DRUG REPORT : telaprevirSUMMARYDrug Name telaprevirCompany Vertex Pharmaceuticals IncLaunchedHighest DevStatusTherapy Areas Hepatitis C virus infectionActions Hepatitis C virus NS3 protease inhibitor; Hepatitis C virus replication inhibitorTechnologies Oral formulation; Tablet formulation; Peptidomimetic; Film coating; Small moleculetherapeuticTarget Hepatitis C virus NS3 proteaseUpdate date21-JUN-2011Reason forSales and Market share UpdatedupdateOVERVIEWVertex Pharmaceuticals and licensees Mitsubishi Tanabe Pharma (formerly Mitsubishi Pharma) and Tibotec Pharmaceuticals, on behalf of Janssen (a subsidiary of Johnson & Johnson), have developed and launched telaprevir (MP-424; VX-950; Incivek), a small-molecule inhibitor of the hepatitis C virus (HCV) NS3/4A protease. The drug is indicated in the US in combination with peginterferon alfa and ribavirin for the oral treatment of genotype 1 chronic HCV infection in adult patients with compensated liver disease, including cirrhosis, whoare treatment-naive or who have been previously treated with interferon-based treatment [250154], [676554], [836299], [1194098].In May 2011, telaprevir was launched in the US for HCV infection in combination with peginterferon alfa and ribavirin [1196977]. In December 2010, a filing was submitted in the EU and was accepted for accelerated approval [1156869], [1162422]. In January 2011, Mitsubishi Tanabe filed for approval in Japan [1164273], [1165340].In January 2011, an sNDA for a twice-daily dosing regimen of telaprevir was planned for 4Q12 [1159870].In October 2009, a phase II study began in HCV patients co-infected with HCV and HIV [1089319]; thiswas ongoing in March 2011 [1172705]. At that time, the company was also planning to evaluate shorter duration telaprevir-based treatment regimens for specific patient populations, as well as planning a phase II trial in patients with recurrent HCV infection who have received a liver transplant and are receiving chronic immunosuppressive treatment [1172705].By March 2011, Vertex was also examining the combination of telaprevir and VX-222 [1172705], [1193121].PATENT INFORMATIONThe US patent covering the composition-of-matter for telaprevir was granted in 2010 with a term that expiresin 2025. In the EU, Vertex expected to obtain extensions to the term of the patent covering the composition-of-matter of telaprevir, thus extending expiry from 2021 to 2026; the company is required to apply separately for the extensions in the EU on a country-by-country basis [1172705].REGULATORY INFORMATIONThe USIn December 2005, the FDA granted telaprevir Fast Track status for HCV treatment [639367].By July 2010, a rolling NDA submission had been initiated; at that time, the CMC section of the NDA had been filed [1119626]. In November 2010, the filing was completed, which included data from both treatment-naive and -experienced HCV patients. The company also requested priority review [1149931], [1159870]. In January 2011, the NDA was accepted for priority review by the FDA, with a PDUFA date of May 23, 2011 [1162422].In April 2011, the FDA's Antiviral Drugs Advisory Committee recommended approval for genotype 1 chronic HCV infection [1187825]. In May 2011, telaprevir was approved for the treatment of chronic HCV infection in combination with peginterferon alfa and ribavirin in adult patients who had either not received interferon-based treatment or who had not responded adequately to prior therapy [1193767]. The drug was launched in the US later that month [1196977].In January 2011, an sNDA for a twice-daily dosing regimen of telaprevir was planned for 4Q12 [1159870]. EuropeIn December 2010, a filing was submitted in the EU for chronic HCV infection, which was accepted by the EMA for accelerated approval [1156869], [1162422]. In May 2011, a decision was anticipated in the second half of 2011 [1188291].JapanIn July 2010, filing was slated for early 2011 [1121439]. In January 2011, Mitsubishi Tanabe filed for approval in Japan [1164273].Rest of the worldIn January 2011, Vertex completed submission of its NDS for telaprevir in Canada; the drug was granted priority review in Canada [1162422].PREMARKETING STUDIESTreatment-naivePhase IIIIn March 2011, Vertex was planning a study to evaluate a short-duration, 12-week telaprevir-based regimen in treatment-naive patients with HCV with the CC IL28B genotype [1180816].In March 2011, a phase III HCV and HIV co-infection study of telaprevir was planned for the end of that year [1172677].In October 2010, the phase IIIb trial (OPTIMIZE) to compare twice-daily telaprevir (1125 mg) with three times-daily telaprevir (750 mg) was initiated in 700 treatment-naive patients with genotype-1 HCV in the US and the EU [1141995]. The randomized, open-label, study would have a primary endpoint of sustained viral response (SVR) 24 weeks after the end of all treatment. The primary objective would be to demonstrate non-inferiorityof twice-daily telaprevir versus telaprevir dosed every 8 h as measured by SVR. SVR data were expected in 2012. Patient screening for enrollment was expected to begin in November 2010 [1141996]. In January 2011, enrollment was ongoing [1159870].In October 2008, a randomized, open-label, active-control, parallel-group, safety and efficacy phase III trial (NCT00780416; G060-A6) was initiated in treatment-naive patients (expected n = 165) with genotype-1 HCV infection in Japan. Patients were to receive telaprevir in combination with peginterferon-alfa-2b (PEG-IFN-a-2b) plus ribavirin, or PEG-IFN-a-2b plus ribavirin alone. The primary endpoint was a sustained viral response(SVR) , defined as an undetectable HCV RNA level 24 weeks after treatment. The trial was expected to be completed in July 2011 [956738]. Development was ongoing in July 2009 [1047222].In September 2008, a randomized, open-label, active control, parallel group supplemental phase III trial(NCT00758043; VX08-950-111; ILLUMINATE) was initiated in treatment-naive patients (expected n = 500) with HCV at sites in the EU and US. Patients who achieved a rapid viral response to a telaprevir-based regimen were to be evaluated after extending total treatment duration from 24 to 48 weeks. The primary endpoint was SVR rate [956721], [1172705]. By January 2009, enrollment was complete [975836]. By August 2009, the telaprevir dosing section of the study had been completed and all patients were beyond week 24 [1031951]. In August 2010, data were reported, which demonstrated that there was no benefit from extending the telaprevir-based treatment to 48 weeks. The SVR rates were 92% (n = 149/162) and 88% (n = 140/160) for the 24 and 48-week treatment groups respectively. Overall, in the intent-to-treat (ITT) analysis, 72% of patients (n = 388/540) in the trial achieved a viral cure, and the safety profile was similar to the phase III ADVANCE study. The most common adverse events reported included fatigue, pruritus, nausea, anemia, rash and headache, and majority were considered mild or moderate [1123095]. In October 2010, data from the trial were presented at the 61st AASLD meeting in Boston, MA. It was demonstrated that 60% of African-Americans and 63% of all patientswith advanced liver fibrosis or cirrhosis achieved SVR with telaprevir-based therapy. Of African-Americans whose virus was undetectable at weeks 4 and 12, 88% achieved SVR in the 24- and 48-week randomized treatment arms. There was no control arm of PEG-IFN and ribavirin alone in the study. A total of 65% of people met the criteria for 24-week total treatment; there was no benefit in extending therapy to 48 weeks. Adverse events resulted in 17% of patients discontinuing the study, mainly due to a severe rash or anemia [1143419], [1146345].In March 2008, patient screening began in a randomized, double-blind, placebo-controlled, parallel-group, three-arm safety and efficacy phase III trial (NCT00627926; ADVANCE; VX07-950-108), which was expected to enroll 1050 treatment-naive patients with genotype-1 chronic HCV. The trial was to be conducted at 114 sites worldwide, including sites in the EU and US. The patients were to receive one of two regimens of telaprevir(8 weeks or 12 weeks) administered in combination with PEG-IFN-a-2a and ribavirin, or placebo. The primary endpoint was an SVR, defined as undetectable HCV RNA, 24 weeks after treatment completion [885649], [885933]. By October 2008, enrollment was completed [956858]. In February 2009, dosing of telaprevir or placebo, 8 or 12 weeks, had been completed [996403]. Data were reported in May 2010, showing that telaprevir was superior to control; SVR was achieved in 69 and 75% of telaprevir-treated patients after 8 and 12 weeks, respectively. After 48 weeks, 44% of patients in the control arm achieved SVR. Rapid viral responses were achieved by 68, 66 and 9% of patients in the 12-week telaprevir arm, the 8-week telaprevir arm and the control arm, respectively. Viral relapse was observed in 9, 10 and 28% of patients in the 12-week telaprevir arm, the8-week telaprevir arm and the control arm, respectively [1103157]. In October 2010, further data from the trial were presented at the 61st AASLD meeting in Boston, MA. It was demonstrated that 62% of African-Americans achieved SVR with telaprevir, compared to 25% of African-Americans treated with PEG-IFN and ribavirin alone.A total of 62% of people with advanced liver fibrosis or cirrhosis achieved SVR with telaprevir, compared to 33% treated with PEG-IFN and ribavirin alone. In the study, 58% of patients met the criteria for 24-week total treatment [1143419]. Further data presented at the meeting concluded that the 12-week regimen of teleprevir (150 mg/8 h) plus PEG-IFN (18 microg/week) and ribavirin (1000 to 1200 mg/day) provided the best benefitto risk profile. The most frequently observed adverse events were nausea, anemia, diarrhea, fatigue and rash [1148314].Phase IIIn May 2011, a US phase II trial to assess the efficacy of telaprevir in combination with PEG-IFN and ribavirin in patients with recurrent HCV following a liver transplant was planned for the fourth quarter of 2011 [1188291].In October 2009, a phase II multicenter, randomized, double-blind, placebo-controlled, two part (part A andpart B) parallel-group, safety and efficacy study (NCT00983853; VX08-950-110) began in the US in patients(n = 68) co-infected with HCV and HIV, who were treatment-naive for HCV. The study was to determine the efficacy of treatment with telaprevir plus peginterferon alfa-2a and ribavirin, with primary endpoints of safety and plasma HCV RNA level. The study was due to complete in June 2012 [1089319]. By October 2010, enrollment of 60 patients had been completed [1141995]. Patients in Part A and Part B of the study were randomized to receive either 12 weeks of telaprevir or placebo in combination with peginterferon alfa-2a and ribavirin followedby 36 weeks of peginterferon alfa-2a and ribavirin alone. Part A (n = 13) of the study enrolled patients who were not receiving antiretroviral therapy for HIV. Part B (n = 47) enrolled patients who were being treated for HIVwith either Atripla (n = 24) or a Reyataz-based regimen (n = 23). In March 2011, interim data (from 4 weeksof treatment) were presented at the 18th Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, MA. The results demonstrated that 70% of patients in the study (Parts A and B) had undetectable HCV after treatment with telaprevir-based combination therapy compared to 5% in those on pegylated-interferonand ribavirin alone at week 4. In addition, HIV viral load and CD4 counts were stable in patients on a telaprevir-based regimen. Final data for sustained viral response (SVR) were expected in 2012 [1172677].In August 2009, a combination study of telaprevir and VX-222 was planned [1031951]. In October 2009, the trial was still expected to start that year, and data were expected by mid-2010 [1052205]. In January 2010, the trial was to begin pending completion of discussions with regulatory authorities [1067607]. In February 2010, the trial was planned to start in the first quarter of 2010 and interim data were expected in the third quarter of 2010. The trial would evaluate the rate of undetectable HCV RNA 24 weeks after the end of treatment with multiple VX-222 and telaprevir dosing regimens [1073316]. In March 2010, the phase II multicenter, randomized, parallel-group, dose-ranging trial (; VX09-222-103) began. The trial was designed to evaluate the safety and efficacy of telaprevir plus VX-222 in treatment-naive patients with genotype I HCV infection (expected n = 150), using a response-guided trial design. The primary endpoint of the trial was safety and tolerability, with a secondary endpoint of proportion of patients achieving SVR; the company stated that it may elect to enroll upto two additional treatment arms. At that time, initial data were expected in 2H10 [1078227], [1089256]. In April 2010, enrollment in the study was expected to be completed in the second quarter of 2010 and interim data were expected in the second half of 2010 [1091125]. In October 2010, Vertex discontinued arm A of the trial due to patients meeting a pre-defined stopping rule related to viral breakthrough in the first 4 weeks of dosing. At that time, an additional three cohorts were continuing and no viral breakthrough had been observed. Data were expected in the first half of 2011 with SVR data in the second half of 2011 [1141995]. In November 2010, the company planned to begin an additional treatment arm evaluating the triple combination regimen of telaprevir, VX-222 and ribavirin (po, bid) for 12-week using a response-guided regimen. Enrollment was expected to begin in the first quarter of 2011. The phase II study also included treatment arms evaluating 12-week, response-guided regimens of four-drug (telaprevir/VX-222 with or without Pegasys and ribavirin) combination therapy. Enrollment in the four drug treatment arm was completed in October 2010. Vertex may add an additional arm based on further results from the ongoing treatment arms [1146979]. In December 2010, the second two-drug treatment arm of telaprevir plus VX-222 (1125mg/400mg) alone was discontinued as a result of a pre-defined stopping rule related to viral breakthrough. The study would continue as planned with three treatment arms of the four-drug combinations, two of which were fully enrolled. At that time, enrollment in the three-drug treatment arm and data from the four-drug treatment arms were expected in the first quarter of 2011 [1157421]. In March 2011, interim data from the 106-patient ZENITH study were presented at the 46th annual meeting of the European Association for the Study of the Liver in Berlin, Germany. At week 12, 90 and 83% of patients treated with 400 and 100 mg VX-222, respectively, in combination with telaprevir, pegylated-interferon and ribavirin, showed undetectable hepatitis C virus. At that time, 50 and 38% of patients in the two groups, respectively, were able to stop all treatment. The remaining patients received a further 12 weeks of pegylated-interferon and ribavirin. At that time, enrollment was underway in an additional arm assessing VX-222, telaprevir and ribavirin [1180638].By February 2008, a phase II viral kinetics trial for HCV genotype-4 had begun [875818]. By July 2008, enrollment was complete [930471].In January 2008, an open-label, single-group, safety and efficacy phase II trial (NCT00621296) was initiatedin subjects (expected n = 16) with chronic HCV in Japan. The subjects were to receive telaprevir 750 mgthree times daily, for 24 weeks. The primary endpoint was to establish HCV RNA kinetics and other viral characteristics. The study was expected to be completed in September 2009 [907396], [904699]. Patient recruitment was ongoing in August 2008 [907396].In October 2007, a randomized, open-label, parallel-group, safety and efficacy phase II trial (NCT00528528;VX-950-TiDP24-C208; CR013516) was initiated in treatment-naive patients (expected n = 160) with genotype-1 chronic HCV in Europe. The patients were randomized to 1 of 4 treatment groups and received telaprevir (750 mg tid or 1125 mg bid) for 12 weeks in combination with PEG-IFN-a-2a plus ribavirin or PEG-IFN-a-2b plusribavirin for 24 weeks [956710]. In July 2008, data were released from the study. No substantial differences were seen in the safety profiles of the twice- and three-times-daily regimens, and both resulted in > 80% of patients with undetectable HCV RNA at weeks 4 and 12. A complete analysis was to be carried out when the study finished in 2009 [930471]. In October 2008, similar data were presented at the 59th Annual Meeting of the American Association for the Study of Liver Diseases in San Francisco, CA [958470]. In April 2009, all dosingin the study had been completed and in August 2009, patients were in the follow-up period. The number of patients with an SVR24 in the bid and tid dose groups would be compared [1031951]. In October 2009, further data were presented . An intent-to-treat analysis of 161 patients showed that SVR rates were 82 and 83% for patients receiving peg-IFN-alfa-2b bid and peg-IFN-alfa-2a bid, respectively, and 81 and 85% for those on peg-IFN-alfa-2b tid and peg-IFN-alfa-2a tid, respectively. RVR rates for the four groups were 67, 83, 69 and 80%, respectively. The most common adverse events were pruritis, rash, nausea, flu-like illness, anemia, headache and fatigue. These were similar in the bid and tid regimens. Of 161 patients, 5% discontinued treatment because of serious adverse events, namely rash and anemia. The data were to be presented at the 60th Annual Meeting of the American Association for the Study of Liver Diseases in Boston, MA [1053696], [1056258]. By January 2010, data from the trial had been submitted to the FDA and discussions were underway with bothUS and EU regulatory authorities regarding development of the drug as part of an every 12 h dosing regimen [1067607].In May 2006, Vertex was planning the phase II study PROVE 2 study in Europe. This would incorporate four,80-patient treatment arms: subjects were to receive telaprevir plus PEG-IFN for 12 weeks; telaprevir with PEG-IFN and ribavirin for 12 weeks; 12 weeks treatment with the triple combination followed by 12 weeks withPEG-IFN and ribavirin alone; or PEG-IFN and ribavirin for 48 weeks. The primary objectives were the sameas for PROVE 1 [668896]. By July 2006, PROVE 2 had started and by January 2007, recruitment had been completed [680324], [755789]. At that time, the company expected to expand clinical development of telaprevir into important HCV sub-populations in 2007, including patients with genotype-2 and genotype-3 HCV infection. The company also anticipated initiating clinical trials exploring twice-daily dosing of telaprevir some time in 2007 [755789]. In June 2007, preliminary data from the PROVE 2 study were reported to be consistent with PROVE 1 study results. Patients treated with telaprevir, PEG-IFN and ribavirin had undetectable HCV RNA levels at 4 and 12 weeks. At 12 weeks, treatment with telaprevir only was associated with antiviral activity that was lower than that in patients that received telaprevir with ribavirin and PEG-IFN, but was higher than that observed in the control arm. Rash, gastrointestinal events and anemia were the most common adverse events that led to discontinuation in the telaprevir arms. Fewer discontinuations were observed in patients that received telaprevir and PEG-IFN [803933]. In November 2007, similar data were presented at the 58th Annual Meeting of the American Association of the Study of Liver Diseases in Boston, MA. The SVR rates were 29, 59 and 65% in the 12-week (without ribavirin), 12-week (plus ribavirin) and 24-week treatment arms, respectively [847055]. In April 2008, similar data from the trial were presented at the 43rd Annual Meeting of the European Association for the Study of the Liver in Milan, Italy [899125]. Similar data were also reported in May 2008 at the DDW meetingin San Diego, CA [906212]. In October 2008, similar data were presented at the 59th Annual Meeting of the American Association for the Study of Liver Diseases in San Francisco, CA. The SVR rates were 30, 60 and69 and 46% in the 12-week (without ribavirin), 12-week (plus ribavirin), 24-week, and 48-week treatment arms, respectively [958470]. In April 2009, similar data were published [1004842], [1004581].In October 2005, Vertex was planning one- and three-month phase II studies of telaprevir in combination with PEG-IFN [626769]. By November 2005, Vertex had submitted an IND to the FDA [634055]. In December 2005, Vertex began a 28-day, US phase II study to evaluate the safety, tolerability and pharmacodynamics of 750 mg of telaprevir given every 8 h in combination with PEG-IFN and ribavirin in 12 treatment-naive subjects [638638]. In January 2006, enrollment was complete [644067]. In February 2006, Vertex reported preliminary results showing that at the end of week 1, plasma HCV RNA was below the limit of quantitation in half of the subjects and undetectable in 2 of the patients. After 4 weeks of dosing, HCV RNA was undetectable in plasma from all 12 patients. There were no treatment discontinuations and no serious adverse events reported [648823]. In May 2006, similar data were presented at the Discovery & Selection of Successful Drug Candidates meeting in Cambridge, MA [667947]. Also in May 2006, similar data were presented at the DDW meeting in Los Angeles, CA. All patients reached undetectable plasma HCV RNA levels within 28 days of dosing and levels remained undetectable after 12 weeks follow-up [667643], [668532].Treatment-experiencedPhase IIIIn October 2008, an open-label, uncontrolled, single-group, safety and efficacy phase III trial (NCT00781274;G060-A9) was initiated in patients (expected n = 30) with genotype-1 HCV who did not respond to previous therapy in Japan. Patients were to receive telaprevir for 12 weeks and peginterferon alfa-2b (PEG-IFN-a-2b) plus ribavirin for 24 weeks. The primary endpoint was an SVR, defined as an undetectable HCV RNA level 24 weeks after treatment. The trial was expected to be completed in January 2011 [956789].In October 2008, an open-label, uncontrolled, single-group, safety and efficacy phase III trial (NCT00780910;G060-A8) was initiated in patients (expected n = 100) with genotype-1 HCV who relapsed following previous therapy in Japan. Patients were to receive telaprevir for 12 weeks and PEG-IFN-a-2b plus ribavirin for 24 weeks. The primary endpoint was a SVR, defined as an undetectable HCV RNA level 24 weeks after treatment. The trial was expected to be completed in January 2011 [956781].In August 2008, Vertex reached agreement with US and EU regulatory authorities to proceed with its planned REALIZE trial (NCT00703118; CR014842) [936309], [956718]. In the 48-week, 650-patient, three-armed multicenter study patients with genotype-1 HCV who had failed to achieve a SVR with prior therapy of PEG-IFN plus ribavirin, would receive 750 mg of telaprevir q8 h plus PEG-IFN-a-2a and ribavirin for 12 weeks, followed by 36 weeks of PEG-IFN-a-2a plus ribavirin alone. Patients in the control arm would receive PEG-IFN-a-2a plus ribavirin alone for 48 weeks. The primary endpoint was undetectable HCV RNA levels 24 weeks after the endof treatment [936309]. By October 2008, patient dosing had begun; the trial was to include null responders, partial responders and relapsers to prior therapy [952629], [956585], and in November 2008, enrollment in Europe began [965253]. In February 2009, enrollment in REALIZE was complete [982641]. By August 2009,the telaprevir dosing section of the study had been completed and all patients were beyond week 24 [1031951]. In September 2010, top-line data were reported, which demonstrated that 65% of HCV patients (total n = 622) treated with telaprevir achieved a SVR compared to 17% in the control group at 24 weeks. In a subgroup analysis, data showed that 86% of relapsed patients treated with telaprevir achieved a SVR compared to 24% for the control. In addition, the SVR rates were 57% and 31% for partial and null responders, respectively, compared to 15% and 5% for the corresponding control arms [1143647]. In March 2011, further data were presented at the International Liver Congress 2011/46th annual meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. No significant improvement in SVR rates and no significant reduction in virologic failure and relapse rates were observed in patients treated with a 4-week lead-in of PEG-IFN-a-2a and ribavirin alone compared with a simultaneous start of telaprevir, PEG-IFN-a-2a and ribavirin [1180788], [1184383].In February 2007, phase III trials were planned, and development of the drug was to be expanded to include HCV genotype-2 and -3 and twice-daily dosing schedules [762718], [762718]. In April 2007, Vertex and Tibotec planned to meet with regulatory authorities to discuss the design of phase III trials [784124], and by October 2007, Vertex and Tibotec were in discussions with the US and EU regulatory authorities to review clinical data and to ascertain how best to evaluate the drug in future trials [845344]. By January 2008, Vertex had submitted a phase III protocol to the FDA. The design included a 48-week control arm and 8 and 12 weeks of telaprevir treatment as part of 24-week combination treatment regimens. Vertex planned to determine which patients should cease treatment at week 24 using rapid viral response (RVR). A meeting with the FDA was scheduled for January 2008 to discuss the protocol [865541].In May 2006, the company began PROVE 1, a randomized, US phase II study, which was expected to enroll 280 patients into 4 treatment arms: 20 patients would receive 750 mg of telaprevir three times a day with PEG-IFN and ribavirin for 12 weeks; two 80-patient groups would take the same combination for 12 weeks followed by 12 or 36 weeks of treatment with PEG-IFN and ribavirin alone; the fourth group of 80 patients would receive PEG-IFN and ribavirin alone for 48 weeks. The primary objective was to determine the number of patients who achieved SVR, defined as undetectable HCV RNA levels 24 weeks after completing treatment. Patients in the 12- and 24-week treatment arms who had undetectable viral levels by the end of week 4 and who maintained this until week 10 or 20, respectively, would stop treatment at 12 or 24 weeks, respectively. Patients who had detectable HCV RNA at the initial time point would continue on PEG-IFN and ribavirin for 48 weeks. Enrollment began in June 2006 [668896]; by September 2006, enrollment in the trial had been completed [735053]. In December 2006, Vertex reported interim data from the study. An independent board compared pooled data from the three telaprevir arms with the control arm. At 12 weeks, 88% telaprevir-treated patients had undetectable HCV RNA levels, compared with 52% patients in the control group. In the telaprevir arms, the discontinuationrate was 9%, compared with 3% in the control arm. Serious adverse events occurred in 3% of telaprevir-treated patients and 1% of patients in the control group [751574], [751209]. In April 2007, further data were presented at the 42nd annual meeting of the European Association for the Study of the Liver in Barcelona, Spain, showing 88 and 79% of patients that received telaprevir achieved plasma HCV RNA levels of < 30 IU/ml and < 10 IU/ ml, respectively, at 4 weeks. Furthermore, 6 of 9 patients in one treatment arm continued to have undetectable HCV RNA 20 weeks after stopping treatment [784124]. In September 2007, data were presented at the 47th ICAAC meeting in Chicago, IL. Interim, 24-week PROVE 1 data demonstrated that telaprevir patients (n = 175) achieved undetectable HCV RNA at weeks 4 (79%) and 12 (70%); in the control arm (n = 75) 11% achieved undetectable HCV RNA at weeks 4 and 39% at week 12. Discontinuations due to adverse events were more frequent in the telaprevir arm at 11%, versus 35% in the control arm [820890]. In November 2007, similar data were presented at the 58th Annual Meeting of the American Association of the Study of Liver Diseases in Boston, MA [847055]. In April 2008, final data from the trial were presented at the 43rd Annual Meeting of the European Association for the Study of the Liver in Milan, Italy. SVRs were seen in 61% of telaprevir recipients, compared with 41% of control patients [899125]. Similar data were reported in May 2008 at the DDW meeting in San Diego, CA [907429]. In April 2009, similar data were published [1004828], [1004581].Phase IIIn September 2007, a non-randomized, open label, uncontrolled, single-group, phase II study (NCT00535847; study 107; VX06-950-107) was initiated in the US, Canada, Germany, France, the Netherlands and Puerto Rico. In the trial, 170 patients with genotype-1 hepatitis C who did not achieve an SVR with previous interferon-based treatment in the control arms of the PROVE 1, PROVE 2 or PROVE 3 trials were to receive telaprevir plus PEG-IFN-a-2a plus ribavirin for 12 weeks, followed by the same regimen without telaprevir for 12 weeks. The trial was expected to be completed in May 2009 [898809], [898686]. Interim data were reported in April 2008 at the 43rd Annual Meeting of the European Association for the Study of the Liver in Milan, Italy. Of the 60 patients treated with the telaprevir combination, 49 achieved HCV RNA levels < 25 IU/ml. This response was maintained, and no viral breakthrough was observed in 36 and 16 patients who had completed 4 and 12 weeks of treatment, respectively. Two patients discontinued treatment due to adverse events, which were similar to those commonly observed with PEG-IFN-a-2a and ribavirin. They included fatigue, nausea, rash and headache [899404]. In October 2008, further data were presented at the 59th Annual Meeting of the American Association for the Study of Liver Diseases in San Francisco, CA. At 4, 12 and 24 weeks, 65.4, 65.6 and 56.9% patients had HCV RNA <10 IU/ml [958470]. In October 2009, further interim data from 94 patients were reported. An SVR was achieved after 24 or 48 weeks of telaprevir-based treatment, by 90% of prior treatment responders and 55% of prior treatment partial responders. After 48 weeks of telaprevir-based treatment, an SVR was achieved by 57% of prior treatment null responders. At that time, adverse events had caused 7% patientsto discontinue treatment [1052655]. In April 2010, data were presented at the 45th Annual Meeting of the European Association for the Study of the Liver in Vienna, Austria. An overall SVR rate of 59% and an overall relapse rate of 16% were observed. In addition, it was reported that 10 patients had discontinued all therapy due to adverse events, with rash being the most common adverse event [1091068]. Further data were presented in May 2010 at the DDW meeting in New Orleans, LA. The viral breakthrough and relapse rates were 25 and 23% in prior null responders, 10 and 22% in prior partial responders, 13 and 0% in prior viral breakthroughs, and 0 and 4% in prior relapsers, respectively [1091233].By January 2007, Tibotec had begun a European phase II viral kinetics trial. The study would evaluate telaprevir in patients with HCV genotypes 2 and 3. At that time, patients were undergoing screening [865541]. By July 2008, enrollment was complete [930471].By October 2006, Vertex was planning PROVE 3, a 400-patient trial in patients with genotype-1 HCV who had failed prior treatment [735053]. In February 2007, Vertex began the phase IIb PROVE 3 trial. The randomized, multicenter, 440-patient, North American and European study assessed 750 mg of telaprevir every 8 h in patients with interferon-refractory, genotype-1 HCV. Patients received one of four treatment regimes: 12 weeks of telaprevir, PEG-IFN alfa-2a and ribavirin, followed by 12 weeks of PEG-IFN-a-2a and ribavirin; 24 weeksof telaprevir and PEG-INF-a-2a; 24 weeks of telaprevir, PEG-IFN-a-2a and ribavirin, followed by 24 weeks of interferon PEG-IFN-a-2a and ribavirin; or 48 weeks of PEG-IFN-a-2a and ribavirin. Patients in the final arm had the option to receive telaprevir if they did not respond to PEG-IFN-a-2a plus ribavirin [762718]. Enrollment of 440 patients was completed in June 2007 [803933]. In January 2008, Vertex was planning to meet with the FDA to discuss the telaprevir development program, once interim results from PROVE 3 were available [865541]. In June 2008, interim data were reported. By that time, patient dosing had been completed. In the first treatment。
