- The supplemental new drug application (sNDA) for brexpiprazole
in combination with sertraline for the treatment of adults with
post-traumatic stress disorder (PTSD) has been accepted and filed
by the FDA.
- The FDA target date (PDUFA date) for completion of the review
is February 8, 2025.
- If approved, brexpiprazole and sertraline combination treatment
would be the first FDA-approved pharmacological option for PTSD in
more than 20 years.
Otsuka Pharmaceutical, Co. Ltd. (Otsuka) and H. Lundbeck A/S
(Lundbeck) announce the U.S. Food and Drug Administration (FDA) has
determined that the supplemental New Drug Application (sNDA) for
brexpiprazole in combination with sertraline for the treatment of
adults with post-traumatic stress disorder (PTSD) is sufficiently
complete to permit a substantive review. The FDA has assigned the
application for a Prescription Drug User Fee Act (PDUFA) target
action date of February 8, 2025.
This press release features multimedia. View
the full release here:
https://www.businesswire.com/news/home/20240625407910/en/
The sNDA submission is based on data from three randomized
clinical trials evaluating the safety and efficacy of brexpiprazole
in combination with sertraline in adult patients with PTSD. 1,2
The primary endpoint for all three trials was the change from
randomization (Week 1) to Week 10 in the Clinician-Administered
PTSD Scale (CAPS-5) total score for brexpiprazole and sertraline
combination therapy versus sertraline plus placebo in patients
diagnosed with PTSD according to the Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition (DSM-5).1
The trials were randomized, double blind, active-controlled, and
Trial 061 (Phase II) and 071 (Phase III) were flexible dose trials,
while Trial 072 (Phase III) was a fixed dose trial.1 In Trial 061
and 071, brexpiprazole in combination with sertraline was
associated with a statistically significant reduction (p<0.05)
in PTSD symptoms compared to sertraline plus placebo, as measured
by the change in the CAPS-5 total score from randomization (Week 1)
to Week 10 (primary endpoint). In Trial 072, while the primary
endpoint was not met, reductions in PTSD symptoms with
brexpiprazole in combination with sertraline were consistent with
Trials 061 and 071. Improvements were consistently observed across
the Clinical Global Impression Severity (CGI-S) scale and the four
CAPS-5 clusters of re-experiencing, avoidance, negative
cognition/mood and arousal/reactivity symptoms in Trials 061 and
071.1,3
Across the three randomized trials, the combination of
brexpiprazole and sertraline in adult patients with PTSD was
generally well-tolerated, and no new safety observations were
identified. The safety and tolerability results were consistent
with the known profile of brexpiprazole in its approved indications
and what has been observed in other clinical trials. The overall
incidence of treatment-emergent adverse events (TEAEs) across the
three trials was 55.5 percent with brexpiprazole plus sertraline,
and 56.2 percent with sertraline plus placebo.2
“Post-traumatic stress disorder is one of the most common mental
health disorders in the United States. Approximately 13 million
adults in the U.S. have PTSD during a given year, and between seven
to eight out of every 100 will experience PTSD at some point in
their lives,”4-10 said John Kraus, M.D., Ph.D., executive vice
president and chief medical officer, Otsuka. “This is a significant
development, and we look forward to continuing our efforts to
provide a treatment option that may benefit the millions of
patients and caregivers who are impacted by the debilitating
effects of PTSD.”
“Brexpiprazole in combination with sertraline could represent an
important advancement over current standard of care, and we look
forward to working with the FDA in the process of seeking approval
of this combination,” said Johan Luthman, Ph.D., executive vice
president, Lundbeck Research & Development. “We are grateful to
the patients and caregivers who participated in these important
trials.”
About CAPS-5
The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a
structured interview designed to assess PTSD diagnostic status and
symptoms severity as defined by the Diagnostic and Statistical
Manual of Mental Disorders, 5th Edition (DSM-5). The interview
consists of 30 items, with a higher score indicating a worse
outcome.
About Post-Traumatic Stress Disorder
PTSD is one of the most common mental health disorders in the
United States, with approximately five percent of the population
affected during a given year.6-10 It may occur in people who have
experienced or witnessed a traumatic event, series of events or set
of circumstances. An individual may experience this as emotionally
or physically harmful or life-threatening and may affect mental,
physical, social, and/or spiritual well-being. Examples include
physical/sexual assault, natural disasters, serious accidents,
terrorist acts, war/combat, historical trauma, intimate partner
violence and bullying.11,12
Symptoms of PTSD are generally grouped into four clusters:
intrusion (re-experiencing), avoidance, negative cognitions and
mood, and marked alterations in arousal and reactivity.7,12
Symptoms can vary over time or vary from person to person.12
Symptoms usually begin within 3 months of the traumatic incident,
but they sometimes emerge later. To meet the criteria for PTSD
diagnosis, symptoms must last longer than one month, and they must
be severe enough to interfere with aspects of daily life, such as
relationships or work. Symptoms also must not be due to
medications, substance use, or a medical condition.7 Guideline
recommended first-line treatment includes psychotherapy (e.g.,
cognitive behavioral therapy) and first line pharmacotherapy
options include certain antidepressants.13
About REXULTI (brexpiprazole)
Brexpiprazole was approved in the U.S. in 2015, as an adjunctive
therapy to antidepressants in adults with major depressive disorder
(MDD) and as a treatment for schizophrenia in adults. Most
recently, brexpiprazole was approved in the U.S. for the treatment
of agitation associated with dementia due to Alzheimer's disease,
in May 2023. Brexpiprazole was also approved by Health Canada for
schizophrenia and adjunctive treatment of MDD in 2017 and 2019,
respectively, and for agitation associated with dementia due to
Alzheimer's disease in 2024. It was approved by the European
Medicines Agency in 2018 for the treatment of schizophrenia and the
Ministry of Health, Labour and Welfare in Japan for the treatment
of schizophrenia and MDD in 2018 and 2023, respectively.14
Brexpiprazole was discovered by Otsuka and is being co-developed
by Otsuka and Lundbeck. The mechanism of action of brexpiprazole is
unknown, however the efficacy of brexpiprazole may be mediated
through a combination of partial agonist activity at serotonin
5-HT1A and dopamine D2 receptors, antagonist activity at serotonin
5-HT2A receptors, as well as antagonism of alpha 1B/2C
receptors.14-16
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 areas
of mental, renal, and cardiovascular health and has additional
research programs in oncology and 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 established a presence in the U.S. in 1973 and today its
U.S. affiliates include Otsuka Pharmaceutical Development &
Commercialization, Inc. (OPDC) and Otsuka America Pharmaceutical,
Inc. (OAPI). These two companies’ 2,250 employees in the U.S.
develop and commercialize medicines in the areas of mental health
and nephrology, using cutting-edge technology to address unmet
healthcare needs.
OPDC and OAPI are indirect subsidiaries of Otsuka Pharmaceutical
Co., Ltd., which is a subsidiary of Otsuka Holdings Co., Ltd.
headquartered in Tokyo, Japan. The Otsuka group of companies
employed 34,400 people worldwide and had consolidated sales of
approximately USD 14.2 billion in 2023.
All Otsuka stories start by taking the road less traveled. Learn
more about Otsuka in the U.S. at www.otsuka-us.com and connect with
us on LinkedIn and Twitter at @OtsukaUS. Otsuka Pharmaceutical Co.,
Ltd.’s global website is accessible at
https://www.otsuka.co.jp/en/.
About Lundbeck
Lundbeck Pharmaceuticals LLC is a wholly owned US subsidiary of
H. Lundbeck A/S (HLUNa / HLUNb, HLUNA DC / HLUNB DC), a global
biopharmaceutical company focused exclusively on neuroscience, with
more than 70 years of experience in improving the lives of people
with neurological and psychiatric diseases.
As a focused innovator, we strive for our research and
development programs to tackle some of the most complex challenges.
We develop transformative medicines targeting people for whom there
are few, if any, treatment options. Our goal is to create long term
value and make a positive contribution to people and societies,
everywhere we operate. We are committed to fighting stigma and
discrimination, and we act to improve health equity for the people
we serve and the communities we are part of.
Too many people worldwide live with brain diseases – complex
conditions often invisible to others that nonetheless take a
tremendous toll on individuals, families and societies. We are
committed to fighting stigma and discrimination against people
living with brain diseases and advocating for broader social
acceptance of people with brain health conditions. Every day, we
strive for improved treatment and a better life for people living
with brain disease.
We have approximately 5,700 employees, and our products are
available in more than 100 countries. Our research programs tackle
some of the most complex challenges in neuroscience, and our
pipeline is focused on bringing forward transformative treatments
for brain diseases for which there are few, if any therapeutic
options. We have research facilities in Denmark and the United
States, and our production facilities are located in Denmark,
France, and Italy.
Lundbeck US comprises the wholly owned US subsidiaries of H.
Lundbeck A/S (HLUNa / HLUNb, HLUNA DC / HLUNB DC) (“Lundbeck”),
including Lundbeck LLC and Lundbeck Pharmaceuticals LLC. With a
workforce of more than 1,000 colleagues, Lundbeck US is deeply
committed to enhancing the lives of patients, families, and
caregivers through focused innovation in neuroscience. For
additional information, please visit Lundbeck.com/us and connect
with us on LinkedIn and X at @LundbeckUS.
INDICATIONS and IMPORTANT SAFETY INFORMATION for
REXULTI® (brexpiprazole)
INDICATIONS:
REXULTI is a prescription medicine used:
- along with antidepressant medicines to treat major depressive
disorder (MDD) in adults
- to treat schizophrenia in adults and children ages 13 years and
older
- to treat agitation that may happen with dementia due to
Alzheimer’s disease
REXULTI should not be used as an “as needed” treatment for
agitation that may happen with dementia due to Alzheimer’s
disease.
It is not known if REXULTI is safe and effective in children
with MDD.
It is not known if REXULTI is safe and effective in children
under 13 years of age with schizophrenia.
IMPORTANT SAFETY INFORMATION:
- Increased risk of death in elderly people with
dementia-related psychosis. Medicines like REXULTI can raise the
risk of death in elderly people who have lost touch with reality
(psychosis) due to confusion and memory loss (dementia). REXULTI is
not approved for the treatment of people with dementia-related
psychosis without agitation that may happen with dementia due to
Alzheimer’s disease.
- Increased risk of suicidal thoughts and actions. REXULTI and
antidepressant medicines may increase suicidal thoughts and actions
in pediatric patients and young adult patients, especially within
the first few months of treatment or when the dose is changed.
Depression and other mental illnesses are the most important causes
of suicidal thoughts and actions. All patients on antidepressants
and their families or caregivers should closely watch for new or
worsening depression symptoms, especially sudden changes in mood,
behaviors, thoughts, or feelings. Report any change in these
symptoms immediately to the doctor.
Do not take REXULTI if you are allergic to brexpiprazole
or any of the ingredients in REXULTI.
REXULTI may cause serious side effects, including:
- Cerebrovascular problems, including stroke, in elderly
people with dementia-related psychosis that can lead to
death.
- Neuroleptic malignant syndrome (NMS) is a serious condition
that can lead to death. Call your healthcare provider or go to
the nearest hospital emergency room right away if you have some or
all of the following signs and symptoms of NMS: high fever; changes
in your pulse, blood pressure, heart rate, and breathing; stiff
muscles; confusion; increased sweating
- Uncontrolled body movements (tardive dyskinesia).
REXULTI may cause movements that you cannot control in your face,
tongue, or other body parts. Tardive dyskinesia may not go away,
even if you stop taking REXULTI. Tardive dyskinesia may also start
after you stop taking REXULTI.
- Problems with your metabolism such as:
- high blood sugar (hyperglycemia) and diabetes. Increases
in blood sugar can happen in some people who take REXULTI.
Extremely high blood sugar can lead to coma or death. Your
healthcare provider should check your blood sugar before you start,
or soon after you start REXULTI and then regularly during long term
treatment with REXULTI. Call your healthcare provider if you
have any of these symptoms of high blood sugar during treatment
with REXULTI:
- feel very thirsty
- feel very hungry
- feel sick to your stomach
- need to urinate more than usual
- feel weak or tired
- feel confused, or your breath smells fruity
- increased fat levels (cholesterol and triglycerides) in your
blood. Your healthcare provider should check the fat levels in
your blood before you start, or soon after you start REXULTI, and
then periodically during treatment with REXULTI.
- weight gain. You and your healthcare provider should
check your weight before you start and often during treatment with
REXULTI.
- Unusual and uncontrollable (compulsive) urges. Some
people taking REXULTI have had strong unusual urges, to gamble and
gambling that cannot be controlled (compulsive gambling). Other
compulsive urges include sexual urges, shopping, and eating or
binge eating. If you or your family members notice that you are
having new or unusual strong urges or behaviors, talk to your
healthcare provider.
- Low white blood cell count. Your healthcare provider may
do blood tests during the first few months of treatment with
REXULTI.
- Decreased blood pressure (orthostatic hypotension) and
fainting. You may feel dizzy, lightheaded or pass out (faint)
when you rise too quickly from a sitting or lying position.
- Falls. REXULTI may make you sleepy or dizzy, may cause a
decrease in your blood pressure when changing position (orthostatic
hypotension), and can slow your thinking and motor skills which may
lead to falls that can cause fractures or other injuries.
- Seizures (convulsions).
- Problems controlling your body temperature so that you feel
too warm. Do not become too hot or dehydrated during treatment
with REXULTI. Do not exercise too much. In hot weather, stay inside
in a cool place if possible. Stay out of the sun. Do not wear too
much clothing or heavy clothing. Drink plenty of water.
- Difficulty swallowing that can cause food or liquid to
get into your lungs.
- Sleepiness, drowsiness, feeling tired, difficulty thinking
and doing normal activities. Do not drive a car, operate
machinery, or do other dangerous activities until you know how
REXULTI affects you. REXULTI may make you feel drowsy.
Before taking REXULTI, tell your healthcare provider about
all of your medical conditions, including if you:
- have or have had heart problems or a stroke
- have or have had low or high blood pressure
- have or have had diabetes or high blood sugar or a family
history of diabetes or high blood sugar.
- have or have had high levels of total cholesterol, LDL
cholesterol, or triglycerides, or low levels of HDL
cholesterol
- have or have had seizures (convulsions)
- have or have had kidney or liver problems
- have or have had a low white blood cell count
- are pregnant or plan to become pregnant. REXULTI may harm your
unborn baby. Taking REXULTI during your third trimester of
pregnancy may cause your baby to have abnormal muscle movements or
withdrawal symptoms after birth. Talk to your healthcare provider
about the risk to your unborn baby if you take REXULTI during
pregnancy.
- Tell your healthcare provider if you become pregnant or think
you are pregnant during treatment with REXULTI.
- There is a pregnancy exposure registry for women who are
exposed to REXULTI during pregnancy. If you become pregnant during
treatment with REXULTI, talk to your healthcare provider about
registering with the National Pregnancy Registry for Psychiatric
Medications. You can register by calling 1-866-961-2388 or visit
http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.
- are breastfeeding or plan to breastfeed. It is not known if
REXULTI passes into your breast milk. Talk to your healthcare
provider about the best way to feed your baby during treatment with
REXULTI.
Tell your healthcare provider about all the medicines you
take, including prescription and over-the-counter medicines,
vitamins, and herbal supplements. REXULTI and other medicines may
affect each other causing possible serious side effects. REXULTI
may affect the way other medicines work, and other medicines may
affect how REXULTI works. Your healthcare provider can tell you if
it is safe to take REXULTI with your other medicines. Do not start
or stop any medicines during treatment with REXULTI without first
talking to your healthcare provider.
The most common side effects of REXULTI include weight
gain, sleepiness, dizziness, common cold symptoms, and restlessness
or feeling like you need to move (akathisia).
These are not all the possible side effects of REXULTI. For more
information, ask your healthcare provider or pharmacist.
You are encouraged to report side effects of REXULTI
(brexpiprazole). Please contact Otsuka America Pharmaceutical, Inc.
at 1-800-438-9927 or FDA at 1-800-FDA-1088
(www.fda.gov/medwatch).
Please read FULL PRESCRIBING INFORMATION, including
BOXED WARNING, and MEDICATION GUIDE
for REXULTI.
References
- Behl S et al. Efficacy of Brexpiprazole in Combination with
Sertraline for Patients with Post-Traumatic Stress Disorder:
Summary of Data from Phase 2 and Phase 3 Randomized Clinical
Trials. Presented at ASCP 2024 (May 28-31).
- Behl S et al. Safety and Tolerability of Brexpiprazole in
Combination with Sertraline for Patients with Post-Traumatic Stress
Disorder: Summary of Data from Phase 2 and Phase 3 Randomized
Clinical Trials. Presented at ASCP 2024 (May 28-31).
- Behl, S. Clinical Program of Brexpiprazole in Combination with
Sertraline for Patients with Post-Traumatic Stress Disorder. Panel
presentation at ASCP May 28, 2024.
- Kilpatrick DG, Resnick HS, Milanak ME, Miller MW, Keyes KM,
Friedman MJ. National estimates of exposure to traumatic events and
PTSD prevalence using DSM-IV and DSM-5 criteria. J Trauma Stress.
2013;26(5):537-547.
- Koenen KC, Ratanatharathorn A, Ng L, et al. Posttraumatic
stress disorder in the World Mental Health Surveys. Psychol Med.
2017;47(13):2260-2274.
- Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen H
-U. Twelve-month and lifetime prevalence and lifetime morbid risk
of anxiety and mood disorders in the United States. Int J Methods
Psychiatr Res. 2012;21(3):169-184.
- Lancaster CL, Teeters JB, Gros DF, Back SE. Posttraumatic
Stress Disorder: Overview of Evidence-Based Assessment and
Treatment. J Clin Med. 2016;5(11):105.
- Lehavot K, Katon JG, Chen JA, Fortney JC, Simpson TL.
Post-traumatic Stress Disorder by Gender and Veteran Status
[published correction appears in Am J Prev Med. 2019
Oct;57(4):573]. Am J Prev Med. 2018;54(1):e1-e9.
- U.S. Department of Veterans Affairs. How Common Is PTSD in
Adults? Last updated: Feb. 3, 2023. Last accessed: April 30, 2024.
Available at:
https://www.ptsd.va.gov/understand/common/common_adults.asp.
- US Census Bureau 2022 Data.
- American Psychiatric Association. What is Posttraumatic Stress
Disorder (PTSD)? Last updated: November 2022. Last accessed: April
30, 2024. Available at:
https://www.psychiatry.org/patients-families/ptsd/what-is-ptsd.
- American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition. Arlington, VA, American
Psychiatric Association, 2013.
- VA/DoD Clinical Practice Guideline for Management of PTSD –
Provider Summary 2023. Version 4.0. US Department of Veterans
Affairs, US Department of Defense; 2023. Last accessed May 22,
2024.
https://www.healthquality.va.gov/guidelines/MH/ptsd/VA-DoD-CPG-PTSD-Provider-Summary.pdf.
- Otsuka. Otsuka Pharmaceutical and Lundbeck Announce Topline
Results from Two Phase 3 Trials of Brexpiprazole as Combination
Therapy with Sertraline for the Treatment of Post-Traumatic Stress
Disorder in Adults. Last accessed: May 20, 2024. Available at:
https://www.otsuka-us.com/news/otsuka-pharmaceutical-and-lundbeck-announce-topline-results-two-phase-3-trials-brexpiprazole.
- Maeda K, Sugino H, Akazawa H, et al. Brexpiprazole I: in vitro
and in vivo characterization of a novel serotonin-dopamine activity
modulator. J Pharmacol Exp Ther. 2014;350(3):589-604.
- REXULTI® (brexpiprazole). Prescribing Information. FDA.
Reference ID: 4911319. May 2023.
© 2024 Otsuka America Pharmaceutical, Inc. All Rights Reserved.
June 2024 11US24EBC0179
View source
version on businesswire.com: https://www.businesswire.com/news/home/20240625407910/en/
Otsuka in the U.S. Robert Murphy Corporate Communications
Otsuka America Pharmaceutical, Inc. robert.murphy@otsuka-us.com +1
609 249 7262
Otsuka outside the U.S. Jeffrey Gilbert Leader,
Pharmaceutical PR Otsuka Pharmaceutical Co., Ltd.
Gilbert.jeffrey.a@otsuka.co.jp
Lundbeck in the U.S. Dyana Lescohier Corporate
Communications Lundbeck US dyle@lundbeck.com +1 847 894 3586