The ASPIRE Trial: TMC435 in treatment-experienced patients...
1
Poster presented at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) 30 March – 3 April, 2011, Berlin, Germany The ASPIRE Trial: TMC435 in treatment-experienced patients with genotype 1 HCV infection who have failed previous PegIFN/RBV treatment: Week 24 interim analysis Stefan Zeuzem, 1 Graham R Foster, 2 Michael W Fried, 3 Christophe Hezode, 4 Gideon M Hirschfield, 5 Igor Nikitin, 6 Fred Poordad, 7 Oliver Lenz, 8 Monika Peeters, 8 Vanitha Sekar, 9 Goedele De Smedt 8 1 J.W. Goethe University Hospital, Frankfurt, Germany; 2 Queen Marys University of London, London, United Kingdom; 3 University of North Carolina at Chapel Hill, North Carolina, USA; 4 Hôpital Henri-Mondor, Université Paris-Est Créteil, France; 5 Toronto Western Hospital Liver Centre, Toronto, Canada; 6 Russian State Medical University, Moscow, Russia; 7 Cedars-Sinai Medical Center, Los Angeles, USA; 8 Tibotec BVBA, Mechelen, Belgium; 9 Tibotec Inc, Yardley, PA, USA INTRODUCTION • TMC435 is an investigational potent, once-daily oral NS3/4A protease inhibitor currently in Phase III clinical development for the treatment of hepatitis C virus (HCV) infection. • Phase I, IIa and IIb studies, in treatment-experienced and/or treatment-naïve patients infected with HCV, have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports a once-daily dosing regimen, and has potent antiviral activity in patients infected with genotypes 1, 2, 4, 5 and 6. 1-7 • Phase III clinical trials are now underway in treatment-naïve patients and in patients who relapsed after previous treatment. • ASPIRE (TMC435-C206; NCT00980330) is a Phase IIb, randomised, double- blind, placebo-controlled trial to investigate the efficacy, tolerability, safety and pharmacokinetics of TMC435 as part of a treatment regimen including pegylated interferon a-2a and ribavirin (PegIFN/RBV). • Patients enrolled in the ASPIRE trial were infected with HCV genotype 1, and had failed to respond or relapsed following at least one course of PegIFN/RBV therapy. METHODS Study Design • The study included seven treatment arms, with a total duration of 72 weeks (Figure 1). This interim analysis was performed when all patients had completed 24 weeks of the study. • Inclusion criteria included documented chronic infection with HCV genotype 1, HCV RNA .10,000 IU/mL at screening, and ≥1 prior documented course of PegIFN a-2a or a-2b/RBV for >12 consecutive weeks which had not been discontinued due to intolerability. • Exclusion criteria included decompensated liver disease and co-infection with HIV or HBV. • Patients were administered TMC435 (100 or 150 mg once daily [QD]) or placebo in combination with PegIFN/RBV. • The patient population was stratified by genotype (1a, 1b, and other), and by prior virologic response (relapsers, partial and null responders were included in a 2:2:1 ratio): – Relapse: HCV RNA undetectable end of treatment; detectable within 24 weeks post-treatment – Partial response: ≥2 log10 reduction HCV RNA at Week 12; detectable HCV RNA at end of treatment – Null response: <2 log10 reduction HCV RNA at Week 12 Virologic Stopping Rules • Patients should stop all medication following lack of on-treatment virologic response or viral breakthrough, defined as: – At Week 4: ,1 log 10 reduction in HCV RNA from baseline – At Week 12: ,2 log 10 reduction in HCV RNA from baseline – At Week 24: HCV RNA confirmed detectable – At Week 36: HCV RNA confirmed detectable – Between Day 1 and Week 48: Confirmed HCV RNA increase .1 log 10 compared to nadir; or confirmed HCV RNA .100 IU/mL if HCV RNA was previously <25IU/mL detectable or undetectable. Antiviral Efficacy • The primary objective of the trial is to evaluate the efficacy of six different regimens of TMC435 in combination with PegIFN/RBV compared with the placebo/PegIFN/RBV control group. • Primary endpoint: The proportion of subjects in TMC435 groups with undetectable HCV RNA (,25 IU/mL undetectable; Roche Taqman v2) 24 weeks after the planned end of treatment (SVR24) compared with the control group, who received PegIFN/RBV and TMC435-matched placebo. – The primary efficacy endpoint will be assessed at Week 72 and is not available for this Week 24 interim analysis. – Here we report the results of the pre-planned Week 24 interim analysis including the proportion of patients with a virologic response at Weeks 4, 12 and 24, HCV RNA change per IL28B genotype, and rates of viral breakthrough. Safety • Secondary objectives of the study include evaluation of the safety and tolerability of TMC435 plus PegIFN/RBV compared with placebo/PegIFN/RBV control group, over the trial period. Adverse events (AEs) were recorded, safety laboratory analyses performed, and vital signs measured. Statistical Analysis • Selected virologic response parameters were compared between TMC435 groups and placebo/PegIFN/RBV control group using a logistic regression model. The model included baseline HCV RNA as covariate and treatment and the stratification parameters, prior response and genotype 1 subtype, as factors. • 95% confidence intervals were constructed for the observed response rates, and for the difference between the TMC435 groups and the placebo/PegIFN/ RBV control group. RESULTS Patient Demographics • Baseline demographics and characteristics were well balanced between treatment groups (Table 1). Patient Disposition • In all subpopulations, more treatment discontinuations were noted in the placebo control group compared with the TMC435 groups. This was noted particularly in null responders, followed by partial responders. • The primary reason for discontinuation was reaching a virologic stopping rule, which was more commonly observed in placebo control patients during the first 12 weeks of therapy (Figure 2). Observed Virologic Response • At Weeks 4, 12, and 24, significantly higher virologic response rates were observed following treatment with TMC435 plus PegIFN/RBV, compared with placebo plus PegIFN/RBV (Figure 3a-c). • In null and partial responders, somewhat higher virologic response rates were observed in TMC435 150 mg dose groups, compared with 100 mg groups, at early timepoints while differences were less pronounced at Week 24 (Figure 3). Viral Breakthrough • Overall, 6% (12/214) of patients in the TMC435 arm and 49% (32/66) of patients in the control group met a virologic stopping rule (excluding viral breakthrough) at week 4, 12, or 24 due to lack of virologic response. • Overall, viral breakthrough was observed in 18.2% (39/214) of patients in the TMC435 arms and 1.5% (1/66) in the control group (Figure 4). • Highest rates of viral breakthrough and virologic failure were observed in null responders, followed by partial responders, with the lowest in relapsers. IL28B Genotype • In TMC435 treatment groups, no major differences in mean change in HCV RNA were observed between different IL28B genotypes (Figure 5). • In the placebo control group, HCV RNA change from baseline was greater for patients with IL28B CC genotype compared with patients with CT and TT genotypes (Figure 5) Adverse Events • Median treatment exposure was higher for TMC435 patients compared with placebo (30 weeks for TMC435 compared to 26 weeks in placebo control group; Table 2), due to higher attrition in the placebo control group which was mainly related to lack or loss of virologic response. This bias should be kept in mind when assessing safety comparisons. • Overall incidence of AEs was similar across treatment groups (Figure 2, Table 2), except for occurrence of influenza-like illness and pruritus, which were more commonly reported in TMC435 patients. • The majority of these AEs were grade 1 or 2 in severity. • Serious AEs were reported in 5.8% of patients treated with TMC435 and in 1.5% of subjects in the placebo control group. No differences were observed between the TMC435 dose groups. • AEs leading to discontinuation of TMC435/placebo were reported in 5.6% of the TMC435 treated patients and in 1.5% of the placebo control patients. • Decreases in hemoglobin, red blood cell, white blood cell, and platelet count were observed in all treatment groups, including control. Mild and reversible increases in bilirubin (total, direct and indirect) were observed in TMC435 dose groups with no major differences between 100 mg and 150 mg (data not shown). CONCLUSIONS • In this Week 24 interim analysis, treatment-experienced patients who previously failed PegIFN/RBV achieved significantly greater on-treatment virologic response rates following treatment with a TMC435-containing regimen, compared with placebo/PegIFN/RBV control. • In TMC435 treatment groups, no major differences were observed in virologic response between different IL28B genotypes. • Safety and tolerability were generally similar between TMC435-containing regimen and placebo/PegIFN/RBV control group. ACKNOWLEDGEMENTS The patients and their families. The investigators and their study staff. Medical writing support was provided by Bethan Lowder, PhD from Complete Medical Communications, funded by Tibotec. Maria Beumont-Mauviel, Joan Cannon, Ronald Kalmeijer and Eric Lefebvre contributed to development of the presentation. REFERENCES 1. Reesink HW et al. Gastroenterology 2010; 138: 913–921. 2. Reesink HW et al. Poster presented at the 60th American Association for the Study of Liver Diseases (AASLD) Meeting, Boston, MA, USA, 30 October–3 November, 2009. 3. Sekar V et al. Poster presented at the 45th Annual Meeting of European Association for the Study of the Liver (EASL), Vienna, Austria, 14–18 April, 2010. 4. Marcellin P et al. Poster presented at the 44th Annual Meeting of European Association for the Study of the Liver (EASL), Copenhagen, Denmark, 22–26 April, 2009. 5. Manns M et al. Oral presentation at the 44th Annual Meeting of European Association for the Study of the Liver (EASL), Copenhagen, Denmark, 22–26 April, 2009. 6. Moreno et al. Poster presented at the 61st American Association for the Study of Liver Diseases (AASLD) Meeting, Boston, MA, USA, 29 October−2 November, 2010. 7. Fried et al. Oral presentation at the 61st American Association for the Study of Liver Diseases (AASLD) Meeting, Boston, MA, USA, 29 October−2 November, 2010. LB Poster 2998 TABLE 2. Treatment exposure and adverse events occurring during treatment phase. TMC12/PR48 100 mg N= 16 TMC24/PR48 100 mg N=16 TMC48/PR48 100 mg N=17 TMC12/PR48 150 mg N=17 TMC24/PR48 150 mg N=17 TMC48/PR48 150 mg N=17 All TMC435 N=100 Pbo24/PR48 N=716 Treatment exposure, median (weeks) Relapsers Partial responders Null responders 30.45 30.86 30.43 28.21 29.71 30.64 29.00 27.86 30.00 30.86 30.71 28.43 30.07 30.79 31.43 28.00 30.21 30.86 31.21 28.86 29.86 30.50 30.29 27.00 30.00 30.75 30.51 28.06 26.14 29.86 24.71 10.93 Five most common adverse events (regardless of severity or causality), % Headache Fatigue Influenza-like illness Pruritus 27.3 42.4 34.8 28.8 24.6 40.0 36.9 30.8 33.3 48.5 31.8 27.3 40.9 36.4 24.2 28.8 36.8 41.2 25.0 32.4 36.9 38.5 21.5 30.8 33.3 41.2 29.0 29.8 33.3 42.4 19.7 13.6 Adverse events of interest (regardless of severity or causality), % Rash (any type) † Anaemia ‡ 13.6 21.2 7.7 16.9 7.6 16.7 13.6 7.6 16.2 22.1 21.5 21.5 13.4 17.7 13.6 15.2 Serious adverse events 3.0 7.7 3.0 9.1 7.4 4.6 5.8 1.5 † Combines all types of reported rash; ‡ reported as an adverse event by study investigator if laboratory abnormalities considered clinically relevant; TMC12PR48, TMC435 for 12 weeks in addition to PegIFN/RBV for 48 Weeks; TMC24PR48, TMC435 for 24 weeks in addition to PegIFN/RBV for 48 Weeks; TMC48PR48, TMC435 for 48 weeks in addition to PegIFN/RBV for 48 Weeks; Pbo24/PR48, Placebo for 24 Weeks in addition to PegIF/RBV for 48 Weeks 1 2 3 4 5 6 7 TMC435 100 mg QD TMC435 + PegIFN/RBV TMC435 + PegIFN/RBV TMC435 + PegIFN/RBV TMC435 + PegIFN/RBV TMC435 + PegIFN/RBV TMC435 + PegIFN/RBV PegIFN/RBV + TMC-matched placebo PegIFN/RBV PegIFN/RBV PegIFN/RBV Post therapy FU Post therapy FU Post therapy FU Post therapy FU Post therapy FU Post therapy FU Post therapy FU PegIFN/RBV N=66 Weeks 12 24 Interim analysis 48 72 N=65 N=66 N=66 N=68 N=65 N=66 TMC435 150 mg QD FU, follow-up FIGURE 1: ASPIRE study design. Proportion of patients (%) 0 *Discontinuation due to AEs included stop of any study drug TMC, TMC435 dose groups combined, TMC435 administered with Peg/IFN/RBV; control, Placebo/PegIFN/RBV 20 40 60 80 100 Other reason Adverse event* Virologic stopping rule TMC 100 mg Control TMC 150 mg Control TMC 150 mg TMC 100 mg TMC 100 mg Control TMC 150 mg Control TMC 150 mg TMC 100 mg Partial responder 12 weeks Null responder Control TMC 150 mg TMC 100 mg Control TMC 150 mg TMC 100 mg Relapser Relapser Partial responder Null responder 12 weeks FIGURE 2: Discontinuation due to AEs or reaching virologic stopping rule. Proportion of patients (%) 0 20 40 60 80 100 Viral breakthrough Met virologic stopping rule at Week 4, 12 or 24 Relapser Pbo PR48, Placebo in addition to PegIFN/RBV for 48 Weeks; PR, PegIFN/RBV; TMC, TMC435 Partial responder TMC435 100 mg + PR (dose groups combined) Null responder Relapser Partial responder TMC435 150 mg + PR (dose groups combined) Null responder Relapser Partial responder Pbo PR48 Null responder FIGURE 4: Patients experiencing viral breakthrough or meeting stopping rules in TMC435 dose groups combined, compared with placebo control group. -8 -6 Mean (90% CI) log HCV RNA change from baseline CC -4 -2 0 0 4 8 12 Weeks 16 20 24 23 22 28 27 7 N= N= N= 5 23 22 23 21 21 28 27 27 26 25 7 5 7 6 6 90 86 90 89 32 N= N= N= 26 90 89 90 86 82 87 89 88 87 85 31 24 29 22 17 23 23 24 22 11 N= N= N= 10 23 23 23 23 22 24 24 24 21 23 11 10 10 11 11 TMC435 100 mg + PR (dose groups combined) TMC435 150 mg + PR (dose groups combined) Pbo PR48 -8 -6 Mean (90% CI) log HCV RNA change from baseline CT -4 -2 0 0 4 8 12 Weeks 16 20 24 -8 -6 Mean (90% CI) log HCV RNA change from baseline TT -4 -2 0 0 4 8 12 Weeks 16 20 24 Pbo PR48, Placebo in addition to PegIFN/RBV for 48 Weeks; PR, PegIFN/RBV; TMC, TMC435 FIGURE 5: Change in HCV RNA (mean and 95% CI) over time, by IL28B genotype: Null responders, partial responders and relapsers combined. TMC12PR48 100 mg N=66 TMC24PR48 100 mg N=65 TMC48PR48 100 mg N=66 TMC12PR48 150 mg N=66 TMC24PR48 150 mg N=68 TMC48PR48 150 mg N=65 Pbo PR48 N=66 All subjects N=462 Patient demographics Male, % 66.7 67.7 68.2 68.2 63.2 73.8 63.6 67.3 Race White, % Black, % Asian, % Other, % 89.4 7.6 1.5 1.5 92.3 3.1 4.6 0 93.9 4.5 1.5 0 92.4 4.5 1.5 1.5 89.7 7.4 0 2.9 96.9 3.1 0 0 93.9 1.5 3.0 1.5 92.6 4.5 1.7 1.0 Age, years, median 51.5 50.0 50.0 48.0 51.5 50.0 50.5 50.0 Body Mass Index, median 27.55 26.50 26.60 26.40 27.45 27.20 27.95 27.20 IL28B* CC, % CT, % TT, % N=43 16.3 74.4 9.3 N=46 17.4 65.2 17.4 N=47 17.0 59.6 23.4 N=43 11.6 69.8 18.6 N=50 18.0 64.0 18.0 N=49 20.4 57.1 22.4 N=50 22.0 64.0 14.0 N=328 17.7 64.6 17.7 Disease characteristics HCV Subtype (NS5B), % 1A 1B 39.4 59.1 44.4 54.0 39.4 59.1 45.5 54.5 45.5 51.5 36.9 63.1 40.9 59.1 41.7 57.2 HCV RNA, >800,000 IU/mL at baseline, % 87.9 90.8 87.9 86.4 85.3 83.1 83.3 86.4 Metavir score F4, % 10.8 20.6 21.2 19.7 19.4 20.3 15.6 18.2 *Data available for patients who consented to DNA research only. IL28B, polymorphism on chromosome 19 s12979860; PegIFN, peginterferon; Pbo PR48, Placebo in addition to PegIFN/RBV for 48 Weeks; RBV, ribavirin; TMC12PR48, TMC435 for 12 weeks in addition to PegIFN/RBV for 48 Weeks; TMC24PR48, TMC435 for 24 weeks in addition to PegIFN/ RBV for 48 Weeks; TMC48PR48, TMC435 for 48 weeks in addition to PegIFN/RBV for 48 Weeks TABLE 1: Baseline demographics and characteristics, per treatment arm. 0 TMC 100 mg + PR dose groups combined (n=79) TMC 150 mg + PR dose groups combined (n=76) Pbo PR48 (n=26) 20 40 Proportion of patients (%) Week 4 60 80 100 0 TMC 100 mg 12W (n=26) TMC 100 mg 24 & 48 W combined (n=50) TMC 150 mg 12W (n=24) 20 40 Proportion of patients (%) Week 24 60 80 100 TMC 150 mg 24 & 48 W combined (n=52) Pbo PR48 (n=24) 0 TMC 100 mg + PR dose groups combined (n=79) TMC 150 mg + PR dose groups combined (n=77) Pbo PR48 (n=26) 20 40 Proportion of patients (%) Week 12 60 80 100 HCV RNA 25 IU/mL undetectable HCV RNA 25 IU/mL detectable HCV RNA 25 IU/mL Pbo PR48, Placebo in addition to PegIFN/RBV for 48 Weeks; PegIFN, peginterferon; RBV, ribavirin; TMC, TMC435 79% 84% 4% 88% 95% 31% 96% 92% 96% 94% 83% FIGURE 3a: Observed virologic response rate at Weeks 4, 12, 24, by treatment group: Relapsers. 0 TMC 100 mg + PR dose groups combined (n=68) TMC 150 mg + PR dose groups combined (n=68) Pbo PR48 (n=23) 20 40 Proportion of patients (%) Week 4 60 80 100 0 TMC 100 mg 12W (n=22) TMC 100 mg 24 & 48 W combined (n=41) TMC 150 mg 12W (n=22) 20 40 Proportion of patients (%) Week 24 60 80 100 TMC 150 mg 24 & 48 W combined (n=44) Pbo PR48 (n=21) 0 TMC 100 mg + PR dose groups combined (n=67) TMC 150 mg + PR dose groups combined (n=65) Pbo PR48 (n=19) 20 40 Proportion of patients (%) Week 12 60 80 100 HCV RNA 25 IU/mL undetectable HCV RNA 25 IU/mL detectable HCV RNA 25 IU/mL Pbo PR48, Placebo in addition to PegIFN/RBV for 48 Weeks; PegIFN, peginterferon; RBV, ribavirin; TMC, TMC435 56% 67% 76% 92% 10% 86% 86% 83% 89% 20% FIGURE 3b: Observed virologic response rate at Weeks 4, 12, 24, by treatment group: Partial responders. HCV RNA 25 IU/mL undetectable HCV RNA 25 IU/mL detectable HCV RNA 25 IU/mL 0 TMC 100 mg + PR dose groups combined (n=47) TMC 150 mg + PR dose groups combined (n=51) Pbo PR48 (n=16) 20 40 Proportion of patients (%) Week 4 60 80 100 0 TMC 100 mg 12W (n=14) TMC 100 mg 24 & 48 W combined (n=28) TMC 150 mg 12W (n=17) 20 40 Proportion of patients (%) Week 24 60 80 100 TMC 150 mg 24 & 48 W combined (n=31) Pbo PR48 (n=9) 0 TMC 100 mg + PR dose groups combined (n=46) TMC 150 mg + PR dose groups combined (n=50) Pbo PR48 (n=14) 20 40 Proportion of patients (%) Week 12 60 80 100 Pbo PR48, Placebo in addition to PegIFN/RBV for 48 Weeks; PegIFN, peginterferon; RBV, ribavirin; TMC, TMC435 36% 40% 63% 64% 21% 70% 74% 70% 87% 45% FIGURE 3c: Observed virologic response rate at Weeks 4, 12, 24, by treatment group: Null responders.
Transcript of The ASPIRE Trial: TMC435 in treatment-experienced patients...
Poster presented at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) 30 March – 3 April, 2011, Berlin, Germany
The ASPIRE Trial: TMC435 in treatment-experienced patients with genotype 1 HCV infection who have failed previous PegIFN/RBV treatment: Week 24 interim analysisStefan Zeuzem,1 Graham R Foster,2 Michael W Fried,3 Christophe Hezode,4 Gideon M Hirschfield,5 Igor Nikitin,6 Fred Poordad,7 Oliver Lenz,8 Monika Peeters,8 Vanitha Sekar,9 Goedele De Smedt8
1J.W. Goethe University Hospital, Frankfurt, Germany; 2Queen Marys University of London, London, United Kingdom; 3University of North Carolina at Chapel Hill, North Carolina, USA; 4Hôpital Henri-Mondor, Université Paris-Est Créteil, France; 5Toronto Western Hospital Liver Centre, Toronto, Canada; 6Russian State Medical University, Moscow, Russia; 7Cedars-Sinai Medical Center, Los Angeles, USA; 8Tibotec BVBA, Mechelen, Belgium; 9Tibotec Inc, Yardley, PA, USA
INTRODUCTION• TMC435 is an investigational potent, once-daily oral NS3/4A protease inhibitor
currently in Phase III clinical development for the treatment of hepatitis C virus (HCV) infection.
• Phase I, IIa and IIb studies, in treatment-experienced and/or treatment-naïve patients infected with HCV, have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports a once-daily dosing regimen, and has potent antiviral activity in patients infected with genotypes 1, 2, 4, 5 and 6.1-7
• Phase III clinical trials are now underway in treatment-naïve patients and in patients who relapsed after previous treatment.
• ASPIRE (TMC435-C206; NCT00980330) is a Phase IIb, randomised, double-blind, placebo-controlled trial to investigate the efficacy, tolerability, safety and pharmacokinetics of TMC435 as part of a treatment regimen including pegylated interferon a-2a and ribavirin (PegIFN/RBV).
• Patients enrolled in the ASPIRE trial were infected with HCV genotype 1, and had failed to respond or relapsed following at least one course of PegIFN/RBV therapy.
METHODSStudy Design• The study included seven treatment arms, with a total duration of 72 weeks
(Figure 1). This interim analysis was performed when all patients had completed 24 weeks of the study.
• Inclusion criteria included documented chronic infection with HCV genotype 1, HCV RNA .10,000 IU/mL at screening, and ≥1 prior documented course of PegIFN a-2a or a-2b/RBV for >12 consecutive weeks which had not been discontinued due to intolerability.
• Exclusion criteria included decompensated liver disease and co-infection with HIV or HBV.
• Patients were administered TMC435 (100 or 150 mg once daily [QD]) or placebo in combination with PegIFN/RBV.
• The patient population was stratified by genotype (1a, 1b, and other), and by prior virologic response (relapsers, partial and null responders were included in a 2:2:1 ratio):– Relapse: HCV RNA undetectable end of treatment; detectable within
24 weeks post-treatment– Partial response: ≥2 log10 reduction HCV RNA at Week 12; detectable
HCV RNA at end of treatment– Null response: <2 log10 reduction HCV RNA at Week 12
Virologic Stopping Rules• Patients should stop all medication following lack of on-treatment virologic
response or viral breakthrough, defined as: – At Week 4: ,1 log10 reduction in HCV RNA from baseline – At Week 12: ,2 log10 reduction in HCV RNA from baseline – At Week 24: HCV RNA confirmed detectable – At Week 36: HCV RNA confirmed detectable – Between Day 1 and Week 48: Confirmed HCV RNA increase .1 log10
compared to nadir; or confirmed HCV RNA .100 IU/mL if HCV RNA was previously <25IU/mL detectable or undetectable.
Antiviral Efficacy• The primary objective of the trial is to evaluate the efficacy of six different
regimens of TMC435 in combination with PegIFN/RBV compared with the placebo/PegIFN/RBV control group.
• Primary endpoint: The proportion of subjects in TMC435 groups with undetectable HCV RNA (,25 IU/mL undetectable; Roche Taqman v2) 24 weeks after the planned end of treatment (SVR24) compared with the control group, who received PegIFN/RBV and TMC435-matched placebo.– The primary efficacy endpoint will be assessed at Week 72 and is not
available for this Week 24 interim analysis.– Here we report the results of the pre-planned Week 24 interim analysis
including the proportion of patients with a virologic response at Weeks 4, 12 and 24, HCV RNA change per IL28B genotype, and rates of viral breakthrough.
Safety• Secondary objectives of the study include evaluation of the safety and
tolerability of TMC435 plus PegIFN/RBV compared with placebo/PegIFN/RBV control group, over the trial period. Adverse events (AEs) were recorded, safety laboratory analyses performed, and vital signs measured.
Statistical Analysis • Selected virologic response parameters were compared between TMC435
groups and placebo/PegIFN/RBV control group using a logistic regression model. The model included baseline HCV RNA as covariate and treatment and the stratification parameters, prior response and genotype 1 subtype, as factors.
• 95% confidence intervals were constructed for the observed response rates, and for the difference between the TMC435 groups and the placebo/PegIFN/RBV control group.
RESULTSPatient Demographics• Baseline demographics and characteristics were well balanced between
treatment groups (Table 1).
Patient Disposition• In all subpopulations, more treatment discontinuations were noted in the
placebo control group compared with the TMC435 groups. This was noted particularly in null responders, followed by partial responders.
• The primary reason for discontinuation was reaching a virologic stopping rule, which was more commonly observed in placebo control patients during the first 12 weeks of therapy (Figure 2).
Observed Virologic Response• At Weeks 4, 12, and 24, significantly higher virologic response rates were
observed following treatment with TMC435 plus PegIFN/RBV, compared with placebo plus PegIFN/RBV (Figure 3a-c).
• In null and partial responders, somewhat higher virologic response rates were observed in TMC435 150 mg dose groups, compared with 100 mg groups, at early timepoints while differences were less pronounced at Week 24 (Figure 3).
Viral Breakthrough• Overall, 6% (12/214) of patients in the TMC435 arm and 49% (32/66) of
patients in the control group met a virologic stopping rule (excluding viral breakthrough) at week 4, 12, or 24 due to lack of virologic response.
• Overall, viral breakthrough was observed in 18.2% (39/214) of patients in the TMC435 arms and 1.5% (1/66) in the control group (Figure 4).
• Highest rates of viral breakthrough and virologic failure were observed in null responders, followed by partial responders, with the lowest in relapsers.
IL28B Genotype• In TMC435 treatment groups, no major differences in mean change in HCV
RNA were observed between different IL28B genotypes (Figure 5).
• In the placebo control group, HCV RNA change from baseline was greater for patients with IL28B CC genotype compared with patients with CT and TT genotypes (Figure 5)
Adverse Events• Median treatment exposure was higher for TMC435 patients compared with
placebo (30 weeks for TMC435 compared to 26 weeks in placebo control group; Table 2), due to higher attrition in the placebo control group which was mainly related to lack or loss of virologic response. This bias should be kept in mind when assessing safety comparisons.
• Overall incidence of AEs was similar across treatment groups (Figure 2, Table 2), except for occurrence of influenza-like illness and pruritus, which were more commonly reported in TMC435 patients.
• The majority of these AEs were grade 1 or 2 in severity.
• Serious AEs were reported in 5.8% of patients treated with TMC435 and in 1.5% of subjects in the placebo control group. No differences were observed between the TMC435 dose groups.
• AEs leading to discontinuation of TMC435/placebo were reported in 5.6% of the TMC435 treated patients and in 1.5% of the placebo control patients.
• Decreases in hemoglobin, red blood cell, white blood cell, and platelet count were observed in all treatment groups, including control. Mild and reversible increases in bilirubin (total, direct and indirect) were observed in TMC435 dose groups with no major differences between 100 mg and 150 mg (data not shown).
CONCLUSIONS• In this Week 24 interim analysis, treatment-experienced patients who previously failed PegIFN/RBV achieved significantly greater on-treatment virologic response rates following treatment with a TMC435-containing regimen, compared with placebo/PegIFN/RBV control.
• In TMC435 treatment groups, no major differences were observed in virologic response between different IL28B genotypes.
• Safety and tolerability were generally similar between TMC435-containing regimen and placebo/PegIFN/RBV control group.
ACKNOWLEDGEMENTSThe patients and their families. The investigators and their study staff. Medical writing support was provided by Bethan Lowder, PhD from Complete Medical Communications, funded by Tibotec. Maria Beumont-Mauviel, Joan Cannon, Ronald Kalmeijer and Eric Lefebvre contributed to development of the presentation.
REFERENCES1. Reesink HW et al. Gastroenterology 2010; 138: 913–921.2. Reesink HW et al. Poster presented at the 60th American Association for the Study of Liver
Diseases (AASLD) Meeting, Boston, MA, USA, 30 October–3 November, 2009.3. Sekar V et al. Poster presented at the 45th Annual Meeting of European Association for the
Study of the Liver (EASL), Vienna, Austria, 14–18 April, 2010.4. Marcellin P et al. Poster presented at the 44th Annual Meeting of European Association for the
Study of the Liver (EASL), Copenhagen, Denmark, 22–26 April, 2009.5. Manns M et al. Oral presentation at the 44th Annual Meeting of European Association for the
Study of the Liver (EASL), Copenhagen, Denmark, 22–26 April, 2009.6. Moreno et al. Poster presented at the 61st American Association for the Study of Liver Diseases
(AASLD) Meeting, Boston, MA, USA, 29 October−2 November, 2010.7. Fried et al. Oral presentation at the 61st American Association for the Study of Liver Diseases
(AASLD) Meeting, Boston, MA, USA, 29 October−2 November, 2010.
LB Poster 2998
TABLE 2. Treatment exposure and adverse events occurring during treatment phase.
TMC12/PR48 100 mgN= 16
TMC24/PR48 100 mgN=16
TMC48/PR48 100 mgN=17
TMC12/PR48 150 mgN=17
TMC24/PR48 150 mgN=17
TMC48/PR48 150 mgN=17
All TMC435N=100
Pbo24/PR48N=716
Treatment exposure, median (weeks)RelapsersPartial respondersNull responders
30.4530.8630.4328.21
29.7130.6429.0027.86
30.0030.8630.7128.43
30.0730.7931.4328.00
30.2130.8631.2128.86
29.8630.5030.2927.00
30.0030.7530.5128.06
26.1429.8624.7110.93
Five most common adverse events (regardless of severity or causality), %
Headache Fatigue Influenza-like illness Pruritus
27.342.434.828.8
24.640.036.930.8
33.348.531.827.3
40.936.424.228.8
36.841.225.032.4
36.938.521.530.8
33.341.229.029.8
33.342.419.713.6
Adverse events of interest (regardless of severity or causality), %
Rash (any type)† Anaemia‡
13.621.2
7.716.9
7.616.7
13.67.6
16.222.1
21.521.5
13.417.7
13.615.2
Serious adverse events 3.0 7.7 3.0 9.1 7.4 4.6 5.8 1.5
†Combines all types of reported rash; ‡reported as an adverse event by study investigator if laboratory abnormalities considered clinically relevant; TMC12PR48, TMC435 for 12 weeks in addition to PegIFN/RBV for 48 Weeks; TMC24PR48, TMC435 for 24 weeks in addition to PegIFN/RBV for 48 Weeks; TMC48PR48, TMC435 for 48 weeks in addition to PegIFN/RBV for 48 Weeks; Pbo24/PR48, Placebo for 24 Weeks in addition to PegIF/RBV for 48 Weeks
1
2
3
4
5
6
7
TMC435 100 mg QD
TMC435 + PegIFN/RBV
TMC435 + PegIFN/RBV
TMC435 + PegIFN/RBV
TMC435 + PegIFN/RBV
TMC435 + PegIFN/RBV
TMC435 + PegIFN/RBV
PegIFN/RBV + TMC-matched placebo
PegIFN/RBV
PegIFN/RBV
PegIFN/RBV Post therapy FU
Post therapy FU
Post therapy FU
Post therapy FU
Post therapy FU
Post therapy FU
Post therapy FU
PegIFN/RBV
N=66
Weeks12 24
Interim analysis
48 72
N=65
N=66
N=66
N=68
N=65
N=66
TMC435 150 mg QD
FU, follow-up
FIGURE 1: ASPIRE study design.
Prop
orti
on o
f pa
tien
ts (
%)
0
*Discontinuation due to AEs included stop of any study drugTMC, TMC435 dose groups combined, TMC435 administered with Peg/IFN/RBV; control, Placebo/PegIFN/RBV
20
40
60
80
100
Other reason
Adverse event*
Virologic stopping rule
TMC
100
mg
Cont
rol
TMC
150
mg
Cont
rol
TMC
150
mg
TMC
100
mg
TMC
100
mg
Cont
rol
TMC
150
mg
Cont
rol
TMC
150
mg
TMC
100
mg
Partialresponder
�12 weeks
Nullresponder
Cont
rol
TMC
150
mg
TMC
100
mg
Cont
rol
TMC
150
mg
TMC
100
mg
Relapser Relapser Partialresponder
Nullresponder
�12 weeks
FIGURE 2: Discontinuation due to AEs or reaching virologic stopping rule.
Prop
orti
on o
f pa
tien
ts (
%)
0
20
40
60
80
100 Viral breakthrough
Met virologic stopping rule at Week 4, 12 or 24
Relapser
Pbo PR48, Placebo in addition to PegIFN/RBV for 48 Weeks; PR, PegIFN/RBV; TMC, TMC435
Partialresponder
TMC435 100 mg + PR (dose groups combined)
Nullresponder
Relapser Partialresponder
TMC435 150 mg + PR (dose groups combined)
Nullresponder
Relapser Partialresponder
Pbo PR48
Nullresponder
FIGURE 4: Patients experiencing viral breakthrough or meeting stopping rules in TMC435 dose groups combined, compared with placebo control group.
-8
-6
Mea
n (9
0% C
I) lo
g H
CV
RN
A
chan
ge f
rom
bas
elin
e
CC
-4
-2
00 4 8 12
Weeks16 20 24
23 2228 277
N=N=N= 5
23 22 23 21 2128 27 27 26 257 5 7 6 6
90 8690 8932
N=N=N= 26
90 89 90 86 8287 89 88 87 8531 24 29 22 17
23 2324 2211
N=N=N= 10
23 23 23 23 2224 24 24 21 2311 10 10 11 11
TMC435 100 mg + PR (dose groups combined)
TMC435 150 mg + PR (dose groups combined)
Pbo PR48
-8
-6
Mea
n (9
0% C
I) lo
g H
CV
RN
A
chan
ge f
rom
bas
elin
e
CT
-4
-2
00 4 8 12
Weeks16 20 24
-8
-6
Mea
n (9
0% C
I) lo
g H
CV
RN
A
chan
ge f
rom
bas
elin
e
TT
-4
-2
00 4 8 12
Weeks16 20 24
Pbo PR48, Placebo in addition to PegIFN/RBV for 48 Weeks; PR, PegIFN/RBV; TMC, TMC435
FIGURE 5: Change in HCV RNA (mean and 95% CI) over time, by IL28B genotype: Null responders, partial responders and relapsers combined.
TMC12PR48 100 mgN=66
TMC24PR48 100 mgN=65
TMC48PR48 100 mgN=66
TMC12PR48 150 mgN=66
TMC24PR48 150 mgN=68
TMC48PR48 150 mgN=65
Pbo PR48N=66 All subjects N=462
Patient demographics
Male, % 66.7 67.7 68.2 68.2 63.2 73.8 63.6 67.3Race
White, %Black, %Asian, %Other, %
89.47.61.51.5
92.33.14.60
93.94.51.50
92.44.51.51.5
89.77.40
2.9
96.93.100
93.91.53.01.5
92.64.51.71.0
Age, years, median 51.5 50.0 50.0 48.0 51.5 50.0 50.5 50.0
Body Mass Index, median 27.55 26.50 26.60 26.40 27.45 27.20 27.95 27.20
IL28B*CC, %CT, %TT, %
N=4316.374.49.3
N=4617.465.217.4
N=4717.059.623.4
N=4311.669.818.6
N=5018.064.018.0
N=4920.457.122.4
N=5022.064.014.0
N=32817.764.617.7
Disease characteristics
HCV Subtype (NS5B), %1A1B
39.459.1
44.454.0
39.459.1
45.554.5
45.551.5
36.963.1
40.959.1
41.757.2
HCV RNA, >800,000 IU/mL at baseline, % 87.9 90.8 87.9 86.4 85.3 83.1 83.3 86.4
Metavir score F4, % 10.8 20.6 21.2 19.7 19.4 20.3 15.6 18.2
*Data available for patients who consented to DNA research only. IL28B, polymorphism on chromosome 19 s12979860; PegIFN, peginterferon; Pbo PR48, Placebo in addition to PegIFN/RBV for 48 Weeks; RBV, ribavirin; TMC12PR48, TMC435 for 12 weeks in addition to PegIFN/RBV for 48 Weeks; TMC24PR48, TMC435 for 24 weeks in addition to PegIFN/RBV for 48 Weeks; TMC48PR48, TMC435 for 48 weeks in addition to PegIFN/RBV for 48 Weeks
TABLE 1: Baseline demographics and characteristics, per treatment arm.
0TMC 100 mg
+ PR dose groupscombined
(n=79)
TMC 150 mg+ PR
dose groupscombined
(n=76)
Pbo PR48(n=26)
20
40
Prop
orti
on o
f pa
tien
ts (
%) Week 4
60
80
100
0TMC 100 mg
12W(n=26)
TMC 100 mg 24 & 48 W combined
(n=50)
TMC 150 mg12W
(n=24)
20
40
Prop
orti
on o
f pa
tien
ts (
%) Week 24
60
80
100
TMC 150 mg 24 & 48 W combined
(n=52)
Pbo PR48(n=24)
0TMC 100 mg
+ PR dose groupscombined
(n=79)
TMC 150 mg+ PR
dose groupscombined
(n=77)
Pbo PR48(n=26)
20
40
Prop
orti
on o
f pa
tien
ts (
%) Week 12
60
80
100
HCV RNA �25 IU/mL undetectable HCV RNA �25 IU/mL detectable HCV RNA �25 IU/mL
Pbo PR48, Placebo in addition to PegIFN/RBV for 48 Weeks; PegIFN, peginterferon; RBV, ribavirin; TMC, TMC435
79%84%
4%
88%95%
31%
96% 92% 96% 94%83%
FIGURE 3a: Observed virologic response rate at Weeks 4, 12, 24, by treatment group: Relapsers.
0TMC 100 mg
+ PR dose groupscombined
(n=68)
TMC 150 mg+ PR
dose groupscombined
(n=68)
Pbo PR48(n=23)
20
40
Prop
orti
on o
f pa
tien
ts (
%)
Week 4
60
80
100
0TMC 100 mg
12W(n=22)
TMC 100 mg 24 & 48 W combined
(n=41)
TMC 150 mg12W
(n=22)
20
40
Prop
orti
on o
f pa
tien
ts (
%)
Week 24
60
80
100
TMC 150 mg 24 & 48 W combined
(n=44)
Pbo PR48(n=21)
0TMC 100 mg
+ PR dose groupscombined
(n=67)
TMC 150 mg+ PR
dose groupscombined
(n=65)
Pbo PR48(n=19)
20
40
Prop
orti
on o
f pa
tien
ts (
%)
Week 12
60
80
100
HCV RNA �25 IU/mL undetectable HCV RNA �25 IU/mL detectable HCV RNA �25 IU/mL
Pbo PR48, Placebo in addition to PegIFN/RBV for 48 Weeks; PegIFN, peginterferon; RBV, ribavirin; TMC, TMC435
56%
67%76%
92%
10%
86% 86%83%89%
20%
FIGURE 3b: Observed virologic response rate at Weeks 4, 12, 24, by treatment group: Partial responders.
HCV RNA �25 IU/mL undetectable HCV RNA �25 IU/mL detectable HCV RNA �25 IU/mL
0TMC 100 mg
+ PR dose groupscombined
(n=47)
TMC 150 mg+ PR
dose groupscombined
(n=51)
Pbo PR48(n=16)
20
40
Prop
orti
on o
f pa
tien
ts (
%) Week 4
60
80
100
0TMC 100 mg
12W(n=14)
TMC 100 mg 24 & 48 W combined
(n=28)
TMC 150 mg12W
(n=17)
20
40
Prop
orti
on o
f pa
tien
ts (
%) Week 24
60
80
100
TMC 150 mg 24 & 48 W combined
(n=31)
Pbo PR48(n=9)
0TMC 100 mg
+ PR dose groupscombined
(n=46)
TMC 150 mg+ PR
dose groupscombined
(n=50)
Pbo PR48(n=14)
20
40
Prop
orti
on o
f pa
tien
ts (
%) Week 12
60
80
100
Pbo PR48, Placebo in addition to PegIFN/RBV for 48 Weeks; PegIFN, peginterferon; RBV, ribavirin; TMC, TMC435
36% 40%
63% 64%
21%
70% 74% 70%
87%
45%
FIGURE 3c: Observed virologic response rate at Weeks 4, 12, 24, by treatment group: Null responders.
