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

 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 profile 1  Viramune extended release formulation (Viramune XR) may increase therapeutic benefit by improving compliance through once- daily (QD) dosing 1. Soriano V. et al Manuscript submitted VERX VE: Rationale for Viramune Extended Release (XR) Formulation

Objective:  To evaluate the efficacy of Viramune XR 400 mg QD vs Viramune IR 200 mg BID, in ARV treatment-naïve, HIV–1-infected patients after 48 weeks of treatment Study design: Double-blind, double-dummy, non-inferiority study 1:1 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 >100,000 copies/mL) VERX VE: Objectives and Study Design

Primary endpoint:  Sustained virologic response at 48 weeks defined as VL <50 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 VERX VE: Study Endpoints

ParameterViramune IRViramune XR Number of patients, N Gender Male, n Female, n7574 Age, mean Region North America/Australia Europe Latin America4958 Africa5749 Baseline HIV-1 viral load, median log 10 copies/mL4.7 CD4+ cell count, mean cells/mm History of AIDS (%)2630 Note: Total randomised=1068, 1011=randomized & treated (full analysis set, FAS), 2 randomized not treated, 55 DC during lead-in VERX VE: Demographic Data

ParameterViramune IRViramune XRTotal Randomized, N 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 events42 (8.3)32 (6.3)74 (7.3) Lost to follow-up7 (1.4)8 (1.6)15 (1.5) Consent withdrawn9 (1.8)4 (0.8)13 (1.3) Non-adherence9 (1.8)6 (1.2)15 (1.5) Lack of efficacy26 (5.1)24 (4.8)50 (4.9) Pregnancy0 (0.0)6 (1.2)6 (0.6) Other1 (0.2)3 (0.6)4 (0.4) VERX VE: Disposition of Randomized Patients Through Week 48 *None of the deaths/events were related to study medication, as judged by the investigators

Proportion of patients with Virologic Response Week 48 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% Virologic response was independent of age, gender, race or geographic region Viramune IRViramune XR VERX VE: Sustained Virologic Response at Week 48 (VL <50 copies/mL, FAS) FAS = Full analysis set

Viramune IR Viramune XR Weeks Proportion of Virologic Responders VERX VE: Proportion with Virologic Response by Visit (VL <50 copies/mL, FAS) FAS = Full analysis set

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 VERX VE: PK Sub-study at Day 28

200 mg NVP IR bid (n=25) 7000 Time [hours] Viramune Plasma (ng/mL) mg NVP XR qd (n=24) (N=25) (N=24) 200mg Viramune IR BID 400mg Viramune XR QD VERX VE: PK Sub-study at Day 28: Results

ParameterViramune IRViramune XR Total number of patients, n/N372/464 (80.2)406/486 (83.5) Geometric mean, trough ss (ng/mL),No. Responders/Total within stratum (n/N) <10003/5 (60.0)3/9 (33.3) 1000–<200025/31 (80.6)46/54 (85.2) 2000–<300050/66 (75.8)124/144 (86.6) 3000–< /125 (86.4)71/90 (86.4) ≥ /237 (78.5)43/57 (80.3) LLOQ (lower limit of quantification) = 50 copies/mL Virologic response rates stratified by geometric mean steady state (ss) trough plasma concentrations (ng/mL) FAS = Full analysis set VERX VE: PK-PD Response Week 48 (FAS): Viramune XR Equivalent to Viramune IR at ≥1000ng/mL

Change in median value from baseline at Week 48 (%) Substrate [mg/dL] Viramune IR (N=406) Viramune XR (N=419) Triglycerides-8 (–9%)-6 (–7%) Cholesterol22 (13%)19 (11%) LDL-c8 (9%)7 (7%) HDL-c12 (32%)10 (27%) Total cholesterol/HDL-c-14%-12% VERX VE: Percentage Change in Lipid Profile Viramune IR vs Viramune XR at Week 48 Viramune XR demonstrated a similar lipid friendly profile to that of Viramune IR

*Investigator defined. Please note: No drug-related fatalities. Atherosclerosis/hypertension; tuberculosis (meningitis); two sepsis, myocardial infarction; respiratory alkalosis. ParameterViramune IRViramune XR Number of patients (N) 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) Deaths5 (1.0)1 (0.2) Drug-related* AEs123 (24.3)100 (19.8) DAIDS Grade 3 or 4 AEs91 (18.0)73 (14.5) DAIDS Grade 4 AEs23 (4.5)16 (3.2) VERX VE: AE Summary Randomized Phase, FAS FAS = Full analysis set

 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 VERX VE: Conclusions

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