Ranexa Supportive Slides

1
RanexaSupportive Slides
18
2
Exercise Duration at Trough at Wk 12 (LOCF) by
Background TherapyCARISA (CVT 3033)
Treatment by background therapy p 0.63 Data
presented as LS mean SE.
3
ETT by Treatment and PeriodMARISA (CVT 3031)
4
End-Exercise Heart Rate, Blood Pressure, RPP, and
Exercise DurationMARISA (CVT 3031) and CARISA
(CVT 3033)
54
MARISA Efficacy data presented are from the
All/Near Completers population (N 175) i.e.,
the primary efficacy analysis. HR/BP and RPP
data are from all randomized patients with at
least one measurement of end-exercise RPP (N
179). Differences from placebo are from ANOVA
model with effects for pooled site, patients
within pooled site, period and treatment. CARISA
HR/BP and RPP data presented are from all
randomized patients at Week 12 (N 737). Note
that the primary efficacy analysis was performed
on Intent-to-Treat at Week 12 using LOCF (N
791) an RPP analysis was not performed on this
population. Differences from placebo are from an
analysis of covariance (ANCOVA) model with
effects for baseline, pooled site, background
therapy and treatment.
5
Rate Pressure Product at PeakWk 12CARISA (CVT
3033)
66

vs_exstage (21NOV03 1450) s\CVT-303\NDA_request
s\CVT3033\table_graph\vs_exstage_est.RTF


Placebo 244 RAN 750 250 RAN 1000 238

NOTE LS means and p-values from repeated-measure
analysis of variance model with effects for
treatment, exercise stage, and treatment by stage
interaction. Data presented as LS mean SE. p lt
0.05 vs placebo
6
Overall Summary of Key Efficacy Results in
Ranolazine IR, Study RAN1514(All Patients
Analysis)
54
NOTE LS means and p-values from analysis of
variance with effects for site, patient within
site, period, treatment,previous treatment and
interactions of site with treatment, and site
with previous treatment.
7
Ranolazine Effect on Exercise Duration Maintained
Over 12 Wk of TherapyCARISA (CVT 3033)
Ranolazine
Ranolazine
Placebo
1000 mg bid
750 mg bid
140


120

100
Change from baseline (trough, sec)
80
60
40
0
2
4
6
8
10
12
Weeks
N 791, ITT/LOCF LS mean SE p lt 0.05, p ?
0.01, and p ? 0.001 for both ranolazine doses
vs placebo..
8
Rebound AssessmentChange From Baseline in
Exercise Treadmill Test Duration at Trough CARISA
(CVT 3033)
243
128
118
120
118
N
Double-blind
Placebo
RAN 750
RAN 1000
RAN 750
RAN 1000
Withdrawal
Placebo
Placebo
Placebo
RAN 750
RAN 1000
Data presented as LS mean SE.
9
Exercise Duration at Trough in Patients by
Revascularization CARISA (CVT 3033)
43
n
70
188
81
191
90
171
ITT population. Data presented as LS mean
SE. PTCA, CABG, or TMR. Treatment by subgroup
interaction p 0.22
10
Exercise Duration at Peak in Patients by
Revascularization CARISA (CVT 3033)
43
n
70
186
80
190
85
170
ITT population. Data presented as LS mean
SE. PTCA, CABG, or TMR. Treatment by subgroup
interaction p 0.60
11
Exercise Duration at Trough in Patients by
Revascularization MARISA (CVT 3031)
43
n
84
90
84
90
85
89
82
87
NOTE All/Near Completers population. Data
presented as LS mean SE. Treatment by subgroup
interaction p .95
12
Exercise Duration at Peak in Patients by
Revascularization MARISA (CVT 3031)
43
n
83
89
84
90
85
89
81
86
NOTE All/Near Completers population. Data
presented as LS mean SE. Treatment by subgroup
interaction p .84
13
Exercise Duration at Trough at Wk 12 (LOCF) by
Background TherapyCARISA (CVT 3033)
Treatment by background therapy p 0.63 Data
presented as LS mean SE.
14
Exercise Duration at Peak at Wk 12 (LOCF) by
Background TherapyCARISA (CVT 3033)
Treatment by background therapy p 0.63 Data
presented as LS mean SE.
15
Estimated Mean Difference From Placebo in
Exercise Tolerance Time Adjusting For Increase in
Ranolazine Concentrations Due to
DiltiazemCARISA (CVT 3033)
45
NDA T6-5.
ITT population. µadj µ fd r µ (1-fd), where
µ is the mean difference from primary efficacy
analysis,fd is the fraction of patients taking
diltiazem, and r is the ratio of ranolazine
plasmaconcentrations in patients not taking
diltiazem to those taking diltiazem.
16
Projected Diltiazem Plasma Concentration Profiles
5
ISE F-6
240
Diltiazem IR 60 mg tid
Diltiazem SR 180 mg qd
200
Diltiazem SR 300 mg qd
Diltiazem SR 360 mg qd
160
Plasma concentration, ng/mL
120
2.5 to 3 hours after dosing with diltiazem IR 60
mg tid, plasma diltiazem levels are in the same
range as with diltiazem 300 mg qd SR at trough
80
40
0
0
4
8
12
16
20
24
Time, hr
2.5h
3h
NDA 20-092, study RG83606-103 comparing Dilacor
XR to dilitiazem IR tablets NDA 20-939study
P97-062-Steady-state pharmacokinetics.
17
DiltiazemPlateau in Efficacy Effect

• Diltiazem IR dose of 60 mg tid results in the
  same predicted plasma diltiazem level at 2.5 to 3
  hr after dosing as diltiazem 300 mg daily at
  steady state trough

Cardizem CD tablets (diltiazem hydrochloride)
US Package Insert. Marion Merrell Dow, Inc. May
1999. Tiazac tablets (diltiazem hydrochloride)
US Package Insert. Marion Merrell Dow, Inc.
Revised June 2000.
18
Calculated Improvement in ETTConverted to Stage
0 Work ConditionsMARISA (CVT 3031) and CARISA
(CVT 3033)
23
19
Exercise Duration at TroughPatients With
DiabetesCARISA (CVT 3033)
5
ISE T-43
n
55
203
68
204
60
201
NOTE ITT population. Data presented as LS mean
SE. Treatment by subgroup interaction p 0.89
20
Exercise Duration at PeakPatients With
DiabetesCARISA (CVT 3033)
5
ISE T-43
n
55
201
67
203
59
196
NOTE ITT population. Data presented as LS mean
SE. Treatment by subgroup interaction p 0.58
21
Exercise Duration at TroughPatients With
DiabetesMARISA (CVT 3031)
5
ISE T-44
42
132
n
42
132
42
132
40
129
NOTE All/Near Completers population. Data
presented as LS mean SE. Treatment by subgroup
interaction p 0.77
22
Exercise Duration at PeakPatients With
DiabetesMARISA (CVT 3031)
5
ISE T-44
n
41
131
42
132
42
132
40
127
NOTE All/Near Completers population. Data
presented as LS mean SE. Treatment by subgroup
interaction p 0.95
23
Exercise Performance in Males vs Females
Ranolazine IR vs AtenololRAN080
23
Table 19
Data presented as LS mean SE.
24
Exercise Duration at Trough at Wk 12 (LOCF) by
SubgroupCARISA (CVT 3033)
23
ISE T 36, 39, 41, 43
In subgroup
Not in subgroup
n 184
n 179
n 185
n 185
n 204
n 201
n 246
n 244
n 79
n 97
NOTE Data presented as LS mean SE. CHF
Congestive heart failure RAD Reactive airway
disease. SBP 100 mm Hg, HR 60 bpm, or PR
interval 200 msec.
25
Exercise Duration at Peak at Wk 12 (LOCF) by
SubgroupCARISA (CVT 3033)
23
ISE T 36, 39, 41, 43
In subgroup
Not in subgroup
n 182
n 174
n 184
n 179
n 203
n 196
n 244
n 238
n 78
n 93
CHF Congestive heart failure RAD Reactive
airway disease. SBP 100 mm Hg, HR 60 bpm, or
PR interval 200 msec.
26
Exercise Duration at Trough by SubgroupMARISA
(CVT 3031)
23
ISE T 36, 39, 41, 43
In subgroup
Not in subgroup
CHF Congestive heart failure RAD Reactive
airway disease. SBP 100 mm Hg, HR 60 bpm, or
PR interval 200 msec.
27
Exercise Duration at Peak by SubgroupMARISA (CVT
3031)
23
ISE T 36, 39, 41, 43
In subgroup
Not in subgroup
CHF Congestive heart failure RAD Reactive
airway disease. SBP 100 mm Hg, HR 60 bpm, or
PR interval 200 msec.
28
Most Common AEs 2 In CHF PatientsPhase 2/3
SR Controlled Studies
14
ISS T-52
29
Relationship Between Plasma Ranolazine Levels and
Adverse Effects
44
30
Ranolazine Reduces Incidence of
Ischemia/Reperfusion VF in Rat Isolated Working
Hearts
Incidence of VF,
Ranolazine, mM
AT 4474
31
Known Risk Factors (Predisposing Conditions) for
TdP With QT-Prolonging Drugs
28

• Predisposing Conditions
• IKr,s blockers
• Na- and Ca-channel openers
• Bradycardia (sinus pauses)
• Hypokalemia, hypomagnesemia
• Ion channel mutations (Pharm. Simulation)
• ? IKs (LQT1) ?? IKr (LQT2) ? INa, late (LQT3)
  
• Heart failure
• Sex (female)
• Epicardial pacing
• Ischemia

Ranolazine NO NO NO NO NO NO NO NO NO
NOno EADs, no ? TDR, no EBs, no VT, no VF
32
Ventricular Arrhythmias During Exercise
Treadmill Testing at PeakMARISA (CVT 3031)
RANO010.ANALYSYS.TABLELIB EXMILL_P.SAS,
QUINTILES (US), 13-SEP-01 1616
33
SS-33
Association of Increased Transmural Dispersion of
Repolarization and Early Afterdepolarizations in
Canine Left Ventricular Myocardium with
Occurrence of Torsade de Pointes in Humans
34
Sensitivity and Specificity of Canine Ventricular
Tissues in Detecting Agents That Predispose to TdP

• Sensitivity 90
• Specificity 100

35
SS-35
Moxilfoxacin Produces a Dramatic Dose-Dependent
Increase in Transmural Dispersion of APD and EADs
M Cell
APD90
TD-APD
Epicardium
36
Electrocardiographic FindingsMARISA (CVT 3031)
37
The Heart in Cirrhosis

• Blunted systolic and diastolic contractile
  responses to stimuli
• ? QTc (40 50)
• No increased risk of torsade de pointes
• Possible mechanisms lipid biochemical changes
  and plasma-membrane bound receptor dysfunction in
  cardiac sarcolemmal membranes

38
Incidence of Nausea, Dizziness, and Postural
Hypotension At High IV DosesCVT 3111
39
Orthostatic Change in SystolicBlood
PressureRAN0201
High dose response in orthostatic BP change
healthy volunteers
40
Table 5-8. Listing of Healthy Subjects With
Syncope (1)
54
Bazett correction Fridericia not
available. Target concentration.
41
Table 5-8. Listing of Healthy Subjects With
Syncope (2)
54
Bazett correction Fridericia not
available. Target concentration.
42
Syncope Occurs Early in Treatment in Patients
Randomized to Higher DosesPhase 2/3 Controlled
Studies
50
10/27/03 NDA requests/ISS
43
Renal ImpairmentCVT 3016
120
100
Severe
Moderate
Mild
Normal
80
60
Oral ranolazine clearance, L/hr
40
20
0
0
10
20
30
40
50
60
70
80
90
100
110
120
130
Creatinine clearance, mL/min
44
Distribution of Ranolazine PK Parameters at
Steady-State in Healthy Controls and Patients
With Hepatic ImpairmentCVT 3018
19
NDA Item 6, T 6.14-2
45
Concomitant Medications in Patients With
SyncopePhase 2/3 Controlled and Open Label
Studies
16
Exposed to ranolazine.
46
Summary of Syncope Patients on Vasoactive
Medications
47
Postural Hypotension and Syncope
16
Physicians Desk Reference. 2003. Phase 2/3
controlled studies.
48
Effect of Ranolazine on CYP2D6 ActivityCVT 301-13
19
NDA Item 6, T 6.13-9
49
Effect of Ranolazine on LVSP and LV dP/dt in
Awake Dogs
1 mM
3 mM
14 mM
18 mM
n 5
n 5
3000
150
120
2000
90
LVSP, mm Hg
LVdP/dt, mm Hg/s
60
1000
30
0
0
0
5
30
45
10
15
20
0
5
30
45
10
15
20
Ranolazine
Ranolazine
Time, min
Time, min
50
Effect of Ranolazine on CBF and CVR in Awake Dogs
1 mM
3 mM
14 mM
18 mM
55
4
n 5
n 5
44
3
33
CBF, ml/min
CVR, mm Hg/ml/min
2
22
1
11
0
0
0
5
30
45
10
15
20
0
5
30
45
10
15
20
Ranolazine
Ranolazine
Time, min
Time, min
51
Change in QTc by Plasma Ranolazine Concentration
in Mild and Moderate Hepatic ImpairmentCVT 3018
80
Moderate
Mild
60
40
20
Change in QTc from baseline, msec
0
-20
-40
0
500
1000
1500
2000
2500
3000
Concentration, ng/mL
52
QTc Values gt 500 msec on Ranolazine Random
Variation Plus a Linear Increase
540
520
500
480
460
2.4 msec per 1000 ng/mL (95prediction interval)
440
Change in QTc from baseline, msec
420
400
380
360
340
320
320
2000
4000
6000
8000
10,000
12,000
14,000
Ranolazine concentration, ng/mL