1. PrEP – New Drugs and Delivery Systems Roy M. Gulick, MD, MPH Chief, Division of Infectious Diseases Professor of Medicine Weill Medical College of Cornell University New York City

2. Criteria for PrEP SafeSafe Penetrates target tissuesPenetrates target tissues Protects against HIV infection in tissuesProtects against HIV infection in tissues Long-lasting activity for convenient dosingLong-lasting activity for convenient dosing Unique resistance profile or high barrier to resistanceUnique resistance profile or high barrier to resistance No significant drug-drug interactionsNo significant drug-drug interactions Possibly, not a part of current rx regimensPossibly, not a part of current rx regimens Affordable, easy to use and implementAffordable, easy to use and implement NIH/NIAID/DAIDS Working Group Report 2009

3. Approved ART: 2013 nucleoside/tide RTIs (NRTIs) zidovudine (ZDV, AZT)zidovudine (ZDV, AZT) didanosine (ddI)didanosine (ddI) stavudine (d4T)stavudine (d4T) lamivudine (3TC)lamivudine (3TC) abacavir (ABC)abacavir (ABC) emtricitabine (FTC)emtricitabine (FTC) tenofovir (TDF)tenofovir (TDF)NNRTIs nevirapine (NVP)nevirapine (NVP) delavirdine (DLV)delavirdine (DLV) efavirenz (EFV)efavirenz (EFV) etravirine (ETR)etravirine (ETR) rilpivirine (RPV)rilpivirine (RPV) protease inhibitors (PIs) saquinavir (SQV)saquinavir (SQV) ritonavir (RTV)ritonavir (RTV) indinavir (IDV)indinavir (IDV) nelfinavir (NFV)nelfinavir (NFV) lopinavir/r (LPV/r)lopinavir/r (LPV/r) atazanavir (ATV)atazanavir (ATV) fosamprenavir (FPV)fosamprenavir (FPV) tipranavir (TPV)tipranavir (TPV) darunavir (DRV)darunavir (DRV) entry inhibitors (EIs) enfuvirtide (T-20, fusion inh)enfuvirtide (T-20, fusion inh) maraviroc (MVC, CCR5 ant)maraviroc (MVC, CCR5 ant) integrase inhibitors (IIs) raltegravir (RAL)raltegravir (RAL) elvitegravir (EVG)elvitegravir (EVG)

4. Approved ART: 2013 nucleoside/tide RTIs (NRTIs) lamivudine (3TC)lamivudine (3TC) emtricitabine (FTC)emtricitabine (FTC) tenofovir (TDF)tenofovir (TDF) entry inhibitors (EIs) maraviroc (MVC, CCR5 inh)maraviroc (MVC, CCR5 inh)

5. Maraviroc (MVC) for PrEP (1) HIV entry inhibitor – CCR5 antagonistHIV entry inhibitor – CCR5 antagonist Not active against X4 virusNot active against X4 virus FDA-approved 2007FDA-approved 2007 Used uncommonly for HIV treatmentUsed uncommonly for HIV treatment Safety profile X 5+ years Gulick IAS 2012 #TUPE029Safety profile X 5+ years Gulick IAS 2012 #TUPE029 Limited clinical safety data in HIV-Limited clinical safety data in HIV- Theoretical safety risksTheoretical safety risks Individuals with CCR5 ∆32 deletion ↑ pathogenicity of some viral infections (e.g., West Nile virus)Individuals with CCR5 ∆32 deletion ↑ pathogenicity of some viral infections (e.g., West Nile virus) Drug resistance is uncommonDrug resistance is uncommon

6. Maraviroc (MVC) for PrEP (2) Achieves high levels in vaginal secretions (3X↑) and rectal tissue (8-26X↑) Dumond JAIDS 2009; Brown JID 2011Achieves high levels in vaginal secretions (3X↑) and rectal tissue (8-26X↑) Dumond JAIDS 2009; Brown JID 2011 Once-daily dosing oral possible Rosario Brit J Clin Pharm 2008Once-daily dosing oral possible Rosario Brit J Clin Pharm 2008 Some potential for drug-drug interactionsSome potential for drug-drug interactions MVC gel and ring formulations Veazey JID 2010; Malcolm AAC 2012MVC gel and ring formulations Veazey JID 2010; Malcolm AAC 2012 Oral and gel MVC prevented HIV infection in mouse model Neff PLoS One 2010; Neff PLoS One 2011Oral and gel MVC prevented HIV infection in mouse model Neff PLoS One 2010; Neff PLoS One 2011 Oral MVC did not prevent HIV infection in macaque model Massud J Virol 2013 [Epub Jun 5]Oral MVC did not prevent HIV infection in macaque model Massud J Virol 2013 [Epub Jun 5]

7. HPTN 069: NEXT-PrEP Design: Phase II, 4-arm, multisite, studyDesign: Phase II, 4-arm, multisite, study Study populationStudy population N=400 at-risk HIV-negative gay men; currently 284/71% N=200 at risk HIV-negative women; currently 20/10%N=400 at-risk HIV-negative gay men; currently 284/71% N=200 at risk HIV-negative women; currently 20/10% Study Treatment:Study Treatment: MVC monotherapyMVC monotherapy MVC + FTCMVC + FTC MVC + TDFMVC + TDF TDF + FTC (control)TDF + FTC (control) Duration: 48 weeksDuration: 48 weeks Primary endpoint: Grade >3 toxicities; time to study treatment discontinuationPrimary endpoint: Grade >3 toxicities; time to study treatment discontinuation

8. Newer ART Agents (partial list) NRTINNRTIPIEntry InhInSTI Phase 3TAF cenicrivirocdolutegravir Phase 2apricitabine BMS-986001 dexelvucitabine festinavir dapivirine BILR 355 doravirine rilpivirine- LA BMS-663068 ibalizumab PF-232798 GSK‘744 Phase 1/2elvucitabine TMC 310911HGS004 Phase 1RDEA 806CTP-298 CTP-518 PPL-100 SPI-256 SCH532706 VIR-576 BI 224436 INH-1001

9. Rilpivirine (RPV)-LA for PrEP (1) HIV NNRTIHIV NNRTI FDA-approved 2011; safety profile X 2+ yearsFDA-approved 2011; safety profile X 2+ years “Alternative drug” in rx guidelines“Alternative drug” in rx guidelines Used commonly for HIV treatmentUsed commonly for HIV treatment Low barrier to drug resistance; cross-resistance to other NNRTILow barrier to drug resistance; cross-resistance to other NNRTI Some drug-drug interactionsSome drug-drug interactions RPV nanoparticle gel Long IAS 2013 #MOPE141RPV nanoparticle gel Long IAS 2013 #MOPE141 RPV-LA IM once-monthly dosing possible Baert Eur J Pharm Biopharm 2009RPV-LA IM once-monthly dosing possible Baert Eur J Pharm Biopharm 2009

10. RPV-LA for PrEP (2) RPV-LA IM achieves tissue levelsRPV-LA IM achieves tissue levels 10X higher in LN (animals) v’ant Klooster AAC 201010X higher in LN (animals) v’ant Klooster AAC 2010 CVF and RT =, VT lower, RF much lower Else PK Workshop 2012CVF and RT =, VT lower, RF much lower Else PK Workshop 2012 RPV-LA IM (investigational formulation)RPV-LA IM (investigational formulation) Single-dose clinical study (N=33) Jackson CROI 2012 #35Single-dose clinical study (N=33) Jackson CROI 2012 #35 Novel combination study Spreen IAS 2013 #WEAB0103Novel combination study Spreen IAS 2013 #WEAB0103 HPTN 076 (phase II): in developmentHPTN 076 (phase II): in development

11. Dapivirine for PrEP Investigational NNRTI (TMC 120)Investigational NNRTI (TMC 120) Phase 1/2 clinical trials as oral agent, but not being developed for HIV treatmentPhase 1/2 clinical trials as oral agent, but not being developed for HIV treatment Ring, gel, film, diaphragm and nanoparticleRing, gel, film, diaphragm and nanoparticle Safety studies of dapivirine ringSafety studies of dapivirine ring IPM 001/008: Phase I Safety/PK Romano AIDS Res Hum Retro 2009; Nel JAIDS 2009IPM 001/008: Phase I Safety/PK Romano AIDS Res Hum Retro 2009; Nel JAIDS 2009 IPM 015: Phase I/II 12-week safety study in 5 African countries (vs. placebo); monthly dosing (N=265): low systemic DPV exposure; well- tolerated; 97% comfortable, willing to use again Nel CROI 2012 #1089IPM 015: Phase I/II 12-week safety study in 5 African countries (vs. placebo); monthly dosing (N=265): low systemic DPV exposure; well- tolerated; 97% comfortable, willing to use again Nel CROI 2012 #1089 IPM 026/MTN 013: Dapivirine/MVC ring (N=48)IPM 026/MTN 013: Dapivirine/MVC ring (N=48)

12. Dapivirine Ring: Two Phase 3 Sister Studies IPM 027 (RING): Safety and EfficacyIPM 027 (RING): Safety and Efficacy 1650 women in South Africa1650 women in South Africa started enrollment April 2012started enrollment April 2012 MTN 020 -- A Study to Prevent Infection with a Ring for Extended Use (ASPIRE): Phase 3 dapivirine ringMTN 020 -- A Study to Prevent Infection with a Ring for Extended Use (ASPIRE): Phase 3 dapivirine ring 3475 women in 5 African countries3475 women in 5 African countries started enrollment July 2012started enrollment July 2012

13. Ibalizumab for PrEP (1) Investigational HIV entry inhibitorInvestigational HIV entry inhibitor Monoclonal antibodyMonoclonal antibody CD4 attachment antagonistCD4 attachment antagonist Weekly subcutaneous injectionsWeekly subcutaneous injections Clinical phase 2b studies in HIV-infected individuals completed Jacobson AAC 2009; Khanlou ICAAC 2011 #H2794bClinical phase 2b studies in HIV-infected individuals completed Jacobson AAC 2009; Khanlou ICAAC 2011 #H2794b Theoretical safety risksTheoretical safety risks Drug resistance not expectedDrug resistance not expected No tissue PK dataNo tissue PK data No drug-drug interactionsNo drug-drug interactions

14. Ibalizumab for PrEP (2) TMB-108: Pilot phase 1 safety study of three-doses, given once-weekly SC as PrEP (N=25) : completedTMB-108: Pilot phase 1 safety study of three-doses, given once-weekly SC as PrEP (N=25) : completed NCT01292174; www.clinicaltrials.gov

15. GSK 1265744 (‘744) for PrEP (1) Investigational II related to dolutegravirInvestigational II related to dolutegravir Other integrase inhibitors (RAL, EVG) used commonly in HIV treatmentOther integrase inhibitors (RAL, EVG) used commonly in HIV treatment Higher barrier to resistanceHigher barrier to resistance 2-2.5 log cps/ml ↓ in HIV+ individuals (5+30 mg oral doses)2-2.5 log cps/ml ↓ in HIV+ individuals (5+30 mg oral doses) Clinical safety data (N=48 healthy volunteers)Clinical safety data (N=48 healthy volunteers) well-toleratedwell-tolerated Long half-life (30 hours) given orallyLong half-life (30 hours) given orally Infrequent parenteral dosing possibleInfrequent parenteral dosing possible Min ICAAC 2009 #H-1228

16. GSK ’744-LAP Nanotechology formulationNanotechology formulation SC + IM injectionsSC + IM injections T ½ 21-50 days! Spreen IAS 2012 #TUPE040T ½ 21-50 days! Spreen IAS 2012 #TUPE040 ↓ release and ↓ clearance↓ release and ↓ clearance Supports quarterly dosingSupports quarterly dosing Safety: ISR and nodules with SC dosingSafety: ISR and nodules with SC dosing Tissue levels Ford PK Workshop 2013 #O-02Tissue levels Ford PK Workshop 2013 #O-02 Cervicovaginal tissue 16-28% of plasmaCervicovaginal tissue 16-28% of plasma Rectal tissue (men) <8% of plasmaRectal tissue (men) <8% of plasma Few drug-drug interactions expectedFew drug-drug interactions expected

17. GSK’744-LAP: PrEP Study in Macaques Study population: male macaques (N=16)Study population: male macaques (N=16) Study treatment:Study treatment: –GSK ‘744-LAP 50mg/kg X 2, 4 weeks apart –Placebo Weekly SHIV rectal challenge X 8Weekly SHIV rectal challenge X 8 Results (preliminary)Results (preliminary) –GSK 744LAP: no infections –Placebo: all infected Andrews CROI 2013 #24LB

18. Combination of GSK ‘744-LAP + RPV-LA for PrEP Phase 1 pilot study, randomized, repeat dose-escalation study with oral lead-in in HIV- individuals Phase 1 pilot study, randomized, repeat dose-escalation study with oral lead-in in HIV- individuals Monthly and quarterly dosing of 744-LAPMonthly and quarterly dosing of 744-LAP Endpoints: Safety, tolerability, PKEndpoints: Safety, tolerability, PK Spreen IAS 2013 #WEAB0103 HPTN 077: Phase II of GSK ‘744 (planned) HPTN 077: Phase II of GSK ‘744 (planned)

19. Summary: New PrEP Drugs mechanismmain dosing route dosing frequency current stage maraviroc (MVC) CCR5 antagonist oralonce dailyPhase 2 enrolling rilpivirine (RPV)-LA NNRTIinjectable, IMonce monthly Phase 1 pilot; Phase 2 planned dapivirineNNRTIringmonthlyPhase 3 enrolling ibalizumabCD4 attachment inhibitor injectable, SConce weekly Phase 1 pilot ‘744-LAPintegrase inhibitor injectable, IMonce quarterly Phase 1 pilot; Phase 2 planned

20. Acknowledgments Cornell HIV Clinical Trials Unit (CCTU)Cornell HIV Clinical Trials Unit (CCTU) Division of Infectious DiseasesDivision of Infectious Diseases Weill Medical College of Cornell UniversityWeill Medical College of Cornell University AIDS Clinical Trials Group (ACTG)AIDS Clinical Trials Group (ACTG) Division of AIDS, NIAID, NIHDivision of AIDS, NIAID, NIH The patient volunteers!The patient volunteers!