Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

1. Safety and efficacy of etravirine in HIV-1-infected, treatment-experienced children and adolescents: PIANO 48-week results Gareth Tudor-Williams,1 Pedro Cahn,2 Kulkanya Chokephaibulkit,3Jan Fourie,4 Christos Karatzios,5 Stephanie Dincq,6 Thomas Kakuda,7 Steven Nijs,6 Lotke Tambuyzer,6 Frank Tomaka7 1Imperial College, London, UK; 2Fundación Huesped, Buenos Aires, Argentina; 3Mahidol University, Bangkok, Thailand; 4Dr Jan Fourie Medical Practice, Dundee, KZN, South Africa; 5McGill University Health Centre, Montréal, Canada; 6Janssen Infectious Diseases BVBA, Beerse, Belgium; 7Janssen Research & Development, LLC, Titusville, NJ, USA Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

2. Pediatric study of Intelence as An NNRTI Option (PIANO) Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

3. Background • The efficacy and safety of the NNRTI etravirine (ETR, TMC125) has been demonstrated in the Phase III DUET trials in treatment-experienced, HIV-1-infected adult patients1–4 • In pediatric patients, there is a need for additional antiretrovirals (ARVs) with unique resistance characteristics and with appropriate dose and formulations • Week 24 results of the PIANO (TMC125-C213; NCT00665847) trial showed that ETR 5.2mg/kg bid (maximum dose 200mg bid) demonstrated safety and efficacy in HIV-1-infected, treatment-experienced children and adolescents aged 6 to <18 years5 • Safety, efficacy and pharmacokinetic results from the Week 48 analysis are presented 1. Madruga J, et al. Lancet 2007;370:29–382. Lazzarin A, et al. Lancet 2007;370:39–48 3. Katlama C, et al. AIDS 2009;23:2289–300 4. Katalama C, et al. Antiviral Ther 2010;15:1045–52 5. Tudor-Williams G, et al. 6th IAS 2011. Abstract TULBPE027 Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

4. Week 48 pooled DUET Phase IIIdata in adults1 Responders (% VL <50 c/mL; ITT-TLOVR) Mean change in CD4 cell count (ITT NC=F) 150 125 100 75 50 25 0 –25 100 90 80 70 60 50 40 30 20 10 0 ETR + BR (n=599) ETR + BR (n=599) Placebo + BR (n=604) Placebo + BR (n=604) +98 61% Mean change in CD4 cell countfrom baseline (cell/mm3) ± SE Responders (%) ± 95% CI +73 40% p<0.0001* p=0.0006† 0 2 4 8 12 16 20 24 32 40 48 0 2 4 8 12 16 20 24 32 40 48 Time (weeks) Time (weeks) • >90% of patients undetectable at 24 weeks were still undetectable at 48 weeks 1. Katlama C, et al. AIDS 2009;23:2289–300 *Logistic regression model; †ANCOVA model

5. PIANO: trial design Phase II, open-label, single-arm trial in HIV-1-infected, treatment-experienced children (6 to <12 years) and adolescents (12 to <18 years) Week 24 primary analysis Week 48 analysis Screening 6 weeks 48-week treatment period Follow-up 4 weeks Target 100 pediatric patients with screening viral load ≥ 500 copies/mL ETR 5.2mg/kg bid (maximum 200mg bid) + OBR OBR = ritonavir-boosted PI plus N(t)RTIs and optional enfuvirtide and/or raltegravir Primary objective: safety and tolerability over 24 weeks • Patients with evidence of ETR resistance (virco®TYPE HIV-1) were excluded • The trial was not powered to make statistical comparisons between children and adolescents OBR = optimized background regimen Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

6. Patient disposition • 76 patients(75%) completed the trial, i.e. received ETR treatment for 48 weeks; most discontinuations were for adverse events (AEs) or trial non-compliance Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

7. Baseline demographics *Race information not available for one child and one adolescent Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

8. Baseline disease characteristics †Actual value at the start of ETR treatment; if this value was missing, it was imputed with the screening value Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

9. Overview of adverse events • No deaths were reported *Only two patients (both children) reported grade 4 AEs (thrombocytopenia) and three patients had a grade 3 AE considered at least possibly related to ETR (two children: one with rash maculo-papular and one with hypersensitivity; one adolescent with diarrhea); †Two patients discontinued due to a grade 2 rash (2%) and two due to a grade 3 rash (2%) Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

10. Most common adverse events *Occurring in ≥10% of patients overall; †grouped term including rash (not further specified), rash maculo-papular, rash generalized, rash erythematous, rash macular, rash papular, and rash pruritic; ‡occurring in ≥2% of patients overall. No cases of Stevens-Johnson Syndrome. Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

11. Grade 3 or 4 treatment-emergent laboratory abnormalities *Fasted values; LDL = low-density lipoprotein; PT = prothrombin time • There were no consistent or clinically relevant changes in lipid parameters over time Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

12. Proportion of patients with viral load <50 or <400 HIV-1 RNA copies/mL at Week 48 (NC=F) 76% 67% 62% 68% 56% Patients with HIV-1 RNA <50 or <400 copies/mLat Week 48, % 48% 31/41 37/60 68/101 28/41 29/60 57/101 • Overall, more than half of patients achieved viral load <50 HIV-1 RNA copies/mL • response was similar at Week 48 compared to Week 24 Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

13. Proportion of patients with viral load <50 HIV-1 RNA copies/mL over 48 weeks (ITT-TLOVR) Children (6 to <12 years) (n=41) Adolescents (12 to <18 years) (n=60) All patients (N=101) 100 90 80 70 60 Responders (%) ± 95% CI 50 40 30 20 10 0 0 2 4 8 12 16 24 32 40 48 Time (weeks) Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

14. Change in CD4 cell count (NC=F) Children (6 to <12 years) (n=41) Adolescents (12 to <18 years) (n=60) All patients (N=101) 250 200 Mean (95% CI) change from baseline in CD4 cell count, cells/mm3 150 +178 +156 100 +141 50 0 0 8 12 2 16 24 4 32 40 48 Time (Weeks) Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

15. Adherence to ETR Proportion of patients, % 46% 39% 35% 17/37 35/89 18/52 69% 65% 61% • Adherence was measured either by pill count ([actual amount taken / amount to be taken] x 100%) and questionnaire (‘have any doses been missed over the last 3 days?’) • Self-reported adherence was higher than adherence estimated by pill count • Adherence by pill count is an independent predictor of virologic response as determined by an exploratory multivariate logistic regression model 27/39 35/57 62/96 Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

16. Virologic failure and resistance *Observed in at least three patients; †Y181C, V90I, L100I, and E138A are known ETR resistance-associated mutations (RAMs); endpoint = the last available on-treatment time point with a genotype after failure Tambuyzer L, et al. Antivir Ther 2012;17 Suppl 1: A58. Abstract 47 Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

17. Box plots of AUC12h and C0h 10,000 100,000 x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x 1,000 x x 10,000 x x x x x x x x x x x x x x x x x x x x 1,000 AUC12h (ng•h/mL) C0h (ng/mL) 100 x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x 10 100 x x x x x x x x 10 1 Children n=41 Adolescents n=60 Adults N=575 Children n=41 Adolescents n=60 Adults N=575 Reference line indicates median AUC12h or median C0h, respectively, in adults in the DUET studies1 AUC12h = area under the plasma concentration-time curve over 12 hours at steady-state and C0h = predose plasma concentration, both derived using population pharmacokinetic model 1. Kakuda TN et al. ClinPharmacolTher 2010;88:695–703 Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

18. Conclusions • ETR 5.2mg/kg bid (maximum dose 200mg bid) demonstrated safety and efficacy in this treatment-experienced population of HIV-1-infected children and adolescents aged 6 to <18 years • While the trial was not designed for comparison between children and adolescents, there were numerically higher virologic responses in children than adolescents • most likely due to less advanced disease, better adherence and less NNRTI use prior to treatment with ETR in children vs adolescents • There is an ongoing program evaluating the efficacy and safety of ETR in younger treatment-experienced children (IMPAACT; NCT01504841) Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

19. Acknowledgements • We would like to express gratitude to • the patients who participated in this trial and their families, the investigators and the trial centre staff • Janssen R&D team members, in particular M Opsomer, J Verspeelt, A Vandingenen, J Vingerhoets and F Blancke, and for their input into this presentation, D Anderson, G De La Rosa, B Hadacek and E Wong • This trial was sponsored by Janssen R&D Ireland • Medical writing support was provided by I Woolveridge of Gardiner-Caldwell Communications, Macclesfield, UK; this support was funded by Janssen. • The authors have the following conflicts of interest to declare: GTW has served as chair or member of the Data Safety and Monitoring Board for GlaxoSmithKline (GSK) and Bristol-Myers Squibb (BMS), and as an advisory board member for ViiV Healthcare, and received funding for travel and accommodation from Janssen; PC has served as an advisory board member for Avexa, Gilead Sciences and Merck, Myriad, Pfizer, Pharmasset, Schering-Plough and Janssen, as an investigator for Abbott Laboratories, Avexa, BoehringerIngelheim (BI), BMS, Gilead Sciences, GSK, Roche, Merck, Pfizer, Pharmasset, Schering-Plough and Janssen, as a speaker for Abbott Laboratories, BMS, BI, GSK, Merck, Pfizer and Janssen, and as a scientific advisor for Avexa, GSK, Merck Sharp & Dohme, Pfizer and Janssen; CK has served as a paid lecturer for Abbott Laboratories (2008–2009) and as a media representative for Janssen upon the approval and launch of darunavir in 2009; SD, SN, LT, TNK and FT are full time employees of Janssen. KC and JF declare they have no conflicts of interest.