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ENTEREGENTEREG®® (Alvimopan) (Alvimopan) Special Safety SectionSpecial Safety Section

Marjorie Dannis, M.D.

Division of Gastroenterology ProductsOffice of Drug Evaluation III

CDER, FDA

The Gastrointestinal Drugs Advisory Committee (GIDAC) MeetingJanuary 23, 2008

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OverviewOverview

•Cardiovascular

•Neoplasms

•Fractures

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CardiovascularCardiovascular Safety Safety

Post-operative Ileus

(POI)

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CV Risk Factors in Worldwide CV Risk Factors in Worldwide POI PopulationPOI Population

CV Risk Factor

Alvimopan

%

(N=2610)

Placebo

%

(N=1365)

Mean age 57 years 58 years

BMI ≥ 30 29 32

Diabetes 12 10

Hypertension 39 43

Smoking 8 10

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Patients Experiencing Death or Serious Patients Experiencing Death or Serious Cardiovascular EventsCardiovascular Events

Total POI PopulationTotal POI Population

Alvimopan

N=2610

n (%)

Placebo

N=1365

n (%)

Relative Risk

(95% CI)

All Cause Death (Total)

- Death from CV events

13 (0.5)

4 (0.2)

9 (0.7)

2 (0.2)

0.8

(0.3,1.7)

1.0

(0.2 ,4.9)

Patients with CV events (Total)

51 (2.0) 39 (2.9) 0.7

(0.4,1.0)

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Cardiovascular Events Cardiovascular Events

Worldwide POI PopulationWorldwide POI PopulationAlvimopan

N=2610

n (%)

Placebo

N=1365

n (%)

Relative Risk

(95%CI)

Ischemic events

- Fatal

17 (0.7)

2 (0.1)

14 (1.0)

0 (0.0)

0.6

(0.3, 1.3)

--

(0.3 ,--)

Other serious CV events

- Fatal

39 (1.5)

2 (0.1)

29 (2.1)

2 (0.2)

0.7

(0.4, 1.1 )

0.5

(0.1, 3.0)

7

0 10 20 30 40Day

0

2

4

6

Per

cen

t o

f S

ub

ject

s A

chie

vin

g a

CV

Eve

nt

(%)

Placebo

Alvimopan

Kaplan-Meier Estimate of Time to a CV Event for POI Studies

Alvimopan

Placebo

2610

1365

2439

1274

2046

1071

865

481

365

216

226

128

164

91

133

67

98

46

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Post Discharge SurveillancePost Discharge SurveillanceWorldwide POI PopulationWorldwide POI Population

Time after last dose

(days)

Alvimopan

N=2610

Placebo

N=1365

Had follow-up phone call

n (%)

Anytime 1874 (72) 1052 (77)

1- 5 332 (13) 164 (12)

6-14 1453 (56) 835 (61)

≥ 15 89 (3) 53 (4)

Had investigator follow-up visit n (%)

Anytime 416 (16) 110 (8)

1-5 22 (<1) 11 (<1)

6-14 374 (14) 94 (7)

≥ 15 19 (<1) 5 (<1)

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Limitations of POI Study Design Limitations of POI Study Design

• Follow-up by phone call only (except 1/9 studies)

• Important safety endpoints such as 30 day and 60 day morbidity/mortality not collected

• CV events not prospectively defined nor consistently assessed post exposure

• Missing data does not imply no CV events

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ConclusionConclusion

POI studies were not designed to adequately establish CV risk estimate in this population

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CardiovascularCardiovascular Safety Safety

Opioid-induced Bowel Dysfunction(OBD)

Non-cancer pain studies Cancer pain studies

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OBD Safety Population (at least 1 dose)OBD Safety Population (at least 1 dose)

Study (Time) Placebo Alvimopan Total

011 (6 wks) 129 393 522

012 (12 wks) 172 346 518

013 (12 wks) 164 321 485

014 (12 mos) 267 538 805

13C217 (phase 2) 4 16 20

13C304 (phase 2) 54 114 168

008 (3-6wks)

684 (< 2 yrs)

70

15

160

50

230

65

Total 860 1888 2748

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Patients Experiencing Death or Serious Patients Experiencing Death or Serious Cardiovascular EventsCardiovascular Events

Non-Cancer Non-Cancer OBD Population*OBD Population*Alvimopan

N=1728

n (%)

Placebo

N=790

n (%)

Relative Risk

(95% CI)

All Cause Death (Total)

- Death from CV events

4 (0.2)

2 (0.1)

2 (0.3)

0 (0.0)

0.9

(0.2, 5.0)

--

(0.2, --)

Patients with CV events (Total)

21 (1.2) 4 (0.5) 2.4

(0.9, 6.7)

*Studies 011,012,013, 014, 13C217, 13C304

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Cardiovascular EventsCardiovascular Events

Non-Cancer Non-Cancer OBD Population*OBD Population*Alvimopan

N=1728

n (%)

Placebo

N=790

n (%)

Relative Risk

(95%CI)

Ischemic events

- Fatal

14 (0.8)

1 (0.1)

3 (0.4)

0 (0.0)

2.1

(0.7, 6.9)

--

(0.1, --)

Other serious CV events

- Fatal

8 (0.5)

1 (0.1)

2 (0.3)

0 (0.0)

1.8

(0.4, 7.6 )

--

(0.1, --)*Studies 011, 012, 013, 014, 13C217, 13C301

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Patients Experiencing Death or Patients Experiencing Death or Serious Cardiovascular EventsSerious Cardiovascular Events

Study 014Study 014Alvimopan

N=538

n (%)

Placebo

N=267

n (%)

Relative Risk

(95% CI)

All Cause Death (Total)

- Death from CV events

2 (0.4)

1(0.2)

2 (0.8)

0 (0.0)

0.5

(0.1, 2.8)

--

(0.1, --)

Patients with CV events (Total)

14 (2.6) 0 (0.0) --

(1.8, --)

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Cardiovascular EventsCardiovascular Events

Study 014Study 014Alvimopan

N-538

n (%)

Placebo

N=267

n (%)

Relative Risk

(95%CI)

Ischemic events

- Fatal

11 (2.1)

1 (0.2)

0 (0.0)

0 (0.0)

--

(1.4, --)

--

(0.1, --)

Other serious CV events

3 (0.6) 0 (0.0) --

(0.4, --)

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Patients Experiencing Death or Serious Patients Experiencing Death or Serious Cardiovascular EventsCardiovascular Events

Total OBD PopulationTotal OBD Population Non-CancerNon-Cancer and and Cancer Studies*Cancer Studies*

Alvimopan

N=1888

n (%)

Placebo

N=860

n (%)

Relative Risk

(95% CI)

All Cause Death (Total)

- Death from CV events

24 (1.3)

5 (0.3)

5 (0.6)

1 (0.1)

2.2

(0.9, 5.5)

2.3

(0.4, 14.7)

Patients with CV events (Total)

26 (1.4) 6(0.7) 2.0

(0.8, 4.7)

*Studies 011, 012, 013, 014, 13C217, 13C304, 008, 684

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Cardiovascular Events Cardiovascular Events Total OBD PopulationTotal OBD Population

Non-CancerNon-Cancer and and Cancer Studies*Cancer Studies*Alvimopan

N-1888

n (%)

Placebo

N=860

n (%)

Relative Risk

(95%CI)

Ischemic events

- Fatal

14 (0.8)

1 (0.1)

4 (0.5)

0 (0.0)

1.6

(0.6, 4.6)

--

(0.1, --)

Other serious CV events

- Fatal

14 (0.8)

4 (0.2)

3 (0.4)

1 (0.1)

2.1

(0.7, 6.9)

1.8

(0.3, 11.1)

*Studies 011, 012, 013, 014, 13C217, 13C304, 008, 684

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Time to All Cardiovascular EventsTime to All Cardiovascular EventsTotal OBD PopulationTotal OBD PopulationAll Studies ≥ 14 DaysAll Studies ≥ 14 Days

Days

Alvimopan

(n=26)

Placebo

(n=6)

14 or less 5 3

15 to 30 3 0

31 to 90 10 2

91 to 180 6 0

181 or more 2 1

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Time to All Ischemic EventsTime to All Ischemic EventsOnly (MI, Angina, CVA)Only (MI, Angina, CVA)Total OBD PopulationTotal OBD Population

All Studies ≥ 14 DaysAll Studies ≥ 14 Days

Days

Alvimopan

(n=13)

Placebo

(n=4)

14 or less 1 1

15 to 30 0 0

31 to 90 8 2

91 to 180 3 0

181 or more 1 1

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5 35 65 95 125 155 185 215 245 275 305 335 365Day

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Per

cen

t o

f S

ub

ject

s A

chie

vin

g a

CV

Eve

nt

(%)

Kaplan-Meier Estimate of Time to a CV Event for All OBD Studies ( 14 Days)

Alvimopan

Placebo

Alvimopan

Placebo

1888

860

1603

733

978

465

1075

523

435

206

418

195

398

185

372

171

361

165

349

158

336

149

328

145

302

135

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Additional ObservationsAdditional Observations

• No differences in patient demographics or underlying CV risk factors:– Between study 014 and other OBD trials – Within study 014

• Study duration of most other OBD studies was 3-12 weeks ; duration of study 014 was 12 months

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Summary and ConclusionsSummary and Conclusions• Numerical imbalance of serious CV events in:

– Pooled analyses of OBD studies– Study 014 alone– Finding not explained by pre-clinical findings

• May suggest that chronic alvimopan use can increase risk of serious CV events in OBD population– Implications for short-term use in POI unclear

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NeoplasmsNeoplasms POI Population

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Neoplasia Events Neoplasia Events

POI StudiesPOI StudiesAlvimopan

N=2610

Placebo

N=1365

Burkitt’s lymphoma 0 1

Bladder neoplasm 0 1

Carcinoma 0 1

Chronic myelogenous

leukemia

1 0

Colon cancer metastatic 1 0

Hepatic neoplasm 1 0

Lymphoma 1 0

Thyroid neoplasm 1 0

TOTAL 5 (0.2%) 3 (0.2%)

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SummarySummary

POI PopulationPOI Population• Number of neoplasms reported in each

treatment group appears to be balanced

• Study design does not allow for significant conclusions to be drawn

• Long term effects unclear

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NeoplasmsNeoplasmsOBD Population

Non-cancer pain studies

Cancer pain studies

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All Neoplasms All Neoplasms

Non-Cancer Non-Cancer OBDOBD Population*Population*Alvimopan

N=1598

n (%)

Placebo

N=732

n (%)

Relative Risk

(95% C.I.)

All Neoplasms

22 (1.4) 4 (0.5) 2.5

(0.9, 7.0)

Malignant Neoplasms

13 (0.8) 3 (0.4) 2.0

(0.6, 6.5)

Benign Neoplasms

9 (0.6) 1 (0.1) 4.12

(0.7, 25.2)

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Neoplasms Neoplasms Study 014Study 014

Alvimopan

N=538

n (%)

Placebo

N=267

n (%)

Relative Risk

(95% C.I.)

All Neoplasms

15 (2.8) 3 (1.1) 2.5

(0.8, 8.0)

Malignant Neoplasms

7 (1.3) 2 (0.7) 1.7

(0.4, 7.3)

Benign Neoplasms

8 (1.5) 1 (0.4) 4.0

(0.7, 24.4)

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Time to Malignant Neoplasm Time to Malignant Neoplasm Non-CancerNon-Cancer OBD Population OBD Population

AlvimopanAlvimopanStudy Malignant Neoplasm Days on

treatment 011 Inoperable pancreatic

CA 4

014 Ulcerated basal cell carcinoma, of nose- Skin cancer

24

012 left ductal carcinoma in situ

29

012 Metastatic breast cancer

48

014 Squamous cell cancer of lung

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013 Breast cancer 62 012 New CLL 88 014 Lung cancer— 133 014 R ear melanoma 175

011 Metastatic non small

cell ca lung- 229

014 Squamous cell carcinoma

270

014 Invasive squamous cell carcinoma of scalp- Skin cancer

289

014 Squamous cell cancer of larynx

316

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Time to Malignant Neoplasm Time to Malignant Neoplasm Non-CancerNon-Cancer OBD Population OBD Population

PlaceboPlaceboStudy Malignant Neoplasm

Days on treatment

014 Metastatic prostate cancer -died

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012 Cancer of caecum 106 014 Non- small cell lung

cancer 50 days after stopping drug (took for 364 days)

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Time to NeoplasmTime to Neoplasm Non-CancerNon-Cancer OBD Population OBD Population

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Most Common Malignancies Most Common Malignancies Non-Cancer Non-Cancer OBD PopulationOBD Population

Neoplasm Type

AlvimopanN=1598

PlaceboN=732

Squamous cell

carcinoma 4 0

Breast cancer

3 0

Lung cancer 3 1

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OBD Studies OBD Studies Cancer PainCancer Pain

• Study 008

• Extension Study 684

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Deaths Reported During OBD Studies in Deaths Reported During OBD Studies in Cancer Pain (Studies 008 and 684)Cancer Pain (Studies 008 and 684)

Study 008 Study 684

(extension study)

Studies 008 and 684 combined

Placebo

N=70

n (%)

Alvimopan

N=160

n (%)

Placebo

N=15

n (%)

Alvimopan

N=50

n (%)

Placebo

N=70

n (%)

Alvimopan

N=160

n (%)

Deaths 1 (1.4) 9 (5.6) 2 (13.0) 11 (22.0) 3 (4.0) 20 (13.0)

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Time to All Cause Death Time to All Cause Death Studies 008 and 684Studies 008 and 684

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Imbalances in Index Cancer DiagnosisImbalances in Index Cancer Diagnosis– In study 008, more subjects with head and neck

cancers received alvimopan (N=14, 9%) than placebo (N=1, 1%), however

• Deaths were almost entirely in Gyn, GU, breast cancers (balanced between treatment groups)

– In study 684, more subjects with non-small cell lung cancer received alvimopan (N=16, 31%) than placebo (N=1, 7%), and

• Most deaths occurred in non-small cell lung CA patients

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Imbalances in BaselineImbalances in BaselineKarnofsky Performance ScoresKarnofsky Performance Scores

• In study 008, Karnofsky Performance Scores appeared balanced between treatment groups.

• In study 684, there was a higher percentage of patients with lower Karnofsky Performance scores in the alvimopan group as compared to the placebo group, 42% vs. 13% respectively.

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Other FactorsOther Factors• Demographic Characteristics (age, race, gender):

– Similar between study 008 and study 684 populations

– Balanced between treatment groups within each study

• Extent of Metastatic Disease:– Similar between study 008 and study 684 populations

– Balanced between treatment groups within each study

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Summary Summary Non-CancerNon-Cancer OBD Population OBD Population

• Alvimopan-treated patients had a higher incidence of neoplasia events as compared to placebo

• Possibly driven by the imbalance in neoplasia events in the only long term safety study for OBD in patients without cancer, study 014– No obvious reason for the observed imbalance

between treatment groups in this placebo controlled study

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Summary Summary Cancer Cancer OBD PopulationOBD Population

• Large discrepancy seen in the death rates between treatment groups in studies 008 and 684– Some differences in index cancer etiology and

patient performance status were noted

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FracturesFractures

POI Population

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Fractures Fractures POI PopulationPOI Population

• One patient with a fracture identified:– Multiple rib fractures secondary to syncope and

subsequent fall after BR surgery

• With only one fracture event reported, no conclusions can be drawn

• Limited follow-up may not adequately assess fracture risk

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FracturesFractures

OBD Population

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Fracture Incidence Fracture Incidence All OBD All OBD

Non-CancerNon-Cancer and and Cancer Cancer Population Population

• Alvimopan: 1.4% (25/1758)

• Placebo: 1.2% (10/802)

• Relative Risk: 1.14 (95% CI: 0.6 to 2.3)

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Fracture Incidence Fracture Incidence Study 014Study 014

• Alvimopan: 3.7% (20/538)

• Placebo: 1.1% (3/267)

• Relative Risk: 3.30 (95% CI: 1.1 to 10.4)

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Fracture Location: All OBD StudiesFracture Location: All OBD StudiesPlacebo

N= 802

n (%)

Alvimopan

N=1758

n (%)

Vertebra 1 (0.1) 2 (0.1)

Rib 2 (0.2) 4 (0.2)

Humerus 0 (0.0) 4 (0.2)

Wrist 1 (0.1) 1 (0.1)

Femur 1 (0.1) 1 (0.1)

Patella/fibula/tibia 2 (0.2) 4 (0.2)

Ankle 1 (0.1) 4 (0.2)

Foot 2 (0.2) 5 (0.3)

Total 10 (1.2) 25 (1.4)

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Time to FractureTime to FractureAll OBD StudiesAll OBD Studies

Time to Fracture

(weeks)

PlaceboN=802

n (%)

AlvimopanN=1758

n (%)

1-5 4 (0.5) 2 (0.1)

5-12 3 (0.4) 5 (0.3)

12-24 0 (0.0) 5 (0.3)

24-36 2 (0.3) 6 (0.3)

36-45 0 (0.0) 6 (0.3)

> 45 1 (0.1) 1 (0.1)

TOTAL 10 (1.2) 25 (1.4)

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Time to Bone Fracture Time to Bone Fracture Study 014Study 014

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Specific Clinical FindingsSpecific Clinical Findings

• Majority of fractures were secondary to falls – Etiologies for increased fall risk (dizziness,

hypotension, syncope, gait instability, etc) were not apparent

• Of subjects reporting fractures, the alvimopan group had a higher percentage of women, more individuals ≥ 65 years of age, and a higher average BMI

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Specific Clinical FindingsSpecific Clinical Findings

• Baseline demographics well balanced between treatment groups in study 014* as well as total OBD population

• The mean opioid daily dose was similar between treatment groups

* (except higher percentage of patients > 65 years in the alvimopan group),

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Summary Summary OBD PopulationOBD Population

– Fractures were not typical osteoporotic fractures, such as hip and vertebrae

– Unclear etiology for imbalance in fracture rates between treatment groups in study 014 (alvimopan > placebo)

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Overall SummaryOverall Summary• A large, long-term safety study of

alvimopan for OBD indication showed potential safety signals in 3 specific areas:– serious cardiovascular events, neoplasms and

fractures

• The POI studies did not show evidence of these safety signals; however, the follow-up of patients was extremely limited