SAN DIEGO, Jan. 6, 2014 /PRNewswire/ -- Neurocrine
Biosciences, Inc. (NASDAQ: NBIX) announced today that NBI-98854, a
small molecule VMAT2 inhibitor, showed a statistically significant
and clinically meaningful reduction in tardive dyskinesia symptoms
in the Phase IIb Kinect 2 study. The pre-specified primary endpoint
was the change-from-baseline in the Abnormal Involuntary Movement
Scale (AIMS) at Week 6 as assessed by central blinded video
raters.
At Week 6, AIMS scores were reduced by 2.6 points in the
NBI-98854 intention-to-treat (ITT) group compared to a reduction of
0.2 points in the placebo arm (p<0.001). Additionally, the
responder rate (>= 50% improvement from baseline) was 49% in the
NBI-98854 ITT group compared to 18% in placebo (p=0.002). In the
per-protocol (PP) group AIMS scores were reduced by 3.3 points for
those subjects taking NBI-98854 (p<0.001), with a corresponding
responder rate of 59% (p<0.001).
"The profound response in this Kinect 2 study demonstrates the
potential of NBI-98854 as both a safe and highly effective
treatment for patients suffering from tardive dyskinesia," said
Christopher F. O'Brien, Chief
Medical Officer of Neurocrine Biosciences. "It is clear from these
results that the use of blinded central AIMS raters coupled with
the ability to titrate up to 75 mg of NBI-98854 were both critical
to the success of this trial."
The improvement in Week 6 AIMS was also corroborated by the
Clinical Global Impression–Tardive Dyskinesia (CGI-TD). Treating
clinicians determined that approximately 67% of the subjects taking
NBI-98854 were "much improved" or "very much improved" at Week 6
compared to only 16% of the placebo subjects (p<0.001) in this
pre-specified key secondary efficacy endpoint.
"The data from this Kinect 2 study allows us to submit an End of
Phase II meeting request as well as finalize the initial draft of a
Phase III protocol, both of which we anticipate filing with the FDA
in the first half of 2014," said Kevin C.
Gorman, President and Chief Executive Officer of Neurocrine.
"Our Phase II studies of NBI-98854 have served to define the study
population, elucidate the primary endpoint, refine our dosing
regimen and provide the necessary efficacy and safety data to
enable pivotal studies."
The pre-specified statistical analysis plan included three data
sets: a safety set (all subjects with at least one dose), an ITT
set (all subjects who had an AIMS assessment at Week 6) and a PP
set (all ITT subjects except those with no detectable drug levels
at the evaluation time point). The table below summarizes the
primary endpoint, LS Mean change-from-baseline AIMS, for both the
ITT and PP populations at Week 6, as well as the responder
analyses.
|
|
Week
6
|
|
|
Placebo
|
NBI-98854
|
p-value
|
AIMS Change from
Baseline
|
|
Baseline
AIMS
|
7.9
|
8.0
|
-
|
|
LS Mean AIMS ANCOVA
(ITT)
|
-0.2
|
-2.6
|
<0.001
|
|
LS Mean AIMS ANCOVA
(PP)
|
-0.3
|
-3.3
|
<0.001
|
|
Responder Rate
(ITT)*
|
18%
|
49%
|
0.002
|
|
Responder Rate
(PP)*
|
18%
|
59%
|
<0.001
|
* a responder is defined as 50% or greater reduction in
AIMS
The table below summarizes the key secondary endpoint, CGI-TD,
for both the ITT and PP populations at Week 6.
|
|
Week
6
|
CGI-TD
|
Placebo
|
NBI-98854
|
p-value
|
|
LS Mean Score
(ITT)
|
3.1
|
2.2
|
<0.001
|
|
LS Mean Score
(PP)
|
3.1
|
2.2
|
<0.001
|
|
Responder Rate
(ITT)*
|
16%
|
67%
|
<0.001
|
|
Responder Rate
(PP)*
|
16%
|
68%
|
<0.001
|
*a responder is defined as "much improved" or "very much
improved" (a "2" or "1", respectively) on the CGI-TD. A "4"
on the CGI-TD indicates "no change"
Subject Profile
The Kinect 2 study randomized 102 subjects. At Week 6, the ITT
population included 44 placebo subjects and 45 subjects who were
randomized to NBI-98854. By Week 6, approximately 70% of the ITT
population, randomized to NBI-98854, were titrated to the 75 mg
dose, approximately 20% were titrated to the 50mg dose and the
remaining subjects received 25 mg of NBI-98854. At Week 6 the PP
population consisted of 44 placebo subjects and 34 subjects
randomized to NBI-98854. The PP Week 6 final titrated dose level of
NBI-98854 was similar to that of the ITT population. The PP
population excluded eleven subjects whose plasma concentrations of
NBI-98854 were below the lower limit of quantitation (i.e., not
detectable). Given the timing of serum samples collections and the
pharmacokinetic profile of NBI-98854, it was determined that these
subjects had not ingested the study drug. The subjects in the
Kinect 2 study had moderate to severe tardive dyskinesia with a
mean baseline video AIMS score of 8.0. Similar to previous studies,
the average age of the trial participants was 56 years with an
average age at onset of tardive dyskinesia of 49 years.
Approximately 60% of the subjects were male.
Safety Profile
In this study NBI-98854 was generally safe and well tolerated.
During the six-week treatment period the frequency of
treatment-emergent adverse events was 33% for placebo and 43% for
NBI-98854. There were no drug related serious adverse events. The
most common treatment emergent adverse events were fatigue in five
subjects (9.8%) randomized to NBI-98854 vs. two subjects (4.1%) in
the placebo group, and headache reported by four subjects (7.8%) on
NBI-98854 vs. two subjects (4.1%) on placebo. Discontinuation rates
were similar in both the NBI-98854 and placebo treatment groups
with five per study arm (none of which were study drug
related).
Participants were assessed utilizing the Barnes Akathisia
Ratings Scale (BARS) for akathisia and the Simpson-Angus Scale
(SAS) for parkinsonism. Both of these scales documented minimal
symptoms at baseline and there was no worsening during the six
weeks of treatment. Clinical hematology, chemistry and ECG
monitoring indicated no emergent safety signals.
There were no drug-drug interactions identified in subjects who
were utilizing a range of psychotropic and other concomitant
medications.
Next Steps for NBI-98854
Data from the Kinect 2 study will be integrated with the Kinect
study data to inform the ultimate design of the next study, Kinect
3. The Company will work with its consultants and scientific
advisors to expand and refine the pharmacokinetic/pharmacodynamic
models as well as to complete the remaining safety and efficacy
analyses from both Kinect and Kinect 2. These data will form the
basis for an End of Phase II briefing package along with the
proposed Phase III protocol.
Kinect 2 Study Design
The Kinect 2 Study was a randomized, parallel, double-blind,
placebo-controlled, dose titration Phase IIb clinical trial
utilizing the capsule formulation of NBI-98854 in moderate to
severe tardive dyskinesia patients with an underlying mood disorder
(e.g., bipolar disorder), schizophrenia or schizoaffective
disorder, or a gastrointestinal disorder with exposure to
metoclopramide. This 100 subject study assessed once-daily
NBI-98854 over a six-week placebo-controlled dosing period. Half of
the randomized subjects received placebo and half received
NBI-98854. The NBI-98854 dosing regimen began with a once-daily
dose of 25 mg for the initial two weeks. At the completion of the
initial two weeks of dosing, based on certain efficacy and safety
criteria, patients were titrated to a once-daily 50 mg dose, or
continued on the once-daily 25 mg dose for the following two-week
period. At the completion of the second two weeks of treatment
another efficacy and safety assessment was performed and patients
were eligible to be titrated to a once-daily 75 mg, 50 mg or 25 mg
dose for the final two weeks of treatment. The primary endpoint of
the study was a comparison of placebo vs. active scores utilizing
the AIMS at the end of Week 6 by blinded central raters.
About the Abnormal Involuntary Movement Scale (AIMS)
The AIMS is a structured neurological examination that was
developed in 1976 and has been used extensively in movement
disorder assessments. It consists of ten distinct ratings of
regional involuntary body movements that are scored on a zero to
four scale with zero being rated as none and four being rated as
severe. The primary endpoint of the Kinect 2 Study is the video
AIMS total dyskinesia score, items one through seven which rate
facial, extremity and trunk movement severity as assessed by
blinded central raters. The raters were movement disorder
neurologists with expertise in dyskinesia assessment.
About Tardive Dyskinesia
Tardive dyskinesia is characterized by involuntary, repetitive
movements of the extremities: lip smacking, grimacing, tongue
protrusion, facial movements or blinking, puckering and pursing of
the lips, or involuntary movements of the limbs. These symptoms are
rarely reversible and there is currently no approved treatment.
About NBI-98854
VMAT2 is a protein concentrated in the human brain that is
primarily responsible for re-packaging and transporting monoamines
(dopamine, norepinephrine, serotonin, and histamine) in
pre-synaptic neurons. NBI-98854, developed in the Neurocrine
laboratories, is a novel, highly-selective VMAT2 inhibitor that
modulates dopamine release during nerve communication, while at the
same time having minimal impact on the other monoamines, thereby
reducing the likelihood of "off target" side effects.
NBI-98854 is designed to provide low, sustained, plasma and brain
concentrations of active drug to minimize side effects associated
with excessive monoamine depletion. The Company has completed
nine-month in-vivo toxicology studies to support longer dosing
regimens in humans.
NBI-98854 may also be useful in other disorders such as
Huntington's chorea, schizophrenia, Tourette's syndrome, and
tardive dystonia.
Conference Call and Webcast Information
The Company will host a live conference call and webcast to
provide additional details of this study on, Monday January 6, 2014 at 5:00 p.m. Eastern Time (2:00 p.m. Pacific Time). Participants can access
the live conference call by dialing 800-894-5910 (US) or
785-424-1051 (International) using the conference ID: NBIX. The
call can also be accessed via the webcast through the Company's
website at http://www.neurocrine.com. Slides will also be made
available through www.neurocrine.com for the conference call and
webcast. If you are unable to attend the webcast and would like
further information on this announcement please contact the
Investor Relations Department at Neurocrine Biosciences at (858)
617-7600. A replay of the Conference Call will be available
approximately one hour after the conclusion of the call by dialing
800-688-4915 (US) or 402-220-1319 (International) using the
conference ID: NBIX. The call will be archived for three weeks.
About Neurocrine Biosciences
Neurocrine Biosciences, Inc. is a clinical stage drug discovery
company primarily focused on neurological and endocrine based
diseases and disorders. The Company discovers and develops
innovative pharmaceuticals, in diseases with high unmet medical
needs or where the existing drug classes are inadequate, through a
disciplined yet entrepreneurial process. Utilizing a portfolio
approach to drug discovery, Neurocrine has multiple small molecule
drug candidates at various stages of pharmaceutical development.
Neurocrine's two lead late stage clinical programs are elagolix, a
GnRH antagonist for women's health that is partnered with AbbVie
Inc., and a wholly owned VMAT2 inhibitor for the treatment of
movement disorders. Neurocrine Biosciences, Inc. news releases are
available through the Company's website via the internet at
http://www.neurocrine.com.
In addition to historical facts, this press release may
contain forward-looking statements that involve a number of risks
and uncertainties. Among the factors that could cause actual
results to differ materially from those indicated in the
forward-looking statements are risks and uncertainties associated
with Neurocrine's business and finances in general, as well as
risks and uncertainties associated with the Company's VMAT2 program
and Company overall. Specifically, the risks and uncertainties the
Company faces with respect to the Company's VMAT2 program include,
but are not limited to; risk that NBI-98854 will not proceed to
later stage clinical trials and risk that the Company's clinical
trials will fail to demonstrate that NBI-98854 is safe and
effective. With respect to its pipeline overall, the Company faces
risk that it will be unable to raise additional funding required to
complete development of all of its product candidates; risk
relating to the Company's dependence on contract manufacturers for
clinical drug supply; risks associated with the Company's
dependence on corporate partners for development, commercial
manufacturing and marketing and sales activities for the Company's
partnered programs; uncertainties relating to patent protection and
intellectual property rights of third parties; risks and
uncertainties relating to competitive products and technological
changes that may limit demand for the Company's products; and the
other risks described in the Company's report on Form 10-K for the
year ended December 31, 2012 and on
Form 10-Q for the quarter ended September
30, 2013. Neurocrine undertakes no obligation to update the
statements contained in this press release after the date
hereof.
SOURCE Neurocrine Biosciences, Inc.