Roy M. Gulick, MD, MPH Rochelle Belfer Professor in Medicine Weill Cornell Medicine New York, New York

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, MPH Rochelle Belfer Professor in Medicine Weill Cornell Medicine New York, New York FORMATTED: MM/DD/YY Antiretroviral Therapy: Investigational New Drugs and New Strategies R.M. , MPH Professor of

1 Antiretroviral Therapy: Investigational New Drugs and New Strategies Roy M. Gulick, MD, MPH Rochelle Belfer Professor in Medicine Weill Cornell Medicine New York, New York FORMATTED: MM/DD/YY Antiretroviral Therapy: Investigational New Drugs and New Strategies R.M. Gulick, MD, MPH Professor of Medicine Chief, Division of Infectious Diseases Weill Cornell Medical College New York City Slide 4 of 38 Newer ART Agents (partial list) NRTI NNRTI PI Entry Inh II Phase 3 doravirine BMS bictegravir ibalizumab (GS-9883) cabotegravir Phase 2 apricitabine BILR 355 dexelvucitabine festinavir cenicriviroc PF PRO140 MI BMS Phase 1/2 elvucitabine TMC HGS004 Slide 6 of 38 Phase 1 MK-8591 (EFdA) CMX157 RDEA 806 CTP-298 CTP-518 PPL-100 SPI-256 BMS BI SCH INH-1001 VIR-576 GSK

Needs: More convenient NRTI Slide 8 of 38 Slide 9 of 38 4 -ethynyl-2-fluoro-2 - deoxyadenosine; EFdA Non-obligate chain terminator Inhibits RT by preventing translocation (NRTTI) Potent antiviral

2 Needs: More convenient NRTI Slide 8 of 38 Slide 9 of ethynyl-2-fluoro-2 - deoxyadenosine; EFdA Non-obligate chain terminator Inhibits RT by preventing translocation (NRTTI) Potent antiviral activity (PBMC EC50 = 0.2 nm) with broad coverage (HIV-1, HIV-2, MDR strains) MK-8591 (EFdA) Grobler CROI 2016 #98 Friedman CROI 2016 #437LB MK-8591 (EFdA) Slide 10 of 38 Grobler CROI 2016 #98 Friedman CROI 2016 #437LB 2

NNRTI Needs: Less toxicity and better tolerability Active against NNRTI-resistant viruses Fewer drug interactions Slide 11 of 38 Doravirine (DOR; MK-1439) Investigational NNRTI Pre-clinical Potent at

3 NNRTI Needs: Less toxicity and better tolerability Active against NNRTI-resistant viruses Fewer drug interactions Slide 11 of 38 Doravirine (DOR; MK-1439) Investigational NNRTI Pre-clinical Potent at low milligram dose Metabolized by CYP3A4; not a CYP450 inhibitor or inducer Active in vitro against viral strains with: K103N Y181C G190A E101K E138K K103N/Y181C Slide 12 of 38 Lai AAC 2014;58: doravirine (DOR): Phase Ib Double-blind, randomized, placebo-controlled Study population: HIV+, treatment-naïve (N=18) Slide 13 of 38 Schurmann AIDS 2016;30:

Gatell CROI 2016 #470 Doravirine Phase 2 Slide 15 of 38 Gatell CROI 2016 #470

4 Doravirine Phase 2 Randomized, double-blind, 2-part study Study population: Rx-naïve participants, VL >1000, CD4 >100 (N=216) TDF/FTC+ Slide 14 of 38 Gatell CROI 2016 #470 Doravirine Phase 2 Slide 15 of 38 Gatell CROI 2016 #470 INSTI Needs: Active against INSTI-resistant virus More convenient Slide 16 of 38 4

Bictegravir (GS-9883): In vitro In vitro EC50 0.

prior INSTI, VL 10K-400K, CD4 >200 (N=20) Slide 18 of 38 ASM Microbe 2016, abstract #415 Bictegravir (GS-9883): Phase 2-3 Phase 2: GS-US-141-1475 US, treatment-naïve (N=98) TAF/FTC + DTG or BIC

5 Bictegravir (GS-9883): In vitro In vitro EC nm against wt clinical isolates of HIV-1 and -2 Slide 17 of 38 Tsiang Antimicrob Agents Chemo 2016 (epub 9/19/16) Bictegravir (GS-9883): Phase 1 Study population: HIV+, naïve/off ART X >12 wks, no prior INSTI, VL 10K-400K, CD4 >200 (N=20) Slide 18 of 38 ASM Microbe 2016, abstract #415 Bictegravir (GS-9883): Phase 2-3 Phase 2: GS-US US, treatment-naïve (N=98) TAF/FTC + DTG or BIC (blinded, placebo-controlled) Phase 3: GS-US US + international, treatment naïve (N=600) ABC/3TC/DTG vs. TAF/FTC/BIC (blinded, placebo-controlled) Phase 3: GS-US US + international, virologically suppressed on 2 NRTIs + boosted ATV or DRV (N=520) Continue boosted PI regimen or SWITCH to TAF/FTC/BIC (open-label) Phase 3: GS-US [OPEN] US + international, virologically suppressed women on TAF/FTC/EVG/c, TDF/FTC/EFV/c, or TDF/FTC/ATV/r (N=400) Continue regimen or SWITCH to TAF/FTC/BIC (open-label) Phase 2-3 PK study in adolescents/children TAF/FTC/BIC [OPEN] Slide 19 of

Cabotegravir (CAB, GSK 1265744) Integrase inhibitor similar to DTG; similar resistance Potent in HIV+

formulation; SC + IM injections T ½ 21-50 days!

Spreen JAIDS 2014;67:481 LATTE-2: CAB + RPV IM Maintenance Phase 2b multicenter, parallel group,

6 Cabotegravir (CAB, GSK ) Integrase inhibitor similar to DTG; similar resistance Potent in HIV+ individuals (5, 10, 30, 60 mg oral) Margolis EACS 2013; Spreen HIV Clin Trials 2013;14:192 Nanotechnology formulation; SC + IM injections T ½ days! Supports monthly or quarterly dosing Safety: ISR (all mild) and nodules with SC dosing Slide 20 of 38 Spreen JAIDS 2014;67:481 LATTE-2: CAB + RPV IM Maintenance Phase 2b multicenter, parallel group, open-label study Study population: Rx-naïve individuals (N=309) Slide 21 of 38 Margolis IAS 2016 #THAB02LB LATTE-2: Virologic Suppression Slide 22 of 38 Margolis IAS 2016 #THAB02LB 6

LATTE-2: Efficacy Slide 23 of 38 Margolis IAS 2016 #THAB02LB LATTE-2: Injection Site Reactions Slide 24 of 38 Margolis CROI 2016 #31LB HPTN 083: PrEP with TDF/FTC

CAB IM Study population: Adult MSM and TGW, at high-risk for HIV acquisition (N=4500) High risk = any non-condom receptive anal intercourse (RAI); >5 partners;

7 LATTE-2: Efficacy Slide 23 of 38 Margolis IAS 2016 #THAB02LB LATTE-2: Injection Site Reactions Slide 24 of 38 Margolis CROI 2016 #31LB HPTN 083: PrEP with TDF/FTC oral vs. CAB IM Study population: Adult MSM and TGW, at high-risk for HIV acquisition (N=4500) High risk = any non-condom receptive anal intercourse (RAI); >5 partners; stimulant drug use; rectal or urethral STI in past 6 months Study regimen: TDF/FTC daily oral vs. CAB q2 month injections double-blind, double-dummy design Design: non-inferiority, efficacy study NY area sites: Bronx-Lebanon, Cornell (Chelsea), Harlem Hospital, NJ Medical School (Newark), NY Blood Center (UES) Slide 25 of 38 7

CD4 Attachment Inhibitor Needs: Novel mechanism of action Slide 26 of 38 HIV Entry Inhibitors CD4 Binding

Cell Membrane Slide 27 of 38 CCR5/CXCR4 (R5/X4) Adapted from Moore JP, PNAS 2003;100:10598-10602.

Prodrug of BMS-626529 Inhibits CD4 binding by binding to gp120 PK suggest QD or BID dosing without boosting

8 CD4 Attachment Inhibitor Needs: Novel mechanism of action Slide 26 of 38 HIV Entry Inhibitors CD4 Binding Coreceptor Binding Virus-Cell Fusion BMS gp41 gp120 V3 loop CCR5 Inhibitors maraviroc enfuvirtide CD4 Cell Membrane Slide 27 of 38 CCR5/CXCR4 (R5/X4) Adapted from Moore JP, PNAS 2003;100: BMS : Oral HIV Attachment Inhibitor Study pop: CD4 >200, VL >5000 off ART X >8 wks or ART-naive (N=50) Prodrug of BMS Inhibits CD4 binding by binding to gp120 PK suggest QD or BID dosing without boosting baseline susceptibility in 12% of pts due to envelope polymorphisms; screened by baseline IC 50 Nettles JID 2012;206:1002 Slide 28 of 38 8

BMS-663068: Phase 2b Phase 2b, randomized, controlled, partially blinded

for 529 (N=254) Slide 29 of 38 Lalezari Lancet HIV 2015;2:e427-37 and

CROI 2016 #472 BMS-663068: Phase 2b Safety Slide 31 of 38 Given FDA

9 BMS : Phase 2b Phase 2b, randomized, controlled, partially blinded (to 068 dose) Study pop: Rx-experienced (>1 wk on >1 ART); IC 50 <100 nm for 529 (N=254) Slide 29 of 38 Lalezari Lancet HIV 2015;2:e and DeJesus CROI 2016 #472 BMS : Phase 2b Efficacy Slide 30 of 38 DeJesus CROI 2016 #472 BMS : Phase 2b Safety Slide 31 of 38 Given FDA Breakthrough Status 7/15 Phase 3 in treatment-experienced enrolled DeJesus CROI 2016 #472 9

resistance Slide 32 of 38 HIV Maturation Inhibitors

10 Maturation Inhibitor Needs: Novel mechanism of action No baseline polymorphisms that confer resistance Slide 32 of 38 HIV Maturation Inhibitors (MI) Slide 33 of 38 Slide 34 of 38 Lataillade CROI 2015, #114LB 10

Study population: HIV+, VL >5K, CD4 >200, PI and MI naive Slide 35 of 38 No serious adverse events, grade 3/4

Subtype B, Rx-naïve, VL>5000, CD4>200 (N=28) Median change in VL (log 10 c/ml) 1 0.5 0 0.5 1 1.5 2 2.

955176 40 mg + ATV 300 mg + RTV 100 mg BMS 955176 40 mg + ATV 400 mg BMS 955176 80 mg + ATV 400 mg Slide 36 of 38

11 Study population: HIV+, VL >5K, CD4 >200, PI and MI naive Slide 35 of 38 No serious adverse events, grade 3/4 events, no d/c due to adverse events Lataillade CROI 2015, #114LB BMS : Phase 2a (Part B) Study population: Subtype B, Rx-naïve, VL>5000, CD4>200 (N=28) Median change in VL (log 10 c/ml) Dosing period Study day TDF/FTC 300 mg/200 mg + ATV 300 mg + RTV 100 mg* BMS mg + ATV 300 mg + RTV 100 mg BMS mg + ATV 400 mg BMS mg + ATV 400 mg Slide 36 of 38 Hwang IAS 2015 #TUAB0106LB Study population: ART naïve or experienced, VL >5000, CD4 >200 (N=19) Hwang EACS 2015 PS 10/5 Slide 37 of 38 11

12 Acknowledgments Cornell HIV Clinical Trials Unit (CCTU) Division of Infectious Diseases Weill Cornell Medical College AIDS Clinical Trials Group (ACTG) HIV Prevention Trials Network (HPTN) Division of AIDS, NIAID, NIH The patient volunteers! Slide 38 of 38 12

13 Dr Gulick Suggested Readings Activity #: HIV 16 NY Page: 1 SUGGESTED READINGS 1. Lalezari JP, Latiff GH, Brinson C, et al. Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS in treatmentexperienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial. Lancet HIV. 2015;2(10):e427-e437. Ref ID: Margolis DA, Brinson CC, Smith GH, et al. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviralnaive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infect Dis. 2015;15(10): Ref ID: Regueiro-Ren A, Liu Z, Chen Y, et al. Discovery of BMS , a second generation HIV-1 maturation inhibitor with broad spectrum antiviral activity. American Chemical Society Medicinal Chemistry Letters. 2016;7: Ref ID: Schurmann D, Sobotha C, Gilmartin J, et al. A randomized, doubleblind, placebo-controlled, short-term monotherapy study of doravirine in treatment-naive HIV-infected patients. AIDS. 2016;30: Ref ID: Stoddart CA, Galkina SA, Joshi P, et al. Oral administration of the nucleoside EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine) provides rapid suppression of HIV viremia in humanized mice and favorable pharmacokinetic properties in mice and the rhesus macaque. Antimicrobial Agents and Chemotherapy. 2015;59: Ref ID: Tsiang M, Jones GS, Goldsmith J, et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrobial Agents and Chemotherapy. 2016;[Epub ahead of print]. Ref ID: 14740

Long-Acting Antiretrovirals for HIV

Long-Acting Antiretrovirals for HIV R.M. Gulick, MD, MPH Rochelle Belfer Professor in Medicine Chief, Division of Infectious Diseases Weill Cornell Medicine New York City Disclosures None Single Tablet