NORTH CHICAGO, Ill.,
Oct. 29, 2021 /PRNewswire/ -- AbbVie
(NYSE: ABBV) today announced top-line results from two Phase 3
clinical trials, Study 3111-301-001 and Study 3111-302-001,
evaluating the efficacy and safety of cariprazine
(VRAYLAR®) as an adjunctive treatment for patients with
major depressive disorder (MDD). In Study 3111-301-001, cariprazine
showed a statistically significant change from baseline to week six
in the Montgomery-Åsberg
Depression Rating Scale (MADRS) total score compared with placebo.
Patients treated with cariprazine at 1.5 mg/day achieved improved
MADRS total score at week six compared to placebo (p-value=0.0050).
Patients treated with cariprazine at 3.0 mg/day demonstrated
improvement in MADRS total score at week six over placebo but did
not meet statistical significance (p-value=0.0727). In Study
3111-302-001, cariprazine demonstrated numerical improvement in
depressive symptoms from baseline to week six in MADRS total score
compared with placebo but did not meet its primary endpoint for
either the 1.5 mg/day or 3.0 mg/day dose.
In a previously published Phase 2/3 registration-enabling study,
RGH-MD-75, patients treated with cariprazine flexible doses of
2.0–4.5 mg/day in addition to ongoing antidepressant therapy (ADT)
met the primary endpoint and achieved improved MADRS total scores
at week eight compared to placebo (p-value=0.0114).
Based on the positive results of studies 3111-301-001 and
RGH-MD-75, and the totality of data reported, AbbVie intends to
submit a supplemental New Drug Application (sNDA) with the U.S.
Food and Drug Administration for the expanded use of cariprazine
for the adjunctive treatment of MDD.
"When added to ongoing antidepressant treatment that has
produced inadequate response in patients with major depressive
disorder, cariprazine has now demonstrated that it can further
improve depressive symptoms by providing statistically significant
and clinically meaningful improvements compared to placebo in two
large, well-controlled registrational clinical trials," said
Michael Severino, M.D., vice
chairman and president, AbbVie. "Major depressive disorder is one
of the most common and serious mental illnesses, and more than half
of these patients never experience satisfactory results from this
debilitating condition. Based on the results, we believe
cariprazine has the potential to benefit these patients as an
adjunctive treatment."
The safety results of cariprazine in all three studies were
consistent with its established safety profile across indications
with no new safety signals identified. The most common adverse
events occurring at >5% in the cariprazine groups during the
six-week study period were akathisia, nausea, insomnia, headache
and somnolence.
Full results from studies 3111-301-001 and 3111-302-001 will be
presented at a future medical meeting.
MDD is a common condition with 19 million people of all ages
affected in the United
States.1 The World Health Organization lists
depression as the third-leading cause of disability worldwide and
as a major contributor to the overall global burden of disease.
Symptoms can include depressed mood, loss of pleasure or interest
in activities, changes in appetite or weight, changes in sleep,
psychomotor agitation, loss of energy, feelings of worthlessness,
indecisiveness, and current thoughts of death.2 In
the United States, the mean age of
onset for the first episode is 26 years old,3 and MDD
represents an estimated $211 billion
economic burden.4
Cariprazine is marketed as VRAYLAR in the United States and is FDA-approved to treat
depressive, acute manic and mixed episodes associated with bipolar
I disorder, as well as schizophrenia in adults. Cariprazine is
being co-developed by AbbVie and Gedeon Richter Plc. More than
8,000 patients worldwide have been treated with cariprazine across
more than 20 clinical trials evaluating the efficacy and safety of
cariprazine for a broad range of psychiatric disorders.
About Studies 3111-301-001 and 3111-302-001
Study
3111-301-001 is a randomized, double-blind, placebo-controlled,
multicenter trial with 759 participants conducted in United
States, Bulgaria, Estonia, Germany, Hungary, Ukraine, and the United Kingdom. Study 311-302-001 is a
randomized, double-blind, placebo-controlled, multicenter trial
with 752 participants conducted in United States, Canada, Czech
Republic, Finland,
Poland, Serbia, and Slovakia. For both studies, following a
screening period of up to 14 days, patients with an inadequate
clinical response to their antidepressant monotherapy (ADT) were
randomized into three treatment groups (1:1:1). The first group
received cariprazine 1.5 mg/day + ADT, the second group received
cariprazine 3.0 mg/day + ADT, and the third group received placebo
+ ADT. For six weeks, the medication was given once daily in
addition to the ongoing ADT treatment, to which the patient had
experienced inadequate clinical response.
About Study RGH-MD-75
Study RGH-MD-75 is a randomized,
double-blind, placebo-controlled, flexible-dose, outpatient,
multicenter trial with 808 participants, conducted in United States, Estonia, Finland, Slovakia, Ukraine and Sweden. After 7-14 days of screening and
washout of prohibited medications, eligible patients entered an
8-week, double-blind treatment period in which they continued
antidepressant treatment and were randomized (1:1:1) to adjunctive
cariprazine 1-2 mg/day, cariprazine 2-4.5 mg/day, or placebo. After
double-blind treatment, patients entered a 1-week safety follow-up
period. Data from Study RGH-MD-75 were published in the Journal
of Clinical Psychiatry.5
More information about studies 3111-301-001, 3111-302-001 and
RGH-MD-75 is available at www.clinicaltrials.gov.
About
VRAYLAR® (cariprazine)
VRAYLAR is an
oral, once-daily atypical antipsychotic approved for the acute
treatment of adults with manic or mixed episodes associated with
bipolar I disorder (3 to 6 mg/day) and for the treatment of
depressive episodes associated with bipolar I disorder (bipolar
depression) in adults (1.5 or 3 mg/day). VRAYLAR is also approved
for the treatment of schizophrenia in adults (1.5 to 6 mg/day).
While the mechanism of action of VRAYLAR is unknown, the
efficacy of VRAYLAR could be mediated through a combination of
partial agonist activity at central dopamine D₂ and serotonin
5-HT1A receptors and antagonist activity at
serotonin 5-HT2A receptors. Pharmacodynamic studies
with cariprazine have shown that it acts as a partial agonist with
high binding affinity at dopamine D3, dopamine
D2, and serotonin 5-HT1A receptors.
Cariprazine demonstrated up to ~8-fold greater in
vitro affinity for dopamine D3 vs
D2 receptors. Cariprazine also acts as an
antagonist at serotonin 5-HT2B and
5-HT2A receptors with high and moderate binding
affinity, respectively as well as it binds to the histamine
H1 receptors. VRAYLAR shows lower binding affinity
to the serotonin 5-HT2C and α1A-
adrenergic receptors and has no appreciable affinity for
cholinergic muscarinic receptors. The clinical significance of
these in vitro data is unknown.
VRAYLAR is being developed jointly by AbbVie and Gedeon
Richter Plc, with AbbVie responsible for commercialization in the
U.S., Canada, Japan,
Taiwan and certain Latin American
countries (including Argentina,
Bolivia, Brazil, Chile, Colombia, Ecuador, Mexico, Peru
and Venezuela).
Visit www.vraylar.com for more information.
Important Safety Information about VRAYLAR
(cariprazine)
|
WARNINGS:
INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED
PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS
|
Elderly patients
with dementia-related psychosis treated with antipsychotic drugs
are at an increased risk of death. VRAYLAR is not approved for
treatment of patients with dementia-related
psychosis.
Antidepressants
increased the risk of suicidal thoughts and behaviors in pediatric
and young adult patients in short-term studies. Closely monitor
antidepressant-treated patients for clinical worsening, and for
emergence of suicidal thoughts and behaviors. Safety and
effectiveness of VRAYLAR have not been established in pediatric
patients.
|
Contraindication: VRAYLAR is contraindicated in
patients with known hypersensitivity. Reactions have included rash,
pruritus, urticaria, and events suggestive of angioedema.
Cerebrovascular Adverse Reactions, Including
Stroke: In clinical trials with antipsychotic drugs,
elderly subjects with dementia had a higher incidence of
cerebrovascular adverse reactions, including fatalities vs placebo.
VRAYLAR is not approved for the treatment of patients with
dementia-related psychosis.
Neuroleptic Malignant Syndrome (NMS): NMS, a
potentially fatal symptom complex, has been reported with
antipsychotic drugs. NMS may cause hyperpyrexia, muscle rigidity,
delirium, and autonomic instability. Additional signs may include
elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis),
and acute renal failure. Manage with immediate
discontinuation, intensive symptomatic treatment, and
monitoring.
Tardive Dyskinesia (TD): Risk of developing TD (a
syndrome of potentially irreversible, involuntary, dyskinetic
movements) and the likelihood it will become irreversible may
increase with the duration of treatment and the cumulative dose.
The syndrome can develop after a relatively brief treatment period,
even at low doses, or after treatment discontinuation. If signs and
symptoms of TD appear, drug discontinuation should be
considered.
Late-Occurring Adverse Reactions: Adverse events may
first appear several weeks after initiation of VRAYLAR, probably
because plasma levels of cariprazine and its major metabolites
accumulate over time. As a result, the incidence of adverse
reactions in short-term trials may not reflect the rates after
longer term exposures. Monitor for adverse reactions, including
extrapyramidal symptoms (EPS) or akathisia, and patient response
for several weeks after starting VRAYLAR and after each dosage
increase. Consider reducing the dose or discontinuing the drug.
Metabolic Changes: Atypical antipsychotics have
caused metabolic changes, such as:
- Hyperglycemia and Diabetes Mellitus: Hyperglycemia,
in some cases associated with ketoacidosis, hyperosmolar coma, or
death, has been reported in patients treated with atypical
antipsychotics. Assess fasting glucose before or soon after
initiation of treatment, and monitor periodically during long-term
treatment.
- Dyslipidemia: Atypical antipsychotics cause adverse
alterations in lipids. Before or soon after starting an
antipsychotic, obtain baseline fasting lipid profile and monitor
periodically during treatment.
- Weight Gain: Weight gain has been observed with
VRAYLAR. Monitor weight at baseline and frequently thereafter.
Leukopenia, Neutropenia, and
Agranulocytosis: Leukopenia/neutropenia have been reported
with antipsychotics, including VRAYLAR. Agranulocytosis (including
fatal cases) has been reported with other antipsychotics. 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 VRAYLAR 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, with the
greatest risk during initial titration and with dose increases.
Monitor orthostatic vital signs in patients predisposed to
hypotension and in those with cardiovascular/cerebrovascular
diseases.
Falls: VRAYLAR may cause somnolence, postural
hypotension, motor and sensory instability, which may lead to falls
and, consequently, fractures, or other injuries. For patients with
diseases, conditions, or medications that could exacerbate these
effects, complete fall risk assessments when initiating
antipsychotics and recurrently for patients on long-term
therapy.
Seizures: Use VRAYLAR with caution in patients with
history of seizures or with conditions that lower the seizure
threshold.
Potential for Cognitive and Motor
Impairment: Somnolence was reported with VRAYLAR. Caution
patients about performing activities requiring mental alertness
(eg, operating hazardous machinery or a motor vehicle).
Body Temperature Dysregulation: Use VRAYLAR with
caution in patients who may experience conditions that increase
body temperature (eg, strenuous exercise, extreme heat,
dehydration, or concomitant anticholinergics).
Dysphagia: Esophageal dysmotility and aspiration
have been associated with antipsychotics. Antipsychotic drugs,
including VRAYLAR, should be used cautiously in patients at risk
for aspiration.
Drug Interactions: Strong CYP3A4 inhibitors increase
VRAYLAR concentrations, so VRAYLAR dose reduction is recommended.
Concomitant use with CYP3A4 inducers is not recommended.
Adverse Reactions: In clinical trials, the most
common adverse reactions (≥5% and at least twice the rate of
placebo) are listed below:
- Schizophrenia: The incidences within the
recommended dose range (VRAYLAR 1.5 – 3 mg/day and 4.5 – 6 mg/day
vs placebo) were: EPS (15%, 19% vs 8%) and akathisia (9%, 13%
vs 4%).
- Bipolar mania: The incidences within the
recommended dose range (VRAYLAR 3 – 6 mg/day vs placebo) were: EPS
(26% vs 12%), akathisia (20% vs 5%), vomiting (10% vs 4%),
dyspepsia (7% vs 4%), somnolence (7% vs 4%), and restlessness (7%
vs 2%).
- Bipolar depression: The incidences within the
recommended doses (VRAYLAR 1.5 mg/day or 3 mg/day vs placebo) were:
nausea (7%, 7% vs 3%), akathisia (6%, 10% vs 2%), restlessness (2%,
7% vs 3%), and EPS (4%, 6% vs 2%).
Please see the full Prescribing Information, including
Boxed Warnings, and Medication Guide.
About AbbVie in Mental Health
AbbVie is driving the
pursuit of better mental health. Over the last 30 years, the
company's scientists and clinicians have worked to tackle the
complexity of mental illness and today offer a portfolio of
medicines and a pipeline of innovation that spans depression,
anxiety, bipolar I disorder, and schizophrenia. To learn more about
AbbVie's work to support individuals throughout their mental health
journey, please visit www.abbvie.com or follow @abbvie on Twitter,
Facebook, Instagram, YouTube and LinkedIn.
About AbbVie
AbbVie's mission is to discover and
deliver innovative medicines that solve serious health issues today
and address the medical challenges of tomorrow. We strive to have a
remarkable impact on people's lives across several key therapeutic
areas: immunology, oncology, neuroscience, eye care, virology,
women's health and gastroenterology, in addition to products and
services across its Allergan Aesthetics portfolio. For more
information about AbbVie, please visit us at www.abbvie.com. Follow
@abbvie on Twitter, Facebook, Instagram, YouTube and LinkedIn.
Forward-Looking Statements
Some statements in this
news release are, or may be considered, forward-looking statements
for purposes of the Private Securities Litigation Reform Act of
1995. The words "believe," "expect," "anticipate," "project" and
similar expressions, among others, generally identify
forward-looking statements. AbbVie cautions that these
forward-looking statements are subject to risks and uncertainties
that may cause actual results to differ materially from those
indicated in the forward-looking statements. Such risks and
uncertainties include, but are not limited to, failure to realize
the expected benefits from AbbVie's acquisition of Allergan plc
("Allergan"), failure to promptly and effectively integrate
Allergan's businesses, competition from other products, challenges
to intellectual property, difficulties inherent in the research and
development process, adverse litigation or government action,
changes to laws and regulations applicable to our industry and the
impact of public health outbreaks, epidemics or pandemics, such as
COVID-19. Additional information about the economic, competitive,
governmental, technological and other factors that may affect
AbbVie's operations is set forth in Item 1A, "Risk Factors," of
AbbVie's 2020 Annual Report on Form 10-K, which
has been filed with the Securities and Exchange Commission, as
updated by its subsequent Quarterly Reports on Form 10-Q. AbbVie
undertakes no obligation to release publicly any revisions to
forward-looking statements as a result of subsequent events or
developments, except as required by law.
References:
- Abuse, S. (2020). Key substance use and mental health
indicators in the United States:
results from the 2019 National Survey on Drug Use and Health.
Available
at: https://www.samhsa.gov/data/sites/default/files/reports/rpt29393/2019NSDUHFFRPDFWHTML/2019NSDUHFFR1PDFW090120.pdf.
Accessed on August 31, 2021.
- World Health Organization. (2021). Depression. Fact Sheet.
Available
at: https://www.who.int/news-room/fact-sheets/detail/depression.
Accessed on September 16, 2021.
- Kessler RC, et al. Psychol Med. 2010;40:225-237.
- Greenberg PE, et al. J Clin Psychiatry.
2015;76(2):155-162.
- Durgam S, Earley W, Guo H, Li D, Németh G, Laszlovszky I, Fava
M, Montgomery SA. Efficacy and safety of adjunctive cariprazine in
inadequate responders to antidepressants: a randomized,
double-blind, placebo-controlled study in adult patients with major
depressive disorder. J Clin Psychiatry. 2016 Mar;77(3):371-8. doi:
10.4088/JCP.15m10070. PMID: 27046309.
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