HIV Entry Inhibitors

1. HIV Entry Inhibitors Trip Gulick, MD, MPH Director, Cornell HIV Clinical Trials Unit Associate Professor of Medicine Weill Medical College of Cornell University

2. Antiretroviral Drugs: Challenges and Needs Challenges Adherence Toxicity Activity Resistance Needs Improve convenience Improve tolerability Reduce toxicity Improve activity wild type virus resistant virus Penetrate reservoirs Exploit new targets

3. Antiretroviral Drug Approval:1987 - 2003

4. ANTIRETROVIRAL DRUGS 2003 nucleoside RTIs zidovudine (AZT, ZDV) didanosine (ddI) zalcitabine (ddC) stavudine (d4T) lamivudine (3TC) abacavir (ABC) NNRTIs nevirapine delavirdine efavirenz nucleotide RTIs tenofovir (PMPA) protease inhibitors saquinavir ritonavir indinavir nelfinavir amprenavir lopinavir entry inhibitors enfuvirtide (T-20)

5. Life Cycle of HIV

7. HIV Entry Inhibitors attachment inhibitors: BMS-806, PRO 542, TNX-355 chemokine receptor inhibitors: CXCR4 inhibitors: AMD-11070 CCR5 inhibitors: AK602, PRO 140, SC-351125 (SCH-C), SCH-D, TAK-220, UK-427,857 fusion inhibitors: enfuvirtide (T-20), T-1249

8. PRO 542: Overview investigational CD4 attachment inhibitor; binds to gp120 tetravalent CD4-IgG2 fusion protein IC90 20 �g/mL, achievable in vivo T1/2: 3-4 days Phase I (N=15): single infusion, dose escalation (0.2, 1, 5, 10 mg/kg), 0.25-0.5 log reductions in VL and viremia demonstrated Jacobson JID 2000;182:326 Phase I/II pediatrics (PACTG 351) (N=18): 6 children received 10 mg/kg q week X 4, 4 of 6 had >0.7 log VL reductions Shearer JID 2000;182:1774

9. SC-351125 (SCH C): Overview Investigational, small molecule CCR5 inhibitor HIV IC90 ~20nM (CCR5 virus) In vitro activity against R5, X4/R5 viral strains; resistance did not lead to co-receptor switch (mice) Orally bioavailable; PK supports bid dosing; not CYP450 metabolized Phase I/healthy volunteers/600 mg single dose: QTc prolongation >50ms (n=1) Phase I/HIV infected (N=12) X 10 days: 25 mg bid (-0.5 log ?) and 50 mg bid (-1.0 log ?)

10. Schering C: Phase IB

11. Inhibition of Fusion

12. Enfuvirtide (T-20) -- Overview FDA-approved fusion inhibitor; 36 AA peptide HIV IC50 1.7 ng/ml Dose: 90 mg sq bid side effects: injection site rxn (common); hypersensitivity reactions (uncommon); eosinophilia (10% >700; 2% >1400); ?increased risk of pneumonia on phase III studies resistance: changes in gp41 (positions 36-43)

14. TRI-003: HIV RNA Mean Change From Baseline: Intent-to-treat

15. TORO 1 Study: Week 24

16. TORO 2: Week 24

18. T-1249: Overview investigational fusion inhibitor hybrid peptide of HIV-1, HIV-2, SIV; 39 amino acids PK supports qd dosing, parenteral 2-100 x more active in vitro than T-20 active against many T-20- resistant-HIV variants (in vitro and in vivo) Resistance: gp41 substitutions (positions 35-71 of HR1) Stage of development: phase I/II completed; phase II planned

19. T1249-101: Virologic Response

20. Investigational Drugs 2002: Other Classes GAG processing inhibitors budding inhibitors DC-SIGN inhibitors defensins si RNAs regulatory protein (e.g., NEF, VIF, TAT) inhibitors uncoating inhibitors RNAase H inhibitors zinc finger (DNA complex) inhibitors capsid protein polymerization inhibitors assembly inhibitors

21. HIV Entry Inhibitors: Conclusions Newer antiretroviral drugs are needed to improve activity against resistant virus and exploit new targets. HIV entry inhibitors are promising agents with a new mechanism of action and demonstrated antiretroviral activity. Further basic and clinical research is needed.

22. Acknowledgments Joe Eron / UNC Diego Miralles and Alex Dusek / Trimeris Bill Olsen / Progenics Greg Reyes and Bahige Baroudy / Schering-Plough