Transcript Slide 1

Efficacy and safety of lersivirine vs efavirenz in
antiretroviral treatment-naïve HIV-1-infected patients:
Week 48 primary analysis results from an ongoing,
multicenter, randomized, double-blind, Phase 2b trial
(Study A5271015)
P Vernazza,1 C Wang,2 A Pozniak,3 E Weil,2 P Pulik,4 DA Cooper,5
R Kaplan,6 A Lazzarin,7 H Valdez,8 J Goodrich,9 C Craig,10 J Mori,10
M Tawadrous2
1Cantonal
Hospital, St. Gallen, Switzerland; 2Pfizer Inc., Groton, CT, USA;
& Westminster Hospital, London, UK; 4Provincial Infectious Hospital of
Warsaw, Warsaw, Poland; 5Kirby Institute, University of New South Wales, Sydney,
Australia; 6Desmond Tutu HIV Foundation, Cape Town, South Africa; 7Universita
Vita-Salute San Raffaele, Milan, Italy; 8Pfizer Inc., New York, NY, USA; 9ViiV
Healthcare, Research Triangle Park, NC, USA; 10Pfizer Global Research &
Development, Sandwich Laboratories, Kent, UK
3Chelsea
6th IAS Conference, July 17-20, 2011, Rome, Italy
Lersivirine: a next-generation NNRTI with unique
binding and potent activity against HIV-1
• Binds to the reverse transcriptase
(RT) enzyme in a novel way1
• Unique resistance profile2
• Antiretroviral (ARV) activity2
Y181
– IC50 = 5.83 nM; 1.81 ng/mL (PBC)
• Resistance generated in vitro2
– V108I pathway to resistance
• Synergy between lersivirine (LRV)
and NRTIs and integrase strandtransfer inhibitors2
Lersivirine
K103
X-ray crystal structure of LRV bound at
the non-nucleoside binding site of
recombinant HIV-1 RT
*PBC= protein binding corrected
1. Phillips C et al. 2007; 2. Corbau R et al. 2010
2
Phase 2b treatment-naïve trial design
LRV 500 mg QD + TDF/FTC
Randomization
1:1:1
LRV 750 mg QD + TDF/FTC
EFV 600 mg QD + TDF/FTC
6 weeks
0
24 wk
Planned
interim
analysis
48 wk
96 wk
Primary endpoint: Patients
achieving
HIV-1 RNA <50 c/mL
• Randomized, double-blind, comparative study
• Selection criteria
–
–
–
–
ARV naïve
HIV-1 RNA ≥1000 c/mL
CD4+ >200 cells/mm3
No RT mutations by standard genotyping
• Stratified by viral load (<100,000 or ≥100,000 c/mL) & geographic region (A & B)
c/mL, copies per milliliter; LRV, lersivirine; QD, once daily; TDF/FTC: tenofovir disoproxil fumarate/emtricitabine
3
Statistical methods
Primary efficacy endpoint
• Percentage of subjects with plasma HIV-1 RNA <50 c/mL
at Week 48 (non-completer/missing=failure), ITT
– Treatment differences estimated by Cochran-MantelHaenszel adjusting for stratification factors
– 2-sided 80% confidence interval
Secondary endpoints
• Change from baseline CD4+ cell counts (LOCF, ITT)
• Fasting change from baseline lipid endpoints (observed
values, completers)
– ANCOVA including stratification factors and baseline
measurements as covariates
– 2-sided 80% confidence interval
ITT, intent-to-treat; LOCF, last observation carried forward. ANCOVA= analysis of covariates
4
Patient disposition
294 subjects screened
99 ineligible
195 randomized
66 randomized to LRV 500 mg
1 did not receive study drug
66 randomized to LRV 750 mg
1 did not receive study drug
65 treated
65 treated
12 Discontinuations
5 Insufficient clinical
response
3 AE
12 Discontinuations
4 Insufficient clinical
response
3 AE
1 Lost to follow-up
3 Others
2 Lost to follow-up
3 Others
- Hypersensitivity*
- ↑ ALT*
- Leukocyturia*
- Vomiting*
- Disturbance in attention*
- B-cell lymphoma
63 randomized to EFV
0 did not receive study drug
63 treated
9 Discontinuations
1 Insufficient clinical
response
5 AE
- ↑ ALT, AST, amylase*
- Psychotic disorder *
- Abnormal dreams, mental
disorder, suicidal ideation *
- Anxiety*
- Disturbance in attention*
0 Lost to follow-up
3 Others
53 remaining in study at
≥48 weeks
53 remaining in study at
≥48 weeks
54 remaining in study at
≥48 weeks
AE, adverse event; “Others”= subjects no longer willing to participate in study, withdrawn due to pregnancy, relocation
* Considered by Investigator to be at least possibly related to study drug
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Demographic and baseline characteristics
Randomized = 195
Treated = 193
LRV 500 mg
N=65
LRV 750 mg
N=65
EFV 600 mg
N=63
37 (24-61)
36 (22-62)
36 (21-61)
Female, n (%)
16 (25)
19 (29)
17 (27)
Race, n (%)
White
Black
Other
40 (62)
18 (28)
7 (11)
38 (59)
22 (34)
5 (8)
34 (54)
24 (38)
5 (8)
Region, n (%)
South Africa
Other
18 (28)
47 (72)
22 (34)
43 (66)
24 (38)
39 (62)
HIV-1 subtype, n (%)
B
C
Other
42 (65)
17 (26)
6 (9)
40 (62)
22 (34)
3 (5)
37 (59)
22 (35)
4 (6)
Screening plasma HIV-1 RNA (c/mL), n (%)
<100,000
≥100,000
45 (69)
20 (31)
44 (68)
21 (32)
41 (65)
22 (35)
4.7 (3.3-5.8)
4.7 (3.2-6.8)
4.7 (3.4-6.0)
320 (183-806)
323 (200-955)
317 (122-553)
Mean Age, years (range)
Screening plasma HIV-1 RNA (log10 c/mL), median (range)
Screening CD4 cell count (cells/mm3), median (range)
6
% of subjects with plasma
HIV-1 RNA <50 c/mL through Week 48
Efficacy results through Week 48
(plasma HIV-1 RNA <50 c/mL, ITT, NC=F)
100
90
54/63 (86%)
51/65 (79%)
51/65 (79%)
80
70
60
50
40
30
LRV 500 mg
20
LRV 750 mg
10
EFV 600 mg
0
0
2
4
8
16
24
32
40
48
Time (weeks)
Week 48
Analysis:
Treatment
N
n
%
LRV 500mg QD
LRV 750mg QD
EFV 600mg QD
65
65
63
51
51
54
79
79
86
Difference
(%)*
-9
-8
NA
SE Diff
(%)*
7
7
NA
80% CILower (%)*
-18.1
-17.0
NA
80% CIUpper (%)*
0.8
1.2
NA
*Cochran-Mantel-Haenszel estimates were adjusted for randomization variables of screening HIV-1 RNA level and geographic region.
A 2-sided 80% confidence interval was used. NA, not applicable; SE, standard error.
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% subjects with plasma
HIV-1RNA <50 c/mL through Week 48
Efficacy by screening plasma HIV-1 RNA and
geographic region (ITT, NC=F)
LRV 500mg
100
90
80
86 88
80
70
LRV 750mg
82
75
81
EFV 600mg
84
87
83
72
62
68
60
50
40
30
20
10
0
N=
45 44 41
20 21 22
N= 47 43 39
<100,000
≥100,000
Region A
Region B
EU, Latin
America,
Australia,
Canada
South
Africa
18 22 24
8
% subjects with plasma
HIV-1RNA <50 c/mL through Week 48
Efficacy in Regions A and B by screening plasma
HIV-1 RNA (ITT, NC=F)
LRV 500mg
100
90
80
87 89
81
81
LRV 750mg
85
77
EFV 600mg
86 87
79
78
70
60
50
50
38
40
30
20
10
0
N=
31 30 26
16 13 13
<100,000
≥100,000
Region A
EU, Latin America, Australia, Canada
N= 14 14 15
<100,000
4
8
9
≥100,000
Region B
South Africa
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Change from baseline CD4+ cell count
(cells/mm3) (LOCF, ITT)
LRV 750 = 195 cells/mm3
LRV 500 = 191 cells/mm3
EFV = 188 cells/mm3
200
3
(cells/mm )
Mean change from baseline
250
150
100
LRV 500 mg (N=65)
50
LRV 750 mg (N=65)
EFV 600 mg (N=63)
0
0
4
8
12
16
24
32
40
48
Time (weeks)
Baseline was the average of all the values obtained predose
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Resistance analysis through 48 weeks
Treatment
1
2
3
4
Clade
On-treatment failure
population genotype2
On-treatment failure FC
IC50
LRV
EFV
FTC
TDF
500 mg QD
500 mg QD
500 mg QD
500 mg QD
B
B
B
C
M184M/I/V, K101E, V108I, H221H/Y
M184M/I/V, Y188Y/H, F227F/L, L234L/I3
M184V, V90I4, F227C5
NM
56
36
69
0.8
3.9
1.6
5.2
0.6
>MAX
>MAX
>MAX
1.3
0.6
0.5
0.6
1.0
1 750 mg QD
2 750 mg QD1
3 750 mg QD
4 750 mg QD1
5 750 mg QD
C
C
B
B
C
M184V, V106M, F227L*
NM
NM
NM
NM*
114*
0.5
0.9
3.6
1.3*
11*
0.5
0.9
2.3
0.7*
>MAX*
1.2
0.9
0.8
1.3*
0.4*
0.8
0.8
1.1
1.1*
1
2
EFV
EFV
B
B
K103N
NM
1.3
0.8
11
0.6
1.3
1.0
1.3
1.0
3
EFV
C
NM
0.8
0.4
1.2
1.0
FC, fold-change IC50 to wild-type reference strain; FTC, emtricitabine; TDF, tenofovir; EFV, efavirenz; NM, no mutation
1Plasma HIV-1 RNA <500 c/mL
2Confirmation of failure, E_Term or Week 48 sample
3 M230I (study exclusion mutation) detected at screening
4V90I detected at screening and baseline (baseline FC=2.1)
5P225P/L detected at failure
* Sample taken outside of 48-week window
Also see Craig, C et al. Minority species resistance present at screening does not affect ourcomes at week 48. IAS Rome. Poster MOPE161.
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Summary of clinical adverse events (AEs)
LRV 500 mg
N = 65
LRV 750 mg
N = 65
EFV 600 mg
N = 63
52 (80)
56 (86)
58 (92)
Serious AE
4 (6)
5 (8)
4 (6)
Grade 3 or 4 AE
4 (6)
9 (14)
14 (22)
Discontinuation due to AE
3 (5)
3 (5)
5 (8)
Deaths
0
1 (2)
0
Category C Events
0
2 (3)
0
Malignancies
0
1 (2)
1 (2)
Number of Subjects with AE,
n (%)
Any AE
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All-causality AEs
(All severities, ≥10% incidence in any group)
Number of Subjects with AE,
n (%)
LRV 500 mg
N = 65
LRV 750 mg
N = 65
EFV 600 mg
N = 63
Nausea
15 (23)
27 (42)
8 (13)
Headache
15 (23)
11 (17)
9 (14)
Abnormal dreams
5 (8)
5 (8)
12 (19)
Dizziness
5 (8)
4 (6)
13 (21)
Rash*
3 (5)
1 (2)
7 (11)
Abdominal pain
2 (3)
6 (9)
7 (11)
Vomiting
2 (3)
10 (15)
9 (14)
Diarrhea
10 (15)
10 (15)
10 (16)
Insomnia
5 (8)
9 (14)
5 (8)
Influenza
3 (5)
7 (11)
7 (11)
Nasopharyngitis
7 (11)
1 (2)
1 (2)
Pharyngitis
2 (3)
2 (3)
6 (10)
Upper respiratory tract infection
8 (12)
11 (17)
9 (14)
*Includes reported terms of: rash erythematous, rash macular, and rash pruritic
Bold text indicates AEs of interest for which there was a higher rate of occurrence in either (i) both LRV groups versus EFV, or (ii) EFV versus
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both LRV groups
Grade 3 or 4 AEs (treatment-related)
Number of subjects with Grade
3-4 AE treatment-related, n (%)
LRV 500 mg
N = 65
LRV 750 mg
N = 65
EFV 600 mg
N = 63
2 (3)
3 (5)
8 (13)
ALT or AST increased
1 (2)
0
2 (3)
Other lab abnormality
1 (2)
0
3 (5)
Gastrointestinal disorder
0
1 (2)
0
Neoplasm/Malignancy
0
0
1 (2)
Nervous system or psychiatric
disorder
0
1 (2)
3 (5)
Other
0
1 (2)
1 (2)
Any Grade 3-4 AE
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatinine phosphokinase
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Summary of laboratory abnormalities1
(Grade 3 or 4)
Laboratory parameter,
n (%)
LRV 500 mg
N = 64
LRV 750 mg
N = 65
EFV 600 mg
N = 63
Hemoglobin (<7.4 g/dL)
Platelets (<50K/mm3)
White Blood Cell Count (<1500/mm3)
Absolute Neutrophil Count (<749/mm3)
1 (2)
0
1 (2)
1 (2)
0
0
0
1 (2)
1 (2)
1 (2)
0
0
Total Bilirubin (>2.6x ULN)
Aspartate aminotransferase (≥5.1x ULN)
Alanine aminotransferase (≥5.1x ULN)
Creatinine (≥1.9x ULN)
Albumin (<2 g/dL)
Potassium (≤2 mEq/L)
Creatine Kinase (>10x ULN)
1 (2)
1 (2)
1 (2)
0
1 (2)
1 (2)
1 (2)
0
2 (3)
2 (3)
1 (2)
0
0
2 (3)
0
1 (2)
3 (5)
0
0
0
2 (3)
LDL cholesterol (>190 mg/dL)
0
0
2 (3)
Total cholesterol (>300 mg/dL)
0
0
1 (2)
Lipase* (≥3.1x ULN)
0
1 (5)
0
*For LRV 500 mg, LRV 750 mg and EFV groups, N=29, 19 and 29, respectively (lipase was tested only if amylase was elevated)
LDL, low-density lipoprotein; ULN, upper limit of normal
1DAIDS – Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 2004
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Effect on serum lipids:
LRV did not increase TC, LDL-C or TG
Change from baseline at 48 weeks
Parameter, Least Squares
Mean (SE)
LRV 500 mg
N = 48
LRV 750 mg
N = 51
EFV 600 mg
N = 48
Total cholesterol (mg/dL)
0.9 (3.7)
-4.2 (3.5)
15.5 (3.6)
LDL cholesterol (mg/dL)
-1.7 (3.0)
-4.6 (2.9)*
4.0 (2.9)
HDL cholesterol (mg/dL)
2.8 (1.3)
1.2 (1.3)
9.3 (1.3)
0.24 (0.24)
-0.06 (0.23)
-0.3 (0.23)
-1.5 (8.2)
-3.1 (7.8)
10.6 (7.8)
Ratio total/HDL cholesterol
Triglycerides (mg/dL)
HDL, high-density lipoprotein
*N=50
Screening HIV-1 RNA level (<100K or ≥100K c/mL), geographic region, and baseline fasting measurements (continuous)
were included as covariates)
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Summary & Conclusions
• Both LRV doses achieved similar viral load
suppression to EFV
– 51/65 (79%) for both doses LRV, 54/63 (86%) for EFV
• Resistance profiles consistent with in vitro data
• LRV+TDF/FTC showed a different AE profile from EFV
–
–
–
–
More nausea in LRV arms
Fewer G3/4, neuropsychiatric AEs (compared to EFV)
Lab AEs infrequent
Neutral effects on lipid levels
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Acknowledgements
•
•
•
•
All patients participating in the A5271015 study
Data Monitoring Committee members
Pfizer and ViiV Healthcare team members
Investigators and study site staff
Canada
Jean-Guy Baril
Jason Brunetta
Benoit Trottier
South Africa
Lerato Mohapi
Richard Kaplan
Ezio Baraldi
Mohammed S. Rassool
Gulam Hoosain Latiff
Mariette E. Botes
Australia
Mark T. Bloch
David A. Cooper
Julian HJ Elliott
United Kingdom
Alan Winston
Anton Pozniak
Martin J. Fisher
Margaret A. Johnson
Lydons Wilkins
Poland
Andrzej Horban
Tomasz Smiatacz
Waldemar Halota
Jan Kuydowicz
Italy
Adriano Lazzarin
Antonella D'Arminio
Monforte Giovanni Di Perri
Argentina
Pablo Scapellato
Edmund Karla
Mexico
Alejandra Romero-Mora
Switzerland
Rainer Weber
Pietro Vernazza
Enos Bernasconi
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