Cambridge, MA, United States

Euthymics Bioscience
Cambridge, MA, United States
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The invention provides novel 1-heteroaryl-3-azabicyclo[3.1.0]hexanes, and related processes and intermediates for preparing these compounds, as well as compositions and methods employing these compounds for the treatment and/or prevention of central nervous system (CNS) disorders, including but not limited to depression and anxiety.

News Article | March 2, 2017

TOKYO--(BUSINESS WIRE)--Otsuka Pharmaceutical Co., Ltd. (OPC) today announces an agreement with Neurovance, Inc. (Neurovance) under which OPC has agreed to acquire Neurovance, a privately held, venture-funded, clinical stage pharmaceutical company focused on attention-deficit hyperactivity disorder (ADHD) and related disorders. Under the terms of the agreement, Otsuka America, Inc. (OAI), a subsidiary of OPC, is to provide an estimated USD $100 million in upfront payments at closing, up to $150 million in additional payments contingent on achievement of development and approval milestones, and future additional payments contingent on achievement of sales milestones. The contract was signed on March 2 (U.S. Eastern Standard Time), and the transaction closing is expected to occur in the second quarter of 2017, subject to customary closing conditions. Neurovance is developing centanafadine (CTN, formerly EB-1020) for the treatment of attention-deficit hyperactivity disorder in adult and pediatric patients. The company is based in Cambridge, Mass., and was established as a spin-off from Euthymics Bioscience, Inc. in 2011. Centanafadine is a non-stimulant, triple reuptake inhibitor that modulates norepinephrine, dopamine and serotonin reuptake with the intent of improving focus, attention, and specific higher level cognitive skills in patients with ADHD. Two phase II clinical trials in adults, including a phase IIb trial, have been completed for centanafadine, setting the stage for the start of phase III trials in ADHD. Tatsuo Higuchi, president and executive director, Otsuka Pharmaceutical Co., Ltd. commented, “Otsuka has been investing prudently in acquiring assets and collaborating on the development of new technologies that address specific patient needs in the central nervous system, cardio-renal and oncology therapeutic areas. Neurovance’s resources will be a welcomed, integral part of our activities in CNS.” The acquisition of Neurovance is an extension to ADHD of Otsuka’s strategy in the CNS therapy area to develop new products that can also address issues of importance to patients such as compliance with medicine taking or the challenging side effects from existing medications. Centanafadine is a non-stimulant drug candidate which in its development to date has shown that it may achieve comparable efficacy to stimulant drugs with a potentially lower risk of abuse. Following the consummation of the transaction, Neurovance will be an indirect, wholly-owned subsidiary of Otsuka Pharmaceutical Co., Ltd. Attention-deficit hyperactivity disorder (ADHD) is a CNS disorder marked by a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development. Some people with ADHD only have problems with one of the behaviors, while others have symptoms of both inattention and hyperactivity-impulsivity. Most children with ADHD have the combined type. ADHD symptoms often appear in childhood and can continue through adolescence and adulthood. Symptoms of ADHD can be mistaken for emotional or disciplinary problems or missed entirely in quiet, well-behaved children, leading to a delay in diagnosis. Adults with undiagnosed ADHD may have a history of problems at work, difficult or failed relationships, or poor academic performance. Scientists are not sure what causes ADHD. Like many other illnesses, a number of factors can contribute to ADHD, such as genes, exposure to cigarette smoking, alcohol use, drug use or environmental toxins during pregnancy, low birth weight, or brain injuries. ADHD is more common in males than females. Other conditions, such as learning disabilities, anxiety disorder, conduct disorder, depression, and substance abuse, are common in people with ADHD.1 Attention-deficit hyper activity disorder affects both children and adults. The lifetime prevalence of ADHD in adolescents aged 13 to 18 in the U.S. is 9%, and of those, 1.8% are classified as “severe.” 2 In U.S. adults aged 18 and older, the lifetime prevalence is 8.1% with the average age of onset being 7.3 The 12-month prevalence in U.S. adults is 4.1%, with 41.3% of those being classified as “severe.”4 The global market size for attention-deficit hyperactivity disorder therapies was USD $11.2 billion in FY 2016.5 Learn more about adult ADHD from the organization ADHD in ADULTS at For additional information on ADHD, please visit the National Institute of Mental Health website. About Otsuka Pharmaceutical Co., Ltd. Otsuka Pharmaceutical 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 for the treatment of diseases 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 is a wholly owned subsidiary of Otsuka Holdings Co., Ltd., the holding company for the Otsuka group of companies that is headquartered in Tokyo, Japan. Otsuka Holdings had consolidated sales of approximately USD 11 billion in 2016 and approximately 31,000 employees at year end. Otsuka Pharmaceutical welcomes you to visit its global website at Learn more about Otsuka in the U.S. at and connect with us on Twitter at @OtsukaUS. Headquartered in Cambridge, MA, Neurovance is a clinical stage neuroscience-focused company. Hypothesis-driven, proprietary research at Neurovance discovered and developed centanafadine (CTN), a triple reuptake inhibitor that represents a novel approach to help adults and children with ADHD, Attention-Deficit Hyperactivity Disorder. Neurovance is funded in a venture capital investment by Novartis Venture Fund, Venture Investors, Tekla Capital Management, GBS Venture Partners, State of Wisconsin Investment Board (SWIB) and Timothy J. Barberich. Certain statements contained in this press release, including without limitation expectations as to future sales and operating results, constitute forward-looking statements. Forward-looking statements in this press release include statements regarding the anticipated benefits of the transaction; statements regarding the anticipated timing of filings and approvals relating to the transaction; statements regarding the expected timing of the completion of the transaction; and any statements of assumptions underlying any of the foregoing. Words such as “expects,” “anticipates,” “believes,” “plans,” “intends,” “estimates,” “projects,” “forecasts,” “outlook,” and similar expressions are also intended to identify forward-looking statements. The statements involve known and unknown risks, uncertainties, and other factors which may cause the company's actual results, earnings, performance, or achievements to be materially different from any future results, performance, or achievements expressed or implied by such forward-looking statements. Such factors include, but are not limited to, the following: general industry and market conditions, general domestic and international economic conditions such as interest rate and currency exchange fluctuations, technological advances and patents attained by competitors, challenges inherent in new product development and clinical trials, claims and concerns about product safety and efficacy, obtaining regulatory approvals, domestic and foreign healthcare reforms, and healthcare cost containment, laws and regulations affecting domestic and foreign operations, and failure to gain market acceptance or third-party consents. Risks and uncertainties that could cause results to differ from expectations also include: uncertainties as to the timing of the offer and merger; uncertainties as to how many Neurovance stockholders will proffer their stock in the offer; the risk that competing offers will be made; and the possibility that various closing conditions for the transaction may not be satisfied or waived, including that a governmental entity may prohibit, delay or refuse to grant approval for the consummation of the transaction. We will not undertake and specifically decline any obligation to update or correct any forward-looking statements to reflect events or circumstances after the date of such statements or to reflect the occurrence of anticipated or unanticipated events. 1 National Institute of Mental Health, Attention Deficit Hyperactivity Disorder. Available at: (Accessed February 2017) 2 Merikangas KR, He J, Burstein M, Swanson SA, Avenevoli S, Cui L, Benjet C, Georgiades K, Swendsen J. Lifetime prevalence of mental disorders in U.S. adolescents: Results from the National Comorbidity Study-Adolescent Supplement (NCS-A). J Am Acad Child Adolesc Psychiatry. 2010 Oct;49(10):980-989. 3 Kessler RC, Berglund PA, Demler O, Jin R, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication (NCS-R). Archives of General Psychiatry. 2005 Jun;62(6):593–602. 4 Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, severity, and comorbidity of twelve-month DSM-IV disorders in the National Comorbidity Survey Replication (NCS-R). Archives of General Psychiatry, 2005 Jun;62(6):617–27 5 IMS MIDAS database (accessed February 2017)

The Report “Major Depressive Disorder - Market Insights, Epidemiology and Market Forecast-2023” Reports provides an overview of the disease and global market trends of the Crohn’s disease for the seven major markets ie: United States, EU5 (France, Germany, Italy, Spain, UK) and Japan. The Report covers the therapeutics market revenue; average cost of therapy, treatment practice and Major Depressive Disorder forecasted market share for ten years to 2023 segmented by seven major markets. In addition, the report also includes global forecast of epidemiology of Major Depressive Disorder till 2023. Key Companies covered in this report are Lundbeck, Forest Laboratories (Actavis), Eli Lilly, Pfizer, Otsuka Pharmaceutical, AstraZeneca, Takeda Pharmaceutical, Alkermes, Euthymics Bioscience, Naurex, e-Therapeutics etc. Get SAMPLE of Report Spread across 100 pages with 20 Figures Now available at

Major depressive disorder, also known as major depression and clinical depression, is a mental disorder characterized by loss of interest and pleasure in enjoyable environment. People are affected in different ways by major depression. Some people have trouble sleeping, feel agitated and irritable, and have sudden weight loss. Moreover, they can have other mental and physical symptoms such as fatigue, memory loss, feeling of hopelessness, body aches, headaches, and thoughts of suicide. Major depressive disorder can affect people in any stage of life. In adults, major depressive disorder is most common in those who are 25-44 years of age. Within an entire lifetime, major depression affects 10% - 25% of women and 5% - 12% of men. It is estimated that 10% - 25% of people who develop major depressive disorder are previously diagnosed with dysthymia (dysthymic disorder), a form of depression. Some people may suffer from dysthymia and major depressive disorder at the same time. The presence of both conditions at the same time is known as double depression. The development of major depressive disorder may be related to certain medical conditions. Approximately 20% - 25% of people who have cancer, diabetes, stroke, and myocardial infarctions are likely to develop major depressive disorder. The global major depressive disorder market is categorized based on various types of therapeutic drugs used to manage this medical condition. Based on type of therapeutic drug, the report covers selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, antidepressants, and antipsychotics. Major brands of selective serotonin-reuptake inhibitors include Lexapro (Escitalopram), Viibryd (Vilazodone), Effexor (Venlafaxine), Cymbalta (Duloxetine), Pristiq (Desvenlafaxine), Fetzima (Levomilnacipran), and Savella (Milnacipran). Antidepressants, such as Noradrenaline, Specific Serotonergic Antidepressants, Norepinephrine-Dopamine Reuptake Inhibitors, Tricyclic Antidepressants, Monoamine Oxidase Inhibitors, and Brintellix (Vortioxetine), are commonly used in the management of major depressive disorder. Major brands of antipsychotics include Abilify (Aripiprazole) and Seroquel XR (Quetiapine). In terms of geography, North America dominates the global major depressive disorder market due to increased awareness about various depression conditions in the region. The U.S. represents the largest market for major depressive disorder in North America, followed by Canada. In Europe, Germany, France, the U.K., Italy, and Spain account for a major share of the major depressive disorder market. This market in Asia is expected to expand at a significant rate over the next five years. This is due to various companies setting up manufacturing facilities in the region. Moreover, increasing awareness about various depression episodes and rise in geriatric population are also driving the growth of the market in the region. India, China, and Japan are expected to be the fastest growing major depressive disorder markets in Asia. In recent times, increased demand for therapeutic products for the treatment of this medical condition is a key driver for the global major depressive disorder market. Increased investments in R&D in the pharmaceutical sector and introduction of innovative drugs have also fueled the growth of this market. The ongoing development of drugs with properties, such as improved safety and high patient compliance, are also supporting the growth of the global major depressive disorder market. Therapies, such as biological therapy, meditation, and physiotherapy, have immense potential to spur the growth of this market. However, stringent regulations imposed by various governments hamper the growth of global major depressive disorder market. Moreover, the patent expiries of some blockbuster drugs (drugs that have an annual sale of USD 1.0 million and above) and risk of complications and side-effects associated with antidepressants have hindered the growth of the market. Increasing mergers and acquisitions of drug manufacturing companies and rapid product launches are some of the major trends in the global major depressive disorder market. Request TOC (desk of content material), Figures and Tables of the report: The major companies operating in this market are H. Lundbeck A/S, Otsuka Pharmaceutical Co., Ltd., AstraZeneca Plc, Alkermes, Takeda Pharmaceutical Company Limited, Naurex, Euthymics Bioscience, Inc., e-Therapeutics plc, Eli Lilly and Company, and Pfizer Inc. Key geographies evaluated in this report are:

Tran P.,Euthymics Bioscience | Skolnick P.,DOV Pharmaceutical | Czobor P.,DOV Pharmaceutical | Huang N.Y.,DOV Pharmaceutical | And 3 more authors.
Journal of Psychiatric Research | Year: 2012

Amitifadine (EB-1010, formerly DOV 21,947) is a serotonin-preferring triple reuptake inhibitor with a relative potency to inhibit serotonin, norepinephrine, and dopamine uptake of ∼1:2:8, respectively. This 6-week, multicenter, randomized, double-blind, parallel, placebo-controlled study evaluated the efficacy and tolerability of amitifadine in 63 patients with major depressive disorder. Eligible patients (17-item Hamilton Depression Rating Scale [HAMD-17] ≥ 22 at baseline) were randomized to amitifadine 25 mg twice daily (BID) for 2 weeks, then 50 mg BID for 4 weeks or placebo. Mean baseline scores in the modified intent-to-treat population (n = 56) were 31.4 for the Montgomery-åsberg Depression Rating Scale (MADRS), 29.6 for the HAMD-17, and 25.4 for the Derogatis Interview for Sexual Functioning - Self Report (DISF-SR). At the end of the 6-week double-blind treatment, estimated least squares mean change from baseline (mixed-model repeated measures [MMRM]) in MADRS total score was statistically significantly superior for amitifadine compared to placebo (18.2 vs. 22.0; p = 0.028), with an overall statistical effect size of -0.601 (Cohen's d). Amitifadine also was statistically significantly superior to placebo (p = 0.03) for the Clinical Global Impression of Change - Improvement. An anhedonia factor score grouping of MADRS Items 1 (apparent sadness), 2 (reported sadness), 6 (concentration difficulties), 7 (lassitude), and 8 (inability to feel) demonstrated a statistically significant difference in favor of amitifadine compared to placebo (p = 0.049). No differences were observed between treatments in DISF-SR scores. Amitifadine was well-tolerated. Two patients on each treatment discontinued the study early due to adverse events; however, no serious adverse events were reported. This initial clinical trial in patients with severe major depression demonstrated significant antidepressant activity with amitifadine, including attenuating symptoms of anhedonia, and a tolerability profile that was comparable to placebo. The efficacy and tolerability of amitifadine for major depressive disorder are being investigated in additional clinical trials. © 2011 Elsevier Ltd.

McKinzie D.L.,Eli Lilly and Company | Bymaster F.P.,Euthymics Bioscience
Handbook of Experimental Pharmacology | Year: 2012

Schizophrenia is a devastating disease with several broad symptom clusters and the current monoamine-based treatments do not adequately treat the disease, especially negative and cognitive symptoms. A proposed alternative approach for treating schizophrenia is through the use of compounds that activate certain muscarinic receptor subtypes, the so-called muscarinic cholinergic hypothesis theory. This theory has been revitalized with a number of recent and provocative findings including postmortem reports in schizophrenia patients showing decreased numbers of muscarinic M 1 and M 4 receptors in brain regions associated with schizophrenia as well as decreased muscarinic receptors in an in vivo imaging study. Studies with M 4 knockout mice have shown that there is a reciprocal relationship between M 4 and dopamine receptor function, and a number of muscarinic agonists have shown antidopaminergic activity in a variety of preclinical assays predictive of antipsychotic efficacy in the clinic. Furthermore, the M 1/M 4 preferring partial agonist xanomeline has been shown to have antipsychotic-like and pro-cognitive activity in preclinical models and in clinical trials to decrease psychotic-like behaviors in Alzheimer's patients and positive, negative, and cognitive symptoms in patients with schizophrenia. Therefore, we propose that an agonist with M 1 and M 4 interactions would effectively treat core symptom clusters associated with schizophrenia. Currently, research is focused on developing subtype-selective muscarinic agonists and positive allosteric modulators that have reduced propensity for parasympathetic side-effects, but retain the therapeutic benefit observed with their less selective predecessors. © 2012 Springer-Verlag Berlin Heidelberg.

Euthymics Bioscience | Date: 2014-07-01

The present disclosure relates to novel methods of treating pain comprising administering to a human in need thereof an effective amount of (1R,5S)-(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free and/or pharmaceutically acceptable salt form, substantially free of the corresponding () enantiomer, wherein the human is a heavy drinker and/or binge drinker and/or wherein the human has compromised liver function and/or wherein the human is a codeine non-responder. The present disclosure also relates to a method of treating pain comprising concurrently or sequentially administering to a patient in need thereof an effective amount of (a) (1R,5S)-(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free and/or pharmaceutically acceptable salt form, and (b) acetaminophen. The present disclosure also relates to a method of treating pain comprising simultaneously or sequentially administering to a patient in need thereof an effective amount of (a) (1R,5S)-(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free and/or pharmaceutically acceptable salt form, and (b) a non-steroidal anti-inflammatory drug.

Euthymics Bioscience | Date: 2014-11-11

Provided is a method of treating female sexual dysfunction comprising administering a therapeutically effective amount of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding () enantiomer, to a female in need thereof.

News Article | October 19, 2012

Neurovance, a spin-out of Euthymics Bioscience, both based in Cambridge, MA, closed a $7 million series A1 funding round on Thursday to advance development of its EB-1020 drug for adult attention deficit hyperactivity disorder, which it says will be less addictive than other treatments on the market. The funding round was led by existing investor Novartis Venture Fund. The National Institute of Mental Health estimates that 4.1 percent of the adult U.S. population has ADHD, about 10 million people in total. Less than 10 percent of this group is getting treatment, however, says Euthymics CEO Anthony McKinney. The leading ADHD treatment is a combination of dextroamphetamine and amphetamine (Adderall), classified as a highly addictive controlled substance by the Drug Enforcement Agency. Consequently, the DEA sets manufacturing quotas and doctor prescribing patterns are closely monitored, leading to regular shortages of this very popular, and frequently abused, drug. EB-1020 targets the same neurotransmitters as Adderall, but McKinney said in an interview that it has a lower risk of abuse because, unlike the popular drug, it gives limited stimulation to the pleasure center of the brain. EB-1020 is not expected to be as powerful as Adderall. “I don’t think anyone expects a non-stimulant to be as effective as these extraordinarily effective drugs,” says McKinney. Still, Neurovance believes the drug will have very good efficacy without the potential for abuse or the difficulties in access, making it a meaningful alternative. Neurovance’s efforts to strike a better balance between efficacy and side effects with EB-1020 mirror those of its parent company, which is working on an antidepressant that boosts mood without negatively affecting patients’ weight or sexual or cognitive function. Neurovance completed a Phase 1 trial of EB-1020 last month and plans to start a Phase 2 trial for the drug next summer, with results reported in the fall, says McKinney. The goal is to eventually test the drug in children as well. McKinney said the global market for ADHD drugs is currently $7 billion annually, with almost all of those sales concentrated in the U.S.

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