New Drug Update: Whats in the pipeline

1
New Drug UpdateWhats in the pipeline

• Jean C. Lee, Pharm D, BCPS
• McAuley Health Center
• Saint Marys Health Care
• Grand Rapids, MI

2
25 years of AIDS / 19 years of ARVs

• Between 87 and 95, 4 antiretrovials were
  launched.
• Since 95, 24 new products have been introduced.

Aptivus
Truvada, Epzicom
Combivir
Viread
Epivir
Rescriptor
Hivid
Ziagen
Emtriva
Viramune
Sustiva
Trizivir
Zerit
Retrovir
Videx
87
91
92
94
95
96
97
98
99
00
88
89
90
01
02
03
93
04 05 06
RTI
Invirase
Viracept
Kaletra
Reyataz
NNRTI
Fortovase
Agenerase
Prezista
PI
Norvir
Multi-class Combination
Atripla
Crixivan
Lexiva
3
Whats in the Pipeline?
PI Brecanavir A-790742
NNRTI TMC-125 TMC-278 BILR 355
CXCR4 AMD 070 KRH 3955 KRH 3140
NRTI DAPD (Amdoxovir) Apricitabine GS9148
CCR5 Maraviroc Vicriviroc
Attachment / CD4 binding inhibitors TNX 355
Integrase Inhibitor MK 0518 GS 9137
Maturation Inhibitor PA-457 UK-201844
Fusion Inhibitor TRI-999 TRI-1144 T-651
4
NRTIs
5
Amdoxovir (DAPD)

• (-)b-D-2,6-diaminopurine dioxolane
• Guanosine analogue
• Activity to HIV and HBV
• PK
• Half-life 7-8 hours
• Suitable for bid dosing

D-diodolane guanine (DXG)
DAPD
Adenosine deaminase
Wang LH, et al. 8th CROI, Abstract 752 Wang LH,
et al. 7th CROI, Abstract 103
6
Amdoxovir Activity

• Strains resistant to AZT/3TC, d4T/3TC (invitro)
• Multi-NRTI resistant strains (codon 69ins)
• Decreased susceptibility K65R and L74V

Lennerstrand J et al. 45th ICAAC. Abstract H-1092
7
DAPD-101 Study (Phase I)

• Open label x 14 days, followed x 7 days

N90 VL 5000 250,000 copies/mL Naïve or
experienced x 6 mo
5 d/c from study
Experienced 49 Monotherapy (20) BID 200,
300, 500mg Add on (29) BID 300, 500mg
Naïve 41 Monotherapy BID 25, 100, 200, 300,
500mg QD 600mg

• 86 Male, 42 Caucasian, 39 African American
• Mean age 38 years (19-57y)
• BL CD4 362 cells/mm3 (49-1578), BL VL 4.53
  log10 (3.02 5.79)

Thompson MA et al. AIDS 2005191607-15
8
DAPD-101 Study

• Mean change from baseline in ART naïve and
  experienced

Change in HIV-RNA from baseline (log10 copies/mL)
Thompson MA et al. AIDS 2005191607-15
9
Treatment experienced group

• Add On Group
• Median decrease from baseline
• 300mg -0.31 log10 copies/mL
• 500mg -0.65 log10 copies/mL (NS)
• Monotherapy Add On Group
• gt -0.5 log10 gt -1.0 log10
• 300mg 36 24
• 500mg 67 38
• 4 patients achieved lt400 copies/mL
• 3 in 500mg cohort

Thompson MA et al. AIDS 2005191607-15
10
Safety

• 43 (48) had 1 ADR (possibly related)
• Most frequent ADR
• Headache 11
• Nausea 10
• Diarrhea 10
• No dose related ADRs
• No reports of visual abnormalities

• 66 with 1 grade 1-4 treatment emergent lab
  abnormality
• Majority were Grade 1-2
• None required dose adjustment
• Grade 3-4 reports
• Naïve 17
• Experienced 28

Thompson MA et al. AIDS 2005191607-15
11
DAPD-150 Study
N18 Tx-experienced
Amdoxovir 300mg bid N8
Amdoxovir 500mg bid N10

• Amdoxovir OBT 40 with gt 0.5 log10 copies/mL
  decrease
• 11/18 discontinued
• 5 Lens opacities (visual acuity not affected)
• 4 Virological failure
• 2 Withdrew/ non-adherent

• 17 male, 18 Caucasian, median 40y
• Median VL 4.41 log 10 copies/mL
• Median CD4 326 cells/mm3
• Background regimen optimized by investigator
• Total 96 weeks, ongoing

Thompson M et al. 10th CROI, Abstract 554
12
ACTG 5118
Amdoxovir 300mg bid Placebo
T-20 OBR

• Randomized, double-blinded, placebo controlled 24
  week study
• Study halted due to uncertainty of long term
  development plan
• Study was unblinded and subjects followed x 48
  weeks
• Data at 24 weeks reported (n18)
• Baseline data
• Median CD4 36 cells/mm3 (11-537)
• Median VL 4.8 log10 copies/mL (3.5-6.3)
• Average number of mutations NRTI 6 PI8
• 3 NNRTI resistance

Gripshover B et al. 12th CROI. Abstract 553
13
ACTG 5118 Efficacy / Safety (24wk)

• Time-average AUC minus baseline
• DAPD -1.1 log10 (95 CI 0.19-2.01)
• Placebo -0.8 log10 (95 CI 0.15-1.45)
• CD4 Response
• DAPD 70 cells/mm3 (95 CI 35-105)
• Placebo 54 cells/mm3 (95 CI 14-94)
• Time to first ADR
• no difference between groups
• Mild decrease in CrCl - equal in both groups
• No reports of ? lens opacity score

Gripshover B et al. 12th CROI. Abstract 553
14
ACTG 5165 DAPD Mycophenolate Mofetil
DAPD 500mg bid MMF Placebo N20
DAPD 500mg bid MMF 500mg bid N20
Vs.

• Phase I/II, randomized, double-blinded placebo
  controlled pilot study
• Experienced patients
• 90 males, 55 Caucasian, 70 40-49y
• BL VL 4.47 copies/mL
• BL CD4 184 cells/mm3
• Results
• No difference between groups
• DAPD -0.35 log10 copies/mL
• DAPD MMF -0.24 log10 copies/mL
• 10 subjects with virological failure by week 2

Margolis D et al. 13th CROI. Abstract 517
15
Apricitabine SPD754

• (-) dOTC (2-deoxy-3-oxa-4-thiocytidine)
• Deoxycytidine analogue
• Structurally similar to 3TC / FTC
• Additive, slightly synergistic activity in
  combination with other agents
• Activity with strains with 184V and TAMS
• PK supports bid dosing
• Invitro data support low potential for
  mitochondrial toxicity

Gu Z et al. Antimicrob Agents Chemother
200650625-31.
16
Apricitabine PK Study

• Randomized, open-label, 3 way crossover
• 21 healthy volunteers

7 day washout
SPD754 600mg bid 3TC 300mg qd X 4 days
SPD754 600mg bid X 4 days
3TC 300mg qd X 4 days
Bethell R et al. 11th CROI. Abstract 138
17
Results

• No difference in PK parameters
• SPD754-TP ? 6-fold with 3TC
• Interaction likely due to competition of same
  phosphorylation enzymes

Bethell R et al. 11th CROI. Abstract 138
18
10 d Randomized Monotherapy trial
N63 Naïve patients CD4 gt250 cells/mm3 VL
5000-100,000 copies/mL
400mg / d 200mg bid N11
800mg /d 800mg qd 400mg bid N12
1200mg / d 1200mg qd 600mg bid N14
1600mg/d 800mg bid N13
Placebo N13
Cahn P et al. AIDS 2006201261-8
19
Results

• All doses superior to placebo at day 7 and day 10
  (plt0.001)
• Reduction in plasma HIV-1 RNA

Log 10 HIV-1 RNA decline (copies/mL)
No clinically relevant changes in CD4 after 10 d
Cahn P et al. AIDS 2006201261-8
20
Results

• All doses well tolerated
• ADRs mild to moderate
• Incidence similar in across all groups
• Preliminary resistance results
• No new mutations in RT likely to cause resistance

Cahn P et al. AIDS 2006201261-8
21
GS-9148 Nucleotide RTI

• Cyclic adenosine monophosphate
• Highly active against HIV-1 subtypes A - D
• Mean EC50 13.1uM
• Mitochondrial effects
• Equivalent to TDF, ABC, FTC
• Superior to d4T, ddI
• Low lactate production
• Low cytotoxicity to a variety of cell types,
  including renal cells
• PK supports once daily dosing

Cihlar T et al. 13th CROI Abstract 45 Ray A et
al. 13th CROI. Abstract 498
22
Unique resistance profile

• Susceptibility
• Full K65R other RT mutations, M184V, L74V
• ? with T69ins TAMS M184V
• 3.16 fold reduced with Q151M complex
• Selects for rare K70E/N mutation in vitro

Cihlar T et al. 13th CROI Abstract 45 Ray A et
al. 13th CROI. Abstract 498
23
NNRTIs
24
Etravirine (TMC-125)

• Diarylpyrimidine derivative with activity against
  NNRTI resistant HIV-1
• Molecular flexibility allows to accommodate
  mutational changes in the binding pocket
• EC50 for WT HIV-1 1.4 nM
• Little or no loss of activity with key NNRTI
  resistant variants
• Strong in vitro activity (IC50 lt10nM)
• Variants with K103N, V106A, Y181C, G190A/S

Andries et al. Antimicrob Agents Chemother
2004484680-6
25
Etravirine activity in naïve(A) experienced(B)
patients
Gruzdev B et al. AIDS 2003172487-94 Gazzard BG
et al. AIDS 200317F49-54
26
Etravirine PK

• Metabolized by 3A4 , glucuronidation
• TPV/r ? Etravirine exposure by 76
• Coadministration not recommended
• New 100mg formulation to be used
• 200mg bid 800mg bid

Scholler M et al. 3rd IAS. Abstract
TuPe3.1B11 Scholler M et al. 13th CROI. Abstract
583
27
Etravirine Comparison to PI based regimen
2 NRTI PI

• PI naïve failing NNRTI regimen
• Data analyzed at Week 12

vs.
2 NRTI Etravirine

• After enrollment of first 54 patients at week 12
• Proportion of patients achieving or maintaining
  lt50 copies/mL favored the PI-based control group
• Study was prematurely discontinued in Nov 2005

www.tibotec.com/news/detail/jhtml?itemnamenews_09
. Accessed Aug 1, 2006
28
Study C223 TMC125 in PatientsWith NNRTI and PI
Resistance
HIV RNA Change at 24 Weeks

• Phase IIb study (n240)
• HIV RNA 4.7 log10 copies/mL
• CD4 99 cells/mm3
• NNRTI resistance (fold change)
• Efavirenz 41.4
• Nevirapine 61.3
• gt3 PI resistance mutations
• Treatment arms
• Active control
• Best available regimen from licensed agents
• TMC125 400 or 800 mg bid background regimen
• Investigator selected NRTIs lopinavir/r
  enfuvirtide

Active control
-0.19
-1.04
TMC125 400 mg bid
Log10 Copies/mL
-1.188
TMC125 800 mg bid
0 4 8 12 16
20 24
Weeks
CD4 Cell Count (cells/mm3)
TMC125 400 mg bid
48
Change From Baseline
47
TMC125 800 mg bid
18
Active control
0 4 8 12 16
20 24
Weeks
Plt0.05 vs active control.
Nadler J, et al. 10th EACS. Dublin, 2005.
Abstract LBPS3.7A.
29
C223 48 week results



patients achieving HIV-1 RNA lt400 copies/mL

Plt0.05 Plt0.001
?CD4 TMC125 (58-61cells/mm3) Control (13
cells/mm3) Common ADR diarrhea, rash, ISR,
pyrexia
Cohen C et al. 12th British HIV Association.
Abstract P2
30
Effect of Baseline Resistance on Response to
Etravirine

• Each of the following mutations, always in
  combination with up to 4 other mutations, was
  associated with a mean FC gt 10
• K101P, V179E, V179F, Y181I, Y181V, G190S, M230L
• For V179E, V179F, G190S or M230L, the additional
  mutations always included Y181C when the FC gt 10
• No single NNRTI drug resistance mutation was
  associated with FC gt 10
• Required multiple mutations ( 4)

Vingerhoets J, et al. J Virol. 20057912773-12782
. Vingerhoets J, et al. CROI 2006. Abstract 154.
31
Study C203 Safety of TMC125 inPatients With
NNRTI and PI Resistance
Montaner J, et al. 10th EACS. Dublin, 2005.
Abstract LBPS3.7B.
32
Pilot study TMC 114 plus Etravirine 3 and 4
class ARV experienced patients

• N 10 on novel combination of 114 / Etravirine
  OB
• PK No impact on 114/r levels modest reduction
  on Etravirine levels
• Week 12 Median -2.76 log decline
• All gt 2 log decline
• All had VL lt 400 c/mL
• Median (range) CD4 increase was 87 (83-171)
  cells/mm3
• No SAE, lab events
• Possible drug related AE mild diarrhea, HA, rash
• All resolve with continuous dosing.

Boffito M, et al. 13th CROI, Denver, CO, February
5-8, 2006. Abst. 575c
33
TMC-278

• Diarylpyrimidine NNRTI
• EC50 for WT HIV-1 0.5nM
• Little / no loss of activity with resistant virus
• EC50 2.7nM (L100I K103N)
• Active against 89 of 1500 resistant isolates
• EC50 lt10nM
• EFV 33 NVP 0
• T1/2 34-55h
• QD dosing
• Minimal renal clearance

de Bethune MP et al. 12th CROI. Abstract 556
34
TMC-278 PK

• Given with food
• Provides modest ? in exposure (45)
• Metabolized by CYP3A4
• Rifampin ? AUC by 80
• Ketoconazole ? AUC by 50

Hoetelmans R et al. 3rd IAS. Abstract
TuPe3.1B10 van Heeswijk R et al. 7th
International Workshop on Clinical Pharmacology o
f HIV Treatment. Abstract 74
35
TMC-278 Drug interactions

• PK not affected when combined with TDF
• TDF exposure ? by 24
• Not clinically relevant
• No dose adjustment necessary
• Interaction with LPV/r cap
• TMC278 AUC ? 52
• No effect on LPV/r

Hoetelmans R et al. 3rd IAS. Abstract
WePe3.3C15 Hoetelmans R et al. 10th EAC. Abstract
PE4.3/1
36
TMC-278 Monotherapy study
HIV infected, naïve CD4 75-500 cells/mm3 VL
gt5000 copies/mL N47
Oral solution Treatment x 7 d Follow up x 30d
Placebo N11
TMC278 150mg/d N9
TMC278 25mg/d N-9
TMC278 100mg/d N9
TMC278 50mg/d N9
100 male, 94 Caucasian, Median VL 4.5
copies/mL (3.5-5.9) Median CD4 292 cells/mm3
(29-590)
Goebel F et al. 12th CROI. Abstract 160
37
Similar efficacy with all doses

• Median change -1.2 (all groups)

Plt0.01
Median CD4 ? of 55 cells/mm3 after 7 days No
NNRTI resistant mutations detected at day 8
Goebel F et al. 12th CROI. Abstract 160
38
Safety Tolerability

• Mild ADRs
• TMC278 22 events Placebo 7 events
• Primarily grade 1 ADR
• 1 grade 3 nausea
• 1 grade 1 rash on day 3 (resolved on day 7)

Goebel F et al. 12th CROI. Abstract 160
39
PIs
40
Brecanavir GW-640385

• Non-peptidic PI
• Binds tightly to HIV protease
• IC50 WT 1.1 nM
• Active against highly PI resistant variants
• Low oral bioavailability
• Use with RTV

Hazen R et al. 2nd IAS. Abstract 541 Reddy S et
al. 43rd ICAAC. Abstract A-1800
41
Study HPR10006

• Brecanavir/rtv 300/100mg bid 2NRTIs (AZT,d4T,
  ddI, 3TC, FTC)
• 48-week study
• N31
• 6 had PI resistance
• HIV RNA 4.71 log10 copies/mL
• CD4 311 cells/mm3
• HIV RNA change
• (log10 copies/mL)
• PI sensitive -3.3
• PI resistant -2.2
• HIV RNA ()
• lt400 copies/mL 81
• lt50 copies/mL 77
• CD4 gain (cells/mm3) 84

Ward D, et al. 45th ICAAC. Washington, DC, 2005.
Abstract H-412.
42
Study HPR10006

• At week 24
• 4 discontinuations
• Most common ADRs
• Fatigue 13
• Nausea 10
• Dyspepsia 10
• ? CK 10
• ? TG 6

Ward D, et al. 45th ICAAC. Washington, DC, 2005.
Abstract H-412.
43
Drug Interaction data TDF

• N35 healthy volunteers
• All meds were well tolerated
• CrCl ? by 15mL/min
• BCV/r inhibition of active tubular secretion may
  account for some of the decreased TDF clearance
  (-30)
• No TDF dosage adjustment is required

Ford SL et al. 45th ICAAC. Washington DC.
Abstract A-1198 Ford SL et al. 7th International
Workshop on Clinical Pharmacology of HIV Therapy.
Lisbon, Portugal. Abstract 38
44
Drug Interactions

• Minimal interaction with LPV/r
• BCV/r and ATV exposure ?
• Higher frequency of Grade 4 ?bilirubin for BCV/r
  ATV
• Clinical significance unknown
• May require reduction of ATV dose

Ford SL et al. 7th International Workshop on
Clinical Pharmacology of HIV Therapy. Lisbon,
Portugal. Abstract 51 Ford SL et al. 7th
International Workshop on Clinical Pharmacology
of HIV Therapy. Lisbon, Portugal. Abstract 76
45
Integrase Inhibitors
46
HIV Integrase Mechanism
www.clinicaloptions.com/hiv
47
MK-0518

• Metabolized by glucuronidation (UGT1A1)
• Potential interaction with atazanavir
• Not a CYP450 metabolite or inhibitor
• No expected significant interactions with most
  antiretrovirals
• Cannot be boosted by ritonavir

www.merck.com/newsroom/press_releases/reasearch_an
d_development/2006_0209.html
48
MK-0518 Monotherapy study
N35 VL 5000 CD4 100 Treatment naive
MK 0518 600mg bid N8
Placebo N7
MK 0518 100mg bid N7
MK 0518 400mg bid N6
MK 0518 200mg bid N7
All arms similar at baseline Mean BL VL 4.7
copies/mL, CD4 425 cells/mm3 Fewer with AIDS
dx in placebo arm
Morales-Ramirez JO, et al. 10th EACS. Dublin,
2005. Abstract LBPS1/6.
49
HIV RNA Change at Day 10
HIV RNA Change at Day 10
50-57 lt400 copies/mL 13-29 lt50 copies/mL
-0.2
Log10 Copies/mL
-1.7
-1.9
-2.0
-2.2
100 200 400 600 Placebo
MK-0518 (mg bid)
Morales-Ramirez JO, et al. 10th EACS. Dublin,
2005. Abstract LBPS1/6.
50
MK-0518

• Generally well tolerated
• No serious ADR or discontinuations
• All events mild, transient
• No grade 3 / 4 lab abnormalities
• 1 patient with ?ALT at day 5, resolved at day 10
• Most common ADR
• Dizziness
• Headache
• Fatigue

Morales-Ramirez JO, et al. 10th EACS. Dublin,
2005. Abstract LBPS1/6.
51
MK-0518 Phase IIb (Protocol 005)
N167 VL 5000 CD4 50 Resistant to 1 NRTI,
NNRTI, PI
Multicenter, randomized, double blind
MK 0518 600mg bid OBR N42
Placebo OBR N7
MK 0518 200mg bid OBR N42
MK 0518 400mg bid OBR N42

• Treatment arms similar at baseline
• Mean duration of HAART 9-11 yrs
• Mean VL 4.6-4.8 log10 copies/mL Mean CD4
  220-283 cells/mm3
• Use of ENF in OBR 33 to 38
• Patients with no active PIs in OBR 84 to 98

Grinsztejn B, et al. 13th CROI, Denver, CO,
February 5-8, 2006. Abst. 159LB
52
MK-0518 Efficacy Results (Wk 16)

• Change in HIV-RNA
• MK 0518 -2.0 log10 copies/mL
• Placebo -0.8 log10 copies/mL

• Change in CD4
• MK 0518 400mg 600mg arms
• 100 cells/mm3
• Placebo 200mg arms
• 25 cells/mm3

Grinsztejn B, et al. 13th CROI, Denver, CO,
February 5-8, 2006. Abst. 159LB
53
MK-0518 Virologic Suppression Through Week 16
Grinsztejn B, et al. 13th CROI, Denver, CO,
February 5-8, 2006. Abst. 159LB
54
MK-0518 Adverse Events

• ADRs similar to placebo
• Most common ADR
• Diarrhea, nausea, fatigue, ISRs, headache,
  pruritus
• Occurring in gt5 of 2 patients per arm

Grinsztejn B, et al. 13th CROI, Denver, CO,
February 5-8, 2006. Abst. 159LB
55
MK-0518 Adverse Events

• 5 Serious ADRs reported
• Acute pancreatitis (secondary to OBT, 200mg)
• Lipoatrophy (blinded)
• Anemia, metabolic acidosis, renal insufficiency,
  death (blinded)
• Hepatomegaly, fever (600 mg arm)
• Lacunar infarction (placebo arm)
• Low frequency Grade 3 / 4 lab abnormalities

Grinsztejn B, et al. 13th CROI, Denver, CO,
February 5-8, 2006. Abst. 159LB
56
GS-9137 / JTK-303

• Dihydroquinoline carboxylic acid
• Strand transfer inhibitor
• Structurally resembles quinolones
• Activity
• Inhibits HIV-1 replication in 8 subtypes (A-G,O)
• Synergistic 3TC
• Additive AZT, TDF, EFV, IDV, NFV

• T1/2 5-6h
• Food ? Cmax, AUC by 3 fold
• Metabolized by CYP 3A
• Moderate inducer of 3A
• RTV ? exposure by 20 fold
• Increasing T1/2 to 9h
• Other drug interactions unknown

Sato M et al. J Med Chem 2006491506-8 Matsuzaki
Y et al. 13th CROI Denver, CO. Abstract 508
Kawaguchi I et al. 13th CROI Denver, CO. Abstract
580 DeJesus E et al. 13th CROI Denver, CO.
Abstract 160LB
57
Integrase Inhibitor GS-9137

• Phase IIa, 10-day monotherapy, placebo controlled
• N 40 HIV patients
• Naïve (n15)
• Off treatment (n25)
• GS-9137 dosing
• 200, 400, 800 mg BID
• 800 mg QD
• 50 mg RTV 100 mg QD
• Dose-dependent response
• RTV boosting allowed lower, once-daily GS-9137
  dosing
• No serious adverse events

• Once-daily dosing with ritonavir to be
  investigated in phase II trial with experienced
  patients

DeJesus E, et al. 13th CROI, Denver, CO, February
5-8, 2006. Abst. 160LB
58
Steady State PK
protein binding adjusted, wild type virus
DeJesus E, et al. 13th CROI, Denver, CO, February
5-8, 2006. Abst. 160LB
59
GS-9137 generally well tolerated

• No serious ADRs
• Similar frequency ADR, lab abnormalities
• Mild diarrhea, nausea, headache, fatigue
• Fatigue greater frequency in GS 9137 groups
• No changes in QT interval
• Grade 3/4 abnormalities

GS 9137 ? TG ? amylase
Placebo ? aminotransferase ? amylase ? CK
DeJesus E, et al. 13th CROI, Denver, CO, February
5-8, 2006. Abst. 160LB
60
Maturation Inhibitor
61
Bevirimat PA-457

• Butulinic acid derivative
• Phase II trials
• Disrupts the final step in the processing of HIV
  Gag protein.
• Inhibits the conversion of the capsid precursor
  (p25) to mature capsid protein (p24)
• Release of non-infectious viral particles and the
  termination of viral replication
• Mutations conferring resistance to PA-457 map to
  the p25 to p24 cleavage site

Li F et al. Proc Natl Acad Sci 200310013555-60
62
Viral Budding and Maturation Mechanism and
Inhibition
www.Clincialoptions.com/hiv
63
Bevirimat

• IC50 for WT 10.3nM
• Active against WT drug resistant HIV-1
• Inactive against HIV-2
• Synergy in combination with ARVs
• Strongest with AZT
• Half-life 60h
• Suitable for QD dosing
• Not metabolized or significantly inhibit CYP450
  enzymes
• Does not interact with human PGP

Li F et al. Proc Natl Acad Sci 200310013555-60 O
gundele A et al. 3rd IAS. Abstract
TuPe3.1B01 Martin DE et al. 11th CROI San
Francisco, CA. Abstract 545 Kilgore N et al. 13th
CROI Denver, CO. Abstract 509
64
Phase II 10-Day Dosing Study

• Phase II monotherapy study
• 33 treatment-naïve patients
• Baseline
• HIV RNA 4.73 log10 copies/mL
• CD4 441 cells/mm3
• Randomized groups
• Placebo
• PA-457 25, 50, 100, 200 mg qd
• No evidence of resistance
• ADRs mild to moderate
• Mostly GI
• No grade 3/4 adverse events
• 1 poorly controlled HTN lacunar stroke ? related

HIV RNA Change at Day 10
-0.03
-0.05
-0.17
-0.48
P0.004
-1.03
Log10 Copies/mL
Plt0.0001
25 50 100 200
Placebo Bevirimat
Beatty G, et al. 45th ICAAC. Washington, DC,
2005. Abstract H-416d
65
General Entry inhibitors
66
HIV-1 Entry Inhibitors
67
HIV-1 Entry Inhibitors TNX-355

• Humanized oral monoclonal Ab 5A8
• IgG subtype 4
• Recognizes unique epitope in domain 2 of the CD4
  receptor
• Inhibits post-HIV-CD4binding entry step
• In vitro
• Active against R5, X4-tropic HIV
• Synergistic activity with ENF
• Single dose showed at least -1.1log10 and dose
  dependent increase in CD4.

Kuritzkes D, et al. J Infect Dis.
2004189286-291. Godofsky E, et al. ICAAC 2005.
Abstract LB26.
68
TNX-355 24 week interim results

• 48-week phase II study
• 3-class experienced (n82)
• Treatment arms
• OBR vs. TNX-355 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
• 10mg/kg 9 cells/mm3
• 15mg/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,
2005. Abstract LB2-26 Tanox Inc. News Release May
2, 2006.
69
CCR5 Inhibitors
70
Vicriviroc

• SCH-D / SCH 417690
• Piperazine based CCR5 antagonist
• Orally bioavailable 80
• IC50 0.1 3 nM
• Phase 1 trials showed -1.6 log10 VL reduction
• T1/2 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.
71
PK Interactions Vicriviroc

• Metabolized via CYP 3A4

• Sansone A, et al. PK Workshop 2005. Abstract 85.
  2. Sansone A, et al. PK Workshop 2005. Abstract
  84. 3. Saltzman M, et al. IAS 2005. Abstract
  TuPe3.1B05. 4. Saltzman M, et al. IAS 2005.
  Abstract TuPe3.1B08.

72
14 day Monotherapy study
Phase II study, randomized, placebo-controlled
trial

• N 92
• Treatment-naive subjects CCR5-tropic virus
• CD4 count gt 150 cells/mm³
• HIV-1 RNA 3000 copies/mL
• No baseline resistance to regimen compounds

Greaves W, et al. CROI 2006. Abstract 161LB.
73
Late Virologic Breakthrough

• Median follow-up 31.8 weeks (1.0-53.8)
• Resistance profile at breakthrough
• 22/26 had evaluable genotypes
• 22/22 had M184V/I
• 1 had M41L
• No change in vicriviroc IC50 noted with virologic
  breakthrough
• Serious ADR
• Vicriviroc 10-12
• Placebo 4
• Grade 3/ 4 ADR similar rate
• DSMB ended this study

Greaves W, et al. CROI 2006. Abstract 161LB.
74
Maraviroc UK-427,857

• Maraviroc inhibits HIV-1 gp120 binding to CCR5
  coreceptor, thereby preventing gp160-CCR5
  mediated cell-cell fusion
• Maraviroc demonstrated no antagonistic effects
  when coadministered with other antiretroviral
  agents

Dorr P et al. Antimicrob Agents Chemother
2005494721-32
75
Maraviroc

• Selective reversible binding to CCR5 receptor
• 2nM antiviral IC90 activity
• Cross clade potency
• Active against current class resistant HIV but
  not CXCR4 virus
• HIV strains resistant to Maraviroc does not lead
  to class resistance

Westby et al. 12th CROI, Boston, MA. Abstract 96
76
Maraviroc PK

• T1/2 13-17h
• 50 reduction in exposure with food
• No effect on antiviral activity
• Metabolized by CYP3A4
• Does not inhibit or induce CYP450 enzymes

Abel S et al. 10th CROI. Boston, MA. Abstract
547 Fatkenheuer G et al. XV IAC. Bangkok,
Thailand. Abstract TuPeB4489
77
Maraviroc PK Interactions

• No interaction between MVC and tipranavir/ritonavi
  r1
• Maraviroc AUC doubled with lopinavir/ritonavir2
• ? MVC dose by 50 when given with most PIs
• Maraviroc AUC ? 50 with efavirenz2
• ? Cmax with NVP

Abel S, et al. EACS 2005. Abstract
LBPE4.3/15. Muirhead G, et al. CROI 2005.
Abstract 663.
78
10d Monotherapy-dose ranging study

• Randomization of 80 HIV infected patients with
  CCR5 tropic virus
• CD4 gt250 cells/mm3
• VL gt5000 copies/mL

• Doses gt100mg/d had gt 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 gt6 mo post study with no evidence of
  clinical progression

Fatkenheuer G et al. XV IAC. Bangcock, Thailand.
Abstract TuPeB4489
79
Maraviroc well tolerated

• Majority ADRs mild moderate
• Asthenia, headache, dizziness
• 2 discontinuations, not treatment related
• No clinically significant lab abnormalities or
  effects on QT interval
• Postural hypotension dose limiting AE in phase I
  study
• Higher rates vs. placebo with doses 600mg
• Sporadic, clinically relevant ?transaminases
• No dose relationship or elevation in bilirubin

Fatkenheuer G et al. XV IAC. Bangcock, Thailand.
Abstract TuPeB4489 McHale et al. 3rd IAS. Rio de
Janerio, Brazil. Oral TuOa0204
80
1 case of Hepatotoxicity

• AZT/3TC Maraviroc 300mg qd
• HCV ()
• Undetectable HCV RNA
• Radiologic evidence of underlying stenosis
• Meds for hypergammaglobinemia and () ANA
• Rash hepatotoxicity after 4 doses
• Maraviroc d/cd, other potentially hepatotoxic
  meds were continued (INH, TMP/SMX, acetaminophen,
  LPV/r)
• Liver transplant

Pfizer Inc. Press Release. December 3, 2005.
81
Maraviroc in Treatment naïve

• Once daily dosing arm in treatment naïve subjects
  was terminated due to inferior performance
  relative to EFV based control arm.
• Ongoing studies in R5 experienced and R5/X4
  experienced patients

82
CXCR4 Inhibitors

• Slower development than R5 inhibitors
• No naturally occurring mutations leading to
  absence of CXCR4
• Deletion of CVCR4 ligand is lethal in mice
• AMD3100 halted due to QT prolongation
• AMD070 in currently in studies
• Dose related increase in WBC
• Preclinical studies KRH-3955 / KRH-3140
• Active against X4 virus
• Increase in WBC

Schols D et al. 12th CROI. Boston, MA. Abstract
545 Tanaka Y et al. 13th CROI. Denver, CO.
Abstract 49LB
83
CCR5 / CXCR4 tropism
84
Chemokine Coreceptor Antagonists

• HIV can enter the cell via various chemokine
  coreceptors
• R5 vs X4 virus
• Mixed and dual-tropic populations
• Start with CCR5 virus, over time change to CXCR4
  virus
• ? Progression of disease
• Relationship between viral tropism and disease
  progression

85
Prevalence of Coreceptor Tropism

• Demarest J, et al. ICAAC 2004. Abstract H-1136.
  2. Brumme ZL, et al. J Infect Dis.
  2005192466-474. 3. Moyle GJ, et al. J Infect
  Dis. 2005191866-872. 4. Melby T, et al.
  CROI 2006. Abstract 233.
• 5. Wilkin T, et al. CROI 2006. Abstract 655.

86
HIV Tropism and Disease Progression
Courtesy GSK interactive CD "Exploring an
allosteric world CCR5 entry inhibitors and HIV"
87
Baseline CD4 strongest predictor of X4 phenotype
Harrigan PR et al. XV IAC. Bangkok, Thailand.
Abstract MoPeB3117
88
Dual tropism Emergence With Maraviroc
Lewis ME, et al. ICAAC 2004. Abstract 584b.
89
Challenges with CCR5 / CXCR4 inhibitors

• Utility may be related to disease stage, rather
  than treatment experience
• Transmissions involving X4 virus associated with
  rapid disease progression
• Unknown long-term safety of CCR5 inhibition
• Uncertain risk/implications of X4 emergence
• Uncertain benefit in patients with mixed
  infection
• Need for laboratory monitoring of viral tropism

90
Investigational Agents for the future
Integrase inhibitors
CCR5 inhibitors
PA-457
Darunavir
Etravirine
Brecanavir
TMC278
CXCR4 inhibitors