# Presentation: 699247

## 	 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**
** **

**Notes:**
I’m going to talk about the several safety issues that were identified

## Overview

- Cardiovascular
- Neoplasms
- Fractures

**Notes:**
. I’m going to talk about the 3 potential safety issues that were identified  in the only long term safety study for OBD, , This is study 014,which was a study of alvimopan in OBD was being reviewed for the short term indication, POI.
These are serious cardiovascular events, neoplasms and fractures. these issues were  retrospectively analyzed in the POI trials.
As previously mentioned

## Cardiovascular Safety

-  Post-operative Ileus
- (POI)

**Notes:**
first, cv safety in the POI program

## CV Risk Factors in Worldwide POI 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 |

## Patients Experiencing Death or Serious Cardiovascular Events Total 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) |

## Cardiovascular Events Worldwide POI Population

|  | Alvimopan
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) |

## Slide 7

## Post Discharge SurveillanceWorldwide 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) |

## 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

**Notes:**
Therefore, there were significant limitations of the study design for the POI trials
Follow up after d/c was by telephone only except in 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

## Conclusion

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

**Notes:**
Study design  not really adequate to  assess CV risk in POI population.

## Cardiovascular Safety

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

**Notes:**
Next we will move on to CV safety in the OBD population
OBD trials divided into studies with patients taking opiates for non-cancer pain and studies with patients taking opiates for cancer pain

## 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 |

**Notes:**
6 main studies in OBD population 
4 in non-cancer pain
2 in cancer pain (1 was an extension study)
As you can see, only one 12 month trial... this is the largest study having 805 patients

## Patients Experiencing Death or Serious Cardiovascular Events  Non-Cancer 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 |  |  |  |

## Cardiovascular Events  Non-Cancer 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 |  |  |  |

## Patients Experiencing Death or Serious Cardiovascular Events  Study 014

|  | Alvimopan
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, --) |

## Cardiovascular Events  Study 014

|  | Alvimopan
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, --) |

## Patients Experiencing Death or Serious Cardiovascular EventsTotal OBD  Population Non-Cancer and 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 |  |  |  |

## Cardiovascular Events  Total  OBD PopulationNon-Cancer and 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 |  |  |  |

## Time to All Cardiovascular EventsTotal OBD  PopulationAll 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 |

## Time to All Ischemic EventsOnly (MI, Angina, CVA)Total OBD  PopulationAll 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 |

## Slide 21

## 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

**Notes:**
In looking for reasons to explain the imbalance, there were No differences in patient demographics or underlying CV risk factors
 Between study 014 and other OBD trials 
Within study 014

No evidence of failed randomization

## 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

## Neoplasms

-  POI Population

**Notes:**
Next we move onto neoplasms

## Neoplasia Events POI Studies

|  | Alvimopan
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%) |

## SummaryPOI 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

**Notes:**
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 of a drug used for a short indication, with limited follow up, may not reliably assess risk.

## Neoplasms

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

**Notes:**
For OBD, I’m going to discuss neoplasms in non-cancer pain studies and then the neoplasm deaths in cancer pain studies.

## All Neoplasms  Non-Cancer OBD 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) |

## Neoplasms Study 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) |

## Time to Malignant Neoplasm  Non-Cancer OBD PopulationAlvimopan

**Notes:**
 The time to malignant neoplasm for alvimopan varied from < 1 week to > 10 months. 6 cases occured in 2 months or less, many of the others occurred after 6 months, all in stydy 014.

All except one of the benign neoplasms occurred in Study 014; the majority occurred after 6 months of treatment.

## Time to Malignant Neoplasm  Non-Cancer OBD PopulationPlacebo

**Notes:**
the 3 placebo cases occurred  from about 6 weeks to > 52 weeks.

##  Time to Neoplasm  Non-Cancer OBD Population

**Notes:**
Time to event analysis is difficult to interpret with such a small # of events, but it suggests that  increased exposure to alvimopan increases neoplasm events as compared to placebo, when the event # is stable with time...........do I need time to malignant events figure?

## Most Common Malignancies   Non-Cancer OBD Population

| Neoplasm Type  | AlvimopanN=1598  | PlaceboN=732 |
| --- | --- | --- |
| Squamous cell carcinoma  | 
4 | 
0 |
| Breast cancer  | 3 | 0 |
| Lung cancer  | 3 | 1 |

**Notes:**
the most common neoplasms reported in the non-cancer studies were squamous cell cancer, breast cancer and lung cancer.

## OBD Studies Cancer Pain

- Study 008
- Extension Study 684

**Notes:**
Study 008 and the Extension Study ABD 101684 were the 2 main OBD Studies in Cancer Related Pain

##  Deaths Reported During OBD Studies in 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)
 |

**Notes:**
There was an imbalance  noticed in the Deaths Reported During OBD Studies in Cancer-Related Pain
 There were 10 deaths in study 008, 9 occured in the alvimopan group:
In study 684, there were 13 deaths, 11 occurred in the alvimopan group.
Combining these studies, 13% of the alvimopan group died as opposed to 4% of the placebo group .Can I say this??

##  Time to All Cause Death Studies 008 and 684

**Notes:**
Difficult to interpret as time increases; there are so few patients left in the study, especially in the placebo group. Is this true?? Can we interpret the beginning of the plot??

## Imbalances 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

## Imbalances in BaselineKarnofsky 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.

**Notes:**
In study 008, Karnofsky Performance Scores appeared balanced between treatment groups.
In study ABD101684, 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. 

## 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

## 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

## 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

## Fractures

- POI Population

**Notes:**
Next, is fractures in the POI population

## 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

**Notes:**
One patient with a fracture identified: This patient had a syncopal event after BR surgery 
And sustained multiple rib fractures.
No real conclusions can be drawn learned from this one case.

## Fractures

- OBD Population

## 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)

## 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)

**Notes:**
 When you look at study 014 alone, the difference between treatment groups is evident .The fracture locations were also mostly in the ribs and extremities

## Fracture Location: All OBD Studies

|  | Placebo
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) |

**Notes:**
The more typical osteoporotic-type fractures to the hip or vertebrae were rare as seen in this Table   The bones most often reported as broken were the ribs and those in the extremities. 

## Time to FractureAll OBD Studies

| Time to Fracture
(weeks) | Placebo
N=802
n (%) | Alvimopan
N=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) |

##  Time to Bone Fracture Study 014

**Notes:**
 The majority of fractures were reported after 120 days of treatment. In the alvimopan group, there appears to be a relationship between duration of treatment and risk of bone fracture.

## 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

**Notes:**
When adverse events were reviewed, there did not seem to be an imbalance between treatment groups for  any of these factors

## 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 *_*>*_* 65 years in the alvimopan group),*

## 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 > placebo)

## 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