Durability of Response and Rate of Re-emergence of Wild Type at Boceprevir (BOC) Resistance-Associated Variant (RAV) Loci in Genotype 1a and 1b Patients:Interim Analysis of Long-Term Follow-Up of Patients Treated With Boceprevir + PegIntron +/-Ribavirin

Richard J.O. Barnard, John Howe, Donald J. Graham, Robert A. Ogert, Jianmin A. Long, Navdeep Boparai, Patricia Mendez, Clifford Brass, Janice Albrecht, Robert Ralston

Summary of Boceprevir

• Boceprevir is a NS3 protease inhibitor that has completed phase 3 clinical trialso RESPOND-1; Phase 2 Dose finding-study in previous null responders +

IFN +/- RBVo SPRINT-1; Phase 2 Safety/Efficacy Study in treatment naïve patients

+IFN/RBVo SPRINT-2; Phase 3; Response-guided therapy vs 48-week therapy

study + IFN/RBV in treatment naïve patients (800mg BOC TID)o RESPOND-2; Phase 3; Response-guided therapy vs 48-week therapy

study + IFN/RBV in previously treated patients (800mg BOC TID)• SVR rates were superior to control arms in RESPOND-2, (59-66% vs

21%) and SPRINT-2 (63-66% vs 38%)• Resistant Associated amino acid Variants (RAVs) were detected in 53%

of non-SVR patients in SPRINT-2/RESPOND-2 studies• As HCV does not integrate into the human genome, the issue of the

longevity of RAVs selected in non-SVR patients is unknown

IFN = Pegylated Interferon, RBV = Ribavirin

In vitro Characterization of Boceprevir NS3 RAVs in Enzymatic Studies

Position 170 is Isoleucine in genotype 1a and Valine in Genotype 1b

0

2

4

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14

16

18

V36Ma T54A T54S V55AR155KaA156SI/V170A

Fold Change Ki*

Genotype 1aGenotype 1b

Majority Variants Detected from Clinical Studies (Present in >25% of Patients)Genotype 1a; V36M, R155KGenotype 1b; T54A, T54S, A156S, V170AVariants also detected at Position V55, V158 and M175L

Long-Term Follow-Up Study

• These analyses were undertaken to characterize the rates of re-emergence of wild-type at boceprevir resistant loci in non-SVR patients with detectable RAVs

• Study Descriptiono Patients are being monitored for at least 3.5 years post-therapyo Resistance variants were detected by population sequencing of the NS3

protease region (aa codons 1-181)

Patients whoreceived atleast one doseof studymedication in a previousPhase 1, 2, or 3BoceprevirClinical Study

EOTa

Study duration max 3.5 years after EOT

Screening/

BaselineMo3

Mo6

Mo12

Year 1

Mo18

Mo24

Year 2

Year 3

Mo30

Mo36

apatients may have rolled over at different times after enrollment in the previous treatment protocol.

Objectives and Criteria for the Interim Analysis of Resistance

• Initial aim was to characterize the presence of boceprevir RAVs over time by population sequencing (~20-25% Sensitivity)

• Patients in interim analysis had to have viruses with at least one of the majority RAVs (detected in ≥25% of non-SVR patients) V36M, T54A/S and/or R155K

• Patients had to have viruses that were wild-type at that position prior to receiving boceprevir

• Patients had to have at least two years of follow-up data (183 patients in this interim analysis); majority of patients from RESPOND-1

Baseline Demographic and Disease Characteristics

• Demographic and baseline characteristics of age, sex, race, ethnicity, weight,  BMI and  viral load are consistent with previously studies in HCV patients

• Patients enrolled in the long-term follow up study were typically white males; average age was 49 to 52  years 

• The distribution of genotypes was similar among the patient groups

• The average length of time since probable exposure to HCV was 25 to 30 years

Return of Wild-Type at Individual RAV Loci by Population Sequencing

Genotype 1b

RAV not detected @ individual RAV Loci, %

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Time Since the End of Treatment (Yrs)

0 0.5 1 1.5 2

T54AT54S*All RAVs

Genotype 1a

*Refers to any Boceprevir RAV (Includes V36, Q41, F43, T54, V55, R155, A156, V158, I/V170)

RAV not detected @ individual RAV Loci, %

2

Time Since the End of Treatment (Yrs)

0.5 1 1.5

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

V36M

T54SR155K

*All RAVs

0

Median Rates of Return of Wild-Type at Specific RAV Loci

#Refers to any Boceprevir RAV (Includes V36, Q41, F43, T54, V55, R155, A156, V158, I/V170)*By population sequencing

Genotype 1A V36M T54S R155K ANY#

% RAVs Return to Wild Type* within 2 Years 88.4% 60.3% 69.8% 56.1%

Median Time Return to Wild Type* in Years (95% CI)

0.78(0.5, 1.0)

1.46(1.1, 1.8)

1.28(1.1, 1.4)

1.53(1.4, 1.9)

Genotype 1B T54A T54S ANY#

% RAVs Return to Wild Type* within 2 Years 100.0% 67.4% 60.0%

Median Time Return to Wild Type* in Years (95% CI)

0.24(0.1, 0.4)

1.24(0.8, 1.8)

1.50(1.1, 2.0)

Individual Viral Load Plots from Patients infected with Genotype 1b Virus

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1

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8

-16 BL 16 32 48 64 80 96 112 128 144 160 172 198

WT

Log10 Viral Load (IU/mL)

T54A/S & V170A

T54S & V55A

T54S

WT WT WT

Time (Weeks)

Genotype 1b Patient 1

Time (Weeks)

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1

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3

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5

6

7

8

WT

-16 BL 16 32 48 64 80 96 112 128 144 160 172 198

WT

T54A

T54AV158I/M

T54A

Log10 Viral Load (IU/mL)

Genotype 1b Patient 2

WT = Wild Type BL = Baseline

IFN/RBV Lead-In

IFN/RBV + BOC

Follow-up

Viral Load Plot from a Patient infected with Genotype 1a Virus

V36MR155K

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25

50

75

100

Variant Frequency, %

Quantification of VariantsBy 454-Sequencing

Week 28

V36MR155K

Week 100

LOQ= Limit of QuantificationWT = Wild-Type

IFN/RBV + BOC

Follow-up

Longitudinal Analysis

75 1000 5 10 15 20 25 30 35 40 45 501

2

3

4

5

6

7Wk 28

Week

Log10 Viral Load (IU/mL)

LOQ

WT

V36M/R155K

V36M/R155K

V36M/R155K

Conclusions

• Different RAVs are selected in genotype 1a and 1b viruses• WT at each RAV loci re-emerged at different rates depending on the

specific RAV selectedo WT re-emerged most rapidly in genotype 1a or 1b viruses with V36M or

T54A, as compared to viruses with either T54S or R155K• Variation in the appearance of resistance and rates of re-emergence

of WT at each loci reflects relative fitness of the specific RAVs in the specific genetic background

• In patients that fail with multiple RAVs, individual RAVs can decline at different rateso Studies are ongoing to analyze the linkage in viruses with multiple

RAVs• The majority of patients in this interim analysis are from phase 2

studies