# Presentation: 134207

## Clinical Efficacy & Safety and Risk Management

**Therese M. Kitt, M.D.**
*Senior Medical Director, Medical Sciences**Astellas Pharma US, Inc.*

## Clinical Trials with Vernakalant Injection

**Phase 1 Studies**
**Single dose infusion**
**Mass balance**
**Phase 2 Studies**
**Electrophysiology study**
**CRAFT: Atrial fibrillation**
**Phase 3 Studies**
**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

|  | Placebo | Vernakalant |
| --- | --- | --- |
| Total exposed  | 341 | 823 |
| Volunteer studies | 6 | 50 |
| All patients | 335 | 773 |

**Source: Page 25**

## Clinical Efficacy and Safety

| Population | Study | Number of Patients |  |
| --- | --- | --- | --- |
|  |  | Placebo | Vernakalant  |
| Primary Efficacy Studies
ACT I and III (AF Only) | ACT I
ACT III | 115
121 | 221
118 |
| Total (ACT I and III)
Pooled Primary Studies* |  | 236 | 339 |
| Post Cardiac Surgery Study(AF Only) | ACT II  | 50 | 100 |
| All Phase 3 Studies |  | 315 | 737 |
| CRAFT (Phase 2) Study |  | 20 | 36 |
| All Patients | Safety Database** 
(AF and AFL) | 335 | 773 |

**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**

## CRAFT (Dose Ranging Study)Number of Subjects in Sinus Rhythm at 60 MinutesMedian Time to Conversion to Sinus Rhythm: 14 minutes

**CRAFT (Dose Ranging Study)***Number of Subjects in Sinus Rhythm at 60 Minutes**Median Time to Conversion to Sinus Rhythm: 14 minutes*

**1/19**

**1/18**

**2/18**

**6/18**

**9/17**

**P=0.0015**

**Vernakalant**

**Source: Figure 3, page 41**
**Roy D et al. JACC 2004.**
**CRAFT CSR - Listing 1.16.1**

## Phase 3 Study DesignPooled Primary (ACT I and III) Studies

**Screening**

**0**

**24 h**

**10**

**25**

**90 min**

**1****st**** Infusion: **
**Vernakalant ****(3 mg/kg)**
**or Placebo**

**2****nd**** Infusion ****(if subject in AF/AFL): **
**Vernakalant (2 mg/kg) ****or Placebo**

**35**

**Discharge**

**Primary Endpoint**
**Efficacy Period**

**7 d**

**Follow-up****Visit**

**Telephone ****Follow-up**

**Time**

**2 h**

**Continuous Heart Rhythm Monitoring**

**Continuous Holter Monitoring**

**Randomization**

**Electrical cardioversion and other treatments permitted**

**30 d**

**Source: Figure 2, page 26**
**AFL=atrial flutter**

## 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**
**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**

## 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) |
| Pacemaker | 11 (5%)  | 12 (4%) |
| Medical History |  |  |
| 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%) |

## Phase 3 EfficacyShort Duration AF (>3h - ≤7d)

**51% conversion in recent-onset atrial fibrillation patients (P<0.0001)**
**vs. 4% placebo conversion rate**
**11 minutes median time to conversion**

**Efficacy – ACT I**

**51% conversion in recent-onset atrial fibrillation patients (P<0.0001)**
**vs. 4% placebo conversion rate**
**8 minutes median time to conversion**

**Efficacy – ACT III**

- P <0.0001(Log-rank Test)

- P <0.0001 (Log-rank Test)

**Vernakalant (n=145)**

**Vernakalant (n=86)**

**Placebo (n=75)**

- Infusion 1

- Infusion 2

- Infusion 1

- Infusion 2

**Placebo (n=84)**

- Time (minutes)

- Proportion of Patients
- Converting to SR

## Vernakalant Conversion of AF to SRPooled Primary (ACT I and III) Studies

**Short-duration**
**(Primary endpoint)**

**Overall population**

**Long-duration**

**P<0.0001**

**P<0.0001**

**P=0.142**

**Source: From table 9, page 43**

## Observed and Modeled Probability of Conversion to SR in 90 Min. by AF DurationACT I and ACT IV Studies

**Observed and Modeled Probability of Conversion to SR in 90 Min. by AF Duration***ACT I and ACT IV Studies*

**>3h - ≤7d**

## Placebo-Subtracted Conversion to SR AF >3h - ≤7dPooled Primary (ACT I and III) Studies

**Vernakalant Better **

**Placebo Better**

**Source: Figure 8, page 53**

## Placebo-Subtracted Conversion to SR AF >3h - ≤7dPooled Primary (ACT I and III) Studies

**Ischemic Heart Disease**

**Congestive Heart Failure**

**Hypertension**

**Placebo-Subtracted Conversion to SR ***AF >3h - ≤7d**Pooled Primary (ACT I and III) Studies*

**Vernakalant Better **

**Placebo Better**

**Source: Figure 8, page 53**

## Patients without AF SymptomsPercent at Minute 90 (AF >3h - ≤7d)

**P=0.0005**

**P=0.0044**

## Conversion to SR Relieves AF Symptoms at Minute 90 (>3h - ≤7d)Pooled Primary (ACT I and III) Studies

**P<0.0001**

**Vernakalant Patients**

## Durability of Sinus RhythmPooled Primary (ACT I and III) Studies

|  | AF Duration >3h - ≤7d(All Responders) |  |
| --- | --- | --- |
| Time Point | Placebo(N=6) | Vernakalant(N=118) |
| 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**

## ACT II Demographics

|  | Placebo
(N=54) | Vernakalant
(N=107) |
| --- | --- | --- |
| Male  | 40 (74%) | 81 (76%) |
| Mean Age (SD)  | 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%) |

**Source: Table 13, page 49**

## ACT IIConversion of AF to SR

**47% conversion rate (P<0.0001)**
**vs. 14% placebo conversion rate**
**12 minutes median time to conversion**

**Source: Figure 6, page 50**

## Consistent Conversion RatesAll Patients

**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**

*****

******

******

******

## 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**

## Safety Presentation

**Adverse Events**
**Serious Adverse Events**
**Deaths**
**Events of Interest**
**Ventricular Arrhythmia****(including QT changes and TdP)**
**Bradycardia**
**Hypotension**

## 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**

## Baseline CharacteristicsAll Patients

|  | Placebo
(N=335) | Vernakalant
(N=773) |
| --- | --- | --- |
| Male | 228 (68.1%) | 526 (68.0%) |
| Mean Age (SD)  | 62.9 (12.0) | 63.2 (13.2) |
| Medical History |   |   |
| CHF | 60 (17.9%) | 115 (14.9%) |
| Ischemic heart disease | 95 (28.4%) | 187 (24.2%) |
| Hypertension | 163 (48.7%) | 402 (52.0%) |
| Background rhythm control medications | 66 (19.7%) | 151 (19.5%) |
| Background rate control medications | 263 (78.5%)  | 554 (73.7%) |

**Source: Table 4, page 28**

## Adverse Events* (First 24 Hours)All Patients

| Preferred Term | Placebo
(N=335) | Vernakalant
(N=773) | Median
Time to Onset (min) | Median
Duration
(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 |

**Source: Table 16, page 58**
*** AE occurring in ≥ 5% and at a higher incidence than placebo **

## 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%) |
| Sinus bradycardia/bradycardia | 2 (0.6%) | 7 (0.9%) |
| Ventricular fibrillation | 0 | 2 (0.3%) |
| Hypotension | 2 (0.6%) | 9 (1.2%) |

**Source: Table 17, page 59**
*** At least 2 subjects in vernakalant group; vernakalant greater than placebo**

## DeathsAll Patients

| Demographics | Primary Cause of Death | Interval from Dose to Occurrence  |
| --- | --- | --- |
| 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**

## 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**

## 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***

## Safety Presentation

**Adverse Events**
**Serious Adverse Events**
**Deaths**
**Events of Interest**
**Ventricular Arrhythmia****(including QT changes and TdP)**
**Bradycardia**
**Hypotension**

## 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 (%) |
| Ventricular tachycardia | 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 |
| 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**

## 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**

## Torsade de PointesAll Patients

|  | Interval from Dose to Occurrence  |
| --- | --- |
| Vernakalant |  |
| 51-year-old male (AFL) | 2 hours 20 minutes after vernakalant and immediately following ibutilide |
| 90-year-old female | 32 hours |
| 69-year-old male  | Day 17 and 18(post valvuloplasty) |
| Placebo |  |
| 53-year-old male  | Day 2, 1 hour after electrical cardioversion while receiving sotalol  |

**Source: Page 63**

## 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.**

## 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)**

## QT Fridericia Correction (msec)All Phase 3 Studies

**QT Fridericia Correction (msec)***All Phase 3 Studies*

**Source: Figure 16, page 93**
**Bars around the means represent the 95% confidence intervals**

## 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**

## QTcF Change from Baseline by GenotypeVernakalant Treated Patients – ACT I, SCENE 2, ACT IV

**Bars around the means represent the 95% confidence intervals**

- Follow-up

****

## BradycardiaAll Phase 3 Studies

| Data Source | 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 (%) |
| 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**

## Heart Rate by Responder Status Over TimeAll Phase III Studies

**Excluding Patients with Pacemaker **

## 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**

## HypotensionAll Phase 3 Studies

**Hypotension***All Phase 3 Studies*

| Data Source | 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 (%) |
| 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**

## 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**

## Clinical Efficacy & Safety and Risk Management

**Therese M. Kitt, M.D.**
*Senior Medical Director, Medical Sciences**Astellas Pharma US, Inc.*

## Clinical Trials with Vernakalant Injection

**Phase 1 Studies**
**Single dose infusion**
**Mass balance**
**Phase 2 Studies**
**Electrophysiology study**
**CRAFT: Atrial fibrillation**
**Phase 3 Studies**
**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

|  | Placebo | Vernakalant |
| --- | --- | --- |
| Total exposed  | 341 | 823 |
| Volunteer studies | 6 | 50 |
| All patients | 335 | 773 |

**Source: Page 25**

## Clinical Efficacy and Safety

| Population | Study | Number of Patients |  |
| --- | --- | --- | --- |
|  |  | Placebo | Vernakalant  |
| Primary Efficacy Studies
ACT I and III (AF Only) | ACT I
ACT III | 115
121 | 221
118 |
| Total (ACT I and III)
Pooled Primary Studies* |  | 236 | 339 |
| Post Cardiac Surgery Study(AF Only) | ACT II  | 50 | 100 |
| All Phase 3 Studies |  | 315 | 737 |
| CRAFT (Phase 2) Study |  | 20 | 36 |
| All Patients | Safety Database** 
(AF and AFL) | 335 | 773 |

**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**

## CRAFT (Dose Ranging Study)Number of Subjects in Sinus Rhythm at 60 MinutesMedian Time to Conversion to Sinus Rhythm: 14 minutes

**CRAFT (Dose Ranging Study)***Number of Subjects in Sinus Rhythm at 60 Minutes**Median Time to Conversion to Sinus Rhythm: 14 minutes*

**1/19**

**1/18**

**2/18**

**6/18**

**9/17**

**P=0.0015**

**Vernakalant**

**Source: Figure 3, page 41**
**Roy D et al. JACC 2004.**
**CRAFT CSR - Listing 1.16.1**

## Phase 3 Study DesignPooled Primary (ACT I and III) Studies

**Screening**

**0**

**24 h**

**10**

**25**

**90 min**

**1****st**** Infusion: **
**Vernakalant ****(3 mg/kg)**
**or Placebo**

**2****nd**** Infusion ****(if subject in AF/AFL): **
**Vernakalant (2 mg/kg) ****or Placebo**

**35**

**Discharge**

**Primary Endpoint**
**Efficacy Period**

**7 d**

**Follow-up****Visit**

**Telephone ****Follow-up**

**Time**

**2 h**

**Continuous Heart Rhythm Monitoring**

**Continuous Holter Monitoring**

**Randomization**

**Electrical cardioversion and other treatments permitted**

**30 d**

**Source: Figure 2, page 26**
**AFL=atrial flutter**

## 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**
**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**

## 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) |
| Pacemaker | 11 (5%)  | 12 (4%) |
| Medical History |  |  |
| 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%) |

## Phase 3 EfficacyShort Duration AF (>3h - ≤7d)

**51% conversion in recent-onset atrial fibrillation patients (P<0.0001)**
**vs. 4% placebo conversion rate**
**11 minutes median time to conversion**

**Efficacy – ACT I**

**51% conversion in recent-onset atrial fibrillation patients (P<0.0001)**
**vs. 4% placebo conversion rate**
**8 minutes median time to conversion**

**Efficacy – ACT III**

- P <0.0001(Log-rank Test)

- P <0.0001 (Log-rank Test)

**Vernakalant (n=145)**

**Vernakalant (n=86)**

**Placebo (n=75)**

- Infusion 1

- Infusion 2

- Infusion 1

- Infusion 2

**Placebo (n=84)**

- Time (minutes)

- Proportion of Patients
- Converting to SR

## Vernakalant Conversion of AF to SRPooled Primary (ACT I and III) Studies

**Short-duration**
**(Primary endpoint)**

**Overall population**

**Long-duration**

**P<0.0001**

**P<0.0001**

**P=0.142**

**Source: From table 9, page 43**

## Observed and Modeled Probability of Conversion to SR in 90 Min. by AF DurationACT I and ACT IV Studies

**Observed and Modeled Probability of Conversion to SR in 90 Min. by AF Duration***ACT I and ACT IV Studies*

**>3h - ≤7d**

## Placebo-Subtracted Conversion to SR AF >3h - ≤7dPooled Primary (ACT I and III) Studies

**Vernakalant Better **

**Placebo Better**

**Source: Figure 8, page 53**

## Placebo-Subtracted Conversion to SR AF >3h - ≤7dPooled Primary (ACT I and III) Studies

**Ischemic Heart Disease**

**Congestive Heart Failure**

**Hypertension**

**Placebo-Subtracted Conversion to SR ***AF >3h - ≤7d**Pooled Primary (ACT I and III) Studies*

**Vernakalant Better **

**Placebo Better**

**Source: Figure 8, page 53**

## Patients without AF SymptomsPercent at Minute 90 (AF >3h - ≤7d)

**P=0.0005**

**P=0.0044**

## Conversion to SR Relieves AF Symptoms at Minute 90 (>3h - ≤7d)Pooled Primary (ACT I and III) Studies

**P<0.0001**

**Vernakalant Patients**

## Durability of Sinus RhythmPooled Primary (ACT I and III) Studies

|  | AF Duration >3h - ≤7d(All Responders) |  |
| --- | --- | --- |
| Time Point | Placebo(N=6) | Vernakalant(N=118) |
| 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**

## ACT II Demographics

|  | Placebo
(N=54) | Vernakalant
(N=107) |
| --- | --- | --- |
| Male  | 40 (74%) | 81 (76%) |
| Mean Age (SD)  | 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%) |

**Source: Table 13, page 49**

## ACT IIConversion of AF to SR

**47% conversion rate (P<0.0001)**
**vs. 14% placebo conversion rate**
**12 minutes median time to conversion**

**Source: Figure 6, page 50**

## Consistent Conversion RatesAll Patients

**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**

*****

******

******

******

## 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**

## Safety Presentation

**Adverse Events**
**Serious Adverse Events**
**Deaths**
**Events of Interest**
**Ventricular Arrhythmia****(including QT changes and TdP)**
**Bradycardia**
**Hypotension**

## 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**

## Baseline CharacteristicsAll Patients

|  | Placebo
(N=335) | Vernakalant
(N=773) |
| --- | --- | --- |
| Male | 228 (68.1%) | 526 (68.0%) |
| Mean Age (SD)  | 62.9 (12.0) | 63.2 (13.2) |
| Medical History |   |   |
| CHF | 60 (17.9%) | 115 (14.9%) |
| Ischemic heart disease | 95 (28.4%) | 187 (24.2%) |
| Hypertension | 163 (48.7%) | 402 (52.0%) |
| Background rhythm control medications | 66 (19.7%) | 151 (19.5%) |
| Background rate control medications | 263 (78.5%)  | 554 (73.7%) |

**Source: Table 4, page 28**

## Adverse Events* (First 24 Hours)All Patients

| Preferred Term | Placebo
(N=335) | Vernakalant
(N=773) | Median
Time to Onset (min) | Median
Duration
(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 |

**Source: Table 16, page 58**
*** AE occurring in ≥ 5% and at a higher incidence than placebo **

## 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%) |
| Sinus bradycardia/bradycardia | 2 (0.6%) | 7 (0.9%) |
| Ventricular fibrillation | 0 | 2 (0.3%) |
| Hypotension | 2 (0.6%) | 9 (1.2%) |

**Source: Table 17, page 59**
*** At least 2 subjects in vernakalant group; vernakalant greater than placebo**

## DeathsAll Patients

| Demographics | Primary Cause of Death | Interval from Dose to Occurrence  |
| --- | --- | --- |
| 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**

## 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**

## 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***

## Safety Presentation

**Adverse Events**
**Serious Adverse Events**
**Deaths**
**Events of Interest**
**Ventricular Arrhythmia****(including QT changes and TdP)**
**Bradycardia**
**Hypotension**

## 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 (%) |
| Ventricular tachycardia | 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 |
| 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**

## 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**

## Torsade de PointesAll Patients

|  | Interval from Dose to Occurrence  |
| --- | --- |
| Vernakalant |  |
| 51-year-old male (AFL) | 2 hours 20 minutes after vernakalant and immediately following ibutilide |
| 90-year-old female | 32 hours |
| 69-year-old male  | Day 17 and 18(post valvuloplasty) |
| Placebo |  |
| 53-year-old male  | Day 2, 1 hour after electrical cardioversion while receiving sotalol  |

**Source: Page 63**

## 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.**

## 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)**

## QT Fridericia Correction (msec)All Phase 3 Studies

**QT Fridericia Correction (msec)***All Phase 3 Studies*

**Source: Figure 16, page 93**
**Bars around the means represent the 95% confidence intervals**

## 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**

## QTcF Change from Baseline by GenotypeVernakalant Treated Patients – ACT I, SCENE 2, ACT IV

**Bars around the means represent the 95% confidence intervals**

- Follow-up

****

## BradycardiaAll Phase 3 Studies

| Data Source | 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 (%) |
| 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**

## Heart Rate by Responder Status Over TimeAll Phase III Studies

**Excluding Patients with Pacemaker **

## 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**

## HypotensionAll Phase 3 Studies

**Hypotension***All Phase 3 Studies*

| Data Source | 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 (%) |
| 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**

## 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**

## 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.***

## 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 |
| Median Joules | 200 | 200 |

**Source: Page 95**

## 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**

## Risk Management and Post-marketing Studies

**Prescribing Information**
**Healthcare Provider Education**
**Pharmacovigilance and Reporting**
**Post-marketing Studies**

## 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**

## 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**

## Vernakalant Education

**Comprehensive for target specific audiences**
**Cardiologists**
**Critical care/ER physicians**
**Allied healthcare personnel **
**Prescribing information is the foundation**

## 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**

## 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**

## 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**