Orexigen's Mysimba™ Approved in Europe for the Treatment of Obesity

SAN DIEGO, March 26, 2015 /PRNewswire/ -- Orexigen Therapeutics, Inc. (Nasdaq: OREX) today announced that the European Commission has granted marketing authorization for Mysimba™ (naltrexone HCl / bupropion HCl prolonged release) as an adjunct to a reduced-calorie diet and increased physical activity, for the management of weight in adult patients (≥18 years) with an initial Body Mass Index (BMI) of ≥ 30 kg/m2 (obese), or ≥ 27 kg/m2 to < 30 kg/m2 (overweight) in the presence of one or more weight-related co-morbidities (e.g., type 2 diabetes, dyslipidaemia, or controlled hypertension). This authorization applies to all 28 European Union (EU) member states.
"The granting of European marketing authorization for Mysimba is a significant milestone for Orexigen.  European approval is an important step in our pursuit to bring new treatment options to the many patients who struggle with obesity in Europe and around the world," said Mike Narachi, CEO of Orexigen.
About obesity in Europe 
Obesity is one of the most significant public health challenges globally and being overweight or obese is a major risk factor for a number of chronic diseases, including diabetes and cardiovascular disease. In Europe, the prevalence of obesity has risen up to three-fold in the last two decades, and the World Health Organization estimates that over 20% of the adult European population is obese (BMI≥30 kg/m2). Adult obesity and overweight are responsible for up to 6% of health care expenditures in Europe; in addition, they impose indirect costs (due to the loss of lives, productivity and related income) that are at least two times higher.
About Mysimba 
Mysimba is a centrally acting anti-obesity product composed of a fixed dose combination of the active substances naltrexone and bupropion. Naltrexone is a mu-opioid antagonist and bupropion is a norepinephrine and dopamine reuptake inhibitor. Both compounds affect key circuitry in two areas of the brain. The first is the arcuate nucleus of the hypothalamus, an area of the brain that plays a critical role in the control of food intake and energy expenditure. The second is the mesolimbic dopaminergic reward system, a region of the brain that is important for processing the rewarding aspects of food and food related stimuli. Both bupropion and naltrexone act in the mesolimbic reward system to influence eating behavior.
Four 56-week multicenter, double-blind, placebo-controlled Phase 3 clinical trials (NB-301, NB-302, NB-303, and NB-304) were conducted to evaluate the effect of Mysimba in conjunction with lifestyle modification in 4,536 subjects randomized to Mysimba or placebo. The NB-301, NB-302, and NB-303 trials enrolled patients with obesity (BMI 30 kg/m2 or greater) or overweight (BMI 27 kg/m2 or greater) and at least one comorbidity (hypertension or dyslipidaemia). The NB-304 trial enrolled patients with BMI of 27 kg/m2 or greater with type 2 diabetes with or without hypertension and/or dyslipidaemia. In these studies, the most common adverse reactions (≥5 percent) seen in patients taking Mysimba included nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, and diarrhea.
The clinical trial program also includes a double-blind, placebo-controlled cardiovascular outcomes trial known as the Light Study. The primary objective of this study is to evaluate the occurrence of major adverse cardiovascular events (MACE) in overweight and obese adults with cardiovascular risk factors receiving Mysimba. An interim analysis of the Light Study, including 94 MACE, was submitted to the European Medicines Agency for their evaluation in response to questions about cardiovascular safety. A second study, designed to address post-approval requirements in both Europe and the United States, is planned in order to further evaluate cardiovascular outcomes.
In the United States, the drug was approved in September 2014 and is marketed under a separate brand name. Further information can be found at http://www.orexigen.com/.
About Orexigen Therapeutics 
Orexigen Therapeutics, Inc., San Diego, California, developed Mysimba™ (naltrexone HCl / bupropion HCl prolonged release) for weight management. Orexigen owns all rights to Mysimba outside of North America, and the Company's strategy is to pursue marketing authorizations worldwide and pharmaceutical partnerships for global commercialization.
Indication and Usage of Mysimba in the EU
Mysimba is indicated, as an adjunct to a reduced-calorie diet and increased physical activity, for the management of weight in adult patients (≥18 years) with an initial Body Mass Index (BMI) of
≥ 30 kg/m2 (obese), or
≥ 27 kg/m2 to < 30 kg/m2 (overweight) in the presence of one or more weight-related co‑morbidities (e.g., type 2 diabetes, dyslipidaemia, or controlled hypertension)
Treatment with Mysimba should be discontinued after 16 weeks if patients have not lost at least 5% of their initial body weight.
Important Safety Information about Mysimba in the EU
Mysimba is contraindicated in patients with hypersensitivity to any of its components, uncontrolled hypertension, seizure disorder, a known central nervous system tumor, in patients undergoing alcohol or benzodiazepine withdrawal, in patients with a history of bipolar disorder, in patients using other bupropion or naltrexone-containing products, in patients with a current or previous diagnosis of bulimia or anorexia nervosa, in patients currently dependent on chronic opioids or opiate agonists, in patients using monoamine oxidase inhibitors (MAOI) or have taken MAOIs in the last 14 days, in patients with severe liver disease, severe or end-stage kidney disease.
Special Warnings and Precautions for Use
Suicide and suicidal behaviour. Mysimba contains bupropion, which is similar to some active substances used for the treatment of depression.  Antidepressants increased the risk of suicidal behaviour in patients less than 25 years old. In clinical trials with Mysimba for the treatment of obesity in adult subjects, no suicides or suicide attempts were reported in studies up to 56 weeks duration with Mysimba, and suicidal ideation was not more commonly reported in subjects treated with Mysimba compared to placebo.
Close supervision of patients and in particular young adult patients and those at high risk should accompany therapy with Mysimba especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Seizures.  Bupropion is associated with a dose‑related risk of seizures. The risk of seizures is also related to patient factors, clinical situations, and concomitant medicinal products, which must be considered in the selection of patients treated with Mysimba. Mysimba should be discontinued and not restarted in patients who experience a seizure while being treated with Mysimba. Use caution when prescribing Mysimba to patients with predisposing factors that may increase the risk of seizure.
The consumption of alcohol during Mysimba treatment should be minimised or avoided.
Allergic reactions.  Anaphylactoid/anaphylactic reactions have been reported in clinical trials with bupropion, as well as rare spontaneous reports of erythema multiforme, Stevens‑Johnson syndrome, and anaphylactic shock. Stop taking Mysimba and consult a doctor if you experience any symptoms of an adverse reaction such as swelling of the throat, tongue, lips or face, difficulty swallowing or breathing, dizziness, fever, rash, pain in the joints or in the muscles, itching or hives.
Elevation of blood pressure.  Mysimba can increase systolic and diastolic blood pressure.  In clinical practice with other bupropion containing products, hypertension, in some cases severe and requiring acute treatment, has been reported.  Discontinue Mysimba in the event of clinically relevant and sustained increases in blood pressure or pulse rate.  Mysimba should be given with caution to patients with controlled hypertension.
Cardiovascular disease.  There is no clinical experience establishing the safety of Mysimba in patients with a recent history of myocardial infarction, unstable heart disease or NYHA class III or IV congestive heart failure.  Mysimba should be used with caution in patients with active coronary artery disease or history of cerebrovascular disease.
Hepatotoxicity.  Naltrexone hydrochloride can cause hepatocellular injury when given in excessive doses (300 mg/day or approximately 10 times the recommended dose of Mysimba).  A patient with elevations of transaminases or bilirubin should stop taking Mysimba and notify their doctor.
Elderly patients.  Mysimba should be used with caution in patients over 65 years of age and is not recommended in patients over 75 years of age.
Renal impairment.  Mysimba is not recommended in patients with moderate renal impairment. 
Hepatic impairment.  Mysimba is not recommended in patients with mild or moderate hepatic impairment.
Neuropsychiatric symptoms and activation of mania.  Mysimba should be used cautiously in patients with a history of mania.
Lactose.  Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose‑galactose malabsorption should not take Mysimba.
Pregnancy and Breast-feeding.  Mysimba should not be used during pregnancy, in women attempting to become pregnant or during breast-feeding.
Children and Adolescents.  Mysimba should not be used in children and adolescents below 18 years.
Adverse Reactions
Very common side effects (may affect more than 1 in 10 people) include:  feeling sick (nausea), being sick (vomiting), pain in the abdomen, constipation, headache, difficulty in sleeping (do not take Mysimba near to bedtime), anxiety, agitation, joint and muscle pain.
A Summary of Product Characteristics and more information about Mysimba for EU patients will be available shortly at www.ema.europa.eu.
Mysimba is a trademark of Orexigen Therapeutics, Inc. registered with the U.S. Patent and Trademark Office.
Forward-Looking Statements 
Orexigen cautions you that statements included in this press release that are not a description of historical facts are forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "indicates," "will," "should," "intends," "potential," "suggests," "assuming," "designed" and similar expressions are intended to identify forward-looking statements. These statements are based on the Company's current beliefs and expectations. These forward-looking statements include a statement regarding: Mysimba being an important next step in our pursuit to bring new treatment options to the many patients in Europe and around the world who struggle with obesity. The inclusion of forward-looking statements should not be regarded as a representation by Orexigen that any of its plans will be achieved. Actual results may differ materially from those expressed or implied in this release due to the risk and uncertainties inherent in the Orexigen business, including, without limitation: the possibility that Orexigen is unable to find a partner for Mysimba in territories outside of North America; the final results of the Light Study or the other cardiovascular outcomes trial may not support continued authorization of Mysimba; the therapeutic and commercial value of Mysimba; and other risks described in Orexigen's filings with the Securities and Exchange Commission. You are cautioned not to place undue reliance on these forward  looking statements, which speak only as of the date hereof, and Orexigen undertakes no obligation to revise or update this news release to reflect events or circumstances after the date hereof. Further information regarding these and other risks is included under the heading "Risk Factors" in Orexigen's Quarterly Report on Form 10-K filed with the Securities and Exchange Commission on February 27, 2015 and its other reports, which are available from the SEC's website (www.sec.gov) and on Orexigen's website (www.orexigen.com) under the heading "Investor Relations." All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of 1995.
Orexigen Contact: 
McDavid Stilwell 
VP, Corporate Communications and Business Development  
(858) 875-8629
Media Contact: 
David Walsey 
(858) 617-0772
SOURCE Orexigen Therapeutics, Inc.