The field of the invention

The present invention relates to uses of a melanin-concentrating hormone receptor 1 (MCHR1) antagonist, e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions thereof for the treatment of Prader-Willi Syndrome (PWS), for improving, alleviating or delaying progression of one or more symptoms of PWS, such as hyperphagia, for maintaining or reducing body weight, or for reducing food intake in a patient afflicted with PWS.

The background of the invention

Prader-Willi syndrome (PWS) is a rare complex neurodevelopmental genetic disorder - resulting from absence of expression of imprinted genes in the paternally derived region of the chromosome 15ql l.2-ql3. PWS is the most common syndromic cause of life-threatening obesity with an estimated incidence of 1/10 000 to 1/25 000 live births, occurring equally in both males and females, and across all ethnicities.

The course and early natural history of PWS can be divided into two distinct clinical stages. The first stage occurs during the neonatal and early infancy periods and is characterized by varying degrees of hypotonia, a weak cry, a narrow forehead, developmental delay, temperature instability, a poor suck reflex, sticky saliva, feeding difficulties sometimes requiring gastrostomy or stomach tube placement, hypogonadism, and underdevelopment of the sex organs. Failure-to-thrive is noted during this first stage. The hypotonia is thought to be central in origin, non-progressive, and on the average begins to improve between 8 and 11 months of age. The delay in achieving motor milestones appears to relate more to psychomotor development than to excessive obesity. The second stage usually begins around 2 years of age and is characterized by continued developmental delay or psychomotor retardation and onset of hyperphagia leading to obesity. Other features noted during the second stage may include speech articulation problems, foraging for food, rumination, unmotivated sleepiness (found in greater than 50% of subjects), physical inactivity, decreased pain sensitivity, skin picking and other forms of self-injurious behavior, prolonged periods of hypothermia, strabismus, hypopigmentation, scoliosis, obstructive sleep apnea, and abnormal i oral pathology. Early in the second stage, infants and toddlers are usually easy-going and affectionate, but in about one half of PWS subject personality problems develop between 3 and 5 years of age. Temper tantrums, depression, stubbornness, obsessive compulsivity, and sudden acts of violence of varying degrees may be observed during this stage. These behavioral changes may be initiated by withholding of food but may occur with little provocation during adolescence or young adulthood. Poor peer interactions, immaturity, and inappropriate social behavior may also occur during this time (Butler, Lee, Whitman, Eds. Springer, Management of Prader-Willi Syndrome, Third Edition, 2006).

Many clinical features in PWS may be subtle or non-specific while other features are more characteristic for the disorder. The primary features of PWS include infantile hypotonia, feeding difficulties, mental deficiency, hypogonadism, behavior problems (temper tantrums, stubbornness, obsessive-compulsive disorder), hyperphagia and early childhood onset of obesity, small hands and feet, endocrine disturbances including recently identified growth hormone deficiency, and a characteristic facial appearance.

Hyperphagia, the key behavioral symptom in PWS has remarkable impact on patient and caregiver well-being that extends far beyond the effect of weight gain alone. Management of hyperphagia is ranked as the highest priority among priorities for PWS treatment goals among caregivers. Caregivers would accept significant risk in exchange for improvement of hyperphagic behavior (Tsai et al., MDM Policy Pract. 2021 Jul-Dec; 6(2): 23814683211039457). Much of the morbidity and mortality in PWS is related to the clinical impact of obesity consequent upon the hyperphagia. Life expectancy for people with PWS is reduced with estimates of a 3% mortality rate per year for those with the syndrome. The behavior of hyperphagia itself, independent of obesity, is commonly associated with choking, gastric rupture, and/or respiratory illness (Bellis et al., E r J Med Genet. 2022 Jan; 65(1): 104379).

It is widely accepted, that hyperphagia is a core symptom of PWS patients from about 4 years of age till early adulthood (Miller et al., Am J Med Genet A. 2011 May; 155 A (5): 1040- 9) and is responsible for enormous burden of the entire family or community (Kayadjanian et al., PLoS ONE 16(3): e0248739).

The mechanisms underlying hyperphagia in PWS remain incompletely understood, and to date no drugs have proven effective in controlling appetite. i

Several compounds with different mechanism of action have been failed during the last decade in demonstration of clinical efficacy in hyperphagia in PWS:

Zafgen’s phase 3 trial of the methionine aminopeptidase 2 Inhibitor ZGN-440 (beloranib) in overweight or obese subjects with PWS was halted and the development was terminated due to high risk of thrombotic events resulting death during the clinical trial (McCandless et al., Diabetes Obes Metab. 2017 Dec;19(12):1751-1761).

56-week long efficacy trial of the somatostatin analogue octreotide investigated whether such long-acting administration decreases acylated and desacyl ghrelin concentrations, body mass, appetite and compulsive behavior towards food in adolescents with PWS. Octreotide did not improve body mass or appetite (De Waele et al., E r J Endocrinol. 2008 Oct; 159(4):381-8).

The ghrelin-O-acyltransferase (GOAT) inhibitor GLWL-01 did not statistically significantly reduce hyperphagia-related behavior or bring about changes in global clinical end points, as assessed by caregivers (Miler et al., J Clin Endocrinol Metab, 2022 May 17;107(6): e2373-e2380).

Millendo Therapeutics ⁴ treatment candidate livoletide (AZP-531) being an unacylated ghrelin analogue failed to significantly reduce hunger and improve food-related behaviors in people with Prader-Willi syndrome (PWS) who are taking part in the pivotal ZEPHYR Phase 2b/3 clinical trial (https://praderwillinews.eom/2020/04/07/millendo-stops-livol etide- development-for-pws-after-failure-in-pivotal-zephyr-trial/).

Rhythm Pharma completed a Phase 2 proof of concept, double -blind, placebo- controlled, randomized clinical trial in PWS with the melanocortin-4 receptor agonist setmelanotide (study RM-493-010), which enrolled 40 patients with PWS. The results of the trial showed modest effects on hyperphagia, which did not approach statistical significance, and no effect on weight (Rhythm Pharmaceuticals Form S-l https ://www . sec .gov/Archives/edgar/data/ 1649904/000104746917006046/a2233203zs- la.htm).

Carbetocin is an oxytocin analog with improved specificity for oxytocin receptors. In phase 2 studies, administration of carbetocin to individuals with PWS improved hyperphagia and some other behavioral measures. Demonstration of dose-response relationship was failed in Phase 3 and FDA rejected the new drug application (https://www.levotx.com/news/levo- receives-crl-for-intranasal-carbetocin/).

0X1 orexin receptor antagonists are of interest to treat, relevant for PWS, personality disorders, eating disorders, or anxiety-related disorders. However, known dual 0X1/0 X2 receptor antagonists (Daridorexant, Lemborexant and Suvorexant) are not suitable due to their sleep-inducing effects; therefore, 0X1 selective antagonist developed with a sufficient window to 0X2-mediated effects. Emotion and reward, cognition, impulse control, regulation of autonomic and neuroendocrine functions, and vigilance are linked to 0X1 receptor (Lessel et al. J. Chem. Inf. Model. 2021, 61:5893-5905). A small study in PWS children and healthy siblings identified 40% higher plasma orexin A level (P<0.006) in inflicted patients (Manzardo et al., Am J Genet. 2016, 170:2328-2333) reinforcing that dysregulation of orexin signaling, as orexin acts as an appetite stimulator, interacting with other neuropeptides to modulate food intake, may contribute to behavioral problems and hyperphagia in PWS (Crino et al., Diabetes Metab Syndr Obes. 2018, 11:579-593). At present no clinical phase development of selective 0X1 recepor antagonist is reported for PWS.

Other medications targeting hyperphagia are under investigation, including oxitocin analogues, cannabinoid receptor agonists, controlled-release diazoxide, and tesofensine- metoprolol combination.

Several MCHR1 antagonists have been failed in demonstrating clinical efficacy:

GW856464 (WO 2005/042541 Al, GSK) was discontinued following phase 1, reportedly because of poor oral bioavailability (GSK MCHR1 antagonist, Last updated 18 April 2011, https://adisinsight.springer.com/drugs/800021434).

AMG-076/071 (WO 2004/043958 Al, Tularik/Amgen) was discontinued following a randomized, multiple-dose, placebo controlled, dose-escalation study evaluated the safety, tolerability, and pharmacokinetics. The 40 subjects enrolled did not experience any clinically significant changes in safety parameters including ECGs, vital signs or laboratory results after having been administered daily doses of 5, 20, 60, 80,120, or 180 mg of AMG 076 for 28 days. Treatment-emergent adverse events were reported in 18 subjects, the most common being headache, dizziness and decreased appetite (AMG 076, Last updated 10 September 2008 https://adisinsight.springer.com/drugs/800019931). i

In a phase 1 clinical trial patients on a high calorie diet received NGD-4715 (WO 2006/009789 A2) twice daily for 14 days and in follow up for 14 days. No serious adverse events were observed, however, vivid dreams and awakenings were reported by 50% during week 1. Following the data, Neurogen decided not to advance the compound into phase II testing (http ://adisinsight. springer.com/downloads/mediarelease/ 1817/809084129.html) .) .

ALB-127158 (WO 2009/089482 Al, Albany) was discontinued following a phase 1 clinincal trial. It was reportedly safe, well-tolerated and at the end of the 14-day MAD >45% reduction in appetite and meal size was observed in overweight patients (Moore et al., Neurobiol Disease 2014, 61:47-54). The same compound later was advertised as a phase 2- ready asset (CSTL100) by Consynance with the indication of obesity, NAFLD and inflammatory bowel disease (Consynance accessed at 14.06.2022., https://www.consynance.com/phase-2-ready-assets). Harmony Biosciences acquired it as a new asset (named HBS-102) in 2021 for the treatment of narcolepsy and other rare neurological diseases. Since then, no further development was reported (HBS, accessed at 14.06.2022 https ://www .harmonybiosciences .com/science)

BMS-830216 (WO 2009/146365 Al, Bristol-Myers Squibb): in a phase 1/2, randomized, double -blind, placebo-controlled, ascending multiple-dose and parallel arm study obese subjects (n = 109) received BMS-830216 at 30, 100, 300, 600 or 1200 mg once daily per os for 28 days. The primary outcome was safety - there was no discernible effect on food intake, and the drug increased body weight. Development was terminated due to the lack of efficacy and weight gain (October 23-25, 2012 Metabolic Disease Drug Development - A Hanson Wade Conference, Boston, MA, USA Yie J).

AZD-1979 (WO 2010/125390 Al, Astrazeneca) single-center, single-blind, pharmacokinetic, randomized, placebo-controlled, single-ascending dose, phase I trial was initiated in March 2014, in healthy male volunteers (expected n = 56) in the US. In March 2014, the trial was initiated; in July 2014, the study was terminated as criteria had been reached at dose level 4 (https://clinicaltrials.gov/ct2/show/NCT02072993).

The melanin-concentrating hormone (MCH) plays a multifaceted role in energy homeostasis and being central to the control of hypothalamic food intake and energy expenditure (Pissios et al., Endocr Rev 2006, 27(6):606-620). The neuropeptide mainly produced in the lateral hypothalamus, and the far-reaching axons of these mainly glutamatergic neurons supplies higher cortical areas, limbic structures and basal ganglia, but i also medullar and spinal regions (Saito et al., J Comp Neurol. 2001 Jun 18, 435(l):26-40; Schneeberger et al., Mol Meatab 2018, 13:83-89). The cognate receptor of MCH is the GPCR MCHR1 and its less characterized variant MCHR2 (Pissios et al., Endocrinology 2003, 144(8):3514-3523; Sailer et al., Proc NatlAcad Sci USA. 2001, 98(13):7564-7569). MCHRs are widely but unevenly expressed in the mammalian brain but are also present in some peripheral tissues like pancreas, GI tract or reproductive organs. MCHR1 is associated with Gaq/11 and Gai/o while MCHR2 only with Gaq (Saito et al., J Comp Neurol. 2001 Jun 18, 435(l):26-40; Hill et al., J Biol Chem 2001, 276(23):20125-20129). Both MCHR1 and MCHR2 are present in humans, rhesus monkeys, ferrets, and dogs while in rodents only MCHR1 could be identified (Saito and Maruyama, J Exp Zool Comp Exp Biol 2006, 305(9):761-768). Comparison of human MCHR1 and MCHR2 sequences revealed only 34% sequence identity while further 36% of the residues were similar (Chen et al., Bioorg Med Chem Let 2012, 22(l):363-366). Comparison of the residues lining the binding pocket indicated 10 identical and 9 homolog residues out of the total 30. There is a great level of homology (>96%) between human and rodent MCHR1 AA sequence (Rokosz and Hobbs, Drug News Perspect 2006, 19(5):273-286).

MCH has attracted considerable attention because of its effects on food intake and body weight and its receptor MCHR1 is still one of the viable targets for obesity therapy (Pissios P., Peptides 2009, 30(l l):2040-2044). MCH is one of the most potent central stimulators of feeding, regulates energy balance and mood (Pissios et al., Endocrinology 2003, 144(8):3514-3523; Pissios et al., Endocr Rev 2006, 27(6):606-620; Forray C., Curr Opin Pharmacol 2003, 3: 85-89; Qu et al., Nature 1996, 380: 243-47; Hervieu G., Expert Opin Ther Targets 2003, 7: 495-511; Chung et al., J Mol Neurosci 2011, 43:115-21).

Structurally different MCHR1 antagonist are known in the art. Typically, a group of MCHR1 antagonists contain an optionally substituted (het)aryl-methylene-oxy-pyridinone moiety e.g., as described in WO 2007/018248 Al, WO 2010/141539 Al, WO 2011/127643 Al, or WO 2015/005489 Al. In a certain subset of MCHR1 antagonists said moiety is linked to a tricyclic group having at least one basic nitrogen e.g., as described in WO 2009/089482 Al, or WO 2016/166684 Al.

Among the pathological conditions that depend on genomic imprinting defects, PWS is a neurodevelopmental disorder that, up to now, best describes the link between metabolism, sleep and imprinted genes. PWS results from the loss of a cluster of paternally expressed genes on the chromosome 15ql 1— ql3 region, many of which are highly expressed in the hypothalamus and characterized by sleep-wake (rapid eye movement [REM] alterations) and metabolic (hyperphagia) abnormalities (Tucci V., PLoS Genet 2016, 12(5): el006004; Tucci et al., Cell 2019, 21:952-965). All these symptoms are generally associated with hypothalamic insufficiency (Swaab DF., Acta Paediatr Suppl. 1997, 423:50-54; Lassi et al., Sleep 2016, 39:637-44). The three main classes of chromosomal abnormalities that result in PWS include paternal copy (micro) deletions (65-75% of patients), uniparental disomy (20-30% of patients), and imprinting defects (1-3% of patients; Cheon CK., Ann. Pediatr. Endocrinol. Metab. 2016, 21, 126-135). Early childhood-onset hyperphagy and consequent obesity associated with type-2 diabetes are characteristic symptoms to the deletion-related PWS (Shepherd et al., Genes 2020, 11:736). The syndromic obesity driven by profound hyperphagia arises from neurodevelopmental consequences of the deletion of the small nucleolar C/D box RNA 116 (SNORD116) cluster that is always involved in paternal copy deletion cases as it is proved to be the minimal deletion region (Holm et al., Pediatrics 1993, 91:398-402; Gunay-Aygun et al., Pediatrics 2001, 108: E95; Duker et al., Eur. J. Hum. Genet. 2010; 18: 1196-201; de Smith et al., Hum. Mol. Genet. 2009, 18:3257-65; Bieth et al., Eur. J. Human Genet. 2015, 23:252-255; Polex-Wolf et al., J. Clin. Invest. 2018, 128:960-969; Tan et al., Genes 2020, 11:128; Chung et al., Open Biology 2020, 10:200195).

SNORD116 in neurons derived from induced pluripotent stem cells from PWS patients showed reduced levels of nescient helix loop helix2 (NHLH2) and the prohormone convertase PCI enzyme (PCSK1). NHLH2 is reported to promote Pcskl expression which in turn promotes the conversion of prohormones into mature hormones. The failure of proper hormone maturation may contribute to the various neuroendocrine phenotypes seen in PWS. In addition, SNORD116 as a translational regulatory RNA has a major impact on prenatal development of hypothalamic cells and among others mainly orexinergic (ORX) neurons are depleted to 40% in PWS mice. At the same time, the MCH-erg cell population remains unaffected (Pace M., JCI Insight 2020, 5:el37495; Pace et al., Hum. Mol. Genet. 2020, 29:2051-2064). The cerebrospinal fluid ORX level also decreased in PWS patients (Omokawa et al., Am. J. Genet A. 2016, 170A: 1181-6).

In the lateral hypothalamus, MCH and ORX neurons are anatomically and functionally intermingled and there is considerable overlap between their projection areas (Saito et al., J Comp Neurol. 2001 Jun 18;435(l):26-40; Kilduff TS., J Comp Neurol 2001, i

435: 1-5; Barson et al., Int J Endocrinol 2013, 2013: 983-64). The two neuropeptide systems are exerting partially antagonistic actions on brain states and energy balance (Linehan et al., Mol. Meatabolism 2020, 36:100977; Kilduff TS., J Comp Neurol 2001, 435: 1-5). Recent studies indicate that the major role of the ORX system is to regulate the circadian rhythm, determine sleep and metabolic status (Barson et al., Int J Endocrinol 2013, 2013: 983-64). There is reciprocal crosstalk between the MCH and ORX neurons (Hassani et al., PNAS 2009, 106:2418-2422).

Uncontrollable appetite, weight gain and impaired reproduction in PWS may be explained by overactive MCH neurons as the “checks and balances” lost because of the reduced ORX population in the lateral hypothalamus. Inhibition of MCHR1 on the remaining ORX cells might lead to restoration of the sleep and arousal abnormalities, as well as regaining control over hyperphagia and obesity driven by unleashed MCH signaling (Linehan et al., Mol. Meatabolism 2020, 36:100977; Linehan et al., J. Physiol 2022, 596:305-316).

It has been demonstrated in lean rodents that ORX neurons decrease their firing during eating and remain in a depressed state throughout the entire eating phase (Gonzalez et al., Current Biol. 2016, 26:2486-2491; Gonzalez et al., Nature Communications 2016, 7:11395). In diet-induced obese (DIO) mice, in the short term ORX neurons receive an increased excitatory drive and may mediate the rewarding aspect of HFD consumption. In the long term ORX signaling diminishes and the increase in excitatory inputs to MCH neurons contribute to the development and maintenance of DIO (Kilduff and de Lecca, J. Comp Neurol 2001, 435:1-5). These findings model the lack of regulatory feedback mechanisms mediated by the ORX system, a phenomenon that can relate to the hyperphagia and obesity phenotype observed in PWS patients (Chung et al. Open Biol 2020, 10:200195). These findings suggest a lack of regulatory feedback mechanisms mediated by the ORX system in relation to food intake in the LH of PWS model mice, a phenomenon that can relate to the hyperphagia and obesity phenotype observed in PWS patients (Pace M., J CI Insight 2020, 5: el37495).

Therefore, the impaired function of ORX neurons results in an enhanced status of the MCH system. Prevention of the MCH overactivation most likely improves the MCH-ORX balance that may ultimately help patients in reducing the feeding-related symptoms.

None of the available genetic mouse models of PWS fully recapitulates the human phenotype (Resnick et al., Mamm Genome. 2013, 24:165-178; Carias and Wevrick, Molecular Therapy: Meth. & Clin. Dev. 2019, 13:344-358 2019). The Prader-Willi region on human chromosome 15 is syntenic to mouse chromosome 7, with the SNORD116 cluster in both species comprising an imprinted array of snoRNA repeats (Vitali et al., J Cell Sci. 2010, 123:70-83). All SNORD116 deletion mouse models reported thus far remain smaller than controls through adulthood and do not transition to obesity as seen in human PWS (Pollex- Wolf 2018). Only one adult-onset brain-specific virus vector mediated SNORD116 deletion could lead to obesity and increased fat mass (Pollex-Wolf et al., J. Clin. Invest. 2018, 128:960-969).

According to the latest preclinical reports the MCH-MCHR1 system is overactivated due to the impaired ORX control, PWS patients could benefit from MCHR1 antagonist treatment to gain control over hyperphagia and obesity (Pace M., J CI Insight 2020, 5:el37495; Pace et al., Hum. Mol. Genet. 2020, 29:2051-2064; Linehan et al., Mol. Meatabolism 2020, 36:100977; Linehan et al., J. Physiol 2022, 596:305-316).

Patients with PWS frequently require medical care for a variety of issues, beginning initially with assistance with management of hypotonia and poor feeding. Caloric goals should be guided by a dietitian and designed to promote moderate rates of weight gain, with appropriate intake of protein and micronutrients. Excessive caloric restriction prior to three years of age (unless deemed medically necessary because of significant obesity). Other interventions are offered to optimize cognitive and physical development. Intensive physical and occupational therapies can assist with muscle tone and strength. Speech therapy may assist with development of swallowing, communication, and enunciation. Controlling obesity through strict limitation of food intake is the cornerstone of effective management of PWS. In spite of the efforts by the families and caregivers, many children and adults with PWS will continue to have severe obesity and associated medical problems (Scheiman AO., Clinical features, diagnosis, and treatment of Prader-Willi syndrome, Last updated: 2022.01.31 https://www.uptodate.com/contents/clinical-features-diagnosi s-and-treatment-of-prader- willi- sy ndrome/print) .

The efficacy of recombinant human growth hormone (rhGH) in children with PWS demonstrated improvements in linear growth, body composition, bone density, physical function, and motor development. The response to rhGH in children with PWS is the greatest during the first 12 months of therapy (Carrel AL., J Clin Endocrinol Metab 2002, 87: 1581.114). Nevertheless, patients have had continued improvement in linear growth, bone io density, and body composition when rhGH has been administered in sufficient doses for as long as five years, however, even with long-term rhGH treatment, body composition is not completely normalized (Obata K., J Pediatr Endocrinol Metab. 2003, 16(2): 155). Beyond these positive effects on growth and body composition growth hormone supplementation does not improve behavioural disturbances including hyperphagia (Davies PSW., Int J Obesity 2001, 25:2-7; Yang X., Neuropeptides 2020, 83:102084).

Treatment with marketed anti-obesity agents such as topiramate has not been effective in controlling appetite in patients with PWS (Consoli A et al., Transl Psychiatry. 2019, 9:274; Shapira AN., Am J Ment Retard. 2004, 109(4):301). Selective serotonin reuptake inhibitors (SSRIs) may be effective for many of the behavioral symptoms in patients with PWS, but there is little evidence that these drugs have specific effects on binge eating or weight gain (Kohn Y., Int J Eat Disord 2001, 30:113-117). Other classes of psychotropic drugs including neuroleptics may be useful in treatment of behavioral symptoms, but their benefits must be weighed against their potential weight-promoting side effects.

The use of glucagon-like peptide- 1 (GLP-1) receptor agonists (liraglutide, exenatide) for individuals with PWS have been described in case reports (Goldman et al., J. Clin. Med. 2021, 10, 4540) with mild-moderate weight loss in individual cases, but existing evidence is insufficient to recommend their use in this population and broader use is limited by tolerability. Recently, it was confirmed in a randomized controlled clinical trial that liraglutide is not effective in reducing hyperphagia in PWS (https://www.clinicaltrialsregister.eu/ctr- search/trial/2014-004415-37/results). This must be the case with semaglutide, beyond beneficial effect on BMI, clinical efficacy over hyperphagia has not yet been demonstrated so far.

Metformin therapy may suppress appetite, food-related anxiety, and sense of satiety but only in selected individuals with elevated insulin levels due to insulin resistance in females but completely lacks efficacy in males with PWS (Miller JL, J Pediatr Endocrinol Metab. 2014 Jan 1, 27(0): 23-29).

There are scattered reports of surgical weight loss procedures in patients with PWS, including gastric bypass, biliopancreatic diversion, and gastric-restrictive procedures. The literature in this area consists of case reports, most with follow-up of less than two years, and results are inconsistent. Some of the reports are more than 20 years old and describe surgical ■ techniques that are no longer used. However, it appears that there may be fewer benefits and greater risks of weight loss surgery for individuals with PWS as compared with other individuals with obesity (Scheiman AO., Clinical features, diagnosis, and treatment of Prader- Willi syndrome, Last updated: 2022.01.31 https://www.uptodate.com/contents/clinical- features-diagnosis-and-treatment-of-prader-willi-syndrome/pr int). PWS patients undergoing weight loss surgery, 63 percent of those undergoing gastric bypass had poor weight loss. There may be some long-term efficacy for the most malabsorptive of these procedures, but these operations also confer increased risks because of chronic malabsorption of micronutrients and electrolytes. Patients with PWS may be at particularly high risk after operations causing malabsorption because they already have an increased risk for osteoporosis (Scheimann AO, J Pediatr Gastroenterol Nutr. 2008, 46(l):80). Surgical interventions in patients with PWS cannot be generally recommended, indeed.

Despite the effort for developing safe and efficacious treatments for PWS, it can be concluded that there is still an unmet medical need for an effective and safe therapy for treating PWS.

Summary of the invention

The disclosure is based on the unexpected discovery that MCHR1 antagonists can be effective in treating PWS.

The present invention relates uses of a melanin-concentrating hormone receptor 1 (MCHR1) antagonist, e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions thereof for the treatment of Prader-Willi Syndrome (PWS), for improving, alleviating or delaying progression of one or more symptoms of PWS, such as hyperphagia, for maintaining or reducing body weight, or for reducing food intake in a patient afflicted with PWS.

Detailed description of the invention

The present invention relates to certain MCHR1 antagonist, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions thereof for use in the treatment of PWS. In an embodiment, the MCHR1 antagonist is a compound of formula (I) wherein

A is CH, or nitrogen;

R is hydrogen, halogen, or Ci-6 straight or branched chain alkyl group;

R ¹ is hydrogen, halogen, Ci-6 straight or branched chain alkyl group, Ci-6 straight or branched chain alkoxy group, or mono- or polyhalogenated Ci-6 straight or branched chain haloalky 1 group;

R ² is hydrogen, halogen, Ci-6 straight or branched chain alkyl group, Ci-6 straight or branched chain alkoxy group or mono- or polyhalogenated C1-4 straight or branched chain haloalky 1 group;

R ³ is hydrogen, Ci-6 straight or branched chain alkyl group optionally substituted with C3-6 cycloalkyl group, or mono- or polyhalogenated C1-6 straight or branched chain haloalkyl group; C3-6 cycloalkyl group, or C1-6 straight or branched chain alkanoyl group; and/or pharmaceutically acceptable salts, and/or geometric isomers, and/or stereoisomers, and/or diastereomers, and/or hydrates, and/or solvates, and/or polymorph modifications thereof.

In an embodiment, the MCHR1 antagonist is a compound of formula (I) wherein R ¹ is hydrogen, halogen, C1-4 straight or branched chain alkyl group optionally mono- or polyhalogenated, or C1-3 alkoxy group; R ² is hydrogen, halogen, trifluoromethyl or C1-3 alkyl group; R ³ is hydrogen, C1-4 straight or branched chain alkyl group optionally substituted with C3-6 cycloalkyl group or fluorine, C3-6 cycloalkyl group, C1-4 straight or branched chain alkanoyl group; and R is hydrogen, or a pharmaceutically acceptable salt thereof.

In an embodiment, the MCHR1 antagonist is a compound of formula (I) wherein R ¹ is hydrogen, fluorine, chlorine, methoxy or trifluoromethyl group; R ² is hydrogen, fluorine, chlorine, or methyl group; R ³ is hydrogen, C1-4 straight or branched chain alkyl group optionally substituted with C3-4 cycloalkyl group or fluorine, C3-4 cycloalkyl group, or acetyl group; and R is hydrogen, or a pharmaceutically acceptable salt thereof. B

In an embodiment, the MCHR1 antagonist is a compound of formula (I) wherein R ¹ is hydrogen, fluorine or chlorine; R ² is hydrogen; R ³ is methyl, ethyl, isopropyl, cyclopropylmethyl, cyclobutyl or fluoroethyl group; and R is hydrogen, or a pharmaceutically acceptable salt thereof.

In an embodiment, the MCHR1 antagonist is a compound of formula (I) wherein R ¹ is fluorine or chlorine; R ² is hydrogen; R ³ is isopropyl or cyclopropylmethyl; R is hydrogen and A is nitrogen, or a pharmaceutically acceptable salt thereof.

In an embodiment, the MCHR1 antagonist is selected from the group consisting of: 4- [(5-chloro-pyridin-2-yl)methoxy] - 1 - { 1H,2H,3H,4H,5H- [ 1 ,4]diazepino[ 1 ,7-a]indol-9-yl } - 1 ,2-dihydropyridin-2-one,

4- [(5-chloro-pyridin-2-yl)methoxy ] - 1 - { 3 -methyl- 1 H,2H,3H,4H,5H- [ 1 ,4]diazepino [1,7- a] indol-9-yl } - 1 ,2-dihydropyridin-2-one,

4- [(5-chloro-pyridin-2-yl)methoxy ] - 1 - { 3 -ethyl- 1 H,2H,3H,4H,5H- [ 1 ,4]diazepino [1,7- a] indol-9-yl } - 1 ,2-dihydropyridin-2-one,

4-[(5-fluoro-pyridin-2-yl)methoxy]-l-[3-(propan-2-yl)-lH, 2H,3H,4H,5H-

[ 1 ,4]diazepino [ 1 ,7-a] indol-9-yl] - 1 ,2-dihydropyridin-2-one, 4-(benzyloxy)-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H-[l,4]diazepi no[l,7-a]indol-9-yl]-l,2- dihydropyridin-2-one, 4-[(5-chloro-pyridin-2-yl)methoxy]-l-[3-(propan-2-yl)-lH,2H, 3H,4H,5H-

[ 1 ,4]diazepino [ 1 ,7-a] indol-9-yl] - 1 ,2-dihydropyridin-2-one,

4- [(4-fluoro-phenyl)methoxy] - 1 - [3 -(propan-2-yl)- 1H,2H,3H,4H,5H- [ 1 ,4]diazepino[ 1 ,7 - a] indol-9-yl] - 1 ,2-dihydropyridin-2-one,

4-[(4-chloro-phenyl)methoxy]-l-[3-(propan-2-yl)-lH,2H,3H, 4H,5H-[l,4]diazepino[l,7- a] indol-9-yl] - 1 ,2-dihydropyridin-2-one,

4- [(2-fluoro-phenyl)methoxy ] - 1 - [3 -(propan-2-yl) - 1 H,2H,3H,4H,5H- [ 1 ,4] diazepino [1,7- a] indol-9-yl] - 1 ,2-dihydropyridin-2-one, l-[ll-chloro-3-(propan-2-yl)-lH,2H,3H,4H,5H-[l,4]diazepino[l ,7-a]indol-9-yl]-4-[(5- chloro-pyridin-2-yl)methoxy ] - 1 ,2-dihydropyridin-2-one, 4-(benzyloxy)-l-[ll-chloro-3-(propan-2-yl)-lH,2H,3H,4H,5H-[l ,4]diazepino[l,7-a]indol- 9-yl]-l,2-dihydropyridin-2-one,

4- [(5-chloro-pyridin-2-yl)methoxy ] - 1 - [3 -(cyclopropylmethyl)- 1 H,2H,3H,4H,5H-

[ 1 ,4]diazepino [ 1 ,7-a] indol-9-yl] - 1 ,2-dihydropyridin-2-one, ■

4- [(5-chloro-pyridin-2-yl)methoxy ] - 1 - { 3 -cyclopropyl- 1 H,2H,3H,4H,5H- [ 1 ,4] diazepino [1,7- a] indol-9-yl } - 1 ,2-dihydropyridin-2-one,

4-[(5-chloro-pyridin-2-yl)methoxy]- 1- { 3 -cyclobutyl- lH,2H,3H,4H,5H-[ 1 ,4]diazepino[ 1 ,7 - a] indol-9-yl } - 1 ,2-dihydropyridin-2-one, 4-[(5-chloro-pyridin-2-yl)methoxy]-l-[l l-methyl-3-(propan-2-yl)-lH,2H,3H,4H,5H-

[ 1 ,4]diazepino [ 1 ,7-a] indol-9-yl] - 1 ,2-dihydropyridin-2-one, in free form, or in a pharmaceutically acceptable salt form.

In a preferred embodiment, the MCHR1 antagonist is 4-[(5-chloropyridin-2- yl)methoxy]-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H-[l,4]diazepino [l,7-a]indol-9-yl]-l,2- dihydropyridin-2-one in free form (referred to hereinafter as Compound A), or in a pharmaceutically acceptable salt form , e.g., the hydrochloride salt.

The compounds of formula (I) in free form, or in a pharmaceutically acceptable salt form are disclosed in WO 2016/166684 Al, thus such compounds are either commercially available or can be made by methods known in the art. Reference is herein made to a parallel patent application filed by the applicant with the title of “ Crystalline forms of 4-[(5- chloropyridin-2-yl)methoxy]-l-[3-(propan-2-yl)-lH,2H,3H,4H,5 H-[l,4]diazepino[l,7- a]indol-9-yl]-l,2-dihydropyridin-2-one and salts thereof method of preparation, and uses thereof wherein specific crystalline forms of Compound A, the hydrochloride salt of Compound A and specific crystalline forms thereof are disclosed in detail.

Unless defined otherwise, all technical and scientific terms used herein are intended to have the same meaning as is commonly understood by a person of ordinary skill in the art.

As used herein, the term ’’one or more symptoms of PWS” refers to behavioral, psychological or psychiatric conditions associated with PWS, sleep disorders, eating disorders, metabolic and hormonal disorders, chronic gastrointestinal, liver or kidney disorders, disorders of musculoskeletal system, disorders of sensory organs and skin. Particularly, said symptom is mood disorders, such as depression or mania, personality disorders, intellectual disability, anxiety, obsessive compulsive disorders, cognitive impairment, psychomotor retardation, irritability, bulimia, hyperphagia, extensive daytime sleepiness, obstructive sleep apnea, narcolepsy, catalepsy, hypogonadism, hypothyreosis, ii hyperthyreosis, decreased growth hormone secretion, impaired glucose tolerance, increased fasting glucose, prediabetes, diabetes mellitus (including insulin dependent and non-insulin- dependent), hyperglycaemia, hyperlipidaemia, hypertrigliceridaemia, hypercholesterinaemia, atherosclerosis, coronary artery disease (CAD), peripheral arterial disease (PAD), cerebrovascular arteriosclerosis, NAFLD, NASH, renal failure, loss of bone mineral density, short stature, muscular hypotonia, inflammatory conditions of the skin, more particularly hyperphagia.

As used herein the term “one or more additional therapeutic agents effective at treating or alleviating one or more symptoms of PWS” refers to prescription or “over the counter” (OTC) drugs or food supplements for weight loss or appetite suppression (such as orlistat, phentermine, topiramate, lorcaserine, bupropion, naltrexone, liraglutide, semaglutide etc.), herbal, fungal or animal extracts irrespectively of origin; antidiabetics (such as insulin, insulin analogues, glucagon, metformin, inhibitors of SGLT2, sulphonylureas, thiazolidinediones, amylin receptor agonists, glucagon-like peptide (GLP) 1 agonists, glucose-dependent insulinotropic polypeptide/gastric inhibitory peptide (GIP) agonists), antidepressants (such as tricyclics, SSRIs, SNRIs, SDRIs, MAO inhibitors, derivates of melatonin), antipsychotics, ghrelin receptor agonists, GHRH, GHRH receptor agonists, alpha-MSH, alpha-MSH receptor agonists, oxytocin, oxytocin receptor agonists, orexin, orexin receptor agonists, BDNF, BDNF receptor agonists, vasopressin, vasopressin receptor agonists, NPY, NPY receptor agonists, PYY, Y2 receptor agonists, AGRP, AGRP receptor agonists, gonadotropin, gonadotropin receptor antagonists and any combinations thereof.

The terms "co-administration" or "combined administration" or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration, in the same composition or at the same time.

The term "pharmaceutical composition" refers to a mixture of a compound of the invention with other chemical components, such as pharmaceutically acceptable excipients e.g., diluents or carriers. The pharmaceutical composition facilitates administration of the compound to the subject.

The term "excipient" defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. The pharmaceutical compositions of the present invention can be formulated in many ways, for instance as tablet, capsule, powder, granules, suspension, emulsion, solution, syrup, aerosol (with a solid or a liquid carrier) soft or hard gelatin capsule, suppository, injection. Preferably, pharmaceutical composition is formulated as a tablet or a capsule.

The pharmaceutical compositions can be in single dosage forms containing predetermined amount of active ingredient. This dosage can contain the therapeutically effective amount of a MCHR1 antagonist, e.g., a compound of formula (I) in free form, such as Compound A, or in a pharmaceutically acceptable salt form, or a given percentage of the therapeutically effective amount in such a way that these single dosage forms for repeated administration can be administered over a given period of time in order to reach the desired therapeutically effective dose. Preferred single dosage forms are those which contain the daily dose or sub-dose or - as it was mentioned above - a given percentage of the active ingredient. Furthermore, these pharmaceutical compositions can be manufactured by methods known in the art.

The term "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g., a MCHR1 antagonist and one or more additional therapeutic agents effective at treating or alleviating one or more symptoms of PWS, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a MCHR1 antagonist and one or more additional therapeutic agents effective at treating or alleviating one or more symptoms of PWS, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the compounds in the body of the patient.

The term “therapeutically effective amount” refers to the amount of the active ingredient - compared to the subject, who did not receive such an amount - which results in the treatment, curing, prevention, alleviation or improvement of an illness, pathological condition, side-effect, one or more symptoms of a disease, such as hyperphagia, for maintaining or reducing body weight or for reducing food intake, or suppresses, or delay the degree of progression of an illness, pathological condition or one or more symptoms of a disease, such as hyperphagia. The term includes the effective amounts required for improving normal physiological functions as well. In the therapeutic applications a MCHR1 antagonist, e.g., a compound of formula (I) in free form, such as Compound A, or in a pharmaceutically acceptable salt form, can be administered in therapeutically effective amount as unformulated drug substances or the active ingredient can be formulated as medicament. The exact therapeutically effective amount of a MCHR1 antagonist, e.g., a compound of formula (I) in free form, such as Compound A, or in a pharmaceutically acceptable salt form, depends on several factors, including - but not exclusively - the age and the bodyweight of the treated subject (patient), the type and the seriousness of the disease to be treated, the type of the pharmaceutical composition/medicament and the way of administration.

In an embodiment the therapeutically effective amount of a MCHR1 antagonist, e.g., a compound of formula (I) in free form, such as Compound A, or in a pharmaceutically acceptable salt form, is a daily dose of at least about 2.5 mg.

In another embodiment the therapeutically effective amount of a MCHR1 antagonist, e.g., a compound of formula (I) in free form, such as Compound A, or in a pharmaceutically acceptable salt form, is a daily dose of from about 2.5 mg to about 22.5 mg.

In a preferred embodiment, the therapeutically effective amount of a MCHR1 antagonist, e.g., a compound of formula (I) in free form, such as Compound A, or in a pharmaceutically acceptable salt form, is a daily dose of from about 2.5 mg to about 7.5 mg.

In a particularly preferred embodiment, the therapeutically effective amount of a MCHR1 antagonist, e.g., a compound of formula (I) in free form, such as Compound A, or in a pharmaceutically acceptable salt form, is a daily dose of about 2.5 mg, about 5 mg or about 7.5 mg.

The term "daily dose" refers to the amount of a MCHR1 antagonist, e.g., a compound of formula (I) in free form, such as Compound A, administered per day. In case of administering pharmaceutically acceptable salts, such as the hydrochloride salt of Compound A, the daily dose is also expressed with the equivalent amount of free base.

The term “effective amount” refers to an amount of a drug or active ingredient which is sufficient, in the subject to which it is administered, to elicit the biological or medical response of a tissue, system, animal (including human) that is being sought, for instance, by a researcher or clinician.

The term “subject” refers to a patient in need of method for treatment, curing, prevention, alleviation or improvement of PWS or one or more symptoms, such as il hyperphagia, thereof, for maintaining or reducing body weight or for reducing food intake, or suppressing, or delaying the degree of progression of the illness, pathological condition or one or more symptoms thereof.

MCHR1 antagonist, e.g., a compound of formula (I) in free form, such as Compound A, or in a pharmaceutically acceptable salt form, can be administered by any appropriate route, for example, by the oral, rectal, transdermal, subcutaneous, local, intravenous, intramuscular, or intranasal route. Preferable administration route is oral.

In a series of further specific or alternative embodiments, the present invention provides:

1.1. A method for treating PWS, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a MCHR1 antagonist, e.g., a compound of formula (I) as defined herein above.

1.2. A method for improving, alleviating or delaying progression of one or more symptoms of PWS, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a MCHR1 antagonist, e.g., a compound of formula (I) as defined herein above.

1.3. A method for maintaining body weight in a patient afflicted with PWS, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a MCHR1 antagonist, e.g., a compound of formula (I) as defined herein above.

1.4. A method for reducing body weight in a patient afflicted with PWS, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a MCHR1 antagonist, e.g., a compound of formula (I) as defined herein above.

1.5. A method for reducing food intake in a patient afflicted with PWS, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a MCHR1 antagonist, e.g., a compound of formula (I) as defined herein above.

1.6. A method for treating hyperphagia in a patient afflicted with PWS, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a MCHR1 antagonist, e.g., a compound of formula (I) as defined herein above.

1.7. A method as indicated above, wherein the MCHR1 antagonist is administered once daily. 1.8. A method as defined above comprising co-administration, e.g., concomitantly or in sequence, of a therapeutically effective amount of a MCHR1 antagonist and one or more additional therapeutic agents effective for treating or alleviating one or more symptoms of PWS.

2. A pharmaceutical composition for use in any one of the methods 1.1 to 1.7, comprising a MCHR1 antagonist, e.g., a compound of formula (I) as defined hereinabove, together with one or more pharmaceutically acceptable excipients.

3. A pharmaceutical combination for use in any one of the methods 1.1 to 1.7, e.g., a kit, comprising a) a first agent which is a MCHR1 antagonist, e.g., a compound of formula (I) as defined herein above, and b) one or more additional therapeutic agents effective at treating or alleviating one or more symptoms of PWS as indicated above, wherein the kit may comprise instructions for its administration.

4. A MCHR1 antagonist, e.g., a compound of formula (I) as defined herein above, for use in any one of the methods 1.1 to 1.7.

5. A MCHR1 antagonist, e.g., a compound of formula (I) as defined herein above, for use in the preparation of a medicament for any one of the methods 1.1 to 1.7.

6. Use of a MCHR1 antagonist, e.g., a compound of formula (I) as defined herein above, for any one of the methods 1.1 to 1.7.

In particular, the MCHR1 antagonists as described herein, e.g., Compound A, is useful for treating hyperphagia in a patient afflicted with PWS.

Utility of MCHR1 antagonists, e.g., the MCHR1 antagonists according to formula (I), as hereinabove specified, may be demonstrated in animal test methods as well as in clinic, for example in accordance with the methods hereinafter described.

n

Example 1 - In vitro studies

Compound A is a selective MCHR1 antagonist displaying high affinity for the human MCHR1 receptor (Ki: 45.3±6.6 nM), its IC50 value in functional assays of human receptor (such as described in WO 2016/166684 Al) is nanomolar (6.2±0.7 nM) and it has more than 1.500-fold greater potency at the MCHR1 than the MCHR2 receptor.

Example 2 - In vivo studies with rodents

In vivo, Compound A exerted pharmacological activities that are consistent with its in vitro effects. Compound A displayed dose-dependent, anti-obesity activity in rodent model of obesity.

Male C57B1/6J mice were fed with 60% caloric content of fat diet ad libitum for 12 weeks prior to the study to reach 40-45 g body weight. Following the weight-gain phase 14- day long oral treatment (twice a day) with Compound A induced a dose-dependent body weight loss in the 0.01-3 mg/kg dose range in DIO mice. The minimal effective dose (MED) was 0.3 mg/kg. The reduction of cumulative caloric intake (cCI) became significant at doses 1 and 3 mg/kg.

Example 3 - In vivo studies with dogs

Diet-induced obese (DIO) beagle dogs are very sensitive to Compound A, 0.6 mg/kg, once daily per os has strong inhibition of food intake and robust body weight reduction. The MED and side effect free 0.02 mg/kg dose are associated with 1.2 ng/ml exposure at the last (7th) day of treatment.

Dog is a species having both MCHR1 and MCHR2 receptors similarly to humans. Adult male beagle dogs (3.5-year-old) were ad libitum fed with high energy diet (30% fat/20% protein) for 10 weeks to establish diet induced obesity. DIO dogs (mean body weight: 16.4 kg) were treated orally in five phases. At each treatment phase 8 animals were treated orally (in capsule), once a day with 0, 0.02, 0.06, 0.2 or 0.6 mg/kg doses of Compound A, for 7 days followed by a 14-day washout phase in a cross-over method. The same high energy diet was applied during the full 105-day treatment period.

The treatment with Compound A significantly and dose-dependently reduced the food intake compared to vehicle in all treated groups. The food intake was decreased from the 1st M day and it dropped to about zero during the treatment with 0.2 and 0.6 mg/kg from the 2nd treatment day. The food intake was restored for the 4th day of washout period.

Treatment with Compound A induced significant and dose-dependent body weight loss compared to vehicle in all treated groups. The body weight reduction reached its maxima at 1-3 days post-treatment. The maximal mean body weight change was -10,4±2,2% at the 0.6 mg/kg/day dose on washout day 3 (p<0.001).

The profound reduction of food intake went with significant reduction of cholesterol, triglyceride and urea nitrogen concentrations in all dose groups treated with Compound A. All other serum chemistry and hematology parameters remained within the normal range.

Example 4 - In vivo studies with non-human primates

Non-human primate studies provided competitive data on metabolic efficacy of Compound A.

Young growing Rhesus macaques respond with significant reduction of instrumental operant food intake following parenteral administration of 1.5 mg/kg.

The study was a double-blinded, vehicle and validating compound controlled. 5-day repeated dose, semi-randomized (fixed dose order with shifted starting dose), 5-arm crossover, instrumental food intake study. Compound A (0.06, 0.3, 1.5 mg/kg. i.m., 25% HPBCD formulation) and exenatide (Byetta, 2 pg/kg, s.c.; serving as positive control) were applied for 5 consecutive dosing days. There were 2 food intake (FI) sessions: SI (120 min) followed by S2 (60 min) with 1-hour delay. Injections were done at Ih prior SI. One-week washout was allowed after each treatment week. High dose of Compound A (1.5 mg/kg) was based on the results of previous rhesus tolerability study.

Example 5 - In vivo studies with non-human primates

Chronic (6 week) oral treatment of obese Cynomolgus macaques with 10 mg/kg once daily per os dose elicits a significant decrease in food intake (41-84 %) from the first day of treatment and marked body weight loss (13 % vehicle corrected body weight loss) at the end of treatment period.

Following the rodent (only MCHR1 expressing), the extremely sensitive obese dog and the non-obese Rhesus macaque experiments, the aim of this study was to confirm the 01 efficacy of Compound A in obese non-human primates (NHP), which also expresses MCHR2, as being evolutionary close to human and models the human disease.

This pilot study was carried out on 18 obese cynomolgus macaques. After 5-week vehicle (2 % Tween 80) treatment monkeys were administered either with vehicle (n=9), or with 10 mg/kg of Compound A (n=9) for 6 weeks. Thereafter, all the animals received vehicle for 4 weeks (recovery phase) and finally the study was finished with a 4-week observatory phase (no treatment). Food intake, body weight, hematology and chemistry panels were measured according to predefined schedule. Chronic (6 weeks) oral treatment of obese cynomolgus monkeys with a 10 mg/kg once daily dose elicited a 13 % body weight loss compared to vehicle with a concomitant, marked decrease (61 %) in food intake from the first day of treatment.

In Examples 1-5, the maleic acid salt of Compound A was used (see WO 2016/166684 Al, Ex.20(b)).

Table 1 shows the plasma exposures obtained from preclinical studies performed in different species (MED = minimal effective dose):

Example 6 - In vivo comparative study with rodent

In vivo studies were carried out with 6-6 male rats with the maleic acid and hydrochloride salt form of Compound A at 30 mg/kg per os in 5% Tween 80 formulation to compare their pharmacokinetic parameters.

In Table 2 the mean (CV%) pharmacokinetic parameters evidence that different salts of Compound A provide equivalent exposure thus pharmacodynamic effects are interchangeable.

Based on the experimental data summarized above obtained from in vitro, ex vivo, and in vivo studies, MCHR1 antagonists, such as Compound A, e.g., hydrochloride salt thereof are potent MCHR1 full antagonists both in vitro and in vivo. MCHR1 antagonists, such as Compound A, e.g., hydrochloride salt thereof displays anti-obesity and food intake inhibitory effect in a variety of animal disease models.

Example 7 - Clinical Trial

In multiple dose phase 1 study to examine the tolerability, safety and pharmacokinetics of different oral doses of Compound A, the hydrochloride salt thereof in overweight or obese otherwise healthy male subjects.

The compound was found to be well-tolerable and safe, also signs of pharmacodynamic effects on appetite and food intake were detected and a promising tendency for preventing weight gain. Table 3 shows human plasma exposures (geometric means) obtained from the phase

1 multiple ascending dose study that are comparable to those of Table 1: Example 8 - Clinical Trial

Investigation of clinical benefit of a MCHR1 antagonist, e.g., a compound of formula (I), such as Compound A, e.g. hydrochloride salt thereof.

Approximately a sum of 176 adult patients with hyperphagia due to PWS receive the hydrochloride salt of Compound A at a daily dosage of 2.5, 5, 7.5 or 22.5 mg per os in a randomized, double-blind, placebo-controlled, multi-centre, 2-part, phase 2 study.

Objectives

Primary Objective:

Part A: to assess short-term efficacy for the treatment of hyperphagia in PWS.

Part B: to assess the efficacy of different doses for the treatment of hyperphagia in PWS.

Secondary Objectives

To assess patient and caregiver burden, quality of life, safety, and tolerability in PWS patients.

To explore the effect of different doses on body weight, body composition and metabolic biomarkers.

Study Desing

Part A: Multicentre, 4-week, placebo-controlled, randomized parallel, 2-arm study

Part B: Multicentre, 13-week, placebo-controlled, randomized parallel, 4-arm study

Number of patients

Part A: approximately 66 patients

Part B: approximately 110 patients

Patient recruitment criteria

Male or female patients aged >17 years with PWS and with high hyperphagia clinical phenotype with stable body weight. Patients should not have severe psychiatric condition, severe or insulin treated diabetes mellitus, hypothyroidism or hyperthyroidism, liver disease, severe obstructive sleep apnea. Weight-lowering pharmacotherapy is prohibited.

Administration schedule

Part A: 22.5 mg once daily

Part B: 2.5 mg, 5 mg, or 7.5 mg once daily li

The general clinical state of the patients is investigated by physical (vital signs, height, weight, BMI, waist circumference etc.) and laboratory examinations (hematology, clinical chemistry, coagulation and lipids, urinalysis,).

Disease states and changes in progression are primarily assessed according to changes from baseline in the 9-item Hyperphagia Questionnaire for Clinical Trials (HQ-CT), and also according to in absolute change from baseline in body weight, percentage change from baseline in body weight, change from baseline in waist circumference, in BMI, in metabolic biomarkers (leptin, ghrelin, adiponectin; fasting plasma/serum glucose , insulin, homeostatic model assessment, uric acid, and high sensitivity C reactive protein), in Clinical Global Impression-Severity (CGI-S) score, in Clinical Global Impression - Improvement (CGI-I) score, in CaGI-S score, in CaGI-C score, in ZB 1-22 total.

Safety: Treatment emergent AEs, clinical laboratory evaluations (hematology, clinical chemistry, coagulation and lipids, thyroid function test, and urinalysis), vital signs measurements (body temperature, pulse rate, respiration rate, BP), 12 lead ECGs, C-SSRS, and physical examinations.

Preparation of pharmaceutical compositions

The following formulation examples illustrate representative pharmaceutical compositions of this invention. The present invention however is not limited to the following pharmaceutical compositions.

A) Solid oral dosage forms

Tablets or Capsules or Filling Sachets

Active substance(s) 0.005 - 90%

Filler 0.1 - 99.9%

Binder 0 - 20%

Disintegrant 0 - 20%

Lubricant 0 - 10%

Glidant 0 - 10%

Other specific excipient(s) 0 - 50% 0

B) Parenteral dosage forms

Intravenous injections

Active substance(s) 0.001 - 50%

Solvent 10 - 99.9%

Co-solvent 0 - 99.9%

Osmotic agent 0 - 50%

Buffering agent q.s.

C) Other dosage forms Suppositories

Active substance(s) 0.0003 - 50% Suppository base 1 - 99.9% Surface-active agents 0 - 20% Lubricant 0 - 20% Preservatives q.s.

From the above description and examples a person of ordinary skill in the art would recognize the basic principles of the present invention and can carry on certain alterations and modifications without varying the essential features and contents of the invention in order to adapt the invention for different applications and conditions. Consequently, the present invention is not limited to the following examples, but the scope of the invention is defined by the claims which follow.