assessment of efficacy and safety for exanta (ximelagatran) ruyi he, m.d. medical team leader the...
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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