# Presentation: 661715

## Tedisamil Efficacy-Safety Matthias Straub, MD 

**Vice President, Global Clinical Development**
** ****Solvay Pharmaceuticals**

## Agenda: Efficacy 

- Clinical Pharmacology
- Dosage regimen
- Clinical Development Program
- Individual Study Results
- Integrated Analyses
- Efficacy Conclusions

## Clinical Pharmacology

- Class III anti-arrhythmic drug
- Tedisamil has a mild heart rate lowering effect
- Tedisamil is hemodynamically neutral with respect to atrial and ventricular function
- Linear pharmacokinetics
- not affected by gender, age and congestive heart failure
- The elimination half-life is 4.5 - 6.9 hrs

## Clinical Pharmacology

- Tedisamil is almost exclusively eliminated as unchanged drug via the renal route
- Cmax is not affected in mild to moderate renal impairment
- No dose adjustment needed in mild to moderate renal impairment
- Metabolism of tedisamil is very limited; no *in vitro* evidence of P450-mediated metabolism
- Tedisamil is not a substrate for CYP2D6, but is a potent inhibitor of CYP2D6
- No effect of P450 inhibitors on PK of tedisamil
- No effect of P450 genotypes (e.g. CYP2D6 poor metabolizer status) on PK of tedisamil

## Summary of Phase II Studies 

| Study | Tedisamil dose (mg/kg) |  |  |  |  | Placebo |  | Infusion
time (min) |  | Total # 
subjects   |  | Subject type |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | 0.16 | 0.24 | 0.32 | 0.48 | 0.64 |  |  | 10 | 30 |  |  |  |
| 2.102 |  |  |  |  |  |  |  |   |  | 26 	 | 20 M  6 F 
 | Sustained
 (3-90 d) AFib/AFl |
|  |  |  |  |  |  |  |  |  |  |  |  |  |

- Briefing Book table 4-1

## Two-Step Infusion RegimenPK/PD Time Profile 

- For the next studies, the infusion time was adapted to a two-step infusion process
- Half the dose in 10 min, half the dose in the remaining 20 min
- First 10 min need to be maximally controlled with low variability to reach Cmax (excluding a short term bolus infusion as an option)
- Regimen was modeled using computer simulation techniques
- Broaden the AUC of the plasma concentration profile to allow cardioversions (QT stable over at least 30 min)
- Not increase Cmax beyond predicted PC to allow for safe administration (QT not exceeding 550ms in majority of patients)
- In summary, our intent was to build a dosing scheme that achieves plasma levels rapidly so cardioversion can result, but also one that doesn’t cause uncontrolled Cmax, causing TdP’s

## Two-Step Infusion RegimenPK/PD Time Profile – Healthy Volunteers

- Two step
- infusion

- Briefing Book figure 3-1

## Summary of Phase II Studies 

| Study | Tedisamil dose (mg/kg) |  |  |  |  | Placebo |  | Infusion
time (min) |  | Total # 
subjects   |  | Subject type |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | 0.16 | 0.24 | 0.32 | 0.48 | 0.64 |  |  | 10 | 30 |  |  |  |
| 2.102 |  |  |  |  |  |  |  |   |  | 26 	 | 20 M  6 F 
 | Sustained
 (3 - 90 days) AFib/AFl |
|  |  |  |  |  |  |  |  |  |  |  |  |  |
| 2.107  |  |  |  |  |  |  |  |  | 

 | 180 	 | 109 M 71 F | Recent onset AFib/AFl
(≤ 48 hrs) |
| 
 |  |  |  |  |  |  |  |  |  |  |  |  |

- Briefing Book table 4-1

## Primary Efficacy Parameter Proof of Principle Study S219.2.107

| Dose, mg/kg | 3 - 48 hrs |  |
| --- | --- | --- |
|  | N | Conversion, n (%) |
| Tedisamil 0.32 | 52 | 24 (46.2)* |
| Tedisamil 0.48 | 42 | 24 (57.1)* |
| Placebo | 46 | 4 (8.7)  |
| *P < 0.001 |  |  |

- Data from BD pg 12 (1111078)

- Data Briefing Book page 32

## Secondary Efficacy ParameterProof of Principle Study S219.2.107

|  |  | Treatment |  |  |
| --- | --- | --- | --- | --- |
| Type of energy | Statistic | Tedisamil | Placebo | Overall |
| Monophasic energy (J) | n | 19 | 13 | 32 |
|  | Mean ± SD | 168.1 ± 88.1 | 250.4 ± 103.9 | 201.5 ± 101.8 |
|  | Median | 200.0 | 300.0 | 200.0 |
|  | Min–Max | 50.0 – 360.0 | 100.0 – 360.0 | 50.0 – 360.0 |
|  | 2-sided Wilcoxon p-value | 0.032 |  |  |
|  |  |  |  |  |
| Biphasic energy (J) | n | 4 | 5 | 9 |
|  | Mean ± SD | 100.0 ± 57.7 | 140.0 ± 82.2 | 122.2 ± 71.2 |
|  | Median | 100.0 | 200.0 | 150.0 |
|  | Min–Max | 50.0 – 150.0 | 50.0 – 200.0 | 50.0 – 200.0 |
|  | 2-sided Wilcoxon p-value | 0.476 |  |  |
|  |  |  |  |  |

## Phase III Timeline

- Initiated Nov 2002
- Suspended Mar 2003
- Review of arrhythmic events in female subjects
- Finding: associated with doses ≥ 0.48 mg/kg
- Consulted with FDA and MHRA
- Program revision to pursue dose-finding by gender
- Restarted program
- Three male- and two female-specific studies

## Phase III Efficacy StudiesMales

| Study | Tedisamil dose  (mg/kg) |  |  |  |  |  |  | Infusion
time (min) | Total # subjects   |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | 0.16 | 0.24 | 0.32 | 0.48 | 0.64 | Placebo |  | 30 |  |  |
| 3.112 |  |  |  |  |  |  |  |  | 	272 | 236 M*  |
|  |  |  |  |  |  |  |  |  |  |  |
| 3.114
 |  |  |  |  |  |  |  |  | 	228 | 228 M |
|  |  |  |  |  |  |  |  |  |  |  |
| 3.117 |  |  |  |  |  |  |  |  | 	117 | 117 M  |
| recent onset AFib/AFl subjects (3 hrs - 45 days)
* 36 F were included pre-amendment |  |  |  |  |  |  |  |  |  |  |

- Briefing Book table 4-1

## Phase III Efficacy Studies Females

| Study | Tedisamil dose (mg/kg) |  |  |  |  |  |  | Infusion time (min) | Total # subjects   |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | 0.16 | 0.24 | 0.32 | 0.48 | 0.64 | Placebo |  | 30 |  |  |
| 3.116 |  |  |  |  |  |  |  |  | 	356 | 356 F |
|  |  |  |  |  |  |  |  |  |  |  |
| 3.118 |  |  |  |  |  |  |  |  | 	152 | 152 F |
| recent onset AFib/AFl subjects (3h - 45 days) |  |  |  |  |  |  |  |  |  |  |

- Briefing Book table 4-1

## Study Design for Efficacy Studies

**Placebo**

**IV Tedisamil**

**Up to 48 hrs**

**24 hr observation**

**4 wks**

- Follow-up Period

**SCREENING**

- Screening

- Double-blind Treatment Period

**RANDOMIZATION**

- Screening

- End-of-24-hr
- observation
- period

- Follow-up

- Randomization

**30 min infusion**

## Phase III 	Study Design 

- Hospitalized and monitored for 24 hrs by Holter
- Central analysis
- Efficacy
- First conversion to NSR
- If converted, assess maintenance over 24 hr monitoring period
- Safety
- Analyzed and coded ventricular tachycardia
- Adjudicated by AOC (Adjudication and Oversight Committee)

## Study Inclusion Criteria 

- _Symptomatic_ AFib/AFl
- Documented by 60 sec rhythm strip
- Duration > 3 hrs to 45 days at the time of randomization
- Hemodynamic stability
- SBP > 90 mmHg
- DBP < 105 mmHg
- At least 18 years of age

## Key Exclusion Criteria

- Congestive heart failure of NYHA class IV
- History of life-threatening ventricular arrhythmias including TdP
- Myocardial infarction within 30 days before randomization
- Severe renal impairment
- Congenital long QT syndrome
- QTc interval > 470 msec before randomization
- Concurrent treatment with antiarrhythmic drugs (except for digitalis, diltiazem or β-blockers)
- Sick sinus syndrome
- Need for internal or external pacemaker

## Baseline CharacteristicsAge, Race

|  | Subjects, % |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Males |  |  | Females |  |
|  | Tedisamil | Placebo |  | Tedisamil | Placebo |
|  | N = 528 | N = 231 |  | N = 403 | N = 239 |
| Age:	< 65 yrs | 60.4 | 62.3 |  | 29.0 | 32.2 |
|           	≥ 65 yrs | 39.6 | 37.7 |  | 71.0 | 67.8 |
| Race:	White | 98.1 | 97.8 |  | 97.5 | 98.7 |

- Note: safety data set

- Briefing Book table 5-2/3; appendix 2

## Baseline CharacteristicsNYHA, Creatinine and Duration of AFib/AFl

|  | Subjects, % |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Males |  |  | Females |  |
|  | Tedisamil | Placebo |  | Tedisamil | Placebo |
|  | N = 528 | N=231 |  | N=403 | N=239 |
| NYHA Classification |  |  |  |  |  |
| 	Class I | 58.7 | 59.3 |  | 38.0 | 39.7 |
| 	Class II | 31.4 | 32.0 |  | 46.2 | 41.4 |
| 	Class III | 4.4 | 3.9 |  | 7.2 | 9.2 |
| Baseline creatinine clearance |  |  |  |  |  |
| 	< 30 mL/min |  0.2 | 0 |  | 0.7 | 2.1 |
| 	≥ 30 - < 60 mL/min | 8.1 | 11.3 |  | 28.3 | 24.7 |
| 	≥ 60 - < 90 mL/min | 35.0 | 32.0 |  | 43.2 | 38.9 |
| 	≥ 90 mL/min | 53.0 | 50.6 |  | 24.6 | 31.4 |
| Baseline duration of AFib/AFl |  |  |  |  |  |
| 	3 - 48 hrs | 55.1 | 56.3 |  | 40.9 | 38.1 |
| 	> 48 hrs - 45 days | 43.4 | 42.0 |  | 58.3  | 60.7 |
| Note: safety data set |  |  |  |  |  |

- Briefing Book table 5-2/3; appendix 2

## Primary Efficacy Parameter

- 	*The percentage of subjects who converted to NSR (for at least 60 seconds) at any time within 2.5 hours after the initiation of the infusion of study drug*

## Primary Efficacy Sample

- Defined a priori in individual studies
- Modified AFib ITT sample
- Defined as all randomized, but excluding subjects
- not receiving study drug treatment, or
- converted before their start of infusion, or
- with no post-baseline efficacy data
- Further exclusions from primary analysis
- DC cardioversions within 2.5 hrs from start infusion

## Secondary Efficacy Parameters

- Percentage of subjects converting to NSR within 2.5 hrs and
- in NSR at 2.5 hrs after start of infusion
- in NSR at 24 hrs
- remaining in NSR for 24 hrs
- in NSR at hospital discharge
- Time to first conversion (time from start of infusion until conversion to NSR)

## Individual Study Efficacy Results Phase III Studies

** **

## Phase III Primary Efficacy – AFib MalesConversion Rates

|  | Subjects, % |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Study | Tedisamil dose (mg/kg) |  |  |  |  |  |  |
|  | 0.16 | 0.24 | 0.32 | 0.48 | 0.64 |  | Placebo |
| 3.112 |  |  | 23.2 | 52.9 | 67.4 |  | 5.7 |
| p-value* |  |  | 0.0096 | < 0.0001 | < 0.0001 |  |  |
| 3.114 | 24.0 |  | 29.4 | 31.1 |  |  | 9.8 |
| p-value* | 0.057 |  | 0.027 | 0.027 |  |  |  |
| 3.117 |  |  |  | 29.2 |  |  | 6.3 |
| p-value |  |  |  | 0.0033 |  |  |  |
| *p-values adjusted for multiple comparisons |  |  |  |  |  |  |  |

**Phase III Primary Efficacy – AFib Males****Conversion Rates**

- BD T1-1, 5-4.

- Briefing Book table 5-4

## Phase III Primary Efficacy – AFib FemalesConversion Rates

|   | Subjects, % |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Study | Tedisamil dose (mg/kg) |  |  |  |  |  |
|  | 0.16 | 0.24 | 0.32 | 0.48 | 0.64 | Placebo |
| 3.116 |  | 9.4 | 21.5 |  |  | 2.9 |
| p-value* |  | 0.047 | < 0.0001 |  |  |  |
| 3.118 |  |  | 17.9 |  |  | 4.5 |
| p-value |  |  | 0.014 |  |  |  |
| *p-values adjusted for multiple comparisons |  |  |  |  |  |  |

**Phase III Primary Efficacy – AFib Females****Conversion Rates**

- BD T1-1.

- Briefing Book table 5-5

## Phase III Studies: Males Atrial Fibrillation

**Phase III Studies: Males Atrial Fibrillation**

- Dose

- Placebo-corrected estimates and CIs (adjusted)

***Difference vs Placebo in percentage of conversion to NSR within 2.5 hrs: 3 hrs ≤ 45 days***

- BD F5-2

- Briefing Book figure 5-2

## Phase III Studies: Females Atrial Fibrillation

- Dose

- Placebo-corrected estimates and CIs (adjusted)

***Difference vs Placebo in percentage of conversion to NSR within 2.5 hrs: 3 hrs ≤ 45 days***

- BD F5-3

- Briefing Book figure 5-3

## Sensitivity Analysis 

- All randomized AFib subjects are included in the analysis
- Subjects who converted to NSR within 2.5 hrs are counted as successes regardless of whether they also received electrical cardioversion or not
- Subjects who converted to NSR before the initiation of the study drug infusion are counted as successes

## Sensitivity Analysis: Conversion Within 2.5 hrs

- S219.3.112 AFib Males

| Sensitivity analysis |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | N | n | % |  | placebo-corrected |  | 
p-value |
| 0.32 | 57 | 14 | 24.6 |  | 17.2 |  | 0.0143 |
| 0.48 | 53 | 28 | 52.8 |  | 45.4 |  | <0.0001 |
| 0.64 | 49 | 32 | 65.3 |  | 57.9 |  | <0.0001 |
| placebo | 54 | 4 | 7.4 |  |  |  |  |

| Dossier

placebo-corrected | p-value |
| --- | --- |
| 17.6 | 0.0096 |
| 47.3 | <0.0001 |
| 61.8 | <0.0001 |

- N = samplen = number of converters

## Conclusion of Individual Studies

- In total 5 phase III studies
- 3 studies with male subjects
- 2 studies with female subjects
- Tedisamil demonstrated efficacy over placebo
- In males
- 0.32 mg/kg in 2 studies
- 0.48 mg/kg in 3 studies
- 0.64 mg/kg in 1 study
- In females
- 0.32 mg/kg in 2 studies
- Exclusion of subjects from analysis had no impact on efficacy findings

## Primary Efficacy by Subgroup: Males

**Primary Efficacy by Subgroup: Males**

***Difference vs Placebo in percentage of conversion to NSR within 2.5 hrs***

- BD F5-4

- 0.48 mg/kg

- Subgroup

- Briefing Book figure 5-4

- Placebo-corrected estimates and 95% CIs (adjusted)

## Primary Efficacy by Subgroup: Females

***Difference vs Placebo in percentage if conversion to NSR within 2.5 hrs***

- BD F5-5

- 0.32 mg/kg

- Subgroup

- Briefing Book figure 5-5

- Placebo-corrected estimates and 95% CIs (adjusted)

## Primary Efficacy-by Duration of Episode 3 hrs - 7 days; 8 - 45 days 

***Difference vs placebo in percentage of conversion to NSR within 2.5 hrs***

**Males**
**0.48 mg/kg**

**Females**
**0.32 mg/kg**

- Placebo-corrected estimates and 95% CIs

**AFib/AFl**

**AFib/AFl**

## Primary Efficacy – Proportion Converting to NSR within 2.5 hrs by Duration of Episode 3 hrs – 7 days; 8 - 45 days 

|  | Duration of Episode AFib+AFl |  |
| --- | --- | --- |
|  | 3 hrs - 7 days
n (%) | 8 - 45 days
n (%)  |
| Males |  |  |
| Tedisamil 0.48 mg/kg  | 51/110 (46.4%) 
p= <0.0001 | 8/61 (13.1%)
p=0.0033  |
| Placebo | 11/122 (9.0%)  | 0/55 (0%) |
|  |  |  |
| Females |  |  |
| Tedisamil 0.32 mg/kg  | 30/114 (26.3%) 
p=<0.0001 | 7/88 (8.0%)
 p=0.19 |
| Placebo | 6/109 (5.5%)  | 3/92 (3.3%) |

## Secondary Efficacy Parameters

- Percentage of subjects converting to NSR within 2.5 hrs and
- in NSR at 2.5 hrs after start of infusion
- in NSR at 24 hrs
- remaining in NSR for 24 hrs
- in NSR at hospital discharge
- Time to first conversion (time from start of infusion until conversion to NSR)

## Secondary Efficacy Parameters – Males

|  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | 

N* | Subjects, n (%) |  |  |  |
|  |  | In NSR at 2.5 hrs  | In NSR at 24 hrs  | Remaining in NSR for 24 hrs | In NSR at hospital discharge  |
| Tedisamil
0.48 mg/kg | 59 | 57 (96.6)  | 56 (94.9)  | 53 (89.8)  | 47 (79.7)  |
| Placebo | 11 | 10 (90.9)  | 10 (90.9) | 10 (90.9) | 9 (81.8) |

- BD T1-3.

- * Subjects that converted within 2.5 hours

- Briefing Book table 5-9

## Secondary Efficacy Parameters – Females

|  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | 

N* | Subjects, n (%) |  |  |  |
|  |  | In NSR at 2.5 hrs | In NSR at 24 hrs | Remaining in NSR for 24 hrs | In NSR at Hospital Discharge |
| Tedisamil0.32 mg/kg | 37 | 36 (97.3) | 35 (94.6)  | 32 (86.5)  | 30 (81.1)  |
| Placebo | 9 | 9 (100)  | 8 (88.9)  | 8 (88.9) | 7 (77.8) |

- BD T1-3.

- * Subjects that converted within 2.5 hrs

- Briefing Book table 5-9

## Secondary Efficacy – Median Time to Conversion

|  | Tedisamil dose | Placebo |
| --- | --- | --- |
| Males | 0.48 mg/kg |  |
|  |  |  |
|    Median time to NSR (min) | 21.0 | 60.0 |
| Females | 0.32 mg/kg |  |
|    Median time to NSR (min) | 20.0 | 94.0 |

- Briefing Book table 5-10

## Overall Efficacy Conclusions 

- Tedisamil is effective at restoring NSR in subjects with AFib/AFl of a duration of 3 hrs to 45 days
- Tedisamil effect was *rapid* and *sustained*
- Tedisamil effect was robust across subgroups of interest
- Tedisamil effect was robust across other methods of handling exclusions from ITT

## Tedisamil Safety  

** **

## Safety Agenda

- Exposure
- Adverse Events
- Total
- Cardiac
- Deaths
- Adjudicated Events
- Monitoring Window
- Dose Selection

## Total Exposure to IV Tedisamil

|  | Subject Type  | Dose 
Range  | Duration  | No of Subjects  |
| --- | --- | --- | --- | --- |
| Tedisamil IV Studies Phase I  | Healthy Volunteers/ Symptomatic Non-CAD subjects | 1-30 
mg/day  | Single 
Dose  | 123  |
| Tedisamil IV Studies AFib/AFl  | AFib/AFl subjects  | 0.16-0.72 
mg/kg  | Single 
Dose  | 931  |
| Tedisamil IV Studies Angina  | CAD subjects with stable Angina  | 0.08-0.32
 mg/kg  | Single 
Dose  | 70  |
| Tedisamil IV Studies Other Cardiac Disorders  | Subjects with IHD and CHF  | 0.3-0.5 
mg/kg  | Single 
Dose  | 13  |
|  |  |  |  | 1137  |

- Briefing Book table 6-1

## Subject Disposition IV Tedisamil AFib/AFl Clinical Program 

- Consented
- 1619

- Randomized
- 1469

- Tedisamil
- 974

- Treated
- 470

- Screen Failures
- 150

- Placebo
- 495

- Not treated
- 25

- Treated
- 931

- Not treated
- 43

## Integrated Safety Database by Subgroups

|  | Subjects, % |  |  |  |
| --- | --- | --- | --- | --- |
|  | Males |  | Females |  |
|  | Tedisamil
N = 528 | Placebo
N = 231 | Tedisamil
N = 403 | Placebo
N = 239 |
| Age < 65 | 60.4 | 62.3 | 29.0 | 32.2 |
| Age ≥ 65 | 39.6 | 37.7 | 71.0 | 67.8 |
| β-blockers = Yes | 68.2 | 68.4 | 76.9 | 78.2 |
| β-blockers = No | 31.8 | 31.6 | 23.1 | 21.8 |
| NYHA I | 58.7 | 59.3 | 38.0 | 39.7 |
| NYHA II/III | 35.8 | 35.9 | 53.3 | 50.6 |
| CrCl < 60 ml/min | 8.3 | 11.3 | 29.0 | 26.8 |
| CrCl ≥ 60 ml/min | 88.1 | 82.7 | 67.7 | 70.3 |

- Briefing Book table 6-3

## Overview of AEs by Dose Over 4 WeeksMales and Females

| Males | Subjects, n (%) |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | Tedisamil dose, mg/kg |  |  |  |  |  |
|  | 0.16N = 66 | 0.24N = 6 | 0.32N = 172 | 0.48N = 207 | 0.64N = 52 | PlaceboN = 231 |
| Death | 0 | 0 | 1 (0.6) | 0 | 0 | 2 (0.9) |
| SAE | 5 (7.6) | 1 (16.7) | 16 (9.3) | 21 (10.1) | 4 (7.7) | 21 (9.1) |
| TESAE | 5 (7.6) | 1 (16.7) | 15 (8.7) | 19 (9.2) | 4 (7.7) | 20 (8.7) |
| Discont. due to TEAE | 1 (1.5) | 0 | 2 (1.2) | 4 (1.9) | 3 (5.8) | 2 (0.9) |
| TEAE | 32 (48.5) | 4 (66.7) | 122 (70.9) | 140 (67.6) | 40 (76.9) | 143 (61.9) |
| Severe TEAE | 4 (6.1) | 1 (16.7) | 10 (5.8) | 12 (5.8) | 3 (5.8) | 11 (4.8) |
|  |  |  |  |  |  |  |
| Females | N = 1 | N = 122 | N = 225 | N = 34 | N = 10 | N = 239 |
| Death | 0 | 2 (1.6) | 2 (0.9) | 0 | 0 | 1 (0.4) |
| SAE | 0 | 14 (11.5) | 21 (9.3) | 5 (14.7) | 3 (30.0) | 23 (9.6) |
| TESAE | 0 | 14 (11.5) | 20 (8.9) | 5 (14.7) | 2 (20.0) | 22 (9.2) |
| Discont. due to TEAE | 0 | 2 (1.6) | 5 (2.2) | 1 (2.9) | 1 (10.0) | 3 (1.3) |
| TEAE | 0 | 76 (62.3) | 146 (64.9) | 28 (82.4) | 9 (90.0) | 150 (62.8) |
| Severe TEAE | 0 | 5 (4.1) | 10 (4.4) | 7 (20.6) | 2 (20.0) | 15 (6.3) |

- Briefing Book table 6-4, 6-5

## TEAEs of Special Interest Non-Cardiac Disorders - Males (1)

- Briefing Book table 6-6

|  | Subjects, n (%) |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Tedisamil (mg/kg) |  |  |  |  |
| System Organ Class
	Preferred Term | 0.16
N = 66 | 0.32
N = 172 | 0.48
N = 207 | 0.64
N = 52 | Placebo 
N = 231 |
| Gastrointestinal disorders |  |  |  |  |  |
|    Hypoesthesia oral | 0 | 0 | 2 ( 1.0)  | 1 ( 1.9) | 0 |
|    Diarrhea | 0  | 4 ( 2.3)  | 1 ( 0.5)  | 0 | 3 ( 1.3) |
| Nervous system disorders |  |  |  |  |  |
|    Dizziness | 0 | 5 ( 2.9) | 3 ( 1.4) | 2 ( 3.8) | 7 ( 3.0) |
|    Headache | 0 | 3 ( 1.7) | 6 ( 2.9)  | 3 ( 5.8) | 5 ( 2.2) |
|    Paresthesia circumoral | 0 | 0 | 2 ( 1.0) | 0 | 0 |
|    Paresthesia oral | 0 | 0 | 4 ( 1.9) | 2 ( 3.8) | 1 ( 0.4) |
| Vascular disorders |  |  |  |  |  |
|    Hypotension | 2 ( 3.0) | 4 ( 2.3) | 3 ( 1.4)  | 2 ( 3.8)  | 2 ( 0.9)  |

## TEAEs of Special Interest Non-Cardiac Disorders - Males (2)

- Briefing Book table 6-6

|  | Subjects, n (%) |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Tedisamil (mg/kg) |  |  |  |  |
| System Organ Class
	Preferred Term | 0.16
N = 66 | 0.32
N = 172 | 0.48
N = 207 | 0.64
N = 52 | Placebo 
N = 231 |
| Gen. disorders & admin. site conditions |  |  |  |  |  |
|    Infusion site burning | 2 ( 3.0)  | 3 ( 1.7)  | 5 ( 2.4)  | 3 ( 5.8) | 1 ( 0.4) |
|    Infusion site pain | 0 | 0 | 1 ( 0.5)  | 0 | 1 ( 0.4) |
|    Infusion site phlebitis | 0 | 0 | 0 | 1 ( 1.9) | 1 ( 0.4) |
|    Infusion site pruritis | 0 | 0 | 1 ( 0.5) | 0 | 0 |
|    Infusion site reaction | 0 | 1 ( 0.6) | 2 ( 1.0) | 0 | 0 |
|    Injection site burning | 0 | 1 ( 0.6) | 3 ( 1.4) | 0 | 0 |
|    Injection site inflammation | 0 | 0 | 1 ( 0.5) | 0 | 0 |
|    Injection site pain | 2 ( 3.0) | 4 ( 2.3) | 5 ( 2.4) | 2 ( 3.8) | 0 |
|    Injection site reaction | 1 ( 1.5) | 0 | 0 | 0 | 0 |
|    Venipuncture site pain | 0 | 1 ( 0.6) | 0 | 0 | 0 |

## TEAEs of Special Interest Non-Cardiac Disorders - Females (1)

- Briefing Book table 6-7

|  | Subjects, n (%) |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Tedisamil (mg/kg) |  |  |  |  |
| System Organ Class
	Preferred Term | 0.24
N = 122 | 0.32
N = 225 | 0.48
N = 34 | 0.64
N = 10 | Placebo
N = 239 |
| Gastrointestinal disorders |  |  |  |  |  |
|   Diarrhea | 3 (2.5) | 3 (1.3) | 1 (2.9) | 0 | 4 (1.7) |
| Nervous system disorders |  |  |  |  |  |
|   Dizziness | 4 (3.3) | 4 (1.8) | 2 (5.9) | 0 | 4 (1.7) |
|   Headache | 5 (4.1) | 8 (3.6) | 1 (2.9) | 1 (10.0) | 8 (3.3) |
|   Paresthesia oral | 1 (0.8) | 2 (0.9) | 1 (2.9) | 0 | 1 (0.4) |
| Vascular disorders |  |  |  |  |  |
|   Hypotension | 2 (1.6) | 5 (2.2) | 1 (2.9)  | 1 (10.0) | 8 (3.3) |
|   Orthostatic hypotension                            | 1 (0.8)  | 1 (0.4) | 0 | 0 | 0 |

## TEAEs of Special Interest Non-Cardiac Disorders - Females (2)

- Briefing Book 6-7

|  | Subjects, n (%) |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Tedisamil (mg/kg) |  |  |  |  |
| System Organ Class
	Preferred Term | 0.24
N = 122 | 0.32
N = 225 | 0.48
N = 34 | 0.64
N = 10 | Placebo
N = 239 |
| Gen  disorders & admin site conditions |  |  |  |  |  |
|   Infusion related reaction | 1 (0.8) | 0 | 0 | 0 | 0 |
|   Infusion site burning | 3 (2.5) | 2 (0.9) | 0 | 1 (10.0) | 1 (0.4) |
|   Infusion site pain | 1 (0.8) | 3 (1.3) | 0 | 0 | 0 |
|   Infusion site reaction | 0 | 3 (1.3) | 0 | 0 | 0 |
|   Injection site burning | 0 | 2 (0.9) | 0 | 0 | 1 (0.4) |
|   Injection site hemorrhage | 1 (0.8) | 0 | 0 | 0 | 0 |
|   Injection site pain | 0 | 3 (1.3) | 1 (2.9) | 1 (10.0) | 0 |

## TEAEs of Special Interest: Selected Cardiac Disorders – Males 

|  | Subjects, n (%) |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Tedisamil (mg/kg) |  |  |  |  |
| 	Preferred Term | 0.16   N = 66 | 0.32N = 172 | 0.48N = 207 | 0.64N = 52 | Placebo N = 231 |
|    Atrial tachycardia | 0 | 0 | 1 (0.5) | 0 | 0 |
|    Bradyarrhythmia | 0 | 0 | 1 (0.5) | 0 | 0 |
|    Bradycardia | 1  (1.5) | 6 (3.5) | 14 (6.8) | 3 (5.8) | 13 (5.6) |
|    Sinus bradycardia | 0 | 3 (1.7) | 12 (5.8) | 4 (7.7) | 6 (2.6) |
|    Sinus tachycardia | 0 | 1 (0.6) | 1 (0.5) | 1 (1.9) | 0 |
|    Superventricular tachycardia | 0 | 0 | 1 (0.5) | 2 (3.8) | 2 (0.9) |
|    Tachyarrhythmia | 0 | 1 (0.6) | 2 (1.0) | 0 | 1 (0.4) |
|    Tachycardia | 0 | 2 (1.2) | 1 (0.5) | 0 | 4 (1.7) |
|    TdP | 0 | 0 | 0 | 0 | 0 |
|    Ventricular tachycardia | 0 | 17 (9.9) | 26 (12.6) | 13 (25.0) | 16 (6.9) |

- Briefing Book table 6-10

## TEAEs of Special Interest: Selected Cardiac Disorders – Females 

|  | Subjects, n (%) |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Tedisamil (mg/kg) |  |  |  |  |
| 		Preferred Term | 0.24 N = 122 | 0.32 N = 225 | 0.48N = 34 | 0.64N = 10 | Placebo N = 239 |
|    Atrial tachycardia | 1 (0.8) | 1 (0.4) | 0 | 0 | 1 (0.4) |
|    Bradyarrhythmia | 0 | 0 | 1 (2.9) | 0 | 0 |
|    Bradycardia | 4 (3.3) | 13 (5.8) | 2 (5.9) | 0 | 8 (3.3) |
|    Sinus bradycardia | 2 (1.6) | 4 (1.8) | 1 (2.9) | 0 | 5 (2.1) |
|    Sinus tachycardia | 0 | 0 | 0 | 0 | 1 (0.4) |
|    Superventricular tachycardia | 1 (0.8) | 1 (0.4) | 0 | 1 (10.0) | 0 |
|    Tachyarrhythmia | 0 | 0 | 1 (2.9) | 0 | 0 |
|    Tachycardia | 1 (0.8) | 3 (1.3) | 0 | 0 | 1(0.4) |
|    TdP | 0 | 0 | 1 (2.9) | 1 (10.0) | 0 |
|    Ventricular tachycardia | 6 (4.9) | 7 (3.1) | 3 (8.8) | 2 (20.0) | 12 (5.0) |

- Briefing Book table 6-11

## Cardiac TESAEs – Males

|  | Subjects, n (%) |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Tedisamil (mg/kg) |  |  |  |  |
| System Organ Class
   Preferred Term | 0.16
N = 66 | 0.32
N = 172 | 0.48
N = 207 | 0.64 N = 52 | Placebo N = 231 |
| Number with at least one TESAE | 5 (7.6) | 15 (8.7) | 19 (9.2) | 4 (7.7) | 20 (8.7) |
| Cardiac disorders | 2 (3.0) | 8 (4.7) | 14 (6.8) | 4 (7.7) | 14 (6.1) |
| Coronary artery disease | 0 | 1 (0.6) | 0 | 0 | 0 |
| Cardiac failure | 0 | 0 | 0 | 1 (1.9) | 0 |
| Cardiac failure congestive | 0 | 0 | 1 (0.5) | 0 | 0 |
| Myocardial infarction acute | 0 | 1 (0.6) | 0 | 0 | 0 |
| Myocardial infarction | 1 (1.5) | 0 | 0 | 2 (3.8) | 1 (0.4) |
| Bradycardia | 1 (1.5) | 0 | 2 (1.0) | 0 | 0 |
| Atrial fibrillation | 1 (1.5) | 4 (2.3) | 9 (4.3) | 2 (3.8) | 7 (3.0) |
| Atrial flutter | 0 | 0 | 1 (0.5) | 1 (1.9) | 3 (1.3) |
| Sick sinus syndrome | 0 | 0 | 0 | 0 | 1 (0.4) |
| Cardiac arrest | 0 | 0 | 0 | 0 | 1 (0.4) |
| Ventricular fibrillation | 0 | 0 | 1 (0.5) | 0 | 3 (1.3) |
| Ventricular tachycardia | 0 | 2 (1.2) | 2 (1.0) | 1 (1.9) | 2 (0.9) |

- Briefing Book table 6-12

## Cardiac TESAEs – Females

|  | Subjects, n (%) |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Tedisamil (mg/kg) |  |  |  |  |
| System Organ Class	Preferred Term | 0.24 N = 122 | 0.32 N = 225 | 0.48
N = 34 | 0.64
N = 10 | Placebo
N = 239 |
| Number with at least one TESAE | 14 (11.5) | 20 (8.9) | 5 (14.7) | 2 (20.0) | 22 (9.2) |
| Cardiac disorders | 8 (6.6) | 12 (5.3) | 3 (8.8) | 1 (10.0) | 10 (4.2) |
|    Cardiac failure | 0 | 3 (1.3) | 0 | 0 | 0 |
|    Cardiac failure congestive | 0 | 0 | 1 (2.9) | 0 | 0 |
|    Acute coronary syndrome | 0 | 1 (0.4) | 0 | 0 | 0 |
|    Myocardial infarction acute | 0 | 2 (0.9) | 0 | 0 | 0 |
|    Myocardial infarction | 0 | 1 (0.4) | 0 | 0 | 1 (0.4) |
|    Bradycardia | 0 | 0 | 0 | 0 | 2 (0.8) |
|    Nodal arrhythmia | 0 | 1 (0.4) | 0 | 0 | 0 |
|    Atrial fibrillation | 6 (4.9) | 3 (1.3) | 1 (2.9) | 0 | 5 (2.1) |
|    Atrial flutter | 1 (0.8) | 1 (0.4) | 0 | 0 | 0 |
|    Cardiac arrest | 0 | 0 | 0 | 0 | 1 (0.4) |
|    TdP  | 0 | 0 | 1 (2.9) | 0 | 0 |
|    Ventricular fibrillation | 0 | 0 | 0 | 1 (10.0) | 1 (0.4) |
|    Ventricular tachycardia | 1 (0.8) | 0 | 1 (2.9) | 0 | 0 |

- Briefing Book table 6-13

## Cardiac TESAEs – Bradycardia

- Males: Two SAEs
- In the first case one patient with Atrial flutter
- Received 0.48 mg/kg tedisamil and experienced significant bradycardia with a subsequent placement of a pacemaker.  The patient was discharged without sequelae. The event was judged possibly related by the investigator
- In the second case the patient with Atrial fibrillation
- Received 0.48 mg/kg tedisamil. The patient was discharged one day later. An SAE of bradycardia was reported 15 days after infusion. The event was judged unrelated to study treatment. Subsequently the patient had a pacemaker implanted without complication

## Cardiac TESAEs – Bradycardia

- Female: Two SAEs
- In two placebo patients bradycardia was reported as serious adverse event. One patient received a pacemaker subsequently

## TEAEs Leading to Study Discontinuation by Gender – Males

|  | Subjects, n (%) |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Tedisamil (mg/kg) |  |  |  |  |
| Preferred Term | 0.16 | 0.32 | 0.48 | 0.64 | Placebo |
| Number with at least one TEAE leading to study disc. | 1 (1.5) | 2 (1.2) | 4 (1.9) | 3 (5.8) | 2 (0.9) |
|  |  |  |  |  |  |
| Acute myocardial infarction                      | 0 | 1 (0.6) | 0 | 0 | 0 |
| Bradycardia | 0 | 0 | 1 (0.5) | 0 | 0 |
| Ventricular extrasystoles | 0 | 0 | 0 | 1(1.9) | 0 |
| Ventricular fibrillation  | 0 | 0 | 0 | 0 | 1(0.4) |
| VT | 0 | 1 (0.6) | 0 | 1 (1.9) | 0 |
| Injection site pain | 1(1.5) | 0 | 0 | 0 | 0 |
| Injection site reaction | 1(1.5) | 0 | 0 | 0 | 0 |
| ECG QT prolonged | 0 | 0 | 3 (1.4) | 2 (3.8) | 0 |
| Pancreatic carcinoma | 0 | 0 | 0 | 0 | 1(0.4) |
| Hypotension | 0 | 0 | 0 | 1 (1.9) | 0 |

- Briefing Book table 6-14

## TEAEs Leading to Study Discontinuation by Gender – Females

|  | Subjects, n (%) |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Tedisamil (mg/kg) |  |  |  |  |
| Preferred Term | 0.24 | 0.32 | 0.48 | 0.64 | Placebo |
| Number with at least one TEAE leading to study disc. | 2 (1.6) | 5 (2.2) | 1 (2.9) | 1 (10.0) | 3 (1.3) |
|  |  |  |  |  |  |
| Acute myocardial infarction | 0 | 1 (0.4) | 0 | 0 | 0 |
| Bradycardia | 0 | 1 (0.4) | 0 | 0 | 0 |
| Extrasystolis | 0 | 1 (0.4) | 0 | 0 | 0 |
| TdP | 0 | 0 | 1 (2.9) | 0 | 0 |
| VT | 0 | 1 (0.4) | 0 | 0 | 0 |
| Pneumonia | 0 | 1 (0.4) | 0 | 0 | 0 |
| Hip fracture | 0 | 0 | 0 | 0 | 1 (0.4) |
| Contusion | 0 | 1 (0.4) | 0 | 0 | 0 |
| Cerebrovascular accidents | 1 (0.8) | 0 | 0 | 0 | 1 (0.4) |
| Apnea | 0 | 0 | 1 (2.9) | 0 | 0 |
| Pulmonary embolism | 1 (0.8) | 0 | 0 | 0 | 0 |
| Hypotension | 0 | 0 | 1 (2.9) | 1 (10.0) | 1 (0.4) |

- Briefing Book table 6-15

## Incidence of Thromboembolic TEAEsMales

|  | Tedisamil dose, mg/kg |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Preferred Term
Safety Sample | 0.16
N = 66 | 0.24
N = 6 | 0.32
N = 172 | 0.48
N = 207 | 0.64
N = 52 |  | Placebo
N = 231 |
|  | Subjects, n (%) |  |  |  |  |  |  |
| Acute Myocardial Infarction | 0 | 0 | 1 (0.6) | 0 | 0 | 0 |  |
| Age Indeterminate Myocardial Infarction | 0 | 0 | 0 | 0 | 0 | 1 (0.4) |  |
| Myocardial Infarction | 1 (1.5) | 0 | 0 | 1 (0.5) | 2 (3.8) | 2 (0.9) |  |
| Arterial Thrombosis Limb | 0 | 0 | 0 | 1 (0.5) | 0 | 0 |  |
| Deep Vein Thrombosis | 1 (1.5) | 0 | 0 | 0 | 0 | 0 |  |
| Ischemic Stroke | 0 | 0 | 1 (0.6) | 1 (0.5) | 0 | 0 |  |
| Cerebrovascular Accident | 1 (1.5) | 0 | 0 | 0 | 0 | 0 |  |
| Post Thrombotic Syndrome | 1 (1.5) | 0 | 0 | 0 | 0 | 0 |  |

## Incidence of Thromboembolic TEAEsFemales

|  | Tedisamil dose, mg/kg |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Preferred Term
Safety Sample | 0.16
N = 1 | 0.24
N = 122 | 0.32
N = 225 | 0.48
N = 34 | 0.64N = 10 | Placebo
N = 239 |
|  | Subjects, n (%) |  |  |  |  |  |
| Acute Myocardial Infarction | 0 | 0 | 2 (0.9) | 0 | 0 | 0 |
| Myocardial Infarction | 0 | 0 | 1 (0.4) | 0 | 0 | 1 (0.4) |
| Ischemic Stroke | 0 | 0 | 1 (0.4) | 0 | 1 (10.0) | 0 |
| Intracardiac Thrombus | 0 | 0 | 1 (0.4) | 0 | 0 | 1 (0.4) |
| Cerebrovascular Accident | 0 | 1 (0.8) | 2 (0.9) | 0 | 0 | 1 (0.4) |
| Pulmonary Embolism | 0 | 1 (0.8) | 0 | 0 | 0 | 1 (0.4) |

## Summary of Deaths

|  | Tedisamil | Placebo |
| --- | --- | --- |
| All | 0.6% (6/944) | 0.6% (3/470) |
| Males | 0.2% (1/512) | 0.9% (2/231) |
| Females | 1.2% (5/402) | 0.4% (1/239) |

## Tedisamil IV: Deaths by Dose – Males

| Study ID | Subject No. | Treatment group | Gender/age | Primary term | AE start/stop | Relationship to study drug* |
| --- | --- | --- | --- | --- | --- | --- |
| S219.2.107 | 90242 | Placebo | M/70 | Pancreatic Cancer | Day 4/19 | Unable to judge |
| S219.3.112 | 22101 | Placebo | M/74 | Ventricular Fibrillation | Day 14/18 | Unrelated |
| S219.3.114 | 44203 | 0.32 mg/kg | M/72 | Acute MI | Day 8/8 | Unrelated |
| *Investigator judgment |  |  |  |  |  |  |

- Briefing Book table 6-9

## Tedisamil IV: Deaths by Dose – Females

| Study ID | Subject No. | Treatment Group | Gender/Age | Primary Term | AE Start/Stop | Relationship to Study Drug* |
| --- | --- | --- | --- | --- | --- | --- |
| S219.3.114 | 43001 | 0.32-0.48 | F/80 | EM dissociation/Cardiac Arrest | Day 3/3 | Unlikely |
| S219.3.116 | 61304 | 0.24 | F/75 | Pulmonary Embolism | Day 1/1 | Unrelated |
|  | 61508 | 0.24 | F/83 | Stroke | Day 9/17 | Unrelated |
|  | 67406 | 0.32 | F/80 | Acute Myocardial Infarction | Day 4/4 | Unrelated |
| S219.3.118 | 82506 | 0.32 | F/90 | Pneumonia/Pneumonia | Day 6/8 | Unrelated |
|  | 82711 | Placebo | F/85 | Stroke | Day 6/8 | Unrelated |
| *Investigator judgment |  |  |  |  |  |  |

## Subject 43001

- Diagnosis on admission and course in hospital
- Atrial fibrillation with recurrent ventricular tachycardia with hypotension
- CAD – old inferior wall MI
- Essential hypertension
- Rheumatic Heart Disease with mild mitral regurgitation

| Age, Gender | 80, Female |
| --- | --- |
| Medical History | Coronary artery disease, MI, hypertension |
| Study Drug Dose | 0.32 – 0.48 mg/kg |

## Subject 43001

- This case occurred in connection with infusion discontinuation due to bradycardia and asystole
- The patient was subsequently receiving CPR, intubated, ventilation
- Two days thereafter extubation, reverted to Atrial fibrillation
- Second attempt to cardiovert, this time with amiodarone: Bradycardia
- Despite pacing efforts subsequently the patient died

| Age, Gender | 80, Female |
| --- | --- |
| Medical History | Coronary artery disease, MI, hypertension |
| Study Drug Dose | 0.32 – 0.48 mg/kg |

## Adjudication and Oversight Committee (AOC) Members 

- _AOC:_
-     ADJUDICATION AND OVERSIGHT COMMITTEE consisting of independent cardiologists to assess safety issues and to advice about whether or not to stop the study or a dose level.
- Members
- Peter R. Kowey, M.D.
- 	President, Main Line Health Heart Center, Professor of Medicine and Clinical Pharmacology, Jefferson Medical College of Thomas Jefferson University
- Paul Dorian, M.D.
- 	Professor of Medicine, Division of Cardiology, St. Michael's Hospital,  Toronto, Ontario, Canada
- Stefan H. Hohnloser, M.D.
- 	Professor of Medicine, Dept. of Medicine Division of Cardiology, J.W. Goethe-University, Frankfurt a. M., Germany

## AOCFlow Chart of Adjudication 

- Holter recording sent to Central ECG Laboratory
- Primary evaluation of VTs
-  time of VT
-  heart rate
-  number of beats
-  polymorphic or monomorphic
-  sustained or non sustained
-  VT torsade-like:   yes / no / unable to determine
- Evaluation results recorded on a Holter Alert form and shipped to AOC members along with Holter Report
- Adjudication by AOC members

## AOCDefinition Ventricular Tachycardias

- Definition of ventricular tachycardias in Holter
- monomorphic: ventricular rhythm equal to or faster than 100 bpm with a regular rate and consistent beat-to-beat morphology
- polymorphic: ventricular rhythm equal to or faster than 100 bpm with frequent changes in QRS morphology and/or axis
- sustained: equal to or longer than 30 seconds
- non-sustained: shorter than 30 seconds
- Torsade-like: polymorphic VT, associated with a preceding prolonged QT or increased U-wave amplitude, starting with a long-short RR interval sequence and changing amplitude, appearing to twist around an iso-electric line

## Ventricular Tachycardia – Holter Analysisas Adjudicated by AOC – Males 

|  | Subjects, n (%) |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | Tedisamil (mg/kg) |  |  |  |  |  |  |
|  | 0.16
N = 58 | 0.32
N = 172 | 0.32-0.48
N = 10 | 0.48
N = 207 | 0.48-0.72
N = 15 | 0.64
N = 52 | Placebo
N = 225 |
| Any VT | 18 (31.0) | 43 (25.0) | 6 (60.0) | 65 (31.4) | 8 (53.3) | 22 (42.3) | 58 (25.8) |
| Monomorphic and non-sustained | 16 (27.6) | 33 (19.2) | 2 (20.0) | 44 (21.3) | 6 (40.0) | 17 (32.7) | 42 (18.7) |
| Monomorphic and sustained | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Polymorphic and non-sustained | 12 (20.7) | 20 (11.6) | 4 (40.0) | 35 (16.9) | 5 (33.3) | 10 (19.2) | 33 (14.7) |
| Polymorphic and sustained | 0 | 0 | 0 | 1 (0.5) | 0 | 1 (1.9) | 0 |
| Torsade-like | 0 | 1 (0.6) | 0 | 1 (0.5) | 1 (6.7) | 2 (3.8) | 1 (0.4) |

- Briefing Book table 6-16

## Ventricular Tachycardia – Holter Analysisas Adjudicated by AOC – Females 

|  | Subjects, n (%) |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | Tedisamil (mg/kg) |  |  |  |  |  |  |
|  | 0.24
N = 120 | 0.32
N = 225 | 0.32 - 0.48N = 7 | 0.48
N = 34 | 0.48 - 0.72N = 4 | 0.64
N = 10 | Placebo
N = 236 |
| Any VT | 21 (17.5) | 40 (17.8) | 3 (42.9) | 9 (26.5) | 1 (25.0) | 5 (50.0) | 36 (15.3) |
| Monomorphic and non-sustained | 15 (12.5) | 27 (12.0) | 1 (14.3) | 6 (17.6) | 1 (25.0) | 5 (50.0) | 24 (10.2) |
| Monomorphic and sustained | 0 | 0 | 0 | 1 (2.9) | 0 | 0 | 0 |
| Polymorphic and non-sustained | 7 (5.8) | 19 (8.4) | 1 (14.3) | 4 (11.8) | 0 | 1 (10.0) | 15 (6.4) |
| Polymorphic and sustained | 0 | 0 | 0 | 1 (2.9) | 0 | 1 (10.0) | 1 ( 0.4) |
| Torsade-like | 0 | 1 (0.4) | 1 (14.3) | 2 ( 5.9) | 0 | 1 (10.0) | 1 ( 0.4)* |

- Briefing Book table 6-17

- * Torsade-like due to non-synchronized DC cardioversion

## Adjudicated Torsade-Like EventsMale Subjects

| Subject No. | Age, yr | Tedisamil, mg/kg | Rhythm preceding event | Type of event | DCcardioversion | Time of event after initiation of infusion | Reported as TdP |
| --- | --- | --- | --- | --- | --- | --- | --- |
| 42301 | 55 | 0.48-0.72 | AFib | NS-PVT | Not done | 18 h | No |
| 22401 | 86 | 0.64 | AFl | NS-PVT | Not done | 48 min | No |
| 25825 | 79 | 0.64 | NSR | S-PVT | Done  NSR  | 15 min | No |
| 41420 | 54 | 0.48 | NSR | S-PVT | Done  NSR  | 40 min | No |
| 41021 | 54 | 0.32 | AFib | S-PVT | Done  NSR  | 11 min | No |
| 42503 | 67 | Placebo | AFib | NS-PVT | Not done | 4.5 h | No |
| S-PVT: sustained polymorphic VTNS-PVT: non-sustained polymorphic VTNSR: normal sinus rhythmAFib: atrial fibrillationAFl: atrial flutter  |  |  |  |  |  |  |  |

- Briefing Book table 6-19

## Adjudicated Torsade-Like EventsFemale Subjects

| SubjectNo. | Age,yr | Tedisamil,
 mg/kg | Rhythm preceding event | Type of event | DCcardioversion | Time of event after initiation of infusion | Reported 
as 
TdP |
| --- | --- | --- | --- | --- | --- | --- | --- |
| 25414 | 64 | 0.64 | NSR | S-PVT | Done  NSR | 30 min | Yes -TEAE |
| 23405 | 61 | 0.48 | AFib | S-PVT | Done  NSR | 20 min | Yes -TESAE |
| 25810 | 74 | 0.48 | AFib | NS-PVT | Not done | 20 min | No |
| 90644* | 87 | 0.48 | NSR | NS-PVT | Not done | 45 min | No |
| 41411 | 76 | 0.32-0.48 | NSR | NS-PVT | Not done | 45 min | No |
| 80613 | 69 | 0.32 | NSR | NS-PVT | Not done | 21 min | No |
| * No Holter, diagnosed from an ECG reading
S-PVT: sustained polymorphic VTNS-PVT: non-sustained polymorphic VTNSR: normal sinus rhythmAFib: atrial fibrillationAFl: atrial flutter  |  |  |  |  |  |  |  |

- Briefing Book table 6-19

## Adjudicated Torsade-Like Events by Dose and Gender

| Dose | Total No. of Subjects | Reported
as TEAEs |  Adj. Torsade-like Events | % | 95% CI |
| --- | --- | --- | --- | --- | --- |
| Male |  |  |  |  |  |
| > 0.48 mg/kg | 67 | 0 | 3 | 4.5 | 0.9, 12.5 |
| 0.48 mg/kg | 217 | 0 | 1 | 0.5 | 0.0, 2.5 |
| 0.32 mg/kg | 172 | 0 | 1 | 0.6 | 0.0, 3.2 |
| 0.16 mg/kg | 66 | 0 | 0 | 0.0 | 0.0, 5.4 |
| Placebo | 231 | 0 | 1 | 0.4 | 0.0, 2.4 |
| Female |  |  |  |  |  |
| > 0.32 mg/kg | 55 | 2 | 5 | 9.1 | 3.0, 20.0 |
| 0.32 mg/kg | 225 | 0 | 1 | 0.4 | 0.0, 2.5 |
| 0.24 mg/kg | 122 | 0 | 0 | 0.0 | 0.0, 3.0 |
| Placebo | 239 | 0 | 0 | 0.0 | 0.0, 1.5 |

- BD T1-4.

- Briefing Book table 6-18

## TEAEs by Subgroup Males

|  | N | Tedisamil 0.48 mg/kgn (%) | N | Placebon (%) |
| --- | --- | --- | --- | --- |
| < 65 yr | 119 | 84 (70.6) | 144 | 84 (58.3) |
| ≥ 65 yr | 88 | 56 (63.6) | 87 | 59 (67.8) |
| NYHA Class I | 123 | 83 (67.5) | 137 | 85 (62.0) |
| NYHA Class II/III | 74 | 51 (68.9) | 83 | 54 (65.1) |
| CrCL < 60 mL/min | 23 | 12 (52.2) | 26 | 19 (73.1) |
| CrCL ≥ 60 mL/min | 177 | 121 (68.4) | 191 | 116 (60.7) |
| Beta-blocking agents (yes) | 137 | 95 (69.3) | 158 | 104 (65.8) |
| Beta-blocking agents (no) | 70 | 45 (64.3) | 73 | 39 (53.4) |

- Briefing Book tables 6-25/26/27/28

## TEAEs by Subgroup Females

|  | N | Tedisamil 0.32 mg/kgn (%) | N | Placebon (%) |
| --- | --- | --- | --- | --- |
| < 65 yr | 69 | 45 (65.2) | 77 | 51 (66.2) |
| ≥ 65 yr | 156 | 101 (64.7) | 162 | 99 (61.1) |
| NYHA Class I | 91 | 58 (63.7) | 95 | 67 (70.5) |
| NYHA Class II/III | 108 | 70 (64.8) | 121 | 66 (54.5) |
| CrCL < 60 mL/min | 63 | 36 (57.1) | 64 | 42 (65.6) |
| CrCL ≥ 60 mL/min | 154 | 105 (68.2) | 168 | 105 (62.5) |
| Beta-blocking agents (yes) | 181 | 119 (65.7) | 187 | 118 (63.1) |
| Beta-blocking agents (no) | 44 | 27 (61.4) | 52 | 32 (61.5) |

- Briefing Book tables 6-25/26/27/28

## TESAEs by Subgroup Males

|  | N | Tedisamil 0.48 mg/kgn (%) | N | Placebon (%) |
| --- | --- | --- | --- | --- |
| < 65 yr | 119 | 11 (9.2) | 144 | 12 (8.3) |
| ≥ 65 yr | 88 | 8 (9.1) | 87 | 8 (9.2) |
| NYHA Class I | 123 | 11 (8.9) | 137 | 9 (6.6) |
| NYHA Class II/III | 74 | 7 (9.5) | 83 | 10 (12.0) |
| CrCL < 60 mL/min | 23 | 1 (4.3) | 26 | 1 (3.8) |
| CrCL ≥ 60 mL/min | 177 | 18 (10.2) | 191 | 17 (8.9) |
| Beta-blocking agents (yes) | 137 | 13 (9.5) | 158 | 18 (11.4) |
| Beta-blocking agents (no) | 70 | 6 (8.6) | 73 | 2 (2.7) |

- Briefing Book tables 6-25/26/27/28

## TESAEs by Subgroup Females

|  | N | Tedisamil 0.32 mg/kgn (%) | N | Placebon (%) |
| --- | --- | --- | --- | --- |
| < 65 yr | 69 | 5 (7.2) | 77 | 4 (5.2) |
| ≥ 65 yr | 156 | 15 (9.6) | 162 | 18 (11.1) |
| NYHA Class I | 91 | 8 (8.8) | 95 | 12 (12.6) |
| NYHA Class II/III | 108 | 8 (7.4) | 121 | 7 (5.8) |
| CrCL < 60 mL/min | 63 | 10 (15.9) | 64 | 12 (18.8) |
| CrCL ≥ 60 mL/min | 154 | 9 (5.8) | 168 | 9 (5.4) |
| Beta-blocking agents (yes) | 181 | 18 (9.9) | 187 | 19 (10.2) |
| Beta-blocking agents (no) | 44 | 2 (4.5) | 52 | 3 (5.8) |

- Briefing Book tables 6-25/26/27/28

## Monitoring Window

** **

## Two Step Infusion RegimenPK/PD Time Profile – Healthy Volunteers

- Two step
- infusion

## Mean Changes From Baseline QTc Bazett Measurements* - Males

|  | msecs | Tedisamil  
0.48 mg/kg 
N = 207 | Placebo

N = 231 |
| --- | --- | --- | --- |
| Baseline | Mean baseline value ± SD
 | 427.1 ± 33.0 | 427.4 ± 49.1 |
| 30 min | Mean change ± SD
 | 41.0 ± 38.1 | –1.3 ± 25.3 |
| 2.5 hr | Mean change ± SD
 | 9.7 ± 30.9 | –1.9 ± 25.2 |
| 4 hr | Mean change ± SD | 5.7 ± 33.2 | –4.2 ± 30.8 |

**Mean Changes From Baseline QTc Bazett Measurements* - Males**

- Briefing Book table 6-22

- * Integrated Safety Sample

## Mean Changes from Baseline QTc Bazett Measurements* - Females

**Mean Changes from Baseline QTc Bazett Measurements* - Females**

|  | msecs | Tedisamil  
0.32 mg/kg 
N = 225 | Placebo 

N = 239 |
| --- | --- | --- | --- |
| Baseline | Mean baseline value ± SD
 | 436.2 ± 32.0 | 434.7 ± 34.9 |
| 30 min | Mean change ± SD
 | 24.7 ± 38.5 | –0.1 ± 23.3 |
| 2.5 hr | Mean change ± SD
 | 7.6 ± 32.2 | 1.9 ± 25.9 |
| 4 hr | Mean change ± SD | –3.0 ± 37.1 | –5.0 ± 29.3 |

- Briefing Book table 6-22

- * Integrated Safety Sample

## ConclusionsMonitoring Window

- During the clinical program torsade-like events occurred within 48 min after start of infusion. One event occurred at 18 hrs, unlikely to be related to tedisamil
- Within 2 hrs, QTcB returns to normal in healthy subjects and the majority of patients in AFib/AFl have substantial reductions after 2.5 hrs
- Based on the above, we are proposing an observation window for at least 2 hrs post infusion
- Patients who have not achieved normal QTcB values within this time window need to be followed up until their QTcB has returned to normal

## Safety Conclusions

** **

## Safety Conclusions (1) 

- Substantial safety database
- 931 subjects
- Balanced male/female exposure
- 4 week follow-up
- Cardiac disorders most common TEAEs and TESAEs
- Incidence of TEAE, TESAE
- Similar for tedisamil and placebo
- Similar in subgroups

## Safety Conclusions (2)

- Incidence of VT
- Slightly higher in tedisamil group (26.4% vs 20.4% for placebo)
- At the recommended doses the incidence of VT was
- 31.4% in males (vs 25.8% placebo)
- 17.8% in females (vs 15.3% placebo)
- Vast majority of events were non-sustained

## Safety Conclusions (3)

- Adjudicated Torsade-like events
- 11 tedisamil (1.2%) and 1 placebo (0.2%) in safety population
- At recommended doses
- 0.4% in females (0.32 mg/kg) , 0% S-PVT requiring DC cardioversion
- 0.5% in males (0.48 mg/kg), 0.5% S-PVT requiring DC cardioversion
- All DC cardioversions successful

## Dose Selection

** **

## Dose SelectionEfficacy AFib/AFl in Episodes 3 hrs - 45 days

**Dose Selection****Efficacy AFib/AFl in Episodes 3 hrs - 45 days**

- Placebo-corrected estimates and 95% CI

- Gender/Dose

## Dose Selection – Safety

*Incidence of Adjudicated Torsade-like events by gender and dose*

| Gender | Dose | TdP Incidence | 95% CI |
| --- | --- | --- | --- |
| Males | > 0.48 mg/kg | 4.5% | 0.9, 12.5 |
|  | = 0.48 mg/kg | 0.5% | 0.0, 2.5 |
|  |  |  |  |
| Females  | > 0.32 mg/kg | 9.1% | 3.0, 20.0 |
|  | = 0.32 mg/kg | 0.4% | 0.0, 2.5 |

## Dose Selection – Recommended Dose

- To optimize benefit while minimizing the risk of TdP, the following doses are recommended
- 0.48 mg/kg in males
- 0.32 mg/kg in females