Overview of the Clinical Development

EMBEDA™(morphine sulfate and naltrexone hydrochloride) Extended

Release Capsules for oral use.

ASENT 12th Annual Meeting

EMBEDA™(morphine sulfate and naltrexone hydrochloride) Extended

Release Capsules for oral use.

ASENT 12th Annual Meeting

#21 Meisner#21 Meisner

EMBEDA™ EMBEDA™

Extended release morphine sulfate with a sequestered core of naltrexone hydrochloride (antagonist) in a ratio of 25:1

Indicated for moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time

Six dosage strengths (20 mg to 100 mg morphine sulfatewith 0.8 to 4 mg naltrexone hydrochloride)

Morphine

SequesteredNaltrexone

Clinical Trials – EMBEDA™ Clinical Trials – EMBEDA™

THE FOLLOWING 12 CLINICAL TRIALS HAVE BEEN CONDUCTED TO DATE1) Three (3) phase 1/2 pharmacodynamic (PD) studies

a) ALO-201 Naltrexone Dose Ranging

b) ALO-205 Oral Drug Liking Study

c) ALO-106 Euphoria Study

2) Six (6) phase 1, single dose pharmacokinetic (PK) studies in healthy subjects

a) ALO-101 Fasting Bioequivalence (vs KADIAN®)

b) ALO-102 Fasting, Fed and Sprinkled Bioequivalence

c) ALO-103 Ethanol Drug Interaction

d) ALO-104 Crush Bioavailability

e) ALO-903 Fed, Fasted

f) ALO-107 withdrawal in patients on chronic opiate therapy (study withdrawn)

3) Three (3) phase II/III efficacy and safety studies

a) ALO-202 Preliminary Efficacy & Safety (vs. Kadian)

b) ALO-301 Pivotal Efficacy (12 week vs. Placebo)

c) ALO-302 Long Term Safety (52 week)

EMBEDA™ – Oral Drug Liking Study (ALO-205)EMBEDA™ – Oral Drug Liking Study (ALO-205)

'DRUG LIKING' AND 'OVERALL DRUG LIKING' WERE SIGNIFICANTLY

LOWER FOR EMBEDA™ CRUSHEDAND WHOLE COMPARED TO

MORPHINE IR (MSS)

'FEELING HIGH', 'GOOD EFFECTS', AND 'BAD EFFECTS' WERE

SIGNIFICANTLY LOWER FOR EMBEDA™ CRUSHED AND WHOLE

COMPARED TO MORPHINE IR (MSS)

0

10

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60

70

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90

100

0 1 2 3 4 5 6 7 8

EMBEDA™ – Euphoria Study (ALO-106)EMBEDA™ – Euphoria Study (ALO-106)

FIGURE. MEAN RESPONSE TO DEQ #5

'HOW HIGH ARE YOU?' OVER TIME

FIGURE. MEAN RESPONSE TO COLE/ARCI

STIMULATION/EUPHORIA SCALE OVER TIMEp-value

(adjusted)

Morphine 30 mg Emax vs Morphine 30 mg + Naltrexone 1.2 mg (4%) < 0.001

Morphine 30 mg + Naltrexone 1.2 mg (4%) vs Placebo < 0.001

Morphine 30 mg Emax vs Placebo < 0.001

Time (hours)

DE

Q #

5 M

ean

Sco

re

n=26

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5

10

15

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25

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45

0 1 2 3 4 5 6 7 8

Time (hours)

Co

le/A

RC

I Eu

ph

ori

a S

cale

Mea

n S

core

p-value(adjusted)

Morphine 30 mg Emax vs Morphine 30 mg + Naltrexone 1.2 mg (4%) < 0.001

Morphine 30 mg + Naltrexone 1.2 mg (4%) vs Placebo < 0.001

Morphine 30 mg Emax vs Placebo < 0.001

EMBEDA™ – Preliminary Efficacy & Safety (ALO-202)EMBEDA™ – Preliminary Efficacy & Safety (ALO-202)

STUDY DESIGN:

Double-blind, two way crossover of EMBEDA™ and KADIAN® [extended release morphine sulfate (ERMS)]

ERMS initiated at 20 mg BID and titrated to a maximum of 160 mg BID

113 patients with Chronic Pain Due to Osteoarthritis of the Hip or Knee enrolled into Period 1, 72 randomized into Period 2 and 69 completed

RESULTS:

Plasma morphine from KADIAN® (ERMS) and EMBEDA™ formulations are bioequivalent limited to extent of exposure at steady state (AUC0-12h)

The minimal release of naltrexone and its metabolite, 6-β-naltrexol, from EMBEDA™ after chronic dosing did not increase pain scores

EMBEDA™ appears to be safe and effective in treating chronic pain of osteoarthritis of the knee and hip

Most patients rated both medications as good or excellent (KADIAN® (ERMS), 78.9%; EMBEDA™, 91.5%)

EMBEDA™ – Pivotal Efficacy Study (ALO-301)EMBEDA™ – Pivotal Efficacy Study (ALO-301)

STUDY DESIGN:Patients with Moderate to Severe Chronic Pain Due to Osteoarthritis of the Hip or Knee

EMBEDA™ initiated at 20mg BID and titrated to maximum of 80mg BID

RESULTS:

Statistically significant improvements in efficacy (primary and secondary) were seen compared to placebo

EMBEDA™

System Organ ClassPreferred Term

EMBEDA™(N=465)

n (%)

Any TEAE 378 (81.3%)Any Related TEAE 288 (61.9%)Gastrointestinal disorders 219 (47.1%) Constipation 145 (31.2%) Diarrhea 10 (2.2%) Dry mouth 17 (3.7%) Nausea 103 (22.2%) Vomiting 37 (8.0%)General disorders and administration site conditions 51 (11.0%) Fatigue 19 (4.1%)Nervous system disorders 99 (21.3%) Dizziness 19 (4.1%) Headache 32 (6.9%) Somnolence 34 (7.3%)Psychiatric disorders 42 (9.0%) Anxiety 10 (2.2%) Insomnia 13 (2.8%)Skin and subcutaneous tissue disorders 52 (11.2%)

Hyperhidrosis 16 (3.4%) Pruritus 26 (5.6%)

TEAEs Related to Study Drug Reported by ≥2% of Subjects—Safety Population

EMBEDA™ – Long Term Safety Study (ALO-302)EMBEDA™ – Long Term Safety Study (ALO-302)

EMBEDA™- Phase IV PlansEMBEDA™- Phase IV Plans

Clinical TrialsPediatric studies in ages 2- <12 years and 12-17 years (post-approval commitment)Effects of crushed EMBEDA™ in opioid tolerant patients (withdrawal study)Abuse potential of EMBEDA™ via intranasal routeRole of EMBEDA™ in the Universal Precautions approach to pain managementSpecific patient populations e.g. fibromyalgia, neuropathic painEMBEDA™ Epidemiology Program-To determine if there is a lower rate of EMBEDA™ abuse compared to other ER opioids, with particular focus on the method of abuse.