Overview of the Clinical
Development
EMBEDA™
(morphine sulfate and naltrexone hydrochloride) Extended
Release Capsules for oral use.
ASENT 12th Annual Meeting
#21 Meisner
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, aroundthe-clock opioid analgesic is needed for an extended period of time
Six dosage strengths (20 mg to 100 mg morphine sulfate
with 0.8 to 4 mg naltrexone hydrochloride)
Sequestered
Naltrexone
Morphine
Clinical Trials – EMBEDA™
THE FOLLOWING 12 CLINICAL TRIALS HAVE BEEN CONDUCTED TO DATE
1)
2)
3)
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
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ALO-107 withdrawal in patients on chronic opiate therapy (study withdrawn)
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 (ALO205)
'DRUG LIKING' AND 'OVERALL DRUG
LIKING' WERE SIGNIFICANTLY
LOWER FOR EMBEDA™ CRUSHED
AND 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)
EMBEDA™ – Euphoria Study (ALO-106)
FIGURE. MEAN RESPONSE TO
DEQ #5
'HOW HIGH ARE YOU?' OVER
p-value
TIME
(adjusted)
Morphine 30 mg +
Naltrexone 1.2 mg (4%)
vs
< 0.001
45
100
Morphine 30 mg +
Naltrexone 1.2 mg (4%)
DEQ #5 Mean Score
90
vs
Placebo
< 0.001
80
Morphine 30 mg Emax
70
vs
Placebo
< 0.001
60
50
40
30
20
10
0
0
1
2
3
4
Time (hours)
5
6
7
n=26
p-value
(adjusted)
8
Cole/ARCI Euphoria Scale Mean Score
Morphine 30 mg Emax
FIGURE. MEAN RESPONSE TO
COLE/ARCI
STIMULATION/EUPHORIA SCALE
OVER TIME
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
40
35
30
25
20
15
10
5
0
0
1
2
3
4
Time (hours)
5
6
7
8
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)
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™
EMBEDA™ – Long Term Safety Study (ALO-302)
TEAEs Related to Study Drug Reported by ≥2% of Subjects—Safety Population
System Organ Class
Preferred Term
EMBEDA™
(N=465)
n (%)
Any TEAE
Any Related TEAE
378 (81.3%)
288 (61.9%)
Gastrointestinal disorders
Constipation
Diarrhea
Dry mouth
Nausea
Vomiting
General disorders and administration site conditions
Fatigue
Nervous system disorders
Dizziness
Headache
Somnolence
Psychiatric disorders
Anxiety
Insomnia
Skin and subcutaneous tissue disorders
Hyperhidrosis
Pruritus
219 (47.1%)
145 (31.2%)
10 (2.2%)
17 (3.7%)
103 (22.2%)
37 (8.0%)
51 (11.0%)
19 (4.1%)
99 (21.3%)
19 (4.1%)
32 (6.9%)
34 (7.3%)
42 (9.0%)
10 (2.2%)
13 (2.8%)
52 (11.2%)
16 (3.4%)
26 (5.6%)
EMBEDA™- Phase IV Plans
Clinical Trials
Pediatric 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 route
Role of EMBEDA™ in the Universal Precautions approach to pain
management
Specific patient populations e.g. fibromyalgia, neuropathic pain
EMBEDA™ 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.