WO2019032469A1 - Traitement du surpoids et de l'obésité associés à une déficience en leptine - Google Patents

Traitement du surpoids et de l'obésité associés à une déficience en leptine Download PDF

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WO2019032469A1
WO2019032469A1 PCT/US2018/045425 US2018045425W WO2019032469A1 WO 2019032469 A1 WO2019032469 A1 WO 2019032469A1 US 2018045425 W US2018045425 W US 2018045425W WO 2019032469 A1 WO2019032469 A1 WO 2019032469A1
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leptin
subject
subjects
treatment
months
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PCT/US2018/045425
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Alison LONG
Gregory FINE
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Aegerion Pharmaceuticals, Inc.
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Publication of WO2019032469A1 publication Critical patent/WO2019032469A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/30—Dietetic or nutritional methods, e.g. for losing weight
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2264—Obesity-gene products, e.g. leptin

Definitions

  • the present invention relates to methods of treating overweight or obesity associated with leptin deficiency and, in some embodiments, one or more weight-related comorbidities.
  • the methods may comprise administration of leptin to a subject in need thereof having said underlying leptin deficiency, including those subjects who are refractory to other methods of treatment.
  • Obesity is a serious and costly health issue in the U.S. In 2015-2016, it was estimated that 93.3 million adults are affected by obesity (Hales et al., NCHS Data Brief, 2017, 288). The high prevalence of obesity among adults— estimated to be about 39.8 %— generates a burden on the health care system, as there are several obesity-related medical conditions, including heart disease, stroke, type 2 diabetes, and certain types of cancer. The estimated annual medical cost of obesity in the U.S. was $147 billion in 2008, and the medical cost for people who have obesity was $1,429 higher than those of normal weight (Finkelstein et al., Health Affairs, 2009;
  • Leptin an adipose tissue-secreted hormone, was once viewed as a potential anti-obesity agent (Friedman et al., Metab Clin Exp, 2015, 64: 1-4), as it is not produced in the leptin- deficient oblob mouse model of obesity. Studies in leptin-deficient mice showed that increases in plasma leptin levels reduced food intake and induced weight loss (Halaas et al., Proc Natl AcadSci USA, 1997, 94: 8878-83).
  • CLD congenital leptin deficiency
  • the present invention relates to a method of treating an above-normal weight condition in a subject with a leptin deficiency, in which the method comprises administering a therapeutically effective amount of leptin to the subject.
  • the above-normal weight condition comprises overweight.
  • Overweight may comprise a BMI of 25 kg/m 2 to 29.9 kg/m 2 , or a BMI of 25 kg/m 2 to less than 30 kg/m 2 , or a BMI of 27 kg/m 2 to less than 30 kg/m 2 , or a BMI of 27.5 kg/m 2 to less than 30 kg/m 2 .
  • the above-normal weight condition comprises obesity.
  • Obesity may comprise a BMI of 30 kg/m 2 or greater.
  • the leptin deficiency comprises a pre-treatment serum leptin concentration of ⁇ about 16 ng/mL if the subject is female, and ⁇ about 5 ng/mL if the subject is male; or ⁇ about 8 ng/mL if the subject is female, and ⁇ about 3 ng/mL if the subject is male; or ⁇ about 5 ng/mL if the subject is female, and ⁇ about 2 ng/mL if the subject is male.
  • the leptin deficiency comprises a pre-treatment serum leptin concentration that is in about the 10th percentile, or about the 2nd percentile, or about the 1st percentile, according to the third National Health and Nutrition Examination Survey
  • the subject has a detectable pre-treatment serum leptin
  • the subject has a weight-related comorbidity.
  • the weight- related comorbidity may be prediabetes, type 2 diabetes mellitus, dyslipidemia, hypertension, cardiovascular disease, cancer, breathing disorders, gallbladder disease, gynecological problems, erectile dysfunction and sexual health issues, liver dysfunction, liver inflammation, liver damage, osteoarthritis, or a combination thereof.
  • the weight-related comorbidity is type 2 diabetes mellitus, hypertension, dyslipidemia, or a combination thereof.
  • the subject is human. In certain embodiments, the subject is an adult human.
  • the subject pre-treatment does not have high insulin levels. In some embodiments, the subject pre-treatment does not have impaired glucose tolerance. In certain embodiments, the subject pre-treatment does not have two or more of the following: high triglycerides or high HDL cholesterol, high blood pressure, or high fasting glucose level. In certain embodiments, the subject does not have metabolic syndrome.
  • the subject does not have congenital leptin deficiency.
  • the leptin is methionyl-human leptin.
  • the therapeutically effective amount of leptin is about 1-50 mg/day, or about 5-20 mg/day.
  • the leptin may be administered once daily as a single or divided dose, or twice daily, to the subject. In some embodiments the leptin is administered in an amount of about 20 mg once daily or about 10 mg once daily.
  • the leptin is administered parenterally. In certain embodiments, the leptin is administered subcutaneously. [021] In certain embodiments, the administration of the leptin decreases body weight of the subject by about 5 % or greater, or by about 10 % or greater, from pre-treatment body weight. In some embodiments, the decrease in body weight is maintained for about a week or longer, or about a month or longer, or about a year or longer.
  • the administration of the leptin reduces BMI of the subject by about 5 % or greater, or about 10 % or greater, from pre-treatment BMI. In some embodiments, the reduction in BMI is maintained for about a week or longer, or about a month or longer, or about 6 months or longer, or about a year or longer.
  • the present invention relates to a method of chronic weight maintenance in a subject having: (a) pre-treatment low leptin, and (b) either (i) a pre-treatment BMI of >30 kg/m 2 (obese), or (ii) a pre-treatment BMI of >27 kg/m 2 (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).
  • a pre-treatment BMI of >30 kg/m 2 (obese) or
  • a pre-treatment BMI of >27 kg/m 2 (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).
  • the pre-treatment low leptin comprises a pre- treatment leptin level of ⁇ 16 ng/mL for females and ⁇ 5 ng/mL for males, or a pre-treatment leptin level of ⁇ 8 ng/mL for females and ⁇ 3 ng/mL for males.
  • the subject has a detectable pre-treatment serum leptin concentration.
  • Figure 1 presents results from a post hoc analysis of five studies that involved subjects who were overweight or obese, as described in Example 1. This figure shows the difference in mean percent change in weight between the metreleptin dose groups and placebo, from baseline to Week 12.
  • Figure 2 presents results from a post hoc analysis of five studies that involved subjects who were overweight or obese, as described in Example 1. This figure shows body weight percent change in subjects administered 20 mg/day metreleptin and who were in the lowest baseline leptin level group (5 ng/mL or less for females, and 2 ng/mL or less for males).
  • Figure 3 presents results from a post hoc analysis of five studies that involved subjects who were overweight or obese, as described in Example 1. This figure shows body weight percent change in subjects administered 20 mg/day metreleptin and who were in the lower baseline leptin level group (8 ng/mL or less for females, and 3 ng/mL or less for males).
  • Figure 4 presents results from a post hoc analysis of five studies that involved subjects who were overweight or obese, as described in Example 1. This figure shows body weight percent change in subjects administered 20 mg/day metreleptin or placebo, who were in the lowest baseline leptin level group (5 ng/mL or less for females, and 2 ng/mL or less for males) or who had a pre-treatment leptin concentration above 5 ng/mL for females, and above 2 ng/mL for males.
  • Figure 5 presents results from a post hoc analysis of five studies that involved subjects who were overweight or obese, as described in Example 1. This figure shows body weight percent change in subjects administered 20 mg/day metreleptin or placebo, who were in the lower baseline leptin level group (8 ng/mL or less for females, and 3 ng/mL or less for males) or who had a pre-treatment leptin concentration above 8 ng/mL for females and above 3 ng/mL for males.
  • Figure 6 presents results from a post hoc analysis of four studies that involved subjects who were overweight or obese, as described in Example 2. This figure shows mean percent change from baseline in weight for subjects administered 20 mg/day metreleptin or placebo.
  • Figure 7 presents results from a post hoc analysis of a study that involved subjects who were overweight or obese, as described in Example 3. This figure shows percent change in weight from baseline to Weeks 12, 16, and 24 for subjects having a lower baseline leptin level and administered metreleptin (20 mg/day or 10 mg/day) or placebo.
  • Figure 8 presents results from a post hoc analysis of a study that involved subjects who were overweight or obese, as described in Example 3. This figure shows difference in mean percent changes in weight between subjects administered 20 mg/day and placebo, over time.
  • Figure 9 presents results from a post hoc analysis of a study that involved subjects who were overweight or obese, as described in Example 4. This figure shows mean percent changes in weight from baseline between subjects administered 20 mg/day, 10 mg/day, and placebo, over time.
  • Figure 10 presents results from a post hoc analysis of five studies that involved pooled subjects who were overweight or obese, as described in Example 4. This figure shows proportion of subjects with greater than/equal to 5 % weight loss among subjects administered 20 mg/day, 10 mg/day, and placebo, at 12 weeks and 24 weeks.
  • the present invention is based, in part, on studies that assessed the effects of metreleptin on subjects who are overweight or obese (unpublished). The studies found that the subjects did not experience a clinically significant loss of weight, with the exception of one subpopulation. This subpopulation, which achieved clinically significant weight loss at 12 and 24 weeks, was found to have subjects with low leptin.
  • Leptin an adipose tissue-secreted hormone, is involved in regulating energy homeostasis, including metabolism of glucose, fatty acids and triglycerides, and other physiological functions. (Friedman et al., Nature, 1998, 395: 763-770).
  • One of the most critical roles of the leptin signaling pathway is protection from reductions in fat stores that could impact reproductive capacity, fertility, and therefore overall survival (Rosenbaum et al., J Endocrinol, 2014, 223: T83-96).
  • a subject with low leptin may experience a centrally controlled starvation signal resulting in heightened appetite and restricted energy expenditure, causing the body to believe that it is starving and to seek to preserve body fat. Consequently, the body increases calorie consumption (hyperphagia) and restricts energy expenditure by limiting high energy functions such as immune system surveillance, reproduction and exercise.
  • administration of leptin may be an effective treatment for subjects who are overweight or obese and who are leptin-deficient.
  • HMD hypoleptinemic metabolic disorder
  • HMD which may also be referred to as "Hypoleptinemic Dysmetabolic Disorder,” “Hypoleptinemic Dysmetabolic Disorder Obesity,” “HDD Obesity,” “Low Leptin Metabolic Dysfunction Spectrum,” or “LMDS”
  • HMD is a recently-identified disorder that is characterized by leptin deficiency and metabolic abnormalities; in some cases, HMD is also characterized by not having lipodystrophy.
  • HMD is distinguished from other obesity-related conditions such as CLD, as CLD is associated with a specific genetic etiology, i.e., a frame-shift mutation in the leptin gene; subjects with HMD do not have this particular leptin gene mutation.
  • HMD is also different than metabolic syndrome.
  • Metabolic syndrome also known as syndrome X, insulin resistance syndrome, or dysmetabolic syndrome
  • SHO World Health Organization
  • EGIR Insulin Resistance
  • NCEP:ATPIII National Cholesterol Education Program-Third Adult Treatment Panel
  • AACE American Association for Clinical Endocrinology
  • IDF International Diabetes Federation
  • Metabolic syndrome includes a requirement of multiple metabolic abnormalities without a single etiological cause.
  • HMD has a single common etiological factor (low leptin) potentially mediating the metabolic abnormalities observed, such as obesity, hyperlipidemia, and Type 2 diabetes.
  • BMI body mass index
  • BP blood pressure
  • HDL high density lipoprotein
  • T2DM type 2 diabetes mellitus
  • WC waist circumference (O'Neill et al., Obes Res, 2015, 16: 1-12).
  • the present invention relates to methods of treating an above-normal weight condition in a subject who has a leptin deficiency.
  • above-normal weight condition refers to "overweight” or “obesity.”
  • Overweight or “obesity” may be defined using various metrics.
  • overweight and “obesity” may be defined based on BMI, in which “overweight” refers to a BMI of 25 kg/m 2 to 29.9 kg/m 2 , or in certain embodiments a BMI of 25 kg/m 2 to less than 30 kg/m 2 , or in some embodiments 27.0 kg/m 2 to less than 30 kg/m 2 , or in other embodiments 27.5 kg/m 2 to less than 30 kg/m 2 .
  • “Obesity” may refer to a BMI of 30 kg/m 2 or higher. Under certain classification systems, “obesity” may also refer to obesity class 1
  • weight and “obesity” may be defined using other techniques known in the art, including body volume index (“BVI”), skinfold calipers, bioelectrical impedance analysis, hydrostatic weighing, dual-energy X-ray absorptiometry (“DEXA”), computerized tomography (“CT”), and magnetic resonance imaging (“MRI”).
  • BVI body volume index
  • DEXA dual-energy X-ray absorptiometry
  • CT computerized tomography
  • MRI magnetic resonance imaging
  • subjects may be identified as being overweight or obese based on a pre-treatment or baseline measurements.
  • measurements of overweight or obesity may be taken at one or more time points after treatment with leptin is initiated, for example, at about 1 week, at about 2 weeks, at about 3 weeks, etc.
  • pre-treatment refers to a time point prior to the first treatment (i.e. first administration) with leptin.
  • This time point may be 8 weeks or less prior to the first treatment, such as about 6 weeks prior to the first treatment, about four weeks or about 1 month prior to the first treatment, about 2 weeks prior to the first treatment, about 1 week prior to the first treatment, or about 6, about 5, about 4, about 3, about 2, or about 1 day prior to the first treatment.
  • the time point may be within about 24 hours prior to the first treatment, including immediately before the first treatment.
  • treatment of or “treating” overweight or obesity may be defined as a lowering of the metric by which overweight and obesity is being measured as compared to a pre-treatment measurement or, in some embodiments, a prior measurement taken after treatment with leptin was initiated.
  • “treatment of or “treating” refers to a reduction in BMI.
  • “treatment of or “treating” refers to a reduction in BVI.
  • the reduction of the metric for measuring overweight or obesity may be a percent reduction from a pre-treatment measurement, for example, a percent reduction of about 1 % to about 50 %, such as about 1 %, or about 2 %, or about 3 %, or about 4 %, or about 5 %, or about 10 %, or about 15 %, or about 20 %, or about 25 %, or about 30 %, or about 40 %, or about 50 %, or any other percent therebetween.
  • the reduction of the metric for measuring overweight or obesity may be a unit reduction from a pre-treatment measurement; for example, if overweight and obesity is determined using the BMI metric, the reduction may be about 0.1 kg/m 2 to about 20 kg/m 2 , such as about 0.1 kg/m 2 , or about 0.2 kg/m , or about 0.3 kg/m , or about 0.4 kg/m , or about 0.5 kg/m , or about 0.6 kg/m , or about 0.7 kg/m , or about 0.8 kg/m , or about 0.9 kg/m , or about 1 kg/m , or about 2 kg/m , or about 3 kg/m 2 , or about 4 kg/m 2 , or about 5 kg/m 2 , or about 7 kg/m 2 , or about 10 kg/m 2 , or about 15 kg/m 2 , or about 20 kg/m 2 , or any other number therebetween.
  • treatment of or "treating" overweight or obesity may also be defined as a lowering of the body weight of the subject as compared to a pre-treatment measurement or, in some embodiments, a prior measurement taken after treatment with leptin was initiated.
  • the reduction in weight may be a percent reduction from a pre-treatment measurement, for example, a percent reduction of about 1 % to about 50 %, such as about 1 %, or about 2 %, or about 3 %, or about 4 %, or about 5 %, or about 10 %, or about 15 %, or about 20 %, or about 25 %, or about 30 %, or about 40 %, or about 50 %, or any other percent therebetween.
  • the reduction of body weight may also be a unit reduction from a pre-treatment measurement such as a reduction of about 0.5 lbs to about 400 lbs, such as about 1 lb, or about 2 lbs, or about 3 lbs, or about 4 lbs, or about 5 lbs, or about 6 lbs, or about 7 lbs, or about 8 lbs, or about 9 lbs, or about 10 lbs, or about 15 lbs, or about 20 lbs, or about 25 lbs, or about 30 lbs, or about 40 lbs, or about 50 lbs, or about 60 lbs, or about 70 lbs, or about 80 lbs, or about 90 lbs, or about 100 lbs, or about 110 lbs, or about 120 lbs, or about 130 lbs, or about 140 lbs, or about 150 lbs, or about 160 lbs, or about 170 lbs, or about 180 lbs, or about 190 lbs, or about 200 lbs, or about 300 lbs, or about 400 lbs, or any other number therebetween.
  • the reduction of body weight such as
  • treatment of or “treating" overweight or obesity may also include a reduction of the metric used to measure overweight or obesity that is maintained for a specified period of time.
  • the reduction of the metric may be maintained for a period of about 1 day to about 5 years, such as a period of about 1 day, or about 1 week, or about
  • the reduction of the metric may be at a time point that is about 1 day to about 5 years after the first treatment, such as about 1 day, or about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about 1 month, or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about 6 months, or about 7 months, or about 8 months, or about 9 months, or about 10 months, or about 11 months, or about 12 months or about 1 year, or about 15 months, or about 18 months, or about 24 months, or about 1.5 years, or about 2 years, or about 3 years, or about 4 years, or about 5 years, or any other time point therebetween.
  • treatment of or “treating” overweight or obesity may refer to chronic weight management of the subject.
  • the administration of leptin may continue for over two years, up to the rest of the subject's life.
  • treatment of or “treating" overweight or obesity may refer to a reduction in weight or BMI in subjects administered with leptin as compared to a reduction in weight or BMI (if any) to subjects not administered with leptin.
  • the subjects who are not administered with leptin may be administered a placebo, may be administered or exposed to a different overweight/obesity treatment, or may not be administered or exposed to any type of treatment.
  • treatment of or “treating” may refer to a reduction in weight or BMI in subjects administered with leptin that is greater than the reduction in weight or BMI in subjects not administered with leptin by about 1 % to about 50 %, such as about 1 %, or about 2 %, or about 3 %, or about 4 %, or about 5 %, or about 10 %, or about 15 %, or about 20 %, or about 25 %, or about 50 %, or any other percent therebetween.
  • treatment of or "treating" overweight or obesity may be assessed by comparing the proportion of subjects administered leptin and who experienced a reduction in weight or BMI to the proportion of subjects not administered leptin and who experienced a reduction in weight or BMI.
  • the proportion of subjects administered leptin and who experienced a reduction in weight or BMI may be about 5 % to about 90 % of those subjects, such as about 5 %, or about 10%, or about 15 %, or about 20 %, or about 25 %, or about 30 % or about 35 %, or about 40 %, or about 45 %, or about 50 %, or about 55 %, or about 60 %, or about 65 %, or about 70 %, or about 75 %, or about 80 %, or about 85 %, or about 90 %, or any other percent therebetween.
  • the reduction in weight or BMI may be a percent reduction of about 1 % to about 50 %, such as about 1 %, or about 2 %, or about 3 %, or about 4 %, or about 5 %, or about 10 %, or about 15 %, or about 20 %, or about 25 %, or about 30 %, or about 40 %, or about 50 %, or any other percent therebetween.
  • the proportion of subjects administered leptin and who experienced that reduction in weight or BMI may be greater than the proportion of subjects not administered leptin and who experienced that reduction in weight or BMI by about 25 % greater, or about 50 % or greater, or about 75 % or greater, or about 100 % or greater, or about 150 % or greater, or about 200 % (double) or greater, or about 250 % or greater, or about 300 % (triple) or greater, or about 350 % or greater, or about 400 % (quadruple) or greater, or about 450 % or greater, or about 500 % (5X) or greater, or about 600 % (6X) or greater, or about 700 % (7X) or greater, or about 800 % (8X) or greater or about 900 % (9X) or greater, or about 1000 % (10X) or greater, or any percent therebetween.
  • the difference between the proportion of subjects administered leptin and who experienced a particular reduction in weight or BMI and the proportion of subjects not administered leptin and who experienced that same reduction in weight or BMI is assessed at a certain time point after the first treatment, including about 1 day to about 5 years after the first treatment, such as about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about
  • I month or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about
  • I I months or about 12 months or about 1 year, or about 15 months, or about 18 months, or about 24 months, or about 1.5 years, or about 2 years, or about 3 years, or about 4 years, or about 5 years, or any other time point therebetween.
  • treatment of or “treating" overweight or obesity may refer to effective weight management if after one year of treatment either of the following occurs: (a) the difference in weight loss between subjects administered leptin and subjects not administered leptin is at least about 5 % and the difference is statistically significant; or (b) the proportion of subjects administered leptin who lose greater than or equal to 5 % of baseline body weight is at least about 35 % and is approximately double the proportion of subjects not administered leptin and who lose greater than or equal to 5 % of baseline body weight, and the difference in weight loss between the subjects administered leptin and the subjects not administered leptin is statistically significant.
  • the metrics used to assess reductions in weight or BMI may be mean values.
  • hypoleptinemic may refer to a condition in which the endogenous concentration of leptin in the subject is considered to be below normal, i.e., a low leptin concentration.
  • concentration may be defined by a serum concentration below a specified threshold such as, for example, a serum concentration within a specified percentile based on the NHANES III.
  • some concentrations may be described by those skilled in the art as “very low” or “ultra-low” leptin levels.
  • a low leptin concentration may be defined by a serum concentration that is about 16 ng/mL or below for a female and about 5 ng/mL or below for a male; a serum concentration that is about 8 ng/mL or below for a female and about 3 ng/mL or below for a male; or a serum concentration that is about 5 ng/mL or below for a female, and about 2 ng/mL or below for a male.
  • the serum concentration may additionally be non-zero, i.e., a detectable amount or above a specified threshold, such as above about 0.1 ng/mL, or about 0.5 ng/mL, or about 1 ng/mL, or about 1.5 ng/mL, or about 2 ng/mL.
  • a detectable amount or above a specified threshold such as above about 0.1 ng/mL, or about 0.5 ng/mL, or about 1 ng/mL, or about 1.5 ng/mL, or about 2 ng/mL.
  • a low leptin concentration may be defined by a serum concentration within about the 15th percentile, or about the 10th percentile, or about the 8th percentile, or about the 5th percentile, or about the second percentile, or about the first percentile per NHANES III.
  • the serum concentration may additionally be above a specified percentile, such as above a half percentile, or the first percentile, or the second percentile, per NHANES III.
  • a low leptin concentration may be defined by a serum concentration that is within a specified percentile adjusted for BMI, gender, and/or other factors.
  • a low leptin concentration may be defined by a serum concentration within about the 10th percentile, or about the 5th percentile, or about the 3rd percentile, or about the second percentile, or about the first percentile per NHANES III, adjusted for BMI.
  • about the 10th percentile of leptin concentration may refer to subjects whose leptin concentration is in the 10th percentile according to NHANES III for subjects with a BMI of 30- 35.
  • Leptin concentration can be measured using methods and techniques known in the art.
  • leptin concentration may be measured in body fluids other than serum, such as urine, whole blood, cerebral spinal fluid, and plasma.
  • Serum leptin may be measured using Enzyme-Linked Immunosorbent Assay ("ELISA") using commercially-available kits, such as Millipore ELISA.
  • ELISA Enzyme-Linked Immunosorbent Assay
  • leptin levels may be measured using a
  • leptin concentration may be assessed prior to the start of the treatment with leptin, such as a pre-treatment leptin concentration measurement. It is recognized by a person of ordinary skill in the art that the levels of leptin in a person may change based on the time of the day and, in certain embodiments, the leptin levels are determined in the morning after fasting.
  • the present invention may relate to methods of treating overweight or obesity in subjects who have a leptin deficiency and who have one or more weight-related comorbidities.
  • the comorbidities may include, but are not limited to, prediabetes or type 2 diabetes mellitus; dyslipidemia; hypertension; cardiovascular disease, based on standardized MedDRA queries (SMQs), ischemic heart disease, cardiac failure, central nervous system hemorrhages, cerebrovascular conditions, embolic and thrombotic events; cancer, including but not limited to cancer of the uterus, cervix, endometrium, ovaries, breast, colon, rectum, esophagus, liver, gallbladder, pancreas, kidney and prostate; breathing disorders, including but not limited to sleep apnea; gallbladder disease; gynecological problems, such as infertility and irregular periods; erectile dysfunction and sexual health issues, liver dysfunction, liver inflammation, and/or liver damage, including nonalcoholic fatty liver disease; osteoarthritis; or a combination thereof.
  • SMQs MedDRA queries
  • the comorbidity is, or includes, type 2 diabetes mellitus.
  • the type 2 diabetes mellitus may be associated with an elevated hemoglobin Ale, which is hemoglobin coated with sugar, i.e., glycated, and is typically tested to diagnose type 1 and type 2 diabetes and/or to gauge how well the diabetes is being managed.
  • Methods for measuring hemoglobin Ale are known in the art, and the test results are typically presented as a percentage of hemoglobin that is glycated.
  • an "elevated" level of hemoglobin Ale may be about 6 % or higher, such as about 6.5 % or higher, or about 7 % or higher, or about 7.5 % or higher, or about 8 % or higher, or any percentage therebetween.
  • subjects may be identified as having elevated hemoglobin Ale based on a pre- treatment measurement.
  • measurements of hemoglobin Ale may be taken at one or more time points after treatment with leptin is initiated, for example, at about 1 week, at about 2 weeks, at about 3 weeks, etc.
  • administration of leptin may reduce hemoglobin Ale as compared to a pre-treatment measurement or, in some embodiments, a prior measurement taken after treatment with leptin was initiated.
  • the reduction may be a percent reduction, for example, a percent reduction of about 1 % to about 35 %, such as about 1 %, or about 2 %, or about 3 %, or about 4 %, or about 5 %, or about 10 %, or about 15 %, or about 20 %, or about 25 %, or about 30 %, or about 35 %, or any percent reduction therebetween.
  • the reduction may be a unit reduction, i.e., a decrease in the percent of glycated hemoglobin, of about 0.1 % to about 5 %, such as about 0.1 %, or about 0.2 %, or about 0.3 %, or about 0.4 %, or about 0.5 %, or about 0.6 %, or about 0.7 %, or about 0.8 %, or about 0.9 %, or about 1 %, or about 2 %, or about 3 %, or about 4 %, or about 5 %, or any other percent therebetween.
  • a unit reduction i.e., a decrease in the percent of glycated hemoglobin
  • Administration of leptin may also result in a reduction in hemoglobin Ale that is maintained during treatment for a specified period of time, such as a period of about 1 day to about 5 years, for example, a period of about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about 1 month, or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about 6 months, or about 7 months, or about 8 months, or about 9 months, or about 10 months, or about 11 months, or about 12 months, or about 1 year, or about 15 months, or about 18 months, or about 24 months, or about 1.5 years, or about 2 years, or about 3 years, or about 4 years, or about 5 years.
  • a specified period of time such as a period of about 1 day to about 5 years, for example, a period of about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about 1 month, or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about 1 month,
  • the present invention relates to a method of treating prediabetes or type 2 diabetes mellitus in an overweight or obese subject who has a leptin deficiency, comprising administering leptin.
  • Administration of leptin can lower hemoglobin Ale, therefore treating prediabetes or type 2 diabetes mellitus.
  • the comorbidity is, or includes, dyslipidemia.
  • the dyslipidemia may be associated with elevated triglyceride level, elevated low-density lipoprotein (LDL) cholesterol level, elevated total cholesterol level, or a combination thereof.
  • LDL low-density lipoprotein
  • Methods for measuring triglycerides are known in the art, and are typically performed as a blood test after the subject has fasted (for example, 8 to 12 hours).
  • an "elevated" level of triglycerides may be about 150 mg/dL or higher, such as about 200 mg/dL or higher, or about 250 mg/dL or higher, or about 300 mg/dL or higher, or about 350 mg/dL or higher, or about 400 mg/dL or higher.
  • a subject may be identified as having an elevated triglyceride level based on a pre-treatment measurement.
  • measurements of triglyceride level may be taken at one or more time points after treatment with leptin is initiated, for example, at about 1 week, at about 2 weeks, at about 3 weeks, etc.
  • an "elevated" level of LDL cholesterol may be about 130 mg/dL or higher, such as about 140 mg/dL or higher, or about 150 mg/dL or higher, or about 160 mg/dL or higher, or about 170 mg/dL or higher, or about 180 mg/dL or higher, or about 190 mg/dL or higher, or about 200 mg/dL or higher.
  • a subject may be identified as having an elevated LDL cholesterol level based on a pre-treatment measurement.
  • measurements of LDL cholesterol level may be taken at one or more time points after treatment with leptin is initiated, for example, at about 1 week, at about 2 weeks, at about 3 weeks, etc.
  • an "elevated" level of total cholesterol may be about 200 mg/dL or higher, such as about 200 mg/dL or higher, or about 240 mg/dL or higher, or about 260 mg/dL or higher, or about 280 mg/dL or higher, or about 300 mg/dL or higher, or about 320 mg/dL or higher, or about 340 mg/dL or higher, or about 350 mg/dL or higher.
  • a subject may be identified as having an elevated total cholesterol level based on a pre-treatment measurement.
  • measurements of total cholesterol level may be taken at one or more time points after treatment with leptin is initiated, for example, at about 1 week, at about 2 weeks, at about 3 weeks, etc.
  • administration of leptin may reduce the triglyceride level as compared to a pre-treatment measurement or, in some embodiments, a prior measurement taken after treatment with leptin was initiated.
  • the reduction may be a percent reduction, for example, a percent reduction of about 1 % to about 50 %, such as about 1 %, or about 2 %, or about 3 %, or about 4 %, or about 5 %, or about 10 %, or about 15 %, or about 20 %, or about 25 %, or about 30 %, or about 40 %, or about 50 %, or any percent reduction therebetween.
  • the reduction may be a unit reduction of about 1 mg/dL to about 300 mg/dL, such as about 10 mg/dL, or about 20 mg/dL, or about 30 mg/dL, or about 40 mg/dL, or about 50 mg/dL, or about 60 mg/dL, or about 70 mg/dL, or about 80 mg/dL, or about 90 mg/dL, or about 100 mg/dL, or about 110 mg/dL, or about 120 mg/dL, or about 130 mg/dL, or about 140 mg/dL, or about 150 mg/dL, or about 160 mg/dL, or about 170 mg/dL, or about 180 mg/dL, or about 190 mg/dL, or about 200 mg/dL, or about 220 mg/dL, or about 240 mg/dL, or about 260 mg/dL, or about 280 mg/dL, or about 300 mg/dL, or any other value therebetween.
  • Administration of leptin may also result in a reduction of triglyceride level that is maintained during treatment for a specified period of time, such as a period of about 1 day to about 5 years, for example, a period of about 1 day, or about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about
  • I month or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about
  • I I months or about 12 months, or about 1 year, or about 15 months, or about 18 months, or about 24 months, or about 1.5 years, or about 2 years, or about 3 years, or about 4 years, or about 5 years.
  • administration of leptin may reduce the LDL cholesterol level as compared to a pre-treatment measurement or, in some embodiments, a prior measurement taken after treatment with leptin was initiated.
  • the reduction may be a percent reduction, for example, a percent reduction of about 1 % to about 50 %, such as about 1 %, or about 2 %, or about 3 %, or about 4 %, or about 5 %, or about 10 %, or about 15 %, or about 20 %, or about 25 %, or about 30 %, or about 40 %, or about 50 %, or any percent reduction therebetween.
  • the reduction may be a unit reduction of about 1 mg/dL to about 100 mg/dL, such as about 1 mg/dL, or about 5 mg/dL, or about 10 mg/dL, or about 15 mg/dL, or about 20 mg/dL, or about 25 mg/dL, or about 30 mg/dL, or about 35 mg/dL, or about 40 mg/dL, or about
  • leptin may also result in a reduction of LDL cholesterol level that is maintained during treatment for a specified period of time, such as a period of about 1 day to about 5 years, such as a period of about 1 day, or about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about
  • I month or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about
  • I I months or about 12 months, or about 1 year, or about 15 months, or about 18 months, or about 24 months, or about 1.5 years, or about 2 years, or about 3 years, or about 4 years, or about 5 years.
  • administration of leptin may reduce the total cholesterol level as compared to a pre-treatment measurement or, in some embodiments, a prior measurement taken after treatment with leptin was initiated.
  • the reduction may be a percent reduction, for example, a percent reduction of about 1 % to about 50 %, such as about 1 %, or about 2 %, or about 3 %, or about 4 %, or about 5 %, or about 10 %, or about 15 %, or about 20 %, or about 25 %, or about 30 %, or about 40 %, or about 50 %, or any percent reduction therebetween.
  • the reduction may be a unit reduction of about 1 mg/dL to about 200 mg/dL, such as about 1 mg/dL, or about 5 mg/dL, or about 10 mg/dL, or about 20 mg/dL, or about 30 mg/dL, or about 40 mg/dL, or about 50 mg/dL, or about 60 mg/dL, or about 70 mg/dL, or about 80 mg/dL, or about 90 mg/dL, or about 100 mg/dL, or about 1 10 mg/dL, or about 120 mg/dL, or about 130 mg/dL, or about 140 mg/dL, or about 150 mg/dL, or about 160 mg/dL, or about 170 mg/dL, or about 180 mg/dL, or about 190 mg/dL, or about 200 mg/dL, or any other value therebetween.
  • Administration of leptin may also result in a reduction of total cholesterol level that is maintained during treatment for a specified period of time, such as period of about 1 day to about 5 years, such as a period of about 1 day, or about 1 week, or about 2 weeks, or about
  • the present invention relates to a method of treating
  • Atherosclerosis and other associated negative cardiovascular outcomes e.g. stroke
  • administering leptin comprising administering leptin.
  • Leptin can lower triglyceride level, lower LDL cholesterol level, lower total cholesterol level, or a combination thereof, therefore treating atherosclerosis and other associated negative cardiovascular outcomes.
  • the comorbidity is, or includes, liver dysfunction.
  • Poor liver health may be associated with elevated alanine aminotransferase (ALT) level, elevated aspartate aminotransferase (AST) level, or a combination thereof.
  • AST aspartate aminotransferase
  • nonalcoholic fatty liver disease may be associated with an AST:ALT ratio of greater than about 1.
  • ALT is an enzyme involved in amino acid metabolism and is found predominantly in the liver. ALT is most commonly used to evaluate hepatocellular injury and to determine liver health. Methods for testing ALT are known in the art, and are typically performed as a blood test. In some embodiments, an "elevated" level of ALT may be about 25 U/L or higher for females, such as about 35 U/L or higher; and about 25 U/L or higher for males, such as about 35 U/L or higher. In the methods of the invention, a subject may be identified as having an elevated ALT level based on a pre-treatment or baseline measurement. In certain embodiments, measurements of ALT level may be taken at one or more time points after treatment with leptin is initiated, for example, at about 1 week, at about 2 weeks, at about 3 weeks, etc.
  • AST is an enzyme involved in amino acid metabolism and is found in the liver, cardiac muscle, skeletal muscle, kidneys, brain, and red blood cells. AST is regarded as an indicator of liver health, although AST levels may be elevated in diseases affecting other organs, such as myocardial infarction, acute pancreatitis, acute hemolytic anemia, severe burns, acute renal disease, musculoskeletal diseases, and trauma. Methods for testing AST are known in the art, and are typically performed as a blood test. In some embodiments, an "elevated" level of AST may be about 20 U/L or higher, such as about 30 U/L or higher, or about 40 U/L or higher, or about 0 U/L or higher, or about 60 U/L or higher.
  • a subject may be identified as having an elevated AST level based on a pre-treatment measurement.
  • measurements of AST level may be taken at one or more time points after treatment with leptin is initiated, for example, at about 1 week, at about 2 weeks, at about 3 weeks, etc.
  • administration of leptin may reduce the ALT level as compared to a pre-treatment measurement or, in some embodiments, a prior measurement taken after treatment with leptin was initiated.
  • the reduction may be a percent reduction, for example, a percent reduction of about 1 % to about 50 %, such as about 1 %, or about 2 %, or about 3 %, or about 4 %, or about 5 %, or about 10 %, or about 15 %, or about 20 %, or about 25 %, or about 30 %, or about 40 %, or about 50 %, or any percent reduction therebetween.
  • the reduction may be a unit reduction of about 1 U/L to about 20 U/L, such as about 1 U/L, or about 2 U/L, or about 3 U/L, or about 4 U/L, or about 5 U/L, or about 6 U/L, or about 7 U/L, or about 8 U/L, or about 9 U/L, or about 10 U/L, or about 11 U/L, or about 12 U/L, or about 13 U/L, or about 14 U/L, or about 15 U/L, or about 16 U/L, or about 17 U/L, or about 18 U/L, or about 19 U/L, or about 20 U/L, or any other value therebetween.
  • Administration of leptin may also result in a reduction of ALT level that is maintained during treatment for a specified period of time, such as a period of about 1 day to about 5 years, such as a period of about 1 day, or about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about
  • I month or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about
  • I I months or about 12 months, or about 1 year, or about 15 months, or about 18 months, or about 24 months, or about 1.5 years, or about 2 years, or about 3 years, or about 4 years, or about 5 years.
  • administration of leptin may reduce the AST level as compared to a pre-treatment measurement or, in some embodiments, a prior measurement taken after treatment with leptin was initiated.
  • the reduction may be a percent reduction, for example, a percent reduction of about 1 % to about 50 %, such as about 1 %, or about 2 %, or about 3 %, or about 4 %, or about 5 %, or about 10 %, or about 15 %, or about 20 %, or about 25 %, or about 30 %, or about 40 %, or about 50 %, or any percent reduction therebetween.
  • the reduction may be a unit reduction of about 1 U/L to about 20 U/L, such as about 1 U/L, or about 2 U/L, or about 3 U/L, or about 4 U/L, or about 5 U/L, or about 6 U/L, or about 7 U/L, or about 8 U/L, or about 9 U/L, or about 10 U/L, or about 11 U/L, or about 12 U/L, or about 13 U/L, or about 14 U/L, or about 15 U/L, or about 16 U/L, or about 17 U/L, or about 18 U/L, or about 19 U/L, or about 20 U/L, or any other value therebetween.
  • Administration of leptin may also result in a reduction of ALT level that is maintained during treatment for a specified period of time, such as a period of about 1 day to about 5 years, such as a period of about 1 day, or about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about 1 month, or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about 6 months, or about 7 months, or about 8 months, or about 9 months, or about 10 months, or about 11 months, or about 12 months, or about 1 year, or about 15 months, or about 18 months, or about 24 months, or about 1.5 years, or about 2 years, or about 3 years, or about 4 years, or about 5 years.
  • a specified period of time such as a period of about 1 day to about 5 years, such as a period of about 1 day, or about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about 1 month, or about 2 months, or about 3 months, or about 4 months, or about 5
  • the present invention relates to a method of treating liver dysfunction, liver inflammation, and/or liver damage in an overweight or obese subject who has a leptin deficiency, comprising administering leptin.
  • Administration of leptin can lower ALT level, AST level, or a combination thereof, which may be indicative of treatment of liver dysfunction, liver inflammation, and/or liver damage.
  • the present invention relates to a method of treating nonalcoholic fatty liver disease in an overweight or obese subject who has a leptin deficiency, comprising administering leptin.
  • Administration of leptin can lower AST level, which may be indicative of treatment of nonalcoholic fatty liver disease.
  • the "leptin" used to administer to subjects according to the invention encompasses naturally occurring human, mouse, rat, and other heterologous species leptins, as well as recombinantly produced mature leptin.
  • mature human leptin is a 146- amino acid polypeptide hormone, which may be represented by the following amino acid sequence (SEQ ID NO: 1):
  • Xaa at position 27 is T or A; and Xaa at position 28 is Q or absent.
  • Leptin may also encompass analogs of leptin, which as used herein refers to a compound that has insertions, deletions and/or substitutions of amino acids relative to leptin.
  • an analog can have at least 50%, for example 50 %, 55 %, 60 %, 65 %, 70 %, 75 %, 80 %, 85 %, 90 %, 95 %, 98 %, or even higher, sequence identity to leptin.
  • metreleptin i.e., r-metHuLeptin
  • Metreleptin may be represented by the following amino acid sequence (SEQ ID NO: 2):
  • amino acids may encompass biologically active fragments, agonist, agonist analogs, variants, fusion proteins, and other derivatives thereof, such as those compounds disclosed in U.S. Patent No. 5,521,283, U.S. Patent No. 5,532,336, U.S. Patent No. 5,552,522, U.S. Patent No. 5,552,523, U.S. Patent No. 5,552,524, U.S. Patent No. 5,554,727, U.S. Patent No. 5,559,208, U.S. Patent No. 5,580,954, U.S. Patent No. 5,594,101, U.S. Patent No. 5,691,309, U.S. Patent No. 5,756,461, U.S. Patent No.
  • Leptin is the polypeptide product, for example, of the ob gene as described in the International Publication No. WO 96/05309, and U.S. Patent No. 6,309,853, each of which is incorporated herein by reference in its entirety.
  • the present invention may relate to leptin as a conjugate, such as those conjugates disclosed in U.S. Publication No. 2012/0149636, U.S. Publication No.
  • the leptin administered to subjects according to the invention may be in a pharmaceutical composition.
  • the pharmaceutical composition may comprise, in addition to leptin, one or more pharmaceutically acceptable excipients or additives that modify, maintain, or preserve, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption, or penetration of the composition.
  • Suitable excipients or additives include, but are not limited to, amino acids (including, but not limited to, glycine, glutamine, asparagine, arginine, or lysine); antimicrobials; antioxidants (including, but not limited to, ascorbic acid, sodium sulfite, or sodium hydrogen sulfite); buffers (including, but not limited to, borate, bicarbonate, Tris HC1, citrates, phosphates, or other organic acids); bulking agents (including, but not limited to, mannitol or glycine), chelating agents (including, but not limited to, ethylenediamine tetraacetic acid (EDTA)); complexing agents (including, but not limited to, caffeine, polyvinylpyrrolidone, beta cyclodextrin, or hydroxypropyl beta
  • amino acids including, but not limited to, glycine, glutamine, asparagine, arginine, or lysine
  • antimicrobials including
  • cyclodextrin fillers; monosaccharides; disaccharides and other carbohydrates (including, but not limited to, glucose, mannose, or dextrins); proteins (including, but not limited to, serum albumin, gelatin, or immunoglobulins); coloring; flavoring and diluting agents; emulsifying agents; hydrophilic polymers (including, but not limited to, polyvinylpyrrolidone); low molecular weight polypeptides; salt forming counterions (including, but not limited to, sodium); preservatives (including, but not limited to, benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide); solvents (including, but not limited to, glycerin, propylene glycol, or polyethylene glycol); sugar alcohols (including, but not limited to, mannitol or sorbitol
  • suspending agents include surfactants or wetting agents (including, but not limited to, pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancing agents (sucrose or sorbitol); tonicity enhancing agents (including, but not limited to, alkali metal halides (in one aspect, sodium or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; and/or pharmaceutical adjuvants (see, e.g., Remington's Pharmaceutical Sciences, 18th Edition, A. R. Gennaro, ed., Mack Publishing Company, 1990).
  • surfactants or wetting agents including, but not limited to, pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, triton, tromethamine, lecithin, cholesterol, ty
  • leptin may be formulated in a composition
  • the composition may be in the form of a lyophilized cake containing 11.3 mg of leptin, and stored or housed in a suitable container or packaging as known in the art.
  • the composition may be stored in glass vials, such as a 5 mL USP Type I glass vials with bromobutyl rubber stoppers, and aluminum seals with plastic flip-off caps.
  • the leptin may be stored refrigerated (between 36 °F and 46 °F, i.e., 2 °C and 8 °C) and protected from light.
  • the cake Upon reconstitution with 2.2 mL of bacteriostatic-water-for-injection (BWFI) or water- for-injection (WFI), the cake yields a 5 mg/mL concentration of leptin.
  • BWFI bacteriostatic-water-for-injection
  • WFI water- for-injection
  • the drug may be used within three days when stored in the refrigerator between 36 °F and 46 °F (2 °C and 8 °C) and protected from light. Before injection, study medication may be allowed to reach room temperature (15 °C to 30 °C).
  • aspects of the present invention relate to methods of (a) treating overweight or obesity in subjects who have a leptin deficiency; or (b) treating overweight or obesity in subjects who have a leptin deficiency and who have one or more weight-related comorbidities; or (c) treating prediabetes or type 2 diabetes mellitus in an overweight or obese subject who has a leptin deficiency; or (d) treating atherosclerosis and other associated negative cardiovascular outcomes (e.g.
  • the methods may comprise administering leptin or a
  • aspects of the present invention relate to the use of leptin, or a pharmaceutical composition comprising leptin, for the preparation of a medicament for (a) treating overweight or obesity in subjects who have a leptin deficiency; or (b) treating overweight or obesity in subjects who have a leptin deficiency and who have one or more weight-related comorbidities; or (c) treating prediabetes or type 2 diabetes mellitus in an overweight or obese subject who has a leptin deficiency; or (d) treating atherosclerosis and other associated negative cardiovascular outcomes (e.g.
  • the treatments may comprise administering leptin or a pharmaceutical composition comprising leptin, as described herein.
  • aspects of the present invention also relate to leptin, or a pharmaceutical composition comprising leptin, for use in: (a) treating overweight or obesity in subjects who have a leptin deficiency; or (b) treating overweight or obesity in subjects who have a leptin deficiency and who have one or more weight-related comorbidities; or (c) treating prediabetes or type 2 diabetes mellitus in an overweight or obese subject who has a leptin deficiency; or (d) treating atherosclerosis and other associated negative cardiovascular outcomes (e.g.
  • the treatments may comprise administering leptin or a pharmaceutical composition comprising leptin, as described herein.
  • aspects of the present invention relate to the use of leptin, or a pharmaceutical composition comprising leptin, for: (a) treating overweight or obesity in subjects who have a leptin deficiency; or (b) treating overweight or obesity in subjects who have a leptin deficiency and who have one or more weight-related comorbidities; or (c) treating prediabetes or type 2 diabetes mellitus in an overweight or obese subject who has a leptin deficiency; or (d) treating atherosclerosis and other associated negative cardiovascular outcomes (e.g.
  • the treatments may comprise administering leptin or a pharmaceutical composition comprising leptin, as described herein.
  • the methods of the invention are to provide chronic weight maintenance in subjects who have (a) pre-treatment low leptin, and (b) either:
  • the low leptin comprise a leptin level of ⁇ 16 ng/mL for females and ⁇ 5 ng/mL for males, or by a leptin level of ⁇ 8 ng/mL for females and ⁇ 3 ng/mL for males.
  • the methods of the invention are to achieve and/or maintain weight loss in subjects with HMD, wherein the subjects have an initial BMI of (i) >30 kg/m 2 (obese), or (ii) >27 kg/m 2 (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia); wherein the subjects have a leptin level of ⁇ 16 ng/mL for females and ⁇ 5 ng/mL for males, or a leptin level of ⁇ 8 ng/mL for females and ⁇ 3 ng/mL for males; and wherein the leptin level is a detectable amount.
  • at least one weight-related comorbid condition e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia
  • the subjects have a leptin level of ⁇ 16 ng/mL for females and ⁇ 5 ng/mL for males,
  • HMD may be characterized as having elevated (above-normal) serum levels of apolipoprotein B (apo-B), follicle stimulating hormone (FSH), or a combination thereof.
  • apo-B apolipoprotein B
  • FSH follicle stimulating hormone
  • HMD may be further characterized as having high cholesterol and/or hypertension.
  • HMD may be further characterized as having a higher likelihood of type 2 diabetes.
  • the leptin may be administered in amounts that are therapeutically effective.
  • a therapeutically effective amount may include a quantity of leptin administered at a particular frequency.
  • the quantity of leptin may be about 0.001 mg/kg body weight to about 1000 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.1 mg/kg to about 100 mg/kg, from about 1.0 mg/kg to about 50 mg/kg, or from about 1 mg/kg to about 20 mg/kg.
  • the quantity of leptin may be measured in international units (IU) ranging from about 0.001 IU/kg body weight to about 1000 IU/kg, from about 0.01 IU/kg to about 100 IU/kg, from about 0.1 IU/kg to about 100 IU/kg, from about 1 IU/kg to about 100 IU/kg, from about 1 IU/kg to about 50 IU/kg, or from about 1 IU/kg to about 20 IU/kg.
  • IU international units
  • the quantity of leptin may be a fixed dose, such as about 1 to about 200 mg, or any dose therebetween, such as about 1 mg, or about 5 mg, or about 10 mg, or about 15 mg, or about 20 mg, or about 25 mg, or about 30 mg, or about 35 mg, or about 40 mg, or about 45 mg, or about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg.
  • leptin may be administered as daily doses or in equivalent doses at longer or shorter intervals, e.g., every other day, twice weekly, thrice weekly, four times a week, five times a week, six times a week, weekly, monthly, semi-annually, or even twice or three times daily. On the days that the dose is administered, it may be given as a single or divided dose.
  • a therapeutically effective amount of leptin may also be in accordance to a titration schedule that involves modifying the quantity or frequency of dosing based on a set schedule or based on the response of the subject.
  • Administration of leptin may be oral, intravenous, subcutaneous, intranasal, inhalation, transdermal, transmucosal, or by any other route known in the art.
  • leptin may be administered parenterally, such as intravenous, intramuscular, of subcutaneous.
  • a composition as disclosed herein can be drawn into a syringe or filled in an intravenous infusion bottle or bag and administered to the human or animal as a bolus and/or continuous infusion.
  • Leptin may also be administered via pen injector, auto injector, dual chamber injector, and the like.
  • leptin may be administered orally.
  • Pharmaceutical compositions that are administered orally may comprise carriers customarily used in the compounding of solid dosage forms such as tablets and capsules.
  • a capsule may be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre systemic degradation is minimized.
  • Additional agents can be included to facilitate absorption of the composition. Diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders may also be employed.
  • leptin may be administered by inhalation.
  • leptin may be in a composition formulated as a dry powder for inhalation.
  • Pharmaceutical composition inhalation solutions may also be formulated with a propellant for aerosol delivery or the solutions may be nebulized.
  • intraparenchymal intracerebroventricular, intraocular, intraarterial, intraportal, intralesional routes, intraarticular, intratumor, cerebrospinal, intrarectal and colon, topical, subconjunctival, intrabladder, intravaginal, epidural, intracostal, intradermal, transdermal, transserosal, intrabuccal, intranasal, dissolution in the mouth or other body cavities, instillation to the airway, insufflation through the airway, injection into vessels, tumors, organ and the like, and injection or deposition into cavities in the body of a mammal.
  • the methods of the invention involve administering leptin to subjects in need thereof.
  • the subjects may be overweight or obese, and have a leptin deficiency.
  • the subjects may have a comorbidity.
  • the subjects of the present invention may have HMD.
  • subjects of the present invention may have previously undergone other treatments to lower weight and/or reduce BMI.
  • treatments include, but are not limited to, diets (e.g., volumetrics, vegan, etc., or commercial diets such as Weight Watchers ® , Jenny Craig ® , etc.), exercise, drugs (e.g., diethylpropion (Tenuate ® ), phentermine (Adipex-P ® ), benzphetamine phendimetrazine, orlistat (Xenical ® ), lorcaserin (Belviq ® ), phentermine-topiramate (Qsymia ® ), naltrexone-bupropion (Contrave ® ), liraglutide (Saxenda ® , etc.), and bariatric surgery (e.g., gastric bypass, sleeve gastrectomy, adjustable gastric band, and biliopancreatic diversion with du
  • drugs e.g
  • the subject does not have other medical conditions that have been associated with leptin deficiency, including, but not limited to, lipodystrophy syndromes, hypothalamic amenorrhea, and congenital leptin deficiency. [0103] In certain embodiments, the subject does not have common obesity.
  • the subject pre-treatment does not have high insulin levels.
  • High insulin levels may be regarded as a fasting insulin level of greater than about 8 ⁇ /mL, or greater than about 10 ⁇ /mL, or greater than about 12 ⁇ /mL.
  • the subject pre-treatment does not have impaired glucose tolerance.
  • Impaired glucose tolerance may be regarded as having a plasma glucose concentration of 140 to 200 mg/dL (7.8 mmol/1 to 1 1.1 mmol/1) two hours after the 75-g oral glucose tolerance test, and/or a fasting blood glucose of less than 7 mmol/L.
  • Impaired glucose tolerance may also be regarded as having a glycated haemoglobin (HbAlc) blood test level of 42 to 47 mmol/mol (6.0 % to 6.5 %).
  • HbAlc haemoglobin
  • then subject pre-treatment does not have does not have two or more of the following: (i) high triglycerides or high HDL cholesterol, (ii) high blood pressure, or (iii) high fasting glucose level.
  • High triglycerides may be as discussed above (e.g., fasting level of about 150 mg/dL or higher).
  • High HDL cholesterol may be regarded as a fasting level of greater than about 35 mg/dL.
  • high HDL cholesterol may differ between genders. For example, high HDL cholesterol for a male may be greater than about 35 mg/dL, or greater than about 40 mg/dL.
  • High HDL cholesterol for a female may be greater than about 39 mg/dL, or greater than about 50 mg/dL.
  • High blood pressure may be regarded as greater than about 120 mm Hg over about 80 mm Hg, or greater than about 130 mm Hg over about 85 mm Hg, or greater than about 140 mm Hg over about 90 mm Hg.
  • the subject does not have metabolic syndrome, which, as described above, has been defined using different criteria by different health organizations (see Table 1) (O'Neill et al., Obes Rev, 2015, 16: 1-12).
  • the subject does not exhibit leptin resistance.
  • Leptin resistance may be caused by a variety of factors, including (i) a failure of circulating leptin to cross the blood-brain-barrier and reach its neuron targets in the brain, (ii) an inhibition of the leptin signaling cascade within neurons in specific brain areas, (iii) a "defensive” decrease in the expression of leptin receptors, and (iv) a desensitization of cellular downstream signaling at central and peripheral level; and may be affected by a variety of factors including inflammation or oxidative stress processes, and the type of diet. (Sainz et al., Metab Clin Exp, 2015, 64: 35- 46). Leptin resistance can be assessed based on knowledge in the art. (Id.)
  • the subject is an animal, such as a mammal.
  • the subject is a human, for example, an adult human.
  • NHANES III ⁇ 10th percentile: ⁇ 16 ng/mL for females, ⁇ 5 ng/mL for males
  • NHANES III -2nd percentile ⁇ 8 ng/mL for females, ⁇ 3 ng/mL for males
  • NHANES III -1st percentile ⁇ 5 ng/mL for females, ⁇ 2 ng/mL for males
  • the analysis did not include an imputation method to account for any missing data points. If a subject did not have a value at a specific visit (for example, at week 12 or week 24,) then no data was analyzed for that subject at that visit.
  • Table 2 presents mean weight at baseline and at Week 12, and the percent change in weight from baseline to Week 12, grouped by baseline leptin level, across the 5 studies. Results are presented separately for subjects who received 20 mg metreleptin, 10 mg metreleptin, or placebo. The difference in percent change between the metreleptin dose groups and placebo is displayed graphically in Figure 1.
  • Table 3 shows a responder analysis across the five studies. The analysis reveals that, across all baseline leptin levels, the proportion of subjects who achieved a >5 % reduction in weight at Week 12 was greater for subjects who received metreleptin 20 mg compared to those who received placebo. Consistent results were noted for a >10 % reduction in weight at this time point. Further, the 10 mg-dose group also showed a higher proportion of subjects who achieved these weight-loss goals compared to placebo at both time points in most baseline leptin levels. The number of subjects with data at Week 24 was limited; however, in general, a higher proportion of subjects who received 20 mg daily of metreleptin achieved these weight loss goals at this time point compared to Week 12.
  • Table 4 shows the change in weight at Week 12 by BMI, which suggests that subjects with lower BMI may be more responsive to the metreleptin treatment.
  • Table 5 shows the change in weight at Week 12 by gender, which suggests that females may be more responsive to metreleptin than males.
  • Example 1 The following describes a post hoc analysis of four of the five studies described in Example 1 involving subjects who were overweight or obese and were administered metreleptin. The analysis compared mean percent loss of body weight in subjects administered either 20 mg or 10 mg of metreleptin and having low ( ⁇ 10th percentile), lower (-2nd percentile), or lowest (-1st percentile) baseline leptin levels.
  • Figure 6 compares weight loss in subject administered the 20 mg metreleptin dose among the three threshold baseline leptin levels. Statistically significant decreases were observed after week 10 for subjects having low ( ⁇ 10th percentile) and lowest (-1st percentile) baseline leptin levels.
  • the analysis did not include an imputation method to account for any missing data points. If a subject did not have a value at a specific visit (for example, at week 12 or week 24,) then no data was analyzed for that subject at that visit.
  • Results to Weeks 12, 16 and 24 are provided in Table 8 and Figure 7. Consistent with the results presented in Example 1, treatment with metreleptin 20 mg daily led to significantly greater weight loss compared to placebo at Week 12 (-4.0 % vs -2.2 %) with continued weight loss that was significantly better than placebo observed at Week 16 (-4.5 % vs -2.1 %) and Week 24 (-7.6 % vs -2.6 %). The weight loss over time is also demonstrated in Figure 8, in which the difference in mean percent change versus placebo was over 7 % at Weeks 28, 32, and 36.
  • Table 8 Summary of Change in Weight from Baseline to Weeks 12, 16, and 24 for Subjects with Low Leptin Levels by Treatment Group (Phase 2 Amgen Study LEPT-980236).
  • Example 3 The following describes a post hoc analysis of the same study described in Example 3 above (LEPT-980236), but a different statistical analysis was used to make allowances for missing data and to determine if overall results were consistent with the statistical method used in Example 3 above.
  • Example 1 A post hoc analysis was conducted of the five studies introduced in Example 1 to assess the effects of metreleptin on reducing levels of various parameters that are associated with comorbidities. This analysis focused on subjects who had elevated pre-treatment levels of HbAlc, triglyceride level, LDL cholesterol level, total cholesterol level, ALT level, or AST level, as defined in Table 10. In addition, the analysis targeted subjects who were administered 20 mg metreleptin daily and had the following baseline leptin levels:
  • NHANES III -2nd percentile ⁇ 8 ng/mL for females, ⁇ 3 ng/mL for males ("lower baseline leptin level");
  • NHANES III -1st percentile ⁇ 5 ng/mL for females, ⁇ 2 ng/mL for males ("lowest baseline leptin level").
  • Subjects who had a lower (2nd percentile) baseline leptin level and an elevated LDL cholesterol level generally experienced a greater decrease in LDL cholesterol level from treatment with metreleptin, as compared to subjects who were not treated with metreleptin (see Table 13 below).
  • subjects with an LDL cholesterol level of > 130 mg/dL who did not receive metreleptin treatment had an increase in LDL cholesterol level.
  • Subjects who had a lower (2nd percentile) baseline leptin level and an elevated total cholesterol level experienced a greater decrease in total cholesterol level from treatment with metreleptin, as compared to subjects who were not treated with metreleptin (see Table 14 below).
  • 2nd percentile baseline leptin level and an elevated total cholesterol level experienced a greater decrease in total cholesterol level from treatment with metreleptin, as compared to subjects who were not treated with metreleptin (see Table 14 below).
  • the lowest (1st percentile) baseline leptin level and a total cholesterol level of > 240 mg/dL one subject was administered metreleptin and experienced a much greater decrease in total cholesterol level as compared to the other subject who did not receive metreleptin.
  • Table 13 Average change in LDL cholesterol level between pre-treatment level and 12-week, 16-week, and last-observed time points in obese subjects with low leptin concentration and an elevated LDL cholesterol level treated with metreleptin.
  • Table 14 Average Change in Total Cholesterol Level Between Pre-Treatment Level and 12-Week, 16-Week, and Last- Observed Time Points in Obese Subjects with Low Leptin Concentration and an Elevated Total Cholesterol Level Treated with Metreleptin.
  • Table 15 Average Change in HDL Cholesterol Level Between Pre-Treatment Level and 12-Week, 16-Week, and Last- Observed Time Points in Obese Subjects with Low Leptin Concentration and an Elevated HDL Cholesterol Level Treated with Metreleptin.
  • Table 17 Average Change in AST Level Between Pre-Treatment Level and 12-Week, 16-Week, and Last-Observed Time Points in Obese Subjects with Low Leptin and an Elevated AST Level Treated with Metreleptin.
  • the primary objectives of the study are to (1) assess weight reduction of obese or overweight leptin-deficient subjects in Stratum 1 (leptin levels ⁇ 8 ng/mL for females, ⁇ 3 ng/mL for males) after 6 months of 20 mg metreleptin treatment, compared to placebo, by calculating the difference in mean percent loss of baseline body weight; and (2) assess weight reduction of obese or overweight leptin-deficient subjects in Stratum 1 (leptin levels ⁇ 8 ng/mL for females, ⁇ 3 ng/mL for males) after 6 months of 20 mg metreleptin treatment, compared to placebo, by determining the proportion of subjects who lose >5 % of baseline body weight.
  • the secondary objectives of the study is to (a) assess weight reduction of obese or overweight leptin-deficient patients in Stratum 1 (leptin levels ⁇ 8 ng/mL for females, ⁇ 3 ng/mL for males) and Stratum 2 (leptin levels >8 and ⁇ 16 ng/mL for females, >3 and ⁇ 5 ng/mL for males) after 6 months of 20 mg metreleptin treatment, compared to placebo, by calculating the difference in mean percent loss of baseline body weight; (b) assess weight reduction of obese or overweight leptin-deficient subjects in Stratum 1 (leptin levels ⁇ 8 ng/mL for females, ⁇ 3 ng/mL for males) and Stratum 2 (leptin levels >8 and ⁇ 16 ng/mL for females, >3 and ⁇ 5 ng/mL for males) after 6 months of 20 mg metreleptin treatment, compared to placebo, by determining the proportion of subjects who lose
  • triglycerides total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol), insulin resistance using the homeostatic model assessment-insulin resistance (HOMA-IR) calculator, waist circumference (inclusive of waist:hip ratio), blood pressure, and heart rate; (ii) determine the proportion of subjects who do not gain weight; (iii) determine the proportion of subjects who achieve >10% weight loss; (iv) analyze percent fat loss versus lean muscle by dual energy X-ray absorptiometry (DXA); (v) analyze resting metabolic rate (RMR) by indirect calorimetry; (vi) assess improvement by relevant Quality of Life assessment tools; (vii) determine the effective dose for weight loss and weight maintenance based on baseline leptin levels; (viii) determine weight loss based on the metreleptin dose and/or achieved leptin levels; and (ix) determine the time to maximum weight loss.
  • HOMA-IR homeostatic model assessment-insulin resistance
  • the study will be a randomized, dose-finding study to determine the safety and efficacy of 5 mg, 10 mg, and 20 mg metreleptin in subjects with HMD.
  • Randomization will be stratified based on screening leptin levels:
  • Subjects in Stratum 1 will be randomized 1 : 1 to either 20 mg metreleptin or matching placebo.
  • the arms in Stratum 1 will open sequentially once the 20 mg metreleptin placebo arm has been filled, subjects in Stratum 1 will be enrolled in the open-label 10 mg metreleptin arm. Once the 10 mg metreleptin arm has been filled, subjects will be enrolled in the open-label 5 mg metreleptin arm.
  • Subjects in Stratum 2 will be randomized 3: 1 to metreleptin or placebo in 1 of 3 treatment arms: 20 mg metreleptin/placebo, 10 mg metreleptin/placebo, or 5 mg metreleptin/placebo.
  • Screening assessments to determine eligibility for the study will be conducted within 2 weeks of randomization and will include demographics, medical and surgical history, physical examination (including height and weight), 12-lead electrocardiogram (ECG), vital signs, urine pregnancy test for women of child-bearing potential, drug and alcohol screens, viral (e.g., HIV, HBV, and HCV) testing (and follow-up testing as needed), complete blood count (CBC), clinical chemistry, thyroid panel, and assessment of prior and concomitant medications. Following screening, eligible subjects will be randomized to study treatment on Day 0 based on their baseline leptin levels. Subjects will undergo baseline assessments on Day 0.
  • ECG electrocardiogram
  • CBC complete blood count
  • Each subject will be instructed on self-administration of study treatment and initiate treatment with metreleptin or placebo on Day 0. Subjects will be asked to return to the clinic at Day 7, Day 14, Day 30, Day 90, Day 180, Day 270, Day 360, Day 367, Day 374, Day 390, Day 450, Day 540, Day 630, and Day 720.
  • the focus of the Day 360 (Month 12) to Day 720 (Month 24) assessments will be to review safety, weight management, and metabolic control procedures.
  • the treatment duration will be approximately 720 days (24 months).
  • a follow-up safety visit will be conducted 30 days after the last dose of study treatment.
  • Subjects will be placed on a daily 500-calorie deficient diet and will be provided with nutrition counseling by a dietician at the start of the study (Day 0). Subjects will also meet with a dietician every 6 months thereafter until Day 720 (Month 24)
  • Subjects must have a leptin level ⁇ 16 ng/mL females; ⁇ 5 ng/mL males.
  • Subjects must have a BMI >30 kg/m 2 (obese) or BMI >27 kg/m 2 (overweight) with at least one weight-related comorbidity, such as type II diabetes, hypertension, or dyslipidemia.
  • hypogonadism must be stably medicated without dose adjustment for a minimum of 3 months prior to screening.
  • Diabetic subjects taking oral hypoglycemic such as dipeptidyl peptidase-4 (DPP-4), glucagon-like peptide 1 (GPL-1), or metformin must be stably medicated without dose adjustment for a minimum of 3 months prior to screening.
  • DPP-4 dipeptidyl peptidase-4
  • GPL-1 glucagon-like peptide 1
  • metformin must be stably medicated without dose adjustment for a minimum of 3 months prior to screening.
  • Subjects on medications that can suppress appetite including agents that block serotonin reuptake or release, such as fluoxetine, sertraline, or paroxetine, must be stably medicated without dose adjustment for a minimum of 3 months prior to screening.
  • Female subjects of childbearing potential i.e., ovulating, premenopausal, and not surgically sterile
  • all male subjects not surgically sterilized or partners of either (not surgically sterilized) must use a medically accepted contraceptive regimen, as defined in this protocol, during the study and for 30 days after the last administration of study drug, o Note: female subjects are considered to be of childbearing potential unless they are at least 50 years of age with a minimum of 12 months of consecutive amenorrhea in the absence of another biological/physiological cause and have not undergone a hysterectomy, bilateral oophorectomy, or tubal ligation within a minimum of 26 weeks prior to screening,
  • Intrauterine device at least 30 days prior to screening in combination with a barrier method.
  • Hormonal contraception oral, implant, injection, ring, or patch
  • ⁇ Hormonal contraception for at least 30 days prior to screening in combination with a barrier method.
  • Diaphragm used in combination with spermicide in combination with a barrier method ⁇ Diaphragm used in combination with spermicide in combination with a barrier method.
  • Subjects must be willing to halt blood donation during the study and for 3 months following administration of the last dose of study drug.
  • Subjects must be willing and able to give informed consent for participation in the study. Subjects must be willing and able to comply with all scheduled study visits,
  • Subjects who have had previous treatment with metreleptin Subjects who have used any investigational medication or device for any indication within the 30 days or 5 half-lives (whichever is longer) prior to screening.
  • Type 2 diabetes defined as HbAlc >7.5 %, or type 1 diabetes mellitus.
  • Subjects with abnormal and/or uncontrolled thyroid function defined as any 1 of the following:
  • Thyroid-stimulating hormone >1.5 the ULN.
  • Subjects who use any weight loss drug or supplement within 3 months prior to screening Subjects who use any weight loss drug or supplement within 3 months prior to screening. Subjects with self-reported or clinically documented history of significant fluctuations (>5 % change) in weight or participation in a formal drug-free weight loss program (investigational or otherwise) not in the maintenance phase within 3 months prior to screening.
  • Subjects with a positive result for human immunodeficiency virus (HIV) at screening Subjects with an acute hepatitis B virus (HBV) infection, as determined by a positive (immunoglobulin m [IgM] antibody against hepatitis B core antigen) IgM anti-HBc result, and/or clinical symptoms of acute viral hepatitis (e.g., anorexia, nausea, vomiting, abdominal pain, acholic stool, fatigue, fever, or jaundice) at screening.
  • HBV acute hepatitis B virus
  • IgM anti-HBc immunoglobulin m
  • Subjects that are chronically infected with HBV may qualify if they meet the following:
  • Subjects with acute hepatitis C virus (HCV) infection as determined by a positive HCV ribonucleic acid result and a positive HCV antibody result, and/or clinical symptoms of acute viral hepatitis (e.g., anorexia, nausea, vomiting, abdominal pain, acholic stool, fatigue, fever, or jaundice) at screening.
  • HCV hepatitis C virus
  • Subjects who are chronically infected with HCV may qualify if they meet the following:
  • liver disease Subjects with a history of liver disease (with exceptions noted in exclusion criterion #14) or nonalcoholic steatohepatitis.
  • Subjects with stroke, myocardial infarction, life-threatening arrhythmia, or coronary re vascularization within the 6 months prior to screening are not permitted to participate.
  • Subjects who have received a blood transfusion within 3 months prior to screening Subjects with unstable nicotine (including tobacco, nicotine patch, and/or other nicotine replacement) use, per the Investigator's discretion, or who stopped nicotine use within the 12 months prior to screening.
  • unstable nicotine including tobacco, nicotine patch, and/or other nicotine replacement
  • Subjects with a history of anorexia nervosa, bulimia, or clinical binge-eating disorder Subjects with a history of laxative abuse (within the past 2 years).
  • Subjects who plan to use or have used chronic systemic steroids (inclusive of oral, intramuscular, intravenous, and intraarticular) (other than sex-hormone replacement on stable medication without dose adjustment for a minimum of 3 months prior to screening) within 3 months prior to screening.
  • Antianxiety agents other than selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors.
  • the primary efficacy parameters include the following:
  • the primary efficacy parameters include the following:
  • the secondary efficacy parameters include the following:
  • Stratum 1 (leptin levels ⁇ 8 ng/mL [females] and ⁇ 3 ng/mL [males]) and Stratum 2 (leptin levels >8 and ⁇ 16 ng/mL [females] and >3 and ⁇ 5 ng/mL [males])
  • Metreleptin for injection or matching placebo will be supplied in vials.
  • the vials will contain a sterile, white, solid, lyophilized cake of either 11.3 mg metreleptin or matching placebo to be reconstituted with 2.2 mL of sterile water for injection in order to deliver 5 mg/mL of metreleptin.
  • the other components of the reconstituted product are 10 mM glutamic acid, 2 % glycine, 1 % sucrose, 0.01 % polysorbate 20, pH 4.25.
  • Study drug is packaged in 5 mL United States Pharmacopeia Type I glass vials with chlorobutyl rubber stoppers, and aluminum seals with plastic flip-off caps.
  • the study drug will be labeled according to the requirements of local law and legislation, as well as current GMP and GCP guidelines. Proof labels, detailing actual label text, will be available in the study files.
  • Subjects will receive vials with cake of either metreleptin or matching placebo to be reconstituted with 2.2 mL of sterile water for injection in order to deliver 5 mg/mL of metreleptin.
  • a separate guidance document will be provided to subjects, which will detail the process for reconstitution.
  • Subjects receiving 20 mg metreleptin or placebo will receive 2 vials of 10 mg metreleptin or matching placebo to be taken subcutaneously (SC) twice daily.
  • Subjects receiving 10 mg metreleptin or placebo will receive 1 vial of 10 mg metreleptin or matching placebo to be taken SC once daily (QD).
  • Subjects receiving 5 mg metreleptin or placebo will receive 1 vial of 10 mg metreleptin or matching placebo and be instructed to take half (5 mg) of the vial SC QD.
  • Subjects will self-administer SC injections of study drug.
  • the amount of study drug administered is based on the treatment arm to which the subject is assigned (5, 10, 20 mg).
  • a separate guidance document will be provided to subjects that will detail the process for reconstitution and administration, including how to reconstitute the study drug, how to prepare the injection site, and how to administer the injection.
  • a subject's dose will be increased if the subject's weight loss from baseline is ⁇ 5 %.
  • a subject's dose will be increased if the subject's weight loss from baseline is ⁇ 10 % for subjects whose baseline BMI was >30 kg/m 2 ; if the subject's baseline BMI was ⁇ 30 kg/m 2 , the dose may be increased per Investigator discretion.
  • the dose will be increased if the subject has a >2 % body weight increase over 6 months.
  • results may show that subjects who taking concomitant medications to treat type 2 diabetes, hypertension, and/or hyperlipidemia will experience a reduction in taking those medications.
  • Subjects will exhibit improvements from baseline in one or more of the following parameters: hemoglobin Ale, liver enzymes (AST, ALT), lipid parameters
  • compositions are described as including components or materials, it is contemplated that the compositions can also consist essentially of, or consist of, any combination of the recited components or materials, unless described otherwise.
  • methods are described as including particular steps, it is contemplated that the methods can also consist essentially of, or consist of, any combination of the recited steps, unless described otherwise.
  • the invention illustratively disclosed herein suitably may be practiced in the absence of any element or step which is not specifically disclosed herein.
  • Xaa at position 27 is T or A; and Xaa at position 28 is Q or absent.

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Abstract

L'invention concerne des méthodes de traitement d'un état de poids supérieur à la normale ou d'une gestion de poids chronique chez un sujet souffrant d'une déficience en leptine impliquant l'administration de leptine au sujet. L'état de poids supérieur à la normale peut être en surpoids ou en obésité. En outre, le sujet peut également avoir une comorbidité liée au poids (liée au surpoids ou à l'obésité), telle que l'hypertension, le diabète sucré de type 2, ou la dyslipidémie.
PCT/US2018/045425 2017-08-07 2018-08-06 Traitement du surpoids et de l'obésité associés à une déficience en leptine WO2019032469A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000020872A1 (fr) * 1998-10-02 2000-04-13 Amgen Inc. Procede permettant de determiner une predisposition a un traitement a la leptine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000020872A1 (fr) * 1998-10-02 2000-04-13 Amgen Inc. Procede permettant de determiner une predisposition a un traitement a la leptine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RUHL ET AL.: "Leptin concentrations in the United States : relations with demographic and anthropometric measures", THE AMERICAN JOURNAL OF CLINICAL NUTRITION, vol. 74, no. 3, 1 September 2001 (2001-09-01), pages 295 - 301, XP055571994 *

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