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 #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

Slide #3

Antiretroviral Drug Approval:1987 - 2003

0

2

4

6

8

10

12

14

16

18

1987 1989 1991 1993 1995 1997 1999 2001 2003

AZTddI

ddCd4T

3TCSQV

RTVIDVNVP

NFVDLV

EFVABC APV

LPV/rTDF ENF

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)

Slide #5

Life Cycle of HIV

DS dna COMPLEX

Protease

HIV Entry Mechanism

3c. FusionComplete

1. CD4Attachment

3b. coil-coilinteraction

CXCR4CCR5

HIV

HIV

gp120

3a. Anchorage

CD4

2. Co-receptorinteraction

Cell

HIV

HIV

HIV

gp41

gp41

HIV

Slide #6

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

Slide #8

PRO 542: Overview

• investigational CD4 attachment inhibitor; binds to gp120• tetravalent CD4-IgG2 fusion protein

• IC90 20 µg/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

Slide #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 )

Baroudy, Barcelona AIDS Conf 2002, abstract #MoOrA138

Slide #10

Schering C: Phase IB

Reynes, 9th CROI, 2002, abst. #1

Slide #11

Inhibition of Fusion

HIV-1

gp 120gp41

gp41

gp 120 ENFENF

ENFENFCD4CD4CCR-5CCR-5

Slide #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)

Slide #13

TRI-001: Monotherapy HIV-RNA Results

-1.5

-1

-0.5

0

1 4 7 11 15 18

3 mg

10 mg

30 mg

100 mg

Days

Cha

nge

from

Bas

elin

eM

ean

Vira

l Loa

d (L

og10

)

Kilby, et al. Nature Medicine 1998;4:1302-7.

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

-1.5

-1.2

-0.9

-0.6

-0.3

0

BASELINE DAY 7 DAY 14 DAY 21 DAY 28

12.5 mg/day CSI 25 mg/day CSI 50 mg/day CSI100 mg/day CSI 50 mg BID SQI 100 mg BID SQI

Ch a

nge

Fro

m B

asel

i ne

Pl a

sma

HIV

RN

A L

og10

(C

opie

s/m

L)

Kilby,AIDS Res Hum Retroviruses 2002;18:685-93

Slide #15

TORO 1 Study: Week 24

-1.70

-0.76

-2

-1

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=326HIV RNA change from baseline

(log10 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

-1

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=335HIV RNA change from baseline(log10 copies/ml)

Clotet B, XIV AIDS Conf., abstract LBOr19B

Slide #17

Anti-HIV Fusion Peptides

HR1 cc HR2FPNH2 COOHtm

T-20T-1249

gp41 molecule

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

-2

-1.5

-1

-0.5

0

0 7 14

Study Day

Med

ian

Cha

nge

from

Bas

elin

e (H

IV R

NA

log1

0)

6.25 mg QD

6.25 mg BID

12.5 mg QD

12.5 mg BID

25 mg QD

25 mg BID

50 mg QD

100 mg QD

150 mg QD

200 mg QD

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 #20Investigational 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