Pr

1
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
2
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 gt 12 months (mean 16 m) AF
Efficacy non-inferiority margin in AF trials
Safety liver toxicity, withdrawal and MI/CAD
3
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, plt0.001).

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

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

4
Efficacy Short-Term Use in TKR (continued)
5
Short-Term Use Bleeding Events
6
Short-Term Use Liver Toxicity
Number of patients with ALAT gt3x 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.

7
Short-Term Use MI/CAD Adverse Events
Statistically significant in a post-hoc analysis
_at_ one sudden death (ID15016) 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
8
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.

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

• Higher incidence of ALT gt3x ULN during 4-6 w F/U
  period, and no long-term (gt 4-6 w) F/U data.

9
Long-term use Efficacy in AF
Sponsors 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))

10
Long-Term Use Liver Toxicity
Studies excluded patients with Known clinically
significant liver disease Persistent ASAT and/or
ALAT gt2-3x ULN Continuous treatment with NSAID
or Known drug addiction and/or alcohol abuse
Before 11/01(60) LFTs monthly x 6 if ALAT gt3x
ULN, then weekly if gt7x ULN, Exanta was stopped.
After 11/01(40) LFTs monthly x 6 if ALAT gt2x
ULN, then weekly if gt5x ULN or gt3x ULN for 4-8
w, Exanta was stopped.
11
Liver Toxicity (continued)
__________________________________________________
______
Exanta Comparators n6948
n 6230 ________________________________
_______________________ ALT gt3x ULN
546 (7.8) 74 (1.1) ALT
gt3x ULN 37 (0.53)
5 (0.08) Bili. gt2x ULN
_________________________________________________
_______ Severe liver injury with mortality of
10 to 50 (Hys Law) 9 of 37 died. 3 deaths
may have been related to Exanta. ITT population.
12
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.
13
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.
14
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
15
Long-Term Exposure Discontinuation of Study
Drug due to an Adverse Event (DAE)
_________________________________________________
_________________________________________ AE
Exanta
comparators
n6931 n6216____________
__________________________________________________
_______________________________________________To
tal 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 sponsors Table
NP 53long-term exposure safety population

16
Long-Term Exposure MI/CAD Events
17
Long-Term Exposure Summary of Safety Concerns
for Exanta

• Higher incidence (0.53) of severe liver injury
  (ALT gt3x ULN T. Bili. gt2x ULN), including 3
  deaths despite protocol specified LFT monitoring
  scheme.

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

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

18
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