Otsuka Pharmaceutical Company, Ltd. (Otsuka) and Lundbeck
announce that the two companies’ third clinical Phase 3 study of
brexpiprazole in the treatment of agitation in patients with
dementia of the Alzheimer's type will commence in June.
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Approximately 300 patients are expected to be enrolled in this
12-week, randomized, double-blind, placebo-controlled trial.
Additional information about the trial will be available in the
near future at clinicaltrials.gov and will be updated periodically
following initiation of the study.
The decision to initiate a third trial follows discussions with
the U.S. Food and Drug Administration (FDA) regarding two Phase 3
clinical trials for the agitation in Alzheimer’s disease indication
that were completed by Otsuka and Lundbeck in 2017. Results for the
two completed trials were announced in May of last year and
presented in poster sessions at the American Association for
Geriatric Psychiatry annual meeting in March of this year.
About Alzheimer's Disease and Related Agitation
Of the approximately 5.5 million people in the U.S. with
dementia, it is estimated that 60-80 percent have Alzheimer’s
disease.i,ii Behavioral symptoms develop in the majority of people
with Alzheimer's disease and many of these symptoms are clinically
diagnosed as agitation, including wandering, restlessness,
significant emotional distress, aggressive behaviors, and
irritability. It is estimated that agitation symptoms affect nearly
50 percent or more of patients with Alzheimer's disease observed
over a multiyear period.iii
Symptoms of agitation place a serious burden on the people
afflicted with the disease and their caregivers, significantly
affecting the quality of life for all concerned. Agitation is often
a determining factor in the decision to place patients in
high-level residential care facilities, contributing to the roughly
USD 259 billion cost burden of Alzheimer's disease in the U.S.
for 2017.i
About Brexpiprazole
Brexpiprazole was approved by the U.S. Food and Drug
Administration in July 2015 to treat patients with schizophrenia
and as an adjunctive treatment for patients with major depressive
disorder. Brexpiprazole was subsequently approved in Canada,
Australia and Japan for the treatment of schizophrenia. In all four
countries brexpiprazole is distributed and marketed under the brand
name REXULTI®. Brexpiprazole is not approved for use in treating
agitation associated with Alzheimer’s disease.
Brexpiprazole was discovered by Otsuka and is being co-developed
by Otsuka and Lundbeck. The mechanism of action for brexpiprazole
in the adjunctive treatment of major depressive disorder or
schizophrenia is not fully understood. However, the efficacy of
brexpiprazole may be mediated through a combination of partial
agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and
antagonist activity at serotonin 5-HT2A receptors. Brexpiprazole
exhibits high affinity (sub-nanomolar) for these receptors as well
as for noradrenaline alpha1B/2C receptors.
INDICATIONS and IMPORTANT SAFETY INFORMATION
forREXULTI® (brexpiprazole)
INDICATIONS
REXULTI is indicated for:
- Use as an adjunctive therapy to
antidepressants in adults with major depressive disorder
- Treatment of schizophrenia in
adults
IMPORTANT SAFETY INFORMATION
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH
DEMENTIA-RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at increased risk of death. REXULTI is not
approved for the treatment of patients with dementia-related
psychosis.
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
Antidepressants increase the risk of suicidal thoughts and
behaviors in patients aged 24 years and younger. Monitor for
clinical worsening and emergence of suicidal thoughts and
behaviors. The safety and effectiveness of REXULTI have not been
established in pediatric patients.
Contraindication: In patients with known hypersensitivity
reaction to brexpiprazole or any of its components. Reactions have
included: rash, facial swelling, urticaria and anaphylaxis.
Cerebrovascular Adverse Events, Including Stroke: In
clinical trials, elderly patients with dementia randomized to
risperidone, aripiprazole, and olanzapine had a higher incidence of
stroke and transient ischemic attack, including fatal stroke.
REXULTI is not approved for the treatment of patients with
dementia-related psychosis.
Neuroleptic Malignant Syndrome (NMS): NMS is a
potentially fatal symptom complex reported in association with
administration of antipsychotic drugs. Clinical signs of NMS are
hyperpyrexia, muscle rigidity, altered mental status and evidence
of autonomic instability. Additional signs may include elevated
creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute
renal failure. Manage NMS with immediate discontinuation of
REXULTI, intensive symptomatic treatment, and monitoring.
Tardive Dyskinesia (TD): Risk of TD, and the potential to
become irreversible, are believed to increase with duration of
treatment and total cumulative dose of antipsychotic drugs. TD can
develop after a relatively brief treatment period, even at low
doses, or after discontinuation of treatment. For chronic
treatment, use the lowest dose and shortest duration of REXULTI
needed to produce a clinical response. If signs and symptoms of TD
appear, drug discontinuation should be considered.
Metabolic Changes: Atypical antipsychotic drugs have
caused metabolic changes including:
- Hyperglycemia/Diabetes Mellitus:
Hyperglycemia, in some cases extreme and associated with
ketoacidosis or hyperosmolar coma or death, has been reported in
patients treated with atypical antipsychotics. Assess fasting
plasma glucose before or soon after initiation of antipsychotic
medication, and monitor periodically during long-term
treatment.
- Dyslipidemia: Atypical
antipsychotics cause adverse alterations in lipids. Before or soon
after initiation of antipsychotic medication, obtain a fasting
lipid profile at baseline and monitor periodically during
treatment.
- Weight Gain: Weight gain has
been observed in patients treated with REXULTI. Monitor weight at
baseline and frequently thereafter.
Pathological Gambling and Other Compulsive Behaviors:
Intense urges, particularly for gambling, and the inability to
control these urges have been reported while taking REXULTI. Other
compulsive urges have been reported less frequently. Prescribers
should ask patients or their caregivers about the development of
new or intense compulsive urges. Consider dose reduction or
stopping REXULTI if such urges develop.
Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia
and neutropenia have been reported with antipsychotics.
Agranulocytosis (including fatal cases) has been reported with
other agents in this class. Monitor complete blood count in
patients with pre-existing low white blood cell count
(WBC)/absolute neutrophil count or history of drug-induced
leukopenia/neutropenia. Discontinue REXULTI at the first sign of a
clinically significant decline in WBC and in severely neutropenic
patients.
Orthostatic Hypotension and Syncope: Atypical
antipsychotics cause orthostatic hypotension and syncope.
Generally, the risk is greatest during initial dose titration and
when increasing the dose. Monitor in patients vulnerable to
hypotension, and those with cardiovascular and cerebrovascular
diseases.
Falls: Antipsychotics may cause somnolence, postural
hypotension, motor and sensory instability, which may lead to falls
causing fractures or other injuries. For patients with diseases,
conditions, or medications that could exacerbate these effects,
complete fall risk assessments when initiating treatment and
recurrently during therapy.
Seizures: REXULTI may cause seizures and should be used
with caution in patients with a history of seizures or with
conditions that lower the seizure threshold.
Body Temperature Dysregulation: Use REXULTI with caution
in patients who may experience conditions that increase body
temperature (e.g., strenuous exercise, extreme heat, dehydration,
or concomitant use with anticholinergics).
Dysphagia: Esophageal dysmotility and aspiration have
been associated with antipsychotics. including REXULTI, and should
be used with caution in patients at risk for aspiration.
Potential for Cognitive and Motor Impairment: REXULTI has
the potential to impair judgment, thinking, or motor skills.
Patients should not drive or operate hazardous machinery until they
are reasonably certain REXULTI does not affect them adversely.
Concomitant Medication: Dosage adjustments are
recommended in patients who are known cytochrome P450 (CYP) 2D6
poor metabolizers and in patients taking concomitant CYP3A4
inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers.
Most commonly observed adverse reactions: In clinical
trials, the most common adverse reactions were:
- Major Depressive Disorder (MDD)
(adjunctive treatment to antidepressant therapy; ≥5% incidence and
at least twice the rate of placebo for REXULTI vs. placebo):
akathisia and weight increase
- Schizophrenia (≥4% incidence and
at least twice the rate of placebo for REXULTI vs. placebo): weight
increased
Dystonia: Symptoms of dystonia may occur in susceptible
individuals during the first days of treatment and at low
doses.
Pregnancy: Adequate and well-controlled studies to assess
the risks of REXULTI during pregnancy have not been conducted.
REXULTI should be used during pregnancy only if the benefit
justifies the risk to the fetus.
Lactation: It is not known if REXULTI is excreted in
human breast milk. A decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America
Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088
(www.fda.gov/medwatch).
Please see FULL PRESCRIBING INFORMATION, including BOXED
WARNING.
About Otsuka
Otsuka Pharmaceutical Co., Ltd. is a global healthcare company
with the corporate philosophy: “Otsuka-people creating new products
for better health worldwide.” Otsuka researches, develops,
manufactures and markets innovative products, with a focus on
pharmaceutical products to meet unmet medical needs and
nutraceutical products for the maintenance of everyday health.
In pharmaceuticals, Otsuka is a leader in the challenging area
of mental health and also has research programs on several
under-addressed diseases including tuberculosis, a significant
global public health issue. These commitments illustrate how Otsuka
is a “big venture” company at heart, applying a youthful spirit of
creativity in everything it does.
Otsuka Pharmaceutical Company is a subsidiary of Otsuka Holdings
Co., Ltd. headquartered in Tokyo, Japan. The Otsuka group of
companies employed 46,000 people worldwide and had consolidated
sales of approximately USD 11.1 billion in 2017.
All Otsuka stories start by taking the road less travelled.
Learn more about Otsuka Pharmaceutical Company on its global
website at https://www.otsuka.co.jp/en. Learn more about Otsuka in
the U.S. at www.otsuka-us.com and connect with us on Twitter at
@OtsukaUS.
About Lundbeck
Lundbeck is a global pharmaceutical company specialized in
psychiatric and neurological disorders. For more than 70 years, we
have been at the forefront of research within neuroscience. Our key
areas of research focus are depression, schizophrenia, Parkinson's
disease and Alzheimer's disease.
An estimated 700 million people worldwide are living with
psychiatric and neurological disorders and far too many suffer due
to inadequate treatment, discrimination, a reduced number of
working days, early retirement and other unnecessary consequences.
Every day, we strive for improved treatment and a better life for
people living with psychiatric and neurological disorders — we call
this Progress in Mind.
Our approximately 5,000 employees in 55 countries are engaged in
the entire value chain throughout research, development,
manufacturing, marketing and sales. Our pipeline consists of
several late-stage development programs and our products are
available in more than 100 countries. We have production facilities
in Denmark, France and Italy.
In the U.S., Lundbeck employs nearly 1,000 people focused solely
on accelerating therapies for brain disorders. With a special
commitment to the lives of patients, families and caregivers,
Lundbeck U.S. actively engages in hundreds of initiatives each year
that support our patient communities. For additional information,
we encourage you to visit our corporate site at www.lundbeckus.com
and connect with us on Twitter at @LundbeckUS.
i Alzheimer’s Association. 2017 Alzheimer’s disease facts and
figures. 2017;13:325-373.ii Alzheimer’s Disease International. The
world Alzheimer’s report 2015; 30.iii Bergh, S.and Selbæk, G. The
prevalence and the course of neuropsychiatric symptoms in patients
with dementia. Norsk Epidemiologi 2012; 22 (2): 225-232.
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Otsuka America Pharmaceutical, Inc.(In U.S.)Kimberly
Whitefield, +1-609-535-9259Corporate
CommunicationsKimberly.whitefield@otsuka-us.comorOtsuka
Pharmaceutical Co., Ltd.(Outside U.S.)Jeffrey Gilbert,
+81-3-6361-7379Leader, Pharmaceuticals Public
RelationsGilbert.jeffrey@otsuka.jporLundbeck U.S.Ashleigh
Duchene, +1-312-802-2906Associate Director, Public
RelationsAduc@lundbeck.com