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-IFNα2 (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 genotype 1: Q4/2010 Filed for approval in HCV genotype 1: Q4/2010 Dosing 750mg q8h 800mg TID Treatment duration Ph3 8 or 12 weeks TVR with 24

• r 48 weeks of PegIFNa-

2a/RBV (RGT naives), 48 weeks PegIFN in Trtexp. 4week LI (P/R), 24/44 weeks BVR with 28 or 48 weeks of PegIFN-2b/RBV (RGT naives), 36 or 48 weeks PegIFN in Trtexp. Adverse events Rash, Anemia Anemia, dysguesia Phase 3: Trt naives SVR: 69-75% SVR control: 44% SVR: 63-66% SVR control: 36% Phase 3: null responder SVR: 29-33% SVR control: 5% Excluded Phase 3: partial responder SVR: 54-59% SVR control: 15% SVR: 40-52% SVR control: 7% Phase 3: relapser SVR: 83-88% SVR control: 24% SVR: 69-75% SVR control: 29% Resistance associated variants V36A/M, T54A/S, R155K/T A156S/V/T V36M, T54A/S, R155K, A156S, V170A

Pordard, NEJM 2011 Bacon, NEJM 2011 Jacobson et al., AASLD 2010 Zeuzem et al., EASL 2011 Kieffer et al., AASLD 2010

TMC435* is a Potent HCV NS3/4A Inhibitor

In vitro:

• Reversible NS3/4A protease inhibitor
• EC50 = 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 IFNα 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 patients1

• TMC435-C206 (ASPIRE): HCV genotype 1

infected treatment experienced patients2

1 Fried et al. AASLD 2010 2 Zeuzem et al. EASL 2011

PILLAR study design

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 μg/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.

Week 12 24 72 48

Pbo & PegIFN/RBV TMC435 75 mg & PegIFN/RBV TMC435 75 mg & PegIFN/RBV TMC435 150 mg & PegIFN/RBV PegIFN/RBV

N=78 N=75 N=79 N=77 N=ITT

TMC12/PR24 75 mg TMC24/PR24 75 mg TMC24/PR24 150 mg Pbo24 / PR48 Pbo & PegIFN/RBV TMC435 150 mg & PegIFN/RBV Pbo & PegIFN/RBV

N=77

TMC12/PR24 150 mg Post-therapy FU Post-therapy FU Post-therapy FU

4

Post-therapy FU

PegIFN/RBV Post-therapy FU

Post-therapy FU Post-therapy FU

PegIFN/RBV Post-therapy FU

Post-therapy FU Post-therapy FU

PegIFN/RBV Post-therapy FU

Post-therapy FU Post-therapy FU

PegIFN/RBV Post-therapy FU

Post-therapy FU

Planned interim analysis. All available data included *

Response-guided treatment duration in TMC435 arms

• End treatment at Week 24, if
• HCV RNA <25 IU/mL detectable or undetectable at Week 4, and
• HCV RNA <25 IU/mL undetectable at Weeks 12, 16, and 20
• All other patients continued Peg/RBV for up to 48 weeks

77 68 76 79 5 91 96 94 97 58 10 20 16 17 11 2 1 3 11

100 80 60 40 20

TMC12/ PR24 75 mg (n=77) TMC24/ PR24 75 mg (n=75) TMC12/ PR24 150 mg (n=76) TMC24/ PR24 150 mg (n=75) Pbo24/ PR48 (n=75) TMC12/ PR24 75 mg (n=78) TMC24/ PR24 75 mg (n=73) TMC12/ PR24 150 mg (n=77) TMC24/ PR24 150 mg (n=77) Pbo24/ PR48 (n=74)

<25 IU/mL undetectable <25 IU/mL detectable >25 IU/mL

Week 4 Week 12

Proportion of patients (%) (observed data) 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 Virologic Response at Weeks 4 and 12

*** *** *** *** *** *** *** ***

• Between 79% and 86% of patients in TMC435 arms ended

therapy at Week 24 as per protocol-defined response criteria

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: Proportion of Patients Achieving Undetectable HCV RNA After Planned End of Treatment

Follow-up after planned end of treatment† TMC12/ PR24 75 mg N=78 TMC24/ PR24 75 mg N=75 TMC12/ PR24 150 mg N=77 TMC24/ PR24 150 mg N=79 SVR4

(4 weeks after planned end

• f treatment)

SVR12

(12 weeks after planned end of treatment)

91%

(59/65*)

97%

(32/33*)

93%

(56/60*)

93%

(27/29*)

93%

(57/61*)

89%

(32/36*)

91%

(62/68*)

88%

(28/32*) * Denominator based on number of patients that stopped treatment for any reason by Week 24 and reached specified timepoint

*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 μg/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: Viral Breakthrough

50 40 30 20 10 TMC12/PR24 75 mg TMC24/PR24 75 mg TMC12/PR24 150 mg TMC24/PR24 150 mg Pbo24/PR48 Proportion of patients with viral breakthrough,* cumulative (%)

Weeks 1-4 Weeks 1-12 Weeks 1-24 6.4% 2.7% 7.8% 2.5% 3.9%

TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon α-2a [180 μg/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

*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

PILLAR Week 24 Analysis: Adverse Events

Preferred term, % TMC12/ PR24 75 mg N=78 TMC24/ PR24 75 mg N=75 TMC12/ PR24 150 mg N=77 TMC24/ PR24 150 mg N=79 All TMC435 N=309 Pbo24/ PR48 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 Fatigue Influenza-like illness Pruritus Nausea 52.6 30.8 26.9 32.1 33.3 45.3 46.7 42.7 22.7 20.0 45.5 41.6 23.4 39.0 26.0 40.5 48.1 34.2 30.4 30.4 46.0 41.7 31.7 31.1 27.5 50.6 46.8 37.7 44.2 27.3

Adverse events of interest

Rash (any type)† Anemia‡ 35.9 17.9 17.3 20.0 29.9 22.1 30.4 17.7 28.5 19.4 27.3 20.8

ASPIRE: Study Design

This interim analysis was performed when all patients had completed 24 weeks of the study. HCV genotype 1 infected patients who failed previous PegIFN/RBV therapy

• 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

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 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) Viral Breakthrough:

• 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.

Viral Resistance in HCV

• HCV displays a high genetic diversity:
• ~1012 of HCV virions are produced daily and each newly generated genome contains ~1

mutation resulting in every single and some double mutations being generated daily1.

• On nucleotide level HCV shows up to 20-25% difference between isolates from different

subtypes and 8-12% within one subtype.2

• Within one patient HCV exists a population of genetically distinct but closely related

variants (quasispecies).3

• Most viral variants with potential resistance to direct acting antivirals are expected to be
• generated. But they are relatively unfit and mostly exist in very low frequency.4
• Resistant virus can emerge in patients failing treatment with direct acting

antivirals (DAA’s).

• HCV replicates in the cytoplasm using RNA intermediates. Potential to archive mutations?
• Maximizing SVR minimizes potential impact of resistance

1 Perelson et al 2010 2 Simmonds et al 2004 3 Domingo et al.1992 4 Kuntzen et al 2008

Viral Resistance in the Telaprevir and Boceprevir Ph3 studies

Majority of patients who did not achieve SVR in Telaprevir (REALIZE) and Boceprevir (SPRINT-2 and RESPOND-2) trials harbored resistant associated viral variants

Boceprevir Telaprevir

De Meyer et al., EASL 2011 Brass et al., EASL 2011

NS3 Mutations associated with reduced in vitro activity for TMC435

Mutations at NS3 position 43, 80, 155, 156, 168 identified in selection experiments

NS3 aa position Fold change in EC50 values 43 12-100 80 2-11 155 0.4-90 156 0.3-170 168 4.3->2000

Mutations at position F43 and A156 have been only in few instances observed in vivo

Resistance Analysis of the Ph2a TMC435-C201 study (OPERA-1)

TMC435 susceptibly in a transient replicon assay

• 8/82 patients who received TMC435 had

viral breakthrough during TMC435 dosing period.

• In all 8 patients emerging mutations at one
• r more of the following positions were
• bserved: Q80R or K, R155K or D168A, E, N
• r V
• Emerging mutation were associated with

significant increases of EC50 values against TMC435 in a transient replicon assay (chimeric genotype 1b assay)

Does Protease Inhibitor resistant virus persist (Example from telaprevir)?

• Re-treatment studies are needed to assess if these findings are clinically

relevant

Zeuzem et al. AASLD 2010 Telaprevir EXTEND study

Conclusion

• Direct acting antivirals such as HCV NS3/4A protease inhibitors have

been shown to improve treatment outcome in genotype 1 HCV infected patients

• In the week 24 interim analyses of Ph2b trials, TMC435 in combination

with PegIFN/RBV has shown higher virologic responses rates compared to PegIFN/RBV alone in HCV genotype 1 infected treatment naïve and experienced patients

• In the same studies, TMC435 was shown to be safe and well tolerated.
• Resistant viral variants can emerge in patients failing DAA based

treatment.

• These variants were no longer detected over time in the majority of
• patients. Impact on re-treatment is unknown.