CCR5 Antagonist Maraviroc (Selzentry) It

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CCR5 AntagonistMaraviroc (Selzentry)Its new,
its novel, its niche?

• Blake Max, PharmD
• RMR CORE Center
• Clinical Assistant Professor, UIC College of
  Pharmacy

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Objectives

• Describe the mechanism of action of CCR5
  antagonist
• Understand the role and importance of the Trofile
  assay in relation to CCR5 antagonist use
• Describe the significant clinical trials in
  tx-naïve and experienced patients
• Infer optimal CCR5 antagonist dose when
  administered with other medications or patient
  populations

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Introduction

• 5 Classes of Antiretroviral Agents
• - NRTIs
• - NNRTIs
• - PIs
• - Integrase Inhibitors
• - Entry Inhibitors
• August 2007 FDA approved maraviroc, a CCR5
  co-receptor antagonist used in combination with
  other antiretroviral agents for treatment in
  adults (gt16 y/o) infected with CCR5-tropic HIV.

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Novel Mechanism of Action

• HIV Entry Inhibitors
• Enfuvirtide- synthetic peptide that mimics amino
  acids of HIV transmembrane protein (gp41), which
  is critical for viral/CD4 cell membrane fusion.
• Maraviroc- HIV surface protein (gp120) binds to
  CD4 surface protein, acting as an anchor, then
  additional interaction with CD4 surface
  co-receptor allows for viral entry. HIV uses two
  co-receptors, CCR5 and CXCR4, maraviroc is a CCR5
  antagonist.
• Vicriviroc- Not FDA approved, in clinical
  trials, same MOA as maraviroc.

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CD4 Co-receptors
CCR5 and CXCR4
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HIV Attachment, Co-receptor Binding, and Fusion
Targets for Inhibition
Adapted from Moore JP, et al. Proc Natl Acad Sci
USA 200310010598602
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Approx. 50 of HIV Tropism is CCR5 in Treatment
Experienced Patients
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R5 Tropism Result is Strongly Associated with
CD4 Cell Count Categories in Treatment
Experienced Patients
South African Cohort (94 clade C)
MOTIVATE 1 and 2 (96 clade B)
R5
D/M
X4
100
100
80
80
60
60
Percent of Tropism Results per CD4 Category
40
40
R5
20
D/M
20
0
X4
lt50
0
gt500
51100
101200
201350
351500
500 (76)
049 (828)
5099 (338)
100199 (549)
200299 (448)
300399 (233)
400499 (113)
N
22
25
68
56
119
11
N
Current CD4 cell count (cells/mm3)
Screening CD4 Category (cells/mm3)
Plt0.0001 for comparison of median screening
CD4 cell counts as a continuous variable
Eng SM et al. 9th Intl Cong. on Drug Ther in HIV
Infect.2008. Poster P198
Clax P et al. EI Wrkshp 2007. Abs 5
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Tropism Testing

• Trofile test should be used whenever the use of
  a CCR5 antagonist is being considered (HIV VL
  must be gt1000 copies/ml)
• An enhanced sensitivity tropism assay has been
  developed to increase detection of minor
  CXCR4-using virus. Second generation Trofile
  assay has improved detection of minor variants
  10-fold. First generation assay was a limitation
  in early maraviroc studies.
• This is critical to the success/failure of these
  drugs.

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Typical HIV Tropism Patterns
CCR5 tropic (R5)
CXCR4 tropic (X4)
Dual/mixed (D/M)
Dual tropic
Mixed tropism
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Trofile Assay

• Developed by Monogram Biosciences and made
  available when FDA approved maraviroc, no other
  similar test available.
• Test is used to determine whether a patients HIV
  uses the CCR5 or CXCR4 co-receptor (or both) to
  enter CD4 cells.
• Similar to phenotype technology used for
  detecting HIV drug resistance. Assay amplifies
  HIV envelop gene from patients blood sample, HIV
  particles are made with the envelop protein and
  used to infect cells that contain CCR5 or CXCR4
  co-receptor on the cell surface. Viral
  replication is measured in-vitro determining the
  tropism of the patients virus.

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Trofile Tropism Assay
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Clinical Trials

• Tx-naïve (MERIT Trial)
• Tx-experience (MOTIVATE I-II)

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MaravirocTreatment-naïve

• Rationale 80-90 of tx-naïve patients harbor R5
  virus
• MERIT Trial Non-inferiority study
• CBV bid MVC 300mg bid vs CBV bid EFV 600
  qd
• 48-week analysis found MVC did not meet
  noninferiority vs EFV (VL lt 50 copies/ml)
• MVC associated with higher CD4 increases
• Limitation with sensitivity/specificity of
  initial Trofile assay

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Percentage of Patients with HIV-1 RNA lt50 c/mL by
Visit
Includes all patients who were identified by the
specified assay as R5 and received at least one
dose of study medication intent-to-treat (ITT)
analysis
MERIT
100
MERIT-ES
100
90
90
80
80
69
68
70
70
60
68
60
64
50
Patients ()
50
40
40
EFV CBV (N361)
EFV CBV (N303)
MVC CBV (N360)
30
30
MVC CBV (N311)
20
20
10
10
0
0
0
4
8
12
16
20
24
28
32
36
40
44
48
0
4
8
16
32
40
48
24
Time (weeks)
Time (weeks)
Missing values classified as failures/non-responde
rs
Saag M, et al. ICAAC/IDSA 2008. Poster H-1232a
MERIT Study ESTA 48 weeks
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Enhanced Phenotype Tropism AssayIn Vitro
Validation

• Original assay validated in clinical trials
• Did not detect minor CXCR4 species comprising
  lt10 of population
• Sensitivity in detecting CXCR4 HIV
• 100 when 10 of population is CXCR4
• 85 when 5 of population is CXCR4
• Enhanced phenotype tropism assay validated using
  in vitro HIV env clones
• Sensitivity in detecting CXCR4 HIV
• 100 when 0.3 of population is CXCR4
• 81 when 0.1 of population is CXCR4

Trinh L, et al. 48th ICAAC. Washington, DC, 2008.
Abstract H-1219.
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MERIT Week 48 Reanalysis by Enhanced Sensitivity
Trofile? Screening Rationale and Methods

• A more sensitive assay for the detection of
  CXCR4-using virus might better select a
  population of patients who would respond to
  maraviroc, decreasing the number of failures
  associated with emergence of CXCR4-using HIV-1
• The enhanced sensitivity Trofile? assay was
  performed on stored env expression vectors pools
  from all 721 patients in MERIT who had an R5
  tropism result by the original Trofile? assay
• Testing was performed by Monogram Biosciences
  Clinical Reference Laboratory

Saag M, et al. ICAAC/IDSA 2008. Poster H-1232a
MERIT Study ESTA 48 weeks
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Summary MVC in Treatment-naive Patients with R5
Virus

• As the original Trofile? assay is no longer
  available, the MERIT-ES reanalysis, while
  retrospective, was critical to inform appropriate
  clinical practice
• The enhanced Trofile? assay reclassified
  approximately 15 of patients as non-R5 HIV at
  screening
• In this retrospective analysis, the lower bound
  of the one-sided 97.5 CI for the treatment
  difference, for both the lt400 and lt50 copies/mL
  endpoints, was above 10 (the prespecified
  noninferiority margin)
• However, as this is a retrospective analysis, the
  confidence intervals presented here are for
  descriptive purposes only

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MOTIVATE 1 2 Trial Design
Randomization 122 MOTIVATE 1 N601MOTIVATE
2 N474
OBT placebo
98/209 (46.9)open-label MVC BID
OBT maraviroc (150 mg QD)
239/414 (57.7)open-label MVC BID
259/426 (60.8) open-label MVC BID
OBT maraviroc (150 mg BID)
Screening6 weeks
0
Week 96
Week 48 Primary endpoint
Patients were stratified by enfuvirtide use and
HIV-1 RNA lt and 100,000 copies/mL

• Patient eligibility criteria
• R5 HIV-1 infection
• HIV-1-RNA 5,000 copies/mL
• Stable pre-study antiretroviral (ARV) regimen, or
  no ARVs for 4 weeks
• Resistance to and/or 6 months experience with
  one ARV from three classes (two for protease
  inhibitors PIs)

Eligible patients (MVC non-failures, PBO failures
or intolerance) were given the option to roll
over to open-label MVC BID at end of blinded
therapy (last patient week 48 visit).
OBT optimized background therapy of 36 ARVs
(PK boosting doses of ritonavir not counted as an
ARV) Patients receiving a PI (except
tipranavir) and/or delavirdine in their OBT
received 150 mg dose of MVC, all other patients
received 300 mg dose of MVC
MOTIVATE 1 and 2 Week 96 Safety and Efficacy
Hardy WD et al. 9th Intl Cong. on Drug Ther in
HIV Infection. Glasgow, UK, Nov 9-13 2008.
Presentation O425
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MOTIVATE 1 2 Percentage of Patients with HIV-1
RNA lt50 copies/mL at Week 96
Includes all patients who received at least one
dose of study medication
100
90
Option to switch to open-label MVC BID
80
70
60
Patients ()
46.5
50
45.1
41.3
40
43.7
43.5
38.9
30
20
23.0
16.7
10
7.2
0
80
0
8
16
24
32
40
48
56
64
72
88
96
Time (weeks)
In this analysis, non-completers were categorized
as failures
MOTIVATE 1 and 2 Week 96
MOTIVATE 1 and 2 Week 96 Efficacy
Hardy WD et al. 9th Intl Cong. on Drug Ther in
HIV Infection. Glasgow, UK, Nov 9-13 2008.
Presentation O425
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Mean Change from Baseline in CD4 Cell Count in
MOTIVATE 1 and 2
PBO OBT (N209)
MVC QD OBT (N413)
MVC BID OBT (N426)
140
124
120
116
100
80
Mean change from baseline CD4 cell count
(cells/mm3)
60
61
40
20
0
0
4
8
12
16
20
24
28
32
36
40
44
48
Time (weeks)
PBO
n
186
205
206
206
206
206
206
206
206
206
MVC QD
n
362
399
405
407
407
407
407
407
407
407
MVC BID
n
386
412
417
418
418
418
418
418
418
418
MOTIVATE 1 and 2- Week 48
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Virologic Response on Maraviroc-based Therapy is
Greatest With a Background Regimen Containing
Several Active Agents
MOTIVATE 1 and 2 Patients receiving maraviroc
with an unchanged OBT across their period of
randomized therapy (non-virologic failures
excluded)

• wOBTSS The Weighted OBT Susceptibility Score --
  a measure of OBT virologic activity

Valdez et al. ICAAC/IDSA 2008, poster H-1221
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More Severely Immunosuppressed Patients Achieve ?
200 CD4 Cell with Maraviroc
All treated patients with valid baseline and
on-treatment measurements (LOCF)
P0.007 for MVC BID compared to placebo
Tressler R. 11th Annual Institute of Human
Virology Meeting 2008
MOTIVATE 1 2 Week 48
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MOTIVATE Immunologic Subanalysis Summary

• In MOTIVATE 1 and 2, highly TE patients receiving
  MVC (QD or BID) OBT experienced early, rapid,
  greater, and persistent CD4 cell count increases
  vs those receiving PBO OBT (P0.0182)
• The CD4 cell count advantage of MVC over PBO was
  driven not only by those patients who achieved
  virologic suppression, but also by those who
  never achieved this goal
• Since treatment group was found to be associated
  with CD4 cell rises, these findings together
  suggest that MVC increases CD4 cell counts above
  and beyond what is expected for a given viral
  load reduction
• Predictors of CD4 cell count rises among
  MVC-treated patients were similar to those
  observed among non-MVC-treated patients

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Adverse Effects

• Dose related postural hypotension and dizziness
• Long-term consequences of blocking chemokine
  receptor?
• - Hepatic abnormalities (aplaviroc)
• - Malignancies (vicriviroc study)
• Most common reported SE higher than placebo were
  diarrhea, fever, bronchitis, upper respiratory
  infection, back pain, dizziness, insomnia, cough,
  and rash.

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MOTIVATESafety Summary

• No new or unique safety findings emerged
• Similar safety profile as OBT alone
• Adverse events
• Severe adverse events
• Laboratory abnormalities (including grade 3/4
  transaminase elevations)
• AIDS-defining events
• Not associated with treatment-emergent X4 virus
• Discontinuations due to adverse events (5-6)
• Maraviroc OBT is not associated with excess
  mortality compared with OBT alone

Gulick RM, et al. N Engl J Med.
20083591429-1441. Fatkenheuer G, et al. N Engl
J Med. 20083591442-1455.
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MOTIVATE 1 and 2 Pooled 48-week Safety Summary
Placebo OBT N 209 Placebo OBT N 209 MVC QD OBT N 414 MVC QD OBT N 414 MVC BID OBT N 426 MVC BID OBT N 426
All-causen () Tx-relatedn () All-causen () Tx-relatedn () All-causen () Tx-relatedn ()
Total exposure, patient-years 111 111 300 300 309 309
Patients with AEs 177 (84.7) 94 (45.0) 375 (90.6) 205 (49.5) 393 (92.3) 219 (51.4)
Patients discontinuing due to AEs 11 (5.3) 6 (2.9) 24 (5.8) 12 (2.9) 21 (4.9) 13 (3.1)
Patients with grade 3 AEs 46 (22.0) 7 (3.3) 84 (20.3) 24 (5.8) 104 (24.4) 22 (5.2)
Patients with grade 4 AEs 16 (7.7) 5 (2.4) 37 (8.9) 3 (0.7) 45 (10.6) 15 (3.5)
Patients with SAEs 35 (16.7) 2 (1.0) 62 (15.0) 7 (1.7) 72 (16.9) 12 (2.8)
Patients with Category C events 16 (7.7) 16 (7.7) 29 (7.0) 29 (7.0) 23 (5.4) 23 (5.4)
Deaths 2 (1.0) 0 6 (1.4) 0 9 (2.1) 0
Tx treatment AEs adverse events SAEs
serious adverse eventsDeaths reported up to 28
days after stopping study drug. No deaths were
related to study drug according to the
investigator
MOTIVATE 1 and 2- Week 48
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MOTIVATE 1 2 Incidence of LFT Abnormalities
(Without Regard to Baseline) at Week 48 and End
of Blinded Therapy
Incidence (unadjusted) n () Incidence (unadjusted) n () Incidence (unadjusted) n () Incidence (adjusted) Event counts adjusted to 100 years of patient exposure Incidence (adjusted) Event counts adjusted to 100 years of patient exposure Incidence (adjusted) Event counts adjusted to 100 years of patient exposure
Placebo OBT MVC QD OBT MVC BID OBT Placebo OBT MVC QD OBT MVC BID OBT
Week 48 Week 48 Week 48 Week 48 Week 48 Week 48 Week 48
AST gt3.0 x ULN 17 (8) 39 (10) 45 (11) 16.2 13.8 15.7
ALT gt3.0 x ULN 13 (6) 29 (7) 37 (9) 12.4 10.1 12.7
Total bilirubin gt1.5 x ULN 30 (14) 66 (16) 51 (12) 31.9 25.3 18.5
End of blinded therapy End of blinded therapy End of blinded therapy End of blinded therapy End of blinded therapy End of blinded therapy End of blinded therapy
AST gt3.0 x ULN 19 (9) 45 (11) 46 (11) 13.3 9.4 9.5
ALT gt3.0 x ULN 15 (7) 37 (9) 39 (9) 10.0 7.8 7.8
Total bilirubin gt1.5 x ULN 31 (15) 68 (17) 54 (13) 23.8 16.0 11.3
MOTIVATE 1 and 2 Week 96 Safety
ULN, upper limit of normalTotal patient-years of
exposure to study drug at Week 48 Placebo OBT
111 MVC QD OBT 300 MVC BID OBT 309 Total
patient-years of exposure to study drug at at end
of blinded therapy Placebo OBT 160 MVC QD
OBT 522 MVC BID OBT 551
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Summary MVC in Treatment-experienced Patients
with R5 Virus

• Maraviroc (QD or BID) OBT demonstrated
  significantly greater virologic suppression rates
  and increases from baseline in CD4 cell counts
  at Weeks 24 and 48 compared to placebo OBT in
  this combined analysis
• Virologic suppression lt50 copies/mL at Week 48 in
  the combined studies was preserved through Week
  96 in 87 of patients receiving MVC BID OBT
• Maraviroc OBT demonstrated a similar safety
  profile compared to placebo OBT

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Maraviroc Pharmacokinetics

• Can be taken with or without food
• Primarily metabolized by CYP3A4 to inactive
  metabolites.
• Approx. 20 renally eliminated
• Half-life 15 hours (bid dosing)
• Substrate of CYP3A4 and p-glycoprotein, but not
  an inducer or inhibitor, therefore MVC does not
  effect the plasma concentrations of other drugs.
• MVC PK are affected by CYP3A4 and p-glycoprotein
  inhibitors and inducers
• Pregnancy category B (no harm in animal models,
  but should only be used in pregnancy if clearly
  needed)

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MVC Dosing Based on Two or Three Simple Questions
YES
Regardless of other agents in the regimen
150 mg
150 mg
YES
300 mg
300 mg
300 mg
300 mg
300 mg
300 mg
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Renal Dosing

• Renal clearance accounts for 25 of total
  clearance

Concomitant Medications Creatinine Clearance Dose Interval
Potent CYP3A4 inhibitors 50-80 ml/min 30 - lt50 ml/min lt30 ml/min Every 24 hours
Without potent CYP3A4 inhibitors 50 -80 ml/min 30 - lt50 ml/min lt 30 ml/min No dose adjustment required
If co-administered with saquinavir/ritonavir 50 80 ml/min 30 - lt50 ml/min lt 30 ml/min Every 24 hours Every 48 hours Every 72 hours
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Advantages of CCR5 Antagonists

• No cross resistance with other HIV medications,
  including enfuvirtide
• Excellent option for treatment experienced pts
• Co-receptor utilization (aka Viral Tropism) is
  associated with CD4 count (R5 more common when
  CD4gt200) and antiretroviral treatment naïve
  patients.
• Well tolerated
• Immunologic benefit?

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Disadvantages of CCR5 Antagonists

• Requires test to determine co-receptor tropism
  (2,000)
• Only active in 50 of tx-experienced pts
• Blocks biologic receptor (long-term
  consequences?)
• ? 32 mutants (1) show no deleterious effects
• Dosing based on co-administration of other
  medications (important for pharmacist)