1. Slide #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. Slide #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. Slide #3 Antiretroviral Drug Approval: 1987 - 2003 AZT ddI ddC d4T 3TC SQV RTV IDV NVP NFV DLV EFV ABC APV LPV/r TDF ENF

4. Slide #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. Slide #5 Life Cycle of HIV DS dna COMPLEX Protease

6. HIV Entry Mechanism 3c. Fusion Complete 1. CD4 Attachment 3b. coil-coil interaction CXCR4 CCR5 HIV gp120 3a. Anchorage CD4 2. Co-receptor interaction Cell HIV gp41 HIV Slide #6

7. Slide #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. Slide #8 PRO 542: Overview investigational CD4 attachment inhibitor; binds to gp120 tetravalent CD4-IgG2 fusion protein IC 90 20 µg/mL, achievable in vivo T 1/2 : 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. Slide #9 SC-351125 (SCH C): Overview Investigational, small molecule CCR5 inhibitor HIV IC 90 ~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  ) Baroudy, Barcelona AIDS Conf 2002, abstract #MoOrA138

10. Slide #10 Schering C: Phase IB Reynes, 9 th CROI, 2002, abst. #1

11. Slide #11 Inhibition of Fusion HIV-1 gp 120 gp41 gp 120 ENF ENF CD4 CCR-5

12. Slide #12 Enfuvirtide (T-20) -- Overview FDA-approved fusion inhibitor; 36 AA peptide HIV IC 50 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)

13. Slide #13 TRI-001: Monotherapy HIV-RNA Results Days Change from Baseline Mean Viral Load (Log 10 ) Kilby, et al. Nature Medicine 1998;4:1302-7.

14. Slide #14 TRI-003: HIV RNA Mean Change From Baseline: Intent-to-treat Change From Baseline Plasma HIV RNA Log10 (Copies/mL) Kilby,AIDS Res Hum Retroviruses 2002;18:685-93

15. Slide #15 TORO 1 Study: Week 24 -1.70 -0.76 -2 0 (Delta=0.93, p<0.0001) Least Squared Means Log Change from Baseline - ITT Population (LOCF) optimized background (OB) regimen alone enfuvirtide (T-20) + OB N=165N=326 HIV RNA change from baseline (log 10 copies/ml) Lalezari, NEJM 2003 (in press) N=491, VL 158K, CD4 80, 3-class experienced (avg. 12 drugs)

16. Slide #16 TORO 2: Week 24 -1.43 -0.65 -2 0 (Delta=0.78, p<0.0001) Least Squared Means Log Change from Baseline - ITT Population (LOCF) optimized background (OB) regimen alone enfuvirtide (T-20) + OB N=169N=335 HIV RNA change from baseline (log10 copies/ml) Clotet B, XIV AIDS Conf., abstract LBOr19B

17. Slide #17 Anti-HIV Fusion Peptides HR1 cc HR2FP NH 2 COOH tm T-20 T-1249 gp41 molecule

18. Slide #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 N=115, VL 186K, CD4 57, 99% with exposure to a mean of 10 agents Gulick, ICAAC 2002, abst. #H-1075 Slide #19

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