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6 th IAS Conference, July 17-20, 2011, Rome, Italy

Efficacy and safety of lersivirine vs efavirenz in antiretroviral treatment-naïve HIV-1-infected patients: Week 48 primary analysis results from an ongoing, multicenter, randomized, double-blind, Phase 2b trial (Study A5271015) .

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6 th IAS Conference, July 17-20, 2011, Rome, Italy

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  1. Efficacy and safety of lersivirine vs efavirenz in antiretroviral treatment-naïve HIV-1-infected patients:Week 48 primary analysis results from an ongoing, multicenter, randomized, double-blind, Phase 2b trial (Study A5271015) P Vernazza,1 C Wang,2A Pozniak,3 E Weil,2 P Pulik,4 DA Cooper,5 R Kaplan,6 A Lazzarin,7 H Valdez,8 J Goodrich,9 C Craig,10 J Mori,10M Tawadrous2 1Cantonal Hospital, St. Gallen, Switzerland; 2Pfizer Inc., Groton, CT, USA; 3Chelsea & Westminster Hospital, London, UK; 4Provincial Infectious Hospital of Warsaw, Warsaw, Poland; 5Kirby Institute, University of New South Wales, Sydney, Australia; 6Desmond Tutu HIV Foundation, Cape Town, South Africa; 7Universita Vita-Salute San Raffaele, Milan, Italy; 8Pfizer Inc., New York, NY, USA; 9ViiV Healthcare, Research Triangle Park, NC, USA; 10Pfizer Global Research & Development, Sandwich Laboratories, Kent, UK 6th IAS Conference, July 17-20, 2011, Rome, Italy

  2. Lersivirine: a next-generation NNRTI with unique binding and potent activity against HIV-1 Binds to the reverse transcriptase (RT) enzyme in a novel way1 Unique resistance profile2 Antiretroviral (ARV) activity2 IC50 = 5.83 nM; 1.81 ng/mL (PBC) Resistance generated in vitro2 V108I pathway to resistance Synergy between lersivirine (LRV) and NRTIs and integrase strand-transfer inhibitors2 Y181 X-ray crystal structure of LRV bound at the non-nucleoside binding site of recombinant HIV-1 RT Lersivirine K103 *PBC= protein binding corrected 1. Phillips C et al. 2007; 2. Corbau R et al. 2010

  3. Phase 2b treatment-naïve trial design Randomized, double-blind, comparative study Selection criteria ARV naïve HIV-1 RNA ≥1000 c/mL CD4+ >200 cells/mm3 No RT mutations by standard genotyping Stratified by viral load (<100,000 or ≥100,000 c/mL) & geographic region (A & B) LRV 500 mg QD + TDF/FTC Randomization 1:1:1 LRV 750 mg QD + TDF/FTC EFV 600 mg QD + TDF/FTC 6 weeks 0 24 wk 48 wk 96 wk Planned interimanalysis Primary endpoint: Patients achieving HIV-1 RNA <50 c/mL c/mL, copies per milliliter; LRV, lersivirine; QD, once daily; TDF/FTC: tenofovir disoproxil fumarate/emtricitabine

  4. Statistical methods Primary efficacy endpoint Percentage of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 (non-completer/missing=failure), ITT Treatment differences estimated by Cochran-Mantel-Haenszel adjusting for stratification factors 2-sided 80% confidence interval Secondary endpoints Change from baseline CD4+ cell counts (LOCF, ITT) Fasting change from baseline lipid endpoints (observed values, completers) ANCOVA including stratification factors and baseline measurements as covariates 2-sided 80% confidence interval ITT, intent-to-treat; LOCF, last observation carried forward. ANCOVA= analysis of covariates

  5. Patient disposition 294 subjects screened 99 ineligible 195 randomized 66 randomized to LRV 750 mg 63 randomized to EFV 66 randomized to LRV 500 mg 1 did not receive study drug 1 did not receive study drug 0 did not receive study drug 65 treated 63 treated 65 treated • Discontinuations • 4 Insufficient clinical • response • 3 AE • - Vomiting* • Disturbance in attention* • - B-cell lymphoma • 2 Lost to follow-up • 3 Others • Discontinuations • 5 Insufficient clinical • response • 3 AE • - Hypersensitivity* • ↑ ALT* • - Leukocyturia* • 1 Lost to follow-up • 3 Others • 9 Discontinuations • 1 Insufficient clinical • response • 5 AE • - ↑ ALT, AST, amylase* • Psychotic disorder * • Abnormal dreams, mental disorder, suicidal ideation * • Anxiety* • Disturbance in attention* • 0 Lost to follow-up • 3 Others 54 remaining in study at ≥48 weeks 53 remaining in study at ≥48 weeks 53 remaining in study at ≥48 weeks AE, adverse event; “Others”= subjects no longer willing to participate in study, withdrawn due to pregnancy, relocation * Considered by Investigator to be at least possibly related to study drug

  6. Demographic and baseline characteristics Randomized = 195 Treated = 193

  7. Efficacy results through Week 48 (plasma HIV-1 RNA <50 c/mL, ITT, NC=F) 0 2 4 8 16 24 32 40 48 54/63 (86%) 51/65 (79%) 51/65 (79%) Week 48 Analysis: • *Cochran-Mantel-Haenszel estimates were adjusted for randomization variables of screening HIV-1 RNA level and geographic region. A 2-sided 80% confidence interval was used. NA, not applicable; SE, standard error.

  8. Efficacy by screening plasma HIV-1 RNA and geographic region (ITT, NC=F) LRV 500mg LRV 750mg EFV 600mg 88 87 86 84 83 82 81 80 75 72 68 62 % subjects with plasma HIV-1RNA <50 c/mL through Week 48 N= N= 45 44 41 20 21 22 47 43 39 18 22 24 <100,000 ≥100,000 Region A Region B EU, LatinAmerica, Australia,Canada SouthAfrica

  9. Efficacy in Regions A and B by screening plasma HIV-1 RNA (ITT, NC=F) LRV 500mg LRV 750mg EFV 600mg 89 87 87 86 85 81 81 79 78 77 50 % subjects with plasma HIV-1RNA <50 c/mL through Week 48 38 N= N= 31 30 26 16 13 13 14 14 15 4 8 9 <100,000 ≥100,000 <100,000 ≥100,000 Region A EU, Latin America, Australia, Canada Region B South Africa

  10. Change from baseline CD4+ cell count (cells/mm3) (LOCF, ITT) 0 4 8 12 16 24 32 40 48 LRV 750 = 195 cells/mm3 LRV 500 = 191 cells/mm3 EFV = 188 cells/mm3 Baseline was the average of all the values obtained predose

  11. Resistance analysis through 48 weeks FC, fold-change IC50 to wild-type reference strain; FTC, emtricitabine; TDF, tenofovir; EFV, efavirenz; NM, no mutation 1Plasma HIV-1 RNA <500 c/mL 2Confirmation of failure, E_Term or Week 48 sample 3 M230I (study exclusion mutation) detected at screening 4V90I detected at screening and baseline (baseline FC=2.1) 5P225P/L detected at failure * Sample taken outside of 48-week window Also see Craig, C et al. Minority species resistance present at screening does not affect ourcomes at week 48. IAS Rome. Poster MOPE161.

  12. Summary of clinical adverse events (AEs)

  13. All-causality AEs(All severities, ≥10% incidence in any group) *Includes reported terms of: rash erythematous, rash macular, and rash pruritic Bold text indicates AEs of interest for which there was a higher rate of occurrence in either (i) both LRV groups versus EFV, or (ii) EFV versus both LRV groups

  14. Grade 3 or 4 AEs (treatment-related) ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatinine phosphokinase

  15. Summary of laboratory abnormalities1(Grade 3 or 4) *For LRV 500 mg, LRV 750 mg and EFV groups, N=29, 19 and 29, respectively (lipase was tested only if amylase was elevated)LDL, low-density lipoprotein; ULN, upper limit of normal1DAIDS – Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 2004

  16. Effect on serum lipids:LRV did not increase TC, LDL-C or TG Change from baseline at 48 weeks HDL, high-density lipoprotein *N=50 Screening HIV-1 RNA level (<100K or ≥100K c/mL), geographic region, and baseline fasting measurements (continuous) were included as covariates)

  17. Summary & Conclusions Both LRV doses achieved similar viral load suppression to EFV 51/65 (79%) for both doses LRV, 54/63 (86%) for EFV Resistance profiles consistent with in vitro data LRV+TDF/FTC showed a different AE profile from EFV More nausea in LRV arms Fewer G3/4, neuropsychiatric AEs (compared to EFV) Lab AEs infrequent Neutral effects on lipid levels

  18. Acknowledgements All patients participating in the A5271015 study Data Monitoring Committee members Pfizer and ViiV Healthcare team members Investigators and study site staff

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