Transcript (OBT) for the

1
Financial Disclosures
● JM Goodrich, E van der Ryst, J Sullivan, M Westby, H Mayer: are full-time employees of Pfizer
Global Research and Development
● M Saag: Has received grant/research support from Achillion Pharmaceutica, BoehringerIngelheim, Gilead Sciences, GlaxoSmithKline, Merck, Panacos, Pfizer/Agouron, Progenics,
Roche Laboratories, Serono, Tibotec, Trimeris, and Vertex; and consulting fees from Achillion
Pharmaceutical, Avexa, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences,
GlaxoSmithKline, Merck, Monogram Biosciences, Panacos, Pfizer/Agouron, Progenics, Roche
Laboratories, Tanox, Tibotec/Virco, Trimeris, and Vertex
● G Fätkenheuer:Has received consulting fees from Pfizer
● B Clotet: Has received consulting fees and lecture fees from Gilead, Roche, Bristol-Myers
Squibb, GlaxoSmithKline, Tibotec-Jansen, Boehringer Ingelheim, Pfizer, Abbot, Merck, and
Panacos
● N Clumeck: Has received reimbursement for either/or: attending a symposium; a fee for
speaking; a fee for organizing education; funds for research; fees for consulting from various
pharmaceutical companies including, Abbott, Boehringer, Merck Sharp & Dohme, Roche,
GlaxoSmithKline, Tibotec
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2
45th IDSA
San Diego, USA, October 4–7, 2007
Presentation LB-2
48-Week Safety and Efficacy of Maraviroc in Combination
with Optimized Background Therapy (OBT) for the Treatment
of Antiretroviral-Experienced Patients Infected with
Dual/Mixed-Tropic HIV-1
JM Goodrich1, M Saag2, E van der Ryst3, G Fätkenheuer4, B Clotet5,
N Clumeck6, J Sullivan3, M Westby3, and H Mayer1
1Pfizer Global Research and Development, New London, USA; 2University
of Alabama at Birmingham, USA; 3Pfizer Global Research and
Development, Sandwich, UK; 4University of Cologne, Cologne, Germany;
5University Hospital Germans Trias i Pujol, Barcelona, Spain; 6St Pierre
University Hospital, Brussels, Belgium
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2
3
Background
● Maraviroc, a CCR5 antagonist, is active against R5 but not X4 or dualtropic HIV-1
● A4001029 is a double-blind, placebo-controlled, Phase 2b study
investigating the safety and efficacy of maraviroc in treatmentexperienced patients with non-R5 HIV-1
● At 24 weeks1, in treatment-experienced patients with D/M-tropic HIV-1
and advanced disease:
– Maraviroc + OBT was generally well tolerated
– HIV-1 RNA changes were not significantly different between either MVC +
OBT group and PBO + OBT
– Maraviroc + OBT was associated with greater increases in CD4+ cell count
than PBO + OBT
OBT = optimized background therapy of 3–6 ARVs (PK boosting doses of RTV not counted as an ARV
D/M = dual/mixed
1. Mayer H et al. XVI IAC 2006; Abstract THLB0215
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2
A4001029: Phase 2b Pilot Study Evaluating the Safety of
Maraviroc in Patients with Non-R5 HIV-1
4
Maraviroc (150 mg* BID) + OBT
Screening
and
randomization
Maraviroc (150 mg* QD) + OBT
Placebo (PBO) + OBT
Screening
(4–6 weeks)
0
Patient eligibility criteria:
• X4 or D/M-tropic HIV-1, or indeterminate
tropism due to repeated assay failure
• At least one active drug in OBT
• HIV-1 RNA ≥5,000 copies/mL
24 wk
Primary
efficacy
endpoint
48 wk
• Stable pre-study ARV regimen, or no ARVs for ≥ 4 weeks
• Dual-class resistance and/or ≥ 3 months’ experience with
≥ one ARV from three classes
OBT = optimized background therapy of 3–6 ARVs (PK boosting doses of RTV not counted as an ARV)
* Patients receiving a PI (except TPV) and/or delavirdine in their OBT received 150 mg dose of MVC,
all other patients received 300 mg dose of MVC
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2
5
Baseline Characteristics
Includes all treated patients with non-R5 virus at screening who received at least one dose of study
medication
Randomized N=190
Treated N=186
PBO + OBT
N=62
MVC QD + OBT
N=63
MVC BID + OBT
N=61
Mean age, yrs (range)
45 (23–65)
43 (16–59)
43 (16–62)
Male, n (%)
53 (85)
53 (84)
55 (90)
White, n (%)
40 (65)
46 (73)
44 (72)
58
57
52
Screening Tropism, n
- D/M*
- X4
- R5
- NP/NR
2
0
2
2
0
3
4
0
5
* Primary study population; all treated patients with D/M-tropic virus at screening who received at least one dose of study
medication
NP/NR - not phenotyped/not reported
D/M - dual/mixed tropic
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2
6
Baseline Characteristics—Primary Study Population
Includes all treated patients with D/M-tropic virus at screening who received at least one dose of study
medication
PBO + OBT
N=58
MVC QD + OBT
N=57
MVC BID + OBT
N=52
42
(2–650)
42
(1–442)
43
(0–615)
Mean HIV-1 RNA*,
log10 copies/mL (range)
5.01
(3.65, 6.15)
5.03
(3.43, 5.94)
5.10
(3.61, 6.67)
Enfuvirtide in OBT, n (%)
30† (56)
35 (61)
29 (56)
≤2 active drugs in OBT, n (%)‡
30 (52)
41 (72)
27 (52)
Treated N=167
Median CD4+ count*,
cells/mm3 (range)
* Mean of up to three pre-dose assessments (screening, randomization, and baseline)
† Data missing for four patients
‡ Data missing for one patient in each treatment group
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2
7
Mean Change in HIV-1 RNA from Baseline
Includes all treated patients with D/M-tropic virus at screening who received at least one dose of study
medication
PBO + OBT (N=58)
MVC QD + OBT (N=57)
MVC BID + OBT (N=52)
Mean change in HIV-1 RNA
from baseline (log10 copies/mL)
Study week
241
0.0
48
-0.5
-0.62
-1.0
-0.97
-0.84
-0.91
-1.20
-1.5
Study A4001029–Week 24 & 48
-1.11
Difference: +0.23*
Difference: +0.06*
(97.5% CI: -0.35, +0.81)
(97.5% CI: -0.53, +0.64)
Difference: -0.26*
Difference: -0.23
(97.5% CI: -0.86, +0.33)
(97.5% CI: -0.83, +0.36)
HIV-1 RNA value imputed as baseline if patient discontinued before 48 weeks
*Treatment difference vs PBO + OBT
1. Mayer H, et al. IAC 2006; Abstract THLB0215
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2
Percentage of Patients with Undetectable HIV-1 RNA Over 48
Weeks
8
Includes all treated patients with D/M-tropic virus at screening who received at least one dose of study
medication
PBO + OBT (N=58)
MVC QD + OBT (N=57)
MVC BID + OBT (N=52)
<400 copies/mL
<50 copies/mL
50
50
Patients (%)
40
31%
30
25%*
24%†
20
31%
22%
21%
40
30
20
10
10
0
0
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (weeks)
Study A4001029–Week 48
27%
27%
21%
22%
18%
16%
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (weeks)
HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 48 weeks
* MVC QD + OBT; † PBO + OBT
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2
Subjects with Viral Load <400 copies/mL and <50 copies/mL
at Week 48 by OSS* at Screening
9
<400 copies/mL at Week 48, % (n/N)
OSS at screening
PBO + OBT
N=58
MVC QD + OBT
N=57
MVC BID + OBT
N=52
0
1
2
0% (0/1)
0% (0/14)
38% (5/13)
0% (0/1)
11% (2/19)
38% (8/21)
0% (0/2)
9% (1/11)
43% (6/14)
≥3
36% (9/25)
33% (5/15)
38% (9/24)
<50 copies/mL at Week 48 , % (n/N)
0
0% (0/1)
0% (0/1)
0% (0/2)
1
0% (0/14)
5% (1/19)
0% (0/11)
2
38% (5/13)
24% (5/21)
43% (6/14)
≥3
32% (8/25)
33% (5/15)
33% (8/24)
Study A4001029–Week 48
*OSS - overall susceptibility score, a reflection of
the number of active drugs in the OBT
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2
10
Mean Change from Baseline in CD4+ Count
Includes all treated patients with D/M-tropic virus at screening who received at least one dose of study
medication
Mean change from
baseline in CD4+ count (cells/mm3)
PBO + OBT (N=54)
MVC QD + OBT (N=57)
MVC BID + OBT (N=52)
150
100
Difference: +24*
(95% CI: –1, +49)
60
50
0
Difference: +27*
(95% CI: +1, +52)
Difference: +28*
Difference: +15* (95% CI: –5, +61)
(95% CI: –18, +47)
78
62
51
65
36
241
48
Study week
Study A4001029–Week 24 & 48
†
Last observation carried forward
*Treatment difference vs PBO + OBT
† Data missing for four patients
1. Mayer H, et al. IAC 2006; Abstract THLB0215
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2
11
Summary of Week 48 Safety Results
Includes all treated patients with non-R5 virus at screening who received at least one dose of study
medication
All causalities and severities, except where
indicated
Total treatment duration, patient-years
Patients with AEs
Patients discontinuing due to AEs
30
94%
8%
MVC QD
+ OBT
N=63
32
87%
2%
Patients with grade 3 AEs
21%
18%
18%
Patients with grade 4 AEs
13%
11%
13%
Patients with SAEs
18%
16%
16%
Patients with Category C events
Malignancies
3%
2%
8%
2%
7%
2%
Deaths*
3%
3%
2%
Study A4001029–Week 48
PBO + OBT
N=62
MVC BID
+ OBT
N=61
36
93%
3%
AEs = adverse events; SAEs = serious adverse events
*Includes deaths reported up to 28 days after stopping study drug
No deaths or malignancies were related to study drug according to the investigator
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2
12
Number of Category C Events
Includes all treated patients with non-R5 virus at screening who received at least one dose of study
medication
PBO + OBT
N=62
MVC QD
+ OBT
N=63
MVC BID
+ OBT
N=61
Total treatment duration, patient-years
30
32
36
Candidiasis
Cytomegalovirus chorioretinitis
Histoplasmosis
1
0
0
0
1
1
3
0
0
Pneumococcal sepsis
0
0
1
Pneumocystis jiroveci pneumonia
0
3
0
Pneumonia
0
0
1
Encephalitis
1
0
0
2
2 patients (3.2%)
5
5 patients (7.9%)
5
4 patients (6.6%)
Event, n
Total number of events
Total number of patients, n (% )
● No Category C malignancies (Kaposi’s sarcoma or Hodgkin’s lymphoma) were reported
● Patients who experienced a Category C event had a lower median CD4+ count and
slightly higher median HIV-1 RNA at baseline vs those who did not
Study A4001029–Week 48
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2
Incidence of Adverse Events Occurring in ≥10% of Patients
in Any Group, Unadjusted for Exposure
13
Includes all treated patients with non-R5 virus at screening who received at least one dose of study
medication
PBO + OBT (N=62)
Patients (%)
50
MVC QD + OBT (N=63)
MVC BID + OBT (N=61)
40
30
20
10
0
Study A4001029–Week 48
ISR = injection site reaction; RTI = respiratory tract infection
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2
Maximum Liver Function Test Values Over 48 Weeks
Without Regard to Baseline
14
PBO + OBT
N=58*
MVC QD
+ OBT
N=62*
MVC BID
+ OBT
N=59*
AST:
Grade 3 > 5.0 to 10.0 x ULN†
Grade 4 > 10.0 x ULN†
2 (3.4)
0
1 (1.6)
1 (1.6)
1 (1.7)
0
ALT:
Grade 3 > 5.0 to 10.0 x ULN†
Grade 4 > 10.0 x ULN†
1 (1.7)
1 (1.7)
1 (1.6)
1 (1.6)
0
0
Total bilirubin:
Grade 3 > 2.5 to 5.0 x ULN†
Grade 4 > 5.0 x ULN†
5 (8.8‡)
1 (1.8‡)
5 (8.1)
0
4 (6.8)
1 (1.7)
All causalities, n (%)
ALT = alanine transaminase; AST = aspartate transaminase
* Total patients evaluated for each laboratory parameter
†
Upper limit of normal
Data missing for 1 patient
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2
‡
Study A4001029–Week 48
15
A4001029: Summary of 48-Week Analysis
48-week results were consistent with 24-week findings:
● Maraviroc (BID or QD) + OBT was generally well tolerated
– The safety profile of MVC + OBT was similar to PBO + OBT
– No new or unique safety findings emerged
– Maraviroc + OBT was not associated with an increase in LFT abnormalities,
Category C events, malignancies, discontinuations due to AEs, or deaths
compared to PBO + OBT
● There was no evidence at Week 48 of an adverse effect on viral load or
CD4+ cell counts when MVC (QD or BID) was added to OBT, compared
to PBO + OBT, in treatment-experienced patients with D/M-tropic HIV-1
and advanced disease
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2
16
Acknowledgments
● Patients who participated in the study
● Investigators and study site staff
● Colleagues from Monogram Biosciences: J Whitcomb, E Coakley,
C Petropoulos
● Colleagues from Pfizer: S Felstead, M McHale, J Sullivan, D Lindell,
D Paige, S Nuttall
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2
17
A4001029: Investigators
USA: Bisher Akil, Paul J Cimoch, Charles
Farthing, Stephen Follansbee, Eliot Godofsky,
David Henry III, Frederick Cruickshank, Robert
Myers Jr., Gerald Pierone Jr., Jayashree
Belgium: Michel Moutschen, Jean Goffard,
Ravishankar, William Robbins, Michael Saag,
Bernard Vandercam, Nathan Clumeck
Kunthavi Sathasivam, Lawrence Schwartz,
Canada: Kevin Gough, Francois Laplante,
Silver Sisneros, Louis Marshall Sloan, Corklin
Benoit Trottier, Christos Tsoukas, Sharon
Steinhart, Melanie Thompson, William Towner
Walmsley, Richard Lalonde, Ethan Rubinstein Jr., David Wheeler, Sally Williams, Bienvenido
Germany: Lutwinus Weitner, Keikawus
Yangco, Barry Zingman, Robert Bolan, Edwin
Arasteh, Andreas Plettenberg, Jan van
DeJesus, Jerome Ernst, Shawn Hassler,
Lunzen, Gerd Faetkenheuer
Stephen Hauptman, Joseph McGowan, Bruce
Rashbaum, Stephen Becker, Nicholaos Bellos,
Netherlands: Andy Hoepelman
Trevor Hawkins, Daniel Klein, Jason Leider,
Spain: Bonaventura Sala, Felix Gutierrez,
Daniel Skiest, Roy Steigbigel, Jorge
Pere Pedrol, Jose Arribas, Antonio Rivero
Rodriquez, Alfred Burnside Jr
Switzerland: Milos Opravil
UK: Martin Fisher, Clifford Leen, Philippa
Easterbrook, Mark Nelson
Australia: David Cooper, Jennifer Hoy,
Richard Moore, Anthony Allworth, Neil
Bodsworth, Cassy Workman
Goodrich JM et al. 45th IDSA 2007; Presentation LB-2