By Baltazar Gomez --
Last Thursday, OREXIGEN Therapeutics, Inc. announced that the U.S. Patent and Trademark Office mailed a Notice of Allowance for a patent application directed to the treatment of obesity using zonisamide, either alone or in combination with other drugs. According to OREXIGEN, the allowed application will complement U.S. Patent No. 7,109,198. Both the recently allowed application (believed to be U.S. Application No. 10/830,071) and the '198 patent, the latter of which OREXIGEN has exclusively licensed from Duke University, will expire in 2023.
OREXIGEN President and CEO, Dr. Gary Tollefson, stated that "[t]his notice from the USPTO is an important milestone toward issuance of the patent and would give us an additional layer of protection for our use of zonisamide in treating obesity." Dr. Tollefson believes that the allowed application will discourage competitors from copying OREXIGEN's approach for treating obesity with zonisamide-based compounds.
Zonisamide is one of the active constituents of EMPATIC, a novel formulation of zonisamide and bupropion. Bupropion is a dopamine and norepinephrine re-uptake inhibitor while zonisamide is an approved anticonvulsant medication. The rationale behind EMPATIC is that the combination of zonisamide and bupropion affects two groups of hypothalamic neurons, the POMC and NPY/AgRP neurons, to reduce the feeling of hunger. The POMC neurons release the hormone alpha-MSH while the NPY/AgRP neurons release AgRP. Both alpha-MSH and AgRP competitively bind to the melanocortin MC4 receptors; alpha-MSH binding increases energy expenditure and reduces hunger, while AgRP binding reduces energy expenditure and increases hunger. In addition, monoamines, such as dopamine, norepinephrine, and serotonin, stimulate the neurons increasing alpha-MSH secretion and reducing AgRP secretion. The novel combination of zonisamide and bupropion exploits the opposing effects of alpha-MSH and AgRP on MC4. Zonisamide increases monoamine secretion which increases alpha-MSH secretion and reduces AgRP secretion, while bupropion increases alpha-MSH secretion by stimulating POMC. The net effect is that alpha-MSH is overproduced and AgRP is reduced, leading to increased energy expenditure and reduced hunger.
Results of clinical studies support OREXIGEN's rationale for weight loss. Studies with EMPATIC have shown that meaningful weight loss is sustainable over long periods. Patients with body mass indices between 30 and 40 lost in excess of 9% of their baseline body weight by week 24. In addition, weight loss continued for another 24 weeks with patients averaging a weight loss of 12% from baseline. The weight loss was dose dependent with the highest dose achieving the greatest weight loss.
OREXIGEN is also pursuing another drug combination, CONTRAVE, which in patient studies has shown weight loss without a plateau after 36 weeks of treatment. CONTRAVE is a combination of bupropion and naltrexone designed to block the natural inhibition of alpha-MSH secretion by ß-endorphin.
Obesity has become a major health problem in the Unites States and around the World. The World Health Organization estimates that there are more than 1 billion overweight adults worldwide, and that at least 300 million of these individuals are clinically obese. In the United States, data from two National Health and Nutrition Examination Surveys show that among adults aged 20-74 years, the prevalence of obesity increased from 15.0% (in the 1976-1980 survey) to 32.9% (in the 2003-2004 survey). But obesity also increases the risk of many serious diseases, such as hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea, respiratory problems, and even cancer. So therapies such as EMPATIC and CONTRAVE represent important advances in the fight against obesity.
Among the allowed claims of the '071 application are independent claims 18, 35, 44, and 53:
18. A method of reducing the weight of an overweight subject, said method comprising: identifying an overweight subject and administering to said overweight subject a pharmaceutical composition comprising zonisamide, or a pharmaceutically acceptable salt thereof, in an amount effective to reduce the weight of said subject.
35. A method of reducing weight in an overweight subject, said method comprising: identifying an overweight subject and administering to said overweight subject a pharmaceutical composition comprising zonisamide, or a pharmaceutically acceptable salt thereof, in an amount effective to induce weight loss in said subject, wherein the weight loss
is ≥ 5%, or wherein said weight loss continues during the period of administration of said composition comprising zonisamide or a pharmaceutically acceptable salt thereof.
44. A method of treating obesity by reducing the weight of an obese subject, said method comprising: identifying an obese subject and administering to said obese subject an effective amount of a pharmaceutical composition comprising zonisamide, or a pharmaceutically acceptable salt thereof.
53. A method of treating obesity by reducing the weight of an obese subject, said method comprising: identifying an obese subject and orally administering to said obese subject a capsule comprising a pharmaceutical composition comprising zonisamide or a pharmaceutically acceptable salt thereof, wherein said subject receives a daily dose of 100 to 600 mg of zonisamide.
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