HCV NS3/4A protease inhibitors for the treatment of HCV infected - PowerPoint PPT Presentation

HCV NS3/4A protease inhibitors for the treatment of HCV infected patients ‐ TMC435 ‐ Oliver Lenz Tibotec BVBA, Beerse, Belgium; AREVIR-GenaFor-Meeting, Bonn 2011

“Current” HCV Treatment • Goal = Sustained Virologic Response • Considered virologic cure • PEG-IFN α 2 (weekly, sc injection)/Ribavirin (BID, oral) is current therapy: • Genotype 2/3: • 24-48 weeks therapy • 70-80% achieve SVR • Genotype 1, 4-6: • 48-72 weeks therapy (Genotype 1, 4-6) • 40%-52% of G1 patients achieve SVR • Lower response rates in previous treatment failures and some patient populations (e.g. HIV/HCV co-infected) • Side-effects include: flu-like symptoms, hematologic abnormalities and neuropsychiatric symptoms

Telaprevir Boceprevir Status Filed for approval in HCV Filed for approval in HCV genotype 1: Q4/2010 genotype 1: Q4/2010 Dosing 750mg q8h 800mg TID Treatment duration Ph3 8 or 12 weeks TVR with 24 4week LI (P/R), 24/44 or 48 weeks of PegIFNa- weeks BVR with 28 or 48 2a/RBV (RGT naives), 48 weeks of PegIFN-2b/RBV weeks PegIFN in Trtexp. (RGT naives), 36 or 48 weeks PegIFN in Trtexp. Adverse events Rash, Anemia Anemia, dysguesia Phase 3: Trt naives SVR: 69-75% SVR: 63-66% SVR control: 44% SVR control: 36% Phase 3: null responder SVR: 29-33% Excluded SVR control: 5% Phase 3: partial responder SVR: 54-59% SVR: 40-52% SVR control: 15% SVR control: 7% Phase 3: relapser SVR: 83-88% SVR: 69-75% SVR control: 24% SVR control: 29% Resistance associated V36A/M, T54A/S, R155K/T V36M, T54A/S, R155K, variants A156S/V/T A156S, V170A Jacobson et al., AASLD 2010 Pordard, NEJM 2011 Zeuzem et al., EASL 2011 Bacon, NEJM 2011 Kieffer et al., AASLD 2010

TMC435* is a Potent HCV NS3/4A Inhibitor In vitro: • Reversible NS3/4A protease inhibitor • EC 50 = 8 nM in a genotype 1b replicon cell line • Minimal impact of functional protein binding (~2 FC of EC50) • High Selectivity across many cell lines and against a broad panel of other RNA/DNA viruses • Additive to Synergistic with IFN α and polymerase inhibitors; additive with ribavirin In Clinical studies: • Once daily dosing of TMC435 results in high Cmin/EC50 ratio • Potent antiviral activity in patients infected with genotypes 1,2,4,5 and 6 • Phase III clinical trials in combination with PegIFN/RBV are underway in G-1 infected treatment-naïve patients and in patients who relapsed after previous treatment *is an investigational agent in clinical development for HCV by Tibotec

Results of week 24 interim analysis of two Ph2b studies are available: • TMC435 C205 (PILLAR): HCV genotype 1 infected treatment naïve patients 1 • TMC435-C206 (ASPIRE): HCV genotype 1 infected treatment experienced patients 2 1 Fried et al. AASLD 2010 2 Zeuzem et al. EASL 2011

PILLAR study design Planned interim analysis. All available data included N=ITT * PegIFN/RBV TMC435 75 mg Pbo & TMC12/PR24 75 mg Post-therapy FU Post-therapy FU N=78 & PegIFN/RBV PegIFN/RBV Post-therapy FU PegIFN/RBV TMC24/PR24 75 mg Post-therapy FU TMC435 75 mg & PegIFN/RBV Post-therapy FU Post-therapy FU N=75 Post-therapy FU PegIFN/RBV Pbo & TMC435 150 mg Post-therapy FU TMC12/PR24 150 mg Post-therapy FU Post-therapy FU N=77 Post-therapy FU & PegIFN/RBV PegIFN/RBV PegIFN/RBV TMC24/PR24 150 mg Post-therapy FU N=79 Post-therapy FU TMC435 150 mg & PegIFN/RBV Post-therapy FU Pbo24 / PR48 PegIFN/RBV Post-therapy FU Pbo & PegIFN/RBV N=77 Week 0 72 4 24 48 12 Response-guided treatment duration in TMC435 arms • End treatment at Week 24, if o HCV RNA <25 IU/mL detectable or undetectable at Week 4, and o HCV RNA <25 IU/mL undetectable at Weeks 12, 16, and 20 • All other patients continued Peg/RBV for up to 48 weeks Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks; TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon α -2a [180 μ g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks; all TMC435 doses administered once-daily; FU, follow-up; IL28B , rs12979860 polymorphism; IP-10, interferon- γ inducible protein 10; ITT, intent to treat; Pbo, placebo; TMC, TMC435.

PILLAR Week 24 Analysis: Proportion of Patients Achieving Virologic Response at Weeks 4 and 12 Week 12 Week 4 *** *** *** *** *** *** *** *** 100 1 3 2 Proportion of patients (%) 17 16 10 80 20 (observed data) 11 60 97 96 94 91 40 79 77 76 68 58 20 11 5 0 TMC12/ TMC24/ TMC12/ TMC24/ Pbo24/ TMC12/ TMC24/ TMC12/ TMC24/ Pbo24/ PR24 PR24 PR24 PR24 PR48 PR24 PR24 PR24 PR24 PR48 75 mg 75 mg 150 mg 150 mg 75 mg 75 mg 150 mg 150 mg (n=77) (n=75) (n=76) (n=75) (n=75) (n=78) (n=73) (n=77) (n=77) (n=74) >25 IU/mL <25 IU/mL undetectable <25 IU/mL detectable HCV RNA ***TMC435 vs placebo: p ≤ 0.001; TMC12/PR24, TMC435 for 12 weeks in addition to Peg/RBV for 24 weeks; TMC24/PR24, TMC435 for 24 weeks in addition to Peg/RBV for 24 weeks; HCV RNA determined using Roche TaqMan v2

PILLAR Week 24 Analysis: Proportion of Patients Achieving Undetectable HCV RNA After Planned End of Treatment • Between 79% and 86% of patients in TMC435 arms ended therapy at Week 24 as per protocol-defined response criteria TMC12/ TMC24/ TMC12/ TMC24/ PR24 PR24 PR24 PR24 Follow-up after planned end of treatment † 75 mg 75 mg 150 mg 150 mg N=78 N=75 N=77 N=79 SVR4 91% 93% 93% 91% (4 weeks after planned end (59/65*) (56/60*) (57/61*) (62/68*) of treatment) SVR12 97% 93% 89% 88% (12 weeks after planned (32/33*) (27/29*) (32/36*) (28/32*) end of treatment) * Denominator based on number of patients that stopped treatment for any reason by Week 24 and reached specified timepoint TMC12/PR24, TMC435 for 12 weeks in addition to PegIFN/RBV for 24 weeks; TMC24/PR24, TMC435 for 24 weeks in addition to PegIFN/RBV for 24 weeks; SVR, sustained virologic response; † not yet defined in the placebo group in this Week 24 analysis as planned end of treatment has not been reached

PILLAR Week 24 Analysis: Viral Breakthrough 50 Proportion of patients with viral breakthrough,* 40 cumulative (%) 30 20 7.8% 6.4% 10 3.9% 2.7% 2.5% 0 TMC12/PR24 TMC24/PR24 TMC12/PR24 TMC24/PR24 Pbo24/PR48 75 mg 75 mg 150 mg 150 mg Weeks 1-4 Weeks 1-12 Weeks 1-24 *Viral breakthrough: confirmed increase of >1 log from nadir or >100 IU/mL if undetectable; TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon α -2a [180 μ g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks; all TMC435 doses were administered once-daily; Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks

PILLAR Week 24 Analysis: Adverse Events TMC12/ TMC24/ TMC12/ TMC24/ PR24 PR24 PR24 PR24 Pbo24/ All TMC435 75 mg 75 mg 150 mg 150 mg PR48 Preferred term, % N=309 N=78 N=75 N=77 N=79 N=77 Adverse events leading to permanent discontinuation of TMC435/Pbo Discontinuation 9.0 2.7 9.1 7.6 7.1 7.8 Most common adverse events* Headache 52.6 45.3 45.5 40.5 46.0 50.6 Fatigue 30.8 46.7 41.6 48.1 41.7 46.8 Influenza-like 26.9 42.7 23.4 34.2 31.7 37.7 illness 32.1 22.7 39.0 30.4 31.1 44.2 Pruritus 33.3 20.0 26.0 30.4 27.5 27.3 Nausea Adverse events of interest Rash (any type) † 35.9 17.3 29.9 30.4 28.5 27.3 Anemia ‡ 17.9 20.0 22.1 17.7 19.4 20.8 *Reported in ≥ 25% of subjects in the ‘All TMC435’ group (all dose groups combined) † Rash (any type) combines all reported types of rash ‡ Reported as an adverse event by study investigator if laboratory abnormalities considered clinically relevant TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon α -2a [180 μ g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks; all TMC435 doses were administered once-daily; Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks

ASPIRE: Study Design HCV genotype 1 infected patients who failed previous PegIFN/RBV therapy Relapse: HCV RNA undetectable end of treatment; detectable within 24 weeks o post-treatment Partial response: ≥ 2 log 10 reduction HCV RNA at Week 12; detectable HCV RNA at o end of treatment Null response: <2 log 10 reduction HCV RNA at Week 12 o This interim analysis was performed when all patients had completed 24 weeks of the study.

ASPIRE Week 24 Analysis: Proportion of Patients Achieving Virologic Response at Weeks 4,12 and 24: RELAPSERS

ASPIRE Week 24 Analysis: Proportion of Patients Achieving Virologic Response at Weeks 4,12 and 24: Partial responders

ASPIRE Week 24 Analysis: Proportion of Patients Achieving Virologic Response at Weeks 4,12 and 24: Null responders

ASPIRE Week 24 Analysis: Viral breakthrough and Virologic failure Patients should stop all medication following lack of on-treatment virologic response or viral breakthrough: At Week 4: <1 log 10 reduction in HCV o RNA from baseline At Week 12: <2 log 10 reduction in HCV o RNA from baseline At Week 24: HCV RNA confirmed o detectable (At Week 36: HCV RNA confirmed o detectable) Viral Breakthrough: Confirmed HCV RNA increase >1 log 10 o compared to nadir; or confirmed HCV RNA >100 IU/mL if HCV RNA was previously <25IU/mL detectable or undetectable.