INTELENCE (Etravirine) UPDATE Global Clinical Research Rekha Sinha, MD January 30, 2009

Etravirine (ETR) Safety and Tolerability - Pooled Data from Phase III Trials - Short-term safety in Pediatric Population Planned Trials with Etravirine Etravirine Resistance Overview of Presentation

Clinical Data: Previous Human Experience Phase I (57 trials) Total N=1167 (healthy) 96 (HIV-1 infected) Phase IIb 6 trials Total N= 442 Phase IIa (POP) 3 trials Total N=48 Phase III (Pivotal) DUET: 2 trials (C206 and C216) Total N=599 Additional ongoing trials Worldwide Expanded Access and CU (9000) DUET rollover trial (N - 300) Pediatric Study Phase I completed N= 41 Phase II ongoing N= 100 NDA 2007 FDA approval January 2008

ETR Safety and Tolerability: DUET Trials (TMC125-C206/C216)

24-week primary analysis DUET-1 and -2 differed only in geographical location; pooled analysis was pre-specified Major inclusion criteria: – Plasma viral load >5,000 HIV-1 RNA copies/mL and stable therapy for ≥8 weeks – ≥1 NNRTI RAM*, at screening or in documented historical genotype – ≥3 primary PI mutations at screening Patients recruited from Thailand, Australia, Europe and the Americas Screening 6 weeks 600 patients target per trial 48-week treatment period with optional 48-week extension *BR = darunavir/ritonavir with optimized NRTIs and optional enfuvirtide TMC125 + BR* Placebo + BR* Follow up 4 weeks *From extended list of 41 NNRTI RAMs (Tambuyzer et al. Abstract 67 EHDRW 2007); BR = background regimen; RAM = resistance-associated mutation Design and Major Inclusion Criteria

Response (<50 copies/mL) at Week 48 (ITT-TLOVR) 61% of patients in the ETR group achieved a confirmed undetectable viral load (<50 copies/mL) compared with 40% in the placebo group (p<0.0001) ITT-TLOVR = intent-to-treat time-to-loss of virologic response; ETR = etravirine; BR = background regimen CIs = confidence intervals; p value from logistic regression model 61% 40% p< Patients with viral load <50 copies/mL at Week 48 (%) (± 95% CIs) Time (weeks) Placebo + BR (n=604) ETR + BR (n=599) Modified from Johnson M et al., 15 th CROI Abstract 791

Overview of AEs (regardless of causality) There were no consistent or clinically relevant trends in laboratory, vital signs or ECG data The profile of laboratory abnormalities, including hepatic and lipid parameters, was generally similar between the ETR and placebo groups Parameter, % ETR + BR (n=599) Placebo + BR (n=604) Any AE (any cause)96 Grade 3 or 4 AE3335 Serious AE2023 Discontinuation due to AE76 Death (any cause)23 Most common AEs Rash (any type)1911 Diarrhea1824 Nausea1513 Headache1113 AEs of interest Nervous system disorders1720 Psychiatric disorders1720 Hepatic AEs76 Johnson M et al., 15 th CROI Abstract 791

Rash (1) In the ETR group – early onset: median 14 days – limited duration: median 15 days – low severity: mostly mild-to-moderate; 1.3% grade 3, no grade 4 ● mostly maculopapular; no mucosal involvement – infrequently led to permanent discontinuation: 2.2% of ETR group, 0% in placebo group ● mostly resolved with continued treatment Investigator assessment of cause of rash, % ETR group (n = 599) Placebo group (n = 604)Significance Any cause P = Rash with etravirine: usually mild-to-moderate and infrequently led to permanent discontinuation

Most common Nervous system events (reported in ≥ 1.0% of patients in the ETR group) Headache Dizziness Somnolence Nervous system* & Psychiatric disorders AEs: similar incidence to placebo, low severity, did not lead to discontinuation *Selected based on the nervous system events commonly associated with approved NNRTIs. Most common psychiatric events (reported in ≥ 1.0% of patients in the ETR group) Insomnia Depression Anxiety Sleep disorder No increased risk in patients with a history of psychiatric disorders Abnormal dreams/nightmares were similar in incidence to placebo (0.8% vs 1.0% for the ETR and Placebo groups respectively) No episodes of hallucinations, suicidal ideation, or manic symptoms in the ETR group

Hepatic AEs and laboratory abnormalities ALT = alanine aminotransferase; AST = aspartate aminotransferase. Hepatic AEs, % ETR group (n = 599) Placebo group (n = 604) Any cause or severity Grade 3/43.0 Leading to discontinuation Laboratory abnormalities ALT elevated (grade 3/4) AST elevated (grade 3/4) 1.6/0.81.2/ /0.41.2/0.2 Hepatic disorders: similar incidence to placebo, low severity, infrequently led to discontinuation

Safety conclusions Safety and tolerability of ETR were generally comparable to placebo, except for the incidence of rash (any type) Overall, most AEs were of low severity and infrequently led to discontinuation Rash, the only AE to occur more frequently with ETR – generally mild-to-moderate – most often resolved with continuing treatment – infrequently led to discontinuation Nature and incidence of nervous system and psychiatric AEs were similar to placebo ETR was not associated with any increase in laboratory abnormalities, including hepatic and lipid parameters

Safety in Pediatric population Phase I trial in children (6-17 years)

40 treatment experienced children on a Stable ARV & Virologically suppressed Group 1  6 to  12 years Group 2  12 to  17 years Screening up to 28 days Treatment Phase 7 days Follow-up 1 month Stage I 20 subjects (10/Group) Dose: 4 mg/kg b.i.d TMC125-C126 Trial Design Stage II 20 subjects (10/Group) Dose: 5.2 mg/kg b.i.d Interim analysis Stable ARV: LPV/rtv and a minimum of 2 NRTIs +/- ENF

Most Common AEs *  10.0% in TMC125 group TMC125-C126 AE regardless of causality*, N ( %) Stage I N=21 Stage II N=21 Infections and infestations 4 (19.0) 3 (14.3) Rhinitis 2 (9.5) Nervous system disorders 3 (14.3) Headache 3 (14.3) Gastrointestinal disorders (9.5) (9.5) Diarrhoea 0 1 (4.8) Nausea 1 (4.8) Skin and subcutaneous tissue disorders 2 (9.5) 1 (4.8) Rash Rash maculopapular 1 (4.8) 0000

Conclusion Based on the comparable exposures of TMC125 in children to that seen in adults from the DUET trials and the overall safety of TMC125 in Stage II of TMC125-C126 The recommended dose per weight band for children and adolescents aged between 6 and 17, inclusive, will be based on 5.2 mg/kg b.i.d.

Planned trials with ETR - New target population - New ARV regimen

ETR, RAL plus 3TC in HIV-infected Early Treatment-Experienced Patients Phase IV Single arm open label design Population: First or Second line failure, VL > 500 c/mL, Sensitive to ETR, Naïve to integrase N= 50 ARV regimen: ETR 200mg/ RAL 400mg/ lamivudine 150mg each b.i.d Duration: 48 week study Objective: To assess the percentage of early treatment- experienced HIV-infected patients that have achieved an HIV RNA <50 copies/mL at week 24

Study of Efavirenz Neuropsychiatric Symptoms versus Etravirine (SENSE) Double blind, active controlled trial Population: Treatment naive, VL > 5000 cp/mL, sensitive to ETR and background regimen (2 NRTIs), no NNRTI resistance N= 150 ARV regimen: ETR 400 mg q.d ( 4 ETR tablets 100 mg each) versus efavirenz 600 mg q.d Duration: 48 week study Objective: To compare neuropsychiatric adverse event profile of ETR versus efavirenz in combination with 2 N(t)RTIs as assessed at Wk 12

ETR in a Nucleoside Sparing Regimen Open label, active controlled trial Population: Treatment experienced, NNRTI resistant, VL > 500 cp/mL, sensitive to ETR and background regimen N= 520 ARV regimen: ETR 200 mg b.i.d plus PI/rtv versus PI/rtv plus 2 N(t)RTIs Duration: 48 week study Objective: Efficacy of ETR given in a PI-containing N(t)RTI-sparing regimen in terms of the proportion of subjects achieving a plasma viral load < 50 HIV-1 RNA copies/mL at Week 24.

ETR Resistance

Table 1. Overview of the NNRTI mutations The list of 44 NNRTI RAMs was expanded to 57 mutations by addition of all mutations at NNRTI resistance amino acid positions 17 NNRTI related mutations that blunt response to ETR identified based on the DUET analysis The frequency and virologic response in patients with the mutations at baseline is shown (if n  5), along with the ETR FC in a site-directed mutant (SDM) ETR RAMs 2008 Response rate below threshold (<51.9%) The following mutations were present in <5 patients at baseline: K101N, K103H, K103T, V106A, V106M, E138G, E138K, V179A, V179E, V179G, Y181F, Y188C, Y188F, Y188H, G190C, G190E, G190Q, G190R, F227C, M230I, M230L, P236L, K238N and N348T ETR FC >3.0 Mutation No. of patients with mutation at baseline No. of patients with <50 cps/mL at Week 24 Response rate (<50 cps/mL) in pooled DUET (%) V90I A98G A98S L100I K101E K101H K101P K101Q K101R K103N K103R K103S V106I NA V108I E138A E138Q V179D V179F V179I V179T Y181C Y181I Y181V Y188L V189I G190A G190S H221Y P225H F227L M230L K238T Y318F N348I NA ETR FC in single SDM

Figure 1. Effect of the ETR RAMs 2008 (n=17) on virologic response Patients with confirmed VL HIV-1 RNA <50 copies/mL (%) *No detectable baseline NNRTI RAM from the list of 44; Mutations in the ETR RAM list of 2008 but not 2007 are underlined % of response in patients without NNRTI RAMs *No mutation L100l G190A V90l E138A Y181l M230L A98G Y181CK101EK101P K101H V179D V106l V179T Y181V G190S V179F

*Median (Q1–Q3) FC for all isolates was 3.0 (1.1–9.3); § V179F was never present as single ETR RAM (always with Y181C) § MedianQ1–Q3n Y181I – High3 Y181V – High3 K101P – High2.5 L100I – Medium2.5 Y181C – Medium2.5 M230L – High2.5 E138A – Medium1.5 V106I – NALow1.5 G190S – Low1.5 V179F 0.7– – 00.1Medium1.5 V90I – Low1 V179D – Low1 K101E – Low1 K101H – Low1 A98G – Low1 V179T – Low1 G190A – Low1 Effect on FC in linear model Weight factor ETR FC in the subset of HIV-1 clinical isolates with 1 ETR RAM (n=1,619), regardless of the presence of other NRTI or NNRTI RAMs* Prevalence (%) in the panel of 4,248 HIV-1 clinical isolatesMutation ETR FC in a single SDM Etravirine Weighted Genotype Score to Predict Response

Effect of ETR FC Increasing ETR FC was associated with a gradual loss in virological response CCOs as defined by Tibotec: FC = 3 and FC = 13 Modified from Peeters, M, et al. IHDRW Poster 121

Patients with confirmed VL HIV-1 RNA <50 copies/mL (%) Highest response Intermediate response Reduced response Weighted score for the 17 ETR RAMs 2008 Figure 6. Relation between the weighted score and the virologic response (<50 copies/mL) Hatched bars indicate virologic response for the entire category 74.4% 52.0% 37.7%  4/131/33/914/2719/3611/156/1137/53115/14832/592/71/54/92/11N Response category

Understanding Etravirine Susceptibility The virologic response is a function of the number and weight of the baseline ETR RAMs Among the 17 ETR RAMs, Y181I and Y181V had the highest weight, followed by L100I, K101P, Y181C and M230L Among the 17 ETR RAMs, mutations with the highest weight had a low prevalence Weighted mutation score of 0-2 Highest response rates (74%) Weighted mutation score of Intermediate response rates (52%) Weighted mutation score of >/=4 Reduced response rates (74%) ·