC with tenofovir or peginterferon
•Clinical implications of a ↓ mean BOC trough concentration when coadministered with efavirenz will be clearer as data from coinfected populations are obtained
•Boceprevir did not affect the exposure to drospirenone/ ethinylestradiol in a manner that would be anticipated to reduce contraceptive efficacy
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