PrEP – New Drugs and Delivery Systems
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Transcript of PrEP – New Drugs and Delivery Systems
PrEP –New Drugs and Delivery SystemsRoy M. Gulick, MD, MPHChief, Division of Infectious DiseasesProfessor of MedicineWeill Medical College of Cornell UniversityNew 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!