Tedisamil Efficacy-Safety Matthias Straub, MD

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Tedisamil Efficacy-Safety Matthias Straub, MD

• Vice President, Global Clinical Development
• Solvay Pharmaceuticals

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Agenda Efficacy

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

3
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

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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

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

Briefing Book table 4-1
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Two-Step Infusion RegimenPK/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
  doesnt cause uncontrolled Cmax, causing TdPs

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Two-Step Infusion RegimenPK/PD Time Profile
Healthy Volunteers
Two step infusion
Briefing Book figure 3-1
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Summary of Phase II Studies
Study Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Placebo Infusion time (min) Infusion time (min) Total subjects Total subjects Subject type
Study 0.16 0.24 0.32 0.48 0.64 Placebo 10 30 Total subjects Total subjects Subject type
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
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Primary Efficacy Parameter Proof of Principle
Study S219.2.107
Data from BD pg 12 (1111078)
Dose, mg/kg 3 - 48 hrs 3 - 48 hrs
Dose, mg/kg N Conversion, n ()
Tedisamil 0.32 52 24 (46.2)
Tedisamil 0.48 42 24 (57.1)
Placebo 46 4 (8.7)
P lt 0.001 P lt 0.001 P lt 0.001
Data Briefing Book page 32
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Secondary Efficacy ParameterProof of Principle
Study S219.2.107
Treatment Treatment
Type of energy Statistic Tedisamil Placebo Overall
Monophasic energy (J) n 19 13 32
Monophasic energy (J) Mean SD 168.1 88.1 250.4 103.9 201.5 101.8
Monophasic energy (J) Median 200.0 300.0 200.0
Monophasic energy (J) MinMax 50.0 360.0 100.0 360.0 50.0 360.0
Monophasic energy (J) 2-sided Wilcoxon p-value 0.032

Biphasic energy (J) n 4 5 9
Biphasic energy (J) Mean SD 100.0 57.7 140.0 82.2 122.2 71.2
Biphasic energy (J) Median 100.0 200.0 150.0
Biphasic energy (J) MinMax 50.0 150.0 50.0 200.0 50.0 200.0
Biphasic energy (J) 2-sided Wilcoxon p-value 0.476

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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

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Phase III Efficacy StudiesMales
Study Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Infusion time (min) Total subjects Total subjects
Study 0.16 0.24 0.32 0.48 0.64 Placebo 30 Total subjects Total subjects
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 recent onset AFib/AFl subjects (3 hrs - 45 days) 36 F were included pre-amendment recent onset AFib/AFl subjects (3 hrs - 45 days) 36 F were included pre-amendment recent onset AFib/AFl subjects (3 hrs - 45 days) 36 F were included pre-amendment recent onset AFib/AFl subjects (3 hrs - 45 days) 36 F were included pre-amendment recent onset AFib/AFl subjects (3 hrs - 45 days) 36 F were included pre-amendment recent onset AFib/AFl subjects (3 hrs - 45 days) 36 F were included pre-amendment recent onset AFib/AFl subjects (3 hrs - 45 days) 36 F were included pre-amendment recent onset AFib/AFl subjects (3 hrs - 45 days) 36 F were included pre-amendment recent onset AFib/AFl subjects (3 hrs - 45 days) 36 F were included pre-amendment recent onset AFib/AFl subjects (3 hrs - 45 days) 36 F were included pre-amendment
Briefing Book table 4-1
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Phase III Efficacy Studies Females
Study Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Infusion time (min) Total subjects Total subjects
Study 0.16 0.24 0.32 0.48 0.64 Placebo 30 Total subjects Total subjects
3.116 ? ? ? ? 356 356 F

3.118 ? ? ? 152 152 F
recent onset AFib/AFl subjects (3h - 45 days) recent onset AFib/AFl subjects (3h - 45 days) recent onset AFib/AFl subjects (3h - 45 days) recent onset AFib/AFl subjects (3h - 45 days) recent onset AFib/AFl subjects (3h - 45 days) recent onset AFib/AFl subjects (3h - 45 days) recent onset AFib/AFl subjects (3h - 45 days) recent onset AFib/AFl subjects (3h - 45 days) recent onset AFib/AFl subjects (3h - 45 days) recent onset AFib/AFl subjects (3h - 45 days) recent onset AFib/AFl subjects (3h - 45 days)
Briefing Book table 4-1
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Study Design for Efficacy Studies
Follow-up Period
Double-blind Treatment Period
Screening
RANDOMIZATION
Placebo
SCREENING
30 min infusion
IV Tedisamil
Up to 48 hrs
24 hr observation
4 wks
Screening
End-of-24-hr observation period
Follow-up
Randomization
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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)

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Study Inclusion Criteria

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

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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 gt 470 msec before randomization
• Concurrent treatment with antiarrhythmic drugs
  (except for digitalis, diltiazem or ß-blockers)
• Sick sinus syndrome
• Need for internal or external pacemaker

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Baseline CharacteristicsAge, Race
Subjects, Subjects, Subjects, Subjects, Subjects,
Males Males Females Females
Tedisamil Placebo Tedisamil Placebo
N 528 N 231 N 403 N 239
Age lt 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
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Baseline CharacteristicsNYHA, Creatinine and
Duration of AFib/AFl
Subjects, Subjects, Subjects, Subjects, Subjects,
Males Males Females Females
Tedisamil Placebo Tedisamil Placebo
N 528 N231 N403 N239
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
lt 30 mL/min 0.2 0 0.7 2.1
30 - lt 60 mL/min 8.1 11.3 28.3 24.7
60 - lt 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
gt 48 hrs - 45 days 43.4 42.0 58.3 60.7
Note safety data set Note safety data set Note safety data set Note safety data set Note safety data set Note safety data set
Briefing Book table 5-2/3 appendix 2
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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

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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

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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)

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Individual Study Efficacy Results Phase III
Studies

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Phase III Primary Efficacy AFib
MalesConversion Rates
Subjects, Subjects, Subjects, Subjects, Subjects, Subjects, Subjects,
Study Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Tedisamil dose (mg/kg)
Study 0.16 0.24 0.32 0.48 0.64 0.64 Placebo
3.112 23.2 52.9 67.4 67.4 5.7
p-value 0.0096 lt 0.0001 lt 0.0001 lt 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 p-values adjusted for multiple comparisons p-values adjusted for multiple comparisons p-values adjusted for multiple comparisons p-values adjusted for multiple comparisons p-values adjusted for multiple comparisons p-values adjusted for multiple comparisons p-values adjusted for multiple comparisons
BD T1-1, 5-4.
Briefing Book table 5-4
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Phase III Primary Efficacy AFib
FemalesConversion Rates
Subjects, Subjects, Subjects, Subjects, Subjects, Subjects,
Study Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Tedisamil dose (mg/kg) Tedisamil dose (mg/kg)
Study 0.16 0.24 0.32 0.48 0.64 Placebo
3.116 9.4 21.5 2.9
p-value 0.047 lt 0.0001
3.118 17.9 4.5
p-value 0.014
p-values adjusted for multiple comparisons p-values adjusted for multiple comparisons p-values adjusted for multiple comparisons p-values adjusted for multiple comparisons p-values adjusted for multiple comparisons p-values adjusted for multiple comparisons p-values adjusted for multiple comparisons
BD T1-1.
Briefing Book table 5-5
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Phase III Studies Males Atrial Fibrillation
Difference vs Placebo in percentage of conversion
to NSR within 2.5 hrs 3 hrs 45 days
BD F5-2
Placebo-corrected estimates and CIs (adjusted)
Dose
Briefing Book figure 5-2
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Phase III Studies Females Atrial Fibrillation
Difference vs Placebo in percentage of conversion
to NSR within 2.5 hrs 3 hrs 45 days
BD F5-3
Placebo-corrected estimates and CIs (adjusted)
Dose
Briefing Book figure 5-3
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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

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Sensitivity Analysis Conversion Within 2.5 hrs

• S219.3.112 AFib Males

Sensitivity analysis Sensitivity analysis Sensitivity analysis Sensitivity analysis
N n placebo-corrected placebo-corrected p-value
0.32 57 14 24.6 24.6 17.2 17.2 0.0143
0.48 53 28 52.8 52.8 45.4 45.4 lt0.0001
0.64 49 32 65.3 65.3 57.9 57.9 lt0.0001
placebo 54 4 7.4 7.4
Dossier placebo-corrected p-value
17.6 0.0096
47.3 lt0.0001
61.8 lt0.0001
N samplen number of converters
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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

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Primary Efficacy by Subgroup Males
Difference vs Placebo in percentage of conversion
to NSR within 2.5 hrs
BD F5-4
Placebo-corrected estimates and 95 CIs (adjusted)
0.48 mg/kg
Subgroup
Briefing Book figure 5-4
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Primary Efficacy by Subgroup Females
Difference vs Placebo in percentage if conversion
to NSR within 2.5 hrs
BD F5-5
Placebo-corrected estimates and 95 CIs (adjusted)
0.32 mg/kg
Subgroup
Briefing Book figure 5-5
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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
Placebo-corrected estimates and 95 CIs
Males 0.48 mg/kg
AFib/AFl
Females 0.32 mg/kg
AFib/AFl
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Primary Efficacy Proportion Converting to NSR
within 2.5 hrs by Duration of Episode 3 hrs 7
days 8 - 45 days
Duration of Episode AFibAFl Duration of Episode AFibAFl
3 hrs - 7 days n () 8 - 45 days n ()
Males
Tedisamil 0.48 mg/kg 51/110 (46.4) p lt0.0001 8/61 (13.1) p0.0033
Placebo 11/122 (9.0) 0/55 (0)

Females
Tedisamil 0.32 mg/kg 30/114 (26.3) plt0.0001 7/88 (8.0) p0.19
Placebo 6/109 (5.5) 3/92 (3.3)
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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)

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Secondary Efficacy Parameters Males

N Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
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
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Secondary Efficacy Parameters Females

N Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
N In NSR at 2.5 hrs In NSR at 24 hrs Remaining in NSR for 24 hrs In NSR at Hospital Discharge
Tedisamil0.32 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
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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
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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

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Tedisamil Safety

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Safety Agenda

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

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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
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Subject Disposition IV Tedisamil AFib/AFl
Clinical Program
Consented 1619
Randomized 1469
Screen Failures 150
Tedisamil 974
Placebo 495
Treated 470
Not treated 25
Treated 931
Not treated 43
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Integrated Safety Database by Subgroups
Subjects, Subjects, Subjects, Subjects,
Males Males Females Females
Tedisamil N 528 Placebo N 231 Tedisamil N 403 Placebo N 239
Age lt 65 60.4 62.3 29.0 32.2
Age 65 39.6 37.7 71.0 67.8
ß-blockers Yes 68.2 68.4 76.9 78.2
ß-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 lt 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
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Overview of AEs by Dose Over 4 WeeksMales and
Females
Males Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
Males Tedisamil dose, mg/kg Tedisamil dose, mg/kg Tedisamil dose, mg/kg Tedisamil dose, mg/kg Tedisamil dose, mg/kg
Males 0.16N 66 0.24N 6 0.32N 172 0.48N 207 0.64N 52 PlaceboN 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
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TEAEs of Special Interest Non-Cardiac Disorders
- Males (1)
Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg) 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)
Briefing Book table 6-6
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TEAEs of Special Interest Non-Cardiac Disorders
- Males (2)
Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg) 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
Briefing Book table 6-6
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TEAEs of Special Interest Non-Cardiac Disorders
- Females (1)
Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg) 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
Briefing Book table 6-7
49
TEAEs of Special Interest Non-Cardiac Disorders
- Females (2)
Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg) 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
Briefing Book 6-7
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TEAEs of Special Interest Selected Cardiac
Disorders Males
Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg)
Preferred Term 0.16 N 66 0.32N 172 0.48N 207 0.64N 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
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TEAEs of Special Interest Selected Cardiac
Disorders Females
Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg)
Preferred Term 0.24 N 122 0.32 N 225 0.48N 34 0.64N 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
52
Cardiac TESAEs Males
Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg) 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
53
Cardiac TESAEs Females
Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg) 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
54
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

55
Cardiac TESAEs Bradycardia

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

56
TEAEs Leading to Study Discontinuation by Gender
Males
Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg) 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
57
TEAEs Leading to Study Discontinuation by Gender
Females
Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg) 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
58
Incidence of Thromboembolic TEAEsMales
Tedisamil dose, mg/kg Tedisamil dose, mg/kg Tedisamil dose, mg/kg Tedisamil dose, mg/kg Tedisamil dose, mg/kg 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 0.64 N 52 Placebo N 231
Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
Acute Myocardial Infarction 0 0 1 (0.6) 0 0 0 0
Age Indeterminate Myocardial Infarction 0 0 0 0 0 1 (0.4) 1 (0.4)
Myocardial Infarction 1 (1.5) 0 0 1 (0.5) 2 (3.8) 2 (0.9) 2 (0.9)
Arterial Thrombosis Limb 0 0 0 1 (0.5) 0 0 0
Deep Vein Thrombosis 1 (1.5) 0 0 0 0 0 0
Ischemic Stroke 0 0 1 (0.6) 1 (0.5) 0 0 0
Cerebrovascular Accident 1 (1.5) 0 0 0 0 0 0
Post Thrombotic Syndrome 1 (1.5) 0 0 0 0 0 0
59
Incidence of Thromboembolic TEAEsFemales
Tedisamil dose, mg/kg Tedisamil dose, mg/kg Tedisamil dose, mg/kg Tedisamil dose, mg/kg Tedisamil dose, mg/kg
Preferred Term Safety Sample 0.16 N 1 0.24 N 122 0.32 N 225 0.48 N 34 0.64N 10 Placebo N 239
Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n () 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)
60
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)
61
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 Investigator judgment Investigator judgment Investigator judgment Investigator judgment Investigator judgment Investigator judgment
Briefing Book table 6-9
62
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 Investigator judgment Investigator judgment Investigator judgment Investigator judgment Investigator judgment Investigator judgment
63
Subject 43001
Age, Gender 80, Female
Medical History Coronary artery disease, MI, hypertension
Study Drug Dose 0.32 0.48 mg/kg

• 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

64
Subject 43001
Age, Gender 80, Female
Medical History Coronary artery disease, MI, hypertension
Study Drug Dose 0.32 0.48 mg/kg

• 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

65
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

66
AOCFlow 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

67
AOCDefinition 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

68
Ventricular Tachycardia Holter Analysisas
Adjudicated by AOC Males
Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg) 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
69
Ventricular Tachycardia Holter Analysisas
Adjudicated by AOC Females
Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg) Tedisamil (mg/kg)
0.24 N 120 0.32 N 225 0.32 - 0.48N 7 0.48 N 34 0.48 - 0.72N 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)
Torsade-like due to non-synchronized DC
cardioversion
Briefing Book table 6-17
70
Adjudicated Torsade-Like EventsMale Subjects
Subject No. Age, yr Tedisamil, mg/kg Rhythm preceding event Type of event DCcardioversion 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 VTNS-PVT non-sustained polymorphic VTNSR normal sinus rhythmAFib atrial fibrillationAFl atrial flutter S-PVT sustained polymorphic VTNS-PVT non-sustained polymorphic VTNSR normal sinus rhythmAFib atrial fibrillationAFl atrial flutter S-PVT sustained polymorphic VTNS-PVT non-sustained polymorphic VTNSR normal sinus rhythmAFib atrial fibrillationAFl atrial flutter S-PVT sustained polymorphic VTNS-PVT non-sustained polymorphic VTNSR normal sinus rhythmAFib atrial fibrillationAFl atrial flutter S-PVT sustained polymorphic VTNS-PVT non-sustained polymorphic VTNSR normal sinus rhythmAFib atrial fibrillationAFl atrial flutter S-PVT sustained polymorphic VTNS-PVT non-sustained polymorphic VTNSR normal sinus rhythmAFib atrial fibrillationAFl atrial flutter S-PVT sustained polymorphic VTNS-PVT non-sustained polymorphic VTNSR normal sinus rhythmAFib atrial fibrillationAFl atrial flutter S-PVT sustained polymorphic VTNS-PVT non-sustained polymorphic VTNSR normal sinus rhythmAFib atrial fibrillationAFl atrial flutter
Briefing Book table 6-19
71
Adjudicated Torsade-Like EventsFemale Subjects
SubjectNo. Age,yr Tedisamil, mg/kg Rhythm preceding event Type of event DCcardioversion 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 VTNS-PVT non-sustained polymorphic VTNSR normal sinus rhythmAFib atrial fibrillationAFl atrial flutter No Holter, diagnosed from an ECG reading S-PVT sustained polymorphic VTNS-PVT non-sustained polymorphic VTNSR normal sinus rhythmAFib atrial fibrillationAFl atrial flutter No Holter, diagnosed from an ECG reading S-PVT sustained polymorphic VTNS-PVT non-sustained polymorphic VTNSR normal sinus rhythmAFib atrial fibrillationAFl atrial flutter No Holter, diagnosed from an ECG reading S-PVT sustained polymorphic VTNS-PVT non-sustained polymorphic VTNSR normal sinus rhythmAFib atrial fibrillationAFl atrial flutter No Holter, diagnosed from an ECG reading S-PVT sustained polymorphic VTNS-PVT non-sustained polymorphic VTNSR normal sinus rhythmAFib atrial fibrillationAFl atrial flutter No Holter, diagnosed from an ECG reading S-PVT sustained polymorphic VTNS-PVT non-sustained polymorphic VTNSR normal sinus rhythmAFib atrial fibrillationAFl atrial flutter No Holter, diagnosed from an ECG reading S-PVT sustained polymorphic VTNS-PVT non-sustained polymorphic VTNSR normal sinus rhythmAFib atrial fibrillationAFl atrial flutter No Holter, diagnosed from an ECG reading S-PVT sustained polymorphic VTNS-PVT non-sustained polymorphic VTNSR normal sinus rhythmAFib atrial fibrillationAFl atrial flutter
Briefing Book table 6-19
72
Adjudicated Torsade-Like Events by Dose and
Gender
Dose Total No. of Subjects Reported as TEAEs Adj. Torsade-like Events 95 CI
Male
gt 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
gt 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
73
TEAEs by Subgroup Males
N Tedisamil 0.48 mg/kgn () N Placebon ()
lt 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 lt 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
74
TEAEs by Subgroup Females
N Tedisamil 0.32 mg/kgn () N Placebon ()
lt 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 lt 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
75
TESAEs by Subgroup Males
N Tedisamil 0.48 mg/kgn () N Placebon ()
lt 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 lt 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
76
TESAEs by Subgroup Females
N Tedisamil 0.32 mg/kgn () N Placebon ()
lt 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 lt 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
77
Monitoring Window

78
Two Step Infusion RegimenPK/PD Time Profile
Healthy Volunteers
Two step infusion
79
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
Briefing Book table 6-22
Integrated Safety Sample
80
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
81
ConclusionsMonitoring 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

82
Safety Conclusions

83
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

84
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

85
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

86
Dose Selection

87
Dose SelectionEfficacy AFib/AFl in Episodes 3
hrs - 45 days
Placebo-corrected estimates and 95 CI
Gender/Dose
88
Dose Selection Safety

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

Gender Dose TdP Incidence 95 CI
Males gt 0.48 mg/kg 4.5 0.9, 12.5
0.48 mg/kg 0.5 0.0, 2.5

Females gt 0.32 mg/kg 9.1 3.0, 20.0
0.32 mg/kg 0.4 0.0, 2.5
89
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