Presentation on theme: "Slide #1 HIV Entry Inhibitors Trip Gulick, MD, MPH Director, Cornell HIV Clinical Trials Unit Associate Professor of Medicine Weill Medical College of."— Presentation transcript:
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
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
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
Slide #11 Inhibition of Fusion HIV-1 gp 120 gp41 gp 120 ENF ENF CD4 CCR-5
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)
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.
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
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)
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
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
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
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
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.
Slide #22 Acknowledgments Joe Eron / UNC Diego Miralles and Alex Dusek / Trimeris Bill Olsen / Progenics Greg Reyes and Bahige Baroudy / Schering-Plough