Douglas T. Dieterich, Juergen K. Rockstroh, Kenneth E. Sherman, Nathalie Adda, Lisa Mahnke, Varun Garg,

Shahin Gharakhanian, Scott McCallister, Vincente Soriano, and Mark S. Sulkowski

On behalf of the Study 110 Team

Interim Analysis of a Phase 2a Double-Blind Study of Telaprevir in Combination with

Peginterferon Alfa-2a and Ribavirin in HIV/HCV Coinfected Patients

Telaprevir: An Orally-Available HCV Protease Inhibitor

• Telaprevir (TVR) is a selective inhibitor of NS3/4A HCV serine protease

• In genotype 1 mono-infected patients, telaprevir with peginterferon alfa-2a/ribavirin (T/PR) led to substantial improvements in SVR in phase 3 studies1-4:o Treatment-naïve patients (ADVANCE trial, N=1088)1,

69-75% vs 44% in controlo Treatment-experienced patients (REALIZE trial, N=662)3:

31% vs 5% in control (prior null responders) 57% vs 15% in control (prior partial responders) 86% vs 24% in control (prior relapsers)

• Modest DDI between TVR and ART (EFV, ATV/r and TDF), no ART dose adjustment was deemed necessary5

• Higher TVR dose (1125 mg q8h) mostly offsets reduced exposures to TVR with EFV5

1Jacobson et al 2010, Hepatology 52(Suppl 4)427A; 2Sherman et al 2010, Hepatology 52(Suppl 4)401A-402A; 3Foster et al 2011 Hepatology Int 52(Suppl.1):14; 4Sherman et al. CROI 2011; Poster 957; 5van Heeswijk et al. CROI 2011; Abstract 146LB

Study Design

Part A: no ART

240 48 72Weeks 12 36

Follow-upPR48 (control)

PR SVR

Pbo + PR

T/PR TVR + PR Follow-upSVR

PR

Follow-upPR48 (control)

PR SVR

Pbo + PR

T/PR TVR + PR Follow-upSVR

PR

Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC)

(EFV)=efavirenz; (TDF)=tenofovir; (FTC)=emtricitabine; (ATV/r)=ritonavir-boosted atazanavir; (3TC)=lamivudine; (T) TVR=telaprevir 750 mg q8h or 1125 mg q8h (with EFV); Pbo=Placebo; (P) Peg-IFN=pegylated interferon alfa-2a (40 kD) 180 µg/wk; (R) RBV=ribavirin 800 mg/day or weight-based (1000 mg/day if weight <75 kg, 1200 mg/day for if weight ≥75 kg; France, Germany) Roche COBAS® TaqMan® HCV test v2.0, LLOQ of 25 IU/mL (pts with values below 25IU/mL were reported as <25 detectable or undetectable)

Principal Eligibility Criteria

• Male and female patients, 18 to 65 years of age with chronic HCV genotype 1/HIV‑1 co‑infection, and treatment‑naïve for HCV

• Liver biopsy within 1 year; compensated cirrhosis permitted

• Part A: up to 20 patients not receiving ART, with CD4 count ≥500 cells/mm3, and HIV RNA ≤100,000 copies/mL

• Part B: up to 48 patients receiving a stable ART regimen o TDF/EFV/FTC, or o ATV/r with TDF and FTC or 3TC, with CD4 count

≥300 cells/mm3, and HIV RNA ≤50 copies/mL

Study Objectives

• Primary Objectives:o Safety and tolerability of telaprevir, peginterferon, and

ribavirino Proportion of patients with HCV RNA undetectable after

12 weeks of telaprevir, peginterferon, and ribavirin

• Secondary Objectives:o Efficacy of telaprevir 24 weeks after last dose (SVR)o Pharmacokinetics of telaprevir, peginterferon and

ribavirino Selection of HCV resistant variantso Part B only: pharmacokinetics of pre-specified ART

medications

Methods

• Interim analysis based on 59 of 60 patients who received at least 1 dose of study drugs; 41/59 patients had reached week 12 at time of analysiso 13 patients from Part A o 46 patients from Part B

24 patients received TDF/EFV/FTC and, 22 patients received ATV/r + TDF + FTC or 3TC

• HIV RNA and CD4: Week 4, 8, 12 during TVR/Pbo• HCV RNA: Day 1, 2,4, and week 1, 2, 3, 4, 8 and 12 during

TVR/Pbo during TVR/Pbo dosing• Proportion of patients with undetectable HCV RNA at

weeks 4 and 12

Predefined Stopping Rules

• Viral breakthrough (in all patients), defined as HCV RNA >100 IU/mL after HCV RNA undetectable or a 1 log10 increase from nadir at Week 4, 8, and 12, discontinue all study drugs

Timepoint PatientsCriteria for Stopping

Action

Week 4 Week 8

Telaprevir patientsHCV RNA >1000 IU/mL

Discontinue TVR, continue PR

Week 12

TVR patients with ≤1000 IU/mL at Week 4 and 8

HCV RNA >1000 IU/mL

Discontinue all study drugs

All other patients HCV RNA <2 log10 decline

Discontinue all study drugs

Week 24 Week 36

All patientsHCV RNA detectable

Discontinue all study drugs

Demographics and Baseline Characteristics

Part A Part B

No ART EFV/TDF/FTC ATV/r + TDF + FTC/3TC

T/PRN=7

PRN=6

T/PRN=16

PRN=8

T/PRN=14

PRN=8

Gender, n (%): Male 6 (86) 4 (67) 16 (100) 7 (88) 12 (86) 7 (88)

Caucasian†, n(%)Black/African American, n(%)

2 (29)4 (57)

3 (50)3 (50)

12 (75)3 (19)

5 (62)3 (38)

12 (86)2 (14)

7 (88)1 (12)

Ethnicity†: Hispanic, n (%) 3 (43) 2 (33) 5 (31) 1 (12) 3 (21) 3 (38)

Age, median years (range) 39 (34-51) 48 (43-65) 48 (31-57) 47 (31-53) 54 (37-60) 39 (26-53)

BMI, median kg/m2 (range) 29 (22-37) 31 (26-37) 24 (21-32) 23 (19-29) 24 (23-33) 25 (22-30)

HCV RNA ≥ 800,000 IU/mL**, n (%)7 (100) 5 (83) 13 (81) 7 (88) 10 (71) 7 (88)

HCV Genotype Subtype*, n (%)1a1b

3 (43)4 (57)

3 (50)2 (33)

12 (75)4 (25)

6 (75)1 (12)

11 (79)3 (21)

5 (62)3 (38)

Bridging Fibrosis, n(%)Cirrhosis, n (%)

1 (14)0 (0)

0 (0)0 (0)

2 (12)2 (12)

1 (12)0 (0)

0 (0)0 (0)

1 (12)0 (0)

HIV RNA median copies/mL (range)

1495(155-53,450)

267(50-21,950)

<50 <50 <50 <50

CD4+ median cells/mm3 (range) 604 (496-759)

672(518-1189)

533 (299-1075)

514 (323-1034)

492(279-874)

535 (302-772)

†Race and ethnicity were self-reported *5’NC InnoLipa line probe assay**Roche COBAS® TaqMan® HCV test v2.0, LLOQ of 25 IU/mL (pts with values below 25IU/mL were reported as <25 detectable or undetectable)

Undetectable HCV RNA at Week 4 (ITT)

5/7 12/16 9/14 0/81/80/6

7175

0

64

12

0

Percent of patients with HCV RNA Undetectable

Telaprevir + PR

n/N =

PR

0

10

20

30

40

50

60

70

80

90

100No ART EFV/TDF/FTC ATV/r+TDF+FTC/3TC

PR

70

26/37 1/22

5

Total

Total

Undetectable HCV RNA at Week 12 (ITT)

5/7 12/16 8/14 1/81/81/6

71 75

17

57

12 12

Percent of patients with HCV RNA Undetectable

Telaprevir + PR

n/N =

PR

0

10

20

30

40

50

60

70

80

90

100

No ART EFV/TDF/FTC ATV/r+TDF+FTC/3TC

PR

68

14

3/2225/37

Total

Total

Median (IQR) Telaprevir Trough Plasma Concentrations were Similar with and without ART

EFV/TDF/FTC (n=6-11)ATV/r + TDF + FTC/3TC (n=6-8)

No ART (n=5-6)

2 4 6 8 10 12

1000

2000

3000

4000

0

Weeks

0

Telaprevir Trough Plasma Concentrations (ng/mL)

IQR: Interquartile range = Q3-Q1

HCV Virological Failure

• 2 telaprevir patients experienced viral breakthrough*:o 1 patient at week 4 (receiving ATV/r + TDF + FTC) o 1 patient at week 8 (receiving EFV/TDF/FTC)

• 4 patients discontinued treatment due to stopping rules:o 1 telaprevir patient (receiving EFV/TDF/FTC) at week

8o 3 placebo patients

• HCV sequencing has not been performed yet

*defined as HCV RNA >100 IU/mL after HCV RNA undetectable or a 1 log10 increase from nadir

Change from Baseline in Median (IQR) ART Trough Plasma Concentrations after T/PR Initiation

Time (Weeks)

Tenofovir (n=14-19)

Efavirenz (n=9-12)

Atazanavir (n=5-6)

Change from Baseline (%)

0 2 4 6 8 10 12

0

20

40

60

80

-20

-40

< 20% median change from baseline concentration

IQR: Interquartile range = Q3-Q1

-2

-1

0

1

4 8 12 Weeks

Mean (SD) Log10 HIV RNA Change

Mean (SD) HIV RNA Changes from Baseline

No ART (T/PR) EFV/TDF/FTC (T/PR) ATV/r+TDF+FTC/3TC (T/PR)No ART (PR) EFV/TDF/FTC (PR) ATV/r+TDF+FTC/3TC (PR)

Most Common Adverse Events*% T/PR

N=37PR

N=22

Fatigue 38% 41%

Nausea 35 14

Pruritus 35 5

Headache 32 27

Dizziness 22 5

Pyrexia 22 9

Anorexia 19 9

Vomiting 19 9

Diarrhea 19 18

Chills 16 18

*Reported in > 15% of patients regardless of severity in any treatment arm, in bold event occurring at > 10% points in any T group vs PR

Mild and moderate rash events occurred in 16% and 11% of T/PR patients, respectively and in 14% and <1% of PR patients

Serious Events and Treatment Discontinuation

Part A Part B

No ART EFV/TDF/FTC ATV/r + TDF + FTC/3TC

T/PRN=7

PRN=6

T/PRN=16

PRN=8

T/PRN=14

PRN=8

Any AE, n(%) 7 (100) 5 (83) 15 (94) 7 (88) 14 (100) 8 (100)

Serious AE*, n (%) 1 (14) 0 0 0 2 (14) 0

Discontinuation of all study drugs due to AE, n (%)

0 0 0 0 2 (14) 0

Due to jaundice 0 0 0 0 1 (7) 0

Due to anemia 0 0 0 0 1 (7) 0

Due to rash 0 0 0 0 0 0

*Bacterial infection (n=2), anemia (n=1)

Interim Analysis Summary

• In this interim analysis, the most common adverse events in telaprevir patients with or without concurrent ART were fatigue, nausea, and headache; no severe rash events were reported

• Patients in the T/PR arms in both parts exhibited a higher on-treatment HCV RNA response at week 4o T12/PR: 26 of 37 patients (70%)o PR: 1 of 22 patients (5%)

• No unexpected trends in HIV viral loads and/or CD4 counts were observed

• No clinically significant PK interactions were observed

Acknowledgements

We thank all the Study 110 trial patients and investigators

France• Vlad Ratziu• Pierre-Marie Girard

Germany• Peter Buggish• Juergen Rockstroh

Spain• Cristina Tural Llacher• Vincent Soriano

USA• Laveesa Bhatti• Edwin De Jesus• Douglas Dieterich• Brad Hare• Gregory Huhn• Dushyantha Jayaweera• Jacob Lalezari• Kenneth Sherman• Mark Sulkowski• David Wyles

We also thank study coordinators, and CROs who participated in the Study 110 trial, Elizabeth Zobre (I3) for statistical analysis, Christina Karunaratne and Dawn Vargas (Vertex Pharmaceuticals) for clinical project management, and Valérie Philippon, PhD, (Vertex Pharmaceuticals) for medical writing