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

Criteria for PrEP• Safe• Penetrates target tissues• Protects against HIV infection in tissues• Long-lasting activity for convenient dosing• Unique resistance profile or high barrier to

resistance• No significant drug-drug interactions• Possibly, not a part of current rx regimens• Affordable, easy to use and implement

NIH/NIAID/DAIDS Working Group Report 2009

Approved ART: 2013nucleoside/tide RTIs (NRTIs)• zidovudine (ZDV, AZT)• didanosine (ddI)• stavudine (d4T)• lamivudine (3TC)• abacavir (ABC)• emtricitabine (FTC)• tenofovir (TDF)

NNRTIs• nevirapine (NVP)• delavirdine (DLV)• efavirenz (EFV)• etravirine (ETR)• rilpivirine (RPV)

protease inhibitors (PIs)• saquinavir (SQV)• ritonavir (RTV)• indinavir (IDV)• nelfinavir (NFV)• lopinavir/r (LPV/r)• atazanavir (ATV)• fosamprenavir (FPV)• tipranavir (TPV)• darunavir (DRV)

entry inhibitors (EIs)• enfuvirtide (T-20, fusion inh)• maraviroc (MVC, CCR5 ant)

integrase inhibitors (IIs)• raltegravir (RAL)• elvitegravir (EVG)

Approved ART: 2013nucleoside/tide RTIs

(NRTIs)• lamivudine (3TC)• emtricitabine (FTC)• tenofovir (TDF)

entry inhibitors (EIs)• maraviroc (MVC, CCR5 inh)

Maraviroc (MVC) for PrEP (1)

• HIV entry inhibitor – CCR5 antagonist• Not active against X4 virus

• FDA-approved 2007• Used uncommonly for HIV treatment• Safety profile X 5+ years Gulick IAS 2012 #TUPE029

• Limited clinical safety data in HIV- • Theoretical safety risks

• Individuals with CCR5 ∆32 deletion ↑ pathogenicity of some viral infections (e.g., West Nile virus)

• Drug resistance is uncommon

Maraviroc (MVC) for PrEP (2)• Achieves 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 2008

• Some potential for drug-drug interactions• MVC 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 2011

• Oral MVC did not prevent HIV infection in macaque model Massud J Virol 2013 [Epub Jun 5]

HPTN 069: NEXT-PrEP• Design: Phase II, 4-arm, multisite, study• Study population

• N=400 at-risk HIV-negative gay men; currently 284/71% N=200 at risk HIV-negative women; currently 20/10%

• Study Treatment:• MVC monotherapy• MVC + FTC• MVC + TDF • TDF + FTC (control)

• Duration: 48 weeks• Primary endpoint: Grade >3 toxicities; time to

study treatment discontinuation

Newer ART Agents (partial list)NRTI NNRTI PI Entry Inh InSTI

Phase 3 TAF cenicriviroc dolutegravir

Phase 2 apricitabine BMS-986001 dexelvucitabinefestinavir

dapivirineBILR 355 doravirinerilpivirine-LA

BMS-663068 ibalizumab PF-232798

GSK‘744

Phase 1/2 elvucitabine TMC 310911 HGS004

Phase 1 RDEA 806 CTP-298 CTP-518 PPL-100 SPI-256

SCH532706 VIR-576

BI 224436 INH-1001

Rilpivirine (RPV)-LA for PrEP (1)

• HIV NNRTI• FDA-approved 2011; safety profile X 2+ years• “Alternative drug” in rx guidelines• Used commonly for HIV treatment• Low barrier to drug resistance;

cross-resistance to other NNRTI• Some drug-drug interactions• RPV nanoparticle gel Long IAS 2013 #MOPE141

• RPV-LA IM once-monthly dosing possible Baert Eur J Pharm Biopharm 2009

RPV-LA for PrEP (2)• RPV-LA IM achieves tissue levels

• 10X higher in LN (animals) v’ant Klooster AAC 2010

• CVF and RT =, VT lower, RF much lower Else PK Workshop 2012

• RPV-LA IM (investigational formulation)• Single-dose clinical study (N=33)

Jackson CROI 2012 #35• Novel combination study

Spreen IAS 2013 #WEAB0103

• HPTN 076 (phase II): in development

Dapivirine for PrEP• Investigational NNRTI (TMC 120)• Phase 1/2 clinical trials as oral agent,

but not being developed for HIV treatment• Ring, gel, film, diaphragm and nanoparticle• Safety studies of dapivirine ring

• IPM 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 #1089

• IPM 026/MTN 013: Dapivirine/MVC ring (N=48)

Dapivirine Ring: Two Phase 3 Sister Studies• IPM 027 (RING): Safety and Efficacy

• 1650 women in South Africa• started enrollment April 2012

• MTN 020 -- A Study to Prevent Infection with a Ring for Extended Use (ASPIRE): Phase 3 dapivirine ring • 3475 women in 5 African countries• started enrollment July 2012

Ibalizumab for PrEP (1) • Investigational HIV entry inhibitor• Monoclonal antibody• CD4 attachment antagonist• Weekly subcutaneous injections• Clinical phase 2b studies in HIV-infected

individuals completed Jacobson AAC 2009; Khanlou ICAAC 2011 #H2794b

• Theoretical safety risks• Drug resistance not expected• No tissue PK data• No drug-drug interactions

Ibalizumab for PrEP (2)

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

GSK 1265744 (‘744) for PrEP (1)• Investigational II related to dolutegravir• Other integrase inhibitors (RAL, EVG) used

commonly in HIV treatment• Higher barrier to resistance • 2-2.5 log cps/ml ↓ in HIV+ individuals

(5+30 mg oral doses) • Clinical safety data (N=48 healthy volunteers)

• well-tolerated

• Long half-life (30 hours) given orally• Infrequent parenteral dosing possible

Min ICAAC 2009 #H-1228

GSK ’744-LAP• Nanotechology formulation• SC + IM injections• T ½ 21-50 days! Spreen IAS 2012 #TUPE040

• ↓ release and ↓ clearance• Supports quarterly dosing• Safety: ISR and nodules with SC dosing• Tissue levels Ford PK Workshop 2013 #O-02

• Cervicovaginal tissue 16-28% of plasma• Rectal tissue (men) <8% of plasma

• Few drug-drug interactions expected

GSK’744-LAP: PrEP Study in Macaques

• Study population: male macaques (N=16)• Study treatment:

– GSK ‘744-LAP 50mg/kg X 2, 4 weeks apart– Placebo

• Weekly SHIV rectal challenge X 8• Results (preliminary)

– GSK 744LAP: no infections– Placebo: all infected

Andrews CROI 2013 #24LB

Combination of GSK ‘744-LAP + RPV-LAfor PrEP• Phase 1 pilot study, randomized, repeat dose-escalation study with oral lead-in in HIV- individuals

• Monthly and quarterly dosing of 744-LAP

• Endpoints: Safety, tolerability, PK

Spreen IAS 2013 #WEAB0103

• HPTN 077: Phase II of GSK ‘744 (planned)

Summary: New PrEP Drugsmechanism main

dosing routedosing frequency

current stage

maraviroc (MVC)

CCR5 antagonist

oral once daily Phase 2 enrolling

rilpivirine (RPV)-LA

NNRTI injectable, IM once monthly

Phase 1 pilot; Phase 2 planned

dapivirine NNRTI ring monthly Phase 3 enrolling

ibalizumab CD4 attachment inhibitor

injectable, SC once weekly

Phase 1 pilot

‘744-LAP integrase inhibitor

injectable, IM once quarterly

Phase 1 pilot; Phase 2 planned

Acknowledgments

• Cornell HIV Clinical Trials Unit (CCTU)

• Division of Infectious Diseases• Weill Medical College of

Cornell University• AIDS Clinical Trials Group

(ACTG)• Division of AIDS, NIAID, NIH• The patient volunteers!