A leptin receptor agonist for use in methods for treating atypical anorexia nervosa and related conditions

Abstract

The invention concerns methods for treating Atypical Anorexia Nervosa (AAN) or Anorexia Nervosa in partial remission (ANpr) or AN associated with a serum leptin level in the normal range (> 5ng / ml) by administration of a leptin receptor agonist, such as metreleptin. Both ANpr and AAN can only be diagnosed in non-underweight individuals. The invention surprisingly shows treatment success in these non-underweight (AAN and ANpr) or underweight, but normoleptinemic individuals with AN (ANnl) who were otherwise not indicated for a leptin replacement or supplementation therapy.

Description

A LEPTIN RECEPTOR AGONIST FOR USE IN METHODS FOR TREATING ATYPICAL ANOREXIA NERVOSA AND RELATED CONDITIONSFIELD OF THE INVENTION[1] The invention concerns methods for treating Atypical Anorexia Nervosa (AAN) or Anorexia Nervosa in partial remission (ANpr) or AN associated with a serum leptin level in the normal range (> 5ng / ml) by administration of a leptin receptor agonist, such as metreleptin. Both ANpr and AAN can only be diagnosed in non-underweight individuals. The invention surprisingly shows treatment success in these non-underweight (AAN and ANpr) or underweight, but normoleptinemic individuals with AN (ANnl) who were otherwise not indicated for a leptin replacement or supplementation therapy.DESCRIPTION[2] Anorexia nervosa (AN) is an eating disorder characterized by an insufficient energy intake to maintain a healthy body weight, odd eating habits or rituals, obsession with having a thin figure, and an irrational fear of weight gain. AN is often coupled with a distorted self-image, which may be maintained by various cognitive biases that alter how individuals evaluate and think about their bodies, food, and eating. Individuals with AN often view themselves as overweight or not thin enough even when they are severely underweight. These individuals achieve underweight by eating small quantities of food and / or by excessive hyperactivity. According to treatment guidelines (Resmark, G., Herpertz, S., Herpertz-Dahlmann, B., & Zeeck, A. (2019). Treatment of Anorexia Nervosa-New Evidence-Based Guidelines. J Clin Med, 8(2). doi:10.3390 / jcm8020153; Crone, C., Fochtmann, L. J., Attia, E., Boland, R., Escobar, J., Fornari, V., . . . Medicus, J. (2023). The American Psychiatric Association Practice Guideline for the Treatment of Patients With Eating Disorders. Am J Psychiatry, 180(2), 167-171. doi:10.1176 / appi.ajp.23180001) the major therapeutic goal is to induce weight gain, because the achievement of a sufficiently high body weight entails the amelioration of both somatic and mental symptoms thereby improving quality of life. However, in a subgroup of individuals, mental symptoms of AN such as excessive thoughts of food, preoccupation with body weight, intense fear of gaining weight or becoming fat persist despite having achieved a body weight, which no longer is in the range of unhealthy underweight; in such individuals the diagnostic criterion for a significantly low body weight has not been met for a sustained period of time. This condition has been termed ANpr.[3] According to the widely used diagnostic classification scheme DSM-5 (American Psychiatric Association. (2013). DSM-5; Diagnostic and statistical manual of mental disorders (5 ed.). Washington, DC), ‘Other Specified Feeding and Eating Disorder’ (OSFED) is a diagnostic category reserved for eating disorders in individuals who do not fulfil the diagnostic criteria for the classical eating disorders such as AN or bulimia nervosa. AAN represents a loosely defined typeof OSFED. AAN is to be diagnosed in individuals with substantial weight loss who display the characteristic psychological and behavioral symptoms of AN, such as an intense fear of weight gain, preoccupation with food and body weight, restrictive eating patterns, and a disturbed body image, but who in contrast to individuals with AN have neither currently nor in the past met the AN diagnostic criterion of a significantly low body weight. In this type of OSFED, individuals have a body weight in the normal or higher body weight range despite the fact that they lost a substantial amount of body weight.[4] AAN as a type of OSFED has received much more attention after publication of DSM-5 in 2013, which led to the diagnostic requirement of a lower weight criterion in comparison to DSM- IV (5th vs. 10th BMI-centile in children and adolescents). There is evidence in the United States and Canada to indicate that AAN may be just as or even more common than AN. Approximately 50% of the patients who were newly diagnosed with anorexia nervosa or atypical anorexia nervosa across six study sites in Canada between 2015 and prior to the first Covid-19 lockdown were diagnosed as AAN (Agostino H, et al. Trends in the Incidence of New-Onset Anorexia Nervosa and Atypical Anorexia Nervosa Among Youth During the COVID-19 Pandemic in Canada. JAMA Netw Open. 2021 Dec 1 ;4(12):e2137395. doi: 10.1001 / jamanetworkopen.2021.37395. PMID: 34874405; PMCID: PMC8652595). During the pandemic the total number of patients with either AN or AAN increased substantially, again about half of these patients were diagnosed as AANIn a meta-analysis encompassing 75 studies published between 2007 and September 2020 including n=17 that assessed the prevalence of AAN in communities, AAN proved to be more common than AN in most studies. In addition, severity and impairment were ranked as similar to AN. Finally, despite presentation at higher weights the required level of care was again ranked as similar to that for AN (Harrop EN, et al. Restrictive eating disorders in higher weight persons: A systematic review of atypical anorexia nervosa prevalence and consecutive admission literature. Int J Eat Disord. 2021 Aug;54(8):1328- 1357. doi: 10.1002 / eat.23519. Epub 2021 Apr 17. PMID: 33864277; PMCID: PMC9035356).[5] Underweight, fear of weight gain, and body image disturbances represent cardinal features of AN1. Somatic and mental symptoms of this eating disorder are intertwined with those of starvation2, which develops from prolonged energy restriction. Loss of fat mass in AN entails a drop in blood levels of the adipocyte-derived hormone leptin3. Ensuing hypoleptinemia represents a key endocrine feature of this eating disorder2 4and acts as the major signal for the adaptation to starvation5. Amenorrhea, hematological alterations, hair loss, depressed mood, insomnia, poor concentration, inflexibility, and repetitive thoughts of food represent clinically relevant examples of both somatic and mental starvation related symptoms, which might be triggered or worsened by hypoleptinemia3. Rodent and human studies also suggest a link between hyperactivity and low circulating leptin levels6. In rats, semi-starvation induced hyperactivity is rapidly amenable totreatment with recombinant leptin6. In light of the potential involvement of the reward system in AN, the role of leptin as a strong modulator of the reward system deserves notices, 7-10.[6] In the general population, serum leptin levels are strongly correlated with body mass index(BMI; kg / m2) and even more so with fat mass (Considine, R. V., Sinha, M. K., Heiman, M. L., Kriauciunas, A., Stephens, T. W, Nyce, M. R., . . . et al. (1996). Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med, 334(5), 292-295. doi:10.1056 / nejm 199602013340503). Serum leptin levels are mostly below the normal range in underweight individuals with AN, thus resulting in absolute hypoleptinemia (Fbcker, M., Timmesfeld, N., Scherag, S., Buhren, K., Langkamp, M., Dempfle, A., . . . Hebebrand, J. (2011). Screening for anorexia nervosa via measurement of serum leptin levels. J Neural Transm (Vienna), 118(4), 571-578. doi:10.1007 / s00702-010-0551 -z; Grinspoon, S., Gulick, T., Askari, H., Landt, M., Lee, K., Anderson, E., . . . Klibanski, A. (1996). Serum leptin levels in women with anorexia nervosa. J Clin Endocrinol Metab, 81 (11), 3861-3863. doi:10.1210 / jcem.81.11.8923829. Hebebrand, J., van der Heyden, J., Devos, R., Kopp, W., Herpertz, S., Remschmidt, H., & Herzog, W. (1995). Plasma concentrations of obese protein in anorexia nervosa. Lancet, 346(8990), 1624- 1625. doi:10.1016 / s0140-6736(95)91955-4), which in turn initiates the adaptation to starvation. This absolute hypoleptinemia is a consequence of the reduced leptin secretion of adipocytes in such individuals whose unhealthy underweight to a substantial degree reflects a loss of fat mass. No systematic studies have assessed serum leptin levels in non-underweight individuals with ANpr or AAN. In light of the substantial weight loss and in particular the loss of fat mass in individuals with AAN, leptin levels must have dropped from the time period preceding the onset of weight loss and the weight with which these individuals present for treatment. In individuals with ANpr who have regained a body weight within the normal range leptin secretion is nevertheless too low to alleviate mental symptoms of starvation. Possible reasons for this relative hypoleptinemia include that the individual may have had a substantially higher leptin level prior to the development of the eating disorder or that other factors in circulating blood reduce the availability of free leptin. Individuals with AN, who have a leptin level in the normal range (> 5ng / ml; ANnl), but nevertheless show the psychological symptoms of AN, may have gained weight, albeit not yet reached a sufficiently high enough fat mass to guarantee a high enough and stable leptin secretion to alleviate the symptoms of starvation. Alternatively, a higher than normal amount of circulating leptin is bound to other factors in blood entailing a too low free leptin index. One last possibility explaining effects of leptin receptor agonists in AAN, ANpr and ANnl warrants consideration: The efficacy of an agonist, such as metreleptin, may rest on a bolus effect. Indeed, treatment with metreleptin has been shown to induce supraphysiological serum concentrations of leptin (the ELISA used for determination of serum leptin cannot differentiate between endogenous leptin and metreleptin) (Milos et al., 2020).[7] The current standard of care for patients diagnosed with ANpr or AAN or ANnl includes medical and nutritional management to enable further weight gain in ANpr and ANnl or initial weight gain in AAN. In addition, psychotherapy, particularly specialized forms such as cognitive- behavioral therapy (CBT) and family-based therapy (FBT), individual and group therapy constitute the core treatment modalities. Treatment for ANpr, AAN and ANnl often requires a multidisciplinary approach involving a team of healthcare professionals, including physicians, psychiatrists, psychologists, dietitians, and other specialists. Collaborative care ensures comprehensive evaluation, treatment planning, and ongoing support for the individual.[8] No drug has been licensed for the treatment of ANpr, AAN or ANnl; diverse medications have been used off-label, none of which overall entail substantial improvement. It is therefore an object of the invention to provide a pharmaceutical option for medical practitioners to supplement therapy of patients suffering from ANpr, AAN or ANnl.BRIEF DESCRIPTION OF THE INVENTION[9] Generally, and by way of brief description, the main aspects of the present invention can be described as follows:

[0010] In a first aspect, the invention pertains to a leptin compound for use in treating ANpr or AAN or ANnl in a subject, comprising an administration of a therapeutically effective amount of the leptin compound to the subject, wherein the leptin compound is selected from leptin, a leptin derivative, and / or a leptin- and / or leptin receptor agonist, preferably wherein the subject is not characterized by an abnormally low leptin level, such as significant hypoleptinemia.

[0011] In a second alternative aspect, the invention pertains to a method for treating ANpr or AAN or ANnl, comprising an administration of a therapeutically effective amount of the leptin compound to the subject, wherein the leptin compound is selected from leptin, a leptin derivative, and / or a leptin- and / or leptin receptor agonist, preferably wherein the subject is not characterized by an abnormally low leptin level, such as significant hypoleptinemia.BRIEF DESCRIPTION OF THE FIGURES

[0012] The figures show:

[0013] Figure 1 : shows in subfigures a to f self-rated Visual Analog Scale (VAS) results for six relevant eating disorder (see captions for each subfigure) items in an individual with AAN. 10: maximal, 1 : absent. Scales were filled in twice daily; dots represent respective daily means prior to dosing (-d4 to -d1) , during dosing (d1 to d 11 ) and after cessation of dosage (d+1 to d+5).

[0014] Figure 2: shows means of self-rated eating disorder associated cognitions and emotions assessed twice daily with VAS (range 1-10) prior to (d-5 to d-1), during (d1 to d15) and after (d+1 to d+12) the first 15-day dosing period of an individual with AN with normoleptinemia (ANnl). 10:maximal, 1 : absent. With respect to AN related cognitions and emotions the reductions in ‘repetitive thoughts of food’, ‘drive for activity’ and ‘inner tension’ are noteworthy.

[0015] Figure 3: shows means of self-rated cognitions, emotions and obsessions / compulsions assessed twice daily with VAS (range 1-10) prior to (d-27, d-26, d-2, and d-1), during (d1 to d7) and after (d+1 to d+8) the second 7-day dosing period of an individual with AN with normoleptinemia (ANnl; same individual as in Figure 2; second dosing period). 10: maximal, 1 : absent (for item sleep quality 10: extremely poor, 1 : excellent). With respect to AN related cognitions and emotions the reductions in ‘urge to vomit’, ‘drive for activity’ and ‘compulsive drinking’ of water are noteworthy.

[0016] Figure 4: shows BMI and leptin values recorded over half a year prior to, during and after the two dosing periods of an individual with AN with normoleptinemia (ANnl; same as in Figures 2-4). Leptin levels were 9.1 ng / ml (55.1 kg) prior to the first dosing (d-5) and 11.5 ng / ml (53.3 kg) prior to the second dosing period (d-2); respective datapoints are indicated in red. Open circles indicate morning values prior to metreleptin administration measured during the first and second dosing periods. Dotted line = trendline showing the extraordinary steep slope for BMI, age and Tanner stage adjusted leptin levels for this patient during weight gain. The two dotted-dashed lines show the 50thand 99thpercentiles for leptin levels (Blum et al., 1997) adjusted for the patient’s BMI, sex, and Tanner stage based on a reference sample of healthy adolescents girls (Blum et al., 1997).

[0017] Figure 5: shows means of six self-rated eating disorder associated cognitions and emotions assessed twice daily with VAS (range 1-10) prior to and during the 8-day dosing period of an individual with AN in partial remission (ANpr). For items ‘repetitive thoughts of food’, ‘feeling full’, ‘and occupied by eating disorder’ 10: maximal, 1 : absent. For items ’social interest’ (interest in social exchanges), ‘motivation to overcome eating disorder (ED)’ and ‘enjoy daily activities’ 10: absent, 1 : maximal.DETAILED DESCRIPTION OF THE INVENTION

[0018] In the following, the elements of the invention will be described. These elements are listed with specific embodiments; however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine two or more of the explicitly described embodiments or which combine the one or more of the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise.

[0019] The present invention provides methods for treating or preventing eating disorders such as ANpr or AAN. In addition the invention provides uses and methods for treating atypical clinical scenarios of classical AN, such as treating AN in a patient with normoleptinemia (ANnl; for patients having a normal leptin levels in the physiological range).

[0020] In a first aspect, the invention pertains to a leptin compound for use in treating an eating disordered subject with AAN, ANpr or ANnl (herein used to refer to a patient suffering from AN but having a leptin level in the physiological range), comprising an administration of a therapeutically effective amount of the leptin compound to the subject, wherein the leptin compound is selected from leptin, a leptin derivative, and / or a leptin- and / or leptin receptor agonist, preferably wherein the subject is not characterized by having an abnormally low leptin level.

[0021] The invention provides in certain embodiments uses and methods for treating clinical scenarios of classical AN i) after the individual has achieved a body weight no longer compatible with a significantly low body weight (ANpr) or ii) the leptin level of the individual is in the physiological range (ANnl).

[0022] In certain embodiments, the invention relates to the use of leptin replacement in context of a treatment of subjects who do not show hypoleptinemia defined as a serum level < 5 ng / ml. The invention surprisingly shows effective treatment of AAN, ANpr and ANnl by administration of metreleptin in AAN, ANpr or in subjects suffering from classical AN but characterized by normoleptinemia (also referred to as ANnl; > 5ng / ml). While such patients in the prior art were not indicated for leptin replacement therapy, the invention shows a surprising clinical effect in the treatment of individuals with AAN, ANpr and ANnl.

[0023] In context of the invention, a subject to be treated is preferably characterized by either (i) suffering from ANpr or AAN (as defined above). Or alternatively by (ii) by the combination of (classical) AN and a serum leptin level that is within the physiological (normal) range or higher (normoleptinemia) for the subject to be treated.

[0024] In some embodiments of the invention, for example in AAN, the subject is a human and has a serum leptin level below the 50thpercentile, below the 25thpercentile and even more preferably below the 10thpercentile, most preferably equal to or below the 5thpercentile according to the subject’s sex, BMI and Tanner stage, and wherein the threshold is according to the Tables A and B.

[0025] In some embodiments of the invention related to ANpr and ANnl, the subject is a human and has a serum leptin level equal to or higher than the 5thpercentile, more preferably the 50thpercentile, and even more preferably higher than the 95thpercentile, most preferably equal to orhigher than the 99thpercentile according to the subject’s age, sex, BMI and Tanner stage, and wherein the threshold is according to the following Tables A and B:

[0026] Table A: Girls (left) or boys (right) at the age of (5.8-19.9y) (from Blum WF, Juul A;Reference ranges of serum leptin, s.318-326. ln:Leptin -the voice of adipose tissue, Blum WF et al, eds., Johann Ambrosius Verlag, Heidelberg, 1997)

[0027] Table B: Adult women (left) or adult men (right)

[0028] As used herein, “treatment” is an approach for obtaining beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: improving, lessening severity, alleviation of one or more symptoms associated with a disease, preferably an abnormal eating disorder as defined herein.

[0029] “Ameliorating” a disease or one or more symptoms of the disease means a lessening or improvement of one or more symptoms associated with the disease as compared to not administering a leptin receptor agonist. “Ameliorating” also includes shortening or reduction in duration of a symptom.

[0030] As used herein, an “effective dosage” or “effective amount” of drug, compound, or pharmaceutical composition is an amount sufficient to effect beneficial or desired results. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the outset of the disease, including biochemical, histological and / or behavioural symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease, in particular as disclosedherein elsewhere. For therapeutic use, beneficial or desired results include clinical results such as reducing intensity, duration, or frequency of attack of the disease, and decreasing one or more symptoms resulting from the disease (biochemical, histological, psychological and / or behavioural), including its complications and intermediate pathological phenotypes presenting during development of the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication, and / or delaying the progression of the disease of patients. An effective dosage can be administered in one or more administrations. For purposes of this invention, an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

[0031] The term “neuropsychiatric condition” as used herein refers to clinical problems of cognition and / or behavior caused by or associated with AAN, ANpr or ANnl. Neuropsychiatric conditions include, but are not limited to, psychotic disorders, cognitive disorders, anxiety disorders, and attention disorders. In preferred embodiments of the methods of the invention, the neuropsychiatric condition is AN including AN in partial remission (ANpr) and AAN as specified in ‘Other Specified Feeding and Eating Disorder’ in DSM-5 (APA, 2013).

[0032] The term “Anorexia Nervosa” (AN) as used herein refers to a psychiatric disorder that may be characterized at least in part by a pathological level of weight loss and / or unhealthy underweight. According to the Diagnostic and Statistical Manual of Mental Disorders, 5th Ed., (DSM-5), diagnostic criteria for AN include: 1) significantly low body weight as a result of an insufficient energy intake to maintain a body weight that's at or above the minimum normal weight for sex, age and height; 2) fear of gaining weight: intense fear of gaining weight or becoming fat, or persistent behavior that interferes with weight gain, such as vomiting or using laxatives, even though you're underweight; and 3) problems with body image: denying the seriousness of having a low body weight, connecting your weight to your self-worth, or having a distorted image of your appearance or shape. In some specific aspects and embodiments, a subject to be treated in accordance with the herein disclosed invention is a subject suffering from and / or diagnosed with classical AN, but having a normal or increased leptin level.

[0033] The term “Atypical Anorexia Nervosa” (AAN) as used herein refers to a psychiatric disorder that meets all qualifications of AN, but where the patient has not been underweight prior to and during the eating disorder. According to the Diagnostic and Statistical Manual of MentalDisorders (DSM-5), AAN qualifies as a mental health disorder and more precisely as a type of the category ‘Other Specified Feeding and Eating Disorder’ (OSFED). The biomedical (other than the significantly low body weight characteristic of AN) and psychological characteristics of people with AAN generally do not differ significantly from individuals with AN. Both individuals with AAN and AN show substantial weight loss. Those with AN achieve an unhealthy underweight usually (DSM-5; APA, 2013) defined via BMI < 18.5 kg / m2in adults and a BMI-for-age and sex centile <5 in children and adolescents.

[0034] In preferred embodiments of the invention relating to AAN, the subject suffering from AAN as defined above may further be characterized by having a normal or abnormal low level of leptin.

[0035] The term “leptin receptor agonist” refers to a leptin protein, a fragment of a leptin protein having physiological properties of the leptin protein, analog (or variant) leptin protein or variant of a fragment of a leptin protein fragment, having physiological properties of the leptin protein, a leptin receptor agonist being a leptin mimic or any combinations thereof.

[0036] Such compounds may be the full (human) leptin protein having a sequence as shown in Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J M. Positional cloning of the mouse obese gene and its human homologue. Nature 1994 1 :372 (6505):425-432. and as indicated in the UniProt database under accession number P41159 in the version of August 24, 2021. In other embodiments the leptin is a pegylated (PEG)-leptin.

[0037] Preferably, the leptin analog is metreleptin, which is also a preferred leptin receptor agonist according to the invention.

[0038] The compounds of the invention can be administered as a “therapeutic composition”, which can refer to any compounds administered to treat or prevent a disease or a symptom(s) thereof, such as complications associated with weight loss or underweight. For example, aspects of the invention are drawn towards uses of therapeutic compositions comprising leptin and / or leptin receptor agonists, such as metreleptin.

[0039] In embodiments, the therapeutic composition can comprise human recombinant leptin and derivatives or fragments thereof. For example, Metreleptin (Myalept) is an FDA-approved treatment for generalized lipodystrophy, and thus could readily be repurposed to treat individuals with AAN, ANpr and ANnl. Thus, embodiments of the invention comprise treatment strategies for utilizing metreleptin to treat or prevent neuropsychiatric conditions associated with weight loss and / or underweight as disclosed herein, and in particular AAN, ANpr and ANnl.

[0040] Compositions as utilized herein can also be provided as therapeutic or prophylactic combination compositions that comprise leptin, fragments thereof, and / or leptin receptor agonists,and one or more additional active agents. For example, a therapeutic or prophylactic combination composition can comprise leptin and an anti-depressant that can be used to prevent and / or treat AAN, ANnl and / or ANpr, as defined herein.

[0041] The therapeutic compositions can be incorporated into pharmaceutical compositions suitable for administration. Such compositions can comprise leptin, fragments thereof, and / or leptin receptor agonists, and a pharmaceutically acceptable carrier. Thus, in some embodiments, the compounds of the invention are present in a pharmaceutical composition. According to the invention, a pharmaceutically acceptable carrier can comprise any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Non-limiting examples of pharmaceutically acceptable carriers comprise solid or liquid fillers, diluents, and encapsulating substances, including but not limited to lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starches, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl benzoate, propyl benzoate, talc, magnesium stearate, and mineral oil. The use of such media and agents for pharmaceutically active substances is well known in the art. Any conventional media or agent that is compatible with the active compound can be used. Supplementary active compounds can also be incorporated into the compositions.

[0042] The term "therapeutically effective amount" can refer to those amounts that, when administered to a subject in view of the nature and severity of that subject's disease or condition, will have a desired therapeutic effect, e.g., an amount which will cure, prevent, inhibit, or at least partially arrest or partially ameliorate a target disease or condition. In some embodiments, the term "therapeutically effective amount" or "effective amount" can refer to an amount of a therapeutic agent that when administered alone or in combination with an additional therapeutic agent to a cell, tissue, or subject is effective to prevent or ameliorate the disease or condition such as AAN, ANpr and / or ANnl or condition or the progression of the disease or condition. A therapeutically effective dose further refers to that amount of the therapeutic agent sufficient to result in amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions. When applied to an individual active ingredient administered alone, a therapeutically effective dose refers to that ingredient alone. When applied to a combination, a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.

[0043] A therapeutically effective dose can depend upon a number of factors known to those of ordinary skill in the art. The dose(s) can vary, for example, depending upon the identity, size, and condition of the subject or sample being treated, further depending upon the route by which thecomposition is to be administered, if applicable, and the effect which the practitioner desires. These amounts can be readily determined by the skilled artisan.

[0044] In some embodiments, the therapeutically effective amount is at least about 0.1 mg / kg body weight, at least about 0.25 mg / kg body weight, at least about 0.5 mg / kg body weight, at least about 0.75 mg / kg body weight, at least about 1 mg / kg body weight, at least about 2 mg / kg body weight, at least about 3 mg / kg body weight, at least about 4 mg / kg body weight, at least about 5 mg / kg body weight, at least about 6 mg / kg body weight, at least about 7 mg / kg body weight, at least about 8 mg / kg body weight, at least about 9 mg / kg body weight, at least about 10 mg / kg body weight, at least about 15 mg / kg body weight, at least about 20 mg / kg body weight, at least about 25 mg / kg body weight, at least about 30 mg / kg body weight, at least about 40 mg / kg body weight, at least about 50 mg / kg body weight, at least about 75 mg / kg body weight, at least about 100 mg / kg body weight, at least about 200 mg / kg body weight, at least about 250 mg / kg body weight, at least about 300 mg / kg body weight, at least about 3500 mg / kg body weight, at least about 400 mg / kg body weight, at least about 450 mg / kg body weight, at least about 500 mg / kg body weight, at least about 550 mg / kg body weight, at least about 600 mg / kg body weight, at least about 650 mg / kg body weight, at least about 700 mg / kg body weight, at least about 750 mg / kg body weight, at least about 800 mg / kg body weight, at least about 900 mg / kg body weight, or at least about 1000 mg / kg body weight. The dosage can vary depending upon known factors such as the pharmacodynamic characteristics of the active ingredient and its mode and route of administration; time of administration of active ingredient; age, sex, health and weight of the recipient; nature and extent of symptoms; kind of concurrent treatment, frequency of treatment and the effect desired; and rate of excretion.

[0045] In further embodiments, metreleptin is administered at 0.06 mg / kg to 10mg per day, once daily, preferably wherein metreleptin is administered at about 3 to 10 mg per day, once daily.

[0046] In accordance with some embodiments of the invention the leptin, or the leptin- and / or leptin receptor agonist, or the leptin analog or derivative thereof, is administered at: from about 1 microgram per day, from about 5 micrograms per day, about 10 micrograms per day, from about 50 micrograms per day, or from about 100 micrograms per day; to about 100 micrograms per day, to about 500 micrograms per day, to about 1 milligram per day, to about 5 milligrams per day, to about 50 milligrams per day, or to about 100 milligrams per day; or from about 0.01 milligram per kilogram to about 0.3 milligram, or from about 0.01 milligram per kilogram to about 20 milligrams per kilogram.

[0047] In preferred embodiments of the invention the metreleptin is administered at: from about 1 milligram per day, from about 5 milligrams per day, to about a maximum of 10 milligrams perday; or from about 0.06 milligram per kilogram per day to about 2.5 milligrams per kilogram per day.

[0048] The term “administration” can refer to introducing a substance, such as leptin, fragments thereof, and / or leptin receptor agonists, or a composition comprising leptin, into a subject. Any route of administration may be utilized. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral, transdermal (topical), transmucosal, and rectal administration. In certain preferred embodiments the leptin, or the leptin- and / or leptin receptor agonist, or the leptin analog or derivative thereof, is administered once daily, or is administered in two or more dose administrations over one day, wherein the sum of doses administered does not exceed the daily dosage of metreleptin.

[0049] In embodiments, the leptin dose can be adjusted. For example, the leptin dose can be adjusted up or adjusted down. For example, the leptin dose can be adjusted up for a period of time, and then down for a period of time. In a clinical setting, for example, leptin can be administered at a dose of about 0.04 mg / kg / day for female patients and 0.02 mg / kg / day for male patients for the first four weeks and doubled after for an additional 16 weeks.

[0050] In further embodiments of the invention the administration of the leptin, or the leptin- and / or leptin receptor agonist, or the leptin analog or derivative thereof, is an administration of metreleptin or PEG-leptin (pegylated leptin) by subcutaneous injection.

[0051] The administration of a therapeutically effective amount of leptin, or the leptin agonist, analog or derivative thereof, to the subject so ameliorates in the subject one or more adverse conditions associated with the neuropsychiatric condition selected from the group consisting of eating disorder specific cognitions, emotions and behaviors including hyperactivity / urge to move / inner restlessness, inner tension, preoccupation with food, rigid thinking, reduced motivation to overcome the condition, reduced ability to concentrate, vomiting and urge to vomit, reduced social interaction, reduced insight into the neuropsychiatric disorder, reduced ability to cope with the disorder and respond to standard therapy, perception of bloating, bloating, fear of weight gain, feeling fat, underweight, loss of hunger and appetite, loss of libido (libido = sexual drive I desire for sexual activity), reduced hematopoiesis, starvation related physical appearance (e.g. brittle hair, reduced skin turgor), hair loss, and constipation.

[0052] A “subject” or “patient” in context of the invention is preferably a mammal such as a primate. Preferred subjects are human subjects and include a female (or male) human.

[0053] Preferred subject indicated for a treatment of the invention is a human and in case of AAN is not underweight or in the case of ANnl is not hypoleptinemic. Preferably the subject suffering from AAN is not markedly underweight, such as exemplary has a BMI that is not < 15 kg / m2.Therefore, the patient preferably has a body mass index (BMI) of more than about 20 kg / m2, more than 19.0 kg / m2, preferably of more than 18.0 kg / m2, more than 17.5 kg / m2, more than 16.5 kg / m2, or more than 16 kg / m2, or more than or equal to 15 kg / m2.

[0054] In another embodiments of the invention the subject indicated for a treatment of the invention is a human patient with AN and is distinguished by having a serum leptin concentration of about more than 5 ng / ml.

[0055] In another preferred embodiment of the invention the subject indicated for a treatment of the invention is a human, who in case of AAN has not had (currently and in the past) a significantly low body weight defined by a BMI < 17.5 or preferably a BMI < 18.5 kg / m2as an adult or a BMI < 5thor preferably < 10thpercentile for age and sex as a child or adolescent.

[0056] In another preferred embodiment of the invention, the subject indicated for a treatment of the invention is a human, who in case of ANpr currently no longer has a significantly low body weight defined by a BMI < 17.5 kg / m2or preferably a BMI < 18.5 kg / m2as an adult or a BMI < 5thor preferably < 10thpercentile for age and sex as a child or adolescent. The individual must, however, have fulfilled all diagnostic requirements of AN in the more recent past. The term ‘more recent past’ can refer to a time period of up to a few years.

[0057] In another preferred embodiment a subject indicated for a treatment of the invention is a human, who in case of ANpr currently no longer has a significantly low body weight defined by a BMI < 17.5 kg / m2or preferably a BMI < 18.5 kg / m2as an adult or a BMI < 5thor preferably < 10thpercentile for age and sex as a child or adolescent. The individual must, however, have fulfilled all diagnostic requirements of AN in the more recent past. The term ‘more recent past’ can refer to a time period of up to a few years.

[0058] Human subjects indicated for the treatments of the invention are usually subjects suffering from AAN, ANpr, or ANnl, optionally characterized by mild to severe hyperactivity and / or mild to severe preoccupation with food and / or reduced hematopoiesis.

[0059] In a second alternative aspect, the invention pertains to a method for treating AAN, ANpr, AAN or ANnl, comprising an administration of a therapeutically effective amount of the leptin compound to the subject, wherein the leptin compound is selected from leptin, a leptin derivative, and / or a leptin- and / or leptin receptor agonist, preferably wherein the subject is not characterized by an abnormally low leptin level.

[0060] In certain embodiments, the subject to be treated in accordance with the invention does not suffer from classical AN, or does suffer from AN but has a normal to high serum leptin level. Preferably, wherein the eating disorder of the subject is selected from (i) or (ii), wherein:(i) atypical AN, or(ii) AN in partial remission entailing that the subject has gained a sufficient amount of weight, which no longer satisfies the AN diagnostic criterion of a significantly low body weight(iii) (classical) AN, wherein the subject presents both with a leptin level in the physiological range and a normal or high serum leptin level adjusted for sex, Body Mass Index (BMI), and optionally Tanner stage (for example a leptin level higher than about 5 ng / ml).

[0061] As used herein, the term “Tanner stage” pertains to a scaling of a child's physical development by measuring primary and secondary sex characteristics. Tanner stages are not representative of chronological age but, rather, is / are used to evaluate pubertal maturity.

[0062] In certain specific embodiments of the aspects of the invention, the subject having AAN does not suffer from marked underweight (such as exemplary a BMI < 17.5 kg / m2, preferably for an adult human of higher than 18,5 kg / m2or a child and adolescent with a BMI < 5thand preferably 10thpercentile for age and sex).

[0063] In other embodiments, the subject has no mutated leptin gene.

[0064] The terms “of the [present] invention”, “in accordance with the invention”, “according to the invention” and the like, as used herein are intended to refer to all aspects and embodiments of the invention described and / or claimed herein.

[0065] As used herein, the term “comprising” is to be construed as encompassing both “including” and “consisting of”, both meanings being specifically intended, and hence individually disclosed embodiments in accordance with the present invention. Where used herein, “and / or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, “A and / or B” is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each is set out individually herein. In the context of the present invention, the terms “about” and “approximately” denote an interval of accuracy that the person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates deviation from the indicated numerical value by ±20%, ±15%, ±10%, and for example ±5%. As will be appreciated by the person of ordinary skill, the specific such deviation for a numerical value for a given technical effect will depend on the nature of the technical effect. For example, a natural or biological technical effect may generally have a larger such deviation than one for a man-made or engineering technical effect. As will be appreciated by the person of ordinary skill, the specific such deviation for a numerical value for a given technical effect will depend on the nature of the technical effect. For example, a natural or biological technical effectmay generally have a larger such deviation than one for a man-made or engineering technical effect. Where an indefinite or definite article is used when referring to a singular noun, e.g. "a", "an" or "the", this includes a plural of that noun unless something else is specifically stated.

[0066] It is to be understood that application of the teachings of the present invention to a specific problem or environment, and the inclusion of variations of the present invention or additional features thereto (such as further aspects and embodiments), will be within the capabilities of one having ordinary skill in the art in light of the teachings contained herein.

[0067] Unless context dictates otherwise, the descriptions and definitions of the features set out above are not limited to any particular aspect or embodiment of the invention and apply equally to all aspects and embodiments which are described.

[0068] All references, patents, and publications cited herein are hereby incorporated by reference in their entirety.EXAMPLES

[0069] Certain aspects and embodiments of the invention will now be illustrated by way of example and with reference to the description, figures and tables set out herein. Such examples of the methods, uses and other aspects of the present invention are representative only, and should not be taken to limit the scope of the present invention to only such representative examples.

[0070] The examples show:

[0071] Example 1 : Treatment of AAN

[0072] The female patient aged 16.75 years at referral for inpatient treatment reported a weight loss of 21 kg (recalled premorbid body weight 80 kg, estimated BMI 27.12 kg / m2) during the preceding six months due to both dietary restriction and excessive physical activity (body weight and BMI at referral 59 kg and 20.0 kg / m2; BMI-percentile 26.2). She suffered from a preoccupation with food and body weight, inability to give up her calorie-restricted diet, self-induced vomiting 1- 2 times a day, strong drive for activity, inner tension, reduced concentration, and depressed mood. Binge eating episodes had not occurred. She had received compliments from friends for her weight loss, which she initially relished. However, as her symptoms worsened, she was no longer able to value such comments in light of her feeling ill. Amenorrhea had set in early after initial weight loss. The patient had a low heart beat rate, which at times dropped below 50 beats per minute. Overall, the symptomatology was so severe, that inpatient treatment was required.

[0073] During the initial three weeks of inpatient treatment, the patient frequently withdrew to her room. Her eating behaviour was restrictive; despite a target weight of 65 kg she continued to maintain a body weight of between 59 and 61 kg. Inner tension was particularly discernible during meals. All lab values including blood cell counts, liver enzymes, and electrolytes were within the normal range with the exception of a subnormal serum level of magnesium. The serum leptin level of 2.4 ng / ml was just within the normal range. However, upon adjustment for BMI, Tanner stage and sex (I BL, 2013) this leptin level was between the first and fifth centiles.

[0074] In light of lack of progress during inpatient treatment, the patient and her parents agreed to off-label treatment with metreleptin. They were extensively informed of our experience with this drug in off-label treatment of patients with AN and all known side effects of metreleptin including the FDA initiated risk management program due to the occurrence of lymphoma in three patients with generalized lipodystrophy and provided written informed consent. The patient was also informed of the necessity to eat three main courses and three snacks throughout the dosing period to avoid the development of hypoglycemia, which represents a potential side effect of metreleptin treatment.

[0075] The inventors used visual analogue scales (VAS) for the documentation of key emotions, cognitions and behaviours, which the patient filled in mornings and evenings (daily means are shown in Fig. 1). The scales ranged from 1 to 10 (1 : symptom absent; 10: extreme). The patient additionally filled in the German versions of Beck Depression Inventory-ll (BDI-II; Hautzinger et al., 2006) and Eating Disorder Inventory-2 (EDI-2; Thiel et al., 1997). She was treated with 3.0 or 5.8 mg / daily, applied subcutaneously at 9:00 am. Otherwise, she received inpatient treatment as usual.Table 2: Eating Disorder Inventory-2 (EDI-2) scores one day prior to dosing (d-1), during dosing (d10) and 10 days after cessation of dosing (d+10)

[0076] The VAS revealed reductions of > 30% for fear of weight gain, feeling fat, feeling full, preoccupation with food, urge to vomit, and mental narrowing (Fig. 1 a-f) and drive for activity (data not shown). Depressed mood and inner tension were initially ranked at 6 and dropped to mostly 4; during the first days of the dosing period an improved mood was primarily reported during the afternoon and evening. At the end of treatment mood was also perceived as better during the morning. Suicidal thoughts (ranked as absent throughout the observation span), tiredness (average score throughout the observation period: 3.6), exhaustion (2.4), hunger (3.6), sleep quality (3.4), urge to binge (1.1), appetite (2.3), nausea (1.35), and interest in social interaction (6.5) remained largely unchanged (data not shown). The scores of the subscales ‘Drive for Thinness’, ‘Bulimia’ and ‘Body Dissatisfaction’, which represent the core eating disorder related subscales of the Eating Disorder Inventory-2 (EDI-2)EDI, decreased after initiation of the dosing period and remained lower than at baseline in the post-dosing period (see Table 2).

[0077] During and after the dosing period, the patient did not vomit, which contrasted with its occurrence during initial inpatient treatment. She reported that respective urges only occurred once daily in contrast to 2-3 times prior to dosing. The strength of urges was reduced; she was better able to distract herself to overcome an urge. She stated perceiving her evening hunger as normalized in contrast to a reduced hunger prior to treatment (VAS for hunger in the evening averaged two prior to dosing and four after initiation of dosing). Preoccupation with food was estimated at 80% and 20-30% before and after the dosing period. In the evening, she no longer needed to reflect on what she had eaten during the day. Whereas she had had an extreme fear of weight gain, she was much better able to accept weight gain at the end of dosing. She reported thoughts of the importance of a sufficient amount of energy. Prior to dosing, she had also known of this importance, but had been unable to act upon it. At the end of the dosing period she experienced weight gains as positive and weight loss as negative. Eating became easier during dosing. At the end of dosing, the patient stated that she slept very well; she perceived a feeling of tiredness in the evening as positive and as an indicator of a fulfilled day. Her ability to concentrate had improved. Body weight remained stable during the dosing period (60.9 kg one day prior to dosing; 60.4 kg last day of dosing; range for the initial ten post-dosing days: 61 .4- 62.0 kg). She entered an intensive home treatment program; during the vacation in a foreign country she relapsed and lost three kgs of body weight. She was able to regain weight after her return and weighed 63.2 kg upon the last observation (d+60).

[0078] This case report is the first of a patient with AAN treated off-label with metreleptin. The results appear promising. No adverse events were observed during or after the 11 -day dosing period.

[0079] In contrast to previously treated patients with AN, the current case presented with a less severe clinical symptomatology. Nevertheless, inpatient treatment had to be initiated in light of failure of outpatient treatment and an inability of the patient to maintain daily functioning. Most of the observed improvements have previously been reported in patients with AN. The inventors for the first time report a decrease in both vomiting and the respective urge. The current patient again reported an increased hunger during dosing.

[0080] Feeling fat and weight phobia were both ranked at the maximal value of ten in the VAS during the pre-dosing period. Upon completion of the dosing period values were approximately halved. The values of approximately 5 at the end of the dosing period reflect the ongoing preoccupation with the former overweight, which appeared more realistic and not as a result of the entrapment in the eating disorder.

[0081] This case report renders support to the hypothesis that symptoms of AAN can be starvation related, too. The adipokine leptin is the master hormone to trigger the neuroendocrine adaptation to starvation and may additionally act directly on leptin receptors enabling intracellularsignalling throughout the brain and in peripheral tissues (Ahima et al., 1996; Hebebrand et al., 2022, 2023). Obviously, the percentage of patients with Atypical AN, who respond favorably to leptin receptor agonists, remains to be determined. The fact that the current patient improved to an extent noticeable by the patient herself, parents and treatment team suggests that as in AN a large subgroup of patients with AAN may respond to a clinically relevant degree. The leptin level prior to initiation of dosing was 2.4 ng / ml and thus minimally above the bottom value of the normal range (2 ng / ml). Upon adjustment of the leptin level for sex, pubertal status and BMI the concentration proved to be below the fifth centile (Blum et al., 1997). It seems that the weight loss of approximately 20 kg in combination with the continuously restricted dietary intake accounted for this low leptin level. Studies are required to assess the range of leptin levels in patients with AAN. Based on a PubMed search using the key words “Atypical Anorexia Nervosa” (or “Eating Disorder Not Otherwise Specified”) and leptin we were able to identify a single study which included two patients with AAN, whose leptin concentrations were < 1.92 ng / ml (Ballauf et al., 1999). The rapid response in our patient may indicate that metreleptin treated patients with AAN respond even more quickly than patients with AN.

[0082] Here it is argued that both absolute and relative hypoleptinemia and the thus induced psychological and behavioral symptoms of starvation may represent a feature common to both AN and AAN. Accordingly, randomized controlled trials are warranted for both disorders to assess the efficacy and safety of metreleptin or other leptin analogues. Absolute hypoleptinemia is defined as a leptin level < 2 ng / ml. The term relative hypoleptinemia is used to indicate a leptin level > 2 ng / ml in an individual who is known to have lost a significant amount of body weight entailing that the leptin level has dropped significantly from the pre-weight loss time period.

[0083] Example 2: Treatment of classical AN in patients with normal or high leptin levels

[0084] Patient T has two sisters including a dizygotic twin and two brothers. The patient and both sisters had postural orthostatic tachycardia syndrome during adolescence, at times occurring on a daily basis. At age 16.1 years, T developed restrictive eating behavior along with a pronounced increment in physical activity. BMI at first inpatient admission at age 16.3 years after loss of nine kg was 16.0 kg / m2(» 1st age and sex adjusted centile; 49.7 kg; 175 cm). Liver enzymes were slightly elevated, phosphate and erythrocyte count reduced. She suffered from continuous preoccupation with food, dieting, and body weight. Therapeutic progress was slow and characterized by a fragile commitment during her second and third inpatient treatment episodes. Her condition intermittently deteriorated requiring nasogastric feeding. She spoke little and appeared socially phobic; she developed NSSI. After the second inpatient episode she was discharged to day care treatment, during which she made little progress over the next 18 weeks. After brief pediatric emergency treatment to control hyponatremia, she was readmitted with a BMI of 18.1 kg / m2(6th BMI centile; 56.2 kg) due to compulsive water drinking of up to twelve litres perday obsessed with the fear that harm would otherwise come upon her twin sister. Her eating disorder cognitions were judged as severe, high inner tension was apparent. Somatic findings included acrocyanotic fingers, tachycardia (up to 141 bpm) and slightly elevated liver enzyme values. The food preoccupation had developed into a feeling of disgust upon looking at or touching food entailing compulsive handwashing lasting for hours. Intermittent vomiting further complicated the clinical situation. Comorbid diagnoses were OCD, NSSI, insomnia, and MDD. The patient was treated with an exposition therapy with response prevention and fluvoxamine which resulted in improvement of compulsive drinking. Concomitantly, her eating disorder cognitions worsened. Because of her serious condition she and her parents were offered off-label treatment with metreleptin despite a high leptin level adjusted for BMI, sex and Tanner stage (d- 5: leptin level 9.1 ng / ml; body weight 55.1 kg, BMI = 17,99 kg / m2; BMI-percentile 5.2).

[0085] Due to the pronounced overall improvement after a 15 day-long dosing period with metreleptin and the long inpatient treatment totalling nine months we supported the patient’s request to be discharged despite reservations as to the medium-term prognosis. Indeed, readmission (BMI 15.9 kg / m2) was required four weeks later due to a renewed weight loss of six kg, daily compulsive drinking of 7.5 litres of water, increased self-injurious behaviour, depression and hyperactivity (30,000 steps / d according to her step counter). She had again developed extensive hand washing fearing contamination with and uptake of food. Physical examination revealed dermatological evidence of self-injurious behaviour due to scratching, rubbing, razorblade cutting, and excessive washing. Leptin level was 7.1 ng / ml upon readmission. Nasogastric feeding was reinitiated in light of insufficient weight gain. During the seven day long second metreleptin dosing period the patient’s condition again improved. The serum leptin level was 11.5 ng / ml (body weight 53.3 kg, BMI = 17.40 kg / m2;BMI-percentile 2.3) prior to the second dosing period (d-2). She for the first time reported having witnessed a sexual abuse of a friend at age nine. She developed infrequent flashbacks; diagnostic criteria for post-traumatic stress disorder (PTSD) were met. She was able to achieve a weight of over 60 kg prior to discharge.

[0086] Two months after discharge she again lost weight (BMI 15.4 kg / m2; 48 kg), which led her to seek inpatient treatment at a psychosomatic hospital for three months. She was discharged recently; her current BMI is 18.2 kg / m2(56.5 kg). She currently suffers from excessive hyperactivity (40,000 steps: seven hours of rapid walking daily including one hour during the night), three hours of handwashing, poor concentration precluding school attendance, insomnia and eating disorder specific cognitions. She contacted her health insurance to request reimbursement of a longer-term metreleptin treatment without success.

[0087] Methods

[0088] Both patient and parents agreed to an off-label treatment with metreleptin and provided written informed consent. The information focused on expected effects of metreleptin, thepresumptive underlying mechanism, and the necessity to use the boost in motivation to gain weight, thus enabling sufficient endogenous leptin secretion.

[0089] Dosing periods: Metreleptin was applied subcutaneously at 9:00 am. Doses from 3 to 5.8 mg / d were applied (dosing period 1 : 3mg: d1 , d2, d5, d10, d12, d15; 5.8mg: d3, d4, d6-d9, d11 ; dosing period 2: 5.8 mg: d1-d6; 3 mg: d7). Visual analogue scales (VAS; means of morning and evening scores per day) were used to track self-rated emotions, cognitions and behaviors on a daily basis (Antel et al., 2021b; Gradl-Dietsch et al., 2022; Milos, Antel, Kaufmann, Barth, Koller, Tan, Wiesing, Hinney, Libuda, Wabitsch, von Kanel, et al., 2020). Children’s Depression Rating Scale-Revised (CDRS-R) (Keller et al., 2011) and self-ratings based on the German versions of Beck Depression Inventory-ll (Hautzinger, Keller, & Kuhner, 2006), and Eating Disorder Inventory- 2 assessments (Thiel, Jacobi, Horstmann, Paul, Nutzinger, & Schussler, 1997) were performed. Serum leptin levels were measured at 9 am (prior to application of metreleptin). The patient was concomitantly treated with fluvoxamine (50-0-75 mg) during the first and second dosing periods. During the second dosing period the patient was additionally treated with sodium glycerophosphate from d-10 to d6 and pantoprazole against heartburn from d-10 to d+10. Oral food intake was complemented with nasogastric feeding with Fresubin™ (500 kcal / d: d-10 to d2; 660 kcal / d: d2 to d5; 330 kcal / d: d6).

[0090] Determination of serum leptin concentrations and sequencing of leptin gene: Two serum samples were measured in parallel with both Mediagnost kit E077 SENSITIVE Leptin for immunoreactive leptin (irLEP) and kit L07 for functional Leptin (bioLEP) two and eight weeks after the second dosing period in order to evaluate receptor binding. E077 measures immunoreactive leptin using two monoclonal antibodies, both of which bind to leptin and thereby generate the measured value (sandwich antibody binding). The assay for functional leptin L07 only quantifies leptin that binds to the leptin receptor detected via an antibody, i.e., functional leptin in terms of binding to the soluble leptin receptor. For non-modified leptin, both test methods give identical results (quotient bioLEP / irLEP = 1).

[0091] Genomic sequences of LEP gene (two coding exons, Chromosome 7: 128,241 ,278- 128,257,629, GRCh38.p13) were extracted from the Ensembl Database. The cDNA and protein sequence of the transcript variant 1. (LEP-201 , ENST00000308868.5) were used. Primer pairs were designed using online software PRIMER3 (https: / / primer3.ut.ee / ). Primers were analyzed using BLAST (https: / / blast.ncbi.nlm.nih.gov / Blast.cgi) of UCSC Genome Browser to verify the designed primer’s specificity. Polymerase chain reaction (PCR) amplified DNA samples were sequenced by Microsynth Seqlab GmbH (Gottingen, Germany). All sequences were analyzed using the SeqMan Pro software by DNAStar, Inc. (version: 10.1.0) and evaluated by two (AH and coworker) experienced scientists.

[0092] Results

[0093] During the first dosing period, AN associated key cognitions and emotions dropped within two days (Figure 2). T reported improved sleep quality; the patient felt less tired and exhausted and showed less mood swings. Repetitive thoughts of food rapidly decreased. The compulsive symptomatology was markedly reduced, including reductions of urges to harm herself, hand washing (decreased feeling of disgust when seeing and touching food), water drinking, and vomiting. Additionally, the preoccupation with the eating disorder was reduced and conversely the motivation for recovery increased; the clinical change was very noticeable to family members and staff. However, VAS items ‘feeling fat’ and ‘fear of weight gain’ (Fig. 2) and EDI-2 raw scores did not change over time. After cessation of dosing, she noticed a decline in sleep quality. Nevertheless, other positive changes persisted for a few weeks. During this time period she viewed herself as for the first time wanting to leave a barren room to which she had withdrawn. The second dosing period was also associated with a rapid improvement of her mental and general condition (Fig. 3).

[0094] Circulating leptin levels were unexpectedly high (9.1 ng / ml; >99th percentile adjusted for BMI, sex and Tanner stage (Blum et al., 1997) five days prior to the first treatment (d-5) and stayed high (9.0 ng / ml >99th percentile at d6) during treatment. Leptin levels measured during treatment capture exogenous and endogenous leptin; with a half-life of 3.8-4.7h for metreleptin (FDA, 2014); blood drawn in the morning prior to dosing should mainly contain endogenous leptin. The overall improvement after this 15-day long dosing period was pronounced.

[0095] During the second seven-day long dosing the same AN associated key cognitions dropped within two days of treatment (compare Figs. 2 and 3). Rapid improvements for the VAS items sleep quality, mood swings, urge to vomit, urge to self-harm, compulsive drinking, and overall compulsiveness (incl. excessive hand washing) were observed (Fig. 3). The feeling of disgust upon seeing and touching food also decreased again. The total raw score of the EDI-2 (64 items) (Thiel, Jacobi, Horstmann, Paul, Nutzinger, & Schussler, 1997) dropped slightly from 244 at d-5 to 213 at d6 to rebound after end of dosing. After cessation of dosing and similar to the first post-dosing period, sleep quality deteriorated and heart palpitations increased again ; nevertheless, other positive changes persisted for a few weeks. This second dosing period also quickly improved her mental and general condition. She showed a strong motivation and reported the “opportunity to briefly distance myself from my problems”. Additionally, the motivation for recovery increased, which was very noticeable to family members and treatment staff, too. She was able to gain weight up to 62.2 kg six weeks after the end of dosing period two.

[0096] Body weight: reveals that the medium-term trends in body weight change were not altered by the 14- and 7-day long metreleptin dosing periods. Weight declined minimally during the first dosing period and increased during the second.

[0097] Leptin levels: Prior to both dosing periods T had normal or high levels of endogenous leptin adjusted for BMI, sex and Tanner stage derived from healthy post-pubertal girls (Fig 4; Mediagnost (Blum et al., 1997)). BMI and leptin levels of the patient were correlated (Fig. 4), but the slope was steep and surpassed the 99th adjusted percentile (Blum et al., 1997).

[0098] In both samples and for unknown reasons, the immunoreactive leptin values were lower than the corresponding values for functional leptin (bioLEP / irLEP quotient = 1 ,0)(Wabitsch et al., 2017). In concordance with the absence of hyperphagia and obesity, sequencing of the leptin gene of patient T revealed no mutations.

[0099] Example 3: Treatment of ANpr with metreleptin

[0100] Patient 3 originally had received inpatient treatment for AN at age 12. Despite regaining weight she continued to suffer from AN-specific eating disorder cognitions and emotions. At age 16.5 she presented with ANpr; in light of continuous symptoms of AN despite a weight in the low normal range off-label metreleptin treatment was initiated on an inpatient basis. Her admission body weight and height were 52.6 kg and 171 cm. The corresponding BMI, BMI-centile and BMI- SDS (German reference data according to Kromeyer-Hausschild et al., 2000) were 17.99 kg / m2, 11 and -1.22. The BMI-centile of 11 is clearly above the recommended DSM-5 (APA, 2013) diagnostic cut-off of 5. As such, the appropriate DSM-5 diagnosis was ANpr. Upon admission the patient showed hypoleptinemia (1.4 ng / ml).

[0101] Treatment was initiated with 6mg metreleptin; this dosage was applied for a total of eight days. The patient filled in VAS scales; the results are shown below. Importantly, ‘repetitive thoughts of food’, ‘feeling full’ and ‘preoccupation with the eating disorder’ decreased during the dosing period, whereas ‘social interest’ increased. The improvement that the patient experienced within this short time span is shown in Figure 5.REFERENCES

[0102] The references are:1. [APA] APA. Diagnostic and Statistical Manual of Mental Disorders, 5th Edn. Arlington, VA: American Psychiatric Publishing; 2013.2. Hebebrand J, Bulik CM. Critical appraisal of the provisional DSM-5 criteria for anorexia nervosa and an alternative proposal. Int J Eat Disord 2011 ;44:665-78.3. Hebebrand J, Milos G, Wabitsch M, et al. Clinical Trials Required to Assess Potential Benefits and Side Effects of Treatment of Patients With Anorexia Nervosa With Recombinant Human Leptin. Front Psychol 2019; 10:769.4. Hebebrand J, Blum WF, Barth N, et al. Leptin levels in patients with anorexia nervosa are reduced in the acute stage and elevated upon short-term weight restoration. Mol Psychiatry 1997;2:330-4.5. Ahima RS, Flier JS. Leptin. Annu Rev Physiol 2000;62:413-37.6. Exner C, Hebebrand J, Remschmidt H, et al. Leptin suppresses semi-starvation induced hyperactivity in rats: implications for anorexia nervosa. Mol Psychiatry 2000;5:476-81.7. Fernandes MF, Matthys D, Hryhorczuk C, et al. Leptin Suppresses the Rewarding Effects of Running via STAT3 Signaling in Dopamine Neurons. Cell Metab 2015;22:741-9.8. Coccurello R, Maccarrone M. Hedonic Eating and the "Delicious Circle": From Lipid- Derived Mediators to Brain Dopamine and Back. Front Neurosci 2018;12:271.9. Monteleone AM, Castellini G, Volpe U, et al. Neuroendocrinology and brain imaging of reward in eating disorders: A possible key to the treatment of anorexia nervosa and bulimia nervosa. Prog Neuropsychopharmacol Biol Psychiatry 2018;80:132-42.10. Khanh DV, Choi YH, Moh SH, Kinyua AW, Kim KW Leptin and insulin signaling in dopaminergic neurons: relationship between energy balance and reward system. Front Psychol 2014;5:846.11 . Brown RJ, Oral EA, Cochran E, et al. Long-term effectiveness and safety of metreleptin in the treatment of patients with generalized lipodystrophy. Endocrine 2018;60:479-89.12. FDA. SUMMARY REVIEW for Regulatory Action; Myalept; Application Number 1253900rig1s000, ed. C.F.D.E.A. RESEARCH. In: Administration FaD, ed. Silver Spring, MD: FDA; 2014.13. Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999;341 :879-84.14. Wabitsch M, Funcke JB, Lennerz B, et al. Biologically inactive leptin and early-onset extreme obesity. N Engl J Med 2015;372:48-54.15. Paz-Filho G, Wong ML, Licinio J. Ten years of leptin replacement therapy. Obes Rev 2011 ;12:e315-23.16. Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004;351 :987-97.17. Chou SH, Chamberland JP, Liu X, et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A 2011 ;108:6585-90.18. Sienkiewicz E, Magkos F, Aronis KN, et al. Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metabolism 2011;60:1211-21.19. Parsa-Parsi R, Blackmer J, Ehni HJ, Janbu T, Kloiber O, Wiesing II. Reconsidering the Declaration of Helsinki. Lancet 2013;382:1246-7.20. WMA. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Fortaleza, Brazil: 64th WMA General Assembly; 2013.21. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62.22. Garner DM. Eating Disorder Inventory-2: Professional manual. Odessa, FL: Psychological Assessment Resources; 1991.23. Beck AT, Steer RA, eds. Beck Depression Inventory - Manual. San Antonio: The Psychological Corporation1987.24. Bruch H. The Golden Cage. The Enigma of Anorexia Nervosa, With a New Foreword by Catherine Steiner-Adair, Ed.D. Boston: Harvard University Press; 2001.25. Fantuzzi G, Faggioni R. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 2000;68:437-46.26. Poeggeler B, Schulz C, Pappolla MA, et al. Leptin and the skin: a new frontier. Exp Dermatol 2010;19:12-8.27. Yarandi SS, Hebbar G, Sauer CG, Cole CR, Ziegler TR. Diverse roles of leptin in the gastrointestinal tract: modulation of motility, absorption, growth, and inflammation. Nutrition 2011 ;27:269-75.28. Auyeung B, Lombardo MV, Baron-Cohen S. Prenatal and postnatal hormone effects on the human brain and cognition. Pflugers Arch 2013;465:557-71.

Claims

CLAIMS1. A leptin compound for use in treating an atypical eating disorder in a subject, comprising an administration of a therapeutically effective amount of the leptin compound to the subject, wherein the leptin compound is selected from leptin, a leptin derivative, and / or a leptin- and / or leptin receptor agonist; and wherein the subject preferably is characterized by being non-underweight and suffering from Atypica Anorexia Nervosa (AAN) or Anorexia Nervosa in partial remission (ANpr) or by suffering from AN but being normoleptinemic (ANnl).

2. The leptin compound for use of claim 1 , wherein the subject does not suffer from classical anorexia nervosa (AN), or suffers from AN but has a normal to high serum leptin level, or is in partial remission (ANpr) and is not underweight.

3. The leptin compound for use of claim 1 or 2, wherein the atypical eating disorder is atypical AN, or AN and the subject presents both with a leptin level in the physiological range and a normal or high serum leptin level adjusted for Body Mass Index (BMI) and sex, and optionally Tanner stage (preferably a leptin level higher than about 5 ng / ml).

4. The leptin compound for use of any one of claims 1 to 3, wherein the subject does not suffer from marked underweight (such as exemplary a BMI < 15 kg / m2).

5. The leptin compound for use of any one of claims 1 to 4, wherein the leptin, or the leptin- and / or leptin receptor agonist, or the leptin analog or derivative thereof, is administered at: from about 1 microgram per day, from about 5 micrograms per day, about 10 micrograms per day, from about 50 micrograms per day, or from about 100 micrograms per day; to about 100 micrograms per day, to about 500 micrograms per day, to about 1 milligram per day, to about 5 milligrams per day, to about 50 milligrams per day, or to about 100 milligrams per day; or from about 0.01 milligram per kilogram to about 0.3 milligram, or from about 0.01 milligram per kilogram to about 20 milligrams per kilogram.

6. The leptin compound for use of any one of claims 1 to 5, wherein the leptin compound is metreleptin.

7. The leptin compound for use of claim 6, wherein metreleptin is administered at: from about 1 milligram per day, from about 5 milligrams per day, to about a maximum of 10milligrams per day; or from about 0.06 milligram per kilogram per day to about 2.5 milligrams per kilogram per day.

8. The leptin compound for use of claim 6 or 7, wherein metreleptin is administered at 0.06 mg / kg to 10mg per day, once daily, preferably wherein metreleptin is administered at about 3 to 10 mg per day, once daily.

9. The leptin compound for use of any one of claims 1 to 8, wherein the leptin, or the leptin- and / or leptin receptor agonist, or the leptin analog or derivative thereof, is administered once daily, or is administered in two or more dose administrations over one day.

10. The leptin compound for use of any one of claims 1 to 9, wherein the administration of the leptin compound is an administration suitable for effective administration of the leptin compound, and may include intranasal administration or administration by subcutaneous injection.

11. The leptin compound for use of any one of claims 1 to 10, wherein the subject is a primate.

12. The leptin compound for use of any one of claims 1 to 11 , wherein the subject is a human, such as a female or male human.

13. The leptin compound for use of any one of claims 1 to 12, wherein the subject is a human and has a body mass index (BMI) that is within a healthy range for the age group and sex of the subject; and optionally is higher than about 17.5 kg / m2.

14. The leptin compound for use of any one of claims 1 to 13, wherein the subject is a human and has a BMI adjusted serum leptin concentration of about 5 ng / ml or more.

15. The leptin compound for use of claim 14, wherein the subject has no mutated leptin gene.

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