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Transcript
CCR5 Antagonist
Maraviroc (Selzentry)
It’s new, it’s novel, it’s niche?
Blake Max, PharmD
RMR CORE Center
Clinical Assistant Professor, UIC College of Pharmacy
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
Introduction
• 5 Classes of Antiretroviral Agents
- NRTIs
- NNRTIs
- PIs
- Integrase Inhibitors
- Entry Inhibitors
• August 2007 FDA approved maraviroc, a CCR5 coreceptor antagonist used in combination with other
antiretroviral agents for treatment in adults (>16 y/o)
infected with CCR5-tropic HIV.
Introduction of Novel Agents Over Time Has Improved Chances of
Achieving Viral Suppression in Treatment-Experienced Patients
HIV RNA <50 Copies/mL (week 24)
63%
60
50
Study drug + OBT
Placebo + OBT
45%
45%
40%
40
Patients (%)
60%
33%
30
23%
23%
20
12%
10
9%
12%
5%
0
2003
Lazzarin A et al. N Engl J Med. 2003;348(22):2186-2195.
Aptivus [package insert]. Ingelheim, Germany: Boehringer Ingelheim International GmbH; 2006.
Clotet B et al. Lancet. 2007;369:1169-1178.
Selzentry [package insert]. New York, NY: Pfizer Pharmaceuticals Inc; 2007.
Isentress [package insert]. Whitehouse Station, NJ: Merck & Co., Inc; 2008.
Intelence [package insert]. Yardley, PA: Tibotec, Inc; 2008.
2008
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.
CD4 Co-receptors:
CCR5 and CXCR4
Binding, and Fusion Targets for
Inhibition
CD4
Attachment
CD4
attachment
inhibitors
gp41
Co-receptor
Binding
CCR5
antagonists
Virus–Cell
Fusion
Fusion
inhibitors
gp120
V3 loop
CD4
Cell
membrane
CCR5 or CXCR4
Adapted from Moore JP, et al. Proc Natl Acad Sci USA 2003;100:10598–602
Approx. 50% of HIV Tropism is
CCR5 in Treatment Experienced
Patients
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
80
60
60
40
0
N= 22
40
R5*
D/M
20
20
X4
25
68
56
119
11
Current CD4+ cell count (cells/mm3)
0
N=
Screening CD4+ Category (cells/mm3)
* P<0.0001 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
Percent of Tropism Results
per CD4+ Category
100
80
Tropism Testing
• Trofile test should be used whenever the use of
a CCR5 antagonist is being considered (HIV VL
must be >1000 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.
Typical HIV Tropism Patterns
CCR5 tropic
(R5)
CXCR4 tropic
(X4)
Dual/mixed (D/M)
Dual tropic
Mixed tropism
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 patient’s 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 patient’s 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 patient’s virus.
Trofile™: Tropism Assay
Clinical Trials
• Tx-naïve (MERIT Trial)
• Tx-experience (MOTIVATE I-II)
Maraviroc
Treatment-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 < 50 copies/ml)
• MVC associated with higher CD4 increases
• Limitation with sensitivity/specificity of initial
Trofile assay
Percentage of Patients with HIV-1 RNA <50 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
100
90
80
70
60
50
40
30
20
10
0
MERIT
100
MERIT-ES
90
Patients (%)
69%
64%
80
70
60
68%
68%
50
EFV + CBV (N=361)
MVC + CBV (N=360)
40
30
EFV + CBV (N=303)
MVC + CBV (N=311)
20
10
0
0 4 8
16
24
32
Time (weeks)
40
48
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (weeks)
Missing values classified as failures/non-responders
Saag M, et al. ICAAC/IDSA 2008. Poster H-1232a
MERIT Study – ESTA 48 weeks
Enhanced Phenotype Tropism Assay:
In Vitro Validation
• Original assay validated in clinical trials
– Did not detect minor CXCR4 species comprising <10% 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.
MERIT Week 48 Reanalysis by Enhanced Sensitivity
Trofile Screening: Rationale and Methods
• A more sensitive assay for the detection of CXCR4using 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
MERIT Study – ESTA 48 weeks
Saag M, et al. ICAAC/IDSA 2008. Poster H-1232a
20
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 <400 and <50 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
21
MOTIVATE 1 & 2: Trial Design
Randomization
1:2:2
MOTIVATE 1 N=601
MOTIVATE 2 N=474
Screening
6 weeks
0
OBT* + placebo
98/209 (46.9%)
open-label MVC BID
OBT* + maraviroc (150 mg† QD)
239/414 (57.7%)
open-label MVC BID
OBT* + maraviroc (150 mg† BID)
259/426 (60.8%)
open-label MVC BID
Week 48
Primary endpoint
Week 96
Patients were stratified by enfuvirtide use and HIV-1 RNA < 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 3–6 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
MOTIVATE 1 & 2: Percentage of Patients with HIV-1 RNA
<50 copies/mL at Week 96
Includes all patients who received at least one dose of study medication
MVC BID + OBT (N=426)
MVC QD + OBT (N=414)
100
Placebo + OBT (N=209)
90
Option to switch
to open-label MVC BID
80
Patients (%)
70
60
50
45.1%
40
43.7%
46.5%
41.3%
38.9%
43.5%
30
20
23.0%
16.7%
10
0
0
8
16
24
32
40
48
56
7.2%
64
72
80
88
96
Time (weeks)
In this analysis, non-completers were categorized as failures
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
Mean Change from Baseline in CD4+ Cell Count
PBO + OBT (N=209)
in MOTIVATE 1 and 2
MVC QD + OBT (N=413)
MVC BID + OBT (N=426)
Mean change from baseline
CD4+ cell count (cells/mm3)
140
124
116
120
100
80
60
61
40
20
0
n=
PBO
MVC QD n =
MVC BID n =
0
4
8
12
16
20
24
28
Time (weeks)
32
186
362
386
205
399
412
206
405
417
206
407
418
206
407
418
206
407
418
206
407
418
MOTIVATE 1 and 2- Week 48
206
407
418
36
40
206
407
418
44
48
206
407
418
Virologic Response on Maraviroc-based Therapy is
Greatest With a Background Regimen Containing Several
Active Agents
Patients (%)
100
90
80
70
60
50
40
30
20
10
0
MOTIVATE 1 and 2: Patients receiving maraviroc with an unchanged OBT
across their period of randomized therapy (non-virologic failures excluded)
Placebo + OBT
MVC QD + OBT
MVC BID + OBT
56
33
51
113
35
72
77
78
33
17
0
N *=
wOBTSS
•
51
70
41
76
<1
81
41
87
1-<2
≥2
wOBTSS: The Weighted OBT Susceptibility Score -- a measure of OBT
virologic activity
Valdez et al. ICAAC/IDSA 2008, poster H-1221
More Severely Immunosuppressed Patients Achieve
 200 CD4+ Cell with Maraviroc
All treated patients with valid baseline and on-treatment measurements (LOCF)
Patients with BL CD4+ cell count <200
Who achieved >200 at Wk 481
70
70
Placebo + OBT
MVC QD + OBT
MVC BID + OBT
60
47*
50
50
43
40
32*
30
Patients (%)
60
Patients (%)
Patients with BL CD4+ cell count between 200 and 349
Who achieved >350 at Wk 48
40
20
10
10
0
0
235
250
59
116
117
38
30
20
N= 118
61
N= 64
*P=0.007 for MVC BID compared to placebo
MOTIVATE 1& 2 – Week 48
Tressler R. 11th Annual Institute of Human Virology Meeting 2008
26
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 (P=0.0182)
• 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
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.
MOTIVATE:
Safety 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. 2008;359:1429-1441.
Fatkenheuer G, et al. N Engl J Med. 2008;359:1442-1455.
MOTIVATE 1 and 2 Pooled 48-week Safety Summary
Placebo + OBT
N = 209
MVC QD + OBT
N = 414
Allcause
n (%)
Allcause
n (%)
Total exposure, patient-years
Patients with AEs
Txrelated
n (%)
111
Txrelated
n (%)
MVC BID + OBT
N = 426
Allcause
n (%)
300
Txrelated
n (%)
309
177
(84.7)
94
(45.0)
375
(90.6)
205
(49.5)
393
(92.3)
219
(51.4)
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)
35
(16.7)
2 (1.0)
62
(15.0)
7 (1.7)
72
(16.9)
12 (2.8)
Patients discontinuing due to
AEs
Patients with SAEs
Patients with Category C
events
Deaths*
16 (7.7)
2 (1.0)
29 (7.0)
0
6 (1.4)
23 (5.4)
0
9 (2.1)
0
MOTIVATE 1 & 2: Incidence of LFT Abnormalities (Without Regard to
Baseline) at Week 48 and End of Blinded Therapy
Incidence (unadjusted)
n (%)
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
AST: >3.0 x ULN
17 (8)
39 (10)
45 (11)
16.2
13.8
15.7
ALT: >3.0 x ULN
13 (6)
29 (7)
37 (9)
12.4
10.1
12.7
Total bilirubin: >1.5
x ULN
30 (14)
66 (16)
51 (12)
31.9
25.3
18.5
AST: >3.0 x ULN
19 (9)
45 (11)
46 (11)
13.3
9.4
9.5
ALT: >3.0 x ULN
15 (7)
37 (9)
39 (9)
10.0
7.8
7.8
Total bilirubin: >1.5 x
ULN
31 (15)
68 (17)
54 (13)
23.8
16.0
11.3
Week 48
End of blinded therapy
MOTIVATE 1 and 2 Week 96 Safety
ULN, upper limit of normal
Total 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
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 <50 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
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)
MVC Dosing: Based on Two or Three Simple Questions
Concomitant treatment
Morning dose
Evening dose
150 mg
150 mg
Includes a potent CYP3A4/P-gp
inhibitor
For example:
protease inhibitors +/- ritonavir (except
tipranavir/r), elvitegravir/r*, delavirdine
ketoconazole, itraconazole,
clarithromycin, telithromycin, nefazadone
YES
Regardless of other
agents in the regimen
NO
Includes a CYP3A4/P-gp inducer
without a CYP3A4/P-gp inhibitor
For example:
efavirenz, etravirine, rifampicin,
carbamazepine, oxcarbazepine,
phenobarbital, phenytoin
YES
300 mg
300 mg
300 mg
300 mg
NO
NO CYP3A4/P-gp inhibitors or inducers
For example:
NRTIs, enfuvirtide, nevirapine, tipranavir/r,
raltegravir, SMX/TMP, ethinyl estradiol,
levonergestrel, midazolam
300 mg
300 mg
Note: Agents specifically studied with MVC are shown in italics
* If elvitegravir/r is co-administered with a ritonavir-boosted PI, then the MVC dose should be adjusted based on MVC dosing recommendations for co-administration with that PI/r
34
Renal Dosing
• Renal clearance accounts
for 25% of total clearance
Concomitant Medications
Creatinine Clearance
Dose Interval
Potent CYP3A4
inhibitors
50-80 ml/min
30 - <50 ml/min
<30 ml/min
Every 24 hours
Without potent
CYP3A4 inhibitors
50 -80 ml/min
30 - <50 ml/min
< 30 ml/min
No dose adjustment
required
If co-administered with
saquinavir/ritonavir
50 – 80 ml/min
30 - <50 ml/min
< 30 ml/min
Every 24 hours
Every 48 hours
Every 72 hours
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 CD4>200) and antiretroviral treatment
naïve patients.
• Well tolerated
• Immunologic benefit?
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?)
Δ 32 mutants (1%) show no deleterious effects
• Dosing based on co-administration of
other medications (important for pharmacist)