# Presentation: 705564

## 	Clinical Evaluation of NDA 21-775ENTEREG® (Alvimopan)Part 1: Efficacy and General Safety Evaluation

- Ruyi He, MD
- Medical Team Leader
**Division of Gastroenterology Products**
**Office of Drug Evaluation III**
**CDER, FDA**
**The Gastrointestinal Drugs Advisory Committee (GIDAC) Meeting**
**January 23, 2008**

## Overview of Presentation

-  Part 1: Efficacy and General Safety
- Alvimopan and  POI
- Regulatory History
- POI Clinical Program
- POI Efficacy Results
- POI General Safety Results
- OBD Clinical Program
-   Part 2: Special Safety Issues
-   Part 3: Non-Clinical Evaluation
-   Part 4: Risk Management

## Alvimopan

-  New Molecular Entity
-  Peripherally-acting opioid-receptor antagonist
-  Low systemic oral bioavailability (about 6%)
-  Tmax about 2 h. Half Life ranged from 4 to 17 h
-  One active metabolite (ADL 08-0011).

## Sponsor’s Proposed Indication 

- Acceleration of time to upper and lower gastrointestinal (GI) recovery following partial large and small bowel resection surgery with primary anastomosis

## Postoperative ileus (POI)

- Transient impairment of GI function after surgery
- Characterized by inability to tolerate liquids and solid food, nausea, vomiting, and/or abdominal pain/bloating
- Complications include prolonged hospitalization, delayed nutrition, et al.
- No product is currently approved for POI in the U.S.
- Off-label therapies include metoclopramide and erythromycin

## Main Regulatory History 

| Date | Event |
| --- | --- |
| Aug. 1998 | Initial IND submitted |
| Feb. 2004 | Fast Track Designation granted for POI |
| June 2004 | Original NDA 21-775 submitted |
| July 2005 | Approvable action, insufficient evidence for efficacy |
| May 2006 | Complete response submitted, serious CV events noted in an ongoing OBD study |
| Nov. 2006 | 2nd approvable action, requested final 12m safety findings and risk management plan |
| April 2007 | Full clinical hold; CV events, neoplasms and bone fractures were identified in OBD studies |
| Aug. 2007 | Complete response submitted. PDUFA due day: 2/10/08 |

## POI Clinical Program

**Six Phase 3 Clinical Studies **
**(302, 306, 308, 313, 001 and 314):**
- Randomized, double-blind, placebo-controlled, multi centered trials in patients undergoing partial large or small BR or total abdominal hysterectomy (TAH) surgery.
- Study 001 was conducted in Europe and Australia. All other studies were conducted in the US and Canada.
- Patients on chronic opioids were excluded from the studies.

## POI Clinical Program

- Since efficacy was not demonstrated in the TAH surgery subgroup in the original NDA submission, the sponsor decided to narrow proposed indication to the BR surgery population only
- Study 306 is not included in the efficacy evaluation, because no BR patient was enrolled in this study (TAH only)

## Treatment

- Initial Dose given 0.5 to 2 h prior to surgery, Subsequent Doses:  12 mg PO, BID from POD 1 until hospital discharge or POD 7
- Maximum number of doses is 15 (maximum of 8 days of therapy)
- Study drugs only administered in hospital

## Key Endpoints

**GI-3:**** **time from end of surgery to time of recovery of both upper  	      and lower GI tract function
- Toleration of solid food;
- First BM or flatus;
- It was the primary EP for Study 302, 308, 313 and 001.
**GI-2** (solid food, first BM).
- GI-2 was the primary EP for Study 314.
- GI-2 maybe a more objective EP than GI-3.
**Ready**: time from end of surgery to time ready for hospital discharge based solely on recovery of GI function as defined by the surgeon.
**DOW**: time from end of surgery to time discharge order is written.

## GI-3 Recovery: Difference from Placebo (Hours)* in BR Patients

| Study | 302 | 308 |  313 | 001 | 314 |
| --- | --- | --- | --- | --- | --- |
| 25th percentile | 4.6 | 11.3 | 6.7 | 3.4 | 12.2 |
| Median | 7.6 | 13.4 | 10.5 | 4.4 | 9.1 |
| 75th percentile | 7.5 | 20.7 | 21 | 14.1 | 15.5 |
| HR 
(95% CI) | 1.295
(0.96, 1.74) | 1.317
(1.03, 1.69) | 1.494
(1.17, 1.91) | 1.132
(0.94, 1.37) | 1.45
(1.23, 1.71) |
| 
P-value | 
0.086 | 
0.029 | 
0.001 | 
0.200 | 
<0.001 |
| *Using Cox Proportional Hazards Models |  |  |  |  |  |

## GI-2 Recovery: Difference from Placebo (Hours)* in BR Patients

| Study | 302 | 308 | 313 | 001 | 314 |
| --- | --- | --- | --- | --- | --- |
| 25th percentile | 11.5 | 5.3 | 14.1 | 2.8 | 9.2 |
| Median | 17 | 13.8 | 21.7 | 4.4 | 16.6 |
| 75th percentile | 19.5 | 21.3 | 28.9 | 18.7 | 20.3 |
| HR 
(95% CI) | 1.40
(1.04, 1.89) | 1.37
(1.06, 1.76) | 1.63
(1.26, 2.10) | 1.30
(1.07, 1.58) | 1.53
(1.29, 1.82) |
| 
P-value | 
0.029 | 
0.017 | 
<0.001 | 
0.008 | 
<0.001 |
| *Using Cox Proportional Hazards Models |  |  |  |  |  |

## Ready: Difference from Placebo (Hours)* in BR Patients

| Study | 302 | 308 | 313 | 001 | 314 |
| --- | --- | --- | --- | --- | --- |
| 25th percentile | 7.7 | 5.5 | 12.8 | 5.3 | 3.2 |
| Median | 14.5 | 8.0 | 17.3 | 10.3 | 10.6 |
| 75th percentile | 20.3 | 20.4 | 24.5 | 6.5 | 21.1 |
| HR 
(95% CI) | 1.52
(1.11, 2.09) | 1.40
(1.09, 1.78) | 1.54
(1.20, 1.96) | 1.11
(0.92, 1.35) | 1.38
(1.17, 1.63) |
| 
P-value | 
0.010 | 
0.008 | 
<0.001 | 
0.287 | 
<0.001 |
| *Using Cox Proportional Hazards Models |  |  |  |  |  |

## Time to DOW (Days)* in BR Patients

| Study | Tx |  | Median | Δ | 75th
Percentile | Δ | HR
(95% CI) | p-value |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 302 | PL
Alv |  | 5.6
4.9 | 0.7 | 6.8
6.0 | 0.8 | 1.29
(0.98, 1.7) | 0.084 |
| 308 | PL
Alv |  | 5.7
5.0 | 0.7 | 7.2
6.0 | 1.2 | 1.56
(1.2, 2.0) | <0.001 |
| 313 | PL
Alv |  | 5.6
4.8 | 0.8 | 7.5
6.0 | 1.5 | 1.42 
(1.1, 1.8) | 0.004 |
| 001 | PL
Alv |  | 8.0
8.0 | 0 | 11.1
10.9 | 0.2 | 1.07
(0.9, 1.3) | 0.838 |
| 314 | PL
Alv |  | 5.0
4.7 | 0.3 | 6.9
5.9 | 1.0 | 1.40
(1.2, 1.7) | <0.001 |
| *Using Cox Proportional Hazards Models |  |  |  |  |  |  |  |  |

## Mean Length of Hospital Stay  (Days)

| Study | 302 | 308 | 313 | 001 | 314 |
| --- | --- | --- | --- | --- | --- |
| Placebo | 6.4 (n=99) | 6.6 (n=142) | 7.4 (n=142) | 9.2
(n=229) | 6.2
(n=312) |
| Alvimopan
12 mg | 6.1 (n=98) | 5.7 (n=139) | 6.1 (n=160) | 8.9
(n=238) | 5.2
(n=317) |
| Difference | 0.3 | 0.9 | 1.3 | 0.2 | 1.0 |

## Efficacy Summary in POI

- Efficacy data demonstrated:  there was acceleration of recovery of upper and lower GI tract function by roughly 20 hours measured by GI2 and reduced length of hospital stay by roughly 1 day in the US.

## Questions 

- What is the minimum acceptable efficacy difference for recovery of GI function measured by GI2 or GI3 for alvimopan relative to placebo? 12h? 24h? 36h? other?
- Do you consider the efficacy results from the POI studies to be clinically meaningful?

## General Safety Evaluation in the POI Population

- A total of 3975 patients are included in the POI safety database
- 1365 patients received placebo
- 2610 patients received alvimopan at doses of 1, 3, 6, or 12 mg

## Demographics-Overall POI Population

| Characteristic  | Pla. N=1365 
n (%) | Alv. N=2610 
n (%) |
| --- | --- | --- |
| Age, Mean | 58 | 57 |
| Age > 65 yr | 491 (36) | 898 (34.4) |
| Race: White | 1156 (84.7) | 2207 (84.6) |
|            Other  | 209 (15.3) | 403 (15.4) |
| Female | 850 (62.3) | 1680 (64.4) |

## POI Safety:  Deaths and SAEs

| n (%) | Placebo
(N=1365) | Alv 6 mg
(N=898) | Alv 12 mg
(N=1650) |
| --- | --- | --- | --- |
| Total Deaths | 9 (0.7) | 5 (0. 6) | 8 (0.5) |
| All Nonfatal SAEs | 250 (18) | 110 (12) | 192 (12) |
|     POI/SBO | 86 (6) | 18 (2) | 32 (2) |
|     Infection | 19 (1) | 10 (1) | 18 (1) |
|     Anastomotic leak | 15 (1) | 12 (1) | 11 (1) |
|     Pulmonary emboli | 13 (1) | 9 (1) | 11 (1) |

## POI:  AEs Leading to Discontinuations

| n (%) | Placebo
(N=1365) | Alv. 6 mg
(N=898) | Alv. 12 mg
(N=1650) |
| --- | --- | --- | --- |
| Total | 162 (12) | 74 (8) | 125 (8) |
|   Nausea | 42 (3) | 19 (2) | 39 (2) |
|   Vomiting | 43 (3) | 17 (2) | 24 (2) |
|   POI | 45 (3) | 11 (1) | 20 (1) |
|   Abd. distension | 11 (1) | 6 (1) | 8 (1) |
|   Diarrhea | 4 (0.3) | 0 | 8 (0.5) |
|   Dyspepsia | 0 | 1 (0.1) | 8 (0.5) |

## Treatment-Emergent Events

| n (%) | Placebo
N=986 | Alv. 6 mg
N=663 | Alv. 12 mg
N=999 |
| --- | --- | --- | --- |
| Nausea  | 491 (49.8) | 246 (37.1) | 433 (43.3) |
| Vomiting  | 209 (21.2) | 111 (16.7) | 141 (14.1) |
| Abd. distension | 137 (13.9) | 59 (8.9) | 120 (12) |
| Pruritus  | 97 (9.8) | 46 (6.9) | 85 (8.5) |
| POI | 113 (11.5) | 33 (5) | 60 (6) |
| Urinary retention | 21 (2.1) | 17 (2.6) | 32 (3.2) |
| Pain | 18 (1.8) | 18 (2.7) | 12 (1.2) |
| SBO | 18 (1.8) | 5 (0.8) | 9 (0.9) |
| Anastomotic leak | 11 (1.1) | 8 (1.2) | 8 (0.8) |

## General Safety Summary in POI

-    Similar or lower incidences of death, nonfatal SAEs, discontinuations due to AEs and treatment-emergent events were identified in the alvimopan groups in comparison with the placebo group in POI population

## Chronic Opioid-Induced Bowel Dysfunction (OBD)

- OBD is chronic condition characterized by decreased frequency of bowel movements and associated symptoms
- Patients in OBD studies were treated for chronic pain with opioids for months, years; instead of days in POI
- Although current submission is only for POI indication, imbalances in CV events, neoplasms and bone fractures were identified in OBD clinical studies

## Dose Regimen in POI & OBD

|  | POI | OBD |
| --- | --- | --- |
| Route | Oral | Oral |
| Dose   Regimen | 12 mg BID 
(up to 7 days postop)  | 0.5 -1 mg QD or BID
(up to one year) |
| Maximum
Daily Dose | 24 mg/day | 1-2 mg/day |
| Duration | Up to 8 days | Up to 1 year  |
| Location | Hospital only | Mostly Outpatient  |

## Thank You

-  Eric Brodsky (Medical Reviewer)
-  Sonia Castillo (Statistician)
-  Joyce Korvick (Deputy Division Director)
-  Julie Beitz (Office Director)
-  Daniel Shames (Deputy Office Director)
-  Matthew Scherer (Projector Manager)
-  Sue Chih Lee (Biopharmaceutics)
-  Tamal Chakraborti (Pharmacologist)
-  Marie Kowblansky (Chemist)
-  And everyone in the review team