1. Future Applications of Antiretroviral Agents in Development
Kathleen E. Squires, MD
Professor of Medicine and Director
Division of Infectious Diseases
Jefferson Medical College
Philadelphia, PA

2. Antiretroviral Drug Development Issues to Address
Current Limitations
Adherence
Toxicity
Activity
Resistance
Ideal Characteristics
Improve convenience
Improve tolerability
Reduce toxicity
Improve activity
Wild-type virus
Resistant virus
Penetrate reservoirs
Exploit new targets

3. Novel Agents in Clinical Development
Phase
Reverse Transcriptase
Inhibitors
Protease
Entry
Integrase/
Maturation
Inhibitors; Immunologics
II/III
Etravirine (TMC 125)
Darunavir
Maraviroc
Vicriviroc
MK-0518 II
BILR 355 BS
TNX-355
GS 9137
I/II
Amdoxovir
Apricitabine
Rilpivirine (TMC 278)
Brecanavir
AMD 070
PRO 542
Bevirimat
CTLA4-mAb I
Fosalvudine
PPL-100
PRO 140
TAK 652
Preclinical 22 7 21 11

4. New Generation NNRTIs Etravirine (TMC125)
Novel NNRTI designed to have a high genetic barrier to development of resistance[1]
Potent in vitro antiviral activity against:
Wild-type and NNRTI resistant HIV-1[2]
Clinical isolates resistant against approved NNRTIs[2]
In a 7-day clinical trial, TMC125 monotherapy produced a median viral load change of –0.89 log10 copies/mL in patients on failing NNRTI therapy[3]
DUET 1 and 2 studies ongoing: etravirine vs placebo, with DRV/r and OBR in patients with both NNRTI and PI resistance
Expanded access just opened
1Vingerhoets J, et al. J Virol 2005 Oct;79(20):
2Andries K, et al. Antimicrob Agents Chemother 2004 Dec;48(12):4680–4686.
3Gazzard BG, et al. AIDS 2003 Dec 5;17(18):F49–F54.

5. TMC125-C223 Study Design Active control* TMC125 400 mg BID + OBR†
Screening
Treatment
4 weeks
48 weeks
Primary Objective:
Proportion of patients with ≥ 1 log10 reduction in HIV RNA from baseline to Week 24
*Active control: best available regimen from licensed agents
†Optimized background regimen: investigator selected NRTIs ± LPV/r ± T-20
Cohen C, et al. 12th Annual Conference of BHIVA; Mar 29-Apr 1, 2006; Brighton, UK. Abstract P2.

6. TMC125-C223 Virologic Response* at Week 4820
Percentage with response 40 60 80
100
23%
400 mg BID (n = 80)
800 mg BID (n = 79)
Active control (n = 40)
22% 0%
<50 copies/mL
<400 copies/mL
≥1 log reduction
in HIV RNA
28%
30% 8%
31%
34%
P < .001
P = .036
P = .009
P = .016
P = .004
* Time-to-Loss of Virologic Response (TLOVR)
P-values versus active control
TMC125, Phase IIb formulation TF035
Cohen C, et al, XVI International AIDS Conference; Aug 13-18, 2006; Toronto, Canada. Abstract TUPE0061.

7. Baseline NNRTI mutations
TMC125-C223 Number of NNRTI Mutations and Virologic Response at Week 48
Baseline NNRTI mutations
in TMC mg BID
Mean change in log10 VL
TMC mg BID
n = 79
Active control 0* 1 2 3
n = 40
–1.01
–0.14
–1.67
–1.38
–0.9
n = 30
–0.54
–0.5
–1.0
–1.5
–2.0
n = 14
n = 19
n = 16
Patients discontinuing the trial for any reason had their VL response imputed as no change from baseline (NC = F)
*All patients had NNRTI mutations from prior genotyping
Cohen C, et al. XVI International AIDS Conference; Aug 13-18, 2006; Toronto, Canada. Abstract TUPE0061.
TMC125, Phase IIb formulation TF035

8. Baseline NNRTI Mutations Associated With TMC125 FC >10 (Arbitrary Threshold)
No single NNRTI mutation was associated with mean FC >10 (arbitrary threshold) to TMC125
Frequency of combinations of NNRTI mutations associated with mean TMC125 FC >10 was low (12%)
Each of the following mutations, always in combination with up to four other mutations, were associated with mean FC >10
K101P, V179E, V179F, Y181I, Y181V, G190S, M230L
For V179E, V179F, G190S, M230L: additional mutations always included Y181C when FC >10
These mutations were previously identified in vitro to be associated with increased FC to TMC125
TMC125, Phase IIb formulation TF035
1. Cohen C, et al. XVI International AIDS Conference; Aug 13-18, 2006; Toronto, Canada. Abstract TUPE0061.
2. Vingerhoets J ,et al. J Virol Oct;79(20):

9. Targets for Antiretroviral Therapy
NRTIs,
NNRTIs
Attachment Inhibitors, Coreceptor Antagonists
Fusion Inhibitor
Entry Inhibitors
Reverse Transcriptase Inhibitors
PIs
Integrase Inhibitors
Protease Inhibitors
Maturation Inhibitors

10. HIV Entry Inhibitors New class of therapy
Works early in life cycle of the HIV virus
Inhibits fusion of viral particle with cell
Subcutaneous injection
Potent antiviral, but need other active antivirals for best effect
Injection site reactions

11. Phase II Study of TNX-355 A Novel Entry Inhibitor
-0.8
-0.4
-1.2
Mean Change in HIV-1 RNA at Week 24 (log10 copies/mL)
OBR Alone
15 mg/kg
10 mg/kg
-0.20
-0.95 (P = .003)
-1.16 (P < .001)
TNX OBR
48-week phase II study
3-class experienced (n=82)
Treatment arms
OBR vs. TNX OBR
15 mg/kg IV q2wks
10 mg/kg IV qwk x 8 wks, then 10 mg/kg q2wks
CD4 response:
OBR: +5 cells/mm3
10 mg/kg: +9 cells/mm3
15 mg/kg: +51 cells/mm3
Well tolerated, no serious ADR related to drug, no ISRs
Results sustained to Wk 48
Norris D, et al. 45th ICAAC. Washington, DC, Abstract LB2-26
Tanox Inc. News Release May 2, 2006.

12. HIV Tropism and Disease Progression
Mixed/Dual
↑ X4
CXCR4- tropic HIV
Dual-tropic HIV
CD4 Cell Count
Limit of tropism assay detection*
Amount of Virus
CCR5- tropic HIV
Time
* Less than 10% of a tropism is not detectable with current tropism assay
Courtesy GSK interactive CD "Exploring an allosteric world: CCR5 entry inhibitors and HIV"

13. CCR5 Inhibitors in Development Maraviroc
Randomization of 80 HIV infected patients with CCR5 tropic virus
CD4 >250 cells/mm3
VL >5000 copies/mL
0.5
-1.5
-1.0
-0.5
Days
300 mg BID
Placebo 15
Placebo 07
25 mg QD
50 mg BID
100 mg QD
100 mg BID
150 mg Fast
150 mg Fed
300 mg QD
Dosing
Median VL Change From
BL (log10 copies/mL) 5 10 15 20 25 30 35 40
-2.0
Doses >100mg/d had > 1.0 log10 decrease
Small  CD4 count with all doses
61/63 had CCR5 tropic virus at BL remained CCR5 tropic at follow up
1 reverted to CCR5 topic at day 40
1 persisted >6 mo post study with no evidence of clinical progression
Fatkenheuer G et al. XV IAC. Bangcock, Thailand. Abstract TuPeB4489

14. CCR5 Inhibitors in Development Vicriviroc
0.5
0.0
-0.5
-1.0
-1.5 5 10 15 20 25 30
Days
Median VL Change From
BL (log10 copies/mL)
10 mg BID
Placebo
25 mg BID
50 mg BID
Dosing
SCH-D / SCH
Piperazine based CCR5 antagonist
Orally bioavailable: 80%
IC50: 0.1 – 3 nM
Phase 1 trials showed log10 VL reduction
T½: ~27h
Chen et al. 9th CROI, Seattle, WA. Abstract 396-T
Schuermann D et al. 3rd IAS Rio de Janeiro, Brazil. Abstract TuOa0205
Schurmann D, et al. 11th CROI, San Francisco, CA. Abstract 140LB.

15. Maraviroc (UK-427,857) CCR5 Receptor Antagonist
Novel entry inhibitor (CCR5 Inhibitor)
Provides 1.5 log decrease as monotherapy
Dosing with food decreases absorption
Other CCR5 blockers retain activity against Maraviroc-resistant virus
Good safety profile
Optimal dose unknown 1

16. Vicriviroc (SCH-D / SCH 417690) CCR5 Receptor Antagonist
Small molecule inhibitor of the CCR5 receptor
Prevents entry of HIV into T-cells
Synergistic activity with existing antiretrovirals
Active against multi-drug/class resistant strains
Dose-limiting toxicity in animals was seizures
Seizure threshold fold above clinical exposures
Rapid, complete absorption in most animals
Consistent PK; manageable drug interactions
Not p-Gp substrate; CYP3A4 substrate, not inhibitor or inducer
Boosted by ritonavir (RTV) [AUC x 5, Cmax x 3]

17. Virologic Breakthrough With Vicriviroc Plus ZDV/3TC
Phase IIb trial of efavirenz vs vicriviroc, each with AZT/3TC
92 antiretroviral-naïve patients
2 week lead-in with either placebo or varying doses of vicriviroc monotherapy (4 arms)
From wk 2 to 48, AZT/3TC/EFV vs AZT/3TC + either 25 mg, 50 mg, or 75 mg of vicriviroc daily
Study stopped by DSMB
Greaves W, et al. CROI Abstract 161LB.

18. ACTG 5211: Study Design Placebo VCV 5 mg qd VCV 10 mg qd VCV 15 mg qd
Day 14
Week 24
Week 48
Study Entry
VCV 5 mg qd
VCV 10 mg qd
VCV 15 mg qd
SCREENING: genotype, phenotype, tropism
Failing ART Regimen
Optimized ART Regimen
Placebo
All regimens include mg RTV
Study powered to detect >0.7 log HIV RNA difference at day 14
Cross-over options (Step 2) following virologic failure (after wk 16)
Gulick R, et al. IAC Abstract THLB0217.

19. ACTG 5211: Baseline Characteristics
118 subjects enrolled
Median age 46
92% men, 8% women
20% black, 12% Hispanic, 66% white, 2% other
Median HIV RNA cps/ml
Median CD4 cell count 146 cells/µL
33% were ENF-experienced
100% had R5-tropic virus at screening
Gulick R, et al. IAC Abstract THLB0217.

20. ACTG 5211: Mean Change in HIV RNA (log10 cps/ml; 24 weeks, ITT)
placebo
VCV 5 mg
OBR 1 3 8 16 24 2 4 12 20
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
Weeks
Mean Change
Placebo vs:
5mg
10mg
15mg
P (wk 24):
0.002
<0.001
VCV 15 mg
VCV 10 mg
Gulick R, et al. IAC Abstract THLB0217.

21. ACTG 5211: Conclusions In treatment-experienced pts:
VCV (5, 10, 15 mg with RTV) demonstrated potent 14-day virologic suppression
Following optimization of background ART, VCV (10, 15 mg with RTV) demonstrated sustained antiretroviral activity over >24 weeks
Subjects with dual/mixed-tropism had a reduced virologic response
VCV was generally well tolerated
The relationship of VCV to malignancy is uncertain
Gulick R, et al. IAC Abstract THLB0217.

22. Screening and randomization Primary efficacy endpoint
Phase IIb Pilot Study Evaluating the Safety of Maraviroc in Patients with Non-R5 HIV-1
Screening and randomization
OBT* + MARAVIROC (150 mg** BID)
OBT* + MARAVIROC (150 mg** QD)
OBT* + Placebo
Weeks
Primary efficacy endpoint
4-6 Weeks 24 48
Randomized, double-blind, placebo-controlled study
Selection criteria:
D/M-tropic, X4-tropic or indeterminate tropism phenotype
Antiretroviral experienced and/or multi-class resistance
At least one active drug in OBT
*OBT = 3 to 6 ARVs (note PK boosting doses of RTV will not be counted as an ARV)
**150 mg maraviroc with PIs provides equivalent dose to 300 mg without PIs

23. Maraviroc: Efficacy Results
All treated patients with D/M-tropic HIV-1
Placebo + OBT
n = 58
MVC QD + OBT n = 57
MVC BID + OBT n = 52
Mean decrease in HIV-1 RNA (log10c/mL)*
-0.97
-0.91
-1.20
Treatment diff (MVC-OBT) in HIV-1 RNA decrease (log10c/mL) (97.5% CI)
(-0.53, +0.64)
-0.23 (-0.83, +0.36)
HIV RNA < 400 c/mL (%)
HIV RNA < 50 c/mL (%)
24.1
15.5
24.6
21.1
30.8
26.9
Mean decrease in HIV-1 RNA in patients using enfuvirtide** (log10c/mL)
-0.89
-1.26
-1.44
OBT - optimized background therapy
D/M - dual/mixed tropic *Primary endpoint
**LOCF
Mayer H, et al IAC Abstract THLB0215.

24. On the Horizon Integrase Inhibitors
MK-0518
GS 9137

25. Integrase Inhibitor (MK-0518) Phase IIa 10-Day Dosing Study
Phase IIa, placebo-controlled, monotherapy study
35 treatment-naïve patients
Baseline HIV RNA
4.53 to 4.97 log10 copies/mL
MK-0518
Doses: 100, 200, 400, 600 mg bid
At day 10
HIV RNA <400 copies/mL: >50%
No significant change in CD4 cell count from baseline
Most common adverse events
Headache, fatigue, and dizziness
Change in HIV RNA
at Day 10
(log10 copies/mL)
Placebo (n=7)
-0.2
MK-0518
(mg bid)
100 (n=7)
-1.9
200 (n=7)
-2.0
400 (n=6)
-1.7
600 (n=8)
-2.2
Morales-Ramirez JO, et al. EACS Abstract LBPS1/6.

26. MK-0518: Phase IIb (Protocol 005)
Multicenter, randomized, double blind
N=167
VL ≥ 5000
CD4 ≥ 50
Resistant to ≥ 1 NRTI, NNRTI, PI
Placebo
+ OBR
N = 43
MK mg bid
+ OBR
N = 42
MK mg bid
+ OBR
N = 40
MK mg bid
+ OBR
N = 42
Treatment arms similar at baseline
Mean duration of HAART: 9-11 yrs
Mean VL: log10 copies/mL
Use of ENF in OBR: 33% to 38%
Patients with no active PIs in OBR: 84% to 98%
Mean CD4: cells/mm3
Grinsztejn B, et al. 13th CROI. Denver, Abstract 159LB.

27. MK-0518 Virologic Suppression Through Week 16
Treatment† n
% < 400 copies
MK mg BID 25 84
MK mg BID 28 73
MK mg BID 67
Placebo 27 24
CI = Confidence Interval. † All subjects received OBT in addition to MK-0518 or placebo.
Grinsztejn B, et al. 13th CROI. Denver, Abstract 159LB.

28. MK-0518: Adverse Events ADRs: similar to placebo Most common ADR
Diarrhea, nausea, fatigue, ISRs, headache, pruritus
Occurring in >5% of 2 patients per arm
Grinsztejn B, et al. 13th CROI. Denver, Abstract 159LB.

29. MK-0518: Study Design Potent Activity of Integrase Inhibitor in Treatment-Naive Patients
Part I Design
8 patients each received MK-0518 at 600, 400, 200, or 100 mg bid or placebo for 10 days monotherapy
30 patients in addition each received one of the MK-0518 doses plus TFV+3TC, or efavirenz plus TFV+3TC, for a total of 38 patients in each arm
Part II Design
Part I patients continued at same dose in Part II ~150 additional patients randomized for Part II
Endpoints
HIV RNA and CD4 counts

30. MK-0518 vs Efavirenz HIV RNA < 50 copies/mL at Week 24 (NC = F)
HIV RNA levels % (95% CI)
Treatment (mg) N
<400 copies/mL
<50 copies/mL
MK-0518 BID
100 18
89 (65, 99)
88 (64, 99)*
200
100 (82, 100)
300 17
94 (71, 100)
400
100 (81, 100)
94 (70, 100)*
Efavirenz BID
600 15
93 (68, 100)
86 (57, 98)*
*One patient was excluded pending additional test results
Markowitz M, et al. IAC Abstract THLB0214.

31. MK-0518 vs Efavirenz Adverse Events
MK-0518* (all doses) N=160
(%)
Efavirenz*
N=38
Nausea 11 13
Headache 9 24
Dizziness 8 26
Diarrhea 7
Insomnia
Abnormal dreams 6 18
Flatulence -
Additional AEs seen at ≥ 5% in Efavirenz group: Nightmare (11%), Vomiting (8%), Malaise (8%), fatigue (5%); attention disturbances (5%); lethargy (5%); anxiety (5%).
* With TFV/3TC
Markowitz M, et al. IAC Abstract THLB0214.

32. Integrase Inhibitor (GS 9137) 10-Day Monotherapy Study
Change in
HIV RNA
at Day 10
(log10 copies/mL)
Placebo
-0.13
GS-9137
800 mg qd
-0.89*
200 mg bid
-1.44*
400 mg bid
-1.98*
800 mg bid
-1.78*
50 mg qd
+ RTV 100mg qd
-2.03*†
Phase IIb, placebo-controlled, monotherapy study
40 treatment-naïve and treatment-experienced patients
Baseline
HIV RNA: 4.75 log10 copies/mL
CD4: 442 cells/mm3
At day 10
>1 log10 reduction in HIV RNA
GS-9137: 83%
Placebo: 0%
No serious adverse events and no study drug discontinuations
Most common adverse events
Fatigue, diarrhea, headache, nausea
*P<0.01 versus placebo.
†P<0.05 versus 800 mg qd.
DeJesus E, et al. 13th CROI. Denver, Abstract 160LB.

33. Maturation Inhibitor PA-457
First maturation inhibitor
Data from a double blind, placebo controlled single dose study of 75mg, 150mg and 250mg and placebo (all n=6); naïve or of-treatment for >4 weeks; two subjects had MDR
Dose related response with median reduction at the highest dose of log10 and a greatest decline of log10. 8/12 in higher doses >0.3 log10
Return to baseline was inhibited for at least 20 days in the 250mg dose arm
Martin D, et al. CROI Abstract 159.

34. Maturation Inhibitor (PA-457) Phase II Dosing Study
Phase II, placebo-controlled, monotherapy study
32 treatment-naïve patients
Baseline
HIV RNA: 4.73 log10 copies/mL
CD4: 441 cells/mm3
Oral doses of PA-457
25, 50, 100, 200 mg qd
At day 11
AUC and trough levels were significantly associated with antiviral response (P<0.01)
Log10 Copies/mL
PA-457 mg qd
0.046
-0.174
-0.483
-1.05
Change in HIV RNA at Day 11
Smith P, et al. 13th CROI. Denver, Abstract 52.

35. New Antiretroviral Agents Conclusions
Newer drugs are needed to improve convenience, tolerability and activity (wild-type and resistant virus)
Promising agents are in development both in existing classes (NNRTI, PI) and new classes (e.g, entry and integrase inhibitors)
Further basic and clinical research is needed