Data were presented in a poster presentation at the annual
SLEEP Meeting; JZP-110 U.S. NDA submission planned for later
this year
DUBLIN, June 6, 2017 /PRNewswire/ -- Jazz
Pharmaceuticals plc (Nasdaq: JAZZ) today presented positive
efficacy results from its global multicenter studies (TONES 3 and
TONES 4) of JZP-110 in adult patients with excessive sleepiness
associated with obstructive sleep apnea (OSA). The data were
presented in a poster session at the 31st Associated
Professional Sleep Societies (APSS) Annual SLEEP Meeting in
Boston.
"Obstructive sleep apnea (OSA) is a serious chronic sleep
disorder in which breathing repeatedly stops and starts during
sleep," said Karen Smith, M.D.,
Ph.D., executive vice president of research and development and
chief medical officer of Jazz Pharmaceuticals. "These
studies suggest that JZP-110 could provide an important treatment
option for patients with excessive sleepiness with OSA who may not
respond to, or may experience inadequate response to, their current
wake-promoting therapies. It also underscores our commitment
to making significant research and development investments to find
innovative treatments for unmet medical needs in sleep
medicine."
"People who experience excessive sleepiness associated with OSA
may have an inadequate response to attempts to treat the OSA,
underscoring the need for new treatment options for residual
sleepiness that may affect their quality of life,"
said Kingman Strohl, M.D., Professor of Medicine, University
Hospitals Case Medical Center and Case School of Medicine,
Cleveland OH. "The
results with JZP-110 show significant increase in a patients'
ability to stay awake and decreased patients' subjective levels of
sleepiness compared to placebo, in a rather customary practice
setting."
The Treatment of OSA and Narcolepsy Excessive Sleepiness (TONES)
Phase 3 program is comprised of four studies, one study evaluating
excessive sleepiness in adult patients with narcolepsy (TONES 2),
two studies evaluating excessive sleepiness in adult patients with
OSA (TONES 3 and TONES 4), and an open-label, long-term safety and
maintenance of efficacy study (TONES 5) in the treatment of
excessive sleepiness in patients with narcolepsy or OSA.
About the Global Phase 3 TONES 3 Study
TONES 3 was a
12-week, 5-arm, parallel-group, double-blind, placebo-controlled,
randomized Phase 3 study that evaluated the safety and efficacy of
JZP-110 at 300 mg, 150 mg, 75 mg, and 37.5 mg compared to placebo,
in adults with excessive sleepiness in OSA. Patients (N=476)
were randomized 1:1:2:2:2 to JZP-110 37.5 mg (n=59), 75 mg (n=61),
150 mg (n=118), 300 mg (n=119), or placebo (n=119). The
co-primary endpoints were the change in mean sleep latency on the
Maintenance of Wakefulness Test (MWT) and in the Epworth Sleepiness
Scale (ESS) score, from baseline to week 12. The key
secondary endpoint was the percentage of patients who reported
improvement on the Patient Global Impression of Change (PGIc)
scale, a patient-reported measure of overall condition from
baseline to week 12.
In adult patients with OSA, JZP-110 at all doses demonstrated
statistically significant improvements on the co-primary endpoints
of mean sleep latency on the MWT and the ESS from baseline to week
12 compared to placebo. The endpoints of MWT and ESS measure
patients' ability to stay awake and patients' subjective levels of
sleepiness, respectively. JZP-110 increased the mean MWT
sleep latency by more than 10 minutes at all time points at the 150
and 300 mg doses. JZP-110 decreased mean ESS scores by more
than 7 points at the 150 and 300 mg doses at week 12.
On the key secondary endpoint of the PGIc scale, patients
reported significant overall improvement compared to placebo at
week 12 on all doses of JZP-110 except for 37.5 mg.
Approximately 90% of patients reported overall improvement on
the 150 and 300 mg doses at week 12.
Results from the primary analysis of the co-primary endpoints of
MWT and ESS, and analysis of the key secondary endpoint of PGIc
were:
TONES 3 Study
Results
(mITT population,
N=459)
|
Change (SE) from
Baseline to Week 12
|
JZP-110
300
mg
(N=115)
|
JZP-110
150
mg
(N=116)
|
JZP-110
75
mg
(N=58)
|
JZP-110
37.5
mg
(N=56)
|
Placebo
(N=114)
|
Mean Sleep Latency
on
Maintenance of
Wakefulness Test
(MWT): Increased ability
to stay awake
|
13.0 min
(1.0)
p<0.0001
|
11.0 min
(1.0)
p<0.0001
|
9.1 min
(1.4)
p<0.0001
|
4.7 min
(1.4)
p<0.05
|
0.2 min
(1.0)
|
Epworth
Sleepiness
Scale (ESS): Decreased
subjective sleepiness
|
-7.9
(0.5)
p<0.0001
|
-7.7
(0.4)
p<0.0001
|
-5.0
(0.6)
p<0.05
|
-5.1
(0.6)
p<0.05
|
-3.3
(0.5)
|
Patient Global
Impression-Change
(PGIc): Minimal, much,
or very much
improvement
|
88.7%
p<0.0001
|
89.7%
p<0.0001
|
72.4%
p<0.05
|
55.4%
p=0.4447
|
49.1%
|
Of the 476 randomized subjects, 404 completed the 12-week
treatment. Twenty-nine patients (6.1%) in the safety
population: four patients (3.4%) on placebo and 25 (7.0%) on
JZP-110, discontinued due to treatment emergent adverse events
(TEAEs). The most commonly reported TEAEs (occurring in
>5% of patients across all doses of JZP-110) in the TONES 3
study were headache, nausea, decreased appetite, anxiety, and
nasopharyngitis. There were seven serious TEAEs reported in
five patients: goiter (n=1), and a motor vehicle accident, back
pain, and sciatica (n=1) in two patients on placebo; bile duct
obstruction (n=1) and streptococcal endocarditis (n=1) in two
patients on JZP-110 37.5 mg; and hyperglycemia (n=1) in one patient
on JZP-110 150 mg. One subject had a non-treatment emergent
SAE of coronary artery disease that started prior to receiving
JZP-110 300 mg and that was not reported until after dosing.
TEAEs and discontinuations due to an AE were most common at the
JZP-110 300 mg dose.
About the Global Phase 3 TONES 4 Study
TONES 4 was a six-week Phase 3 study comprising a two-week
flexible-dose titration phase followed by two-weeks of stable dose
treatment. Patients who reported 'much' or 'very much' improvement
and who had numerical improvements on the MWT and ESS at the end of
the stable dose phase (week 4) then entered a two-week,
placebo-controlled, double-blind randomized withdrawal phase. In
this study, 174 patients were titrated to a maximum tolerated dose
over a two-week period, and 157 patients continued on that dose for
two weeks in the stable dose phase. The primary analysis
(n=122 in the modified intent to treat (mITT) population) evaluated
the difference between JZP-110 treatment versus placebo on the
co-primary endpoints of MWT and ESS, measured from the end of the
stable dose phase at week 4 to the end of the randomized withdrawal
phase at week 6.
Patients who completed the 4-week treatment and remained on
JZP-110 did not demonstrate loss of efficacy relative to those who
were randomized to placebo.
Results from the primary analysis of the co-primary endpoints of
MWT and ESS, and analysis of the key secondary endpoint of PGIc
were:
TONES 4 Study
Results
(mITT population)
|
Change (SE) from
Week 4 to Week 6
|
JZP-110
(N=60)
|
Placebo
(N=62)
|
Mean Sleep Latency
on Maintenance of
Wakefulness Test (MWT): Ability to stay
awake
|
-1.0 min
(1.4)
p<0.0001
|
-12.1 min
(1.3)
|
Epworth Sleepiness
Scale (ESS): Subjective
sleepiness
|
-0.1
(0.7)
p<0.0001
|
4.5
(0.7)
|
Patient Global
Impression-Change (PGIc): Minimally, much, or very much
worse
|
20.0%
p<0.0001
|
50.0%
|
During the double-blind withdrawal phase (weeks 4 to 6),
patients who continued on JZP-110 remained improved on the MWT and
ESS. Patients who switched to placebo showed worsening of
sleepiness, with mean MWT sleep latency decreased by 12.1 minutes
from week 4 to week 6 (compared with a decrease of 1.0 minute for
those who remained on JZP-110, p<0.0001) and mean ESS scores
increased by 4.5 minutes (compared to a mean decrease of 0.1
minutes for those who stayed on JZP-110, p<0.0001).
A significantly higher percentage of patients who were switched
to placebo experienced a worsening of their overall condition on
the PGIc as compared with patients who stayed on JZP-110
(p<0.0001).
There were no serious TEAEs. Six patients (3.4%) withdrew
from the study due to TEAEs. Most TEAEs occurred during the
titration phase of the study. The most common TEAEs
(occurring in ≥5% patients) during the titration phase were
headache, dry mouth, nausea, dizziness, and insomnia.
Full details of the APSS annual SLEEP meeting can be found at
http://www.sleepmeeting.org/.
About OSA and Excessive Sleepiness
OSA is a highly prevalent disease (as high as 24% in men and 9% in
women1) with excessive sleepiness reported as one of the
most frequent symptoms. Excessive sleepiness is associated
with impairments in function, vigilance, concentration, thinking,
social interactions and quality of life. Positive airway
pressure (PAP) therapy, commonly referred to as continuous positive
airway pressure (CPAP), has been shown to be an effective therapy
for sleep-related airway obstruction, with frequent improvement in
excessive sleepiness in many patients; however, approximately
25-50% of patients with OSA experience difficulty with PAP therapy.
In addition, many patients treated with PAP therapy continue
to experience persistent sleepiness, despite successful use of
PAP.
About JZP-110
JZP-110 is a selective dopamine and norepinephrine reuptake
inhibitor (DNRI) in development for treatment of excessive
sleepiness in adult patients with narcolepsy, OSA, and Parkinson's
disease. In 2014, Jazz Pharmaceuticals acquired a license to
develop and commercialize JZP-110 from SK Biopharmaceuticals, which
discovered the compound. Jazz Pharmaceuticals has worldwide
development, manufacturing, and commercialization rights to
JZP-110, excluding certain jurisdictions in Asia. SK Biopharmaceuticals maintains
rights in Korea, Japan,
China, Taiwan, Singapore, Indonesia, India, Philippines, Thailand, Malaysia, Vietnam, and Hong
Kong. JZP-110 has orphan drug designation in
the United States for narcolepsy.
Across the entire JZP-110 development program, over 2,000
subjects have enrolled in 20 studies. The JZP-110 Phase 3 clinical
program includes one study evaluating excessive sleepiness in adult
patients with narcolepsy (TONES 2), two studies evaluating
excessive sleepiness in adult patients with OSA (TONES 3 and TONES
4), and an open-label, long-term safety and maintenance of efficacy
study (TONES 5) in the treatment of excessive sleepiness in
patients with narcolepsy or OSA. Enrollment is complete in all
studies that are expected to support Jazz Pharmaceuticals' planned
JZP-110 New Drug Application (NDA) submission to the U.S. Food and
Drug Administration (FDA) in late 2017.
About Jazz Pharmaceuticals
Jazz Pharmaceuticals plc (Nasdaq: JAZZ) is an international
biopharmaceutical company focused on improving patients' lives by
identifying, developing and commercializing meaningful products
that address unmet medical needs. The company has a diverse
portfolio of products and product candidates, with a focus in the
areas of sleep and hematology/oncology. In these
areas, Jazz Pharmaceuticals markets Xyrem® (sodium
oxybate) oral solution, Erwinaze® (asparaginase Erwinia
chrysanthemi) and Defitelio® (defibrotide sodium) in the U.S.
and markets Erwinase® and Defitelio® (defibrotide) in countries
outside the U.S. For more information, please
visit www.jazzpharmaceuticals.com.
"Safe Harbor" Statement under the Private Securities
Litigation Reform Act of 1995
This press release contains forward-looking statements, including,
but not limited to, statements related to JZP-110 as a potential
treatment for excessive sleepiness in adult patients with OSA, the
company's commitment to making significant research and development
investments to find innovative treatments for unmet medical needs
in sleep medicine, the company's plans for submission of an NDA for
JZP-110 with the FDA and the timing thereof, and other
statements that are not historical facts. These
forward-looking statements are based on the company's current
plans, objectives, estimates, expectations and intentions and
inherently involve significant risks and uncertainties. Actual
results and the timing of events could differ materially from those
anticipated in such forward-looking statements as a result of these
risks and uncertainties, which include, without limitation, risks
and uncertainties associated with: pharmaceutical product
development and clinical success thereof; the regulatory approval
process, including the risk that the company may be unable to
obtain approval by the FDA for JZP-110 in a timely manner
or at all; and effectively commercializing JZP-110; and other risks
and uncertainties affecting the company and its development
programs, including those described from time to time under the
caption "Risk Factors" and elsewhere in Jazz Pharmaceuticals
plc's Securities and Exchange Commission filings and reports
(Commission File No. 001-33500), including the company's Quarterly
Report on Form 10-Q for the quarter ended March 31,
2017 and future filings and reports by the company.
Other risks and uncertainties of which the company is not currently
aware may also affect the company's forward-looking statements and
may cause actual results and the timing of events to differ
materially from those anticipated. The forward-looking
statements herein are made only as of the date hereof or as of the
dates indicated in the forward-looking statements, even if they are
subsequently made available by the company on its website or
otherwise. The company undertakes no obligation to update or
supplement any forward-looking statements to reflect actual
results, new information, future events, changes in its
expectations or other circumstances that exist after the date as of
which the forward-looking statements were made.
Reference:
- Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The
occurrence of sleep-disordered breathing among middle-aged adults.
N Engl J Med. Apr 29
1993;328(17):1230-1235
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