Integrated Executive Summary

of FDA Review for NDA 21-686

Exanta (Ximelagatran)

> NDA: 21-686
>
> Sponsor: AstraZeneca
>
> Drug name: Exanta (ximelagatran) Tablets

Indications:

1)  Prevention of venous thromboembolism in patients undergoing knee
    replacement surgery;

2)  Long-term secondary prevention of VTE after standard treatment for
    an episode of acute VTE;

3)  Prevention of stroke and other thromboembolic complications

> associated with atrial fibrillation (AF).

Date submitted: December 23, 2003

Summary completed: August 11, 2004

Integrated by: Ruyi He, M.D.

Medical Officer, the Division of Gastrointestinal and Coagulation

Drug Products, CDER

Table of Contents

I. Introduction and
Background...........................................3

A.
Exanta..........................................................................3

B. State of Armamentarium for
Indication(s)....................................3

II\. Summary of Clinical
Findings..........................................4

A. Brief Overview of Clinical Program 4

B. Efficacy 5

C. Safety 8

III. **Review of Risk Minimization Action Plan for
     Exanta.............12**

IV. **Summary of Pre-clinical
    Evaluation..................................15**

####### **V. Summary of Human Pharmacokinetics and Pharmacodynamics** 

#######  **Evaluation...............................................................\....16** {#evaluation....16 .unnumbered}

VI. **Questions to the Committee
    .......................................\......17**

VII. **Appendix**

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A.  Medical Officer Review by Dr. Ruyi He, from the Division of
    Gastrointestinal and Coagulation Drug Products

> B. Statistical Review by Dr. Dionne Price, from the Division of
> Biometrics II

C.  Medical Officer Review by Dr. Mehul Desai, from the Division of
    Cardio-Renal Drug Products

D.  Statistical Review by Dr. John Lawrence, from the Division of
    Biometrics I

E.  Review of Risk Minimization Action Plan by the Division of Drug Risk
    Evaluation and the Division of Surveillance, Research and
    Communication Support, Office of Drug Safety (ODS)

F.  Clinical White Paper, CDER-PHRMA-AASLD Conference 2000

I. Introduction and Background

> **A. Exanta (ximelagatran)**

Exanta ® (ximelagatran) is an oral anticoagulant and a prodrug of
melagatran, a potent, reversible, competitive and direct inhibitor of
thrombin.

Marketing approval of ximelagatran is being sought for the following 3
indications: prevention of venous thromboembolism (VTE) (defined as deep
vein thrombosis \[DVT\], pulmonary embolism \[PE\], or both), in
patients undergoing knee replacement surgery; long-term secondary
prevention of VTE after standard treatment for an episode of acute VTE;
and prevention of stroke and other thromboembolic complications
associated with atrial fibrillation (AF). All 3 indications are for the
adult population only.

For the indication of prevention of VTE in patients undergoing knee
replacement surgery, the proposed dosing is EXANTA 36 mg twice-daily for
a treatment period of 7 to 12 days.

Provided hemostasis has been established, the first dose should be given
the morning after surgery, but no sooner than 12 hours from the time of
surgery. For the indication of long-term secondary prevention of VTE, it
is proposed that patients who have received standard anticoagulant
treatment for DVT or PE be treated with EXANTA 24 mg twice-daily for an
additional 18 months. For the indication of prevention of stroke and
other thromboembolic complications associated with atrial fibrillation,
the proposed dosing is EXANTA 36 mg twice-daily. The first indication
(in patients undergoing knee replacement surgery) is a short-term
therapy (7 to 12 days); however, the 2^nd^ indication (secondary
prevention of VTE) and 3^rd^ indication (in patients with AF) are
long-term therapy (18 months or life-long, respectively).

### B. State of Armamentarium for Indication(s)  {#b.-state-of-armamentarium-for-indications .unnumbered}

Warfarin is approved for:

-   the prophylaxis and/or treatment of venous thrombosis and its
    extension, and PE;

-   the prophylaxis and/or treatment of the thromboembolic complications
    associated with atrial fibrillation and/or cardiac valve
    replacement;

-   reducing the risk of death, recurrent myocardial infarction (MI),
    and thromboembolic events such as stroke or systemic embolization
    after MI.

The "Dosage and Administration" section of warfarin labeling refers to
"longer term therapy" for indications such as VTE, in patients with
A-Fib or mechanical and bioprosthetic heart valves. It also states that
the duration of therapy in each patient should be individualized and
anticoagulant therapy should be continued until the danger of thrombosis
and embolism has passed. Thus, the indications and dosing
recommendations for warfarin are sufficiently broad to encompass
extended prophylaxis of DVT.

Other drugs approved for the indication of the prophylaxis of VTE in
patients undergoing knee replacement surgery include Lovenox (enoxaparin
sodium) injection, a low molecular weight heparin, and Arixtra
(fondaparinux sodium) injection, a synthetic inhibitor of activated
Factor X (Xa). Both Lovenox and Arixtra are for subcutaneous injection.
No oral medication has been approved so far for this short-term use to
prevent VTE in patients undergoing elective knee replacement surgery.

Except warfarin, no other agents are approved for long-term
thrombo-prophylaxis after treatment of DVT or PE, or for chronic
thrombo-prophylaxis in patients with atrial fibrillation.

## II. Summary of Clinical Findings  {#ii.-summary-of-clinical-findings .unnumbered}

### A. Brief Overview of Clinical Program {#a.-brief-overview-of-clinical-program .unnumbered}

The clinical studies were designed to demonstrate that fixed doses of
ximelagatran, without coagulation monitoring or dosage adjustment, offer
superiority to placebo (long-term secondary prevention of VTE),
superiority to warfarin (prevention of VTE in patients undergoing knee
replacement surgery), and non-inferiority to warfarin (prevention of
stroke associated with atrial fibrillation).

The development program includes 5 major efficacy and safety studies for
the indications being sought and 77 additional clinical studies with
ximelagatran and/or melagatran (a total of 60 Phase 1 studies and 22
Phase 2 and 3 studies). These studies have involved a total of 30,698
subjects of whom 17,593 received the oral prodrug ximelagatran, or the
active drug melagatran. In the long-term treatment populations, 6931
patients received ximelagatran (5024 for at least 6 months and 3509 for
at least a year).

All 5 major Phase 3 studies were conducted as a multi-center,
randomized, parallel-group, comparator-controlled design. All studies
were double-blind except for SH-TPA-0003 (SPORTIF III for the indication
of prevention of stroke in patients with AF; which was open-label in
design). All studies used a central laboratory for all
protocol-specified laboratory measurements.

For the indication of prevention of VTE in patients undergoing elective
knee replacement surgery, the sponsor conducted three Phase 3 studies in
comparison with warfarin in patients undergoing primary, elective total
knee replacement (TKR) surgery (EXULT A, EXULT B and SH-TPO-0006).
Ximelagatran 36 mg bid was used in both studies EXULT A and EXULT B.
Ximelagatran 24 mg was used in study SH-TPO-0006. A total of 5284
patients were randomized in these three studies (1927 to ximelagatran 36
mg bid, 2247 to warfarin, and 1110 to ximelagatran 24 mg bid).

To support the indication of prolonged prophylaxis of VTE after a
six-month anticoagulation treatment for VTE, the sponsor provided only
one 18-month study, SH-TPV-0003 (THRIVE III). A total of 1233 patients
were randomized, with 903 completing the study (468 on ximelagatran 24
mg bid and 435 on placebo).

For the indication of prevention of stroke and systemic embolic events
in patients with nonvalvular atrial fibrillation, two pivotal Phase 3
studies, one double-blind and one open-label, 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 two 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 {#b.-efficacy .unnumbered}

**Indication 1: Prevention of VTE in patients undergoing elective total
knee replacement (TKR) surgery**

In study EXULT A ximelagatran 24 mg and 36 mg were compared to warfarin.
In EXULT B ximelagatran 36 mg was compared to warfarin. Oral
ximelagatran 36 mg bid was superior to warfarin in reducing total VTE
and/or all-cause mortality at end of 7-12 days therapy among patients
undergoing TKR surgery in these two Phase 3 studies.

In the pooled analyses (study EXULT A and study EXULT B), the incidence
of total VTE and/or all-cause mortality among patients undergoing TKR
was 21.7% for patients in the ximelagatran 36 mg group and 30.2% for
patients in the warfarin group (p\<0.001). However, the benefit was
mainly due to a reduction in asymptomatic distal DVT diagnosed by
venography which is not clinically meaningful. There were no clinically
or statistically significant differences between ximelagatran and
warfarin groups in reducing the frequency of proximal DVT, PE, and/or
all-cause mortality in this population (Table 1).

**Table 1 Objectively confirmed symptomatic and asymptomatic
thromboembolic**

**events over the entire study (efficacy ITT population) -- EXULT A
and**

**EXULT B 36 mg bid**

![](media/image1.png){width="5.996527777777778in"
height="3.720833333333333in"} Sponsor's table from Module 2; vol. 1,
page 90.

There are several major problems with using warfarin as an active
comparator in these two studies. Warfarin is not approved for this
short-term indication. The comparison is unfair, because warfarin will
take about 3-5 days to reach therapeutic level, while Exanta reaches
therapeutic levels within hours. Mean days of exposure were 8.1 days for
ximelagatran and 6.7 days for warfarin in these two studies. The results
show that 33.1% - 35.2% of patients receiving warfarin had an INR less
than 1.8 at postoperative day 3, and 24.0 -- 26.9% % of patients
receiving warfarin had an INR less than 1.8 at end of treatment (day 7
-- 12). Because of the superiority study design, however, efficacy
results for ximelagatran in these studies may still be acceptable, since
warfarin may be considered to be placebo.

In EXULT A ximelagatran 24 mg bid was not superior to warfarin in
reducing total VTE and/or all-cause mortality (27.6% warfarin vs 24.9%
ximelagatran 24 mg) at end of 7-12 days therapy.

For detailed efficacy evaluation on the indication of prevention of VTE
in patients undergoing elective TKR surgery, please see Appendix A,
Medical Officer's Review by Dr. Ruyi He, and Appendix B, Statistical
Review by Dr. Dionne Price.

#####  {#section .unnumbered}

**Indication 2: Long-term secondary prevention of VTE after standard
treatment for an**

**episode of acute VTE**

Ximelagatran significantly reduced the recurrence rate of symptomatic,
objectively confirmed VTE (the primary variable of the study) as
compared to placebo over 18 months of treatment (cumulative risk of 2.8%
versus 12.6%; hazard ratio 0.16; p\<0.0001). The number of patients with
a VTE event was 12 in the ximelagatran group and 71 in the placebo
group. The number of patients with a PE event was lower in the
ximelagatran group compared to the placebo group (2 and 23)
respectively. The results for the secondary variable, all-cause
mortality, showed no significant difference between the treatment groups
(1.1% vs 1.4% for patients on ximelagatran and placebo, respectively)
during the 18 months.

For detailed efficacy evaluation on the indication of long-term
secondary prevention of VTE, please see Appendix A, Medical Officer's
Review by Dr. Ruyi He, and Appendix B, Statistical Review by Dr. Dionne
Price.

### Indication 3: Prevention of stroke and other thromboembolic complications associated with atrial fibrillation  {#indication-3-prevention-of-stroke-and-other-thromboembolic-complications-associated-with-atrial-fibrillation .unnumbered}

###  {#section-1 .unnumbered}

SPORTIF III and SPORTIF V are two Phase 3, active control,
non-inferiority studies that were provided in support of EXANTA for
long-term use in patients with atrial fibrillation. 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 percentage points in the
event rate in both studies. However, the margin was not agreed to by the
Agency and its derivation from referenced historical trials is unclear.
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 (Table
2) while in SPORTIF III, the event rate was higher in the warfarin arm
compared to the ximelagatran arm (Table 3). Comparing the event rates in
common arms 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, the results from
the double-blind study could be considered more reliable. The event rate
in both studies was primarily driven by the occurrence of ischemic
strokes and more than 80% of the events in both studies were ischemic
strokes.

The results of the primary pre-specified endpoint from SPORTIF V and
SPORTIF III are summarized in Table 2 and Table 3 below, respectively.

^Table\ 2:\ Number\ of\ patients\ with\ stroke\ and/or\ systemic\ embolic\ event\ (SEE)\ by\ treatment\ group\ (SPORTIF\ V)^a

  ---------------- ------------- ---------- ---------- -------- -------- ---------
                                            Event      95% CI            

                                 Patient    Rate                         

  Treatment group  Events^b,c^   Years      (%/year)   Lower    Higher   p-value

  Ximelagatran     51            3160       1.61       1.17     2.06     

  Warfarin         37            3186       1.16       0.79     1.54     

  Ximelagatran --                           0.45       -0.13    1.03     0.133
  warfarin                                                               
  ---------------- ------------- ---------- ---------- -------- -------- ---------

^a^Data in this table obtained from Table 45 of SPORTIF V CSR

^b^Events represent CEAC adjudicated events

^c^This table only informs of the number of patients with their first
event. If a patient had more than one event, it is not reflected in this
table.

Table 3: Number of patients with stroke and/or SEE by treatment group
(SPORTIF III)^a^

  ----------------------- --------------- ----------- -------------- ----------- ------------ -------------
                          **Events^b^**   **Patient   **Event rate** **95% CI**               **p-value**
                                          years**                                             

                                                      **(%/year)**   **Lower**   **Higher**   

  Ximelagatran            40              2446        1.64           1.13        2.14         

  Warfarin                56              2440        2.29           1.69        2.9          

  Ximelagatran-Warfarin                               -0.66          -1.45       0.13         0.100
  ----------------------- --------------- ----------- -------------- ----------- ------------ -------------

^a^Data in this table obtained from Table 39 of SPORTIF III CSR

^b^Events represent CEAC adjudicated events

For detailed efficacy evaluation on the indication of prevention of
stroke associated with atrial fibrillation, please see Appendix C,
Medical Officer's Review by Dr. Mehul Desai, and Appendix D, Statistical
Review by Dr. John Lawrence.

###  {#section-2 .unnumbered}

### C. Safety {#c.-safety .unnumbered}

**C.1. Safety of ximelagatran in patients undergoing a surgical
procedure (use [\<]{.underline} 35 days)**

A total of 1913 patients were exposed to ximelagatran 36 mg bid, 1097
patients were exposed to ximelagatran 24 mg bid, and 2226 patients were
exposed to warfarin with a mean duration of exposure of 8 days for the
ximelagatran groups.

Overall, more than 55% of patients in each treatment group experienced
at least 1 adverse event (AE). Post-operative complications were mostly
related to bleeding and were reported at a higher frequency in the
ximelagatran groups (17% at 36 mg, 23% at 24 mg) than in the warfarin
groups (15% and 20%, respectively).

There were 18 deaths (12 patients exposed to ximelagatran and 6 patients
exposed to warfarin). Of the 12 deaths reported among the 3010 patients
who received ximelagatran, 2 were fatal bleeding events (both on
ximelagatran 36 mg). Six were fatal events in which 'PE could not be
excluded'. The remaining 4 deaths in patients who received ximelagatran
were adjudicated by the sponsor as 'death not associated with VTE or
bleeding'. For these the investigators reported the causes of death in 1
patient on treatment as sudden death, and in the other 3 patients after
treatment as intestinal perforation, acute MI, and pneumonia. Of the 6
deaths reported among the 2226 patients who received warfarin (0.3%), 2
were fatal events in which 'PE could not be excluded'. The causes of
death in 2 patients on treatment were arrhythmia and MI and in the other
2 after treatment were colon carcinoma and AMI.

There were more discontinuations of study drug due to adverse events in
the ximelagatran 36 mg group (2.6%) than in the warfarin group (2.0%)
and in the ximelagatran 24-mg group compared to warfarin group (3.1%
versus 2.1%, respectively). The most common adverse event leading to
study drug discontinuation was postoperative complication.

With respect to on-treatment adjudicated events, major bleeding occurred
in 0.9% of patients treated with ximelagatran 36 mg, compared to 0.5% of
patients treated with warfarin. There were 2 fatal bleeding events (both
on ximelagatran 36 mg). Major/minor bleeding occurred in 5.1% of
patients treated with ximelagatran 36 mg and 4.1% of patients treated
with warfarin.

Incidences of alanine aminotransferase (ALAT) elevation reported as
adverse events (AEs) were higher in the 36 mg ximelagatran group (2.1%)
than other groups (1.3-1.5% warfarin; 1.4% ximelagatran 24 mg). There
were no hepatobiliary fatal adverse events, non-fatal severe AEs or
discontinuation of study drug due to adverse events in either
ximelagatran group. During the follow-up period (4-6 weeks), 8 patients
in the ximelagatran group, and 1 in the warfarin group had their first
ALAT elevation \>3x upper limit of normal (ULN). However, patients were
followed up for only 4-6 weeks post operation. Drug effects on liver
toxicity beyond 4-6 weeks are unknown. It should be noted that in
studies with long-term exposure to ximelagatran elevation of hepatic
enzymes was typically seen between the 2^nd^ and 6^th^ month after
starting ximelagatran.

In both studies Exult A and Exult B, the proportion of patients with
coronary artery disease adverse events (MI or ischemia/angina) was
significantly higher in the ximelagatran groups than in the warfarin
groups. In patients undergoing TKR surgery (Exult A and Exult B), the
proportion of patients with coronary artery disease adverse events was
statistically significantly higher in the ximelagatran group (20/2677,
0.75%) than in the warfarin group (5/1907, 0.26%) (p=0.02800). The
proportion of patients with myocardial infarction (MI) was also higher
in the ximelagatran group (16/2677, 0.60%) than in the warfarin group
(4/1907, 0.21%) in the TKR population (p=0.04951). There were no
appreciable differences between the treatment groups for underlying
diseases including hypertension, hypercholesterolemia, diabetes
mellitus, coronary atherosclerosis, as well as age, gender and weight.
Considering ximelagatran as an anticoagulant with potential to treat MI,
these results are unexpected and worrisome.

Overall, these studies raised some safety concerns for use of oral
ximelagatran 36 mg bid for 7 to 12 days after surgery (beginning the
morning after surgery) in the prevention of VTE in patients undergoing
elective knee replacement surgery. There is a potential risk of higher
coronary artery disease adverse events including acute myocardial
infarction. Potential for long-term use (\>12 days) that will cause
liver toxicity is high. Also, major bleeding events were more common in
patients treated with ximelagatran than in patients treated with
warfarin. A study with longer follow up (6 months) may also be
considered in the assessment of liver toxicity with short-term use of
ximelagatran.

For detailed safety evaluation of ximelagatran in patients undergoing a
surgical procedure (use [\<]{.underline} 35 days), please see Appendix
A, Medical Officer's Review by Dr. Ruyi He.

**C.2. Safety of ximelagatran in patients with long-term exposure (\> 35
days)**

A total of 6931 patients received doses of 20 to 60 mg of ximelagatran,
for a median of 370 days. A total of 5024 patients were exposed to
ximelagatran for at least 6 months and 3509 for at least 12 months. A
total of 6216 patients were exposed for a median of 455 days to warfarin
(n=4967) and placebo (n=1249).

**C.2.1. Deaths**

There were 224 deaths during active treatment, 112 in the ximelagatran
treatment groups and 112 in the comparator groups. A further 331
patients died after stopping study drug (166 in the ximelagatran group
and 165 in the comparator group). There were no differences between the
treatment groups. The most common fatal SAE was myocardial infarction.
Nine ximelagatran-treated patients died with concomitant ALAT \>3xULN
and bilirubin \>2xULN.

**C.2.2. Non-fatal Severe Adverse Events (SAE)**

A total of 26.3% of patients in the ximelagatran group and 27.1% of
patients in the comparator group experienced a non-fatal SAE during
treatment. A further 5.5% of patients in the ximelagatran group and 4.3%
of patients in the comparator group experienced a non-fatal SAE after
stopping study drug. The most common non-fatal SAEs were cardiovascular
events. The most common non-fatal SAEs considered to be causally related
to ximelagatran were increases in hepatic transaminases.

**C.2.3. Discontinuation**

The proportion of patients who discontinued study drug was higher in the
ximelagatran group (1189/6931, 17.2%) than in the comparator group
(801/6216, 12.9%). This was mostly due to the discontinuation of study
drug due to elevated hepatic transaminases. Data from discontinuation of
ximelagatran secondary to adverse events indicate that "coronary artery
disorders (CAD)" were more common in the ximelagatran group than in the
comparator group (0.6% vs. 0.3%, respectively) whereas thromboembolic
events were less common in the ximelagatran group (0.4% vs.1.3%,
respectively), because of a placebo control. Other common causes of
discontinuations included bleeding events, with no difference between
ximelagatran and the comparators, except for hematuria and rectal
hemorrhage/ melaena, which caused slightly more discontinuations in the
ximelagatran group than in the comparator groups.

**C.2.4. Bleeding Events**

In patients with atrial fibrillation (AF), in terms of major bleeding
events, the total number of bleeds was numerically lower in the
ximelagatran arms of both SPORTIF studies. However, there were no
significant differences for major bleeding events between the groups in
each of the 2 pivotal studies (SH-TPA-0003 and STP-0005). In patients
with acute venous thromboembolism (VTE), ximelagatran 36 mg was
associated with numerically fewer major bleeding events than
enoxaparin/warfarin. In patients undergoing extended secondary
prophylaxis for VTE, ximelagatran 24 mg was associated with a similar
incidence of major bleeding events compared to placebo. A total of 38
patients experienced bleeding-related severe AEs with a fatal outcome,
19 cases in each treatment group (ximelagatran or comparator).

**C.2.5. Hepatobiliary Toxicity**

In patients receiving long-term administration of ximelagatran (\>35
days) an increase in ALAT \>3xULN occurred in 6-13% (average 7.6%,
531/6948) compared to 0-2% (average 1.1%, 68/6230) of patients receiving
comparator treatments. Including local laboratory data, 620 patients
showed an ALAT elevation \>3xULN during the studies, 546 patients in the
ximelagatran group (cumulative incidence 7.8%) and 74 patients in the
comparator group (cumulative incidence 1.1%). Among the 531 patients in
the ximelagatran group who presented with an ALAT \>3xULN, 206 (39%)
completed the study on study drug. The remaining 325 patients (61%)
discontinued study drug prematurely.

The time pattern of ALAT elevations was consistent across patients. The
increase typically occurred between 1 and 6 months after the initiation
of ximelagatran. Before and after this time frame, the incidence of ALAT
increase was similar to that in the comparator groups. Of the 531
ximelagatran-treated patients who had an ALAT elevation \>3xULN recorded
by the central laboratory, 502 (95%) had their ALAT return to \<2xULN
(235 with study drug continued). Most cases show a peak of ALAT within
the first 2 to 3 months post-randomization and a decline back towards
baseline within about 6 months post-randomization in patients who
discontinued or in patients continued on ximelagatran.

Eighteen patients who discontinued study drug with elevations of ALAT
subsequently resumed treatment after ALAT had returned to the normal
range. Of these 18 patients, 2 again experienced elevations of ALAT
after drug was resumed.

An evaluation of potential risk factors for increase in ALAT indicated
an increased risk in the post acute coronary syndrome (ACS) population
(p=0.0009), VTE-treatment (VTE-T) (p=0.0003) populations, in female
patients (p=0.0002) patients, in low BMI (\<27 kg/m^2^) population
(p\<0.0001), and in patients receiving concomitant treatment with
statins (p=0.019). Asian patients were found to have a decreased risk
(p=0.0038). Although a single factor identified above may not be strong
enough to eliminate the subgroup population, consideration may be given
to contraindicating ximelagatran in patients who have 2 or more risk
factors, such as, female patients with low body weight or who are taking
statin.

ALAT \>3xULN was associated with bilirubin \>2xULN (within one month
following the rise in

ALAT) in 0.53% (37/6948) of all patients who were exposed to
ximelagatran \>35 days as compared to 0.08% (5/6230) of patients exposed
to comparators. Nine ximelagatran-treated patients (24.3%, 9/37) died
with concomitant ALAT \>3xULN and bilirubin \>2xULN. Among these, 3 died
from heart failure; 3 died from carcinomas with hepatic metastases; 2
(ID# 7259, and 7859) died from GI bleeding with coagulopathy (1 with
biopsy documented hepatic necrosis) and 1 (ID# 5442) died from hepatitis
B. Liver failure/toxicity by ximelagatran might have caused or at least
contributed to these deaths. Only one autopsy was done in these 9 deaths
and it showed a small, friable and diffusely mottled liver suggestive of
severe diffuse hepatic necrosis.

**C.2.6. Adverse Events of Coronary Artery Disease**

In all study populations except the post acute coronary syndrome, the
proportion of patients with coronary artery disease adverse events was
higher in the ximelagatran groups than in the comparator groups (7.0%
and 6.7% for the AF pool, 1.3% and 0.1% for the VTE-treatment (VTE-T)
pool and 2.6% and 2.0% for the VTE-prevention (VTE-P) pool, for the
ximelagatran and comparator groups, respectively). This trend was
consistent across the pools for myocardial infarction.

The proportion of patients with coronary artery disease adverse events
was statistically significantly higher in the ximelagatran group
(32/1848, 1.7%) than in the warfarin/placebo group (12/1859, 0.7%) in
the VTE population (p=0.00411, the combination of VTE-Treatment and +
VTE-Prevention population). The proportion of patients with MI was also
significantly higher in the ximelagatran group (13/1848, 0.7%) than in
the warfarin/placebo group (3/1859, 0.16%) in the VTE population
(p=0.01183). There were no appreciable differences between the treatment
groups for underlying diseases including hypertension, diabetes
mellitus, hypercholesterolemia, coronary atherosclerosis, as well as
age, gender and weight. Considering ximelagatran as an anticoagulant
with potential to treat MI, these results are worrisome.

For detailed safety evaluation of ximelagatran in patients with
long-term exposure (use \> 35 days), please see Appendix A, Medical
Officer's Review by Dr. Ruyi He and Appendix C, Medical Officer's Review
by Dr. Mehul Desai.

###  {#section-3 .unnumbered}

####### **III. Review of risk minimization action plan**  {#iii.-review-of-risk-minimization-action-plan .unnumbered}

The Office of Drug Safety (ODS) has reviewed the Exanta (ximelagatran)
Risk Minimization Action Plan (RiskMAP) submitted by AstraZeneca as part
of its new drug application (NDA 21-686) to address the risk of
hepatotoxicity associated with long-term ximelagatran therapy. The
RiskMAP does not address the possible risks of delayed hepatotoxicity
after short-term use with ximelagatran, or the risk of myocardial
infarction (MI) that was identified in the FDA Clinical Safety Review.
In addition, reversal of excessive ximelagatran-induced bleeding was not
addressed by the sponsor.

Ximelagatran is an anticoagulant and if approved, will be the first
available oral direct thrombin inhibitor. The sponsor is seeking
approval for three indications: 1) for the short term prevention of
venous thrombo-embolism (VTE) in patients undergoing knee replacement
surgery; 2) for the long-term prevention of stroke and other
thromboembolic complications associated with atrial fibrillation; and 3)
for the long term secondary prevention of VTE after standard treatment
for an episode of acute VTE. In this document, we occasionally refer to
the combined safety experience with long term exposure (LTE), which
includes the treatment populations for indications (2) and (3).

######## A. Long-term Use (\>35 days) {#a.-long-term-use-35-days .unnumbered}

During clinical development, at least 37 cases of severe liver injury
\[defined as alanine aminotransferase (ALAT) \> 3 x upper limit of
normal (ULN) with concurrent increase in total bilirubin (TBL) \>2 x
ULN\] were observed among patients randomized to ximelagatran. The
relative risk of severe liver injury was 6.6 (95% CI 2.6 -- 16.9)
compared to warfarin/placebo, with one affected person in 200 treated
with ximelagatran. Preliminary analyses suggest the risk of severe liver
injury begins within the first month of therapy.

Based on the observation of Hy Zimmerman[^1] that at least 10% of
individuals with severe drug-induced liver injury (as defined above)
progress to liver failure, liver transplant, or death,
ximelagatran-associated fatal liver injury or liver failure could occur
in as many as 1 in 2,000 patients treated long-term (i.e., 10% of 1 in
200). Consistent with this prediction, three deaths associated with
severe liver injury occurred in the ximelagatran long-term exposure
clinical development program, for a proportion of one fatal liver injury
in 2,300 patients exposed to ximelagatran (n=6948 ximelagatran treated
patients, mean treatment duration of 357 days).

To address ximelagatran-induced hepatotoxicity associated with long-term
use, the sponsor proposes an ALT-monitoring program similar to the
program used during clinical development. This program consisted of
baseline and monthly ALT assessments, with more frequent testing and
discontinuation linked to different thresholds of ALT elevation relative
to the upper limit of normal. The initial algorithm specified an ALT \>7
times the ULN as a threshold for drug discontinuation, but this was
revised to 5 times the ULN after the occurrence of a death associated
with severe liver injury. Cases of severe liver injury and a case of
fatal liver injury continued to be observed after the implementation of
the revised algorithm. More conservative algorithms were not tested, so
it remains unknown whether timely discontinuation with any ALT elevation
can prevent irreversible life-threatening liver injury with
ximelagatran.

The sponsor's proposed RiskMAP targets \[ \] compliance with ALT
monitoring and algorithm-triggered discontinuation. In the clinical
development program, severe liver injury, including fatal liver injury
occurred even though compliance with ALT testing and discontinuation met
or exceeded 83%. The sponsor has not provided sufficient evidence about
whether timely transaminase monitoring and early discontinuation of the
drug at the first signs of liver toxicity could prevent severe liver
injury and associated fatalities with ximelagatran. Even if evidence
were sufficient to support the claim that monitoring can reduce the risk
of severe liver injury and associated fatalities, the sponsor's
projected lower adherence with recommended ALT monitoring in clinical
use has the potential to result in a *higher* rate of severe liver
injury and liver failure/fatal liver injury than was observed in
clinical development.

The demonstrated severity and rate of hepatotoxicity is substantial with
long term treatment with ximelagatran. Since no adequate mechanism to
prevent or limit this toxicity has been demonstrated, there is no basis
for proposing RiskMAP tools to reliably limit hepatotoxicity risk in
individual patients.

Should it be determined that ximelagatran offers selected populations of
patients sufficient benefits to counter the hepatotoxicity risk,
consideration should be given to a restrictive RiskMAP that would limit
risk on a population basis. One example might be a performance-linked
access system with a registry for patients entering long-term
ximelagatran therapy. Such a system should focus on appropriate
education of patients and providers about risk, and appropriate patient
selection. We would also advocate further quantification of the risk of
hepatotoxicity over time, and clarification of the ability of ALT
monitoring and early discontinuation of the drug to mitigate the risk of
severe liver injury and liver failure/fatal liver injury.

##### **B. Short-term Use**  {#b.-short-term-use .unnumbered}

In comparison to warfarin controls, there does not appear to be an
elevated risk of severe liver injury during the short-term use (\<12
days) of ximelagatran. However, in the two pivotal studies of total knee
replacement (TKR) patients, an imbalance in ALT \> 3 x ULN was observed
at the follow-up visit approximately 6 weeks after surgery in
ximelagatran-treated patients (8 ximelagatran- vs. 1 warfarin-treated
subject). Whether delayed onset of severe liver injury after short-term
ximelagatran treatment could occur is unknown, since no additional
routine study visits were conducted.

Analysis of data from the long-term exposure population shows that
initial signs of liver injury (ALT \> 3 x ULN) were observed during the
first month of ximelagatran therapy in 6 of 37 patients who went on to
develop severe liver injury (ALT \> 3 x ULN and TBL \> 2 x ULN). This
suggests that severe liver injury can potentially begin during the first
month of treatment with ximelagatran. Since practice guidelines
recommend anticoagulation of certain high risk patients with TKR for
more than 12 days, we anticipate physicians will want to treat some TKR
patients for a longer period with ximelagatran. Since the risk of severe
liver injury could increase with longer duration of ximelagatran
therapy, even during the first month, "short-term" duration of use after
TKR would need to be strictly limited to prevent potential severe liver
injury.

The sponsor did not submit a RiskMAP to constrain ximelagatran use to a
defined period (i.e., 7-12 days). Again, we remain concerned about the
intrinsic risk and poorly characterized pace of hepatotoxicity with
ximelagatran. Should the benefit of ximelagatran therapy be sufficient
to warrant approval for short-term prevention of VTE in patients
undergoing TKR, we recommend implementation of a RiskMAP to assure that
total duration of therapy in individual patients does not exceed 12 days
or whatever interval is found to be appropriate.

####### We note other safety risks of ximelagatran may merit serious consideration. These include (1) the risk of MI identified in the FDA Clinical Safety Review, and (2) the absence of clear methods to control excessive bleeding with ximelagatran should it occur. Neither of these risks was addressed by the sponsor, and one or both may warrant exploration of various risk management tools.  {#we-note-other-safety-risks-of-ximelagatran-may-merit-serious-consideration.-these-include-1-the-risk-of-mi-identified-in-the-fda-clinical-safety-review-and-2-the-absence-of-clear-methods-to-control-excessive-bleeding-with-ximelagatran-should-it-occur.-neither-of-these-risks-was-addressed-by-the-sponsor-and-one-or-both-may-warrant-exploration-of-various-risk-management-tools. .unnumbered}

For detailed risk evaluation of ximelagatran, please see Appendix E,
Review of Risk Minimization Action Plan by the Division of Drug Risk
Evaluation and the Division of Surveillance, Research and Communication
Support, Office of Drug Safety. Please also see Appendix F, Clinical
White Paper, CDER-PHRMA-AASLD Conference 2000 for more information
regarding evaluation of drug-induced liver toxicity.

####### **IV. Summary of Pre-clinical Evaluation** {#iv.-summary-of-pre-clinical-evaluation .unnumbered}

Ximelagatran (H 376/95) is quickly metabolized to melagatran (H 319/68).
Two intermediates, hydroxy-melagatran (H 415/04) and ethyl-melagatran (H
338/57) are formed during conversion of ximelagatran to melagatran. They
are measurable in human plasma. In vitro studies indicated that
melagatran is a potent and selective thrombin inhibitor.
Ethyl-melagatran is also pharmacologically active and its potency is
similar to that of melagatran. Ximelagatran and hydroxy-melagatran are
less potent.

The results of the cardiovascular pharmacology studies with ximelagatran
did not reveal any significant effects at oral doses up to 95 mg/kg in
rats and i.v. doses up to 36 mg/kg in dogs. Intravenous administration
of melagatran did not reveal any significant effects at doses up to 6.5
mg/kg in rats and dogs.

The toxicity profiles of ximelagatran and melagatran have been
characterized in 1- to 6-month oral toxicity studies in rats and 1- to
12-month oral toxicity studies in dogs. The toxicity profiles of
melagatran have been also characterized in 4-week i.v. toxicity studies
in rats and dogs. The major treatment-related toxicity identified in
these studies was the exaggerated pharmacological activity including
prolongation of clotting times and hemorrhages. In these studies, there
were no toxicological effects on the liver.

Ximelagatran and its intermediate, ethyl-melagatran, were positive in
the mouse lymphoma cell (L5178Y/TK^±^) forward gene mutation tests.
Ximelagatran was not genotoxic in the following tests: Ames, rat
hepatocyte unscheduled DNA synthesis (UDS) test, and *in vivo* mouse
micronucleus test. Melagatran was not genotoxic in the following tests:
Ames, human lymphocyte chromosome aberration test, mouse lymphoma cell
(L5178Y/TK^±^) forward gene mutation test, and mouse micronucleus test.
The intermediate, hydroxy-melagatran, was not genotoxic in the mouse
lymphoma (L5178Y/TK^±^) forward gene mutation test.

In a 2-year oral carcinogenicity study in rats, ximelagatran at doses of
19, 38, 76 or 114 mg/kg/day produced pancreatic acinar cell hyperplasia,
adenoma, and carcinoma. The dose of 19 mg/kg/day was about 3 times the
recommended human maintenance dose of 48 mg/day based on body surface
area. Ximelagatran was not tumorigenic in the 2-year oral
carcinogenicity study in mice at doses up to 85 mg/kg/day, which was
about 7 times the recommended human maintenance dose of 48 mg/day based
on body surface area.

Ximelagatran was found to have no adverse effects in the reproductive
toxicology studies in rats, rabbits, and mini-pigs.

####### **V. Summary of Clinical Pharmacology Evaluation** {#v.-summary-of-clinical-pharmacology-evaluation .unnumbered}

Data from 60 Clinical Pharmacology studies, 23 Biopharmaceutics-related
studies and several *in vitro* mechanistic studies were submitted in
support of this application.

Following oral administration, ximelagatran is rapidly absorbed with a
mean absolute bioavailability of melagatran estimated at 20%.
Ximelagatran is activated to melagatran by hydrolysis of the ethyl ester
(H338/57) and reduction of the N-hydroxyamidine function (H415/04). The
conversion of ximelagatran to melagatran does not appear to be mediated
by CYP 450 enzymes. Following oral administration of ^14^C-labeled
ximelagatran, approximately 71% and 25% of the administered
radioactivity were recovered in feces and urine, respectively.

Melagatran is a potent direct inhibitor of thrombin with a Ki of 2
nmol/L. H 338/57, one of the two intermediates, was shown to have potent
direct thrombin inhibition activity *in vitro* (Ki 1.3 nmol/L). However,
the mean AUC value for H 338/57 corresponds to only 3.2% of melagatran
AUC. Melagatran is not highly bound to plasma proteins (15%) and is
mainly excreted unchanged in urine (\~80%) with the renal clearance
corresponding to glomerular filtration rate. Dose linearity of
melagatran was demonstrated following administration of single oral
doses of ximelagatran ranging from 5 to 98 mg. There was also minimal
accumulation (10-15%) of melagatran following administration of BID
doses of ximelagatran oral solution 20 mg for 5 days to healthy
subjects.

The clinical trial- and Phase 2 formulations were shown to be
bioequivalent while the To-Be-Marketed commercial ximelagatran tablet
formulation was deemed equivalent to the Phase 3 tablet based on *in
vitro* dissolution data. Concomitant administration of ximelagatran with
food has no significant effect on AUC and Cmax of melagatran. Crushed
ximelagatran tablet contents sprinkled in applesauce and ximelagatran
tablet dissolved in water and administered via nasogastric tube were
shown to be bioequivalent to the intact ximelagatran tablet.

Administration of ximelagatran in patients with hepatic disease is not
recommended in the package insert due to the potential hepatotoxic
adverse events associated with ximelagatran. Administration of
ximelagatran in patients with severe renal impairment increases Cmax and
AUC by five fold and two fold, respectively, relative to patients with
mild renal impairment. The proposed labeling for ximelagatran states
that use of ximelagatran in patients with severe renal impairment is not
recommended. There are no recommendations, however for dosage adjustment
in patients with mild to moderate renal impairment.

Oral administration of ximelagatran in patients resulted in higher
melagatran systemic exposure and longer half-life (t~1/2~ \~ 5 hours)
relative to that in healthy subjects (t~1/2~ \~ 3 hours). This was
attributed by the sponsor to age-related lower renal function in
patients. In addition, the inter-individual variability in melagatran
exposure was markedly higher in patients (50%) relative to healthy
subjects (20%).

C~max~ and AUC of melagatran were elevated in elderly subjects relative
to young male subjects. The oral bioavailability, Cmax and AUC values of
melagatran in healthy elderly subjects increased by 23%, 47% and 38%,
respectively relative to young subjects. The decrease in CL in elderly
subjects is likely due to reduced renal function with age.

No clinically significant pharmacokinetic drug-drug interactions were
observed between ximelagatran and either CYP 3A4 substrates (nifedipine,
atorvastation, amiodarone and diazepam), CYP 2C9 substrates (diclofenac)
or CYP 2C19 substrates (diazepam). Co-administration of melagatran 36 mg
with erythromycin increased mean AUC and Cmax values of melagatran by
82% and 74%, respectively. No potentially clinically significant
pharmacodynamic drug-drug interactions were observed between
ximelagatran and either acetylsalicylic acid, diclofenac, amiodarone or
clopidogrel.

Exposure response (E/R) analysis of melagatran with respect to efficacy
and safety using pooled data from long-term studies (treatment \> 6
months) showed that there was a relationship between melagatran exposure
and both bleeding events and ALAT \> 3 X ULN.

###  {#section-4 .unnumbered}

## VI. Considerations for the Committee {#vi.-considerations-for-the-committee .unnumbered}

##  {#section-5 .unnumbered}

## A. Short-term Use: prevention of VTE in patients undergoing elective total knee replacement surgery {#a.-short-term-use-prevention-of-vte-in-patients-undergoing-elective-total-knee-replacement-surgery .unnumbered}

##  {#section-6 .unnumbered}

1.  In studies with long-term exposure to ximelagatran, elevation of
    hepatic enzymes was typically seen between the 2^nd^ and 6^th^ month
    after starting ximelagatran. The initial signs of liver injury (ALT
    \> 3 x ULN) were observed during the first month of ximelagatran
    therapy in 6 of 37 patients who went on to develop severe liver
    injury (ALT \> 3 x ULN and TBL \> 2 x ULN). This suggests that
    severe liver injury can potentially begin during the first month of
    treatment with ximelagatran. For study Exult A and Exult B in
    patients undergoing TKR, during the follow-up period (4-6 weeks), 8
    patients in the ximelagatran group, and 1 in the warfarin group had
    their first ALAT elevation \>3x ULN. However, patients were followed
    up for only 4-6 weeks post operation. Drug effects on liver toxicity
    beyond 4-6 weeks are unknown.

> Do you recommend additional safety studies with longer follow-up to
> address this issue?

2.  Because severe liver toxicity is associated with long-term use of
    ximelagatran, do you recommend a risk management program to restrict
    distribution and use to short-term use ([\<]{.underline}12 days) in
    this indication?

## Regarding the potential risk of myocardial infarction/coronary artery disease (MI/CAD) with short-term exposure to ximelagatran ([\<]{.underline}12 days) in patients undergoing TKR, do you recommend a study to further investigate the risk of MI/CAD? If yes, should the study be done prior to approval or as a Phase 4 commitment (post-marketing)? What type of study do you recommend?

3.  No oral medication has been approved for short-term use to prevent
    VTE in patients undergoing TKR. Exanta will provide an alternative
    choice to patients who prefer oral medication to subcutaneous
    injection. However, the demonstrated efficacy benefit is mainly
    reduction of asymptomatic distal DVT diagnosed by venography and
    there are some safety concerns as list above.

> Do benefits of Exanta exceed risks for this indication?

**B. Long-term Use: secondary prevention of VTE after 6 months standard
treatment for an episode of acute VTE**

##  {#section-7 .unnumbered}

## 5. Ximelagatran significantly reduced the recurrence rate of symptomatic, objectively confirmed VTE as compared to placebo over 18 months of treatment. However, ximelagatran-associated fatal liver injury or liver failure could occur in as many as 1 in 2,000 patients treated long-term, MI/CAD may be a potential risk of ximelagatran in the VTE population and warfarin is currently available therapy.  {#ximelagatran-significantly-reduced-the-recurrence-rate-of-symptomatic-objectively-confirmed-vte-as-compared-to-placebo-over-18-months-of-treatment.-however-ximelagatran-associated-fatal-liver-injury-or-liver-failure-could-occur-in-as-many-as-1-in-2000-patients-treated-long-term-micad-may-be-a-potential-risk-of-ximelagatran-in-the-vte-population-and-warfarin-is-currently-available-therapy. .unnumbered}

> Do benefits of Exanta exceed risks for this indication?

## Long-term Use: prevention of stroke and systemic embolic events in patients with atrial fibrillation

The sponsor is seeking an indication for ximelagatran to prevent stroke
and systemic embolic events in patients with atrial fibrillation. This
claim is based upon two \"non-inferiority\" trials with warfarin.
SPORTIF III was an open-label comparison in 3407 subjects and SPORTIF V
was a double-blind study with 3922 subjects.

The expected effect of warfarin was based on 6 placebo-controlled
studies (4 open-label) performed 10 to 15 years ago. The sponsor\'s
meta-analysis of these data concluded that warfarin reduced the risk of
stroke by 64% (95% CI of 52 to 73%). The sponsor proposed that
ximelagatran be considered \"non-inferior\" if the absolute event rate
was not 2% higher on ximelagatran than on warfarin, i.e., if
ximelagatran preserved nominally about 50% of the effect of warfarin.

<table style="width:100%;">
<colgroup>
<col style="width: 12%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 14%" />
<col style="width: 8%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 9%" />
<col style="width: 15%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2"></td>
<td colspan="3">Stroke/SEE (# events/ 100 patient-years)</td>
<td colspan="2">Discontinued</td>
<td colspan="2">Major bleed (# events/ 100 patient-years)</td>
<td colspan="2">Hy’s Law cases: ALT &gt;3xULN followed by bili &gt;
2xULN within one month</td>
</tr>
<tr class="even">
<td>Xim</td>
<td>War</td>
<td><p>Delta</p>
<p>(95% CI)</p></td>
<td>Xim</td>
<td>War</td>
<td>Xim</td>
<td>War</td>
<td>Xim</td>
<td>War</td>
</tr>
<tr class="odd">
<td>SPORTIF III</td>
<td>1.64%</td>
<td>2.30%</td>
<td><p>-0.66</p>
<p>(-1.45, 0.13)</p></td>
<td>10.9%</td>
<td>5.9%</td>
<td>1.3%</td>
<td>1.7%</td>
<td>0.5%</td>
<td>0.06%</td>
</tr>
<tr class="even">
<td>SPORTIF V</td>
<td>1.61%</td>
<td>1.16%</td>
<td><p>0.45</p>
<p>(-0.13, 1.03)</p></td>
<td>18.1%</td>
<td>15.4%</td>
<td>2.4%</td>
<td>3.1%</td>
<td>0.5%</td>
<td>0.05%</td>
</tr>
</tbody>
</table>

Event rates on warfarin in the two studies were 2.3% (SPORTIF III) and
1.2% (SPORTIF V), quite different from one another despite similar study
designs, and not similar to the expected event rate of 3.1%, from which
the non-inferiority margin was derived.

In SPORTIF III, there were 96 events, with nominal risk reduction of 29%
on ximelagatran (95% CI for relative risk is 48% to 106%). In SPORTIF V
there were 88 subjects with events, nominally 39% more on ximelagatran
(95% CI for relative risk is 91% to 212%).

7\. Without monitoring, major bleeding was reduced by about 0.7%
absolute with ximelagatran. However, ximelagatran is associated with
hepatotoxicity, which can be expected to be sometimes fatal. Does the
margin of 2% ensure ximelagatran is non-inferior to warfarin with
respect to efficacy and in light of safety concerns? Do benefits exceed
risks for this indication?

D.  **General**

8\. Based on currently available data, is it possible to identify
patients who are at risk for developing severe liver toxicity after
exposure to ximelagatran?

9\. Does the RiskMAP as proposed by the sponsor effectively mitigate the
risk of severe liver injury and liver failure?

[^1]: Zimmerman HJ. Drug-induced liver disease. In: [Hepatotoxicity The
    Adverse Effects of Drugs and Other Chemicals on the
    Liver.]{.underline} Appleton-Century-Crofts, New York, 1978, 1999.