alvimopan

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ENTEREG (Alvimopan) Special Safety Section

• Marjorie Dannis, M.D.

Division of Gastroenterology Products Office of
Drug Evaluation III CDER, FDA The
Gastrointestinal Drugs Advisory Committee (GIDAC)
Meeting January 23, 2008
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Overview

• Cardiovascular
• Neoplasms
• Fractures

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Cardiovascular Safety

• Post-operative Ileus
• (POI)

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CV Risk Factors in Worldwide POI Population
CV Risk Factor Alvimopan (N2610) Placebo (N1365)
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
Cardiovascular Events Total POI Population
Alvimopan N2610 n () Placebo N1365 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 Worldwide POI Population
Alvimopan N2610 n () Placebo N1365 n () Relative Risk (95CI)
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)
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Post Discharge SurveillanceWorldwide POI
Population
Time after last dose (days) Alvimopan N2610 Placebo N1365
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 (lt1) 11 (lt1)
6-14 374 (14) 94 (7)
15 19 (lt1) 5 (lt1)
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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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Conclusion

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

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Cardiovascular Safety

• Opioid-induced Bowel Dysfunction
• (OBD)
• Non-cancer pain studies
• Cancer pain studies

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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 (lt 2 yrs) 70 15 160 50 230 65
Total 860 1888 2748
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Patients Experiencing Death or Serious
Cardiovascular Events Non-Cancer OBD
Population
Alvimopan N1728 n () Placebo N790 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 Studies 011,012,013, 014, 13C217, 13C304 Studies 011,012,013, 014, 13C217, 13C304 Studies 011,012,013, 014, 13C217, 13C304
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Cardiovascular Events Non-Cancer OBD
Population
Alvimopan N1728 n () Placebo N790 n () Relative Risk (95CI)
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 Studies 011, 012, 013, 014, 13C217, 13C301 Studies 011, 012, 013, 014, 13C217, 13C301 Studies 011, 012, 013, 014, 13C217, 13C301
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Patients Experiencing Death or Serious
Cardiovascular Events Study 014
Alvimopan N538 n () Placebo N267 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 Events Study 014
Alvimopan N-538 n () Placebo N267 n () Relative Risk (95CI)
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
Cardiovascular EventsTotal OBD Population
Non-Cancer and Cancer Studies
Alvimopan N1888 n () Placebo N860 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 Studies 011, 012, 013, 014, 13C217, 13C304, 008, 684 Studies 011, 012, 013, 014, 13C217, 13C304, 008, 684 Studies 011, 012, 013, 014, 13C217, 13C304, 008, 684
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Cardiovascular Events Total OBD
PopulationNon-Cancer and Cancer Studies
Alvimopan N-1888 n () Placebo N860 n () Relative Risk (95CI)
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 Studies 011, 012, 013, 014, 13C217, 13C304, 008, 684 Studies 011, 012, 013, 014, 13C217, 13C304, 008, 684 Studies 011, 012, 013, 014, 13C217, 13C304, 008, 684
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Time to All Cardiovascular EventsTotal OBD
PopulationAll Studies 14 Days
Days Alvimopan (n26) Placebo (n6)
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 EventsOnly (MI, Angina,
CVA)Total OBD PopulationAll Studies 14 Days
Days Alvimopan (n13) Placebo (n4)
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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Additional 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 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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Neoplasms

• POI Population

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Neoplasia Events POI Studies
Alvimopan N2610 Placebo N1365
Burkitts 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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SummaryPOI 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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Neoplasms

• OBD Population
• Non-cancer pain studies
• Cancer pain studies

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All Neoplasms Non-Cancer OBD Population
Alvimopan N1598 n () Placebo N732 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 Study 014
Alvimopan N538 n () Placebo N267 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 Non-Cancer OBD
PopulationAlvimopan
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Time to Malignant Neoplasm Non-Cancer OBD
PopulationPlacebo
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Time to Neoplasm Non-Cancer OBD Population
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Most Common Malignancies Non-Cancer OBD
Population
Neoplasm Type AlvimopanN1598 PlaceboN732
Squamous cell carcinoma 4 0
Breast cancer 3 0
Lung cancer 3 1
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OBD Studies Cancer Pain

• Study 008
• Extension Study 684

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Deaths Reported During OBD Studies in Cancer
Pain (Studies 008 and 684)
Study 008 Study 008 Study 684 (extension study) Study 684 (extension study) Studies 008 and 684 combined Studies 008 and 684 combined
Placebo N70 n () Alvimopan N160 n () Placebo N15 n () Alvimopan N50 n () Placebo N70 n () Alvimopan N160 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 Studies 008 and 684
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Imbalances in Index Cancer Diagnosis

• In study 008, more subjects with head and neck
• cancers received alvimopan (N14, 9) than
• placebo (N1, 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 (N16, 31) than
  placebo (N1, 7), and
• Most deaths occurred in non-small cell lung CA
  patients

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Imbalances in BaselineKarnofsky 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 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 Non-Cancer 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 Cancer OBD 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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Fractures

• POI Population

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Fractures POI 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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Fractures

• OBD Population

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Fracture Incidence All OBD Non-Cancer and
Cancer 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 Study 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 Studies
Placebo N 802 n () Alvimopan N1758 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 FractureAll OBD Studies
Time to Fracture (weeks) Placebo N802 n () Alvimopan N1758 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)
gt 45 1 (0.1) 1 (0.1)
TOTAL 10 (1.2) 25 (1.4)
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Time to Bone Fracture Study 014
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Specific 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 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 gt 65
  years in the alvimopan group),

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Summary OBD 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
  gt placebo)

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Overall 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