Folie 1

1
VERX VE
Comparison of 48 week efficacy and safety of
400mg QD nevirapine (NVP) extended release
formulation (Viramune XR) versus 200mg BID
nevirapine immediate release formulation
(Viramune IR) in combination with
emtricitabine/tenofovir in antiretroviral (ARV)
naïve HIV-1 infected patients (VERxVE)
J. Gathe, JR. Bogner, S. Santiago, A. Horban, M.
Nelson, P. Cahn, J. Andrade, D. Spencer, C. Yong,
T. Nguyen, W. Zhang, M. Drulak and A. Quinson
Boehringer Ingelheim Pharmaceuticals Inc,
Ridgefield, CT, USA
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VERX VE Rationale for Viramune Extended Release
(XR) Formulation

• Viramune 200mg immediate release (IR) is a well
  established component of effective antiretroviral
  therapy in HIV-1 infected patients
• Viramune 200mg IR plus emtricitabine/tenofovir
  (FTC/TDF) recently demonstrated similar efficacy
  to atazanavir/ritonavir plus FTC/TDF, with a more
  favourable lipid profile1
• Viramune extended release formulation (Viramune
  XR) may increase therapeutic benefit by improving
  compliance through once-daily (QD) dosing

• 1. Soriano V. et al. 2010 Manuscript submitted

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VERX VE Objectives and Study Design

• Objective
• To evaluate the efficacy of Viramune XR 400 mg QD
  vs Viramune IR 200 mg BID, in ARV
  treatment-naïve, HIV1-infected patients after 48
  weeks of treatment
• Study design
• Double-blind, double-dummy, non-inferiority study
• 11 randomization to Viramune XR or Viramune IR
  after 14-day Viramune IR lead-in 200 mg QD dose
  (given to all patients)
• Emtricitabine/tenofovir (FTC/TDF) fixed-dose
  background ARV treatment
• Baseline viral load (VL) stratification
  (100,000 vs gt100,000 copies/mL)

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VERX VE Study Endpoints

• Primary endpoint
• Sustained virologic response at 48 weeks defined
  as VL lt50 copies/mL prior to and at week 48,
  without virologic rebound or change of ARV
  therapy
• Secondary endpoints
• Time-to-loss of virologic response (TLOVR)
• Time to new AIDS or AIDS-related progression
  event or death
• Genotypic resistance associated with virologic
  failure
• AEs, SAEs, AEs leading to discontinuation
  laboratory parameters

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VERX VE Demographic Data
Parameter Viramune IR Viramune XR
Number of patients, N 508 505
Gender
Male, n 433 431
Female, n 75 74
Age, mean 38.0 38.3
Region
North America/Australia 150 141
Europe 252 257
Latin America 49 58
Africa 57 49
Baseline HIV-1 viral load, median log10 copies/mL 4.7 4.7
CD4 cell count, mean cells/mm3 227 229
History of AIDS () 26 30
Note Total randomised1068, 1011randomized
treated (full analysis set, FAS), 2 randomized
not treated, 55 DC during lead-in
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VERX VE Disposition of Randomized Patients
Through Week 48
Parameter Viramune IR Viramune XR Total
Randomized, N 508 505 1013
Treated with blinded dose, n () 506 (100.0) 505 (100.0) 1011 (100)
Completed Week 48 visit, n () 409 (80.1) 421 (83.4) 830 (82.1)
Prematurely discont. prior to Week 48 visit, n () 97 (19.2) 84 (16.6) 181 (17.9)
Reasons for discont., n ()
Death/events leading to death 3 (0.6) 1 (0.2) 4 (0.4)
Adverse events 42 (8.3) 32 (6.3) 74 (7.3)
Lost to follow-up 7 (1.4) 8 (1.6) 15 (1.5)
Consent withdrawn 9 (1.8) 4 (0.8) 13 (1.3)
Non-adherence 9 (1.8) 6 (1.2) 15 (1.5)
Lack of efficacy 26 (5.1) 24 (4.8) 50 (4.9)
Pregnancy 0 (0.0) 6 (1.2) 6 (0.6)
Other 1 (0.2) 3 (0.6) 4 (0.4)
None of the deaths/events were related to study
medication, as judged by the investigators
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VERX VE Sustained Virologic Response at Week 48
(VL lt50 copies/mL, FAS)
Viramune IR
Viramune XR
100
90
80.99
80
75.89
Viramune IR 75.89 (384/506) Viramune XR 80.99
(409/505) Adjusted difference 4.92 in favour
of Viramune XR, with 95 CI of (-0.11, 9.96)
Viramune XR shows non-inferiority to Viramune
IR within pre-specified margin of -10
70
Proportion of patients with Virologic Response
Week 48
60
50
40
30
20
10
0
Virologic response was independent of age,
gender, race or geographic region
FAS Full analysis set
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VERX VE Proportion with Virologic Response by
Visit (VL lt50 copies/mL, FAS)
100.00
80.00
60.00
Proportion of Virologic Responders
40.00
Viramune IR
20.00
Viramune XR
0.00
0
2
4
6
8
12
16
24
32
40
48
Weeks
FAS Full analysis set
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VERX VE PK Sub-study at Day 28

• Designated trial centres participated in a
  pharmacokinetic sub-study, involving 30 patients
  from each treatment arm
• Blood samples collected intensively for 24 hr
  following morning NVP administration in week 4
  (visit 4) day 28
• Plasma NVP levels measured by tandem mass
  spectrometry (LC-MS/MS)
• Arithmetic mean (SD) plasma concentration of NVP
  following 400mg QD and 200mg BID dosing
  determined

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VERX VE PK Sub-study at Day 28 Results
200 mg NVP IR bid (n25)
(N25) (N24)

200mg Viramune IR BID 400mg Viramune XR QD
200 mg NVP XR qd (n24)
7000
6000
5000
Viramune Plasma (ng/mL)
4000
3000
2000
24
0
4
8
12
16
20
Time hours
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VERX VE PK-PD Response Week 48 (FAS) Viramune
XR Equivalent to Viramune IR at 1000ng/mL
Virologic response rates stratified by geometric
mean steady state (ss) trough plasma
concentrations (ng/mL)
Parameter Viramune IR Viramune XR
Total number of patients, n/N 372/464 (80.2) 406/486 (83.5)
Geometric mean, trough ss (ng/mL), No. Responders/Total within stratum (n/N) No. Responders/Total within stratum (n/N)
lt1000 3/5 (60.0) 3/9 (33.3)
1000lt2000 25/31 (80.6) 46/54 (85.2)
2000lt3000 50/66 (75.8) 124/144 (86.6)
3000lt4000 108/125 (86.4) 71/90 (86.4)
4000 186/237 (78.5) 43/57 (80.3)
LLOQ (lower limit of quantification) 50
copies/mL
FAS Full analysis set
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VERX VE Percentage Change in Lipid Profile
Viramune IR vs Viramune XR at Week 48
Change in median value from baseline at Week 48 () Change in median value from baseline at Week 48 ()
Substrate mg/dL Viramune IR (N406) Viramune XR (N419)
Triglycerides -8 (9) -6 (7)
Cholesterol 22 (13) 19 (11)
LDL-c 8 (9) 7 (7)
HDL-c 12 (32) 10 (27)
Total cholesterol/HDL-c -14 -12
Viramune XR demonstrated a similar lipid friendly
profile to that of Viramune IR
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VERX VE AE Summary Randomized Phase, FAS
Parameter Viramune IR Viramune XR
Number of patients (N) 506 505
Any AE, n () 452 (89.3) 443 (87.7)
AEs leading to discontinuation, n () 45 (8.9) 32 (6.3)
Serious AEs, n () 54 (10.7) 58 (11.5)
Deaths 5 (1.0) 1 (0.2)
Drug-related AEs 123 (24.3) 100 (19.8)
DAIDS Grade 3 or 4 AEs 91 (18.0) 73 (14.5)
DAIDS Grade 4 AEs 23 (4.5) 16 (3.2)
Investigator defined. Please note No
drug-related fatalities. Atherosclerosis/hypertens
ion tuberculosis (meningitis) two sepsis,
myocardial infarction respiratory alkalosis.
FAS Full analysis set
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VERX VE Conclusions

• Pivotal Trial (VERXVE) demonstrated
• non-inferior efficacy for Viramune XR to Viramune
  IR
• similar safety and tolerability for both
  formulations no new AEs identified
• the combination of Viramune IR or Viramune XR
  with FTC/TDF is an effective ARV treatment
• PK PD
• Similar efficacy noted across many PK strata
  indicating adequate trough drug exposure for
  Viramune XR
• Consistent relative trough exposure of Viramune
  XR to IR across gender, region, and baseline
  viral-load strata
• Once-daily dosing with VIRAMUNE XR provides
  patients with a more convenient treatment regimen
  with comparable efficacy and safety to VIRAMUNE
  IR

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VERX VE
Comparison of 48 week efficacy and safety of
400mg QD nevirapine extended release formulation
(Viramune XR) versus 200mg BID nevirapine
immediate release formulation (Viramune IR) in
combination with Truvada in antiretroviral (ARV)
naïve HIV-1 infected patients (VERxVE)
J. Gathe, JR. Bogner, S. Santiago, A. Horban, M.
Nelson, P. Cahn, J. Andrade, D. Spencer, C. Yong,
T. Nguyen, W. Zhang, M. Drulak and A. Quinson
Boehringer-Ingelheim Pharmaceuticals Inc,
Ridgefield, CT, USA