FUTURE

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FUTURE THERAPEUTICS
Michael Kolber, PhD, MD Miller School of
Medicine University of Miami
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FUTURE THERAPEUTICS
Time (yrs)
Protease Inhibitors Non-nucleoside Reverse
Transcriptase Inhibitors Entry Blockers,
Integrase Inhibitors Vaccines Biologics
1-2
2-3
2-4
4
4
3
RESIST-1 Phase 3 Study of Tipranavir/Ritonavir
Patients failing PI-containing HAART VL gt
1000 Any CD4
Interim analysis,Wk 24
HIV resistance expert panel
Wk 48
Best PI choice
TPV/r arm (n 311)
Computerizedrandomization to OBR plus
Preselection of regimenby investigator CPI
OBR ( enfuvirtide)
Baseline genotypic resistance testing
CPI arm LPV/r, IDV/r, SQV/r, APV/r (n 309)
Failures in CPI arm after Wk 8 could receive
TPV/r in rollover study
CPI, comparator PI OBR, optimized background
Entry criteria ? 1 primary PI mutation at
codons 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or
90M ? 2 mutations at codons 33, 82, 84, or 90
Hicks C, et al. ICAAC 2004. Abstract 1137a.
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RESIST-1 Baseline Phenotypic Susceptibility and
Agents Prescribed

• Baseline median VL, 4.8 log10 copies/mL
• Baseline CD4 cell count, 123 cells/mm3
• 30 uptake of expert advice
• Preselected comparator PIs
• LPV/RTV 61.0
• IDV/RTV4.4
• SQV/RTV 20.6
• APV/RTV 14.0
• Enfuvirtide included in regimen, 36.1

77.8
80
60
39
Median Baseline FC in IC50
40
27.2
20
12.2
1.9
0
TPV
LPV
IDV
SQV
APV
229
231
227
229
228
n
Hicks C, et al. ICAAC 2004. Abstract 1137a.
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RESIST-1 Superior Virologic Responses With
Tipranavir/Ritonavir
Patients with 1 log10 VL reduction (ITT, NCF)
80
TPV/r (n 311)
60
CPI/r (n 309)
50
41.5
40
Responders,
30
22.3
20
10
P lt .0001
0
0
4
8
12
16
20
24
Wks
Hicks C, et al. ICAAC 2004. Abstract 1137a.
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RESIST-1 Undetectable Viral Load and Impact of
Enfuvirtide (ITTNCF)
100
100
TPV/r (n 311)
TPV/r (n 311)
CPI/r (n 309)
CPI/r (n 309)
80
80
60
60
HIV-1 RNA lt 400 copies/mL,
HIV-1 RNA lt 50 copies/mL,
34.7
40
40
25.1
16.5
20
20
10.0
P lt .001
P lt .001
0
0
0
4
8
12
16
20
24
0
4
8
12
16
20
24
Wk
Wk
Hicks C, et al. ICAAC 2004. Abstract 1137a.
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RESIST-1 Impact of Enfuvirtide on Virologic
Responses
100
lt 400 at Wk 24
lt 50 at Wk 24
80
47.1
60
Patients ()
32.8
34.7
40
21.9
25.1
14.3
16.5
10.0
20
0
All
ENF
All
ENF
All
ENF
All
ENF
TPV/r
CPI/r
TPV/r
CPI/r
Hicks C, et al. ICAAC 2004. Abstract 1137a.
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RESIST-1 Significantly More Grade 3/4 Lab
Abnormalities With Tipranavir/Ritonavir

• Similar safety profile except ? incidence of
  elevated ALT, AST, triglycerides, and cholesterol
  
• 19/22 TPV/r patients with Grade 3/4 ALT/AST were
  asymptomatic and continued treatment
• 64/66 patients with Grade 3/4 triglycerides
  continued treatment
• Discontinuations through Wk 24
• Virologic failure (n) 13 on TPV/r , 109 on CPI/r
• Adverse events (n) 25 on TPV/r, 9 on CPI/r

Hicks C, et al. ICAAC 2004. Abstract 1137a.
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TMC-114 (TIBOTEC)

• Pharmacokinetics
• Rapidly Absorbed-improved with food by 42
• Boosted with Ritonavir
• Elimination t1/2 10 hrs

• Safety and Tolerability
• Most common Side Effects GI Headache
• AEs usually mild to moderate

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Antiviral Activity of TMC-114
To evaluate the efficacy of TMC114/r in 3-class
experienced patients in a 24 wk interim analysis
497 HIV-1 infected subjects Median VL
4.6log10c/ml, CD4 141cells/mm3 gt 3-class
experienced with gt1 primary PI-mutation, prior
use of gt1 PI, and HIV VLgt1000c/ml

• Randomization protocol
• TMC114/rtvOBR 4 dosing regimens
• Investigator Selected Control PI (CPI) OBR

Primary endpoint viral load reduction from
baseline to wk 24 Secondary endpoint patients
with gt1 log10 decease in VL
Abst164LB CROI 12, 2005
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Antiviral Activity of TMC-114
Abst164LB CROI 12, 2005
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Non-Nucleoside Reverse Transcriptase Inhibitors
Chemical structures of the three approved
non-nucleoside reverse transcriptase inhibitors
(NNRTIs) nevirapine (Viramune), delavirdine
(Rescriptor) and efavirenz (DMP266, Sustiva)
and of the next-generation NNRTIs in clinical
development capravirine (S-1153 AG1549) and the
DAPY analogue TMC125.
Pauwels Curr Opin Pharmacol. 2004 Oct4(5)437-46
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TMC125 NNRTI (TIBOTEC)

• DAPY compoundFlexible molecule
• Potency wild-type HIV
• EC50 1.4 nM
• EC90 2.9 nM
• Cytotoxicity MT4 cells
• CC50 gt 100 µM
• SI gt 71,429

TMC125 was selected because of its unique
activity profile against NNRTI resistant strains
Diarylpyrimidine
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Pharmacokinetics of TMC125

• TMC125 is highly lipophilic
• 99.9 bound to plasma proteins
• Tablet code for Phase IIb is TF035
• 200 mg TMC125 base per tablet
• Extensive distribution to tissues
• Long elimination half-life (35 h)
• Variability between subjects ca. 40
• Steady-state is reached after 5 days of bid
  dosing
• Dose-proportional pharmacokinetics for doses
  studied in TMC125-C223

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Steady-State Pharmacokinetics (12 h)
TMC125 conc. (ng/mL)
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Activity of TMC125 Against Single Mutants
gt
EFV
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Activity of TMC125 Against Single Mutants
gt
4 mutants with increased FC
Y181I (1.4) F227C (0.01) Y181V (0.97) M230L
(0.98)
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Activity of TMC125 Against Double Mutants
gt
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Activity of TMC125 Against Double Mutants
gt
EFV
TMC125
1 double mutant with increased FC V179F Y181C
(0.53)
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Site-Directed Mutants Conclusions

• TMC125 retains potent antiviral activity against
  the majority of tested mutations
• Only less prevalent mutations are associated with
  a decreased susceptibility to the compound
• 4 single mutations and 1 double mutation were
  associated with decreased susceptibility to
  TMC125
• Prevalence of these mutations in a database of
  gt7,000 NNRTI-resistant viruses was lt2
• Changes at positions 101, 179, 181, and possibly
  227 and 230, may play a role in decreased
  susceptibility to TMC125

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Activity Against NNRTI-Resistant Clinical Isolates
(N 983)
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NNRTI-Resistant Clinical Isolates Conclusions

• The majority of circulating strains (gt90) were
  inhibited by TMC125, with an EC50 below 10 nM
• TMC125 also inhibited 80 of the
  NNRTI-resistant strains (defined as an FC in
  EC50 of gt10 for at least 1 NNRTI), whereas EFV
  inhibited only 29 of these isolates
• Using the biological cut-off of EFV (equally
  potent against wild-type), the activity of TMC125
  on clinical isolates with up to 4 NNRTI mutations
  is comparable to wild-type (FC lt6)

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Food Interaction TMC125

• TMC125 is highly lipophilic
• Intake with food increases exposure to TMC125, in
  the current formulation, by 4-fold
• TMC125 must always be taken with food

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Food Interaction TMC125 (cont)
Mean TMC125 conc. (ng/mL)
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Interaction Profile TMC125

• Like other NNRTIs, TMC125 induces CYP450 (and
  decreases exposure of unboosted PIs)
• Exposure to TMC125 is increased by inhibitors of
  CYP3A4
• TMC125 is metabolized via glucuronidation
  high-dose ritonavir reduces exposure to TMC125
• No interactions with NRTIs or T20 anticipated

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Interaction TMC125 LPV/RTV
Lopinavir
P NS
n 14
n 13
Ratio (95 CI) With TMC125/Alone AUC12h 80
(49107) P 0.13 Cmax 85 (62105) P
0.13 Cmin 92 (15168) P 0.82
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Interaction TMC125 LPV/RTV (cont)

• When LPV/RTV and TMC125 are combined
• Non-significant decrease (20) of lopinavir
  exposure
• Non-significant increase (17) of TMC125 exposure
• No significant drug interaction in healthy
  volunteers for the combination LPV/RTV 400/100 mg
  bid and TMC125 1600 mg bid

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TMC125 Safety Overview

• Non-clinical toxicology has not identified any
  clear target organ
• No consistent abnormalities in hematology,
  biochemistry, ECG, or vital signs
• Most common AEs in healthy volunteers are
• Neurologic, GI, skin
• Most common AEs in 7-day POP trials in subjects
  are
• GI, neurologic
• Most common AEs in longer-term ongoing patient
  trials are
• GI, respiratory, neurologic, general disorders,
  infections
• ?15

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Capravirine (Lexigen Pharm.) a NNRTI in Patients
Infected with HIV-1 A Phase 1 Study
Gewurz et al. The Journal of Infectious
Diseases    20041901957-1961
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Capravirine (Lexigen Pharm.) a NNRTI in Patients
Infected with HIV-1 A Phase 1 Study
Gewurz et al. The Journal of Infectious
Diseases    20041901957-1961
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L-000900612 AN INTEGRASE INHIBITOR (Merck)

• A selective inhibitor of HIV-1 integrase
  catalyzed strand transfer-a phosphotransferase
  (IC5010nM)
• Primarily eliminated by metabolism
• Not a potent inhibitor of the P-450
  microsomal system

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Antiretroviral Effect of L-000870810, a Novel
HIV-1 Integrase Inhibitor, in HIV-1 Infected
Patients S. Little et al, Abst 37 12th CROI,
Boston
? METHODS Multicenter, double-blind,
randomized, placebo-controlled study ?
monotherapy for 10 days in 2 groups of HIV-1
patients on no ART ? Subjects received 400mg
or 200mg BID ? RESULTS 400mg N16 Mean
?VL1.77Log10 200mg N5 Mean ?
VL1.77Log10
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Inhibitors of HIV-1 entry
D. Kuritzkes,MD CROI Feb 2005
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Potential advantages of CCR5 inhibitors

• Novel class
• Cellular target
• Extracellular locus of action
• R5 viruses predominate in early infection
• Naturally occurring homozygous deletions

D. Kuritzkes,MD CROI Feb 2005
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CHEMOKINE RECEPTOR ANTAGONISTS

• CCR5 Receptor Blockers
• GW 873140 (GSK)
• UK 427,857 (Pfizer)
• Sch 417690 (Schering)

• CXCR4 Receptor Blockers
• AMD-3100 (AnorMed)

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UK-427,857 Pre-clinical Profile

• Selective, reversible binding to the CCR5
  receptor
• 2 nM antiviral IC90 (primary isolates in PBMCs)
• Excellent cross-clade potency against primary
  CCR5-tropic isolates
• Active vs. current class-resistant HIV but not
  against X4 virus

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UK-427,857 pharmacokinetics

• Rapid absorption Tmax 0.5-4.0 hours
• Terminal T1/2 follow IV dosing of 13 hours
• Administration with food caused 50 reduction
  in systemic exposure at clinically relevant doses
• Metabolized primarily by CYP3A4
• Drug-drug interaction data suggest 0.5X doses
  adjustment with potent CYP3A4 inhibitors
• Does not inhibit or induce p450 enzymes
• 5-15 of dose excreted unchanged in urine
• PK similar between males and females
• PK similar between patients and volunteers

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UK-427,857 Summary of Healthy Volunteer Data

• gt400 healthy volunteers have received single or
  multiple doses of UK-427,857
• Safe and well tolerated in single doses up to 900
  mg, and multiple doses up to 300 mg BID for up to
  28 days
• Most frequent AEs seen after multiple dosing were
  headache, asthenia, flatulence, dizziness, and
  nausea
• Dose-limiting AE is postural hypotension
  (primarily at gt600 mg), which appears to be
  related to Cmax
• No evidence of QTc prolongation following single
  doses of 900 mg or multiple doses 1200 mg QD

Study A4001001/1002/1005/1016/1019
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SCH 417690 - Overview

• Small molecule (MW 650) CCR5 receptor inhibitor
• Orally bioavailable (80)
• Long t½ allows once daily dosing
• Exposure boosted by ritonavir
• Additive-synergistic activity with existing
  classes of antiretrovirals

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Phase 1b Study Design

• Ascending dose, randomized (within dose),
  placebo-controlled trial in Rx-naïve
  HIV-1-infected subjects
• No detectable X4 virus at screening
• 10 mg, 25 mg, 50 mg po BID x 14 days
• HIV RNA q day x 7 days q 2 days x 3 weeks
• No concomitant antiretroviral agents
• First 7 days administered in hospital
• 14-day follow-up after dosing

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SCH 417690 Phase 1b Safety data

• Generally well tolerated with mostly mild, non
  dose-related adverse events
• Two SAEs (not dose-related)
• VDRL () patient developed 2º syphilis
• Prolonged hospitalization for undiagnosed febrile
  illness
• No emergence of resistance to SHC 417690
• No total shift in tropism from R5 to X4
• Mixed X4/R5 phenotype emerged in 1 patient
• Exhibited viral suppression on treatment
• Reverted to R5 by 14 days off treatment

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AMD-3100 (AnorMed)
CXCR4 Antagonist
J Acquir Immune Defic Syndr. 2004 Oct
137(2)1253-1262.
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AMD-3100

• 40 patients enrolled on mono-therapy
• No decrease in pVL at study endpoint (day 11)
• At baseline X4 virus was detected in 20 samples
• (19) X4/R5 (dual or mixed tropic)
• (1) X4 only
• (20) R5 only
• Baseline X4 lt 10... X4 not detected at day 11
• Baseline X4 gt 25... X4 detection variable at day
  11
• gt 40 µg/kg/hr . . . X4 not detected
• lt 40 µg/kg/hr . . . X4 detected
• Pure X4 virus. . . 0.89 log10 VL reduction at day
  11

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ADM-3100 Safety Profile

• Common (gt20)
• GI disturbance (gt48)
• Tachycardia
• Dizzyness
• Paresthesias

Of those in the low dose continuous infusion
2.5-20 mg/kg/ml-71 of 24 subjects had GI
complaints Of those in the high dose continuous
infusion 40-160 mg/kg/ml-100 of 24 subjects had
GI complaints
8 of 40 had SAEs, and 4 of 40 stopped because of
AEs
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TNX-355 (Tanox, Inc.)

• Anti-CD4 antibody (Hu5A8)
• Binds to a unique epitope of the
  extracellular portion of the CD4 (to domain 2
  which is not immune suppressive)
• Inhibits post-binding entry of the virus.

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TNX-355 (Tanox, Inc.)
Kuritzkes DR, et al. The Journal of Infectious
Diseases 2004189286-291
PURPOSE Phase I. Proof of concept to
evaluate-safety, pharmacokinetics and anti-viral
activity STUDY DESIGN 30 participants
multicenter, open-label single IV infusion of
0.3, 1.0, 3.0, 10 or 25 mg/kg (N6/group)-stable
VLgt5000.
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TNX-355 (Tanox, Inc.)
SAFETY 66.7 Experienced gt1 AE No SAEs
Headaches (13.3) and rash (10) were the most
common-followed by pruritus, urticaria and nasal
congestion (6.7).
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VACCINES
Trivalent HIV-1 Vaccine MRKAd5 HIV-1
gag/pol/nef Collaborative effort HIV Vaccine
Trials Network (HVTN) and Merck Co.

• Proof of Concept trial involving 1500 infected
  individuals
• Randomized placebo controlled
• At risk individuals for contracting HIV