NDA 21-686

Ximelagatran (H376/95)

Indication: Prevention of stroke and thromboembolic complications associated with atrial fibrillation

Mehul Desai, M.D.

Medical Officer

Division of Cardiovascular and Renal Drug Products

NOTE: This is a preliminary/draft review that is not intended to provide any recommendations on the approvability of NDA 21,686. Any opinions expressed in the review do not necessarily reflect those of the Division/Office.
Table of Contents

I. Recommendations............................................................................................................... 10

A. Recommendation on Approvability................................................................................ 10

B. Recommendation on Phase 4 Studies and/or Risk Management Steps............................ 11

II. Summary of Clinical Findings............................................................................................... 11

A. Brief Overview of Clinical Program............................................................................... 11

B. Efficacy........................................................................................................................ 12

C. Safety........................................................................................................................... 12

D. Dosing.......................................................................................................................... 13

E. Special Population........................................................................................................ 14

Clinical Review................................................................................................................................ 15

III. Introduction and Background............................................................................................... 15

A. Drug Established and Proposed Trade Name, Drug Class, Sponsor’s Proposed Indication(s), Dose Regimens, Age Groups............................................................................................................................ 15

B. State of Armamentarium for Indication(s)...................................................................... 15

C. Important Milestones in Product Development............................................................... 15

IV. Clinically Relevant Findings from From Chemistry, Animal Pharmacology and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other Consultant Reviews...................................................... 16

V. Human Pharmacokinetics and Pharmacodynamics................................................................ 16

A. Pharmacokinetics.......................................................................................................... 16

B. Pharmacodynamics....................................................................................................... 19

VI. Description of Clinical Data and Sources.............................................................................. 22

A. Overall Data................................................................................................................. 22

B. Tables Listing the Clinical Trials..................................................................................... 23

C. Postmarketing Experience............................................................................................. 23

D. Literature Review......................................................................................................... 24

VII. Clinical Review Methods..................................................................................................... 31

A. How the Review was Conducted.................................................................................. 31

B. Overview of Materials Consulted in Review.................................................................. 31

C. Overview of Methods Used to Evaluate Data Quality and Integrity................................ 31

D. Were Trials Conducted in Accordance with Accepted Ethical Standards....................... 31

E. Evaluation of Financial Disclosure.................................................................................. 32

VIII. Integrated Review of Efficacy.............................................................................................. 32

A. Brief Statement of Conclusions...................................................................................... 32

B. General Approach to Review of the Efficacy of the Drug............................................... 33

C. Detailed Review of Trials by Indication.......................................................................... 33

1. SPORTIF V........................................................................................................... 33

a. Study dates......................................................................................................... 33

b. Protocol amendments:......................................................................................... 33

c. Study Design:...................................................................................................... 35

d. Rationale for doses selected................................................................................. 38

e. Blinding/Randomization........................................................................................ 38

f. Pre-specified Study Objectives............................................................................ 39

g. Definitions of study endpoints............................................................................... 39

h. Inclusion/Exclusion Criteria.................................................................................. 41

i. Statistical considerations (please refer to statistical review for details).................... 42

j. Study patient disposition...................................................................................... 45

k. Protocol deviations.............................................................................................. 47

l. Demographics and other patient characteristics..................................................... 48

m. Primary endpoint results....................................................................................... 52

n. Secondary and Tertiary endpoint results............................................................... 54

o. Adequacy of anticoagulation in the warfarin arm................................................... 56

2. SPORTIF III.......................................................................................................... 57

a. Study dates......................................................................................................... 57

b. Protocol Amendments......................................................................................... 57

c. Study Design:...................................................................................................... 59

d. Rationale for doses selected................................................................................. 60

e. Blinding/Randomization:....................................................................................... 60

f. Pre-specified study objectives.............................................................................. 60

g. Definitions of study endpoints............................................................................... 60

h. Inclusion/Exclusion Criteria:................................................................................. 60

i. Statistical Considerations (please refer to the statistical review for details):............. 60

j. Study patient disposition...................................................................................... 60

k. Protocol deviations.............................................................................................. 62

l. Demographics and other patient characteristics..................................................... 63

m. Primary endpoint results....................................................................................... 67

n. Secondary and Tertiary endpoint results............................................................... 69

o. Adequacy of anticoagulation in the warfarin arm................................................... 70

D. Efficacy Conclusions..................................................................................................... 71

IX. Integrated Review of Safety................................................................................................. 72

A. Brief Statement of Conclusions...................................................................................... 72

B. Description of Patient Exposure.................................................................................... 73

C. Methods and Specific Findings of Safety Review........................................................... 74

1. Study population definitions..................................................................................... 74

2. Deaths.................................................................................................................... 75

3. Serious Adverse Events other than death.................................................................. 76

4. Discontinuations due to Adverse Events................................................................... 78

5. Adverse Bleeding Events......................................................................................... 79

6. Hepatobiliary Adverse Events.................................................................................. 84

7. Most commonly reported adverse events (AE’s)...................................................... 90

8. Pancreatic Adverse Events...................................................................................... 91

9. Other Laboratory Test Adverse events.................................................................... 92

10. Adverse events related to vital signs, ECG, physical findings..................................... 93

D. Adequacy of Safety Testing.......................................................................................... 93

E. Summary of Critical Safety Findings and Limitations of Data.......................................... 93

X. Dosing, Regimen, and Administration Issues......................................................................... 93

XI. Use in Special Populations................................................................................................... 94

A. Evaluation of Sponsor’s Gender Effects Analyses and Adequacy of Investigation........... 94

B. Evaluation of Evidence for Age, Race, or Ethnicity Effects on Safety or Efficacy............. 94

C. Evaluation of Pediatric Program.................................................................................... 94

D. Comments on Data Available or Needed in Other Populations....................................... 94

XII. Conclusions and Recommendations..................................................................................... 94

A. Conclusions.................................................................................................................. 94

B. Recommendations........................................................................................................ 95

XIII. Appendix............................................................................................................................ 95

A. Other Relevant Materials.............................................................................................. 95

1. SPORTIF II............................................................................................................ 95

2. SPORTIF IV.......................................................................................................... 96

B. Individual More Detailed Study Reviews (if performed)................................................. 97

List of Tables

Table I: Cumulative risk of major bleeding with increasing exposure of study drug in SPORTIF III/V. 13

Table II: Cumulative risk of ALAT >3x ULN with increasing exposure of study drug in SPORTIF III/V 14

Table III: Important milestones in Product development.................................................................... 15

Table IV: Effects of renal impairment on the pharmacokinetics of melagatran, the active metabolite of ximelagatran. Values represent the ratio of subjects with renal impairment to patients with normal renal function......... 18

Table V: Summary of the clinical trials submitted in support of the atrial fibrillation indication.............. 23

Table VI: Summary of randomized controlled trials of warfarin in patients with atrial fibrillation........... 26

Table VII: Summary of the issue dates of the original protocol and protocol amendments to Study 0005 34

Table VIII: Table summarizing the primary reason for discontinuing study drug (ITT population)^a....... 46

Table IX: Comparison of total study drug discontinuation rates including and excluding patients with ALAT > 3x ULN^a 46

Table X: Summary of inclusion/exclusion criteria violations by treatment groups (Please refer to inclusion/exclusion criteria section of this review to match the number with the description of the criteria)^a.......................... 47

Table XI: Number (%) of patients by total days of treatment interruption, and treatment group^a......... 48

Table XII: INR measurements for warfarin patients in SPORTIF V.................................................. 48

Table XIII: Patient characteristics at screening: number (%) of patients by treatment group (ITT population)^a 49

Table XIV: Mean (+SD) of patient characteristics at screening (ITT population)^a.............................. 50

Table XV: Number (%) of patients with the presence of the listed risk factor at study entry............... 50

Table XVI: Number (%) of patients with concomitant medication use at study entry by treatment group (ITT population)^a............................................................................................................................................... 51

Table XVII: Proportion of time patients took concomitant ASA between the first and last dose of study drug (ITT population)^a............................................................................................................................. 51

Table XVIII: Number (%) of patients using other cardiovascular medications between the first and last dose of study drug, by treatment group (ITT population)^a....................................................................................... 52

Table XIX: Number of patients with stroke and/or SEE by treatment group (primary prespecified endpoint)^a 52

Table XX: Breakdown of primary endpoint by type of event and whether fatal or non-fatal^a.............. 53

Table XXI: Number of patients with all cause mortality/stroke/ SEE/AMI by treatment group (secondary prespecified endpoint based on OT analysis)^a.............................................................................................. 55

Table XXII: Number of patients with ischemic stroke/TIA/SEE by treatment group (secondary prespecified endpoint based on OT analysis)^a...................................................................................................................... 55

Table XXIII: Number of patients with strokes with a poor outcome by treatment group (tertiary prespecified endpoint based on ITT analysis)^a...................................................................................................................... 55

Table XXIV: Number of patients with stroke or SEE as a function of age (<, > 75 years of age) (tertiary prespecified endpoint based on ITT analysis)^a.............................................................................................. 56

Table XXV: Original Protocol and Protocol Amendment Issue dates for SPORTIF III.................... 57

Table XXVI: Summary of the reasons for discontinuing study drug (ITT population)^a......................... 62

Table XXVII: Comparison of total study drug discontinuation rates including and excluding patients with ALAT > 3x ULN^a............................................................................................................................................... 62

Table XXVIII: Number of patients that discontinued the study and had missing vital status or primary event data at time of study closure procedures but were asked to re-consent to provide follow-up information.......... 62

Table XXIX: Inclusion/exclusion criteria violations by treatment group.............................................. 63

Table XXX: Number (%) of patients by total days of treatment interruption, and treatment group^a..... 63

Table XXXI: Patient characteristics at screening: number (%) of patients by treatment group (ITT population)^a 64

Table XXXII: Mean (+SD) of patient characteristics at screening (ITT population)^a.......................... 65

Table XXXIII: Number (%) of patients with presence of the listed risk factor at study entry^a............. 65

Table XXXIV: Number (%) of patients with concomitant medication use at study entry by treatment group (ITT population)^a............................................................................................................................................... 66

Table XXXV: Proportion of time patients took concomitant ASA between the first and last dose of study drug (ITT population)^a............................................................................................................................. 66

Table XXXVI: Number (%) of patients using other cardiovascular medications between the first and last dose of study drug, by treatment group (ITT population)^a....................................................................................... 67

Table XXXVII: Number of patients with stroke and/or SEE by treatment group (primary prespecified endpoint)^a 67

Table XXXVIII: Listing of the individual components of the primary endpoint in SPORTIF III^a......... 67

Table XXXIX: Number of patients with all cause mortality/stroke/ SEE/AMI by treatment group (secondary prespecified endpoint based on OT analysis)^a.............................................................................................. 69

Table XL: Number of patients with ischemic stroke/TIA/SEE by treatment group (secondary prespecified endpoint based on OT analysis)^a........................................................................................................................... 70

Table XLI: Number of patients with strokes with a poor outcome by treatment group (tertiary prespecified endpoint based on ITT analysis)^a...................................................................................................................... 70

Table XLII: Number of patients with stroke or SEE as a function of age (<, > 75 years of age) (tertiary prespecified endpoint based on ITT analysis)^a.............................................................................................. 70

Table XLIII: Demographic description of Safety population............................................................. 73

Table XLIV: Summary of Exposure Data......................................................................................... 74

Table XLV: Listing of the most common adverse events leading to death^a(PLEASE NOTE THAT NUMBER OF EVENTS RATHER THAN PERCENTAGES ARE REPORTED)......................................................... 75

Table XLVI: Listing of serious adverse events not leading to death^{a, b, c, d, e} (PLEASE NOTE THAT NUMBER OF EVENTS RATHER THAN PERCENTAGES ARE REPORTED).......................................... 76

Table XLVII: Listing of study drug discontinuations due to adverse events. Listed are the total number of AE’s occurring at a frequency of > 1% in the ximelagatran group or were > 2x fold higher in the ximelagatran arm relative to the warfarin arm^a (PLEASE NOTE THAT NUMBER OF EVENTS RATHER THAN PERCENTAGES ARE REPORTED) 78

Table XLVIII: Summary Table of Major bleeding events (Based on On Treatment – OT Analysis)^a.. 79

Table XLIX: Number of patients with major bleeding events according to the CEAC, by criteria for judgment according to local criteria assessed and by treatment group (OT analysis)^a.................................................... 82

Table L: Locations/subtypes of major bleeds^a................................................................................... 82

Table LI: Frequency of patients with elevated ALAT, ASAT, ALP, and Bilirubin (ITT population)^a (PLEASE NOTE THAT NUMBER OF EVENTS RATHER THAN PERCENTAGES ARE REPORTED)................. 84

Table LII: Number of Patients with ALAT > 3x ULN followed by a bilirubin level > 2x ULN within one month of the elevated ALAT (PLEASE NOTE THAT NUMBER OF EVENTS RATHER THAN PERCENTAGES ARE REPORTED) ......................................................................................................................... 85

Table LIII: Pattern of liver enzyme progression for Patient 7259....................................................... 88

Table LIV: Pattern of liver enzyme progression for patient 7859....................................................... 89

Table LV: Most common AE’s with an absolute frequency > 5% (based on the ximelagatran arm) or were > 2 fold higher than on the control group (warfarin)^a........................................................................................ 90

Table LVI: Summary of pancreatic adverse events in SPORTIF III and SPORTIF V....................... 91

Table LVII: Comparison of cholecystokinin plasma concentrations at month 3 in a subset of patients in the SPORTIF V study^a...................................................................................................................................... 91

Table LVIII: Pancreatic volume obtained via CT scan: mean change from screening to last available value. (SPORTIF V study)^a..................................................................................................................................... 92

Table LIX: Summary of safety findings from SPORTIF II study (shown are the numbers of patients with events) 96

Table LX: Summary of findings from the SPORTIF IV study............................................................ 97

Table LXI: Pattern of liver enzyme progression in patient 3174......................................................... 98

Table LXII: Pattern of liver enzyme progression for patient 1967...................................................... 99

Table LXIII: Pattern of liver enzyme progression for patient 7986................................................... 100

Table LXIV: Pattern of liver enzyme progression for patient 5402................................................... 101

Table LXV: Pattern of liver enzyme progression for patient 8387.................................................... 101

List of Figures

Figure 1: The metabolic pathways of ximelagatran for the formation of melagatran (Figure taken from Figure 1 of Summary of Clinical Pharmacology Studies)............................................................................................ 17

Figure 2: Mean CrCL (ml/min) versus CL/F (l/h) after oral ximelagatran administration (This figure taken from Figure 11:9 of Sponsor’s Clinical Pharmacology Study Report for study SH-TP1-0026)................................. 19

Figure 3: Relationship between aPTT levels and plasma concentrations of melagatran (obtained from Figure 18 of the Sponsor’s Summary of Clinical Pharmacology Studies)............................................................ 20

Figure 4: Relationship between the PK time course of melagatran and the PD time course of aPTT (obtained from Figure 19 of the Sponsor’s Summary of Clinical Pharmacology Studies)................................................... 21

Figure 5: INR values plotted versus plasma melagatran concentration (Figure obtained from Figure 27 of Summary of Clinical Pharmacology Studies)................................................................................................ 22

Figure 6: Study Schema for SPORTIF V (Figure taken from Figure 1 of SPORTIF V CSR)............ 36

Figure 7: Patient disposition in SPORTIF V (Figure taken from Figure 4 of SPORTIF V CSR)......... 45

Figure 8: Cumulative proportion of patients with stroke and/or SEE over time-estimated Kaplan-Meier curves (Figure taken from Figure 12 of SPORTIF V CSR)...................................................................................... 53

Figure 9: Event rate difference (ximelagatran – warfarin) for the primary endpoint (stroke and/or SEE) according to prognostic factors (Figure taken from Figure 16 of SPORTIF V CSR)..................................... 54

Figure 10: Adequacy of anticoagulation as assessed by INR in patients assigned to warfarin (OT population); (Figure taken from Figure 23 of SPORTIF V CSR)...................................................................................... 56

Figure 11: Study Schema for SPORTIF III (Figure obtained from Figure 1 of SPORTIF III CSR).... 59

Figure 12: Patient disposition in SPORTIF III (Figure obtained from Figure 4 of SPORTIF III CSR) 61

Figure 13: Cumulative proportion of patients with stroke and/or SEE (primary endpoint) over time – estimated Kaplan-Meier curves (This figure obtained from Figure 12 of SPORTIF III CSR)................................. 68

Figure 14: Event rate difference (ximelagatran – warfarin) for the primary endpoint (stroke and/or SEE) according to prognostic factors (This figure obtained from Figure 13 of SPORTIF III CSR)......................... 69

Figure 15: Adequacy of anticoagulation as assessed by INR in patients assigned to warfarin (OT population) (This figure was obtained from Figure 25 of SPORTIF III CSR)................................................................ 71

Figure 16: Cumulative percentage of patients with major bleeding events over time – Estimated Kaplan-Meir Curves (OT analysis) for SPORTIF III study (Obtained from Figure 32 of Sponsor’s SPORTIF III Clinical Study report) 81

Figure 17: Cumulative percentage of patients with major bleeding events over time; estimated Kaplan-Meier curves (OT Analysis). (Obtained from Figure 25 of Sponsor’s SPORTIF V Clinical Study report).............. 81

Figure 18: Summary of safety comparison: ximelagatran vs. warfarin (difference in percent events, with 95% CI) for major bleed events, according to prognostic factors (OT analysis) (SPORTIF III) (Obtained from Figure 33 of SPORTIF III CSR)...................................................................................................................................... 83

Figure 19: Summary of safety comparison: ximelagatran vs. warfarin (difference in percent events, with 95% CI) for major bleed events, according to prognostic factors (OT analysis) (SPORTIF V) (Obtained from Figure 26 of SPORTIF V CSR)...................................................................................................................................... 84

Figure 20: Cumulative risk of ALAT > 3x ULN versus time after randomization (ITT population) (Figure obtained from Figure 36 of SPORTIF III CSR)............................................................................................. 86

Figure 21: Cumulative risk of ALAT > 3x ULN versus time after randomization (ITT population) (Figure obtained from Figure 33 of SPORTIF V CSR).............................................................................................. 86

Figure 22: Summary of patients on ximelagatran with an ALAT > 3x ULN in SPORTIF III............... 87

Figure 23: Estimated within-group ratios relative to baseline (each patient’s mean of all measurements post-randomization divided by baseline) with 95% CI. Between-group comparisons for those ratios made with unpaired t-test (OT analysis) (Figure taken from Figure 41 of SPORTIF V CSR)................................................... 92

Executive Summary

I. Recommendations

A. Recommendation on Approvability

The sponsor of NDA 21-686 is currently seeking approval of ximelagatran (H376/95) for 3 different indications. The indication that is the focus of this review is the prevention of stroke and other thromboembolic complications associated with atrial fibrillation. Two pivotal phase 3 studies (SPORTIF III and SPORTIF V) have been submitted in support of the stated indication. The two studies are active controlled studies designed to show that ximelagatran is non-inferior or “as efficacious as” treatment with warfarin, the current standard of care. The active controlled, non-inferiority design of the SPORTIF studies makes interpretation of efficacy relatively more complicated compared to a design involving a placebo control. An important step in interpreting the effectiveness of ximelagatran in the SPORTIF studies is to understand the benefit of warfarin relative to placebo. The benefit of warfarin relative to placebo was derived from several placebo controlled trials conducted approximately 10 to 15 years ago and published in the peer reviewed medical literature. A summary of these studies is discussed in detail elsewhere in this review. Based on these studies, the relative risk reduction for stroke appears to be approximately 64% (95% CI à 47%, 75%).

The 2 SPORTIF studies compared the effectiveness of a fixed dose of ximelagatran, 36 mg administered twice a day, to warfarin, targeting an INR of 2 – 3 in patients with nonvalvular atrial fibrillation and at least one additional risk factor for stroke. SPORTIF III and SPORTIF V were similar in design except that the former was open-label while the latter was blinded. The primary endpoint was a composite of all strokes (ischemic and hemorrhagic) and systemic embolic events. The sponsor pre-specified a non-inferiority margin of 2% in the event rate. Ximelagatran would be called non-inferior if an excess of 2% per year in the event rate relative to warfarin could be confidently excluded. A margin of this magnitude could leave open the possibility that ximelagatran was only half as effective as warfarin and still be considered non-inferior to warfarin. The magnitude of this non-inferiority margin was not formally agreed upon by the reviewing division within the Agency and marked as a point of future review/discussion.

The two SPORTIF studies produced divergent results despite similar designs. In SPORTIF III, the primary event rate was numerically higher in the warfarin arm compared to the ximelagatran arm. In SPORTIF V, the primary event rate was numerically higher in the ximelagatran arm compared to the warfarin arm. Comparing the event rates in the common arm of both SPORTIF studies, the rate in the ximelagatran arm was practically the same in both studies while the event rate in the warfarin arm varied by nearly two-fold. The variable event rate on warfarin in the two studies could potentially be attributed to the fact that patients in the two studies were slightly different at baseline. Patients in SPORTIF V were slightly older, had lower blood pressures on average, had fewer patients with histories of transient ischemic attacks (TIA’s) or strokes, and had greater consumption of HMG CoA reductase inhibitors than did patients enrolled in SPORTIF III. It is puzzling why differences in patient populations of both studies would lead to differences in event rates in the warfarin arms while leaving the event rate in the ximelagatran arms unaffected. In such a setting where two similarly designed studies produce divergent results, I would favor the results from a double-blind study.

In terms of safety, liver toxicity as assessed by serum aminotransferase abnormalities occurred approximately 6 times more often on ximelagatran compared to warfarin and was consistent across both trials. There was one well documented case (and most probably a second case) of drug induced liver failure leading to coagulopathy and death among the approximately 3700 patients randomized to ximelagatran. Intense protocol mandated liver enzyme monitoring did not prevent serious liver toxicity in these two cases although in some other cases it did prevent serious adverse outcomes. These two cases highlight the possibility that liver enzyme monitoring as a risk management strategy may not be entirely fool proof. In terms of major bleeding events, the total number of bleeds was numerically lower in the ximelagatran arm of both studies. In neither of the studies did the difference achieve statistical significance. The majority of major bleeds in both studies were due to bleeding with a fall in the hemoglobin level of > 2g/dL or due to overt bleeding requiring > 2 units of whole blood. Bleeding events leading to death were relatively few in both studies and similar in the two treatment arms.

With respect to dosing, there is a strong correlation between the oral clearance of melagatran (the active metabolite of ximelagatran) and creatinine clearance. Thus exposure to melagatran will be affected by renal impairment. Varying degrees of renal impairment are expected in the patient population for which this therapy is targeted and will potentially be a significant factor affecting exposure to melagatran. There is a clear relationship between higher exposures to melagatran and increased risk of major bleeds and elevations in aminotransferases. A strategy of fixed dosing as is being proposed for ximelagatran is concerning.

B. Recommendation on Phase 4 Studies and/or Risk Management Steps

The sponsor has proposed a risk management program that is intended to minimize the risk of severe hepatic injury that could occur in the setting ximelagatran use. One of the key features of this program involves liver enzyme (ALAT) monitoring. The method of monitoring proposed in the risk management plan is similar in intensity to the monitoring that was conducted in the pivotal clinical trials. Unfortunately, the relatively intense liver enzyme monitoring in the clinical trials did not prevent two cases of drug induced liver failure/death in the SPORTIF V study.

The experience of the FDA in using liver enzyme monitoring as a risk management tool has been disappointing particularly in the case of troglitazone. Troglitazone was an antidiabetic agent that was approved in 1997 but taken off the market in 2000 because of numerous cases of liver failure reported post marketing. Despite labeling changes, Dear doctor letters and other risk management strategies, baseline testing of liver enzymes was conducted in less than one-half of the patients that were started on troglitazone (Graham et al JAMA 2001;286:831-833).

II. Summary of Clinical Findings

A. Brief Overview of Clinical Program

One of the indications that ximelagatran is being developed for is the prevention of stroke and other thromboembolic complications associated with atrial fibrillation. Two pivotal phase 3 studies have been submitted in support of the stated indication. In the atrial fibrillation development program a total of approximately 7,300 patients were followed for an average of 1.4 years. The two studies were active controlled studies designed to show that ximelagatran is “non-inferior” to treatment with warfarin, the current standard of care. The 2 SPORTIF studies compared the effectiveness of fixed doses of ximelagatran 36 mg administered twice a day versus warfarin, targeting an INR of 2 – 3 in patients with nonvalvular atrial fibrillation and at least one additional risk factor for stroke.

B. Efficacy

SPORTIF III and SPORTIF V are two Phase III, active control, non-inferiority studies that were provided in support of NDA21-686. Both studies compared the effectiveness of a fixed dose of ximelagatran, 36 mg administered twice a day to warfarin targeting an INR of 2 to 3 in patients with nonvalvular atrial fibrillation and at least one additional risk factor for stroke. The studies were very similar in design except that SPORTIF III was open label while SPORTIF V was double-blind. The primary endpoint was the composite of all strokes (fatal and non-fatal) and systemic embolic events. The sponsor pre-specified a non-inferiority margin of 2% points in the event rate in both studies. A margin of that size could leave open the possibility that ximelagatran is only half as effective as warfarin and still be considered “non-inferior.”

In both studies, the efficacy of ximelagatran was within the sponsor’s pre-specified non-inferiority margin of 2% and it was concluded by the sponsor that ximelagatran was as efficacious as warfarin. While the two studies could be considered “successes” based on the sponsor’s pre-specified margin, the margin chosen was too liberal.

The two SPORTIF studies produced divergent results despite their similar designs and patient populations studied. In SPORTIF V, the event rate was higher in the ximelagatran arm compared to the warfarin arm while in SPORTIF III, the event rate was higher in the warfarin arm compared to the ximelagatran arm. Comparing the event rates in common arm of both studies, the event rate in the ximelagatran arm of both SPORTIF studies were similar at approximately 1.6%. However, the event rate in the warfarin arm varied by almost two-fold: 1.2% in SPORTIF V versus 2.3% in SPORTIF III. Differences in the patient populations in the two studies at baseline could be a possible explanation of the differences in the event rate in the treatment arms. However, it is difficult to explain why such differences would lead to differences in event rates in the warfarin arm while leaving the event rate in the ximelagatran arm unaffected. In a setting where two similarly designed studies produce divergent results, I would favor the results from a double-blind study. It is important to note that the event rate in both studies was primarily driven by the occurrence of ischemic strokes. More than 80% of the events in both studies were ischemic strokes.

C. Safety

In SPORTIF III, there were a total of 145 deaths that occurred on drug or during the follow-up period: 75 Ximelagatran, 70 Warfarin. In SPORTIF V, there were a total of 237 deaths occurring on drug or during the follow-up period: 116 Ximelagatran, 121 Warfarin. The etiologies of deaths were consistent with what is to be expected from an elderly population with co-morbidities. The most common etiologies of death included sudden death, heart rate and rhythm disorders, myocardial infarctions, and congestive heart failure.

In terms of serious adverse events (SAE’s) not leading to death, the reporting rate was lower in SPORTIF III compared to SPORTIF V. The etiologies of the SAE’s not leading to death were also consistent with what would be expected in an elderly population. The most common etiologies of SAE’s included congestive heart failure, cerebrovascular disorders, myocardial infarctions, GI hemorrhage, pneumonia, and angina pectoris.

Discontinuations due to adverse events were numerically greater in the ximelagatran arms of both SPORTIF studies. The most common reason for study drug discontinuation from ximelagatran was liver and biliary system disorders. The frequency of aminotransferase abnormalities was significantly higher on ximelagatran compared to warfarin regardless of the criteria used to define abnormal (e.g. ALAT or ASAT > 3x ULN, > 5x ULN, or > 10 x ULN). The majority of patients that developed liver enzyme abnormalities did so beginning 2 to 4 months after starting ximelagatran therapy. There was one case of a biopsy documented drug induced liver failure leading to death. There was a second probable case of drug induced liver failure leading to coagulopathy and subsequently death. In addition there were multiple cases of aminotransferase abnormalities greater than 3 times the upper limit of normal temporally associated with a bilirubin increase of greater than 2 times the upper limit of normal. The cases fitting the description of “Hy’s Law” and their associated narratives are listed in the Appendix of this review. In most of these cases the patients were asymptomatic. Liver enzyme abnormalities returned to normal after drug discontinuation in these patients.

In terms of major bleeding events, the total number of bleeds was numerically lower in the ximelagatran arm of both SPORTIF studies. In neither of the studies did this difference achieve statistical significance. The majority of major bleeds in both studies was due to bleeding with a fall in the hemoglobin level of greater than or equal to 2 g/dL or due to overt bleeding requiring > 2 units of whole blood.

D. Dosing

A fixed dose of ximelagatran 36mg bid was studied in the SPORTIF trials. The sponsor’s preliminary labeling proposes for the use of fixed doses of ximelagatran without recommending dose adjustment.

There is a strong correlation between creatinine clearance and the apparent oral clearance of melagatran, the active metabolite of ximelagatran. As creatinine clearance decreases, there is a proportional decrease in melagatran clearance. In the sponsor’s proposed labeling there are no provisions for dose adjustment in patients with varying degrees of renal impairment. The proposed labeling would only contradict the use of ximelagatran in patients with a creatinine clearance less than 30 ml/min. Not allowing for dose adjustment in renal impairment may compromise safety because the risk of serious adverse events increases as the exposure to drug increases as shown in Table I and Table II below.

Table I below shows that as the exposure to melagatran increases as measured by the area under the plasma concentration time curve increases, the cumulative risk of major bleeding increases by a factor of about 4 fold.

Table I: Cumulative risk of major bleeding with increasing exposure of study drug in SPORTIF III/V

Study (SPORTIF III/V)		AUC value	Cumulative Risk (%)	95%CI
Study (SPORTIF III/V)		AUC value	Cumulative Risk (%)	Lower (%)	Upper (%)
	Lowest 5%	2.06	1.00	.64	1.37
	Lowest 25%	2.77	1.29	0.89	1.70
	Median	3.46	1.65	1.21	2.10
	Highest 75%	4.38	2.29	1.74	2.85
	Highest 95%	6.19	4.37	3.05	5.69

Obtained from Table 27 of Summary of Clinical Pharmacology Studies Study Report

Similar to the previous table, Table II below shows that as the exposure to melagatran increases, the cumulative risk of hepatotoxicity (as measured by an ALAT > 3x ULN) increases. The increased risk of toxicity with increased exposures to melagatran appears to be slightly less pronounced for hepatotoxicity than that for major bleeding.

Table II: Cumulative risk of ALAT >3x ULN with increasing exposure of study drug in SPORTIF III/V

Study (SPORTIF III/V)		AUC value	Cumulative Risk (%)	95%CI
Study (SPORTIF III/V)		AUC value	Cumulative Risk (%)	Lower (%)	Upper (%)
	Lowest 5%	2.06	5.13	4.02	6.23
	Lowest 25%	2.77	5.59	4.64	6.55
	Median	3.46	6.08	5.22	6.94
	Highest 75%	4.38	6.80	5.83	7.77
	Highest 95%	6.19	8.47	6.38	10.6

Obtained from Table 27 of Summary of Clinical Pharmacology Studies Study Report

E. Special Population

Just under 1/3 of the patients randomized in the SPORTIF studies were females. The direction and magnitude of the ximelagatran effect with respect to the primary efficacy endpoint was similar in males and females.

Less than 5% of the study population in the SPORTIF studies was Black and thus limited conclusions can be made of efficacy or safety of ximelagatran in that population.

It was not unexpected that both SPORTIF studies randomized predominantly a geriatric population with a mean age of just over 70 years as the prevalence of atrial fibrillation increases with increasing age.

Melagatran, the active metabolite of ximelagatran is predominantly excreted in the urine unchanged. Thus, patients with severe renal impairment can have up to 5 times the exposure compared to those with normal renal function.

There are no adequate and well controlled studies of ximelagatran use in pregnant women. Reproductive toxicity studies with ximelagatran in pregnant rats, rabbits, and minipigs have been conducted and have not shown any risk of harm to the fetus at doses that do not produce maternal bleeding. Please refer to the Pharmacology/Toxicology review for further details.

Clinical Review

III. Introduction and Background

A. Drug Established and Proposed Trade Name, Drug Class, Sponsor’s Proposed Indication(s), Dose Regimens, Age Groups

Proposed trade name: EXANTA^Ò

Drug Class: Reversible, oral thrombin inhibitor

Proposed indications: The sponsor is seeking a total of 3 indications. Two of the indications are related to the prevention and treatment of venous thromboembolism. The third indication that is the purpose of this review is “prevention of stroke and other thromboembolic complications associated with atrial fibrillation.”

Dose/Regimen: Fixed dose of 36 mg orally twice daily

Age groups: Older adults will be the primary recipients of this therapy. The prevalence of atrial fibrillation is much higher in older adults than in younger adults. Chronic ximelagatran therapy has not been studied in pediatric populations because atrial fibrillation is a rare, atypical arrhythmia in children.

B. State of Armamentarium for Indication(s)

EXANTA is the first in a new class of oral anticoagulants. The primary mechanism of action involves reversible inhibition of thrombin. The most commonly used oral anticoagulants worldwide are the vitamin K antagonists. Warfarin is an approved Vitamin K antagonist that is available in the U.S. Warfarin is generally recognized as a very effective oral anticoagulant. Its main side effect is risk of bleeding that is predictable from its pharmacologic action. One drawback of using warfarin is that it requires therapeutic drug monitoring to ensure that efficacy is being maximized while minimizing bleeding risk.

C. Important Milestones in Product Development

Table III: Important milestones in Product development

January 16, 1998	Patent issue date
August 14, 1998	IND filed for the oral tablet formulation of ximelagatran
June 16, 2000	End of Phase 2 meeting to discuss SPORTIF protocols
July 14, 2003	Pre-NDA meeting
October 9, 2003	Meeting to discuss risk management strategies
December 23, 2003	NDA filed to Division of GI/Coagulation Drug Products

IV. Clinically Relevant Findings from From Chemistry, Animal Pharmacology and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other Consultant Reviews

Please refer to the Medical Officer Review by Dr. Ruyi He (Primary Medical Officer in Division of GI/Coagulation Drug Products) for further details.

V. Human Pharmacokinetics and Pharmacodynamics

Please refer to the Clinical Pharmacology, Biopharmaceutics Review for details.

Melagatran is a potent, competitive and reversible direct inhibitor of the serine protease a-thrombin. Thrombin converts fibrinogen to fibrin in the coagulation cascade. In addition thrombin also produces platelet aggregation. Inhibition of thrombin by ximelagatran prevents thrombus development and reduces platelet aggregation. Melagatran inhibits both free and fibrin-bound thrombin and thrombin-induced aggregation of platelets.

A. Pharmacokinetics

Ximelagatran is a prodrug, which after oral administration yields melagatran as the dominant metabolite. As shown in Figure 1 below, there are two intermediate metabolites in the pathway from the prodrug to melagatran: ethyl-melagatran and OH-melagatran. Ximelagatran and OH-melagatran are essentially inactive as thrombin inhibitors while melagatran and ethyl-melagatran are both active inhibitors of thrombin. The formation of melagatran primarily occurs via formation of the OH-melagatran intermediate metabolite. The formation of melagatran via ethyl-melagatran is a relatively minor pathway.

Figure 1: The metabolic pathways of ximelagatran for the formation of melagatran (Figure taken from Figure 1 of Summary of Clinical Pharmacology Studies).

The conversion (hydrolysis) from ximelagatran to OH-melagatran is rapid and mediated primarily by esterases. The reduction reaction from OH-melagatran to melagatran is a reduction reaction through a yet unidentified metabolic pathway. No cytochrome P450 enzymes have been identified in the reduction of OH-melagatran to melagatran.

Ximelagatran, melagatran, ethyl-melagatran, or OH-melagatran has not been shown shown to inhibit human drug metabolizing enzymes in various in vitro studies (e.g. human liver microsomes). In vivo studies in rats showed that ximelagatran did not induce P450 enzymes that were studied.

Melagatran is eliminated primarily by excretion in urine with a renal clearance that corresponds to the glomerular filtration rate.

Summary of key pharmacokinetic (PK) findings in healthy subjects

· The pharmacokinetics are dose proportional

· The bioavailability is approximately 20%

· The half-life of melagatran is approximately 3 hours

· Inter-individual variability in exposure: CV = 20%, while intra-individual variability in exposure: CV = 10%

· Melagatran is main excreted unchanged in urine

Summary of key PK findings in patients

The pharmacokinetics are dose proportional
The half-life of melagatran is approximately 5 hours
Inter-individual variability in exposure: CV = 50%, Intra-individual variability in exposure: CV = 25%

Effects of renal impairment on PK of melagatran

The effects of renal impairment on ximelagatran PK were evaluated in an open-label, randomized, single dose study. Subjects enrolled in this study were given single oral doses of Ximelagatran 24 mg. Plasma concentrations and amount of melagatran, the active metabolite of ximelagatran, excreted in urine were measured up to 24 hours post dose.

Study subjects were between the ages of 20 to 80 yeas old and were enrolled into 3 groups. Note that the creatinine clearance (CrCL) was calculated according to the Cockcroft & Gault formula.

Group 1 CrCL > 50 ml/min/1.73m²

Group 2 CrCL 20-30 ml/min/1.73m²

Group 3 CrCL 10-19 ml/min/1.73m²

12 subjects were enrolled into Group 1 and this group was considered as having normal renal function. Groups 2 and 3 were lumped together as one group and were considered as having renal impairment. There were a total of 12 subjects in these 2 groups. In Group 1, the mean Cr CL (using Cockcroft Gault) was 107.7 + 24.3 ml/min (min 63.9 ml/min and max 151.1 ml/min). In groups 2 and 3, the mean CrCL was 27.1 + 9.7 ml/min (min 13.9 ml/min and max 43.1 ml/min).

The effects of renal impairment on melagatran PK are summarized in

Table IV below. As shown in the table, the exposure to melagatran in terms of AUC is approximately 5 fold higher in patients with renal impairment compared to “Normals.” Similarly C_max is about 2 fold higher.

Table IV: Effects of renal impairment on the pharmacokinetics of melagatran, the active metabolite of ximelagatran. Values represent the ratio of subjects with renal impairment to patients with normal renal function.

Variable	Group comparison	Estimate		95% CI
			Lower		Upper
AUC	Renally impaired/normal	5.33	3.76		7.56
C_max	Renally impaired/normal	1.83	1.42		2.37
t1/2	Renally impaired/normal	2.60	2.07		3.26
F_rel	Renally impaired/normal	1.32	1.04		1.67
CL/F	Renally impaired/normal	0.188	0.132		0.266
CLR	Renally impaired/normal	0.106	0.065		0.173

Data in this table obtained from synopsis report of study SH-TP1-0026

The oral clearance (CL/F) of melagatran correlates very well with CrCL calculated using Cockcroft Gault as shown in Figure 2 below. This type of relationship makes justification of a fixed dose of ximelagatran for all patients rather problematic particularly in the setting of increased risk of serious adverse events with increasing exposure to drug.

Figure 2: Mean CrCL (ml/min) versus CL/F (l/h) after oral ximelagatran administration (This figure taken from Figure 11:9 of Sponsor’s Clinical Pharmacology Study Report for study SH-TP1-0026)

Effect of hepatic impairment on PK of melagatran

An open-label, single dose study was conducted in patients with hepatic impairment and controls matched in terms of age, sex, and weight. A total of 12 liver patients and 12 controls were studied. The subjects ranged in age from 45-69 years. Among the patients with hepatic impairment, 7 had mild impairment (Child Pugh A) while 5 had moderate impairment (Child Pugh B). The results of this study showed that the pharmacokinetics of melagatran were similar in patients with or without hepatic impairment.

B. Pharmacodynamics

Melagatran, the active metabolite of ximelagatran, prolongs the activated partial thromboplastin time (aPTT) and INR ratio. Melagatran is an inhibitor of thrombin which happens to be Factor II in the coagulation cascade. aPTT is prolonged by abnormalities in factors involved in the intrinsic coagulation cascade (e.g. FVIII, FIX, XI, XII, etc), fibrinogen, and also factors in the common pathway (e.g. FII, V, X). Prolongation of aPTT occurs in a concentration dependent manner and is non-linear. The relationship between melagatran concentrations and aPTT prolongation is illustrated in Figure 3 and Figure 4 below. It is important to note that the pharmacodynamic data in the figures below has been generated from healthy subjects.

Figure 3: Relationship between aPTT levels and plasma concentrations of melagatran (obtained from Figure 18 of the Sponsor’s Summary of Clinical Pharmacology Studies).

As shown in Figure 4 below, after oral dosing with ximelagatran, the aPTT starts to prolong within 20 minutes of dosing and peak prolongations are observed 2 hours post dosing. The effect of ximelagatran on aPTT at the end of 12 hours is approximately at the same level seen pre-dose. Based on this figure it appears as though a once a day dosing strategy would be sub-optimal. It can not be determined from this trial whether a more than twice a day dosing regimen would result in greater efficacy compared to twice a day dosing.

Figure 4: Relationship between the PK time course of melagatran and the PD time course of aPTT (obtained from Figure 19 of the Sponsor’s Summary of Clinical Pharmacology Studies)

In addition to effects on aPTT, ximelagatran can also affect the prothrombin time (PT) and INR. In vitro studies in human plasma have demonstrated that the PT was prolonged by melagatran but that the corresponding INR varied considerably depending on the ISI of the thromboplastin. It is predicted that INR’s of approximately 1.2 to 1.8 are expected at steady-state trough and peak plasma concentrations of melagatran in atrial fibrillation receiving 36 mg bid. At very high plasma melagatran concentrations the INR ranged from approximately 2.8 to 6 depending on the ISI of the thromboplastin used. Figure 5 below summarizes the relationship between melagatran plasma concentrations and INR based on an in vitro study using two different thromboplastins with differing ISI levels.

Figure 5: INR values plotted versus plasma melagatran concentration (Figure obtained from Figure 27 of Summary of Clinical Pharmacology Studies)

VI. Description of Clinical Data and Sources

A. Overall Data

The sources of data used in generating this review include:

· Electronic NDA submission for N21686

· Sponsor’s reply to an Information Request dated March 23, 2004, June 3, 2004

· NDA21686 4-month Safety Update Report

B. Tables Listing the Clinical Trials

Table V: Summary of the clinical trials submitted in support of the atrial fibrillation indication

SPORTIF V

“Efficacy and Safety of the Oral Direct Thrombin Inhibitor H376/95 Compared with Dose-Adjusted Warfarin (Coumadin) in the Prevention of Stroke and Systemic Embolic Events in Patients with Atrial Fibrillation.”

Pivotal Phase 3 study
Randomized, Double-blind

· U.S. and Canada

· Active control (warfarin INR 2 – 3)

· Fixed dose ximelagatran 36 mg bid

· Patients with nonvalvular atrial fibrillation + at least one additional risk factor for stroke

SPORTIF III

Pivotal Phase 3 study

· randomized, Unblind

· Europe and Asia

· Active control (warfarin INR 2 – 3)

· Fixed dose of ximelagatran 36 mg bid

· Population of patients with nonvalvular atrial fibrillation + at least one additional risk factor for stroke

SPORTIF II, SPORTIF IV

Non-pivotal, phase 2 studies

· Unblind with respect warfarin arm

· Dose ranging (20 mg, 40mg, 60mg)

· Active control (warfarin INR 2 – 3)

· Primarily designed to assess long term safety of ximelagatran

C. Postmarketing Experience

No post-marketing safety data are available. Marketing authorization was received in France in December 2003 for the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee replacement surgery. However, ximelagatran has not yet obtained full approval by the European Union and thus is not commercially available as of April 2004.

D. Literature Review

The studies in support of the efficacy of ximelagatran (H376/95) are active control, non-inferiority trials. The active control chosen for both studies was warfarin titrated to an INR of 2 to 3. One aspect in trying to understand whether ximelagatran is non-inferior to warfarin is to understand the efficacy of warfarin over placebo.

Table VI below summarizes a total of 6 randomized controlled trials of warfarin in patients with chronic, non-rheumatic atrial fibrillation. The 6 studies (or portions of them) listed in the table were used to derive the benefit of warfarin relative to placebo. Please refer to Dr. John Lawrence’s Statistical Review for further details regarding the benefit of warfarin over placebo to use in the non-inferiority analysis.

Similarities and differences in terms of study design

In terms of study design, 2 of the listed studies were blinded while 4 were unblind. One of the SPORTIF trials was blinded while the other was not. Also in terms of design, the studies differed significantly from each other and from the SPORTIF studies with respect to the target INR (e.g. BAATAF Target INR 1.5 – 2.7, AFASAK Target INR 2.8 – 4.2). In the SPORTIF studies the target INR was 2 – 3.

Lack of blinding may be less problematic for “hard” endpoints such as death or severely disabling stroke. However, lack of blinding may be more problematic when evaluating “softer” endpoints such as TIA’s.

Similarities and differences with respect to patient demographics

Patients in the 6 listed warfarin studies were similar in age and gender to those patients in the SPORTIF studies. However, in 5/6 listed studies, fewer patients had a prior history of stroke/TIA compared to the SPORTIF studies. In addition, there were fewer patients with a history of hypertension in the 6 warfarin studies compared to the SPORTIF studies.

Similarities and differences with respect to endpoints

The definitions of stroke varied in some of the studies. For example in the Veterans Affairs Stroke Prevention study (5^th study in Table VI), stroke was defined as a new neurologic deficit that persisted for longer than 12 hours. Most other studies used a new neurologic deficit lasting > 24 hours to define stroke. The AFASAK study (1^st study in Table VI) defined a “minor stroke” as a focal neurologic deficit lasting more than 24 hours but less than one week. Most of the other studies did not define such a subgroup of patients. Also in terms of differences in endpoints, the EAFT study included death from vascular disease and non-fatal MI in its primary endpoint and thus the overall event rate was significantly higher in that study compared to either of the SPORTIF studies.

It is important to note that in many of the studies listed in Table VI, intracranial bleed/hemorrhage was not included as part of the primary efficacy endpoint but was rather a secondary endpoint or assessed as a safety endpoint. On the other hand, in the two SPORTIF studies, the primary endpoint included all strokes both ischemic and hemorrhagic. In addition, the two SPORTIF studies did not include TIA’s as part of their primary endpoint unlike what was done in the AFASAK study. Hemorrhagic strokes or TIA’s did not occur in large numbers in any of the studies listed in Table VI.

In summary, it seems acceptable to use the studies listed in Table VI to define the benefit of warfarin relative to placebo despite differences in study design, endpoints, target INR’s, and patient population. Based on the 6 studies in this table, the benefit of warfarin over placebo appears to be a rather large 64% (95% CI à 47%, 75%) relative risk reduction. The studies listed in Table VI clearly suggest that warfarin is an effective oral anti-coagulant in terms of preventing the composite endpoint of stroke and systemic embolic events.