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PrEP – New Drugs and Delivery Systems

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

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PrEP – New Drugs and Delivery Systems

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  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 • 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

  3. nucleoside/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: 2013

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

  5. 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

  6. 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]

  7. 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

  8. Newer ART Agents (partial list)

  9. 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 BaertEur J PharmBiopharm 2009

  10. RPV-LA for PrEP (2) • RPV-LA IM achieves tissue levels • 10X higher in LN (animals) v’antKlooster 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

  11. 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)

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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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)

  19. Summary: New PrEP Drugs

  20. 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!

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