Compositions and methods for reducing major adverse cardiovascular events
Inventors
Klassen, Preston • Taylor, Kristin
Assignees
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Publication Number
US-10835527-B2
Publication Date
2020-11-17
Expiration Date
Abstract
The present application relates to compositions, kits, uses, systems and methods of using naltrexone and bupropion, or pharmaceutically acceptable salts thereof, for reducing the risk of adverse cardiovascular outcomes or events, including Major Adverse Cardiovascular Events (MACE) in subjects, preferably those at increased risk of adverse cardiovascular outcomes or MACE, that may be overweight or obese. The present application also relates to compositions, kits, uses, systems and methods of using naltrexone and bupropion or pharmaceutically acceptable salts thereof for treatment of overweight or obesity in subjects, preferably at increased risk of adverse cardiovascular outcomes or MACE, wherein the treatment reduces the risk of MACE.
Core Innovation
The described invention provides a method of treating overweight or obesity in a subject having an increased risk of adverse cardiovascular outcomes. The method comprises administering a daily dose of naltrexone (4–50 mg) or a pharmaceutically acceptable salt thereof together with bupropion (50–400 mg) or a pharmaceutically acceptable salt thereof for a period of at least 12 weeks.
The document frames a problem in which subjects with overweight or obesity also have increased risk for adverse cardiovascular outcomes, including cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The described method targets that combined need by using naltrexone together with bupropion administered as daily doses over extended periods.
As described in the provided content, the invention contemplates subject-selection features that characterize increased cardiovascular risk, including histories of cardiovascular conditions and specific test results. It also encompasses formulations such as sustained release naltrexone and sustained release bupropion, and it includes contemplated cardiovascular efficacy outcomes expressed using expanded MACE and hazard ratio (HR).
Claims Coverage
The document contains one independent method claim for treating overweight or obesity in an increased cardiovascular risk population. The dependent claims refine the independent claim by adding cardiovascular-risk criteria, tightening treatment duration, specifying sustained release formulations, and narrowing the definition of adverse cardiovascular outcome events, yielding multiple inventive features across dependent claim families.
Treating overweight or obesity with naltrexone and bupropion for at least 12 weeks
A method of treating overweight or obesity in a subject having an increased risk of adverse cardiovascular outcomes by administering a daily dose of 4–50 mg naltrexone (or a pharmaceutically acceptable salt thereof) and 50–400 mg bupropion (or a pharmaceutically acceptable salt thereof) for a period of at least 12 weeks.
Cardiovascular risk selection using specified cardiovascular histories and tests
The method wherein the subject has one or more specified cardiovascular conditions or test results, including a history of documented myocardial infarction, history of coronary revascularization, history of carotid revascularization, history of peripheral revascularization, angina with ischemic changes, ECG changes, a graded exercise test, a positive cardiac imaging study, an ankle brachial index below 0.9, or greater than 50% arterial stenosis within 2 years prior to treatment.
Four-week escalation followed by continued daily dosing
A method in which escalating daily doses of naltrexone (or a pharmaceutically acceptable salt thereof) and bupropion (or a pharmaceutically acceptable salt thereof) are administered over four weeks, with specified mg amounts for weeks 1–4 and the same amounts continued for any subsequent weeks.
Extended treatment duration of at least 20 weeks
The method wherein the period of treatment is at least 20 weeks.
Using sustained release naltrexone and sustained release bupropion
The method wherein sustained release naltrexone (or a pharmaceutically acceptable salt thereof) and sustained release bupropion (or a pharmaceutically acceptable salt thereof) are administered to decrease the subject’s risk of a major adverse cardiovascular outcome.
Major adverse cardiovascular outcome limited to defined event types
The method wherein the adverse cardiovascular outcome is selected from cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.
Overall claim coverage centers on daily combination administration of naltrexone and bupropion for overweight or obesity in subjects with increased risk of adverse cardiovascular outcomes, with further narrowing through cardiovascular-risk selection criteria, optional sustained release formulations, longer treatment duration, and a defined set of adverse cardiovascular outcome event types.
Stated Advantages
Reduce risk of major adverse cardiovascular outcomes in overweight or obese subjects with increased cardiovascular risk.
Fewer first MACE events with naltrexone/bupropion versus placebo, as reported by interim results.
Reductions observed in cardiovascular death and other secondary endpoints (as reported in the provided interim results).
Documented Applications
Treatment of overweight or obesity in subjects having increased risk of adverse cardiovascular outcomes, including use in overweight/obese high-risk patients described by the interim double-blind randomized placebo-controlled cardiovascular outcomes study.
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