WO2023287755A1 - High dose histamine h2-receptor antagonists for the treatment of hypoleptinemia and associated metabolic disorders including methods and compositions to said treatment - Google Patents

Abstract

There is significant evidence that implicates the use of leptin or leptin analogs as a treatment approach for certain metabolic disorders and associated eating disorders. Currently, the only regulatory approval for use of leptin is a leptin analog, metreleptin (Myalept), marketed and sold for the treatment of congenital or acquired generalized lipodystrophy. There is growing evidence in support for leptin administration in treating a variety of disorders related to loss of appetite that is based upon the understanding of its central action on feeding circuitry in the brainstem, hypothalamus and reward centers. Our discovery that high dose H2 receptor antagonists (H2RA) can stimulate sufficient endogenous leptin release from gastric epithelial cells supports its effects as an alternative approach for the treatment of lipodystrophy, but also as an appetite stimulant.

Description

High Dose Histamine H2-Receptor Antagonists for the Treatment of Hypoleptinemia and Associated Metabolic Disorders Including Methods and Compositions to Said

Treatment

Related Application

This application claims the benefit of U.S. Provisional Application No. 63/220,957, filed on July 12, 2021. The entire teachings of the above application are incorporated herein by reference.

Background

Leptin is a protein codified by the obesity gene (ob), which is known to mediate its activity through the central nervous system (CNS) as a signal to regulate body weight and energy homeostasis [Halaas JL et al., 1995], Initially, leptin was considered an anti-obesity hormone, but evidence has shown that this molecule participates in many metabolic and endocrine processes [Ahima RS et al., 2008], Leptin is largely synthesized and released from adipose tissue and has been detected in the human placenta, ovaries and muscles. Leptin and its receptor are also present in the human gastric mucosa demonstrating that leptin also is a stomach derived protein in humans [Ciniti et al., 2000], The gastric mucosa has been shown to secrete large amounts of leptin. Detection of leptin in rat gastric epithelium prompted investigation into the presence and role of leptin and receptors in the human stomach (Bado et al., 1998). Immunohistochemistry revealed that Chief cells of the gastric mucosa contain leptin in their secretory granules. Upon stimulation by nervous system or hormonal factors, leptin is released into the gastric juice linked to a protein of high molecular weight, and this complex is targeted in its intact form to the duodenum where it is absorbed by the capillaries into the systemic circulation [Cammisotto P et al., 2012], These findings suggest that human gastric epithelial cells maybe direct targets for pharmacological intervention. Our discovery that H2RAs mediate release of gastric derived leptin provides a novel method for the treatment of lipodystrophy and other metabolic disorders that result from insufficient leptin.

A complete understanding of the role of leptin in humans is a matter of profound interest. A fuller understanding of mechanism of action of leptin and the modulation of peripheral targets involved in its regulation may offer meaningful clinical approaches to therapy that extend beyond the treatment of lipodystrophy, the only currently FDA approved indication for leptin replacement therapy. In particular, the use of leptin analogs or leptin modulating agents that restore normative levels of leptin in the circulation may offer the opportunity for replacement therapy in conditions where low-leptin states have been implicated, including, but not limited to lipodystrophy, anorexia nervosa, ARFID (acute restrictive food intake disorder), bulimia, cancer cachexia and aging, including sarcopenia. Other disorders of relative hypoleptemia include diabetes, Alzheimer's disease, Parkinson's disease, depression, hypothalamic amenorrhea, lipoatrophy, chronic inflammatory_'· disease, autism, stroke, HIV infection and menopause. Subjects may be diagnosed with one or more than one of these metabolic disorders (e.g., a subject may be both diabetic and bulimic or diabetic without an eating disorder diagnosis).

The subject can also be diagnosed with a cachectic state hyperactivity. A recent study demonstrated that normalization of low circulating leptin levels in patients with anorexia nervosa ameliorates hyperactivity in seriously ill females when treated with Myalept™ metre! eptin for subcutaneous use. The beneficial effects of leptin treatment appeared to be maintained with leptin level above approximately 2ng/ml. Further, the leptin induced alterations result were clinically evident within 24-48 hours [Milos G et al 2020],

Metrel eptin is an FDA-approved leptin analog as an adjunct to diet as replacement therapy to treat the complications associated with leptin deficiency in patients with congenital or acquired generalized lipodystrophy. However, exogenously administered metroleptin is associated with a number of adverse effects including hypoglycemia, anxiety and weight loss [Myaiept EPAR, 2020], In a recent study, the safety analysis set showed nearly 35% of patients had a serious adverse event (SAE). Ten patients experienced hypoglycemia with eight events judged to be treatment related [Brown RJ et al, 2019]. Other side effects associated with Myaiept include upper respiratory infections, abdominal pain, fatigue and nausea, decreased appetite, back pain, diarrhea, numbness and tingling, and ovarian cysts. Myaiept is self-administered once a day, and patients typically use 14 vials per month at a list price of $5,297 per vial (2021). Since Myaiept is the sole option to control the deficiency, more affordable and safer therapeutic interventions are needed.

Summary of the Invention

To this end, we have discovered that oral administration of H2RA can stimulate the gastric leptin pathway, which offers a more economical, better safety profile and thus an alternative treatment approach, particularly in patients where decreased weight, anxiety, abdominal pain and hypoglycemia are contraindicated, such as anorexia nervosa and cancer cachexia. For example, a menopausal patient was treated for erosive esophagitis with famotidine 40mg orally BID and noticed changes in her behavior and appetite. PEPCID®, or famotidine, was investigated and linked to pepsinogen secreting cells, gastric chief cells. A review showed gastric chief cell as source of gastric leptin. Therefore, we then administered the H2RA famotidine to menopausal patients with low leptin levels in a proof of concept study and explored the physiologic benefits of leptin replacement therapy. These studies were performed based upon the hypothesis that H2RA might increase serum leptin levels and therefore potentially useful in the treatment of metabolic disorders.

The proposed rationale for expanding the label of H2RA and clinical study is based upon the proposed mechanism for gastric leptin release through H2RA. In particular, this class of agents significantly increases gastrin and histamine by inhibition of gastric acid secretion and more gastrin is released and less histamine is lost, which in turn stimulates the release of endogenous stores of leptin from storage granules in Chief cells [see The Figure], Gastrin plays a critical role in stimulating clinical meaningful significant circulating levels leptin release from chief cells after the administration of the potent H2RA famotidine (Example 1). Intravenous infusions of pentagastrin caused an increase in circulating leptin levels and release into the gastric juice. Pentagastrin is a synthetic form of hormone gastrin [Sobhani I et al., 2000], Elevated gastrin levels had been shown with H2RA. Ohsawa showed that gastrin level in the fasting state was significantly higher (p = .01) with famotidine than with cimetidine and after cessation of the drug therapy, the fasting serum gastrin level was significantly lower than that during H2RA therapy. In the meal stimulated gastrin test, the AUC of gastrin during treatment with H2RA treatment was significantly higher (p= .002) with famotidine than with cimetidine [Ohsawa et al., 2002], Histamine also plays a critical role in leptin release given histamine stimulates chief cells. Elevated histamine gastric mucosal levels had been shown with H2RA cimetidine. Man and colleagues looked at patients suffering from various gastrointestinal disorders where gastric mucosal histamine was assayed before and after receiving cimetidine. The study showed a mean rise of 80% in histamine content during treatment with cimetidine. In patients infused intravenously with cimetidine for only 48 hours, mucosal histamine increased and continued to increase significantly after 6 weeks of oral cimetidine [Man WK et al., 1981],

Brief Description of the Drawing

The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawing in which like reference characters refer to the same parts throughout the different views. The drawing is not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.

The Figure shows H2RA significantly increases gastrin and histamine by inhibition of gastric acid secretion and more gastrin is released and less histamine is lost so that endogenous stores are increased.

In our preliminary studies we examined the effect of the H2RA famotidine given that it is 20 times more potent than cimetidine on an equimolar basis [Berardi RR et al., 1988], Generally, famotidine is well tolerated in patients with renal, cardiac and hepatic dysfunctions, moreover it is considered to have an excellent safety profile [Howden CW et al., 1996], Taken together, we chose to examine the effect of famotidine in stimulating leptin levels in patients with low leptin levels and eating disorders.

Famotidine is poorly water soluble. Bioavailability can be improved with various formulation techniques. For example, the H2RA, e.g., famotidine, can be formulated in a water-solubilizing excipient, such as a cyclodextrin, including 2-HydroxyPropyl-B- cyclodextrin (HR-b-CyD) or a sulfobutyl ether B- cyclodextrin (CAPTISOL® by Ligand Pharmaceuticals, Inc.) HR-b-CyD has been approved by the FDA as an excipient for poorly soluble active pharmaceutical ingredients. Islam and colleagues have demonstrated that famotidine can be effectively formulated into inclusion complexes and fast dissolving tablets with significantly enhanced solubility and gastrointestinal absorption (Islam MS et al., 1991). We view increased bioavailability and rapid achievement of circulating plasma leptin levels as a significant advantage in our invention. We anticipate less variability in drug levels and effect and the ability to generate both rapid release and biological effects less subject to pharmacogenetic differences in ADME and response.

Our pilot study also looked at the possibility that orally delivered H2RA might affect behavioral changes. This is based upon the view of the postulated beneficial effect on starvation-related emotions and cognitions, such hyperactivity and fear of weight and feeling fat, leptin treatment allows anorexia patients to think outside the "cage " meaning that they were less hyperactive which allowed them to view themselves realistically without being constrained by their eating disorder [Milos G et al., 2020], Interestingly, patients with schizoaffective disorder were given famotidine lOOmg/day and were rated by using a brief psychiatric rating scale. On outcome measure, statistically significant improvement in score suggestive of a beneficial behavioral effect of famotidine was found. Famotidine was well tolerated by study subjects. There was a wide range of famotidine blood levels observed and the patients with the greatest improvement in score had some of the higher famotidine levels found in the study [Rosse RB et al., 1996], Another study showed that after one week the behavioral symptoms of persons suffering from schizophrenia started to decrease and continued to decrease statistically significantly with high dose famotidine 200 mg/ daily treatment [Meskanen K et al, 2013], Therefore, an observable behavioral effect of H2RA on leptin levels is more likely to occur with a dosage form able to achieve higher famotidine serum concentration levels. This invention also points to the use of solubilized formulations of H2RA to achieve a rapid increase in leptin levels in achieving normative metabolic function.

High dose famotidine is generally safe and well- tolerated. For example, patient- reported outcome measures for 10 consecutively enrolled non-hospitalized patients with COVID-19 noticed improvements in their condition in correlation with famotidine use at doses ranging from 60 mg to 240 mg daily. Based on published pharmacokinetic data for famotidine, we estimate that these treatment regimens would have resulted in peak plasma concentrations of approximately 0.5-2 μM and average plasma concentrations of approximately 0.15-0.7 μM famotidine, assuming normal kidney function. In concordance with the clinical evidence and consensus that famotidine is safe across a wide range of doses and frequencies, famotidine was very well tolerated by all patients. Given that famotidine has only minimal inhibitory effect on the hepatic cytochrome p450 system and low risk of clinically significant alterations in oxidative drug metabolism, it may be a safe drug in clinical setting where patients can self-administer high dose famotidine (240mg/daily) in an out-patient setting [Janowitz T et al., 2020],

Overall, cachexia related conditions are associated with low leptin levels, increase activation of POMC neurons and decreased expression of AgRP neurons despite low appetite. [Engineer DR et al., 2012, Palmiero M et al., 2002] [Table 1], Table 1 : Summary of markers of appetite regulation in cachectic states

Our pilot study also looked at the H2RA effects on delayed puberty given it is one of the cardinal features of and risk factors for anorexia nervosa and is associated with hypothalamic dysfunction. Only single studies have addressed the relationship between leptin and the hypothalamus-pituitary -gonadal axis (HPG) in anorexia nervosa (AN). In one study 18 female adolescents with AN were investigated during weight gam. Leptin, LH, F8H, BMI were measured in the 1 (si), 3(rd), 7(th) and 11 (th) week of inpatient treatment. The results demonstrate a critical leptin level of 1.2 ng/ml for an increase of FSH and confirmed a leptin threshold level of 1.85 ng/ml for LH. it may be concluded that leptin represents a metabolic gate to gonadotropin secretion. Once this is exceeded other biological mechanisms seem to be important for the complete recovery' of the reproductive function and the resumption of puberty [Holtkamp et ai., 2003],

Altogether, the invention relates to the administration of high dose famotidine with methods to achieve a therapeutically induced rapid resolution of somatic and behavioral signs and symptoms resulting from increasing gastric leptin in patients characterized by low leptin levels.

Detailed Description of the Invention

The present invention provides the use of H2RA, in particular, the potent antagonist, famotidine preferably in high doses, in treating subjects, such as humans, with eating disorders and its associated metabolic abnormalities, and provides a method and compositions to said treatment for parenteral or injectable administration. In a preferred embodiment, famotidine can be formulated in an inclusion complex with 2-Hydroxypropyl- beta-cyclodextrin (HPCD), enabling solubilized drug optimized for oral, intravenous, intramuscular or sub-q injection and the ability to achieve a high Cmax with less active pharmaceutical ingredient in achieving an acute effect. The complex is markedly more soluble than the pure drug resulting in an increase in its dissolution rate. Parenterally delivered famotidine is sufficient to observe increases in blood levels of leptin. In assessing the predisposition of eating disorder patient to treatment with famotidine, serum concentration of leptin may be determined. Preferably, a patient with serum leptin concentration of less than 2ng/ml are candidates for famotidine treatment.

In a preferred embodiment, the invention provides a method of treating a subject with an eating disorder comprising administering to the subject an appetite-stimulating amount of an H2 receptor antagonist (H2RA). The subject can be a human or an animal, e.g., for veterinary or model purposes. In addition to human subjects, companion animals, such as dogs, cats, rabbits, hamsters, ferrets, rats, mice, guinea pigs and horses can be treated. Farm animals can also be treated, preferably mammals, such as cows, pigs, goats, horses, minks and sheep. Human subjects are preferred.

The method, in part, is based on the discovery that H2 receptor antagonists increase, or restore, leptin plasma levels. Thus, in an embodiment, the subject has a leptin plasma level of 2ng/ml of less prior to administration of H2 receptor antagonist. After treatment, as described in more detail below, leptin plasma levels of 2ng/ml or more can be achieved with H2 receptor antagonist treatment. Target leptin plasma levels can be between about 2ng/ml and about 9ng/ml. Thus, it can be advantageous for the method to further comprise the step of assaying leptin plasma levels of the subject before and/or after the administration of the H2 receptor antagonist.

The hypoleptinemia metabolic disorder can be lipoatrophy or generalized, partial, or acquired lipodystrophy. The hypoleptinemia metabolic disorder can be, a subject in a cachectic state and can, optionally, be associated with cachectic state hyperactivity or cachectic state delayed puberty. The metabolic disorder can also be selected from the group consisting of anorexia nervosa, acute restrictive food intake disorder (ARFID), cancer cachexia, aging, sarcopenia, orthorexia, bulimia and other specified feeding or eating disorders (OSFED or Eating Disorder Not Otherwise Specified). Subjects can be diagnosed consistent with the practices of the American Psychiatric Association, in particular with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), pages 329- 354, incorporated herein by reference.

Subjects winch have hypoleptinemia or at risk of a metabolic disorder include subjects diagnosed with diabetes, Alzheimer's disease, Parkinson's disease, depression, autism, chronic inflammatory disease, stroke, menopause and HIV infection, for example. Thus, the methods of the invention include treating subjects with a comorbidity of metabolic disorder and one or more of these disorders or conditions. In addition, a subject can be diagnosed with one of these disorders, preferably also shown to possess leptin plasma levels of less than about 2 ng/ml, and treated to prevent developing a metabolic disorder.

The method can further increase gonadotropin levels and/or improved reproductive function in patients. The term "treating", as used herein, means relieving, lessening, reducing, eliminating, modulating, or ameliorating, i.e., causing regression of the disease state or condition. Treating can also include inhibiting, i.e., arresting the development, of an existing disease state or condition, and relieving or ameliorating, i.e., causing regression of an existing disease state or condition, for example when the disease state or condition may already be present.

The term "preventing", as used herein means, to completely or almost completely stop a disease state or condition, from occurring in a patient or subject, especially when the patient or subject is predisposed to such or at risk of contracting a disease state or condition.

The H2 receptor antagonists are generally known in the art and include a compound selected from the group consisting of famotidine, cimetidine, ranitidine, nizatidine, SKF 93474, dimetidine, roxatidine, ebrotidine, burimamide, metiamide, tiotidine and oxmetidine.

Famotidine is a particularly potent H2RA and has the chemical structure:

A number of H2 receptor antagonists are known in the literature. The inventors contemplate the use of the SAR available on these compounds to design additional potent H2RA compounds. As used herein, the invention contemplates analogs of the listed H2RA compounds. The term "analog" refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar to or comparable in function and appearance to the reference compound.

The compound can be administered as a free base or as a salt. "Pharmaceutically acceptable salts," or "salts," include the salt of a proton pump inhibitor prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, beta-hydroxybutyric, galactaric and galacturonic acids.

In one embodiment, acid addition salts are prepared from the free base forms using, for example, methodologies involving reaction of the free base with a suitable acid. Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

The H2 receptor antagonist can be administered orally, parenterally, intravenously, intramuscularly or subcutaneously in a pharmaceutically acceptable composition comprising one or more pharmaceutically acceptable excipients.

The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention Formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or Formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; com oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the Formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray.

The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the Formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the Formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical Formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic Formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Solubilizing agents, such as cyclodextrins, including 2-HydroxyPropyl-B- cyclodextrin (HR-b-CyD) or a sulfobutyl ether B- cyclodextrin (CAPTISOL® by Ligand Pharmaceuticals, Inc.) can be used to improve bioavailability. Alternatively, surface stabilizers on drug nanoparticles, as described by Liversidge et al. (US 5,145,684) can be used.

In one embodiment, the pharmaceutical composition is a controlled release composition comprising an H2RA and one or more pharmaceutically acceptable carriers. The controlled release composition provides a therapeutically effective amount of compound to a subject for at least about 4 hours, or at least about 8 hours to at least about 24 hours.

As used herein, "controlled-release" means a dosage form in which the release of the active agent is controlled or modified over a period of time. Controlled can mean, for example, sustained, delayed or pulsed-release at a particular time. For example, controlled- release can mean that the release of the active ingredient is extended for longer than it would be in an immediate-release dosage form, i.e., at least over several hours.

As used herein, "immediate-release" means a dosage form in which greater than or equal to about 75% of the active ingredient is released within two hours, or, more specifically, within one hour, of administration. Immediate-release or controlled-release may also be characterized by their dissolution profiles.

Formulations may also be characterized by their pharmacokinetic parameters. As used herein, "pharmacokinetic parameters" describe the in vivo characteristics of the active ingredient over time, including for example plasma concentration of the active ingredient. As used herein, "Cmax" means the measured concentration of the active ingredient in the plasma at the point of maximum concentration. "Tmax" refers to the time at which the concentration of the active ingredient in the plasma is the highest. "AUC" is the area under the curve of a graph of the concentration of the active ingredient (typically plasma concentration) vs. time, measured from one time to another.

The controlled-release formulations provided herein provide desirable properties and advantages. For example, the formulations can be administered once daily, which is particularly desirable for the subjects described herein. The formulation can provide many therapeutic benefits that are not achieved with corresponding shorter acting, or immediate- release preparations. For example, the formulation can maintain lower, more steady plasma peak values, for example, Cmax, so as to reduce the incidence and severity of possible side effects.

Dual release formulations can combine the active ingredient in immediate release form with additional active ingredient in controlled-release form. For example, a bilayer tablet can be formed with one layer containing immediate release active ingredient and the other layer containing the active ingredient embedded in a matrix from which it is released by diffusion or erosion. Alternatively, one or more immediate release beads can be combined with one or more beads which are coated with a release rate-controlling membrane in a capsule to give a dual release formulation. Sustained release formulations in which the active ingredient is present in a core provided with an outer coating impermeable to the active ingredient, the outer coating having an aperture (which may be drilled) for release of the active ingredient, can be coated with drug in immediate release form to give a dual release formulation. Dual release formulations can also combine drug in immediate release form with additional drug in pulsed release form. For example, a capsule containing an erodible plug could liberate drug initially and, after a predetermined period of time, release additional drug in immediate- or sustained-release form.

Appropriate dosing will depend on the size and health of the subject and can be readily determined by a trained clinician. The preliminary oral dose of famotidine was found to be successful between about 60 rng and about 240 mg daily. The H2 receptor antagonist can be administered successfully orally dosed daily, twice daily, three times daily or four times daily.

The following examples are used to describe the present invention. It is understood that they are merely exemplary and are understood not to limit the breadth of the invention in any way.

Example 1

To determine if famotidine treatment will increase fasting serum leptin levels in humans. To determine if famotidine treatment would cause serious adverse event hypoglycemia with hypoglycemia being defined as occurring when the level of glucose drops below 70 mg/dl.

The patients were female who had been given a diagnosis of menopause. The group was chosen as a cohort for metabolic disorder anorexia as both groups have low leptin and low estradiol serum levels. In addition, menopause is characterized by a decrease in the expression of the obesity leptin gene [Cento RM et al., 1999], The study was designed as a prospective open-labeled pilot study. The goal in this study was to achieve a leptin rising rate [leptin after [LA]/leptin before [LB] x 100] comparable to pituitary suppressed reproductive age females then subsequently taking high dose estradiol valerate (3mg/day) therapy for 10 days [Geber S et al., 2012], The cohort was given famotidine 80mg/day therapy. The effect of famotidine on fasting serum leptin after 7 days of therapy is shown in Table 2. The effects of famotidine on fasting glucose pre dose and then 2 hours after post dose after 7 days of treatment (Table 3). Table 2: Serum Leptin (ng/ml) levels measured before and after treatment

Table 3: Serum Fasting Glucose (mg/dl) pre-dose and 2 hours post-dose

Discussion

The leptin rate was calculated to evaluate the rising rate of leptin levels from the first to the second analysis. We detected similar leptin rates between menopausal women and pituitary suppressed reproductive age women. The mean leptin rate in the menopausal group was 140.2 and 136.7 in the estradiol group. The difference between these two groups was not significant. This is the first evidence that famotidine might display agonistic activity for gastric leptin in vivo in humans. Serious adverse event hypoglycemia was not observed with famotidine use even in the fasting stage and two hours post dose suggesting that high dose famotidine is a safe option for leptin replacement therapy. Example 2

Brief Summary

This open-label pilot study (n= 20) seeks to investigate the safety and efficacy of famotidine in adolescent persons (11-14 years old) with anorexia nervosa (AN) and hypoleptinemia. Famotidine has previously been demonstrated to increase leptin levels. The investigators seek to determine whether similar changes can be safely produced in people with AN when famotidine is administered in a supportive setting with close follow-up. The investigators' specific aim is that famotidine is safe to administer in people with AN, that it will increase serum leptin levels, and that it will lead to increased quality of life. The investigators will also assess a number of exploratory measures related to eating disorder pathophysiology.

Rationale

Specifically, the study will examine famotidine effects on serum leptin and LH (luteinizing hormone) as markers of gonadal activity, in order to assess the restoration of reproductive function in adolescent patients with anorexia nervosa (AN). Delayed puberty is a very common condition that manifests in adolescent AN patients with low gonadotrophins and leptin levels. It is known that AN of early onset occurring during the course of puberty may have a devasting effect on a girl's physical development. More seriously, it may interfere permanently with growth in stature and breast development. Thus, a method of treatment that normalizes the disordered eating behavior of AN results in much better long term physiological and emotional outcomes. For example in one study, Leptin (p = 0.0039) and LH (p = 0.0323) and were important predictors of reproductive recovery in patients with anorexia nervosa. Among aforementioned parameters, leptin (p = 0.0057) appeared to be the most important [Cetkovic A et ah, 2006]. The study will also examine AN effects of hyperactivity given it's a common behavioral manifest in AN patients, which has been linked to hypoleptemia. In Rodent, semi-starvation hyperactivity proved to be rapidly amenable to the treatment with leptin [Exner C et ah, 2000], There is growing support that leptin behavioral effects are largely mediated through the central nervous system. Leptin suppresses the rewarding effects of running via STATS signaling in Dopamine neurons. Leptin inhibits hyperactivity and 'runners high' during semi-starvation [Fernandez M et al. 2015], Lastly, hypoglycemia is a safety issue with any treatment for hypoleptinemia. Given reported serious adverse event hypoglycemia with metreleptin, we will analyze the effects of famotidine on fasting blood glucose levels in AN patients.

Specific Aim: It is hypothesized that adolescent AN patients, being leptin deficient, would respond to orally administered famotidine with hyperactivity being alleviated by increasing serum leptin and increase gonadotropins to assist in recovery of reproductive function. Therefore, high dose famotidine (120mg/daily) was administered to AN patients over 14 days with concomitant measurement of fasting serum leptin, LH, and glucose at baseline, day 2, 7, and 14. Fasting serum leptin level taken before dosing is the best indicator of steady state endogenous leptin serum levels [Wong et al., 2004], All patients filled in an 8-item visual analog scale (VAS), scaled 1-10, for the assessment of key emotions before and after treatment; the items are hunger, fear of gaining weight, depressed mood, inner tension, drive for activity, feeling full, feeling fat and repetitive thoughts of food.

Results

The mean serum fasting leptin concentration was less than 2ng/rnL at baseline which increased with therapy. Therefore, high dose famotidine at the doses used in this study resulted in the restoration of serum leptm to normal levels in AN patients.

Discussion

These results indicate the potential use of high dose H2 receptor antagonists for the restoration of physiological normal levels of circulating leptin in modulating hypoleptinemia associated metabolic disorders where normative behaviors are associated with normal leptin levels. The ability to peripherally modulate leptin release through the gastric mucosa through administration of the potent H2RA famotidine chronically offers the ability to restore metabolic and endocrinologic function in patients where either genetic or behavioral anomalies have led to metabolic syndromes or diseases that lead to poor health and morbidities associated with hypoleptinemia. This preliminary study also offers the opportunity to explore additional modes of delivery in pharmaceutical composition designed for the acute restoration of leptin in patients unable to take medications orally, including cachectic patients hospitalized who refuse to eat to cancer patients where loss of appetite is often associate with cancer treatment.

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

All References cited herein are incorporated by reference in their entirety.

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Patent citations

1. US7,183,254: Use of leptin for treating human lipoatrophy and methods of determining predisposition to said treatment.

2. US 9,962,344: Chemosensory receptor ligand-based therapies. 3. US 6,750,234: Method for increasing leptin levels using nicotinic compounds.

Claims

CLAIMS What is claimed:

1. A method of treating a subject with a condition of a hypoleptinemia associated metabolic disorder, which comprises administering to a patient a dose of histamine-2 receptor antagonist effective to treat the said condition.

2. Tire method of claim 1, wherein the subject is a human.

3. The method of claim 2, wherein the H2 receptor antagonist increases leptin plasma levels.

4. The method of claim 3, wherein the subject has a leptin plasma level of 2ng/ml of less prior to administration of H2 receptor antagonist.

5. The method of claim 4, wherein the subject has a leptin plasma level of 2ng/ml or more with H2 receptor antagonist treatment.

6. The method of claim 5, wherein the method further comprises the step of assaying the leptin levels of a patient before and/or after the administration of the H2 receptor antagonist.

7. The method of claim 1, wherein the eating disorder is a cachectic state.

8. The method of claim 7, wherein the method alleviated cachectic state hyperactivity.

9. The method of claim 1, wherein the eating disorder is selected from the group consisting of anorexia nervosa, acute restrictive food intake disorder (ARFID), cancer cachexia, aging, sarcopenia, orthorexia, and bulimia.

10. The method of claim 1, wherein the subject has been diagnosed with diabetes, Alzheimer's disease, Parkinson's disease, depression, autism, chronic inflammatory disease, stroke, menopause and HIV infection.

11. The method of claim 1, wherein said H2 receptor antagonist is administered orally, parenteraliy, intravenously, intramuscularly or subcutaneously,

12. The method of claim 1, wherein the method further increased gonadotropin levels and/or improved reproductive function.

13. The method of claim 12, wherein the H2 receptor antagonist increases leptin plasma levels.

14. The method of claim 1, wherein the subject has been diagnosed with lipoatrophy or generalized, partial, or acquired lipodystrophy.

15. The method of claim 1, wherein the leptin level range is between 2ng/ml and 9ng/ml with H2 receptor antagonist treatment.

16. The method of claim 1, wherein the H2 receptor antagonist is selected from the group consisting of famotidine, cimetidine, ranitidine, nizatidine, SKF 93474, dimetidine, roxatidine, ebrotidine, burimamide, metiamide, tiotidine and oxmetidine.

17. The method of claim 16, wherein the oral dose of famotidine is between about 60 mg and about 240 mg daily.

18. The method of claim 1, wherein said H2 receptor antagonist is administered daily, twice daily, three times daily or four times daily.

19. The method of claim 1, wherein said H2 receptor antagonist is administered together with a pharmaceutically acceptable carrier.

20. The method of claim 1, wherein said H2 receptor antagonist is orally administered in a pharmaceutically acceptable diluent that increases dissolution rate and aqueous solubility of the H2 receptor antagonist.

21. The method of claim 16, wherein said H2 receptor antagonist is administered in a pharmaceutically acceptable diluent 2-Hydroxypropyl-beta-cyclodextrin.