Transcript Antiretroviral effect of MK-0518, a novel HIV

CROI 2006 ABSTRACT #159LB, Grinsztejn
Potent Antiretroviral Effect of MK-0518,
a Novel HIV-1 Integrase Inhibitor, in
Patients with Triple-class Resistant Virus
1Grinsztejn,
B.; 2Nguyen, B-Y.; 3Katlama, C.;
4Gatell, J.; 5Lazzarin, A.; 6Vittecoq, D.; 7Gonzalez,
C.; 2Chen, J.; 2Isaacs, R.; Protocol 005 Team
1Evandro
Chagas Clinical Research Institute/ Oswaldo Cruz Foundation, Rio de
Janeiro, Brazil; 2Merck Research Laboratories, P.A., USA; 3Hosp. Pitié
Salpêtrière, Paris, France; 4 Univ. of Barcelona, Spain; 5 San Raffaele Sci. Inst.,
Milan, Italy; 6Hosp. Paul Brousse, Villejuif, France; 7New York Univ. School of
Medicine, New York, New York
MK-0518
A Novel HIV-1 Integrase Inhibitor
CROI 2006 ABSTRACT #159LB
• HIV integrase inhibition: a new mechanism of action
• Potent in vitro activity
• IC95 = 33 nM  23 nM in 50% human serum
• Active against:
– multi-drug resistant HIV-1
– CCR5 and CXCR4 HIV-1
• HIV resistant to MK-0518 remain sensitive to other ARTs
• Synergistic with all ARTs
• Potent activity in ART-naive patients after 10 days of
monotherapy (Morales-Ramirez et al, EACS 2005)
• HIV RNA  of 1.7 – 2.2 log10 copies/mL
MK-0518
A Novel HIV-1 Integrase Inhibitor
CROI 2006 ABSTRACT #159LB
• Preclinical evaluation
– Predominantly metabolized via glucuronidation (UGT1A1)
– Not a potent inhibitor or inducer of CYP3A4
• Does not require “ritonavir boosting”
– No substantive issues from preclinical studies
• Phase I
– Data support dosing 100 - 800 mg po bid without regard to
food
• At 100mg b.i.d, mean C12hr > IC95
– Drug interaction studies support dosing of MK-0518 with
other ARTs without dose adjustment
CROI 2006 ABSTRACT #159LB
Protocol 005 – Study Design
• Randomized, double-blind
– 200, or 400, or 600 mg MK-0518 b.i.d. p.o. vs Placebo
• All in combination with optimized background therapy (OBT)
– Baseline stratification
• Use of T-20 in OBT
• Degree of HIV resistance to PI at entry
– To evaluate potential atazanavir (UGT1A1 inhibitor) effect
• Sub-study A (non-ATV containing OBT) (hypothesis testing)
• Sub-study B (ATV containing OBT)
• Key Inclusion Criteria
– Documented genotypic/phenotypic resistance to  1 drug in
each of 3 classes (NNRTI + NRTI + PI)
– HIV RNA > 5000 copies/mL and CD4 > 50 cells/mm3
• Endpoints
– HIV RNA and CD4 counts
– Adverse experiences
CROI 2006 ABSTRACT #159LB
Protocol 005 – Interim Analysis
• Similar treatment effect observed across Sub-Study A
and B
– Data presented are combined from 2 sub-studies
• All approaches (e.g. Observed data, NC = F) show
similar results due to small number of
discontinuations
– Discontinuations prior to Week 16
• 1 patient due to lack of efficacy
• 1 death (suicide)
 Observed data are presented
CROI 2006 ABSTRACT #159LB
Baseline Patients Characteristics
MK-0518*
Placebo*
200mg
N=40
400mg
N=42
600mg
N=42
N=43
43
44
44
43
83%
91%
91%
88%
Mean log10HIV RNA
4.6
4.8
4.7
4.7
Mean CD4 Count (/mm3)
244
220
226
283
Median Years of Prior ARTs
9
11
9
10
OBT: Median # of ARTs
4
4
4
4
Median Age (yrs)
Male
OBT: # of pts using T-20 (%)
13 (33%)
16 (38%) 16 (38%) 16 (38%)
PSS§: 0 to all ARTs
16 (40%)
24 (57%) 21 (50%) 17 (40%)
PSS§: 0 to PI
39 (98%)
40 (95%) 37 (88%) 36 (84%)
*
* + OBT ; § PSS = Phenotypic sensitivity score;
Enfurvitide is not included in the scores since there is no clinical cut-off.
CROI 2006 ABSTRACT #159LB
Percent of Patients With
HIV RNA <400 Copies/mL
Proportion of patients (95% CI) with
HIV RNA < 400 copies/mL
100
80
60
40
20
0
0
MK-0518 200 mg
MK-0518 400 mg
MK-0518 600 mg
OBT Alone
2
4
8
Week
12
16
40
42
42
43
39
39
40
43
35
36
35
36
31
32
33
31
25
28
28
27
m518p5.r400.1 Jan. 12, 2006
CROI 2006 ABSTRACT #159LB
Percent of Patients With
HIV RNA <50 Copies/mL
Proportion of patients (95% CI)
with HIV RNA < 50 copies/mL
100
80
60
40
20
0
0
MK-0518 200 mg
MK-0518 400 mg
MK-0518 600 mg
OBT Alone
2
4
8
Week
12
16
40
42
42
43
38
39
40
43
35
36
35
36
31
31
32
31
25
27
28
27
m518p5.r50.1 Jan. 12, 2006
CROI 2006 ABSTRACT #159LB
MK-0518 200
MK-0518 400
200
MK-0518 600
OBT Alone
150
100
Change from Baseline
in HIV RNA
(Log10 Copies/mL)
50
0
0
-1
-2
-3
0
2
4
8
12
Week
m518p5.cdr1.rna.1 Jan. 10, 2006
16
Change from Baseline
in CD4 Cell Count
Mean change from baseline (95% CI) in
HIV RNA and CD4 cell count
CROI 2006 ABSTRACT #159LB
Protocol 005 Safety
• MK-0518 safety profile similar to placebo (both with OBT)
• Most clinical adverse experiences (AE): mild to moderate
Most Common Drug-Related Clinical AE
(Incidence  5% or 2 pts in at least one treatment group)
MK-0518*
Diarrhea
Nausea
Fatigue
Injection site reaction
Headache
Pruritus
200 mg
N = 42
2 (5%)
2 (5%)
3 (7%)
1 (2%)
4 (10%)
0 (0%)
400 mg
N = 43
1 (2%)
2 (5%)
0 (0%)
3 (7%)
0 (0%)
1 (2%)
Placebo*
600 mg
N = 44
1 (2%)
5 (11%)
1 (2%)
4 (9%)
2 (5%)
3 (7%)
N = 45
4 (9%)
5 (11%)
1 (2%)
1 (2%)
2 (4%)
0 (0%)
* + OBT
Drug-related SAEs:
• Acute Pancreatitis after 2 doses, considered 2º to OBT (200 mg)
• Lacunar infarction by CT (placebo)
• Lipoatrophy (blinded)
• Anemia; metabolic acidosis; renal insufficiency; death (blinded)
• Hepatomegaly tenderness; fever (600 mg)
Protocol 005 Safety
Grade 3/4 Laboratory Abnormalities
CROI 2006 ABSTRACT #159LB
200 mg
N = 42
n/m§ (%)
0
MK-0518*
400 mg
N = 43
n/m§ (%)
0
600 mg
N = 44
n/m§ (%)
0
N = 45
n/m§ (%)
1/43 (2)
 Platelet
0
0
1/39 (3)
0
 Cholesterol
0
0
0
1/29 (3)
 Triglycerides
2/26 (8)
0
0
1/29 (3)
 Total bilirubin†
3/39 (8)
2/41 (5)
3/39 (8)
1/43 (2)
 AST
1/39 (3)
1/41 (2)
0
0
 ALT
0
1/41 (2)
0
0
 Alkaline phosphatase
1/39 (3)
0
0
0
 Serum lipase
1/39 (3)
1/41 (2)
0
0
0
0
2/39 (5)
0
 Neutrophil
 Serum pancreatic amylase
Placebo*
* + OBT ; § n/m = # of pts with Gr 3 or 4/ # of pts with lab test
†
CROI 2006 ABSTRACT #159LB
Conclusions
•
MK-0518 is a promising new HIV integrase inhibitor
•
In patients with advanced HIV infection, failing ARTs
with triple-class resistant virus, and with limited active
ARTs in OBT, MK-0518 at all doses studied
– was generally well tolerated
– had potent antiretroviral activity
56-72% with HIV RNA < 50 copies/mL at Wk 16
Acknowledgements
All patients in Protocol 005
Investigators
B. Grinsztejn
C. Katlama
J. Gatell
A. Lazzarin
D. Vittecoq
C. Gonzalez
J. Sierra
G. Carosi
S. Little
M. Moroni
J. Rockstroh
M. Kozal
R. Liporace
E. Jones-Lopez
B. Clotet
S. Staszewski
Brazil
France
Spain
Italy
France
USA
Mexico
Italy
USA
Italy
Germany
USA
USA
USA
Spain
Germany
D. McMahon
P. Kumar
C. Lee
K. Squires
M. Opravil
N. Clumeck
J. Lennox
J. Eron
J. Gallant
M. Nelson
S. Brown
K. Tashima
V. Soriano
C. Crumpacker
D. Kuritzkes
USA
USA
Malaysia
USA
Switzerland
Belgium
USA
USA
USA
UK
USA
USA
Spain
USA
USA
Merck Research Labs
B-Y. Nguyen
J. Chen
R. Isaacs
C. Harvey
H. Teppler
L. Wenning
M. Miller
D. Hazuda
M. Rowley
V. Summa
J. Vacca
CROI 2006 ABSTRACT #159LB