Transcript Clinical Efficacy & Safety and Risk Management Therese M. Kitt, M.D.

Clinical Efficacy & Safety
and Risk Management
Therese M. Kitt, M.D.
Senior Medical Director, Medical Sciences
Astellas Pharma US, Inc.
1
Clinical Trials
with Vernakalant Injection
• Phase 1 Studies
– Single dose infusion
– Mass balance
• Phase 2 Studies
– Electrophysiology study
– CRAFT: Atrial fibrillation
• Phase 3 Studies
–
–
–
–
–
2
ACT I: Atrial fibrillation (AF)
ACT III: Atrial fibrillation or flutter (AF/AFL)
ACT II: AF/AFL post CABG or valvular surgery
ACT IV: AF open label
Scene 2: Atrial flutter
Dose Exposure
Total exposed
Volunteer studies
All patients
Source: Page 25
3
Placebo
Vernakalant
341
823
6
50
335
773
Clinical Efficacy and Safety
Number of Patients
Population
Study
Placebo
Vernakalant
Primary Efficacy Studies
ACT I and III (AF Only)
ACT I
ACT III
115
121
221
118
236
339
50
100
All Phase 3 Studies
315
737
CRAFT (Phase 2) Study
20
36
335
773
Total (ACT I and III)
Pooled Primary Studies*
Post Cardiac Surgery Study
(AF Only)
All Patients
ACT II
Safety
Database**
(AF and AFL)
Source: Table 3, page 25
*Over all population, AF duration >3 hours to ≤ 45 days
**Includes: CRAFT, ACT I, ACT III, ACT II and ACT IV
4
CRAFT (Dose Ranging Study)
Number of Subjects in Sinus Rhythm at 60
Minutes
Median Time to Conversion to Sinus Rhythm: 14 minutes
53%
P=0.0015
9/17
33%
6/18
11%
0%
5.3%
5.6%
1/19
1/18
Placebo
2/18
0.5 mg/kg + 1.0 mg/kg
2 mg/kg + 3 mg/kg
Vernakalant
Source: Figure 3, page 41
Roy D et al. JACC 2004.
CRAFT CSR - Listing 1.16.1
5
Phase 3 Study Design
Pooled Primary (ACT I and III) Studies
Continuous Holter Monitoring
Continuous Heart Rhythm Monitoring
Discharge
Randomization
Follow-up
Visit
Screening
Telephone
Follow-up
Primary Endpoint
Efficacy Period
Time
0
10
1st Infusion:
Vernakalant
(3 mg/kg)
or Placebo
Source: Figure 2, page 26
AFL=atrial flutter
6
25
35
90 min 2 h
2nd Infusion
(if subject in AF/AFL):
Vernakalant (2 mg/kg)
or Placebo
24 h
7d
30 d
Electrical cardioversion
and other treatments
permitted
Key Inclusion and Exclusion Criteria
Pooled Primary (ACT I and III) Studies
• Inclusion
– Symptomatic AF or AFL sustained for >3 hours
and ≤45 days as documented by 12-lead ECG
– Adequate anticoagulant therapy in accordance with
ACC/AHA/ESC practice guidelines
• Exclusion
–
–
–
–
–
7
Prolonged QT interval >440 ms
Symptomatic bradycardia or rate <50 bpm
QRS >140 ms
Previously failed electrical cardioversion
Received intravenous class I or III antiarrhythmic drugs
or IV amiodarone within 24 hours
– Class IV CHF
– MI, ACS, or cardiac surgery within 30 days prior
to randomization
– Systolic blood pressure ≥90 mmHg
Phase 3 Endpoints
Pooled Primary (ACT I and III) Studies
• Primary Endpoint:
– Conversion of AF to SR within 90 minutes
of study drug initiation in patients with
AF duration >3h to ≤7d
• Secondary and Exploratory Endpoints:
– Time to conversion to SR
– Conversion of AF to SR in patients with
AF duration >3h and ≤45d
– AF symptom relief
– Maintenance of SR after conversion
8
Phase 3 Baseline Characteristics
Pooled Primary (ACT I and III) Studies
Placebo
(N=236)
Vernakalant
(N=339)
Male
153 (65%)
240 (71%)
Mean Age (SD)
61.6 (12.6)
61.8 (14.2)
11 (5%)
12 (4%)
CHF
40 (17%)
55 (16%)
Ischemic heart disease
38 (16%)
60 (18%)
Hypertension
98 (42%)
148 (44%)
Background rhythm control medications
55 (23%)
82 (24%)
Background rate control medications
194 (82%)
256 (76%)
Pacemaker
Medical History
9
Phase 3 Efficacy
Short Duration AF (>3h - ≤7d)
Efficacy – ACT I
Efficacy – ACT III
• 51% conversion in recent-onset atrial
fibrillation patients (P<0.0001)
− vs. 4% placebo conversion rate
• 51% conversion in recent-onset atrial
fibrillation patients (P<0.0001)
− vs. 4% placebo conversion rate
• 11 minutes median time to conversion
• 8 minutes median time to conversion
0.6
Proportion of Patients
Converting to SR
0.6
0.5
Vernakalant
(n=145)
0.5
0.4
0.4
0.3
0.3
0.2
P <0.0001(Log-rank Test)
0.2
0.1
0.1
0.0
0.0
Vernakalant
(n=86)
P <0.0001 (Log-rank Test)
Placebo (n=75)
0
10 20 30 40
Infusion 1 Infusion 2
50
60
70
80
90
100
Time (minutes)
10
Placebo (n=84)
0
10 20 30
Infusion 1 Infusion 2
40
50
60
70
80
90
100
Vernakalant Conversion of AF to SR
Pooled Primary (ACT I and III) Studies
P<0.0001
Vernakalant
Placebo
51.0%
P<0.0001
37.0%
P=0.142
3.8%
1.3%
3h-7d
3h-45d
8-45d
Short-duration
(Primary endpoint)
Overall population
Long-duration
Source: From table 9, page 43
11
3.0%
6.5%
Observed and Modeled Probability of
Conversion to SR in 90 Min. by AF Duration
Probability (%) of conversion to SR within 90 minutes
0
10
20
30
40
50
60
ACT I and ACT IV Studies
GAM
95% Wald CI for GAM
>3h - ≤7d
0
12
10
20
30
Days of AF duration
40
Placebo-Subtracted Conversion to
SR
AF >3h - ≤7d
Pooled
(n=390) (ACT I and III) Studies
Overall Treatment
EffectPrimary
Age
<65 (n=242)
≥65 (n=148)
Sex
Male (n=268)
Female (n=122)
Use of
Rate Control Medications
Yes (n=288)
Use of
Rhythm Control Medications
Yes (n=108)
No (n=102)
No (n=282)
-10% 0% 10% 20% 30% 40% 50% 60% 70% 80%
Source: Figure 8, page 53
13
Placebo Better
Vernakalant Better
Placebo-Subtracted Conversion to SR
AF >3h - ≤7d
Pooled Primary (ACT I and III) Studies
Overall Treatment Effect
n=(390)
Yes (n=50)
Ischemic Heart Disease
No (n=340)
Yes (n=42)
Congestive Heart Failure
No (n=348)
Hypertension
Yes (n=232)
No (n=158)
-10%
Source: Figure 8, page 53
14
Placebo Better
0%
10% 20% 30% 40% 50% 60% 70% 80%
Vernakalant Better
Patients without AF Symptoms
Percent at Minute 90 (AF >3h - ≤7d)
P=0.0044
P=0.0005
50.0%
48.3%
28.6%
24.0%
ACT I
ACT III
Vernakalant
15
Placebo
Patients without AF Symptoms
Conversion to SR Relieves
AF Symptoms at Minute 90 (>3h ≤7d)
Pooled Primary
(ACT I and III) Studies
68.6%
P<0.0001
28.8%
Conversion to SR (n=118)
16
Remained in AF (n=113)
Vernakalant Patients
Durability of Sinus Rhythm
Pooled Primary (ACT I and III) Studies
Time Point
2 Hours
83.3%
98.2%
4 Hours
83.3%
98.2%
8 Hours
83.3%
98.2%
24 Hours
83.3%
97.2%
Source: Table 10, page 45
17
AF Duration >3h - ≤7d
(All Responders)
Placebo
Vernakalant
(N=6)
(N=118)
ACT II Demographics
Placebo
(N=54)
Vernakalant
(N=107)
40 (74%)
81 (76%)
68 (6.4)
68 (7.7)
Surgery type
CABG
Valvular
Both
37 (69%)
10 (19%)
7 (13%)
71 (66%)
28 (26%)
8 (8%)
Medical History
CHF
Ischemic heart disease
Hypertension
5 (9%)
42 (78%)
40 (74%)
9 (8%)
80 (75%)
72 (67%)
Male
Mean Age (SD)
Source: Table 13, page 49
18
ACT II
Conversion of AF to SR
• 47% conversion rate (P<0.0001)
− vs. 14% placebo conversion rate
• 12 minutes median time to conversion
Proportion of Patients
Converting to SR
0.6
Vernakalant (N=100)
0.4
P = 0.0001 (Log-Rank Test)
0.2
Placebo (N= 50)
0.0
0
20
40
60
80
Time from First Dose to Conversion to SR (Minutes)
Source: Figure 6, page 50
19
100
Consistent Conversion Rates
All Patients
52.9%
*
**
**
**
51.2%
51.0%
50.9%
47.0%
14.0%
5.3%
CRAFT
4.0%
ACT I
3.6%
ACT III
Vernakalant
ACT II
ACT IV
Placebo
Source: Figure 7, page 52
CRAFT: Dosing was 2+3 mg/kg; data represents % converted at 60 min post last dose; AF duration 3-72 hours
ACT I, III & IV: AF <7 days
ACT II: Post CABG and valvular AF study; AF duration 3-72 hours
* P=0.0015
ACT IV: A placebo group was not included in the ACT IV study
** P≤0.0001
20
Vernakalant Efficacy Summary
• Effective conversion
• Rapid – median time to conversion
10 minutes
• Efficacy not affected by age, sex,
rate or rhythm control, or concomitant
illnesses (e.g. Hx of hypertension or IHD)
• Reduction of AF symptoms
• Durability of sinus rhythm out to 24h
21
Safety Presentation
• Adverse Events
• Serious Adverse Events
• Deaths
• Events of Interest
– Ventricular Arrhythmia
(including QT changes and TdP)
– Bradycardia
– Hypotension
22
Comprehensive Safety Assessments
• Adverse events
• 12 lead ECG and vital signs
– Recorded every 5 minutes from the
start of the infusion to minute 50, then at
90 minutes, 2h, 4h, and 8h, at the time of
discharge/24h and on day 7
• 24 hour Holter Recording
23
Baseline Characteristics
All Patients
Placebo
(N=335)
Male
Mean Age (SD)
Vernakalant
(N=773)
228 (68.1%) 526 (68.0%)
62.9 (12.0)
63.2 (13.2)
CHF
60 (17.9%)
115 (14.9%)
Ischemic heart disease
95 (28.4%)
187 (24.2%)
Hypertension
163 (48.7%) 402 (52.0%)
Medical History
Background rhythm control medications
66 (19.7%)
Background rate control medications
263 (78.5%) 554 (73.7%)
Source: Table 4, page 28
24
151 (19.5%)
Adverse Events* (First 24 Hours)
All Patients
Placebo
(N=335)
Vernakalant
(N=773)
Median
Time to Onset
(min)
Dysgeusia
8 (2.4%)
158 (20.4%)
7
11
Sneezing
0
116 (15.0%)
8
5
Paresthesia
5 (1.5%)
68 (8.8%)
9
8
Nausea
4 (1.2%)
50 (6.5%)
35
16
Hypotension
12 (3.6%)
45 (5.8%)
34
20
Preferred Term
Source: Table 16, page 58
* AE occurring in ≥ 5% and at a higher incidence than placebo
25
Median
Duration
(min)
Common Treatment Emergent
Serious Adverse Events* (First 24 Hours)
All Patients
Preferred Term
Placebo
(N=335)
Vernakalant
(N=773)
Any SAE
13 (3.9%)
32 (4.1%)
AV block complete
0
2 (0.3%)
Sinus arrest
0
2 (0.3%)
2 (0.6%)
7 (0.9%)
0
2 (0.3%)
2 (0.6%)
9 (1.2%)
Sinus bradycardia/
bradycardia
Ventricular fibrillation
Hypotension
Source: Table 17, page 59
* At least 2 subjects in vernakalant group; vernakalant greater than placebo
26
Deaths
All Patients
Demographics
Primary Cause of Death
64-year-old
male
Aortic stenosis
Ventricular fibrillation
59 minutes
68-year-old
female
Rupture of dissecting
aortic aneurysm
28 hours
67-year-old
male
Pneumonia
Lung cancer
8 days
70-year-old
female
GI Hemorrhage
Breast cancer
24 days
90-year-old
female
Pulmonary edema
26 days
Source: Page 75-76
27
Interval from Dose to
Occurrence
Related Death
All Patients
• 64-year-old man with critical aortic stenosis
(120 mmHg) and dilated LV; CHF (EF 40%)
– Admitted with acute STEMI
– Became hypotensive following administration
of metoprolol
– Became hypotensive following administration
of vernakalant
– Developed ventricular fibrillation
– Resuscitation attempts were not successful
– Autopsy showed critical aortic stenosis,
myocardial hypertrophy
Source: Page 76
28
Other Deaths
All Patients
• 68-year-old woman died during a gastroscopy procedure
and 28 hours after receiving vernakalant. Autopsy
revealed a ruptured dissecting aortic aneurysm.
• 67-year-old man with lung cancer, pneumonia, and
respiratory arrest died following family decision to remove
life support 8 days after receiving vernakalant
• 70-year-old woman with breast cancer died from a
gastrointestinal hemorrhage 24 days after receiving
vernakalant
• 90-year-old woman died of congestive heart failure
26 days after receiving vernakalant
None of these deaths were considered by the investigator
to be related to vernakalant
29
Safety Presentation
• Adverse Events
• Serious Adverse Events
• Deaths
• Events of Interest
– Ventricular Arrhythmia
(including QT changes and TdP)
– Bradycardia
– Hypotension
30
Ventricular Arrhythmias
(First 24 Hours)
All Phase 3 Studies
0-2 Hours
Post-Dose
2-24 Hours
Post-Dose
Placebo
N=315
n (%)
Vernakalant
N=737
n (%)
Placebo
N=315
n (%)
Vernakalant
N=737
n (%)
9 (2.9%)
23 (3.1%)
38 (12.1%)
63 (8.5%)
Torsade de pointes
0
0
0
1 (0.1%)
Ventricular fibrillation*
0
1 (0.1%)
0
0
Ventricular tachycardia
VT defined as ≥ 3 consecutive beats at a rate of ≥ 100 bpm on Holter
Source: Table 18, page 61
* Does not include patient from Phase 2 CRAFT study
31
Resuscitated Ventricular Fibrillation
CRAFT Phase 2 Study
• 24-year-old female with AF and rapid ventricular
response
• Did not convert after vernakalant
(1.5 mg/kg total dose)
• Underwent electrical cardioversion 1 hr. 54 mins.
after initiation of vernakalant infusion
• A nonsynchronized shock was delivered resulting
in ventricular fibrillation
• Immediate defibrillation restored normal sinus
rhythm
Investigator assessed as not related to vernakalant, but
due to the delivery of a nonsynchronized electrical shock.
Source: Page 63
32
Torsade de Pointes
All Patients
Interval from
Dose to Occurrence
Vernakalant
51-year-old male (AFL)
90-year-old female
69-year-old male
2 hours 20 minutes after
vernakalant and immediately
following ibutilide
32 hours
Day 17 and 18
(post valvuloplasty)
Placebo
53-year-old male
Source: Page 63
33
Day 2, 1 hour after
electrical cardioversion
while receiving sotalol
Torsade de Pointes (<24 Hours)
All Patients
• Vernakalant:
– 51-year-old male with AFL who did not convert.
Ibutilide was given 2 hours 20 minutes after
vernakalant. TdP occurred immediately following
ibutilide.
34
Torsade de Pointes (>24 Hours)
All Patients
• Vernakalant:
– 90-year-old female developed TdP 32 hours
after receiving vernakalant
– 69-year-old male developed TdP 17 and 18
days after receiving vernakalant and 3 days
after aortic and tricuspid valve surgery
• Placebo:
– 53-year-old male who did not convert.
He developed TdP following administration of
sotalol and 1 hour after electrical
cardioversion (46 hours after receiving
placebo)
35
QT Fridericia Correction (msec)
QT Fridericia Correction
(msec)
All Phase 3 Studies
500
Placebo
480
460
440
420
400
Infusion #1
Infusion #2
Other therapies permitted
380
BL 5 10 15 20 25 30 35 40 45 50
minutes
1.5 2
4
8 24 F/U
hours
Time
Source: Figure 16, page 93
Bars around the means represent the 95% confidence intervals
36
Vernakalant
QTcF Outliers
All Phase 3 Studies
• QTcF >550 msec
– 0-2 hrs post-dose:
Vernakalant
0.6% (4/685)
Placebo
0.4% (1/284)
– After minute 30:
No difference between vernakalant and placebo
• QTcF >500 msec
– 0-2 hrs post-dose:
Vernakalant
7.2% (49/683)
Placebo
2.8% (8/282)
– After minute 90:
No difference between vernakalant and placebo
Excluding Patients with Pacemakers and missing baseline values
37
QTcF Change from Baseline by Genotype
Vernakalant Treated Patients –
ACT I, SCENE 2, ACT IV
45
EM (n = 360)
 QT Correction Fridericia
40
PM (n = 15)
35
30
25
20
15
10
5
0
-5
-10
-15
-20
Infusion #1
Infusion #2
Other therapies permitted
-25
0
5
10
15
20
25
30
minute
s
35
40
Time
Bars around the means represent the 95% confidence intervals
38
45
50
1.5
2
4
hour
8
24 Follow-up
Bradycardia
All Phase 3 Studies
Data Source
2-24 Hours
Post-Dose
Placebo
N=315
n (%)
Vernakalant
N=737
n (%)
Placebo
N=315
n (%)
Vernakalant
N=737
n (%)
AE
3 (1.0%)
33 (4.5%)
9 (2.9%)
18 (2.4%)
Holter
HR <40 bpm
6 (1.9%)
14 (1.9%)
28 (8.9%)
20 (2.7%)
12 Lead ECG
HR <40 bpm
1 (0.3%)
9 (1.2%)
3 (1.0%)
3 (0.4%)
Source: Table 19, page 66
39
0-2 Hours
Post-Dose
Heart Rate
by Responder Status Over Time
All Phase III Studies
Vernakalant Responder (n = 277)
Vernakalant Non-Responder (n = 465)
Placebo-all (n = 319)
120
Heart Rate (BPM)
110
100
90
80
70
Infusion #1
Infusion #2
Other therapies permitted
60
Baseline
10
20
30
minutes
Excluding Patients with Pacemaker
40
40
Time
50
2
8
hours
Followup
Serious Adverse Events or
Discontinuation Due to Bradycardia
0-24 Hours – All Patients
• 13 vernakalant patients (1.7%)
– Onset during the first or second infusion or within
10 minutes of the end of the infusion
– 4/13 occurred around the time of conversion
– Duration: <1 minute to 4 days
– Responded to discontinuation of the infusion,
atropine, or pacing
• 2 placebo patients (0.6%)
– 1 occurred after electrical cardioversion (atropine)
– 1 occurred 20 hours after placebo (pacemaker)
Source: Table 21, pages 68-69
41
Hypotension
All Phase 3 Studies
Data Source
2-24 Hours
Post-Dose
Placebo
N=315
n (%)
Vernakalant
N=737
n (%)
Placebo
N=315
n (%)
Vernakalant
N=737
n (%)
AE
3
(1.0%)
40
(5.4%)
8
(2.5%)
10
(1.4%)
SBP <90 mmHg
16
(5.1%)
45
(6.1%)
13
(4.1%)
18
(2.4%)
Source: Table 22, page 71
42
0-2 Hours
Post-Dose
5/23/2016 6:16 PM
Serious Adverse Events or
Discontinuation Due to Hypotension
0-24 Hours – All Patients
• 10 vernakalant patients (1.3%)
– Onset during the first or second infusion or within
15 mins of the end of the infusion; one case at 7 hours
– Duration: 2 minutes to 2 hours 16 minutes
– Responded to discontinuation of the infusion,
Trendelenburg position and saline
– 1 patient was treated with norepinephrine and one with
phenylephrine
• 2 placebo patients (0.6%)
– 1 occurred after electrical cardioversion (atropine)
– 1 at 5 hours (saline and Trendelenburg)
Source: Table 23, pages 72-74
43
Clinical Efficacy & Safety
and Risk Management
Therese M. Kitt, M.D.
Senior Medical Director, Medical Sciences
Astellas Pharma US, Inc.
44
Clinical Trials
with Vernakalant Injection
• Phase 1 Studies
– Single dose infusion
– Mass balance
• Phase 2 Studies
– Electrophysiology study
– CRAFT: Atrial fibrillation
• Phase 3 Studies
–
–
–
–
–
45
ACT I: Atrial fibrillation (AF)
ACT III: Atrial fibrillation or flutter (AF/AFL)
ACT II: AF/AFL post CABG or valvular surgery
ACT IV: AF open label
Scene 2: Atrial flutter
Dose Exposure
Total exposed
Volunteer studies
All patients
Source: Page 25
46
Placebo
Vernakalant
341
823
6
50
335
773
Clinical Efficacy and Safety
Number of Patients
Population
Study
Placebo
Vernakalant
Primary Efficacy Studies
ACT I and III (AF Only)
ACT I
ACT III
115
121
221
118
236
339
50
100
All Phase 3 Studies
315
737
CRAFT (Phase 2) Study
20
36
335
773
Total (ACT I and III)
Pooled Primary Studies*
Post Cardiac Surgery Study
(AF Only)
All Patients
ACT II
Safety
Database**
(AF and AFL)
Source: Table 3, page 25
*Over all population, AF duration >3 hours to ≤ 45 days
**Includes: CRAFT, ACT I, ACT III, ACT II and ACT IV
47
CRAFT (Dose Ranging Study)
Number of Subjects in Sinus Rhythm at 60
Minutes
Median Time to Conversion to Sinus Rhythm: 14 minutes
53%
P=0.0015
9/17
33%
6/18
11%
0%
5.3%
5.6%
1/19
1/18
Placebo
2/18
0.5 mg/kg + 1.0 mg/kg
2 mg/kg + 3 mg/kg
Vernakalant
Source: Figure 3, page 41
Roy D et al. JACC 2004.
CRAFT CSR - Listing 1.16.1
48
Phase 3 Study Design
Pooled Primary (ACT I and III) Studies
Continuous Holter Monitoring
Continuous Heart Rhythm Monitoring
Discharge
Randomization
Follow-up
Visit
Screening
Telephone
Follow-up
Primary Endpoint
Efficacy Period
Time
0
10
1st Infusion:
Vernakalant
(3 mg/kg)
or Placebo
Source: Figure 2, page 26
AFL=atrial flutter
49
25
35
90 min 2 h
2nd Infusion
(if subject in AF/AFL):
Vernakalant (2 mg/kg)
or Placebo
24 h
7d
30 d
Electrical cardioversion
and other treatments
permitted
Key Inclusion and Exclusion Criteria
Pooled Primary (ACT I and III) Studies
• Inclusion
– Symptomatic AF or AFL sustained for >3 hours
and ≤45 days as documented by 12-lead ECG
– Adequate anticoagulant therapy in accordance with
ACC/AHA/ESC practice guidelines
• Exclusion
–
–
–
–
–
50
Prolonged QT interval >440 ms
Symptomatic bradycardia or rate <50 bpm
QRS >140 ms
Previously failed electrical cardioversion
Received intravenous class I or III antiarrhythmic drugs
or IV amiodarone within 24 hours
– Class IV CHF
– MI, ACS, or cardiac surgery within 30 days prior
to randomization
– Systolic blood pressure ≥90 mmHg
Phase 3 Endpoints
Pooled Primary (ACT I and III) Studies
• Primary Endpoint:
– Conversion of AF to SR within 90 minutes
of study drug initiation in patients with
AF duration >3h to ≤7d
• Secondary and Exploratory Endpoints:
– Time to conversion to SR
– Conversion of AF to SR in patients with
AF duration >3h and ≤45d
– AF symptom relief
– Maintenance of SR after conversion
51
Phase 3 Baseline Characteristics
Pooled Primary (ACT I and III) Studies
Placebo
(N=236)
Vernakalant
(N=339)
Male
153 (65%)
240 (71%)
Mean Age (SD)
61.6 (12.6)
61.8 (14.2)
11 (5%)
12 (4%)
CHF
40 (17%)
55 (16%)
Ischemic heart disease
38 (16%)
60 (18%)
Hypertension
98 (42%)
148 (44%)
Background rhythm control medications
55 (23%)
82 (24%)
Background rate control medications
194 (82%)
256 (76%)
Pacemaker
Medical History
52
Phase 3 Efficacy
Short Duration AF (>3h - ≤7d)
Efficacy – ACT I
Efficacy – ACT III
• 51% conversion in recent-onset atrial
fibrillation patients (P<0.0001)
− vs. 4% placebo conversion rate
• 51% conversion in recent-onset atrial
fibrillation patients (P<0.0001)
− vs. 4% placebo conversion rate
• 11 minutes median time to conversion
• 8 minutes median time to conversion
0.6
Proportion of Patients
Converting to SR
0.6
0.5
Vernakalant
(n=145)
0.5
0.4
0.4
0.3
0.3
0.2
P <0.0001(Log-rank Test)
0.2
0.1
0.1
0.0
0.0
Vernakalant
(n=86)
P <0.0001 (Log-rank Test)
Placebo (n=75)
0
10 20 30 40
Infusion 1 Infusion 2
50
60
70
80
90
100
Time (minutes)
53
Placebo (n=84)
0
10 20 30
Infusion 1 Infusion 2
40
50
60
70
80
90
100
Vernakalant Conversion of AF to SR
Pooled Primary (ACT I and III) Studies
P<0.0001
Vernakalant
Placebo
51.0%
P<0.0001
37.0%
P=0.142
3.8%
1.3%
3h-7d
3h-45d
8-45d
Short-duration
(Primary endpoint)
Overall population
Long-duration
Source: From table 9, page 43
54
3.0%
6.5%
Observed and Modeled Probability of
Conversion to SR in 90 Min. by AF Duration
Probability (%) of conversion to SR within 90 minutes
0
10
20
30
40
50
60
ACT I and ACT IV Studies
GAM
95% Wald CI for GAM
>3h - ≤7d
0
55
10
20
30
Days of AF duration
40
Placebo-Subtracted Conversion to
SR
AF >3h - ≤7d
Pooled
(n=390) (ACT I and III) Studies
Overall Treatment
EffectPrimary
Age
<65 (n=242)
≥65 (n=148)
Sex
Male (n=268)
Female (n=122)
Use of
Rate Control Medications
Yes (n=288)
Use of
Rhythm Control Medications
Yes (n=108)
No (n=102)
No (n=282)
-10% 0% 10% 20% 30% 40% 50% 60% 70% 80%
Source: Figure 8, page 53
56
Placebo Better
Vernakalant Better
Placebo-Subtracted Conversion to SR
AF >3h - ≤7d
Pooled Primary (ACT I and III) Studies
Overall Treatment Effect
n=(390)
Yes (n=50)
Ischemic Heart Disease
No (n=340)
Yes (n=42)
Congestive Heart Failure
No (n=348)
Hypertension
Yes (n=232)
No (n=158)
-10%
Source: Figure 8, page 53
57
Placebo Better
0%
10% 20% 30% 40% 50% 60% 70% 80%
Vernakalant Better
Patients without AF Symptoms
Percent at Minute 90 (AF >3h - ≤7d)
P=0.0044
P=0.0005
50.0%
48.3%
28.6%
24.0%
ACT I
ACT III
Vernakalant
58
Placebo
Patients without AF Symptoms
Conversion to SR Relieves
AF Symptoms at Minute 90 (>3h ≤7d)
Pooled Primary
(ACT I and III) Studies
68.6%
P<0.0001
28.8%
Conversion to SR (n=118)
59
Remained in AF (n=113)
Vernakalant Patients
Durability of Sinus Rhythm
Pooled Primary (ACT I and III) Studies
Time Point
2 Hours
83.3%
98.2%
4 Hours
83.3%
98.2%
8 Hours
83.3%
98.2%
24 Hours
83.3%
97.2%
Source: Table 10, page 45
60
AF Duration >3h - ≤7d
(All Responders)
Placebo
Vernakalant
(N=6)
(N=118)
ACT II Demographics
Placebo
(N=54)
Vernakalant
(N=107)
40 (74%)
81 (76%)
68 (6.4)
68 (7.7)
Surgery type
CABG
Valvular
Both
37 (69%)
10 (19%)
7 (13%)
71 (66%)
28 (26%)
8 (8%)
Medical History
CHF
Ischemic heart disease
Hypertension
5 (9%)
42 (78%)
40 (74%)
9 (8%)
80 (75%)
72 (67%)
Male
Mean Age (SD)
Source: Table 13, page 49
61
ACT II
Conversion of AF to SR
• 47% conversion rate (P<0.0001)
− vs. 14% placebo conversion rate
• 12 minutes median time to conversion
Proportion of Patients
Converting to SR
0.6
Vernakalant (N=100)
0.4
P = 0.0001 (Log-Rank Test)
0.2
Placebo (N= 50)
0.0
0
20
40
60
80
Time from First Dose to Conversion to SR (Minutes)
Source: Figure 6, page 50
62
100
Consistent Conversion Rates
All Patients
52.9%
*
**
**
**
51.2%
51.0%
50.9%
47.0%
14.0%
5.3%
CRAFT
4.0%
ACT I
3.6%
ACT III
Vernakalant
ACT II
ACT IV
Placebo
Source: Figure 7, page 52
CRAFT: Dosing was 2+3 mg/kg; data represents % converted at 60 min post last dose; AF duration 3-72 hours
ACT I, III & IV: AF <7 days
ACT II: Post CABG and valvular AF study; AF duration 3-72 hours
* P=0.0015
ACT IV: A placebo group was not included in the ACT IV study
** P≤0.0001
63
Vernakalant Efficacy Summary
• Effective conversion
• Rapid – median time to conversion
10 minutes
• Efficacy not affected by age, sex,
rate or rhythm control, or concomitant
illnesses (e.g. Hx of hypertension or IHD)
• Reduction of AF symptoms
• Durability of sinus rhythm out to 24h
64
Safety Presentation
• Adverse Events
• Serious Adverse Events
• Deaths
• Events of Interest
– Ventricular Arrhythmia
(including QT changes and TdP)
– Bradycardia
– Hypotension
65
Comprehensive Safety Assessments
• Adverse events
• 12 lead ECG and vital signs
– Recorded every 5 minutes from the
start of the infusion to minute 50, then at
90 minutes, 2h, 4h, and 8h, at the time of
discharge/24h and on day 7
• 24 hour Holter Recording
66
Baseline Characteristics
All Patients
Placebo
(N=335)
Male
Mean Age (SD)
Vernakalant
(N=773)
228 (68.1%) 526 (68.0%)
62.9 (12.0)
63.2 (13.2)
CHF
60 (17.9%)
115 (14.9%)
Ischemic heart disease
95 (28.4%)
187 (24.2%)
Hypertension
163 (48.7%) 402 (52.0%)
Medical History
Background rhythm control medications
66 (19.7%)
Background rate control medications
263 (78.5%) 554 (73.7%)
Source: Table 4, page 28
67
151 (19.5%)
Adverse Events* (First 24 Hours)
All Patients
Placebo
(N=335)
Vernakalant
(N=773)
Median
Time to Onset
(min)
Dysgeusia
8 (2.4%)
158 (20.4%)
7
11
Sneezing
0
116 (15.0%)
8
5
Paresthesia
5 (1.5%)
68 (8.8%)
9
8
Nausea
4 (1.2%)
50 (6.5%)
35
16
Hypotension
12 (3.6%)
45 (5.8%)
34
20
Preferred Term
Source: Table 16, page 58
* AE occurring in ≥ 5% and at a higher incidence than placebo
68
Median
Duration
(min)
Common Treatment Emergent
Serious Adverse Events* (First 24 Hours)
All Patients
Preferred Term
Placebo
(N=335)
Vernakalant
(N=773)
Any SAE
13 (3.9%)
32 (4.1%)
AV block complete
0
2 (0.3%)
Sinus arrest
0
2 (0.3%)
2 (0.6%)
7 (0.9%)
0
2 (0.3%)
2 (0.6%)
9 (1.2%)
Sinus bradycardia/
bradycardia
Ventricular fibrillation
Hypotension
Source: Table 17, page 59
* At least 2 subjects in vernakalant group; vernakalant greater than placebo
69
Deaths
All Patients
Demographics
Primary Cause of Death
64-year-old
male
Aortic stenosis
Ventricular fibrillation
59 minutes
68-year-old
female
Rupture of dissecting
aortic aneurysm
28 hours
67-year-old
male
Pneumonia
Lung cancer
8 days
70-year-old
female
GI Hemorrhage
Breast cancer
24 days
90-year-old
female
Pulmonary edema
26 days
Source: Page 75-76
70
Interval from Dose to
Occurrence
Related Death
All Patients
• 64-year-old man with critical aortic stenosis
(120 mmHg) and dilated LV; CHF (EF 40%)
– Admitted with acute STEMI
– Became hypotensive following administration
of metoprolol
– Became hypotensive following administration
of vernakalant
– Developed ventricular fibrillation
– Resuscitation attempts were not successful
– Autopsy showed critical aortic stenosis,
myocardial hypertrophy
Source: Page 76
71
Other Deaths
All Patients
• 68-year-old woman died during a gastroscopy procedure
and 28 hours after receiving vernakalant. Autopsy
revealed a ruptured dissecting aortic aneurysm.
• 67-year-old man with lung cancer, pneumonia, and
respiratory arrest died following family decision to remove
life support 8 days after receiving vernakalant
• 70-year-old woman with breast cancer died from a
gastrointestinal hemorrhage 24 days after receiving
vernakalant
• 90-year-old woman died of congestive heart failure
26 days after receiving vernakalant
None of these deaths were considered by the investigator
to be related to vernakalant
72
Safety Presentation
• Adverse Events
• Serious Adverse Events
• Deaths
• Events of Interest
– Ventricular Arrhythmia
(including QT changes and TdP)
– Bradycardia
– Hypotension
73
Ventricular Arrhythmias
(First 24 Hours)
All Phase 3 Studies
0-2 Hours
Post-Dose
2-24 Hours
Post-Dose
Placebo
N=315
n (%)
Vernakalant
N=737
n (%)
Placebo
N=315
n (%)
Vernakalant
N=737
n (%)
9 (2.9%)
23 (3.1%)
38 (12.1%)
63 (8.5%)
Torsade de pointes
0
0
0
1 (0.1%)
Ventricular fibrillation*
0
1 (0.1%)
0
0
Ventricular tachycardia
VT defined as ≥ 3 consecutive beats at a rate of ≥ 100 bpm on Holter
Source: Table 18, page 61
* Does not include patient from Phase 2 CRAFT study
74
Resuscitated Ventricular Fibrillation
CRAFT Phase 2 Study
• 24-year-old female with AF and rapid ventricular
response
• Did not convert after vernakalant
(1.5 mg/kg total dose)
• Underwent electrical cardioversion 1 hr. 54 mins.
after initiation of vernakalant infusion
• A nonsynchronized shock was delivered resulting
in ventricular fibrillation
• Immediate defibrillation restored normal sinus
rhythm
Investigator assessed as not related to vernakalant, but
due to the delivery of a nonsynchronized electrical shock.
Source: Page 63
75
Torsade de Pointes
All Patients
Interval from
Dose to Occurrence
Vernakalant
51-year-old male (AFL)
90-year-old female
69-year-old male
2 hours 20 minutes after
vernakalant and immediately
following ibutilide
32 hours
Day 17 and 18
(post valvuloplasty)
Placebo
53-year-old male
Source: Page 63
76
Day 2, 1 hour after
electrical cardioversion
while receiving sotalol
Torsade de Pointes (<24 Hours)
All Patients
• Vernakalant:
– 51-year-old male with AFL who did not convert.
Ibutilide was given 2 hours 20 minutes after
vernakalant. TdP occurred immediately following
ibutilide.
77
Torsade de Pointes (>24 Hours)
All Patients
• Vernakalant:
– 90-year-old female developed TdP 32 hours
after receiving vernakalant
– 69-year-old male developed TdP 17 and 18
days after receiving vernakalant and 3 days
after aortic and tricuspid valve surgery
• Placebo:
– 53-year-old male who did not convert.
He developed TdP following administration of
sotalol and 1 hour after electrical
cardioversion (46 hours after receiving
placebo)
78
QT Fridericia Correction (msec)
QT Fridericia Correction
(msec)
All Phase 3 Studies
500
Placebo
480
460
440
420
400
Infusion #1
Infusion #2
Other therapies permitted
380
BL 5 10 15 20 25 30 35 40 45 50
minutes
1.5 2
4
8 24 F/U
hours
Time
Source: Figure 16, page 93
Bars around the means represent the 95% confidence intervals
79
Vernakalant
QTcF Outliers
All Phase 3 Studies
• QTcF >550 msec
– 0-2 hrs post-dose:
Vernakalant
0.6% (4/685)
Placebo
0.4% (1/284)
– After minute 30:
No difference between vernakalant and placebo
• QTcF >500 msec
– 0-2 hrs post-dose:
Vernakalant
7.2% (49/683)
Placebo
2.8% (8/282)
– After minute 90:
No difference between vernakalant and placebo
Excluding Patients with Pacemakers and missing baseline values
80
QTcF Change from Baseline by Genotype
Vernakalant Treated Patients –
ACT I, SCENE 2, ACT IV
45
EM (n = 360)
 QT Correction Fridericia
40
PM (n = 15)
35
30
25
20
15
10
5
0
-5
-10
-15
-20
Infusion #1
Infusion #2
Other therapies permitted
-25
0
5
10
15
20
25
30
minute
s
35
40
Time
Bars around the means represent the 95% confidence intervals
81
45
50
1.5
2
4
hour
8
24 Follow-up
Bradycardia
All Phase 3 Studies
Data Source
2-24 Hours
Post-Dose
Placebo
N=315
n (%)
Vernakalant
N=737
n (%)
Placebo
N=315
n (%)
Vernakalant
N=737
n (%)
AE
3 (1.0%)
33 (4.5%)
9 (2.9%)
18 (2.4%)
Holter
HR <40 bpm
6 (1.9%)
14 (1.9%)
28 (8.9%)
20 (2.7%)
12 Lead ECG
HR <40 bpm
1 (0.3%)
9 (1.2%)
3 (1.0%)
3 (0.4%)
Source: Table 19, page 66
82
0-2 Hours
Post-Dose
Heart Rate
by Responder Status Over Time
All Phase III Studies
Vernakalant Responder (n = 277)
Vernakalant Non-Responder (n = 465)
Placebo-all (n = 319)
120
Heart Rate (BPM)
110
100
90
80
70
Infusion #1
Infusion #2
Other therapies permitted
60
Baseline
10
20
30
minutes
Excluding Patients with Pacemaker
83
40
Time
50
2
8
hours
Followup
Serious Adverse Events or
Discontinuation Due to Bradycardia
0-24 Hours – All Patients
• 13 vernakalant patients (1.7%)
– Onset during the first or second infusion or within
10 minutes of the end of the infusion
– 4/13 occurred around the time of conversion
– Duration: <1 minute to 4 days
– Responded to discontinuation of the infusion,
atropine, or pacing
• 2 placebo patients (0.6%)
– 1 occurred after electrical cardioversion (atropine)
– 1 occurred 20 hours after placebo (pacemaker)
Source: Table 21, pages 68-69
84
Hypotension
All Phase 3 Studies
Data Source
2-24 Hours
Post-Dose
Placebo
N=315
n (%)
Vernakalant
N=737
n (%)
Placebo
N=315
n (%)
Vernakalant
N=737
n (%)
AE
3
(1.0%)
40
(5.4%)
8
(2.5%)
10
(1.4%)
SBP <90 mmHg
16
(5.1%)
45
(6.1%)
13
(4.1%)
18
(2.4%)
Source: Table 22, page 71
85
0-2 Hours
Post-Dose
5/23/2016 6:16 PM
Serious Adverse Events or
Discontinuation Due to Hypotension
0-24 Hours – All Patients
• 10 vernakalant patients (1.3%)
– Onset during the first or second infusion or within
15 mins of the end of the infusion; one case at 7 hours
– Duration: 2 minutes to 2 hours 16 minutes
– Responded to discontinuation of the infusion,
Trendelenburg position and saline
– 1 patient was treated with norepinephrine and one with
phenylephrine
• 2 placebo patients (0.6%)
– 1 occurred after electrical cardioversion (atropine)
– 1 at 5 hours (saline and Trendelenburg)
Source: Table 23, pages 72-74
86
Patients with a History of CHF
• 110 patients received vernakalant
• 54 patients received placebo
• During the 0-24 hour time period:
– Trend toward increased incidence of
hypotension in vernakalant patients
– No difference from placebo for bradycardia
The safety database in patients with a history of CHF
is limited. Vernakalant injection should be used
with caution in patients with a history of CHF.
Further studies are needed.
87
No Effect on
Electrical Cardioversion
All Phase 3 Studies
Placebo
(N=315)
Vernakalant
(N=737)
Successful ECV
90% (166/184)
88% (237/270)
Median Number
of Shocks
1
1
200
200
Median Joules
Source: Page 95
88
Vernakalant Safety Summary
All Patients
• One related death
• Transient increases in QRS, QT, QTcB
and QTcF
• Events of interest 0-24 hours:
– Ventricular arrhythmia: 1 event of TdP
(0.13%, 1/773) in first 24 hours after vernakalant and
immediately following an infusion of ibutilide
– Bradycardia (SAE or d/c): 1.7% (13/773) vernakalant;
0.6% (2/335) placebo associated with cardioversion
– Hypotension (SAE or d/c): 1.3% (10/773) vernakalant;
0.6% (2/335) placebo peri-infusional, transient,
responded to saline, 2 patients required pressors
89
Risk Management and
Post-marketing Studies
• Prescribing Information
• Healthcare Provider Education
• Pharmacovigilance and Reporting
• Post-marketing Studies
90
Prescribing Information Content
• Indication: AF duration ≤ 7days
• Patient selection
– Hemodynamically stable
– Symptomatic where conversion to SR is indicated
– Adequately anticoagulated according to the
guidelines
– QT <440 msec
• Warnings and Precautions
– Do not administer to patients with acute MI, ACS or
symptomatic and/or decompensated CHF
– Not evaluated in patients with MI or ACS within
previous 30 days
– Administer with caution to stable patients with a
history of CHF
91
Prescribing Information Content
• Clinical setting for administration
– Acute care clinical setting
– Resuscitation equipment available
• Monitoring
– Minimum of 90 minutes following the completion
of the infusion or until clinical and ECG
parameters have stabilized
• Identification and management of adverse
events
– Discontinuation if clinically significant ECG
changes, bradycardia or hypotension
– Treat symptomatically with appropriate medical
management
92
Vernakalant Education
• Comprehensive for target specific
audiences
– Cardiologists
– Critical care/ER physicians
– Allied healthcare personnel
• Prescribing information is the foundation
93
Pharmacovigilance
• Adverse event reports with emphasis
on events of ventricular arrhythmia
and deaths
• Literature reports
• Data mining (AERS and others)
• Periodic Adverse Drug Experience
Reports to FDA
• Signal detection and analysis
94
Additional Studies
• Non-clinical (ongoing)
– Effect of vernakalant on P-glycoprotein
transporters
– Effect on ventricular defibrillation threshold
• Clinical (ongoing)
– PK in hepatically impaired patients
– PK in renally impaired patients
• Clinical (planned)
– Prospective studies
• Efficacy and safety trial in EU
• Non-Caucasian patients
• Patients with history of CHF
– Observational study
95
Post-marketing
Observational Study
• Assess real world AE experience
– TdP, VF, bradycardia, hypotension, death
• Registry and/or mining of managed care
or hospital databases
• Sample size ~2000 patients
96