Efficacy and Safety of Doravirine 100mg QD vs Efavirenz 600mg QD with TDF/FTC in ART-Naive HIV-Infected Patients: Week 24 Results

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1 Efficacy and Safety of Doravirine 1mg QD vs Efavirenz 6mg QD with TDF/FTC in ART-Naive HIV-Infected Patients: Week 24 Results Jose M. Gatell, Francois Raffi, Andreas Plettenberg, Don Smith, Joaquin Portilla, Christian Hoffmann, Keikawus Arasteh, Melanie Thompson, Debbie P. Hagins, Javier O. Morales-Ramirez, Xia Xu, Hedy Teppler Abstract TUAB4 TDF/FTC + Doravirine vs EFV: Study Design Patients: HIV-1+ ART-naïve HIV RNA 1, c/ml CD4 count 1 cells/µl Part 1 Dose Ranging Phase (N=21) DOR 25 mg DOR 5 mg DOR 1 mg (n=42) DOR 2 mg EFC mg (n=42) DOR 1 mg Continue EFV Part 1 Extension Phase Week 24 Week 48 Week 96 DOR 1 mg (n=66) EFC 6 mg (n=66) Part 2 Additional Patients (N=132) Week 24 Week 48 Week 96 Note: blinding maintained through Week 96 study visit Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB4.

2 TDF/FTC + Doravirine vs EFV: Baseline Characteristics Doravirine 1 mg (N=18) Efavirenz 6 mg (N=18) % Male Age (years), median (range) 35 (19 67) 34 (2 57) % White % with AIDS HIV RNA (log 1 c/ml), median (range) 4.6 ( ) 4.6 (3. 6.7) % with HIV RNA >1, c/ml, at screening CD4 Count (cells/µl), median (range) 42 (92 111) 43 ( ) % with CD4 count 2 cells/µl % with Clade B viral subtype Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB4. TDF/FTC + Doravirine vs EFV: Primary Endpoint Percentage < 4 cop/ml at 24 weeks Doravirine 1mg Efavirenz Δ(95% CI): -1.2 (-13., 1.5) Treatment Week Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB4.

3 Patients with HIV RNA <2 c/ml, % (95% CI) Non-completer = Failure Approach Δ(95% CI): 1.9 (-7., 11.) Treatment Week Doravirine 1mg Efavirenz Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB4. TDF/FTC + Doravirine vs EFV: Results by Baseline HIV RNA 1 1, c/ml >1, c/ml n/n: 55/66 54/63 25: 51/66 58/63 11: 23/38 25/38 35/38 36/38 % <4 c/ml % <2 c/ml % <4 c/ml % <2 c/ml Doravirine 1 mg q.d. Efavirenz 6 mg q.d. Virologic failures: DRV 17, EFV mostly due to low-level viremia at week 24 (no resistance detected) 1 or more CNS adverse events: DRV 27%, EFV 46% -- difference -19.4% (95% CI -31.7, -6.6) Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB4.

4 Protocol-defined Virologic Failures by Week 24 Doravirine 1 mg (N=18) Efavirenz 6 mg (N=18) Virologic failure 4 c/ml, n (%) Non-response 17 (15.7) 1 (9.3) Rebound 1 (.9) Virologic failure 2 c/ml, n (%) Non-response 4 (3.7) Rebound 1 (.9) Resistance testing performed* 1 1 NNRTI mutations detected NRTI mutations detected Non-response: patient did not achieve vrna <4 (or <2) c/ml by Week 24. Rebound: after initial response of vrna <4 (or <2) c/ml, patient had 2 consecutive measurements 4 (or 2) c/ml at least 1 week apart, at or after Week 24. (Rebound after Week 24 not included here.) * vrna > 5 copies/ml required for resistance testing. Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB4. Number of Protocol-defined Virologic Failures by Week 24 ( 4 c/ml, confirmed) vrna (copies/ml) at time of Virologic Failure Type of VF 4-5 >5-1 >1-2 >2 Total Rebound Doravirine Efavirenz 1 1 Non-Response Doravirine Efavirenz Rebound: after initial response of vrna <4 (or <2) c/ml, patient had 2 consecutive measurements 4 (or 2) c/ml at least 1 week apart, at or after Week 24. (Rebound after Week 24 not included here.) Non-response: patient did not achieve vrna <4 (or <2) c/ml by Week 24. Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB4.

5 Primary Safety Comparison: CNS Events, All Causality Significantly fewer patients on DOR had 1 CNS event by week 24 (p<.1) Suicidal ideation Somnolence Depressive symptom Hallucination Attention disturbance Depression Nightmares Abnormal dreams Insomnia Dizziness % of Patients with 1 CNS Event DOR 1 mg (N=18) 17.6 EFV (N=18) Δ (95% CI) 26.9% 46.3% (-31.7, -6.6) Efavirenz 6 mg Doravirine 1 mg % of patients with at least one CNS event by week 24 Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB4. Second-Generation HIV-1 Maturation Inhibitor : Antiviral Activity and Safety with Atazanavir ± Ritonavir Carey Hwang, Dirk Schürmann, Christian Sobotha, Marta Boffito, Heather Sevinsky, Neelanjana Ray, Palanikumar Ravindran, Hong Xiao, Mark Krystal, Ira Dicker, Dennis Grasela, and Max Lataillade Abstract TUAB16LB

6 HIV-1 Life Cycle Maturation Maturation inhibitor Release Assembly/ cleavage Budding Lataillade et al. CROI 215, Abstract 114LB. Attachment Inhibitor: Study Design TDF/FTC 3/2 mg + ATV 3 mg + RTV 1 mg N=4 4 mg + ATV 3 mg + RTV 1 mg N=8 4 mg + ATV 4 mg N=8 8 mg + ATV 4 mg N=8 Days 1 28 Day 3 Days 35 Day 42 Inpatient days: Day -1 to Day 3 Objectives Change in plasma HIV-1 RNA levels from baseline to Day 28 Safety and tolerability of during combination therapy Dosing period Furloughed Outpatient visits Discharge Key Inclusion Criteria HIV-1 subtype B-infected subjects Treatment-naïve (<1 week of antiretroviral treatment) or -experienced (PI naïve) subjects Plasma HIV-1 RNA 5, c/ml CD4+ T-cell count 2 cells/µl Hwang C, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB16LB

7 Attachment Inhibitor: Median Change in HIV-1 RNA Median change in HIV-1 RNA at Day 29 was between and log 1 c/ml for the arms and was log 1 c/ml for the standard of care arm Median Change in HIV-1 RNA (log 1 c/ml) from Baseline Dosing Period Study Day TDF/FTC 3 mg/2 mg + ATV 3 mg + RTV 1 mg 4 mg + ATV 3 mg + RTV 1 mg 4 mg + ATV 4 mg 8 mg + ATV 4 mg Hwang C, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB16LB Attachment Inhibitor: Maximum Median Decline in HIV-1 RNA from Baseline Maximum median change in HIV-1 RNA (log 1 copies/ml) TDF/FTC 3/2 mg + ATV 3 mg + RTV 1 mg (n=4) mg + ATV 3 mg + RTV 1 mg (n=8) mg + ATV 4 mg (n=8) mg + ATV 4 mg (n=8) mg + ATV and 4 mg + ATV + RTV had similar maximum median changes in HIV-1 RNA compared with the standard of care arm Greatest elevations in bilirubin seen in maturation inhibitor plus boosted ATV (arm 2) Hwang C, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB16LB

8 AI4682: Median Change in Bilirubin at Day 28 from Baseline 7 Median change in total bilirubin at Day 28 from Baseline, (μmol/l, SI Units) TDF/FTC 3/2 mg + ATV 3 mg + RTV 1 mg* 6. 4 mg + ATV 3 mg + RTV 1 mg mg + ATV 4 mg mg + ATV 4 mg Hwang C, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB16LB Conclusions is a potent, once-daily, second-generation MI 8 mg + ATV and 4 mg + ATV + RTV demonstrated similar antiviral activity (~2.2 log 1 c/ml median decline) compared to the standard of care control over the 28-day treatment period was generally well tolerated There were no SAEs or AEs leading to discontinuation + unboosted ATV was associated with lower median changes from baseline in bilirubin levels compared to the arms with boosted ATV A Phase IIb study investigating + ATV in a booster-sparing and nucleot(s)ide-sparing regimen in treatment-experienced patients initiated July 215 Hwang C, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB16LB