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US20150297610A1 - Method of weight management - Google Patents

Method of weight management Download PDF

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Publication number
US20150297610A1
US20150297610A1 US14/002,235 US201214002235A US2015297610A1 US 20150297610 A1 US20150297610 A1 US 20150297610A1 US 201214002235 A US201214002235 A US 201214002235A US 2015297610 A1 US2015297610 A1 US 2015297610A1
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individual
tetrahydro
chloro
benzazepine
methyl
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Matilde Sanchez
William R. Shanahan
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Arena Pharmaceuticals Inc
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Arena Pharmaceuticals Inc
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Assigned to ARENA PHARMACEUTICALS, INC. reassignment ARENA PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SANCHEZ, Matilde, SHANAHAN, WILLIAM R.
Assigned to ARENA PHARMACEUTICALS, INC. reassignment ARENA PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SANCHEZ, Matilde, SHANAHAN, WILLIAM R.
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    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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    • A—HUMAN NECESSITIES
    • A63—SPORTS; GAMES; AMUSEMENTS
    • A63B—APPARATUS FOR PHYSICAL TRAINING, GYMNASTICS, SWIMMING, CLIMBING, OR FENCING; BALL GAMES; TRAINING EQUIPMENT
    • A63B24/00—Electric or electronic controls for exercising apparatus of preceding groups; Controlling or monitoring of exercises, sportive games, training or athletic performances
    • A63B24/0075—Means for generating exercise programs or schemes, e.g. computerized virtual trainer, e.g. using expert databases
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • G—PHYSICS
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    • G09B—EDUCATIONAL OR DEMONSTRATION APPLIANCES; APPLIANCES FOR TEACHING, OR COMMUNICATING WITH, THE BLIND, DEAF OR MUTE; MODELS; PLANETARIA; GLOBES; MAPS; DIAGRAMS
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Definitions

  • Obesity is a life-threatening disorder in which there is an increased risk of morbidity and mortality arising from concomitant diseases such as type II diabetes, hypertension, stroke, cancer and gallbladder disease.
  • Obesity is now a major healthcare issue in the Western World and increasingly in some third world countries.
  • the increase in numbers of obese people is due largely to the increasing preference for high fat content foods but also the decrease in activity in most people's lives.
  • Currently about 30% of the population of the USA is now considered obese.
  • BMI body mass index
  • BMT body mass that is muscle in relation to fat (adipose tissue).
  • obesity can also be defined on the basis of body fat content: greater than 25% in males and greater than 30% in females.
  • Kidney disease also called nephropathy
  • Diabetes occurs when the kidney's “filter mechanism” is damaged and protein leaks into urine in excessive amounts and eventually the kidney fails. Diabetes is also a leading cause of damage to the retina at the back of the eye and increases risk of cataracts and glaucoma.
  • diabetes is associated with nerve damage, especially in the legs and feet, which interferes with the ability to sense pain and contributes to serious infections. Taken together, diabetes complications are one of the nation's leading causes of death.
  • the first line of treatment is to offer diet and life style advice to patients such as reducing the fat content of their diet and increasing their physical activity.
  • patients find this difficult and need additional help from drug therapy to maintain results from these efforts.
  • Orlistat a drug that prevents absorption of fat by the inhibition of pancreatic lipase
  • Sibutramine ReductilTM
  • XenicalTM a drug that prevents absorption of fat by the inhibition of pancreatic lipase
  • Sibutramine ReductilTM
  • side effects associated with these products may limit their long-term utility.
  • Treatment with XenicalTM is reported to induce gastrointestinal distress in some patients, while Sibutramine has been associated with raised blood pressure in some patients.
  • Serotonin (5-HT) neurotransmission plays an important role in numerous physiological processes both in physical and in psychiatric disorders.
  • 5-HT has been implicated in the regulation of feeding behavior. 5-HT is believed to work by inducing a feeling of satiety, such that a subject with enhanced 5-HT stops eating earlier and fewer calories are consumed. It has been shown that a stimulatory action of 5-HT on the 5-HT 2C receptor plays an important role in the control of eating and in the anti-obesity effect of d-fenfluramine. As the 5-HT 2C receptor is expressed in high density in the brain (notably in the limbic structures, extrapyramidal pathways, thalamus and hypothalamus i.e.
  • a selective 5-HT 2C receptor agonist can be a more effective and safe anti-obesity agent. Also, 5-HT 2C knockout mice are overweight with cognitive impairment and susceptibility to seizure.
  • the 5-HT 2C receptor may play a role in obsessive compulsive disorder, some forms of depression, and epilepsy. Accordingly, agonists can have anti-panic properties, and properties useful for the treatment of sexual dysfunction.
  • the 5-HT 2C receptor is a receptor target for the treatment of obesity and psychiatric disorders, and it can be seen that there is a need for selective 5-HT 2C agonists which safely decrease food intake and body weight.
  • Compounds and formulations presented herein can comprise the selective 5-HT 2C -receptor agonist (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 1), and are useful for, inter alia, weight management, including weight loss and the maintenance of weight loss.
  • Compound 1 is disclosed in PCT patent publication WO2003/086303, which is incorporated herein by reference in its entirety.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (lorcaserin hydrochloride) is an agonist of the 5-HT 2C receptor and shows effectiveness at reducing obesity in animal models and humans.
  • Arena Pharmaceuticals submitted a New Drug Application, or NDA, for lorcaserin to the FDA.
  • the NDA submission is based on an extensive data package from lorcaserin's clinical development program that includes 18 clinical trials totaling 8,576 patients.
  • the pivotal phase 3 clinical trial program evaluated nearly 7,200 patients treated for up to two years, and showed that lorcaserin consistently produced significant weight loss with excellent tolerability. About two-thirds of patients achieved at least 5% weight loss and over one-third achieved at least 10% weight loss.
  • the individual is a responder if the individual has achieved a threshold effect after said first time period of administration.
  • composition for use in a method of weight management in an individual comprising
  • kits for use in a method of weight management in an individual comprising
  • FIG. 1 provides data for the percentage of patients achieving ⁇ 5% weight loss or ⁇ 10% weight at 52 weeks for both responders and non-responders.
  • the top panel is for patients with type 2 diabetes mellitus.
  • the bottom panel is for patients without type 2 diabetes mellitus.
  • FIG. 2 shows the Week 52 weight loss in lorcaserin Week 12 responders with type 2 diabetes was 9.3 kg (20 lbs), with 71% and 36% achieving 5% and 10% weight loss, respectively.
  • FIG. 2 shows weight loss through Week 52 for Week 12 responders and non-responder with and without diabetes.
  • an “individual” is a human. An individual can be an adult or prepubertal (a child) and can be of any gender. The individual can be a patient or other individual seeking treatment. The methods disclosed herein can also apply to non-human mammals such as livestock or pets.
  • PLURALITY OF INDIVIDUALS As used herein, a “plurality of individuals” means more than one individual.
  • ADMINISTERING means to provide a compound or other therapy, remedy or treatment.
  • a health care practitioner can directly provide a compound to an individual in the form of a sample, or can indirectly provide a compound to an individual by providing an oral or written prescription for the compound.
  • an individual can obtain a compound by themselves without the involvement of a health care practitioner.
  • Administration of the compound may or may not involve the individual actually internalizing the compound. In the case where an individual internalizes the compound the body is transformed by the compound in some way.
  • PRESCRIBING means to order, authorize or recommend the use of a drug or other therapy, remedy or treatment.
  • a health care practitioner can orally advise, recommend or authorize the use of a compound, dosage regimen or other treatment to an individual.
  • the health care practitioner may or may not provide a prescription for the compound, dosage regimen or treatment.
  • the health care practitioner may or may not provide the recommended compound or treatment.
  • the health care practitioner can advise the individual where to obtain the compound without providing the compound.
  • a health care practitioner can provide a prescription for the compound, dosage regimen or treatment to the individual.
  • a health care practitioner can give a written or oral prescription to an individual.
  • a prescription can be written on paper or on electronic media such as a computer file, for example, on a hand held computer device.
  • a health care practitioner can transform a piece of paper or electronic media with a prescription for a compound, dosage regimen or treatment.
  • a prescription can be called in (oral) or faxed in (written) to a pharmacy or a dispensary.
  • a sample of the compound or treatment can be given to the individual.
  • giving a sample of a compound constitutes an implicit prescription for the compound.
  • Different health care systems around the world use different methods for prescribing and administering compounds or treatments and these methods are encompassed by the disclosure.
  • a prescription can include, for example, an individual's name and/or identifying information such as date of birth.
  • a prescription can include, the medication name, medication strength, dose, frequency of administration, route of administration, number or amount to be dispensed, number of refills, physician name, physician signature.
  • a prescription can include a DEA number or state number.
  • a healthcare practitioner can include, for example, a physician, nurse, nurse practitioner or other related health care professional who can prescribe or administer compounds (drugs) for weight management.
  • a healthcare practitioner can include anyone who can recommend, prescribe, administer or prevent an individual from receiving a compound or drug including, for example, an insurance provider.
  • the term “prevent,” “preventing” or “prevention” such as prevention of obesity means prevention of the occurrence or onset of one or more symptoms associated with a particular disorder and does not necessarily mean the complete prevention of a disorder.
  • the term “prevent,” “preventing” and “prevention” refers to the administration of therapy on a prophylactic or preventative basis to an individual who may ultimately manifest at least one symptom of a disease or condition but who has not yet done so. Such individuals can be identified on the basis of risk factors that are known to correlate with the subsequent occurrence of the disease. Alternatively, prevention therapy can be administered without prior identification of a risk factor, as a prophylactic measure. Delaying the onset of the at least one symptom can also be considered prevention or prophylaxis.
  • TREAT, TREATING, OR TREATMENT refers to the administration of therapy to an individual who already manifests at least one symptom of a disease or condition or who has previously manifested at least one symptom of a disease or condition.
  • “treating” can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylacticly and/or therapeutically.
  • treating a disorder means a reduction in severity of one or more symptoms associated with a particular disorder. Therefore, treating a disorder does not necessarily mean a reduction in severity of all symptoms associated with a disorder and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with a disorder.
  • a method for treatment of obesity can result in weight loss; however, the weight loss does not need to be enough such that the individual is no longer obese. It has been shown that even modest decreases in weight or related parameters such as BMI, waist circumference and percent body fat, can result in improvement of health, for example, lower blood pressure, improved blood lipid profiles, or a reduction in sleep apnea.
  • weight management means controlling body weight and in the context of the present disclosure is directed toward weight loss and the maintenance of weight loss (also called weight maintenance herein).
  • weight management includes controlling parameters related to body weight, for example, BMI, percent body fat and waist circumference.
  • BMI body weight
  • weight management for an individual who is overweight or obese can mean losing weight with the goal of keeping weight in a healthier range.
  • weight management for an individual who is overweight or obese can include losing body fat or circumference around the waist with or without the loss of body weight.
  • Maintenance of weight loss includes preventing, reducing or controlling weight gain after weight loss. It is well known that weight gain often occurs after weight loss.
  • Weight loss can occur, for example, from dieting, exercising, illness, drug treatment, surgery or any combination of these methods, but often an individual that has lost weight will regain some or all of the lost weight. Therefore, weight maintenance in an individual who has lost weight can include preventing weight gain after weight loss, reducing the amount of weigh gained after weight loss, controlling weight gain after weight loss or slowing the rate of weight gain after weight loss.
  • weight management in an individual in need thereof refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from weight management treatment. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner's expertise, but that includes the knowledge that the individual has a condition that is treatable by the methods disclosed herein.
  • DECREASING FOOD INTAKE As used herein, “decreasing food intake in an individual in need thereof” refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from decreasing food intake. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner's expertise, but that includes the knowledge that the individual has a condition, for example, obesity, that is treatable by the methods disclosed herein.
  • an individual in need of decreasing food intake is an individual who is overweight.
  • an individual in need of decreasing food intake is an individual who is obese.
  • SATIETY As used herein, “satiety” is the quality or state of being fed or gratified to or beyond capacity. Satiety is a feeling that an individual has and so it is often determined by asking the individual, orally or in writing, if they feel full, sated, or satisfied at timed intervals during a meal. For example, an individual who feels sated may report feeling full, feeling a decreased or absent hunger, feeling a decreased or absent desire to eat, or feeling a lack of drive to eat. While fullness is a physical sensation, satiety is a mental feeling. An individual who feels full, sated or satisfied is more likely to stop eating and therefore inducing satiety can result in a decrease in food intake in an individual.
  • inducing satiety in an individual in need thereof refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from inducing satiety. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner's expertise, but that includes the knowledge that the individual has a condition, for example, obesity, that is treatable by the methods of the disclosure.
  • treatment of obesity in an individual in need thereof refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from treatment of obesity. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner's expertise, but that includes the knowledge that the individual has a condition that is treatable by the methods of the disclosure.
  • a body weight a body mass index (BMI)
  • BMI body mass index
  • waist circumference or a body fat percentage of the individual to determine if the individual meets a body weight threshold
  • a BMI threshold a waist circumference threshold or a body fat percentage threshold.
  • prevention of obesity in an individual in need thereof refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from prevention of obesity. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner's expertise, but that includes the knowledge that the individual has a condition that is treatable by the methods disclosed herein.
  • an individual in need of prevention of obesity is an individual who is overweight (also called pre-obese).
  • an individual in need of prevention of obesity is an individual who has a family history of obesity.
  • a body weight a body mass index (BMI)
  • BMI body mass index
  • waist circumference a body fat percentage of the individual to determine if the individual meets a body weight threshold
  • BMI threshold a waist circumference threshold or a body fat percentage threshold.
  • ADVERSE EVENT OR TOXIC EVENT is any untoward medical occurrence that may present itself during treatment.
  • Adverse events associated with treatment with Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof include, for example, abdominal pain, diarrhea, dyspepsia, stomach discomfort, and worsening renal impairment, dizziness, headache.
  • Other possible adverse effects based on observations from studies in monkeys include emesis, decreased food intake, weight loss, decreased activity, spontaneous penile erection, tremors or seizures. Additional possible adverse effects include, for example, nausea, blurred vision, paresthesias, dry mouth and fatigue.
  • the term adverse event can be replaced by other more general terms such as toxicity.
  • the term “reducing the risk” of an adverse event means reducing the probability that an adverse event or toxic event could occur.
  • phentermine refers to 1,1-dimethyl-2-phenyl-ethylamine, including phentermine derivatives and pharmaceutically acceptable salts thereof, such as, but not limited to, chlorphentermine (2-(4-chloro-phenyl)-1,1-dimethyl-ethylamine) and the like.
  • phentermine is in the HCl salt form of 1,1-dimethyl-2-phenyl-ethylamine.
  • the term “greater than” is used interchangeably with the symbol > and the term less than is used interchangeably with the symbol ⁇ . Likewise the term less than or equal to is interchangeably with the symbol ⁇ .
  • the term “about” can be inserted before the integer.
  • the term “greater than 29 kg/m 2 ” can be substituted with “greater than about 29 kg/m 2 ”.
  • composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.
  • a method that recites prescribing or administering (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine can be separated into two methods; one reciting prescribing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and the other reciting administering (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
  • a method that recites prescribing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and a separate method of the invention reciting administering (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine can be combined into a single method reciting prescribing and/or administering (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
  • the individual is a responder if the individual has achieved a threshold effect after said first time period of administration.
  • the individual is a responder if the individual has achieved a threshold effect after said first time period of administration.
  • an individual in need of weight management is an individual who is overweight. In some embodiments, an individual in need of weight management is an individual who has excess visceral adiposity. In some embodiments, an individual in need of weight management is an individual who is obese. To determine whether an individual is overweight or obese one can determine a body weight, a body mass index (BMI), a waist circumference or a body fat percentage of the individual to determine if the individual meets a body weight threshold, a BMI threshold, a waist circumference threshold or a body fat percentage threshold.
  • BMI body mass index
  • Determination of body weight can be through the use of a visual estimation of body weight, the use of a weight measuring device, such as an electronic weight scale or a mechanical beam scale.
  • a weight measuring device such as an electronic weight scale or a mechanical beam scale.
  • an individual in need of weight management is an adult male with a body weight greater than about 90 kg, greater than about 100 kg, or greater than about 110 kg.
  • an individual in need of weight management is an adult female with a body weight greater than about 80 kg, greater than about 90 kg, or greater than about 100 kg.
  • the individual is prepubertal and has a body weight greater than about 30 kg, greater than about 40 kg, or greater than about 50 kg.
  • the healthy range of BMI, and other measures of whether one is overweight or obese, can also be dependent on genetic or racial differences. For example, since Asian populations develop negative health consequences at a lower BMI than Caucasians, some countries have redefined obesity for their populations. For example, in Japan any BMI greater than 25 is defined as obese and in China any BMI greater than 28 is defined as obese. Similarly, different threshold values for body weight, waist circumference or body fat percentage can be used for different populations of individuals. The WHO recommends that countries should use all categories for reporting purposes with a view to facilitating international comparisons.
  • Determination of BMI can be through the use of a visual estimation of BMI, the use of a height measuring device such as a stadiometer or a height rod and the use of a weight measuring device, such as an electronic weight scale or a mechanical beam scale.
  • the individual in need of weight management is an adult with a BMI of greater than about 25 kg/m 2 , greater than about 26 kg/m 2 , greater than about 27 kg/m 2 , greater than about 28 kg/m 2 , greater than about 29 kg/m 2 , greater than about 30 kg/m 2 , greater than about 31 kg/m 2 , greater than about 32 d kg/m 2 , greater than about 33 kg/m 2 , greater than about 34 kg/m 2 , greater than about 35 kg/m 2 , greater than about 36 kg/m 2 , greater than about 37 kg/m 2 , greater than about 38 kg/m 2 , greater than about 39 kg/m 2 , or greater than about 40 kg/m 2 .
  • the individual is prepubertal with a BMI of greater than about 20 kg/m 2 , greater than about 21 kg/m 2 , greater than about 22 kg/m 2 , greater than about 23 kg/m 2 , greater than about 24 kg/m 2 , greater than about 25 kg/m 2 , greater than about 26 kg/m 2 , greater than about 27 kg/m 2 , greater than about 28 kg/m 2 , greater than about 29 kg/m 2 , greater than about 30 kg/m 2 , greater than about 31 kg/m 2 , greater than about 32 kg/m 2 , greater than about 33 kg/m 2 , greater than about 34 kg/m 2 , or greater than about 35 kg/m 2 .
  • Determination of waist circumference can be through the use of a visual estimation of waist circumference or the use of a waist circumference measuring device such as a tape measure.
  • Determinations of the healthy range of waist circumference and percentage body fat in an individual are dependent on gender. For example, women typically have smaller waist circumferences than men and so the waist circumference threshold for being overweight or obese is lower for a woman. In addition, women typically have a greater percentage of body fat than men and so the percentage body fat threshold for being overweight or obese for a woman is higher than for a man. Further, the healthy range of BMI and other measures of whether one is overweight or obese can be dependent on age. For example, the body weight threshold for considering whether one is overweight or obese is lower for a child (prepubertal individual) than for an adult.
  • the individual in need of weight management is an adult male with a waist circumference of greater than about 100 cm, greater than about 110 cm, or greater than about 120 cm, or an adult female with a waist circumference of greater than about 80 cm, greater than about 90 cm, or greater than about 100 cm.
  • the individual is prepubertal with a waist circumference of about of greater than about 60 cm, greater than about 70 cm, or greater than about 80 cm.
  • Determination of body fat percentage can be through the use of a visual estimation of body fat percentage or the use of a body fat percentage measuring device such as bioelectric impedance, computed tomography, magnetic resonance imaging, near infrared interactance, dual energy X ray absorptiometry, use of ultrasonic waves, use of body average density measurement, use of skinfold methods, or use of height and circumference methods.
  • the individual in need of weight management is an adult male with a body fat percentage of greater than about 25%, greater than about 30%, or greater than about 35%, or an adult female with a body fat percentage of greater than about 30%, greater than about 35%, or greater than about 40%.
  • the individual is prepubertal with a body fat percentage of greater than about 30%, greater than about 35%, or greater than about 40%.
  • the individual has an initial body mass index ⁇ 25 kg/m 2 .
  • the individual has an initial body mass index ⁇ 25 kg/m 2 and at least one weight related comorbid condition.
  • the weight related comorbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance and sleep apnea.
  • the weight related comorbid condition is selected from: hypertension, dyslipidemia, and type 2 diabetes.
  • the individual has an initial body mass index ⁇ 27 kg/m 2 . In some embodiments, the individual has an initial body mass index ⁇ 27 kg/m 2 and at least one weight related comorbid condition. In some embodiments, the weight related comorbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance and sleep apnea. In some embodiments, the weight related comorbid condition is selected from: hypertension, dyslipidemia, and type 2 diabetes.
  • the individual has type 2 diabetes.
  • the individual has impaired fasting glucose. In some embodiments, the individual has a fasting glucose of less than about 100 mg/dL. In some embodiments, the individual has a fasting glucose of less than about 70 mg/dL. In some embodiments, the individual has a fasting glucose of less than about 65 mg/dL. In some embodiments, the individual has a fasting glucose of less than about 50 mg/dL.
  • the individual has an initial body mass index ⁇ 30 kg/m 2 . In some embodiments, the individual has an initial body mass index ⁇ 30 kg/m 2 and at least one weight related comorbid condition. In some embodiments, the weight related comorbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance and sleep apnea. In some embodiments, the weight related comorbid condition is selected from: hypertension, dyslipidemia, and type 2 diabetes.
  • the first time period of administration is from about 2 weeks to about 6 months. In some embodiments, the first time period of administration is from about 4 weeks to about 4 months. In some embodiments, the first time period of administration is about 12 weeks.
  • the threshold effect comprises a decrease in an assessment of weight.
  • a decrease in an assessment of weight comprises weight loss of at least about 1%.
  • a decrease in an assessment of weight comprises weight loss of at least about 1% and said first time period of administration is about 2 weeks. In some embodiments, a decrease in an assessment of weight comprises weight loss of at least about 1.5% and said first time period of administration is about 2 weeks.
  • a decrease in an assessment of weight comprises weight loss of at least about 2%.
  • a decrease in an assessment of weight comprises weight loss of at least about 2% and said first time period of administration is about 4 weeks. In some embodiments, a decrease in an assessment of weight comprises weight loss of at least about 2.5% and said first time period of administration is about 4 weeks.
  • a decrease in an assessment of weight comprises weight loss of at least about 3%.
  • a decrease in an assessment of weight comprises weight loss of at least about 3% and said first time period of administration is about 8 weeks. In some embodiments, a decrease in an assessment of weight comprises weight loss of at least about 3.5% and said first time period of administration is about 8 weeks. In some embodiments, a decrease in an assessment of weight comprises weight loss of at least about 3.9% and said first time period of administration is about 8 weeks.
  • a decrease in an assessment of weight comprises weight loss of at least about 4%.
  • a decrease in an assessment of weight comprises weight loss of at least about 4% and said first time period of administration is about 12 weeks. In some embodiments, a decrease in an assessment of weight comprises weight loss of at least about 4.5% and said first time period of administration is about 12 weeks. In some embodiments, a decrease in an assessment of weight comprises weight loss of at least about 4.6% and said first time period of administration is about 12 weeks.
  • a decrease in an assessment of weight comprises weight loss of at least about 5%.
  • a decrease in an assessment of weight comprises weight loss of at least about 5% and said first time period of administration is about 12 weeks.
  • a decrease in an assessment of weight comprises weight loss of at least about 6%.
  • a decrease in an assessment of weight comprises weight loss of at least about 6% and said first time period of administration is about 12 weeks. In some embodiments, a decrease in an assessment of weight comprises weight loss of at least about 6% and said first time period of administration is about 24 weeks. In some embodiments, a decrease in an assessment of weight comprises weight loss of at least about 6.1% and said first time period of administration is about 24 weeks. In some embodiments, a decrease in an assessment of weight comprises weight loss of at least about 5.9% and said first time period of administration is about 24 weeks.
  • a decrease in an assessment of weight comprises weight loss of at least about 9%.
  • a decrease in an assessment of weight comprises weight loss of at least about 8.5% and said first time period of administration is about 24 weeks. In some embodiments, a decrease in an assessment of weight comprises weight loss of at least about 9% and said first time period of administration is about 24 weeks.
  • a decrease in an assessment of weight comprises a decrease in BMI.
  • a decrease in an assessment of weight comprises a decrease in percent body fat.
  • a decrease in an assessment of weight comprises a decrease in waist circumference.
  • achievement of a threshold effect after the first time period of administration correlates with a likelihood of the individual achieving one or more additional beneficial effects after a second time period of administration.
  • the second time period of administration is about one year.
  • the one or more additional beneficial effects comprises an additional decrease in an assessment of weight.
  • the one or more additional beneficial effects are chosen from a decrease in an assessment of weight, an improvement in cardiovascular indications and/or an improved glycemia.
  • the one or more additional beneficial effects comprise a decrease in an assessment of weight.
  • the decrease in an assessment of weight comprises weight loss.
  • the weight loss in an individual without type 2 diabetes is between about 10 and 12 kg. In some embodiments, the weight loss in an individual without type 2 diabetes is about 10 kg. In some embodiments, the weight loss in an individual without type 2 diabetes is about 10.5 kg.
  • the weight loss in an individual with type 2 diabetes is at least about 5 kg. In some embodiments, the weight loss in an individual with type 2 diabetes is between about 5 and 10 kg. In some embodiments, the weight loss in an individual with type 2 diabetes is about 9 kg.
  • the weight loss in an individual with baseline impaired fasting glucose is at least about 5 kg. In some embodiments, the weight loss in an individual with baseline impaired fasting glucose is at least about 10 kg. In some embodiments, the weight loss in an individual with baseline impaired fasting glucose is between about 10 and 15 kg. In some embodiments, the weight loss in an individual with baseline impaired fasting glucose is about 11 kg.
  • the decrease in an assessment of weight comprises a decrease in hunger, a decrease in food cravings, or an increase in intermeal interval.
  • the one or more additional beneficial effects comprise an improvement in one or more cardiovascular indications.
  • the improvement in one or more cardiovascular indications comprises one or more of a reduction in systolic and diastolic blood pressure (SBP and DBP, respectively), a decrease in heart rate, a decrease in total cholesterol, a decrease in LDL cholesterol, a decrease in HDL cholesterol, and/or a decrease in triglyceride levels.
  • the one or more additional beneficial effects comprise a reduction in SBP.
  • the reduction in SBP in an individual without type 2 diabetes is at least about 2 mmHg. In some embodiments, the reduction in SBP in an individual without type 2 diabetes is between 2 and 5 mmHg. In some embodiments, the reduction in SBP in an individual without type 2 diabetes is about 3 mmHg. In some embodiments, the reduction in SBP in an individual without type 2 diabetes is about 3.5 mmHg.
  • the reduction in SBP in an individual with type 2 diabetes is at least about 2 mmHg. In some embodiments, the reduction in SBP in an individual with type 2 diabetes is between about 2 and 5 mmHg. In some embodiments, the reduction in SBP in an individual with type 2 diabetes is about 2.5 mmHg. In some embodiments, the reduction in SBP in an individual with type 2 diabetes is about 3 mmHg.
  • the reduction in SBP in an individual with baseline impaired fasting glucose is at least about 1 mmHg. In some embodiments, the reduction in SBP in an individual with baseline impaired fasting glucose is between about 1 and 5 mmHg. In some embodiments, the reduction in SBP in an individual with baseline impaired fasting glucose is about 1.5 mmHg. In some embodiments, the reduction in SBP in an individual with baseline impaired fasting glucose is about 2 mmHg.
  • the one or more additional beneficial effects comprise a reduction in DBP.
  • the reduction in DBP in an individual without type 2 diabetes is at least about 1 mmHg. In some embodiments, the reduction in DBP in an individual without type 2 diabetes is at least between about 1 and 5 mmHg. In some embodiments, the reduction in DBP in an individual without type 2 diabetes is about 2 mmHg. In some embodiments, the reduction in DBP in an individual without type 2 diabetes is about 2.5 mmHg. In some embodiments, the reduction in DBP in an individual without type 2 diabetes is about 3 mmHg.
  • the reduction in DBP in an individual with type 2 diabetes is at least about 1 mmHg. In some embodiments, the reduction in DBP in an individual with type 2 diabetes is between about 1 and 5 mmHg. In some embodiments, the reduction in DBP in an individual with type 2 diabetes is about 1.5 mmHg. In some embodiments, the reduction in DBP in an individual with type 2 diabetes is about 2 mmHg.
  • the reduction in DBP in an individual with baseline impaired fasting glucose is at least about 1 mmHg. In some embodiments, the reduction in DBP in an individual with baseline impaired fasting glucose is between about 1 and 5 mmHg. In some embodiments, the reduction in DBP in an individual with baseline impaired fasting glucose is about 1.5 mmHg. In some embodiments, the reduction in DBP in an individual with baseline impaired fasting glucose is about 2 mmHg.
  • the one or more additional beneficial effects comprise a reduction in heart rate.
  • the reduction in heart rate in an individual without type 2 diabetes is at least about 2 BPM. In some embodiments, the reduction in heart rate in an individual without type 2 diabetes is between about 2 and 5 BPM. In some embodiments, the reduction in heart rate in an individual without type 2 diabetes is about 2 BPM. In some embodiments, the reduction in heart rate in an individual without type 2 diabetes is about 2.5 BPM. In some embodiments, the reduction in heart rate in an individual without type 2 diabetes is about 3 BPM.
  • the reduction in heart rate in an individual with type 2 diabetes is at least about 2 BPM. In some embodiments, the reduction in heart rate in an individual with type 2 diabetes is between about 2 and 5 BPM. In some embodiments, the reduction in heart rate in an individual with type 2 diabetes is about 3 BPM. In some embodiments, the reduction in heart rate in an individual with type 2 diabetes is about 3.5 BPM.
  • the reduction in heart rate in an individual with baseline impaired fasting glucose is at least about 2 BPM. In some embodiments, the reduction in heart rate in an individual with baseline impaired fasting glucose is between about 2 and 5 BPM. In some embodiments, the reduction in heart rate in an individual with baseline impaired fasting glucose is about 3.5 BPM. In some embodiments, the reduction in heart rate in an individual with baseline impaired fasting glucose is about 4 BPM.
  • the improvement in glycemia comprises a decrease in total cholesterol level.
  • the decrease in total cholesterol level in patients without type 2 diabetes is at least about 1 mg/dL. In some embodiments, the decrease in total cholesterol level in patients without type 2 diabetes is at least about 1.5 mg/dL. In some embodiments, the decrease in total cholesterol level in patients without type 2 diabetes is between about 1.5 and 2 mg/dL. In some embodiments, the decrease in total cholesterol level in patients without type 2 diabetes is about 1.7 mg/dL.
  • the decrease in total cholesterol level in patients with type 2 diabetes is at least about 0.5 mg/dL. In some embodiments, the decrease in total cholesterol level in patients with type 2 diabetes is between about 0.5 and 1 mg/dL. In some embodiments, the decrease in total cholesterol level in patients with type 2 diabetes is about 0.7 mg/dL.
  • the decrease in total cholesterol level in patients with baseline impaired fasting glucose is at least about 2 mg/dL. In some embodiments, the decrease in total cholesterol level in patients with baseline impaired fasting glucose is between about 2 and 3 mg/dL. In some embodiments, the decrease in total cholesterol level in patients with baseline impaired fasting glucose is about 2.3 mg/dL.
  • the improvement in glycemia comprises a decrease in LDL cholesterol level.
  • the decrease in LDL cholesterol level in patients without type 2 diabetes is at least about 1 mg/dL. In some embodiments, the decrease in LDL cholesterol level in patients without type 2 diabetes is between about 1 and 2 mg/dL. In some embodiments, the decrease in LDL cholesterol level in patients without type 2 diabetes is about 1.1 mg/dL.
  • the decrease in LDL cholesterol level in patients with type 2 diabetes is at least about 1 mg/dL. In some embodiments, the decrease in LDL cholesterol level in patients with type 2 diabetes is between about 1 and 1.5 mg/dL. In some embodiments, the decrease in LDL cholesterol level in patients with type 2 diabetes is about 1.4 mg/dL.
  • the decrease in LDL cholesterol level in patients with baseline impaired fasting glucose is at least about 2 mg/dL. In some embodiments, the decrease in LDL cholesterol level in patients with baseline impaired fasting glucose is between about 2 and 3 mg/dL. In some embodiments, the decrease in LDL cholesterol level in patients with baseline impaired fasting glucose is about 2.5 mg/dL.
  • the improvement in glycemia comprises a decrease in HDL cholesterol level.
  • the decrease in HDL cholesterol level in patients without type 2 diabetes is at least about 4 mg/dL. In some embodiments, the decrease in HDL cholesterol level in patients without type 2 diabetes is between about 3 and 6 mg/dL. In some embodiments, the decrease in HDL cholesterol level in patients without type 2 diabetes is about 4.6 mg/dL.
  • the decrease in HDL cholesterol level in patients with type 2 diabetes is at least about 5 mg/dL. In some embodiments, the decrease in HDL cholesterol level in patients with type 2 diabetes is at least about 7 mg/dL. In some embodiments, the decrease in HDL cholesterol level in patients with type 2 diabetes is between about 7 and 10 mg/dL. In some embodiments, the decrease in HDL cholesterol level in patients with type 2 diabetes is about 8.8 mg/dL.
  • the decrease in HDL cholesterol level in patients with baseline impaired fasting glucose is at least about 2 mg/dL. In some embodiments, the decrease in HDL cholesterol level in patients with baseline impaired fasting glucose is between about 2 and 3 mg/dL. In some embodiments, the decrease in HDL cholesterol level in patients with baseline impaired fasting glucose is about 2.1 mg/dL.
  • the one or more additional beneficial effects comprise an improvement in glycemia.
  • the improvement in glycemia comprises a reduction in fasting plasma glucose and/or a reduction in glycated hemoglobin (A1C) levels.
  • the improvement in glycemia comprises a reduction in fasting plasma glucose.
  • the reduction in fasting plasma glucose in patients without type 2 diabetes is at least about 1 mg/dL. In some embodiments, the reduction in fasting plasma glucose in patients without type 2 diabetes is at least about 1.5 mg/dL. In some embodiments, the reduction in fasting plasma glucose in patients without type 2 diabetes is between about 1 and 4 mg/dL. In some embodiments, the reduction in fasting plasma glucose in patients without type 2 diabetes is about 2.2 mg/dL.
  • the reduction in fasting plasma glucose in patients with type 2 diabetes is at least about 10 mg/dL. In some embodiments, the reduction in fasting plasma glucose in patients with type 2 diabetes is between about 10 and 40 mg/dL. In some embodiments, the reduction in fasting plasma glucose in patients with type 2 diabetes is about 25 mg/dL. In some embodiments, the reduction in fasting plasma glucose in patients with type 2 diabetes is about 30 mg/dL.
  • the reduction in fasting plasma glucose in patients with baseline impaired fasting glucose is at least about 5 mg/dL. In some embodiments, the reduction in fasting plasma glucose in patients with baseline impaired fasting glucose is between about 5 and 10 mg/dL. In some embodiments, the reduction in fasting plasma glucose in patients with baseline impaired fasting glucose is about 7 mg/dL. In some embodiments, the reduction in fasting plasma glucose in patients with baseline impaired fasting glucose is about 8 mg/dL.
  • the improvement in glycemia comprises a reduction in glycated hemoglobin (A1C) levels.
  • A1C glycated hemoglobin
  • the reduction in glycated hemoglobin (A1C) level in patients without type 2 diabetes is at least about 0.1%. In some embodiments, the reduction in glycated hemoglobin (A1C) level in patients without type 2 diabetes is between about 0.1 and 0.2%. In some embodiments, the reduction in glycated hemoglobin (A1C) level in patients without type 2 diabetes is about 0.15%. In some embodiments, the reduction in glycated hemoglobin (A1C) level in patients without type 2 diabetes is about 0.18%.
  • the reduction in glycated hemoglobin (A1C) level in patients with type 2 diabetes is at least about 0.5%. In some embodiments, the reduction in glycated hemoglobin (A1C) level in patients with type 2 diabetes is between about 1 and 2%. In some embodiments, the reduction in glycated hemoglobin (A1C) level in patients with type 2 diabetes is about 1.2%.
  • the reduction in glycated hemoglobin (A1C) level in patients with baseline impaired fasting glucose is at least about 0.05%. In some embodiments, the reduction in glycated hemoglobin (A1C) level in patients with baseline impaired fasting glucose is between about 0.05 and 0.2%. In some embodiments, the reduction in glycated hemoglobin level (A1C) in patients with baseline impaired fasting glucose is about 0.1%.
  • the improvement in glycemia comprises a decrease in triglyceride levels.
  • the decrease in triglyceride level in patients without type 2 diabetes is at least about 5 mg/dL. In some embodiments, the decrease in triglyceride level in patients without type 2 diabetes is between about 5 and 20 mg/dL. In some embodiments, the decrease in triglyceride level in patients without type 2 diabetes is about 14 mg/dL. In some embodiments, the decrease in triglyceride level in patients without type 2 diabetes is about 14.5 mg/dL.
  • the decrease in triglyceride level in patients with type 2 diabetes is at least about 10 mg/dL. In some embodiments, the decrease in triglyceride level in patients with type 2 diabetes is between about 10 and 20 mg/dL. In some embodiments, the decrease in triglyceride level in patients with type 2 diabetes is about 17 mg/dL. In some embodiments, the decrease in triglyceride level in patients with type 2 diabetes is about 17.8 mg/dL.
  • the decrease in triglyceride level in patients with baseline impaired fasting glucose is at least about 5 mg/dL. In some embodiments, the decrease in triglyceride level in patients with baseline impaired fasting glucose is between about 5 and 20 mg/dL. In some embodiments, the decrease in triglyceride level in patients with baseline impaired fasting glucose is about 15 mg/dL.
  • the individual is a responder if the individual has achieved a threshold effect after said first time period of administration.
  • a measurement that the individual is a responder or is selected for treatment indicates that the individual is suitable for prescription of a therapeutically effective amount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • a measurement that the individual has achieved a threshold effect after said first time period of administration indicates that the individual is a responder and is suitable for prescription of a therapeutically effective amount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof to an individual.
  • modifying the administration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof comprises increasing the dose and/or frequency of administration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • modifying the administration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof comprises prescribing or administering a weight loss compound or procedure to the individual to be used in combination with the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the weight loss compound is selected from amphetamine, caffeine, bromocriptine, ephedrine, pseudoephedrine, phenylpropanolamine, diethylpropion, benzphetamine, rimonabant, mazindol, surinabant, orlistat, cetilistat, sibutramine, bupropion, citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, milnacipran, mirtazapine, venlafaxine, desvenlafaxine, topiramate, zonisamide, metformin, exenatide, pramlintide, liraglutide, obinepitide, naltrexone, phentermine, phendimetrazine, insulin, dexfenfluramine, fenfluramine, leptin, naltrexone, and pharmaceutically acceptable salts and combinations thereof.
  • amphetamine caffeine
  • modifying the administration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof comprises prescribing or administering to the individual a weight loss compound chosen from cannabinoid CB1 receptor antagonists, lipase inhibitors, monoamine reuptake inhibitors, anticonvulsants, glucose sensitizers, incretin mimetics, amylin analogs, GLP-1 analogs, Y receptor peptides, 5HT2C serotonin receptor agonists, opioid receptor antagonists, appetite suppressants, anorectics, and hormones.
  • a weight loss compound chosen from cannabinoid CB1 receptor antagonists, lipase inhibitors, monoamine reuptake inhibitors, anticonvulsants, glucose sensitizers, incretin mimetics, amylin analogs, GLP-1 analogs, Y receptor peptides, 5HT2C serotonin receptor
  • modifying the administration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof comprises prescribing or administering to the individual a weight loss compound chosen from amphetamine, caffeine, bromocriptine, ephedrine, pseudoephedrine, phenylpropanolamine, diethylpropion, benzphetamine, rimonabant, mazindol, surinabant, orlistat, cetilistat, sibutramine, bupropion, citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, milnacipran, mirtazapine, venlafaxine, desvenlafaxine, topiramate, zonisamide, metformin, exenatide, pramlintide, liraglutide, obinepitide,
  • modifying the administration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof comprises discontinuing the prescribing or administering of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the procedure comprises a surgical weight loss procedure.
  • the methods for weight management further comprise prescribing and/or administering a reduced-calorie diet.
  • the methods for weight management further comprise prescribing and/or administering a program of regular exercise.
  • the methods for weight management further comprise prescribing and/or administering phentermine to the individual.
  • weight management comprises weight loss.
  • weight management comprises maintenance of weight loss.
  • the terms “(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof” and “(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and pharmaceutically acceptable salts, solvates, and hydrates thereof” as used herein encompass any one of the following salts, or a Markush group comprising any combination of the following salts:
  • the terms “(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof” and “(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and pharmaceutically acceptable salts, solvates, and hydrates thereof” as used herein encompass any one of the following salts, or a Markush group comprising any combination of the following salts:
  • the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride or a solvate or hydrate thereof.
  • the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride hemihydrate.
  • the dosage forms described herein may comprise, as the active component, either a compound described herein or a pharmaceutically acceptable salt or as a solvate or hydrate thereof.
  • various hydrates and solvates of the compounds described herein and their salts will find use as intermediates in the manufacture of pharmaceutical compositions. Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned herein, are well known to those in the art; see for example, pages 202-209 of K. J. Guillory, “Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids,” in: Polymorphism in Pharmaceutical Solids, ed. Harry G. England, Vol.
  • one aspect of the present disclosure pertains to methods of administering hydrates and solvates of compounds described herein and/or their pharmaceutical acceptable salts, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (XRPD), Karl Fisher titration, high resolution X-ray diffraction, and the like.
  • TGA thermogravimetric analysis
  • TGA-mass spectroscopy TGA-mass spectroscopy
  • TGA-Infrared spectroscopy powder X-ray diffraction (XRPD)
  • Karl Fisher titration high resolution X-ray diffraction
  • the present disclosure includes all isotopes of atoms occurring in the present salts and crystalline forms thereof.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • One aspect of the present invention includes every combination of one or more atoms in the present salts and crystalline forms thereof that is replaced with an atom having the same atomic number but a different mass number.
  • One such example is the replacement of an atom that is the most naturally abundant isotope, such as 1 H or 12 C, found in one the present salts and crystalline forms thereof, with a different atom that is not the most naturally abundant isotope, such as 2 H or 3 H (replacing 1 H), or 11 C, 13 C, or 14 C (replacing 12 C).
  • isotopically-labeled A salt wherein such a replacement has taken place is commonly referred to as being isotopically-labeled.
  • isotopes of hydrogen include 2 H (deuterium) and 3 H (tritium).
  • isotopes of carbon include 11 C, 13 C, and 14 C.
  • Isotopes of nitrogen include 13 N and 15 N.
  • Isotopes of oxygen include 15 O, 17 O, and 18 C.
  • An isotope of fluorine includes 18 F.
  • An isotope of sulfur includes 35 S.
  • An isotope of chlorine includes 36 Cl.
  • Isotopes of bromine include 75 Br, 76 Br, 77 Br, and 82 Br.
  • Isotopes of iodine include 123 I, 124 I, 125 I, and 131 I.
  • Another aspect of the present invention includes compositions, such as, those prepared during synthesis, preformulation, and the like, and pharmaceutical compositions, such as, those prepared with the intent of using in a mammal for the treatment of one or more of the disorders described herein, comprising one or more of the present salts and crystalline forms thereof, wherein the naturally occurring distribution of the isotopes in the composition is perturbed.
  • compositions and pharmaceutical compositions comprising salts and crystalline forms thereof as described herein wherein the salt is enriched at one or more positions with an isotope other than the most naturally abundant isotope.
  • Methods are readily available to measure such isotope perturbations or enrichments, such as, mass spectrometry, and for isotopes that are radio-isotopes additional methods are available, such as, radio-detectors used in connection with HPLC or GC.
  • composition for use in a method of weight management in an individual comprising:
  • kit for use in a method of weight management in an individual comprising:
  • the kit further comprises phentermine.
  • the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to or less than 20 mg per day.
  • the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to or less than 10 mg twice per day.
  • the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered in a tablet suitable for oral administration.
  • Liquid preparations for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions and syrups.
  • the oral preparations can be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavorings and colorants can be added to the liquid preparations.
  • Parenteral dosage forms can be prepared by dissolving the compound in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms. Suitable pharmaceutically-acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20 th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.)
  • a compound for use in the prophylaxis or treatment, can, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.
  • Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption in an efficient manner with minimal degradation of the drug.
  • transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner.
  • compositions and unit dosage forms thereof can thus be placed into the form of pharmaceutical formulations and unit dosages thereof and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof can comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the pharmaceutical composition can be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.
  • the dose when using the compounds provided herein can vary within wide limits and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed, on whether an acute or chronic disease state is treated or prophylaxis conducted or on whether further active compounds are administered in addition to the compounds provided herein.
  • Representative doses include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, about 0.001 mg to about 500 mg, about 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about 25 mg.
  • Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4 doses. Depending on the individual and as deemed appropriate from the healthcare provider it may be necessary to deviate upward or downward from the doses described herein.
  • the amount of active ingredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician.
  • a model system typically an animal model
  • these extrapolations may merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors.
  • Representative factors include the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, whether an acute or chronic disease state is being treated or prophylaxis conducted or whether further active compounds are administered in addition to the compounds provided herein such as part of a drug combination.
  • the dosage regimen for treating a disease condition with the compounds and/or compositions provided herein is selected in accordance with a variety factors as cited above. Thus, the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods disclosed herein.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • the daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3 or 4 part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.
  • the compounds provided herein can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the dosage forms may comprise, as the active component, either a compound provided herein or a pharmaceutically acceptable salt, solvate or hydrate of a compound provided herein.
  • Some embodiments include a method of producing a pharmaceutical composition for “combination-therapy” comprising admixing at least one compound according to any of the compound embodiments disclosed herein, together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable carrier.
  • APD356-009 (“BLOOM”) was a 104-week, placebo controlled study that assessed the safety and efficacy of lorcaserin 10 mg BID in overweight and obese patients, with concurrent behavior modification.
  • the primary efficacy objective during Year 1 was to evaluate weight loss; the primary objective during Year 2 was to assess the ability of lorcaserin to maintain body weight loss that was achieved during Year 1.
  • each patient received randomized, double blind treatment assignments for Year 1 and for Year 2 (all patients were given a new randomization number for Year 2 to assure that patients and study personnel remained blinded to treatment assignments). All patients assigned to placebo during Year 1 (50% of randomized population) remained on placebo in Year 2.
  • APD356-010 (BLOOM-DM) was a 52-week, placebo controlled study that evaluated the effect of two lorcaserin doses (10 mg BID and 10 mg QD) on categorical and total weight loss with concurrent behavior modification in 604 patients with type 2 diabetes mellitus managed with oral hypoglycemic agents. Randomization to the 10 mg once daily group was halted by protocol amendment in order to accelerate enrollment, resulting in final group sizes of 253 (placebo), 95 (lorcaserin QD) and 256 (lorcaserin BID). Lorcaserin at both doses met the three pre-defined co-primary efficacy endpoints for efficacy. Greater proportions of patients treated with lorcaserin achieved 5% and 10% categorical weight loss as compared to patients treated with placebo, and patients on lorcaserin achieved a significantly greater mean weight loss.
  • APD356-011 (“BLOSSOM”) was a 52-week, placebo controlled study that evaluated the effect of two lorcaserin doses (10 mg BID and 10 mg QD) on categorical and total weight loss with concurrent behavior modification. Patients were randomized in a ratio of 2:1:2 to lorcaserin 10 mg BID, 10 mg QD, or placebo. Lorcaserin 10 mg QD and BID met the pre-defined co-primary efficacy endpoints.
  • AUC area under the curve
  • ROC receiver operating characteristic
  • the optimal thresholds were 4.6% and 5.9% weight loss for predicting at least 5% and at least 10% weight loss at Week 52.
  • the optimal weight loss thresholds were 6.1% and 8.5%, respectively (Table 1 and Table 2).
  • the positive and negative predictive values for this criterion were 85.5% and 74.0% for 5% weight loss at Week 52, and 49.8% and 95.3% for 10% weight loss at Week 52 (Table 3).
  • Table 3 and Table 4 provide the sensitivity, specificity, positive predicted value (PPV) and negative predictive value (NPV) at Weeks 12 and 24 for at least about 5% and at least about 10% weight loss at Week 52 in different studies.
  • the rounded percent weight loss at Week 12 for at least 5% and at least about 10% weight loss at Week 52 are about 5% and about 6%, respectively.
  • Using the about 6% weight loss at Week 12 as a criterion enhances the PPV for both about 5% and about 10% categorical weight loss at Week 52, but at the expense of excluding about 10% and about 4% more of the about 5% categorical responders at Week 52 in patients without and with diabetes, respectively, based upon NPV.
  • the rounded optimal thresholds at Week 24 for at least about 5% and at least about 10% weight loss at Week 52 are about 6% and about 9%, respectively.
  • Using the 9% weight loss criterion at Week 24 enhances the PPV for both about 5% and about 10% categorical weight loss at Week 52, but at the expense of excluding about 19% and about 9% more of the about 5% categorical responders at Week 52 in patients without and with diabetes, respectively, based upon NPV.
  • patients achieving this milestone will achieve an average of about 10.8% weight loss in patients without diabetes and about 9.1% weight loss in patients with diabetes at Week 52.
  • the proportion of non-diabetic patients who achieved at least 5% total body weight loss at Week 52 was greater for Week 12 responders than for Week 12 non-responders (see Table 5 and FIG. 1 ).
  • Week 12 Week 12 a (MITT with LOCF) ⁇ 5% wt loss 1,251/2,537 (49.3%) 1,070/1,251 (85.5%) ⁇ 5% wt loss 1,286/2,537 (50.7%) 335/1,286 (26.0%) a Percentage calculated based on number of patients with observed Week 12 data
  • Week 52 weight loss in non-diabetic drug Week 12 responders was 10.6 kg (23 lbs), and 86% and 50% of patients achieved at least 5% and 10% weight loss.
  • results were 9.3 kg (20 lbs), 71%, and 36%.
  • Week 52 reductions in FPG and A1C in diabetic drug Week 12 responders were 29.3 mg/dL and 1.2%, and were 7.8 mg/dL and 0.4% in drug Week 12 responders with impaired fasting glucose (IFG) at baseline.
  • Week 52 reductions in systolic and diastolic BP and heart rate were 3.4 mmHg, 2.5 mmHg, and 2.5 BPM in non-diabetic drug Week 12 responders, and 2.6 mmHg, 1.9 mmHg, and 3.2 BPM in drug Week 12 responders with T2DM.
  • achievement of ⁇ 5% weight loss by Week 12 is a strong predictor of robust one-year responses in weight, cardiovascular vital signs, and glycemia.
  • drug should not be administered to an individual not losing at least about 5% at Week 12 (i.e., are not Week 12 responders).
  • IGF impaired fasting glucose
  • Week 52 shows weight loss through Week 52 for Week 12 responders and non-responders with and without diabetes in both treatment groups.
  • change in HbA1c at Week 52 was ⁇ 1.2% for lorcaserin Week 12 responders vs. ⁇ 0.84% in non-responders (see Table 4).
  • Week 52 reductions in systolic and diastolic blood pressure and heart rate were 3.4 mmHg, 2.5 mmHg, and 2.5 bpm in lorcaserin responders without diabetes, and 2.6 mmHg, 1.9 mmHg, and 3.2 bpm in lorcaserin responders with type 2 diabetes (Table 10).
  • Form III of Compound 1 hydrochloride salt hemihydrate can be prepared as described in WO 2003/086303, WO 2005/019179, WO 2006/069363, WO 2007/120517, WO 2008/070111, and WO 2009/111004, WO 2010/148207, WO/2011/153206, WO/2012/030939, WO/2012/030938, WO/2012/030951, WO/2012/030953, WO/2012/030957, and WO/2012/030927, each of which is incorporated herein by reference in its entirety.

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