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Tedisamil Efficacy-Safety Matthias Straub, MD

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.

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Tedisamil Efficacy-Safety Matthias Straub, MD

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  1. Tedisamil Efficacy-SafetyMatthias Straub, MD Vice President, Global Clinical Development Solvay Pharmaceuticals

  2. 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

  4. 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

  5. Summary of Phase II Studies Briefing Book table 4-1

  6. 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 doesn’t cause uncontrolled Cmax, causing TdP’s

  7. Two-Step Infusion RegimenPK/PD Time Profile – Healthy Volunteers Two step infusion Briefing Book figure 3-1

  8. Summary of Phase II Studies Briefing Book table 4-1

  9. Primary Efficacy Parameter Proof of Principle Study S219.2.107 Data from BD pg 12 (1111078) Data Briefing Book page 32

  10. Secondary Efficacy ParameterProof of Principle Study S219.2.107

  11. 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

  12. Phase III Efficacy StudiesMales Briefing Book table 4-1

  13. Phase III Efficacy Studies Females Briefing Book table 4-1

  14. Study Design for Efficacy Studies Double-blind Treatment Period Follow-up Period Screening RANDOMIZATION Placebo SCREENING 30 min infusion IV Tedisamil Up to 48 hrs 24 hr observation 4 wks Screening Randomization End-of-24-hr observation period Follow-up

  15. 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)

  16. 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

  17. 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

  18. Baseline CharacteristicsAge, Race Note: safety data set Briefing Book table 5-2/3; appendix 2

  19. Baseline CharacteristicsNYHA, Creatinine and Duration of AFib/AFl Briefing Book table 5-2/3; appendix 2

  20. 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

  21. 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

  22. 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)

  23. Individual Study Efficacy Results Phase III Studies

  24. Phase III Primary Efficacy – AFib MalesConversion Rates BD T1-1, 5-4. Briefing Book table 5-4

  25. Phase III Primary Efficacy – AFib FemalesConversion Rates BD T1-1. Briefing Book table 5-5

  26. 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

  27. 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

  28. 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

  29. Sensitivity Analysis: Conversion Within 2.5 hrs • S219.3.112 AFib Males N = samplen = number of converters

  30. 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

  31. 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

  32. 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

  33. 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

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

  35. 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)

  36. Secondary Efficacy Parameters – Males BD T1-3. * Subjects that converted within 2.5 hours Briefing Book table 5-9

  37. Secondary Efficacy Parameters – Females BD T1-3. * Subjects that converted within 2.5 hrs Briefing Book table 5-9

  38. Secondary Efficacy – Median Time to Conversion Briefing Book table 5-10

  39. 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

  40. Tedisamil Safety

  41. Safety Agenda • Exposure • Adverse Events • Total • Cardiac • Deaths • Adjudicated Events • Monitoring Window • Dose Selection

  42. Total Exposure to IV Tedisamil Briefing Book table 6-1

  43. Subject Disposition IV Tedisamil AFib/AFl Clinical Program Consented 1619 Randomized 1469 Screen Failures 150 Tedisamil 974 Placebo 495 Treated 931 Not treated 43 Treated 470 Not treated 25

  44. Integrated Safety Database by Subgroups Briefing Book table 6-3

  45. Overview of AEs by Dose Over 4 WeeksMales and Females Briefing Book table 6-4, 6-5

  46. TEAEs of Special Interest Non-Cardiac Disorders - Males (1) Briefing Book table 6-6

  47. TEAEs of Special Interest Non-Cardiac Disorders - Males(2) Briefing Book table 6-6

  48. TEAEs of Special Interest Non-Cardiac Disorders - Females(1) Briefing Book table 6-7

  49. TEAEs of Special Interest Non-Cardiac Disorders - Females(2) Briefing Book 6-7

  50. TEAEs of Special Interest: Selected Cardiac Disorders – Males Briefing Book table 6-10

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