A novel use of pitolisant for the treatment of severe fatigue

Abstract

The present invention relates to the treatment of severe fatigue (SF), particularly in patients suffering from narcolepsy, comprising the administration of high doses of pitolisant or a pharma- ceutically acceptable salt thereof, such as the monohydrochloride salt.

Description

[Technical field]

[0001] The present invention relates to the therapeutic treatment of severe fatigue. [Background technology]

[0002] Severe fatigue (SF) is defined as the subjective experience of mental or physical tiredness that does not disappear after sleep (Vercoulen et al J. Psychosom. Res. 1994, 38, 383-392).

[0003] SFs are found in a high percentage of patients with chronic neurological disorders, such as Parkinson's disease (Friedman et al., Mov. Disorder, 2007, 22, 297-308), multiple sclerosis (van der Werf et al., J. Neurol. Sci., 1998, 160, 164-170), and neuromuscular disorders (Kalkman et al., J. Psychosom. Res., 2007, 62, 571-579). In these disorders, severe fatigue has been shown to have important clinical consequences, such as increased functional limitations and reduced general health status (Kalkman et al., J. Neurol. Neurosurg. Psychiatry, 2005, 76, 1406-1409).

[0004] Science fiction is also associated with narcolepsy.

[0005] The core effects of narcolepsy include excessive daytime sleepiness (EDS) and cataplexy. EDS is defined as the inability to remain awake and alert during the major waking episodes of the day, resulting in involuntary drowsiness and / or sleep (Droogleever Fortuyn et al J. Sleep Res. 21, 2, 2012, 163-169).

[0006] Although patients may have difficulty distinguishing between daytime sleepiness due to narcolepsy and physical fatigue, excessive daytime sleepiness and fatigue are distinct symptoms that have been shown to occur independently and together in patients with sleep disorders (Lichstein et al Behav. Res. Ther. 1997, 35, 733-740; Merckelbach et al J Sleep Res. 2006 Mar;15(1):105-6).

[0007] Droogleever Fortuyn et al, 2011 also reported that SF is frequently seen in patients with narcolepsy, but should be separated from EDS. Thus, treatment of EDS does not necessarily improve SF symptoms. This is illustrated, for example, by a meta-analysis of clinical trials of the psychostimulant modafinil in various neurological conditions: it was concluded that the drug was generally effective in EDS, while having no clear effect on fatigue (Sheng et al PLoS One. 2013 Dec 3;8(12):e81802). A similar conclusion was reached in a trial of traumatic brain injury (Kaiser et al. Neurology. 2010 Nov 16;75(20):1780-5). In all, a wide variety of data indicates that in some neurological disorders, SF and EDS often coexist, but that they are clearly distinct pathological conditions. In a recent validation study of one of the currently most used fatigue scales, the Fatigue Severity Scale (FSS), in a cohort study of 429 patients with sleep-wake disorders, Valko et al Sleep, 2008, 31, 1601-1607 showed that a subgroup of patients with narcolepsy had the highest fatigue scores.

[0008] Droogleever Fortuyn et al, 2011 determined the prevalence of SF in a group of 80 patients with a diagnosis of narcolepsy with cataplexy associated with excessive daytime sleepiness, psychological distress, functional impairment, and quality of life and its relationship to excessive daytime sleepiness, psychological distress, functional impairment, and quality of life. Fatigue was measured using the Checklist Individual Strength (CIS). In addition, psychological distress, including depressive symptoms, functional impairment, and quality of life, was assessed. More than 60% of patients in this group were found to exhibit SF. There were no age or gender differences between patients with and without SF.

[0009] Importantly, fatigued and non-fatigued patients had similar amounts of daytime sleepiness (Epworth Sleepiness Score 14.3 ± 4.2 vs. 13.1 ± 4.4, P = 0.22), confirming a dissociation between sleepiness and fatigue. Severe fatigue was associated with significantly increased functional disability, increased depressive symptoms, and decreased general quality of life.

[0010] As a result, the majority of patients with narcolepsy suffer from severe fatigue that can be distinguished from daytime sleepiness, resulting in severe functional impairment.

[0011] Despite numerous trials, no clear evidence has emerged so far regarding the pharmacological treatment of SF in narcolepsy or other neurological disorders.

[0012] For example, in a recent Cochrane meta-analysis of SF in cancer and chronic disease, Mucke et al. (Cochrane Database Syst Rev. 2015(5):CD006788. doi: 10.1002 / 14651858.CD006788.pub3. PMID: 26026155; PMCID: PMC6483317) concluded that "based on limited evidence, no specific medication can be recommended for the treatment of fatigue. Research on fatigue in palliative care appears to have focused on modafinil and methylphenidate, which may be beneficial for the treatment of palliative care-associated fatigue, but further research on their efficacy is needed." As another example, Nourbakhsh et al. (Lancet Neurol. 2021, 20(1):38-48) conducted a large-scale double-blind placebo-controlled trial of amantadine, modafinil, and methylphenidate for SF in multiple sclerosis and concluded that "amantadine, modafinil, and methylphenidate were not superior to placebo for improving fatigue in multiple sclerosis and caused a high frequency of adverse events. The results of this study do not support the indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis."

[0013] Conventional wake-promoting medications used to promote wakefulness and reduce EDS do not appear to be effective in treating SF, and in particular, SF in patients with narcolepsy is not indicated for treatment, as is the case for other neurological disorders where evidence for the efficacy of treatment is lacking.

[0014] It would therefore be desirable to provide new and effective candidates for the treatment of SF. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] WO 2006 / 103546 [Non-patent literature]

[0016] [Non-licensed document 1] VercoulenらPsychosom. Res. 1994, 38, 383-392 [Non-licensed document 2] FriedmanらMov. Disorder, 2007, 22, 297-308 [Non-licensed document 3] van der WerfらJ. Neurol. Sci., 1998, 160, 164-170

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[0017] The formula for pitolisant (3-(4-chlorophenyl)propyl 3-piperidinopropyl ether) is: [ka]

[0018] This is a novel histamine H3 receptor antagonist that induces enhanced brain histamine release. Histamine is known to be the main neurotransmitter promoting wakefulness (Schwartz et al Physiol Rev. 1991 Jan; 71(1):1-51).

[0019] The use of pitolisant for the treatment of sleep and vigilance disorders associated with Parkinson's disease, obstructive sleep apnea syndrome, narcolepsy, dementia with Lewy bodies and / or vascular dementia, e.g. EDS, is disclosed in WO 2006 / 103546. [Means for solving the problem]

[0020] Pitolisant monohydrochloride is approved in Europe and the United States and is marketed under the trade name Wakix for the treatment of adult narcolepsy with or without cataplexy, and for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy. It is the first commercially available drug in the histamine H3 receptor antagonist / inverse agonist class. The recommended dose for the treatment of narcolepsy and / or EDS is 10 to 40 mg once daily.

[0021] This dose is consistent with studies reporting high occupancy of brain histamine H3 receptors at a 40 mg dose of pitolisant hydrochloride (Rusjan PBr J Pharmacol. 2020 Aug;177(15):3464-3472).

[0022] Pitolisant monohydrochloride, at doses of 20 to 40 mg once daily, has been shown to improve EDS and cataplexy in patients with narcolepsy, but its effect on SF was not evaluated in these patients with narcolepsy.

[0023] In patients with obstructive sleep apnea (OSA), pitolisant monohydrochloride 20 mg once daily reduced EDS in two studies, whereas SF assessed by the Pichot scale was statistically different from placebo in one study (Dauvilliers Y,et al. Am J Respir Crit Care Med. 2020 May 1;201(9):1135-1145) and not in the other (Pepin et al Chest 2021, 159(4), 1598-1609). This further substantiates the conclusion that fatigue and EDS are distinct entities that respond differentially to treatment and that the use of pitolisant to treat patients with OSA has not been established so far.

[0024] Furthermore, activity of pitolisant in fatigue associated with other conditions has not been reported.

[0025] In a study conducted by the applicant, it was found that fatigue was not improved by a 30 mg dosage of pitolisant in 24-hour sleep-deprived volunteers.

[0026] The effect of pitolisant on fatigue is therefore very unclear.

[0027] It would therefore be desirable to provide new treatments for fatigue, particularly fatigue associated with narcolepsy or other conditions.

[0028] It has now been determined that pitolisant is effective in patients suffering from fatigue, particularly narcolepsy.

[0029] More specifically, pitolisant has been found to be effective even in high doses without side effects.

[0030] According to a first object of the present invention, there is provided a method for treating and / or preventing severe fatigue (SF) comprising administering to a patient suffering from a disorder associated with SF a dose comprised between 50 mg and 240 mg of pitolisant or one of its pharma- ceutically acceptable salts, hydrates or hydrated salts, or crystalline polymorphic structures of these compounds, or optical isomers, racemates, diastereomers or enantiomers thereof, once a day.

[0031] As used hereinafter, "pitolisant" also encompasses its pharma- ceutically acceptable salts, hydrates, or hydrated salts, or crystalline polymorphic structures of these compounds, or optical isomers, racemates, diastereomers, or enantiomers thereof.

[0032] As used herein, the terms "severe fatigue," "SF," "excessive fatigue," or "fatigue" are used interchangeably to refer to a condition characterized by mental or physical tiredness that does not subside after sleep (Vercoulen et al J. Psychosom. Res. 1994, 38, 383-392).

[0033] No animal models of fatigue are available. In humans, SF can be measured using various tests, e.g., the Pichot Fatigue Scale, the Checklist Individual Strength (CIS) or the Flicker Fusion Test. The CIS is a validated measurement with good internal consistency and international recognition. This test can be used to assess the severity of SF using the Fatigue Severity Scale (FSS) with a score range of 8 to 56. In this scale, the population mean is approximately 16 and the cutoff for SF is 35 points (Vercoulen et al, 1994; Droogleever Fortuyn et al, 2011). The flicker fusion frequency (FFF) is defined as the frequency in flickers per second at which an interrupted light appears as a steady light. It has been established that the scores obtained in such tests can be used as a measure of fatigue (Luczak A, et al. Ergonomics, 2005 Dec 15;48(15):1770-92; Ma et al PLoS One, 2014 Feb 5;9(2):e87121; Maeda et al Jpn J Radiol. 2011 Aug;29(7):483-7). The activity of pitolisant in SF can be assessed by its ability to improve the score of any of the above tests, preferably the Flicker Fusion Test.

[0034] As used herein, "pharmaceutically acceptable salts" refers to derivatives of pitolisant modified by making its acid or base salts. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of pitolisant formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid; and the salts are also prepared from organic acids, for example, acetic acid, propionic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, glucuronic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, and the like. Further addition salts include ammonium salts, for example, tromethamine, meglumine, epolamine, and the like, metal salts, for example, sodium, potassium, calcium, zinc, or magnesium, and the like. Hydrochloride and oxalate salts are preferred.

[0035] The pharma- ceutically acceptable salts of the present invention are synthesized from pitolisant by conventional chemical methods.Generally, such salts can be prepared by reacting the free acid or free base form of pitolisant with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of both.Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is incorporated herein by reference.

[0036] The monohydrochloride salt of pitolisant is preferred.

[0037] According to a further object, the present invention relates to a method for treating and / or preventing severe fatigue (SF), said method comprising administering to a patient suffering from a disorder associated with SF and in need thereof a dose comprised between 60 mg and 240 mg of pitolisant, or one of its pharma- ceutically acceptable salts, hydrates or hydrated salts, or crystalline polymorphic structures of these compounds, or optical isomers, racemates, diastereomers or enantiomers thereof, once daily.

[0038] Generally speaking, the identification of subjects in need of treatment for the diseases and conditions described herein is well within the ability and knowledge of one of ordinary skill in the art, and a clinician of ordinary skill in the art can readily identify subjects in need of such treatment through the use of clinical tests, physical examination, genetic testing, and medical / family history.

[0039] According to one embodiment, the patient suffers from narcolepsy, obstructive sleep apnea (OSA), multiple sclerosis, Parkinson's disease, cancer, depression, bipolar disorder, post-stroke symptoms, post-COVID symptoms, chronic fatigue syndrome, fibromyalgia, traumatic brain injury, or inflammatory bowel disease.

[0040] According to certain embodiments, the patient does not suffer from OSA.

[0041] In more particular embodiments, the patient suffers from narcolepsy, for example narcolepsy associated with cataplexy or narcolepsy without cataplexy.

[0042] According to the present invention, the dosage between 50 mg and 240 mg once daily refers to the actual dose (i.e., base form) of pitolisant, while pitolisant or any pharma- ceutically acceptable salt, hydrate or hydrated salt, or crystalline polymorph thereof may be administered.

[0043] According to one embodiment, the recommended dosage of pitolisant may be comprised between 50 and 120 mg, and preferably between 60 and 120 mg.

[0044] It should also be understood that this dosage range is for adult patients and that equivalent doses for children can be adjusted accordingly.

[0045] Administration is once daily (od), preferably in the morning. According to one embodiment, pitolisant is administered upon waking, before breakfast.

[0046] The adjustment of dosage and / or administration time can be easily determined by the attending diagnostician as a person skilled in the art by using conventional techniques and observing the results obtained under similar circumstances. In determining the therapeutically effective amount, several factors are considered by the attending diagnostician, including, but not limited to, the species of the subject; the size, age and general health condition; the specific disease involved; the severity or relevance of the disease; the response of the individual subject; the specific compound administered; the form of administration; the bioavailability characteristics of the administered formulation; the selected dosage regimen; the use of concomitant drugs; and other relevant circumstances. The amount of pitolisant required to achieve the desired biological effect varies depending on several factors, including the dosage of the drug administered, the chemical properties (e.g., hydrophobicity) of the compound employed, the potency of the compound, the type of disease, the disease state of the patient, and the route of administration.

[0047] "Pharmaceutically" or "pharmacologically acceptable" refers to molecular entities and compositions that do not produce adverse events, allergic reactions, or other untoward reactions when administered to an animal or human, as appropriate.

[0048] In the context of the present invention, the terms "treat" or "treatment" as used herein refer to ameliorating, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0049] "Therapeutically effective amount" refers to an amount of a compound / drug according to the invention effective to produce a desired therapeutic effect.

[0050] According to the present invention, the term "patient" or "patient in need thereof" contemplates a human or non-human mammal suffering or likely to suffer from a neuropsychological disorder. Preferably, the patient is a human.

[0051] In general terms, pitolisant may be provided as a pharmaceutical composition associated with one or more pharma- ceutically acceptable excipients.

[0052] As used herein, "pharmaceutically acceptable excipient" includes any diluent, adjuvant, or vehicle, such as preservatives, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonicity agents, and absorption retardants. The use of media and agents for pharma-ceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. Supplementary active ingredients can also be incorporated into the composition.

[0053] According to one embodiment, pitolisant may be administered in a unit dosage form, where the term "unit dosage" refers to a single dosage that can be administered to a patient and that can be easily handled and packaged and remains as a physically or chemically stable unit dosage containing either pitolisant itself or a pharma- ceutically acceptable composition as described below.

[0054] Pitolisant may be formulated into a pharmaceutical composition by admixture with one or more pharma- ceutically acceptable excipients.

[0055] The compositions may be conveniently administered in unit dosage form and prepared by any methods well known in the art of pharmacy, e.g., as described in Remington: The Science and Practice of Pharmacy, 20th ed.; Gennaro, AR, Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition.

[0056] According to one embodiment, pitolisant is suitable for oral administration, particularly in tablet form.

[0057] Tablets and the like may contain one or more of any of the following compounds or compounds of a similar nature: binders, such as microcrystalline cellulose or gum tragacanth; diluents, such as starch or lactose; disintegrants, such as starch and cellulose derivatives; lubricants, such as magnesium stearate; lubricants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; flavorings, such as peppermint or methyl salicylate. In addition, dosage unit forms may contain various other materials that modify the physical form of the dosage unit, such as coatings of sugar, shellac, or enteric agents. Oral syrup or elixir dosage forms may contain sweeteners, preservatives, dyes, colorings, and flavorings.

[0058] Preferred formulations include pharmaceutical compositions in which pitolisant is formulated for oral administration, more preferably as tablets. Oral compositions generally contain an inert diluent carrier or an edible carrier. Preferred tablets include any combination of lactose, cornstarch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, or talc. [Brief description of the drawings]

[0059] [Figure 1]FIG. 1 illustrates the absolute difference (post-treatment-pre-treatment) in Flicker fusion thresholds for treatment groups (control or pitolisant monohydrochloride 20 mg, 40 mg or 60 mg (* indicates significant change 1.5 h or 11 h after treatment with pitolisant)). EXAMPLES

[0060] Example 1 Critical Flicker Fusion Test (CFFT) in healthy volunteers

[0061] In healthy human volunteers, fatigue was assessed at the end of the day, when fatigue tends to increase, using the Flicker Fusion Test reported by Luczak A, et al. Ergonomics, 2005 Dec 15;48(15):1770-92; Ma et al PLoS One, 2014 Feb 5;9(2):e87121; Maeda et al Jpn J Radiol. 2011 Aug;29(7):483-7., a known psychometric test.

[0062] In a group of 36 healthy volunteers, changes in fusion frequency were assessed several times throughout the day after administration of increasing doses (20, 40 or 60 mg) of either placebo or pitolisant monohydrochloride. Fusion frequency changed especially at the end of the day, at which point a 60 mg dose of pitolisant monohydrochloride given orally reversed the changes, whereas lower doses failed to provide significant changes (see FIG. 1).

[0063] In contrast, in the same group of subjects, alertness was assessed by analysis of electroencephalogram spectra and was found to be significantly improved already at a dose of 40 mg of pitolisant monohydrochloride (not shown).

[0064] This indicates a greater sensitivity to pitolisant during wakefulness compared to fatigue, which requires higher dosages to produce significant improvement.

[0065] Example 2 Sleep-deprived subjects

[0066] Pitolisant hydrochloride was administered at a dose of 30 mg once daily to human volunteers who were sleep deprived for 24 hours. Fatigue in these volunteers, as assessed by fusion frequency, was not altered by either placebo or pitolisant at this dose.

[0067] conclusion Thus, the Flicker fusion test does not appear to be improved by treatment with 30 to 40 mg of pitolisant hydrochloride, which is known to improve EDS in patients with narcolepsy at these doses.

[0068] In contrast, when 60 mg of pitolisant hydrochloride was administered to fatigued healthy volunteers, the Flicker fusion test improved significantly.

[0069] Example 3 side effects

[0070] It has been found that pitolisant can be used in doses of up to 240 mg once daily without any apparent side effects.

[0071] Groups of 24 healthy volunteers received placebo or pitolisant monohydrochloride at doses of 160, 200, or 240 mg. This last dose corresponds to six times the maximum dose recommended for narcolepsy. Blood samples analyzed for pitolisant and metabolite levels showed dose proportionality. The number and nature of adverse events did not differ between pitolisant-treated and placebo-treated subjects.

[0072] No significant abnormalities were recorded in laboratory parameters, vital signs, physical examination findings, or electrocardiogram parameters. Furthermore, few abnormalities were reported in all treatment groups.

[0073] Considering these results, it was concluded that doses of 160 mg, 200 mg and 240 mg of pitolisant were safe and well tolerated.

[0074] Example 4 Brain histamine H3 receptor occupancy Six healthy volunteers were administered 40 mg of pitolisant monohydrochloride. PET scans were performed. The authors reported that the therapeutic dose of pitolisant occupied the majority (84 ± 7% (mean ± SD)) of histamine H3 receptors (Rusjan PBr J Pharmacol. 2020 Aug;177(15):3464-3472), and based on the high occupancy, it was suggested that activity of pitolisant in various central nervous system disorders related to H3 receptors may be expected at this therapeutic dose.

[0075] This is consistent with the significant efficacy of pitolisant at this therapeutic dose in EDS and cataplexy in patients with narcolepsy.

[0076] Therefore, the lack of improvement in the Flicker fusion test at this dose of pitolisant hydrochloride, known to improve EDS in patients with narcolepsy, was unexpected.

[0077] Also, the threshold dose of pitolisant hydrochloride was not expected to be higher than the dose that already achieved high occupancy to improve SF.

Claims

1. Pitolisant for use in the treatment and / or prevention of severe fatigue (SF) comprising administering to a patient suffering from a disorder associated with SF a dose comprised between 50 mg and 240 mg of pitolisant, or one of its pharma- ceutically acceptable salts, hydrates, or hydrated salts, or crystalline polymorphic structures of these compounds, or optical isomers, racemates, diastereomers, or enantiomers thereof, once daily.

2. Pitolisant for use according to claim 1, wherein the pitolisant is administered in a dose comprised between 50 mg and 120 mg.

3. Pitolisant for use according to any of the preceding claims, wherein the patient suffers from narcolepsy, obstructive sleep apnea syndrome, multiple sclerosis, Parkinson's disease, cancer, depression, bipolar disorder, sequelae of stroke, sequelae of COVID-19, chronic fatigue syndrome, fibromyalgia, traumatic brain injury, inflammatory bowel disease.

4. Pitolisant for use according to any of the preceding claims, wherein the patient suffers from narcolepsy.

5. Pitolisant for use according to claim 4, wherein the patient suffers from narcolepsy associated with cataplexy.

6. Pitolisant for use according to claim 4, wherein the patient suffers from non-cataplexy narcolepsy.

7. Pitolisant for use according to any of the preceding claims, wherein the salt is the monohydrochloride salt.

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