Transcript Slide 1

Sodium Oxybate in the Treatment of
Fibromyalgia: Results from an International
Phase 3 Clinical Trial
Norman Rosenthal, MD
Medical Director
Capital Clinical Research Associates
Rockville, MD
Sodium Oxybate is not FDA approved for the treatment of Fibromyalgia
Fibromyalgia (FM)
• Chronic condition characterized by widespread
musculoskeletal pain.
• Associated symptoms: fatigue, sleep disturbance,
tenderness, functional disability, depression and
cognitive difficulty.1
• Prevalence of FM 2 - 5% worldwide.2
• Impact of FM on patient function: increased disability
and reduced productivity.3
• Associated with high health care costs.4
1
Mease et al. J Rheum 2009;36(10):2318;
Branco et al. Semin Arthritis Rheum. 2009 ePub ahead of press
3 Al-Allaf J Clin Rheum 2007;13:199-201;
4 Boonen A et al. Ann Rheum Dis 2005;64:396-402
2
Current FDA Approved Treatments for FM
• Pregabalin: anti-convulsant that binds the α2-δ subunit
of the voltage-gated Ca2+ channel; approved in 2007 for
the management of FM
• Duloxetine: selective serotonin and norepinephrine
reuptake Inhibitor (SSNRI) approved in 2008 for the
management of FM
• Milnacipran: selective serotonin and norepinephrine
reuptake inhibitor (SSNRI) approved in 2009 for the
management of FM
Sodium Oxybate (SXB)
• Sodium salt of -hydroxybutyrate (GHB), an endogenous
neurotransmitter and/or neuromodulator and metabolite of
GABA1
• Approved for treatment of narcolepsy symptoms (EU, US,
Canada) 2
– Standard of care for narcolepsy 3
• Approved in some EU countries as an IV anesthetic and for
treatment of alcohol withdrawal
• Increases slow-wave-sleep and reduces sleep disruption 1
1Pardi
et al. CNS Drugs 2006;20:993-1018
(sodium oxybate) oral solution, product labeling
3Morgenthaler TI et al. Sleep 2007; 30:1705-11
2XYREM®
Study Design - Sodium Oxybate for Fibromyalgia
•
•
Design: Randomized, double-blind, placebo-controlled,
parallel-group design at 108 sites US and EU (n=573)
Treatment Groups:
– Sodium oxybate 4.5 g/night (SXB4.5g)
– Sodium oxybate 6 g/night (SXB6g)
– Placebo (PBO)
Data on file, Jazz Pharmaceuticals, Inc.
Study Objectives
Primary outcome
• Pain VAS ≥30% reduction
Secondary outcomes
• Patient Function
• Fibromyalgia Impact Questionnaire (FIQ)
• Patient’s Report of Improvement
• Patient Global Impression of Change (PGIC)
• Fatigue
• Fatigue VAS
• Sleep Quality
• Jenkins Sleep Scale (JSS)
• Functional Outcomes Sleep Questionnaire (FOSQ)
• HRQoL (SF-36)
Data on file, Jazz Pharmaceuticals, Inc.
Subject Baseline Disposition & Demographics
# of Subjects
PBO
SXB
4.5g
SXB
6g
Screened
Total
Demographic Characteristics
1544
Age mean, years (SD)
46.6 (10.7)
Randomized
(ITT)
188
195
190
573
Gender n(%)
513 (90%)
females
Completed
70%
66%
61%
66%
Race n(%)
524 (91%)
Caucasian
14%
Body Mass Index, kg/m2
mean (SD)
11%
Time Since First FM
Symptoms, years
mean (SD)
Dropout Due
to AE
Dropout Due
to Lack of
Efficacy
6%
12%
Data on file, Jazz Pharmaceuticals, Inc.
15%
9%
21%
10%
27.6 (4.6)
9.7 (8.8)
Pain VAS Responders at Week 14 (LOCF)
PBO (n=183)
SXB 4.5 g (n=193)
SXB 6 g (n=183)
Data on file, Jazz Pharmaceuticals, Inc.
Pain VAS- Mean Change from Baseline over Time (LOCF)
Data on file, Jazz Pharmaceuticals, Inc.
FIQ & PGIC Responders – Week 14 (LOCF)
FIQ
Data on file, Jazz Pharmaceuticals, Inc.
PGIC
Most Common Treatment-Emergent AEs
with incidence ≥ 5% and at least twice the rate of placebo
Placebo
(n=188)
SXB 4.5g
(n=194)
SXB 6g
(n=189)
16 ( 9%)
37 (19%)
40 (21%)
Dizziness
3 ( 2%)
23 (12%)
25 (13%)
Vomiting
6 ( 3%)
10 ( 5%)
16 (9%)
Anxiety
3 ( 2%)
10 ( 5%)
15 ( 8%)
Edema, peripheral
4 ( 2%)
3 ( 2%)
12 ( 6%)
Somnolence
3 ( 2%)
7 ( 4%)
11 ( 6%)
Fatigue
4 (2%)
6 (3%)
11 (6%)
Muscle Spasms
2 (1%)
8 (4%)
10 (5%)
Insomnia
6 (3%)
15 (8%)
8 (4%)
Event
Nausea
Data on file, Jazz Pharmaceuticals, Inc.
Conclusions - Efficacy
Sodium oxybate administration resulted in statistically
significant and clinically meaningful improvements in:
• Pain (≥ 30% and ≥ 50% reduction)
• ≥ 30% pain reduction seen as early as 1 week
• Patient Functionality (FIQ ≥ 30%)
• Patient’s Global Impression of Change (PGIC)
Conclusions – Safety
• Generally well-tolerated
• Adverse event (AE) profile similar in FM clinical studies to
that seen in the narcolepsy population
Overall Conclusion
Data from this study is comparable with previous Phase 2 and
Phase 3 clinical trials of SXB treatment in fibromyalgia.
References:
1.
Scharf et al. 2003 J Rheum 30(5): 1070-1074.
2.
Russell et al. 2009 Arthritis Rheum 60(1):299-309
3.
Russell et al 2009 Arthritis Rheum 60 (Suppl 10): 1410
4.
Mease et al 2009 Arthritis Rheum 60 (Suppl 10): 1412
Disclosures
• This study was supported by Jazz Pharmaceuticals,
Inc. (JPI)
• Dr. Norman Rosenthal received research support from
JPI in conducting this study.
Baseline Fibromyalgia Symptom Scores
Baseline Statistic*
Placebo SXB4.5g
(n=188) (n=195)
SXB6g
(n=190)
Pain VAS [0–100mm]
72.6 (12.9)
70.5 (13.0)
72.2 (14.0)
FIQ Score [0–100]
63.7 (14.1)
62.3 (15.2)
62.1 (15.1)
Fatigue VAS [0–100mm]
73.5 (15.0)
71.1 (15.4)
71.5 (17.2)
4.3 (1.1)
4.5 (1.0)
4.4 (1.0)
15.6 (4.4)
15.0 (4.6)
14.9 (4.7)
CGI-s [1–7]
JSS Total Score [0–20]
* Reported as Mean (SD)
FIQ=Fibromyalgia Impact Questionnaire; CGI-s=clinical global impression of severity;
JSS=Jenkins Sleep Score
Data on file, Jazz Pharmaceuticals, Inc
Sleep Quality (Jenkins Sleep Score)
• How often in the past month
did you:
1. Have trouble falling asleep?
2. Wake up several times per
night?
3. Have trouble staying asleep
(including waking up too
early)?
4. Wake up after your usual
amount of sleep feeling tired
and worn out?
Data on file, Jazz Pharmaceuticals, Inc.
•
Results: LS mean change from BL
showed that treatment with both
doses of SXB had greater reductions
in sleep disturbance compared to
placebo (both p<0.001).
GHB and Sodium Oxybate (SXB)
History of Medicinal Use
• GHB widely available in health food stores until banned by FDA (1990)
• Developed in US as pharmaceutical agent at request of FDA1 (1994)
• SXB/GHB approved in
– Germany (Somsanit®) as an anesthetic
– Italy and Austria (Alcover®) for alcohol and opiate withdrawal
– US, EU, Canada (Xyrem® )for the treatment of cataplexy in narcolepsy and
•
excessive daytime sleepiness (sch.)
• EU Schedule IV for medicinal use, non-restricted distribution
• US ( ) and Canada special distribution; very low rate of abuse (0.039%),
dependence (0.016%), and diversion (0.0009%)1
• Standard of care for the treatment of narcolepsy (American Academy of
Sleep Medicine, 2007)2
Scheduled by DEA (2000)3
1 Wang YG et al. J Clin Sleep Med 2009 5(4):365
2 Mongenthaler TI et al. Sleep 2007; 30:1705-11.
3 Neuman Ariel. Available at: http://leda.law.harvard.edu/leda/data/629/Neuman.html. Accessed March 18, 2008.
GHB and Sodium Oxybate (SXB)
•
Reported abuse, misuse
(including facilitated
sexual assault),
dependence, respiratory
depression, coma, and
death (since 1980’s)
1 Drug
Emergency Department visits1
History of Abuse and Misuse
Abuse Warning Network (DAWN) 2006 report.
http://dawninfo.samhsa.gov/files/ED2006/DAWN2k6ED.pdf
Accessed April 28, 2008.
GHB = gamma-hydroxybutyrate
COC = cocaine
BZP = benzodiazepine
COD = oxycodone/combinations
Post-marketing Data of Sodium Oxybate (Xyrem®)1
Abuse, Misuse, Dependence and Diversion
• Post-marketing data since Xyrem® was introduced onto
market (2002) through March 2008:
– 26,000 patients received SXB
– Spontaneous AE reports from 15 countries
• Abuse: 10 cases (0.039%)*
• Dependence: 4 cases (0.016%)*
• Misuse: 2 confirmed cases (0.008%) of SXB-facilitated sexual
assault
• Diversion: 5 incidents (0.009%)†
1
Wang et al. 2009 J Clin Sleep Med; 5(4):365
*DSM-IV criteria
† 600,00 bottles distributed during this period