Viramune XR

Report
Comparison of 48 week efficacy and safety of 400mg QD
nevirapine (NVP) extended release formulation (Viramune XR)
versus 200mg BID nevirapine immediate release formulation
(Viramune IR) in combination with emtricitabine/tenofovir in
antiretroviral (ARV) naïve HIV-1 infected patients (VERxVE)
J. Gathe, JR. Bogner, S. Santiago, A. Horban, M. Nelson, P.
Cahn, J. Andrade, D. Spencer, C. Yong, T. Nguyen, W. Zhang, M.
Drulak and A. Quinson*
*Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA
VERX VE: Rationale for Viramune Extended Release (XR)
Formulation
 Viramune 200mg immediate release (IR) is a well established component of effective antiretroviral therapy in
HIV-1 infected patients
 Viramune 200mg IR plus emtricitabine/tenofovir (FTC/TDF) recently demonstrated similar efficacy to
atazanavir/ritonavir plus FTC/TDF, with a more favourable lipid profile1
 Viramune extended release formulation (Viramune XR) may increase therapeutic benefit by improving
compliance through once-daily
(QD) dosing
1. Soriano V. et al. 2010 Manuscript submitted
VERX VE: Objectives and Study Design
Objective:
 To evaluate the efficacy of Viramune XR 400 mg QD vs Viramune IR 200 mg BID, in ARV treatmentnaïve, HIV–1-infected patients after 48 weeks of treatment
Study design:
• Double-blind, double-dummy, non-inferiority study
• 1:1 randomization to Viramune XR or Viramune IR after 14-day Viramune IR lead-in 200 mg QD dose
(given to all patients)
• Emtricitabine/tenofovir (FTC/TDF) fixed-dose background
ARV treatment
• Baseline viral load (VL) stratification
(≤100,000 vs >100,000 copies/mL)
VERX VE: Study Endpoints
Primary endpoint:
 Sustained virologic response at 48 weeks defined as VL <50 copies/mL prior to and at week 48, without
virologic rebound or change of ARV therapy
Secondary endpoints:
 Time-to-loss of virologic response (TLOVR)
 Time to new AIDS or AIDS-related progression event or death
 Genotypic resistance associated with virologic failure
 AEs, SAEs, AEs leading to discontinuation; laboratory parameters
VERX VE: Demographic Data
Parameter
Viramune IR
Viramune XR
508
505
Male, n
433
431
Female, n
75
74
38.0
38.3
North America/Australia
150
141
Europe
252
257
Latin America
49
58
Africa
57
49
Baseline HIV-1 viral load, median log10 copies/mL
4.7
4.7
CD4+ cell count, mean cells/mm3
227
229
History of AIDS (%)
26
30
Number of patients, N
Gender
Age, mean
Region
Note: Total randomized=1068, 1011=randomized & treated (full analysis set, FAS), 2 randomized not
treated, 55 DC during lead-in
VERX VE: Disposition of Randomized Patients Through Week
48
Parameter
Viramune IR
Viramune XR
Total
508
505
1013
Treated with blinded dose, n (%)
506 (100.0)
505 (100.0)
1011 (100)
Completed Week 48 visit, n (%)
409 (80.1)
421 (83.4)
830 (82.1)
Prematurely discont. prior to Week 48 visit, n (%)
97 (19.2)
84 (16.6)
181 (17.9)
Death/events leading to death*
3 (0.6)
1 (0.2)
4 (0.4)
Adverse events
42 (8.3)
32 (6.3)
74 (7.3)
Lost to follow-up
7 (1.4)
8 (1.6)
15 (1.5)
Consent withdrawn
9 (1.8)
4 (0.8)
13 (1.3)
Non-adherence
9 (1.8)
6 (1.2)
15 (1.5)
Lack of efficacy
26 (5.1)
24 (4.8)
50 (4.9)
Pregnancy
0 (0.0)
6 (1.2)
6 (0.6)
Other
1 (0.2)
3 (0.6)
4 (0.4)
Randomized, N
Reasons for discont., n (%)
*None of the deaths/events were related to study medication, as judged by the investigators
VERX VE: Sustained Virologic Response at Week 48 (VL <50 copies/mL, FAS)
Proportion of patients with Virologic Response Week 48
Viramune IR
100
90
80
70
60
50
40
30
20
10
0
Viramune XR
80.99
75.89
Viramune IR: 75.89% (384/506)
Viramune XR: 80.99% (409/505)
Adjusted difference
4.92% in favour of Viramune XR, with 95% CI of (−0.11, 9.96)
Viramune XR shows non-inferiority to Viramune IR within
pre-specified margin of −10%
Virologic response was independent of age, gender, race or geographic region
FAS = Full analysis set
VERX VE: Proportion with Virologic Response by Visit (VL <50
copies/mL, FAS)
Proportion of Virologic Responders
100.00
80.00
60.00
40.00
Viramune IR
Viramune XR
20.00
0.00
0 2 4 6 8
FAS = Full analysis set
12
16
Weeks
24
32
40
48
VERX VE: PK Sub-study at Day 28
•
Designated trial centres participated in a pharmacokinetic sub-study, involving ~25 patients from each
treatment arm
•
Blood samples collected intensively for 24 hr following morning NVP administration in week 4 (visit 4): day
28
•
Plasma NVP levels measured by tandem mass spectrometry (LC-MS/MS)
•
Arithmetic mean (±SD) plasma concentration of NVP following 400mg QD and 200mg BID dosing
determined
VERX VE: PK Sub-study at Day 28: Results
200mg Viramune IR BID (N=25)
400mg Viramune XR QD (N=24)
Viramune Plasma (ng/mL)
7000
6000
5000
4000
3000
2000
0
4
8
12
Time [hours]
16
20
24
VERX VE: PK-PD Response Week 48 (FAS): Viramune XR Equivalent to Viramune IR at
≥1000ng/mL
Virologic response rates stratified by geometric mean steady state
(ss) trough plasma concentrations (ng/mL)
Parameter
Viramune IR
Viramune XR
Total number of patients, n/N
372/464 (80.2)
406/486 (83.5)
Geometric mean, trough ss (ng/mL),
<1000
No. Responders/Total within stratum (n/N)
3/5 (60.0)
3/9 (33.3)
1000–<2000
25/31 (80.6)
46/54 (85.2)
2000–<3000
50/66 (75.8)
116/144 (86.6)
3000–<4000
108/125 (86.4)
127/147 (86.4)
≥4000
186/237 (78.5)
114/142 (80.3)
LLOQ (lower limit of quantification) = 50 copies/mL
FAS = Full analysis set
VERX VE: Percentage Change in Lipid Profile Viramune IR vs Viramune XR at
Week 48
Change in median value from baseline at Week 48 (%)
Substrate
Viramune IR
Viramune XR
[mg/dL]
(N=406)
(N=419)
Triglycerides
-8 (–9%)
-6 (–7%)
Cholesterol
22 (13%)
19 (11%)
LDL-c
8 (9%)
7 (7%)
HDL-c
12 (32%)
10 (27%)
-14%
-12%
Total cholesterol/HDL-c
Viramune XR demonstrated a similar lipid profile to that of Viramune IR
VERX VE: AE Summary Randomized Phase, FAS
Parameter
Viramune IR
Viramune XR
506
505
452 (89.3)
443 (87.7)
AEs leading to discontinuation, n (%)
45 (8.9)
32 (6.3)
Serious AEs, n (%)
54 (10.7)
58 (11.5)
5 (1.0)
1 (0.2)
Drug-related* AEs
123 (24.3)
100 (19.8)
DAIDS Grade 3 or 4 AEs
91 (18.0)
73 (14.5)
DAIDS Grade 4 AEs
23 (4.5)
16 (3.2)
Number of patients (N)
Any AE, n (%)
Deaths
*Investigator defined. Please note: No drug-related fatalities. Atherosclerosis/hypertension; tuberculosis (meningitis); two sepsis, myocardial
infarction; respiratory alkalosis.
FAS = Full analysis set
VERX VE: Conclusions
 Pivotal Trial (VERXVE) demonstrated:
 Non-inferior efficacy for Viramune XR to Viramune IR
 Similar safety and tolerability profiles for both formulations
 The combination of Viramune IR or Viramune XR with FTC/TDF is an effective ARV treatment
 PK – PD:
 Similar efficacy noted across many PK strata indicating adequate trough drug exposure for Viramune XR
 Consistent relative trough exposure of Viramune XR to IR across gender, region, and baseline viral-load
strata
 Once-daily dosing with VIRAMUNE XR provides patients with a more convenient treatment regimen with
comparable efficacy and safety to VIRAMUNE IR
VERX VE: Acknowledgments
We would like to thank all the patients and investigators for their involvement
and
dedicated support in this trial

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