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Clinical Evaluation of NDA 21-775ENTEREGENTEREG®® (Alvimopan) (Alvimopan)

Part 1: Efficacy and General Safety EvaluationPart 1: Efficacy and General Safety Evaluation

Ruyi He, MD

Medical Team LeaderDivision of Gastroenterology Products

Office of Drug Evaluation IIICDER, FDA

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

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Overview of PresentationOverview of Presentation Part 1: Efficacy and General Safety

Alvimopan and POIRegulatory HistoryPOI Clinical Program POI Efficacy ResultsPOI General Safety ResultsOBD Clinical Program

Part 2: Special Safety Issues Part 3: Non-Clinical Evaluation Part 4: Risk Management

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AlvimopanAlvimopan

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).

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Sponsor’s Proposed IndicationSponsor’s Proposed Indication

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

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Postoperative ileus (POI)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

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Main Regulatory HistoryMain 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 2006Complete response submitted, serious CV events noted in an ongoing OBD study

Nov. 20062nd approvable action, requested final 12m safety findings and risk management plan

April 2007Full clinical hold; CV events, neoplasms and bone fractures were identified in OBD studies

Aug. 2007 Complete response submitted. PDUFA due day: 2/10/08

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POI Clinical ProgramPOI Clinical ProgramSix 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.

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POI Clinical ProgramPOI 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)

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TreatmentTreatment

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

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Key EndpointsKey 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.

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

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

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

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

Study Tx Median Δ75th

PercentileΔ

HR

(95% CI)p-value

302PL

Alv

5.6

4.90.7

6.8

6.00.8

1.29

(0.98, 1.7)0.084

308PL

Alv

5.7

5.00.7

7.2

6.01.2

1.56

(1.2, 2.0)<0.001

313PL

Alv

5.6

4.80.8

7.5

6.01.5

1.42

(1.1, 1.8)0.004

001PL

Alv

8.0

8.00

11.1

10.90.2

1.07

(0.9, 1.3)0.838

314PL

Alv

5.0

4.70.3

6.9

5.91.0

1.40

(1.2, 1.7)<0.001

*Using Cox Proportional Hazards Models

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Mean Length of Hospital Stay (Days)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 mg6.1

(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

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Efficacy Summary in POIEfficacy 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.

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QuestionsQuestions

• 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?

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General Safety Evaluation in the POI General Safety Evaluation in the POI PopulationPopulation

• 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

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Demographics-Overall POI Demographics-Overall POI PopulationPopulation

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)

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POI Safety: Deaths and SAEsPOI 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)

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POI: AEs Leading to DiscontinuationsPOI: 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)

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Treatment-Emergent EventsTreatment-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)

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General Safety Summary in POIGeneral 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

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Chronic Opioid-Induced Bowel Chronic Opioid-Induced Bowel Dysfunction (OBD)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

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Dose Regimen in POI & OBD Regimen in POI & OBD

POI OBDRoute 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 Dose24 mg/day 1-2 mg/day

Duration Up to 8 days Up to 1 year

Location Hospital only Mostly Outpatient

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Thank YouThank 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