Future Applications of Antiretroviral Agents in Development

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
4
New Generation NNRTIs Etravirine (TMC125)

• Novel NNRTI designed to have a high genetic
  barrier to development of resistance1
• Potent in vitro antiviral activity against
• Wild-type and NNRTI resistant HIV-12
• Clinical isolates resistant against approved
  NNRTIs2
• 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
  therapy3
• 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
Oct79(20)12773-12782. 2Andries K, et al.
Antimicrob Agents Chemother 2004
Dec48(12)46804686. 3Gazzard BG, et al. AIDS
2003 Dec 517(18)F49F54.
5
TMC125-C223Study Design

• 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-C223Virologic Response at Week 48
Cohen C, et al, XVI International AIDS
Conference Aug 13-18, 2006 Toronto, Canada.
Abstract TUPE0061.
7
TMC125-C223Number of NNRTI Mutations and
Virologic Response at Week 48

• 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 gt10 (Arbitrary Threshold)

• No single NNRTI mutation was associated with mean
  FC gt10 (arbitrary threshold) to TMC125
• Frequency of combinations of NNRTI mutations
  associated with mean TMC125 FC gt10 was low (12)
• Each of the following mutations, always in
  combination with up to four other mutations, were
  associated with mean FC gt10
• K101P, V179E, V179F, Y181I, Y181V, G190S, M230L
• For V179E, V179F, G190S, M230L additional
  mutations always included Y181C when FC gt10
• 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. 2005 Oct79(20)12773-82.
9
Targets for Antiretroviral Therapy
EntryInhibitors
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-355A Novel Entry Inhibitor

• 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
• 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,
2005. Abstract LB2-26 Tanox Inc. News Release May
2, 2006.
12
HIV Tropism and Disease Progression
CXCR4-tropic HIV
? X4
R5
Mixed/Dual
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 gt250 cells/mm3
• VL gt5000 copies/mL

0.5

• 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
14
CCR5 Inhibitors in Development 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
• 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

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 10-20 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 2006. Abstract 161LB.
18
ACTG 5211 Study Design

• All regimens include 100-800 mg RTV
• Study powered to detect gt0.7 log HIV RNA
  difference at day 14
• Cross-over options (Step 2) following virologic
  failure (after wk 16)

Gulick R, et al. IAC 2006. 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 36380 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 2006. Abstract THLB0217.
20
ACTG 5211 Mean Change in HIV RNA (log10 cps/ml
24 weeks, ITT)
VCV 15 mg
VCV 10 mg
Gulick R, et al. IAC 2006. 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 gt24 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 2006. Abstract THLB0217.
22
Phase IIb Pilot Study Evaluating the Safety of
Maraviroc in Patients with Non-R5 HIV-1

• 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
OBT - optimized background therapy D/M -
dual/mixed tropic Primary endpoint LOCF
Mayer H, et al IAC 2006. Abstract THLB0215.
24
On the HorizonIntegrase Inhibitors

• 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 lt400 copies/mL gt50
• No significant change in CD4 cell count from
  baseline
• Most common adverse events
• Headache, fatigue, and dizziness

Morales-Ramirez JO, et al. EACS 2005. Abstract
LBPS1/6.
26
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 N 42
Placebo OBR N 43
MK-0518 400mg bid OBR N 42
MK-0518 200mg bid OBR N 40

• Mean VL 4.6-4.8 log10 copies/mL
• Use of ENF in OBR 33 to 38
• Patients with no active PIs in OBR 84 to 98
• Mean CD4 220-283 cells/mm3

• Treatment arms similar at baseline
• Mean duration of HAART 9-11 yrs

Grinsztejn B, et al. 13th CROI. Denver, 2006.
Abstract 159LB.
27
MK-0518Virologic Suppression Through Week 16
Grinsztejn B, et al. 13th CROI. Denver, 2006.
Abstract 159LB.
28
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, 2006.
Abstract 159LB.
29
MK-0518 Study DesignPotent 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 TFV3TC, or efavirenz plus
  TFV3TC, 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 EfavirenzHIV RNA lt 50 copies/mL at
Week 24 (NC F)
Markowitz M, et al. IAC 2006. Abstract THLB0214.
31
MK-0518 vs Efavirenz Adverse Events
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 2006. Abstract THLB0214.
32
Integrase Inhibitor (GS 9137)10-Day Monotherapy
Study

• 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
• gt1 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

Plt0.01 versus placebo. Plt0.05 versus 800 mg qd.
DeJesus E, et al. 13th CROI. Denver, 2006.
Abstract 160LB.
33
Maturation InhibitorPA-457

• First maturation inhibitor
• Data from a double blind, placebo controlled
  single dose study of 75mg, 150mg and 250mg and
  placebo (all n6) naïve or of-treatment for gt4
  weeks two subjects had MDR
• Dose related response with median reduction at
  the highest dose of -0.51 log10 and a greatest
  decline of -0.73 log10. 8/12 in higher doses gt0.3
  log10
• Return to baseline was inhibited for at least 20
  days in the 250mg dose arm

Martin D, et al. CROI 2005. 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 (Plt0.01)

Smith P, et al. 13th CROI. Denver, 2006. Abstract
52.
35
New Antiretroviral AgentsConclusions

• 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