Assessment of Efficacy and Safety for Exanta (Ximelagatran)

Ruyi He, M.D.

Medical Team Leader

The Division of Gastrointestinal and Coagulation Drug Products

September 10, 2004

Advisory Committee Meeting September 10, 2004

Outline

Short-Term Use Exanta 36 mg bid for 7-12 d (mean 8 d) :

total knee replacement surgery (TKR)

Efficacy: asymptomatic distal DVT

Safety: bleeding, liver toxicity, MI/CAD

Long-Term Use

Exanta 24 mg bid for 18 months : VTE-P

Exanta 36 mg bid for > 12 months (mean 16 m): AF

Efficacy: non-inferiority margin in AF trials

Safety: liver toxicity, withdrawal and MI/CAD

Efficacy: Short-Term Use in TKR

Exanta was significantly better than Warfarin for primary endpoint: the incidence of total VTE and/or all-cause

mortality (21.7% in Exanta group, 30.2% in Warfarin group, p<0.001).

– Efficacy result on Exanta is driven by decrease in asymptomatic distal DVT which is not clinically meaningful.

– There are no appreciable differences between groups for symptomatic DVT, proximal DVT, PE or death.

Efficacy: Short-Term Use in TKR (continued)

Short-Term Use: Bleeding Events

AdjudicatedBleedingEvents

Exanta36 mg bidn=1913

Exanta24 mg bidn=1097

WarfarinDose adjusted

n=2978

Major or MinorBleeding

98 (5.1%) 63 (5.7%) 128 (4.3%)

Major Bleeding 18 (0.9%) 10 (0.9%) 17 (0.5%)

Fatal Bleeding 2 (0.1%) 0 0

Exposed safety population

Short-Term Use: Liver Toxicity

Number of patients with ALAT >3x ULN on treatment (OT) or follow-up (F/U) period

__________ ______________________________________

Exult A + B Exanta 36 mg Warfarin____________________________

___________________

OT (7-12 d) 13/1818 (0.72%) 18/1791 (1.0%)

4-6 w F/U 7/1784 (0.4%) 1/1776 (0.05)

________________________________________________

No fatal or non-fatal liver SAEs during OT and 4-6 w F/U period.Summarized from Table SP 42.

Short-Term Use: MI/CAD Adverse Events

*Statistically significant in a post-hoc analysis

@ one sudden death (ID#:15016) in W group is included as MI and 2 sudden deaths (ID#: 14366 and 12122) in X group are excluded from the analysis.

Noted: 4 cases who did not take study drugs were excluded from this analysis (3 in X group: # 3206, 7086, 10944 and 1 in w group: # 9089).

Summarized from Module 5, Table 54, Table 11.3.5.1 and Table 11.3.5.2

Exult A Exult B@ Exult A and BEvent: N (%) Exanta

n=1526Warfarin

n=759Exantan=1151

Warfarinn=1148

Exantan=2677

Warfarinn=1907

MI 11(0.72)

1(0.13)

5(0.43)

3(0.26)

16*(0.60)

4*(0.21)

Other CAD(Angina/ischemia)

3(0.2)

0 1(0.17)

1(0.09)

4(0.15)

1(0.05)

Total 14(0.92)

1(0.13)

6(0.7)

4(0.35)

20*(0.75)

5*(0.26)

Short-Term Use: Summary of Safety Concerns for Exanta

2-fold higher incidence of major bleeding events

~3-fold higher incidence of acute MI/CAD.

• Higher incidence of ALT >3x ULN during 4-6 w F/U period, and no long-term (> 4-6 w) F/U data.

• Potential for duration of treatment to be > 12 d in clinical practice.

Long-term use: Efficacy in AF

Sponsor’s pre-specified 2% non-inferiority margin too liberal

SPORTIF III & V produced divergent results

• Based on the double-blind, SPORTIF V study, it could not be ruled out that the risk of stroke/SEE was 2-fold greater on Exanta compared to Warfarin (95% CI = (0.91, 2.12))

Long-Term Use: Liver Toxicity

Studies excluded patients with:

Known clinically significant liver disease

Persistent ASAT and/or ALAT >2-3x ULN

Continuous treatment with NSAID or

Known drug addiction and/or alcohol abuse

Before 11/01(60%)

LFTs monthly x 6; if ALAT >3x ULN, then weekly; if >7x ULN, Exanta was stopped.

After 11/01(40%)

LFTs monthly x 6; if ALAT >2x ULN, then weekly; if >5x ULN or >3x ULN for 4-8 w, Exanta was stopped.

Liver Toxicity (continued)

________________________________________________________

Exanta Comparators

n=6948 n= 6230

_______________________________________________________

ALT >3x ULN 546 (7.8%) 74 (1.1%)

ALT >3x ULN + 37 (0.53%)** 5 (0.08%)

Bili. >2x ULN*

________________________________________________________

* Severe liver injury with mortality of 10 to 50% (Hy’s Law)

** 9 of 37 died. 3 deaths may have been related to Exanta.

ITT population.

Case 1 (#7259): 80 y, M, on Exanta 36 mg bid for AF

Day Event

1 ALT: 16

30 ALT: Normal

56 ALT: 2x ULN

85 ALT: 20x ULN (970). Exanta discontinuation

100 ALT: 30x ULN (1502), T. Bili. 2.4

108 Liver Biopsy: acute submassive necrosis

114 INR: 1.7, Alb: 2.9, T. Bili: 10.7, PT: 16.3,

119 INR: 1.8, Alb: 2.5, T. Bili: 17.1

145 Died GI bleeding with coagulopathy

Autopsy: a small, friable and diffusely mottled liver with extensive liver necrosis, hepatocyte dropout and bile duct proliferation.

Case 2 (#7859): 77y M on Exanta 36 mg bid for AF

Day Event

1 LFT: normal, Alb: 3.6

30 LFT: normal

63 ALT: 216 (4.5x ULN), T. Bili: 1.3

67 Weekly test, result unknown

81 Bloody stools, BP: 76/45, Hb: 7, PT: 37, aPTT: 69,

INR: 3.4, plasma melagatran: 0.25 M (therapeutic

range) ALT: 569, Alb: 2.0, pRBC 19U, FF plasma 15U,

cryoprecipitate 30U, vit. K and fluids.

82 T. Bili: 10.4 (D. Bili: 5.2), gastroscopy: active bleeding, more pRBC, FFP, platelets and fluids, died from GI bleeding with profound coagulopathy. No autopsy.

Case 3 (#5442): 73y, M on Exanta 36 mg bid for DVT

Day Event

1 ALT: 1.9x ULN

12 ALT: 4.5x ULN

18 ALT: 7.8x ULN, Hepatitis B diagnosed

22 ALT: 367, T. Bili: 1.8

24 Exanta discontinuation

26 ALT: 518, T. Bili: 4, INR: 2.3

42 ALT: 189, T. Bili: 26.8, hepatic encephalopathy

44 Died from liver failure

Long-Term Exposure: Discontinuation of Study Drug due to an Adverse Event (DAE) __________________________________________________________________________________________ AE Exanta comparators n=6931 n=6216_____________________________________________________________________________________________________________Total DAE 1189 (17.2) 801 (12.9)

LFT abnormal 319 (4.6) 18 (0.3)MI/CAD 196 (2.8) 121 (1.9)Bleeding 83 (1.2) 43 (0.7)Cerebrovasc. Disorder 70 (1.0) 57 (0.9)DVT/PE 44 (0.6) 116 (1.8)*____________________________________________________________________*Placebo controlSummarized from sponsor’s Table NP 53long-term exposure safety population

Long-Term Exposure: MI/CAD Events

Population withCoronary artery diseases(CAD) Adverse Events

Ximelagatran(AF, n= 3836)

(VTE-T, n=1236)(VTE-P, n=612)

n %

(AF, n= 3719, Warfarin)(VTE-T, n=1248, Warfarin)

(VTE-P, n=611, placebo)n %

AF: Total CADMI

268 7.0 62 1.6

248 6.752 1.4

VTE-T: Total CADMI

16 1.3*3 0.2

1 0.1*0 0

VTE-P: Total CADMI

16 2.610 1.6

12 2.03 0.5

VTE: Total CADMI

32 1.7*13 0.7*

13 0.7*3 0.16*

*Statistically significant in a post-hoc analysis. VTE = VTE-T + VTE-PIn post ACS population, total CAD events was 27% in the Exanta 36 mg bid + ASA group (n=303), and 30% in theplacebo + ASA group (n=638).

Long-Term Exposure: Summary of Safety Concerns for Exanta

• Higher incidence (0.53%) of severe liver injury (ALT >3x ULN + T. Bili. >2x ULN), including 3 deaths despite protocol specified LFT monitoring scheme.

• Higher incidence of withdrawal due to AE, including acute MI/CAD and bleeding events.

• In VTE population, higher incidence of acute MI/CAD with Exanta, including in placebo control study.

Acknowledgments

All members of the Exanta Review Team

Especially

Dionne Price, Ph.D., Division of Biometrics II

Suliman Al-Fayoumi, Ph.D., Division of Biopharmaceutics I

Maria Ysern, M.Sc. Division of New Drug Chemistry II

Mehul Desai, M.D., Divison of Cardio-Renal Drug Products

John Lawrence, Ph.D., Divison of Biometrics I

Alice Kacuba, RN, MSN, RAC, Regulatory Project Manager

Ke Zhang, Ph.D, Division of Gastrointestinal and Coagulation Drug Products