Questions from the Committee Victor Raczkowski, MD, MS

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Questions from the Committee Victor Raczkowski,
MD, MS

• Vice President, US Regulatory Affairs
• Solvay Pharmaceuticals

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BACKUP SLIDES
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Serious Adverse Events Time of Onset Females
Day 0-1 Day 0-1 Day 2-7 Day 2-7 8-28 day 8-28 day
Tedi Plac Tedi Plac Tedi Plac
Deaths 1 (0.2) 0 2 (0.4) 0 2 (0.4) 1 (0.4)
Hypotension 2 (0.5) 1 (0.4) 0 1 (0.4) 0 0
Myocardial Infarction 0 0 2 (0.5) 1 (0.4) 1 (0.2) 0
Ventricular Tachycardia 2 (0.5) 0 0 0 0 0
Thrombo-embolic Events 1 (0.2) 0 3 (0.7) 3 (1.3) 2 (0.5) 0
TdP 1 (0.2) 0 0 0 0 0
Bradycardia 1 (0.2) 1 (0.4) 1 1 (0.4) 0 0
4
Serious Adverse Events Time of Onset Males
0-1 Day 0-1 Day 2-7 Days 2-7 Days 8-28 Days 8-28 Days
Tedi Plac Tedi Plac Tedi Plac
Deaths 0 0 0 0 2 (0.4) 1 (0.4)
Hypotension 0 0 0 1 (0.4) 0 0
Myocardial Infarction 0 0 3 (0.6) 1 (0.4) 1 (0.2) 0
Ventricular Tachycardia 4 ( 0.8) 0 0 3 (1.2) 1 (0.2) 0
Thromboembolic Events 0 0 3 (0.6) 0 1 (0.2) 0
TdP 0 0 0 0 0 0
Bradycardia 0 0 2 (0.4) 0 1 (0.2) 0
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Serious Adverse Events Time of Onset Females
Day 0-1 Day 0-1 Day 2-7 Day 2-7 8-28 day 8-28 day
Tedi Plac Tedi Plac Tedi Plac
Deaths 1 (0.2) 0 2 (0.5) 0 2 (0.5) 1 (0.4)
Hypotension 2 (0.5) 1 (0.4) 0 1 (0.4)
Myocardial Infarction 0 0 2 (0.5) 1 (0.4) 1 (0.2) 0
Pulmonary Oedema 0 0 1 (0.2) 0
Thrombo-embolic Events 1 (0.2) 0 3 (0.7) 2 () 2 (0.5) 0
TdP 1 (0.2) 0 0 0 0 0
Bradycardia 1 (0.2) 1 (0.4) 1 (0.2) 1 (0.4) 0 0
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Serious Adverse Events Time of Onset Males
0-1 Day 0-1 Day 2-7 Days 2-7 Days 8-28 Days 8-28 Days
Tedi Plac Tedi Plac Tedi Plac
Deaths 0 0 0 0 1 (0.2) 2 (0.5)
Hypotension 0 0 0 1 (0.4) 0 0
Myocardial Infarction 0 0 3 (0.6) 1 (0.4) 1 (0.2) 0
Pulmonary Oedema 0 0 1 (0.2) 0 0 0
Thromboembolic Events 0 0 3 (0.6) 0 1 (0.4) 0
Bradycardia 0 0 2 (0.5) 0 0 0
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Medical History Females
Tedisamil (N 476) n () Placebo N 211 n ()

Coronary Artery Disorder NEC 74 ( 19.3) 50 ( 22.0)
Heart Failure NEC 73 ( 19.1) 37 ( 16.3)
Myocardial Infarction 19 ( 5.0) 12 ( 5.3)
Acute Myocardial Infarction 3 ( 0.8) 4 ( 1.8)
Mitral Valvular Disorders 22 ( 5.7) 17 ( 7.5)
Central Nervous System Haemorrhages and Cerebrovascular Accidents 18 ( 4.7) 13 ( 5.7)
Vascular Hypotensive Disorders 2 ( 0.5) 1 ( 0.4)

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Medical History Males
Tedisamil (N 476) n () Placebo N 211 n ()

Coronary Artery Disorder NEC 116 ( 24.4) 53 ( 25.1)
Cardiac Valve Disorders NEC 1 ( 0.2) 1 ( 0.5)
Heart Failure NEC 91 ( 19.1) 39 ( 18.5)
Myocardial Infarction 43 ( 9.0) 20 ( 9.5)
Age Indeterminate Myocardial Infarction 3 ( 0.6) 1 ( 0.5)
Acute Myocardial Infarction 5 ( 1.1) 4 ( 1.9)
Mitral Valvular Disorders 19 ( 4.0) 11 ( 5.2)
Central Nervous System Haemorrhages and Cerebrovascular Accidents 14 ( 2.9) 8 ( 3.8)
Vascular Hypotensive Disorders 0 2 ( 0.9)

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QTcB Change from Baseline (SD) in Normal
Subjects and Subjects with Moderate Renal
Impairment
QTc prolongation (mean change from baseline) QTc prolongation (mean change from baseline) QTc prolongation (mean change from baseline) QTc prolongation (mean change from baseline) QTc prolongation (mean change from baseline)
Combined Tedisamil Combined Tedisamil Placebo Placebo
CrCl lt60 ml/min CrCl 60 ml/min CrCl lt60 ml/min CrCl 60 ml/min
N161 N738 N90 N359
QTc Bazett
Baseline 428.6 38.8 426.2 33.7 433.8 32.7 428.9 34.5
30 min 29.9 40.0 31.6 37.1 -0.2 22.7 -1.2 24.7
2.5 hrs 7.0 31.4 9.0 28.8 2.9 26.2 -1.1 25.5
4 hrs -1.7 35.4 3.3 31.1 -0.5 32.6 -5.9 29.0
8 hrs -0.9 34.1 2.5 30.3 -2.5 28.8 -7.2 32.9
12 hrs 3.0 26.4 3.8 27.3 -3.3 20.5 -1.9 25.7
24 hrs -2.2 31.5 -3.6 29.4 -2.7 27.9 -7.6 30.4
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Integrated Safety Database TEAEs Converters vs
Non-converters Females
System organ class Preferred term Subjects who Converted to NSR 0.48 mg/kg Subjects who did not convert to NSR 0.48 mg/kg
Subjects with at least 1 TEAE 27 (61.4) 119 (65.7)
Blood and lymphatic system disorders - 3 ( 1.7)
Cardiac disorders 20 (45.5) 71 (39.2)
Endocrine disorders - 8 ( 4.4)
Eye disorders 1 ( 2.3) 1 ( 0.6)
Gastrointestinal disorders 5 (11.4) 8 ( 4.4)
Gen. disorders admin. site conditions 9 (20.5) 17 ( 9.4)
Infection and infestations 3 ( 6.8) 10 ( 5.5)
Injury, poisoning and procedural complications 1 ( 2.3) 2 ( 1.1)
Investigations 2 ( 4.5) 18 ( 9.9)
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FDA Analysis Sensitivity Analysis ITT as in
file Conversion Within 2.5 hrs
3.112 AFib males AFib males
FDA Analysis FDA Analysis Sensitivity Analysis Sensitivity Analysis Sensitivity Analysis Dossier Dossier
mg/kg Placebo-corrected P-value Placebo-corrected P-value P-value Placebo-corrected P-value
0.32 17 0.014 17.2 0.014 0.014 17.6 0.0096
0.48 45 lt0.001 45.4 lt0.0001 lt0.0001 47.3 lt0.0001
0.64 56 lt0.001 57.9 lt0.0001 lt0.0001 61.8 lt0.0001
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Randomized but not TreatedReasons AFib/AFl ITT
Sample
Total N1169 n () Total N1169 n () Tedisamil N775 n () Tedisamil N775 n () Placebo N394 n () Placebo N394 n ()
Randomized but not treated 42 (3.6) 27 (3.5) 15 (3.8)

Conversions 28 (2.4) 15 (1.9) 13 (3.3)

Non-conversions 14 (1.2) 12 (1.5) 2 (0.5)
QTc too high 3 (0.3) 2 (0.3) 1 (0.3)
AE 2 0.2) 2 (0.3) 0 (0.0)
Other safety exclusion criteria 3 (0.3) 2 (0.3) 1 (0.3)
Withdrew consent 3 (0.3) 3 (0.4) 0 (0.0)
Unknown 3 (0.3) 3 (0.4) 0 (0.0)
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Definition of Sensitivity Analysis

• All randomized AFib subjects are included in the
  analysis
• Subjects who converted to NSR within 2.5 hours
  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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Listing of Subjects with DC Cardioversion within
2.5 hrs after start of infusion
SubjID Study Treatment Gender
25825 3.112 0.64 mg/kg M
41021 3.114 0.32 mg/kg M
41420 3.114 0.48 mg/kg M
86405 3.118 Placebo F

23405 3.112 0.48 mg/kg F Females in 3.112 not part of primary efficacy analysis
25414 3.112 0.64 mg/kg F Females in 3.112 not part of primary efficacy analysis

90136 2.107 0.32 mg/kg F 2.107 was not part of primary efficacy
DC cardioversion was unsuccessful
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Reasons for Exclusions from AFib/AFl ITT sample -
BB page 35
tedisamil placebo Total
All randomized 3.112/.114/116/117/118 30-min AFib/AFl All randomized 3.112/.114/116/117/118 30-min AFib/AFl All randomized 3.112/.114/116/117/118 30-min AFib/AFl All randomized 3.112/.114/116/117/118 30-min AFib/AFl 775 394 1169
Excluded - not treated Excluded - not treated Excluded - not treated Excluded - not treated 27 (3.5) 15 (3.8) 42 (3.6)
Conversion before infusion (treated) Conversion before infusion (treated) Conversion before infusion (treated) Conversion before infusion (treated) 3 (0.4) 0 3 (0.3)
No post-baseline Holter/ECG No post-baseline Holter/ECG No post-baseline Holter/ECG No post-baseline Holter/ECG 1 (0.1) 0 1 (0.1)
AFib/AFl ITT sample AFib/AFl ITT sample AFib/AFl ITT sample AFib/AFl ITT sample 744 379 1123
Excluded from analysis - DC cardioversion within 2,5 hrs Excluded from analysis - DC cardioversion within 2,5 hrs Excluded from analysis - DC cardioversion within 2,5 hrs Excluded from analysis - DC cardioversion within 2,5 hrs Excluded from analysis - DC cardioversion within 2,5 hrs 5 1 6


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Exclusions from AFib/AFl ITT Sample - Summary

• all exclusions of randomized subjects from ITT
  analyses were pre-specified
• all exclusions were done without knowledge of
  treatment assignment
• 4 categories
• number of exclusions were balanced between
  treatment groups, or very low
• no bias expected
• sensitivity analyses were performed
• including DC cardioversions as failures (dossier)
• including all randomized (additional analysis)
• no impact on efficacy findings

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Number of Randomized Subjects per Country
Country Study Number Study Number Study Number Study Number Study Number Study Number Study Number Study Number Study Number Total per Country
Country 2.102 2.107 3.111 3.112 3.113 3.114 3.116 3.117 3.118 Total per Country
Argentina 10 9 19
Bulgaria 60 60
Canada 27 27
Czech Republic 5 25 23 53
Germany 59 2 15 4 1 81
Greece 2 2
Hungary 42 42
India 5 5
Israel 32 20 52
Italy 4 4
Lithuania 2 13 15
Poland 16 6 76 70 40 35 243
Romania 24 16 40
Russian Federation 8 97 58 21 184
Serbia and Montenegro 17 23 40
Slovakia 1 34 60 95
South Africa 6 2 8
Sweden 2 2
Ukraine 89 137 77 30 333
United Kingdom 2 2 4
United States 26 94 1 16 1 9 13 160
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Number of Randomized Subjects by Country
Argentina 19
Bulgaria 60
Canada 27
Czech Republic 53
Germany 81
Greece 2
Hungary 42
India 5
Israel 52
Italy 4
Lithuania 15
Poland 243
Romania 40
Russian Federation 184
Serbia and Montenegro 40
Slovakia 95
South Africa 8
Sweden 2
Ukraine 333
United Kingdom 4
USA 160

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Pharmacokinetics in Obese Subjects
Dose Gender/BMI N Cmax ng/ml AUC (ngh/mL)
0.32 mg/kg Female 28 kg/m2 92 984 3237
0.32 mg/kg Female gt 28 kg/m2 109 1014 3175
0.48 mg/kg Male 28 kg/m2 92 1227 3593
0.48 mg/kg Male gt 28 kg/m2 77 1428 4052
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Effect of Bodyweight

• Tedisamil is a non-lipophilic drug
• Distribution over total body water only
• ? basis for mg/kg dosing on BW
• For subjects BMIgt 28 kg/m2
• limit the dose to prevent high Cmax
• dosing based on BW associated with a fixed BMI of
  28 kg/m2
• Meta-analysis LBM major effect on Volume of
  ditribution supports for mg/kg dosing on BW

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Tedisamil CL Decreases up to 42 in Patients with
Moderate Renal Impairment, with no Substantial
Effect on Cmax following a Single Dose Short
Infusion
Tedisamil 0.32 mg/kg
Tedisamil (ng/mL)
Time (hrs)
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Reasons for Stopping the Infusion Prematurely
Study 3.118
0.32mg/kgN PlaceboN
Safety sample ( treated) Safety sample ( treated) 77 75
Infusion prematurely stopped Infusion prematurely stopped 1 0
Reason Reason
- Adverse events 1
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Reasons for Stopping the Infusion Prematurely
Study 3.116
0.24mg/kgN 0.32 mg/kgN PlaceboN
Safety sample ( treated) Safety sample ( treated) 120 120 118
Infusion prematurely stopped Infusion prematurely stopped 2 3 2
Reason Reason
Systolic BP lt 90 mmHg 1
QRS duration increase gt 30 1 3 1
Conversion into NSR 1
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Reasons for Stopping the Infusion Prematurely
Study 3.117
0.48 mg/kgN PlaceboN
Safety sample ( treated) Safety sample ( treated) 59 58
Infusion prematurely stopped Infusion prematurely stopped 1 1
Reason Reason
- Patient converted to sinus rhythm 1
- QRS duration increase gt 30 1
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Reasons for Stopping the Infusion Prematurely
Study 3.114 30-Minute Infusion
0.16 mg/kgN 0.32 mg/kgN 0.48 mg/kgN PlaceboN
Safety sample ( treated) Safety sample ( treated) 58 59 54 57
Infusion prematurely stopped Infusion prematurely stopped 0 3 2 0
Reason Reason
- QT interval gt 550 ms and/or gt 20 increase from baseline, measured after conversion 1
- Conversion to sinus rhythm 1
- Conversion to sinus rhythm, bradycardia 1
- Due to administrator reason protocol violation 1
Onset of ventricular tachycardia 1
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Reasons for Stopping the Infusion
PrematurelyStudy 3.112 Females
0.32 mg/kgN 0.48 mg/kgN 0.64 mg/kgN PlaceboN
Safety sample ( treated) 6 11 10 9
Infusion prematurely stopped 1 1 1 0
Reason
Systolic BP lt 90 mmHg 1 0
Threatening change in rhythm or AV conduction 1 1
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Reasons for Stopping the Infusion
PrematurelyStudy 3.112 Males
0.32 mg/kgN 0.48 mg/kgN 0.64 mg/kgN PlaceboN
Safety sample ( treated) Safety sample ( treated) 65 59 50 62
Infusion prematurely stopped Infusion prematurely stopped 1 3 4 0
Reason Reason
- Threatening change in rhythm or AV conduction 1 1
- QT interval gt 550 ms and/or gt 20 increase from baseline, measured after conversion 1 2 2
- Systolic BP lt 90 mmHg, QT interval gt 550 ms and/or gt 20 increase from baseline, measured after conversion 1
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Primary Efficacy Parameter Study S219.3.118
Dose (mg/kg) 3h-45d 3h-45d 48h 48h gt48h gt48h
Dose (mg/kg) n -conversion n -conversion n -conversion
0.32 67 12 (17.9) 19 8 (42.1) 16 4 (8.3)
placebo 67 3 (4.5) 48 2 (12.5) 52 1 (2.0)
P lt 0.01
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Primary Efficacy Parameter Study S219.3.117
Dose (mg/kg) 3h-45d 3h-45d 48h 48h gt48h gt48h
Dose (mg/kg) n -conversion n -conversion n -conversion
0.48 48 14 (29.2) 23 13 (56.5) 25 1 (4.0)
placebo 48 3 (6.3) 32 3 (9.4) 16 0
P lt 0.01
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Primary Efficacy Parameter Study S219.3.116
Dose (mg/kg) Dose (mg/kg) 3h-45d 3h-45d 48h 48h gt48h gt48h
Dose (mg/kg) Dose (mg/kg) n -conversion n -conversion n -conversion
0.24 106 106 10 (9.4) 32 13 (35.1) 74 2 (2.7)
0.32 107 107 23 (21.5) 37 8 (25.0) 70 10 (14.3)
placebo 105 105 3 (2.9) 32 1 (3.1) 73 2 (2.7)
P lt 0.001
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Primary Efficacy Parameter Study S219.3.114
Dose (mg/kg) 3h-45d 3h-45d 48h 48h gt48h gt48h
Dose (mg/kg) n -conversion n -conversion n -conversion
0.16 50 12 (24.0) 26 11 (42.3) 24 1 (4.2)
0.32 51 15 (29.4) 18 11 (61.1) 33 4 (12.1)
0.48 45 14 (31.1) 20 10 (50.0) 24 4 (16.7)
placebo 51 5 (9.8) 19 5 (26.3) 32 0
P lt 0.05
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Primary Efficacy ParameterStudy S219.3.112
Dose (mg/kg) 3h-45d 3h-45d 48h 48h gt48h gt48h
Dose (mg/kg) n -conversion n -conversion n -conversion
0.32 56 13 (23.2) 26 9 (34.6) 30 4 (13.3)
0.48 51 27 (52.9) 28 18 (64.3) 23 9 (39.1)
0.64 44 29 (65.9) 27 19 (70.4) 17 10 (62.5)
placebo 53 3 (5.7) 28 3 (10.7) 25 0
P lt 0.01 P lt 0.001
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Concomitant Medications of Special
InterestFemales ITT sample
Subjects, n () Subjects, n () Subjects, n ()
0.32 mg/kg N 222 Tedisamil N 383 Placebo N 227
Agents Acting on RAS 156 (70.3) 271 (70.8) 165 (72.7)
Antithrombotic Agents 211 (95.0) 361 (94.3) 217 (95.6)
ß-blocking Agents 178 (80.2) 297 (77.5) 181 (79.7)
Calcium Channel Blockers 53 (23.9) 105 (27.4) 69 (30.4)
Cardiac Therapy 157 (70.7) 266 (69.5) 162 (71.4)
Diuretics 98 (44.1) 172 (44.9) 122 (53.7)
Drugs used in Diabetes 28 (12.6) 55 (14.4) 39 (17.2)
Lipid Lowering Agents 52 (23.4) 81 (21.1) 51 (22.5)
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Concomitant Medication Taken by 5 of Subjects
(1) ITT Sample
ATC Second Level Subgroup Combined Tedisamil N 859 n () Placebo N 438 n ()
Agents acting on the Renin-Angiotensin System 546 (63.6) 280 (63.9)
All other Therapeutic Products 43 (5.0) lt 5
Analgesics 120 (14.0) 52 (11.9)
Anesthetics 224 (26.1) 133 (30.4)
Antibacterials for Systemic Use 61 (7.1) 37 (8.4)
Antihistamines for Systemic Use lt 5 lt 5
Antihypertensives lt 5 28 (6.4)
Anti-inflammatory and Anti-rheumatic Products lt 5 lt 5
Anti-thrombotic Agents 815 (94.9) 412 (94.1)
Beta-Blocking Agents 637 (74.2) 333 (76.0)
Blood Substitutes and Perfusion Solutions 97 (11.3) 68 (15.5)
Calcium Channel Blockers 197 (22.9) 117 (26.7)
Cardiac Therapy 574 (66.8) 312 (71.2)
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Baseline CharacteristicsHistory of AFib/AFl
Males Males Females Females
Tedisamil Placebo Tedisamil Placebo
N 476 N 211 N 383 N 227
Subjects with first episode, n () 237 (49.8) 95 (45.0) 175 (45.7) 106 (46.7)
Subjects with recurrent episode, n () 239 (50.2) 116 (55.0) 208 (54.3) 121 (53.3)
Atrial Fibrillation 190 (79.5) 95 (81.9) 178 (85.6) 99 (81.8)
Atrial Flutter 19 (7.9) 13 (11.2) 10 (4.8) 6 (5.0)
Both 30 (12.6) 8 (6.9) 20 (9.6) 15 (12.4)
Mean duration of AFib/AFl in yrs SD 5.0 5.8 4.5 5.4 3.3 3.5 3.3 3.4
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Baseline Characteristics Predominant Rhythm
Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n () Subjects, n ()
Males Males Males Females Females Females
0.48 mg/kg Combined Tedisamil Placebo 0.32 mg/kg Combined Tedisamil Placebo
AFib 174 (84.1) 449 (85.0) 191 (82.7) 199 (88.4) 351 (87.1) 217 (90.8)
AFl 33 (15.9) 79 (15.0) 40 (17.3) 26 (11.6) 52 (12.9) 22 (9.2)
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Baseline CharacteristicsHistory of AFib/AFl
Males Males Females Females
Tedisamil Placebo Tedisamil Placebo
N 476 N 211 N 383 N 227
Subjects with first episode, n () 237 (49.8) 95 (45.0) 175 (45.7) 106 (46.7)
Subjects with recurrent episode, n () 239 (50.2) 116 (55.0) 208 (54.3) 121 (53.3)
Mean Duration of AFib/AFl in yrs SD 5.0 5.8 4.5 5.4 3.3 3.5 3.3 3.4
for those with a recurrent episode
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Primary Efficacy Parameter Conversion to NSR
within 2.5 hrs By History of AFIB/AFL
Dose, mg/kg Male Male Male Male Female Female Female Female
Dose, mg/kg First episode First episode Recurrent episode Recurrent episode First episode First episode Recurrent episode Recurrent episode
Dose, mg/kg n Converting, n Converting, n Converting, n Converting,
0.16 34 6 (17.6) 24 6 (25.0) 0 - 0 -
0.24 0 - 0 - 63 7 (11.1) 55 5 (9.1)
0.32 53 9 (17.0) 69 19 (27.5) 90 15 (16.7) 112 22 (19.6)
0.48 99 29 (29.3) 72 30 (41.7) 2 1 (50.0) 8 1 (12.5)
0.64 24 17 (70.8) 25 15 (60.0) 3 1 (33.3) 8 2 (33.3)
Placebo 83 6 (7.2) 94 5 (5.3) 94 3 (3.2) 107 6 (5.6)
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Primary Efficacy Parameter Conversion to NSR
Within 2.5 hrs By Predominant Rhythm
Dose, mg/kg Male Male Male Male Male Female Female Female Female Female
Dose, mg/kg AFib AFib AFl AFl AFib AFib AFl AFl
Dose, mg/kg n Converting, n Converting, n Converting, n Converting,
0.16 50 12 (24.0) 8 0 0 - 0
0.24 0 - 0 - 106 10 (9.4) 12 2 (16.7)
0.32 107 28 (26.2) 15 0 179 36 (20.1) 23 1 (4.3)
0.48 144 55 (38.2) 27 4 (14.8) 8 2 (25.0) 2 0
0.64 43 29 (67.4) 6 3 (50.0) 2 2 (33.3) 3 1 (33.3)
Placebo 152 11 (7.2) 25 0 180 6 (3.3) 21 3 (14.3)
40
HemodynamicsK.219.5005
Table 6 Effects of Tedisamil on Pulmonary and
Cardiac Pressure Indices differences post-drug
and pre-drug
Dosage group (mg/kg) Dosage group (mg/kg) PAP(mmHg) PCWP(mmHg) PAEDP(mmHg) PRA(mmHg) PRV(mmHg)
0.1 Rest -2.1 -1.4 -2.5 -0.3 0.0
Max workload -0.6 -0.9 -3.1
0.2 Rest -1.6 -0.9 -1.3 -0.3 -0.4
Max workload 1.0 -1.4 0.5
0.3 Rest 1.8 2.3 1.6 0.9 0.9
Max workload 2.6 4.8 4.3
0.4 Rest 3.3 2.8 2.6 1.5 1.5
Max workload -1.8 -0.1 -1.0
Mean values plt0.05 plt0.01 Mean values plt0.05 plt0.01 Mean values plt0.05 plt0.01 Mean values plt0.05 plt0.01 Mean values plt0.05 plt0.01 Mean values plt0.05 plt0.01 Mean values plt0.05 plt0.01
41
HemodynamicsK.219.5005

• Study K.219.5005
• Single, intravenous, rising dose, open study of
  tedisamil dihydrochloride (KC 8857) investigating
  hemodynamics in patients with documented ischemic
  heart disease.

42
HemodynamicsS219.3.109
Secondary Parameter Pulmonary Capillary Wedge
Pressure (PCWP) at Rest Per-protocol patient
sample (N 56)
Visit Tedisamil(N 24) Placebo(N 32) p-value for difference
RAP (mmHg) Baseline 7.4 3.7 7.3 3.7
RAP (mmHg) Visit 9 (Wk 12) 5.2 3.4 5.0 5.5
RAP (mmHg) Change from baseline -2.4 3.5 -2.9 4.8 0.784

ESRVP (mmHg) Baseline 39.7 12.1 42.7 15.8
ESRVP (mmHg) Visit 9 (Wk 12) 38.4 14.2 41.2 19.2
ESRVP (mmHg) Change from baseline -1.3 10.3 -1.1 12.3 0.999

EDRVP (mmHg) Baseline 3.6 2.5 3.7 2.6
EDRVP (mmHg) Visit 9 (Wk 12) 3.0 2.7 3.0 4.0
EDRVP (mmHg) Change from baseline -0.8 2.6 -0.6 3.9 0.849
RAP right atrial pressure ESRVP endsystolic right ventricular pressure EDRVP enddiastolic right ventricular pressure. RAP right atrial pressure ESRVP endsystolic right ventricular pressure EDRVP enddiastolic right ventricular pressure. RAP right atrial pressure ESRVP endsystolic right ventricular pressure EDRVP enddiastolic right ventricular pressure. RAP right atrial pressure ESRVP endsystolic right ventricular pressure EDRVP enddiastolic right ventricular pressure. RAP right atrial pressure ESRVP endsystolic right ventricular pressure EDRVP enddiastolic right ventricular pressure.
43
HemodynamicsS219.3.109
Primary Parameter Pulmonary Capillary Wedge
Pressure (PCWP) at Rest Per-protocol patient
sample (N 56)
PCWP at rest (mmHg) Tedisamil (N 24) mean SD Placebo (N 32) mean SD p-value for equivalence
Baseline 18.1 5.4 19.4 6.2
Visit 9 (wk 12) 16.0 6.2 16.2 8.8
Visit 9 - baseline -2.0 5.6 -3.2 7.5 0.070

44
HemodynamicsS219.3.109

• Study S219.3.109
• Double-blind randomized study comparing the
  hemodynamic effects of oral tedisamil and placebo
  in patients with symptomatic congestive heart
  failure

45
In Normal Sinus Rhythm at 24 hrs
Males Males Males
0.48 mg/kg Tedisamil Placebo
NSR at 24 hrs 88/172 (51) 84/177 (47)
no DC 61/133 (46) 36/122 (30)
DC 27/39 (69) 48/55 (87)
Females Females Females
0.32 mg/kg Tedisamil Placebo
NSR at 24 hrs 80/202 (40) 69/202 (34)
no DC 49/163 (30) 27/152 (18)
DC 31/39 (79) 42/50 (84)
46
Conversion to NSR Male
AFib/AFl Duration
3 48 hrs 48 hrs 7 days 8 45 days
tedisamil 0.48 mg/kg 52.4 28.6 13.1
Placebo 12.4 0 0
Change 40.0 28.6 13.1
47
Conversion to NSR Female
AFib/AFl Duration
3 48 hrs 48 hrs 7 days 8 45 days
tedisamil 0.32 mg/kg 32.4 16.3 8.0
Placebo 10.0 0 3.3
Change 22.4 16.3 4.7