Novel synergistic combinations based on FENM and acetylcholinesterase inhibitors

Abstract

The present invention relates to a composition comprising a synergistic combination of fluoroethylnormemantine (FENM) and at least one acetylcholinesterase inhibitor.More particularly, the present invention relates to said composition for its use as a medicine, and even more particularly, to said composition for its use in treating the condition of pathology selected from tauopathy, synucleinopathy, amyloidopathy, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, and amyotrophic lateral sclerosis.

Description

[Technical field]

[0001] The present invention relates to the field of neurodegenerative diseases. More particularly, the present invention relates to compositions comprising a synergistic combination of 3(2-fluoroethyl)tricyclo[3.3.1.13,7]decan-1-amine (fluoroethylnormemantine, FENM) and at least one acetylcholinesterase inhibitor. The invention also relates to these combinations or compositions comprising them for their use in the treatment of neurodegenerative pathologies, and more particularly in the prevention and / or treatment of cognitive impairment in these pathologies. [Background technology]

[0002] The World Health Organization (WHO) estimates that by 2050, the number of people over 60 years of age will reach 2 billion. This unprecedented aging of the world's population implies that age-related chronic diseases will put a strain on the healthcare system. Dementia is one of them. Thus, the WHO estimates that the total number of dementia patients is expected to exceed 150 million by 2050. Dementia is characterized by the deterioration of cognitive functions, especially memory and reasoning, which affects the patient's behavior and their ability to perform daily tasks. Dementia is a syndrome that includes pathologies with diverse etiologies that affect different areas of the brain and other areas of the central nervous system, including, in particular, neurodegeneration and death of nerve cells. Directly related to aging, mitochondrial dysfunction and oxidative stress play an important role in the pathogenesis of neurodegenerative diseases. These pathologies and syndromes are also often associated with the abnormal accumulation of certain proteins, as observed in Aβ amyloidosis, tauopathy, synucleinopathy, aggregation of superoxide dismutase-1 (SOD1), polyglutamine, TDP-43 protein, and / or the accumulation of mutated and / or misfolded proteins. Alzheimer's disease is the most common cause of dementia and is thought to be responsible for 60-70% of cases (WHO).

[0003] Today, several molecules are approved for the symptomatic treatment of Alzheimer's disease. These include anticholinesterases, such as donepezil, rivastigmine, or galantamine, which have benefited from marketing approval as monotherapy in mild, moderate, or moderately severe stages of the disease. Memantine, a noncompetitive voltage-dependent antagonist of the NMDA receptor, is approved in moderate and severe stages of the disease, but not in the mild stages. These compounds are not recommended in the early stages of the disease, due to their poor clinical efficacy. In addition, their effects are symptomatic and limited, and have only been demonstrated in the short term (average 6 months) in almost two-thirds of the patients included in clinical trials (source, Haute Autorite de Santé, France). The combined treatment of donepezil and memantine under the brand name Acrescent® has been denied its Marketing Authorization (MA) by the European Medicines Agency (EMA) because the benefits of this combination (memantine 20 mg / donepezil 10 mg) are lower compared to the compounds used alone (EMA, 18 October 2012). The only concern seems to be the need to take one tablet instead of two in patients with cognitive impairment; however, this treatment is approved by the FDA in the United States. Furthermore, the claimed efficacy of anticholinesterases in early stages of the disease is based on a single study carried out specifically in patients at this stage, where a modest benefit was observed only in patients who tolerated a dose of 10 mg / day of donepezil. The French health authorities consider this study inconclusive regarding the interest of starting this treatment at mild stages of the disease (source Haute Autorite de Santé, France, 2012).

[0004] Acetylcholinesterase inhibitors also carry the risk of serious adverse effects, or adverse effects that may alter the quality of life and / or require discontinuation of treatment. These may include gastrointestinal disorders (diarrhea, vomiting), cardiovascular disorders (bradycardia, syncope), or even neuropsychiatric disorders (dizziness, confusion) that may be counterproductive in the case of dementia treatment. Beyond six months, the limited benefits, as well as the increasing risk of adverse effects with the duration of treatment, strongly outweigh the potential for its short-term use. Indeed, these treatments are applied to patients whose cognitive abilities are already impaired in the moderate or even advanced stages of the disease. WO 2014 / 191424 describes a method for marking NMDA receptors in order to study their distribution and their response to drug treatment. 18 FENM marked with F and their visualization by positron emission tomography are described. WO 2019 / 115833 describes FENM in the treatment of anxiety-related disorders and depression. WO 2013 / 064579 describes the combination of a connexin blocker (e.g., meclofenamic acid) and an acetylcholinesterase inhibitor (e.g., donepezil) for its use in the treatment of cognitive impairment.

[0005] Aducanumab is an anti-amyloid monoclonal antibody used to reduce the amyloid burden in the brain. Aducanumab received an MA issued by the FDA in 2021 for the treatment of early or prodromal Alzheimer's disease with the proven presence of amyloid deposits. Given that the results regarding less cognitive decline in treated patients were not replicated, and in light of the lack of a therapeutic solution, the MA was contingent on a reevaluation of the product to confirm its clinical interest (<www.fda.gov> Approximately 35% of treated patients developed cerebral microbleeds and cerebral edema (Source: France Alzheimer,<www.francealzheimer.org> The cost of the treatment, which requires monthly intravenous infusions, is estimated at $56,000 per year. Early diagnosis of dementia or Alzheimer's disease results in a significant need for treatment by patients and their families to stop or slow the progression of the disease as soon as possible. Currently, this need is unmet. Also, in patients at later stages of the disease, there is a significant need for treatments that are more effective both in terms of symptoms treated and the duration of effective treatment. Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention aims to improve the shortcomings of the prior art. In particular, the present invention aims to propose a new treatment for cognitive impairment in neurodegenerative diseases, in particular Alzheimer's disease (AD). This new treatment is based on the action of the combination of fluoroethylnormemantine (FENM) and at least one acetylcholinesterase inhibitor. The synergistic effect identified between these molecules makes it possible, on the one hand, to obtain a particularly effective effect in preserving cognitive performance and / or to reduce the doses used for these compounds. This reduction makes it possible to reduce the risk of adverse effects or even increase the possible treatment period, while achieving greater improvements, especially at lower doses. This improved efficacy makes it possible to consider the use of this treatment even in the early stages of the disease. [Means for solving the problem]

[0007] The applicants have demonstrated that the combined effect of FENM and that of an acetylcholinesterase inhibitor may be involved in the suppression of amyloid peptide oligomers β 25-35 (Aβ 25-35 It has been discovered, very unexpectedly, that intracerebral administration of 1,2-diphenylmethane (DMSO) has a synergistic effect in the treatment of cognitive symptoms in a mouse model of intoxication. This synergy is observed in cognitive tests of short-term working memory and also of long-term contextual memory. Such a synergy makes it possible to investigate more effective treatments than those currently applied and to widen the patient population to which these treatments can be applied compared to current practice. Thus, one object of the present invention relates to a composition comprising a synergistic combination of 3-(2-fluoroethyl)adamantan-1-amine (FENM) or any one of its pharma- ceutically acceptable salts, and at least one acetylcholinesterase inhibitor or any one of its pharma- ceutically acceptable salts.

[0008] In a particular embodiment, the at least one acetylcholinesterase inhibitor is selected from among donepezil, galantamine, rivastigmine, tacrine, or any one of their pharmaceutically acceptable salts. Indeed, these molecules benefit from MA or have already been tested in humans, and their pharmacokinetic and pharmacodynamic properties are already known, which is particularly advantageous. According to another characteristic of the composition according to the invention, - the compounds may be formulated together or separately; - FENM and / or said at least one acetylcholinesterase inhibitor are mixed with a pharma- ceutically acceptable excipient. The synergistic interaction between FENM and acetylcholinesterase inhibitors discovered by the inventors allows for a better therapeutic management of patients, with increased treatment efficacy and / or reduced doses administered, compared to monotherapy, and thus reduced side effects that may be associated with the active compounds of the composition of the invention, i.e. FENM and at least one acetylcholinesterase inhibitor, while still maintaining or even improving the therapeutic benefits at these lower doses.

[0009] Thus, in a particular independent embodiment, in the composition according to the invention, - FENM dosage is compatible with FENM dosage of 20 mg / day or less; - the at least one acetylcholinesterase inhibitor is donepezil, present in a dose suitable for a daily dosage of less than or equal to 10 mg; - the at least one acetylcholinesterase inhibitor is rivastigmine, present in a dose suitable for a daily dosage of 3 mg or less; and / or - said at least one acetylcholinesterase inhibitor is galantamine present in a dose suitable for a daily dosage of less than or equal to 16 mg; In another particular embodiment thereof, in the composition according to the invention, the molar ratio of FENM / at least one acetylcholinesterase inhibitor is 4 or less, 3 or less, preferably 2 or less, preferably 1 or less. A particular object of the present invention relates to a composition as described herein above in any one of its embodiments, for use as a medicament.

[0010] More specifically, as demonstrated in the experimental section, the composition comprising the synergistic combination of FENM and at least one acetylcholinesterase inhibitor is particularly effective in combating cognitive dysfunction in neurodegenerative pathology models.Therefore, another object of the present invention relates to the composition of any one of its above-mentioned embodiments for its use in treating pathology selected from among tauopathy, synucleinopathy, amyloidopathy, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, Lewy body dementia, amyotrophic lateral sclerosis. In the composition of the present invention, for any one of the purposes of use described above, FENM and at least one acetylcholinesterase inhibitor are administered separately, simultaneously or sequentially.For example, this can be done by using a specific formulation of FENM on the one hand and at least one acetylcholinesterase inhibitor on the other hand, so that a distinct infusion kinetics is obtained for each of the compounds contained in the unit composition; or according to another embodiment, at least FENM on the one hand and at least one acetylcholinesterase inhibitor of the combination on the other hand are formulated and administered in individualized galenical form.

[0011] Another object of the present invention is FENM or a pharma- ceutically acceptable salt thereof in synergistic combination with at least one acetylcholinesterase inhibitor selected from among any one of donepezil, galantamine, rivastigmine, tacrine, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a condition selected from among tauopathies, synucleinopathies, amyloidopathies, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, amyotrophic lateral sclerosis. [Brief description of the drawings]

[0012] [Figure 1] (A) Symptomatic effect of FENM, donepezil (DPZ), or the combination of FENM-DPZ on memory dysfunction induced by oligomerized Aβ25-35 peptides in the Y-maze test; data ± standard error. ANOVA: F(14,200)=2.511, p=0.0026, n=30-31 / group for non-addicted controls treated with vehicle and 11-20 for treated groups. **p<0.01, ***p<0.001 vs. vehicle-treated and non-addicted; #p<0.05, ##p<0.01, ###p<0.001 vs. Aβ25-35 oligomer-addicted and vehicle-treated; Dunnett's test. (B) Protection scale showing the level of protection (PP) provided by donepezil (DPZ), FENM, or the mix (MIX) of FENM-donepezil. The calculated combination index is less than 1. 100% corresponds to the performance level of mice not intoxicated with Aβ25-35 oligomers and treated with vehicle. 0% protection corresponds to the performance level of intoxicated mice treated with vehicle. S: synergy; V: vehicle. [Diagram 2](A) Symptomatic effect of donepezil FENM (DPZ) or the combination FENM-DPZ on memory impairment induced by intoxication with oligomerized Aβ25-35 peptides in the passive avoidance test. Results are non-parametric data and are presented as median and 25%-75% deviation. Training is performed on day 9, 48 h after the last treatment. Retention was tested on day 10, 24 h after training. Kruskal-Wallis ANOVA: H=54.27, p<0.0001, n=34-36 / group for non-intoxicated control animals treated with vehicle and 11-20 for groups intoxicated with Aβ25-35 oligomers and treated with compound. *p<0.05, **p<0.01, ***p<0.001 vs. non-intoxicated and vehicle-treated group; #p<0.05, ##p<0.01, ###p<0.001 vs. Aβ25-35 intoxicated and vehicle-treated group; Dunn's test. (B) Protection scale showing the level of protection (PP) provided by donepezil (DPZ), FENM, or a mix of FENM-donepezil (MIX). The calculated combination index is less than 1. 100% corresponds to the performance level of mice not intoxicated with Aβ25-35 oligomers and treated with vehicle. 0% protection corresponds to the performance level of intoxicated mice treated with vehicle. S: synergy; V: vehicle. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] definition In the context of the present invention, reference to a particular drug or compound includes not only the specifically named drug or compound, but also the active molecule of the drug or any salt, hydrate, derivative, isomer, racemate, enantiomerically pure composition, conjugate, or corresponding pharmaceutically acceptable prodrug.Preferably, reference to a compound includes the specifically named compound as well as any salt, hydrate, isomer, racemate, isomer, enantiomerically pure pharmaceutically acceptable composition of said compound.More preferably, the designation of a compound is intended to designate the specifically named compound itself as well as any pharmaceutically acceptable salt thereof.However, unless otherwise indicated, reference to the amount of a compound of a composition or combination according to the present invention in units of mass or units of mass per day means the named compound itself.

[0014] By "pharmaceutically acceptable salts" in the sense of the present invention is to be understood a pharmaceutically acceptable relatively non-toxic inorganic or organic acid addition salt of the compound of the present invention. The formation of pharmaceutical salts involves combining an acidic, basic or zwitterionic drug molecule with a counterion to create a salt water version of the drug. A variety of chemical species can be used in the neutralization reaction. Thus, the pharmaceutically acceptable salts of the present invention include those obtained by reacting the compound with an inorganic or organic acid to form a salt when the compound functions as a base, such as, for example, a salt of acetic acid, nitric acid, tartaric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid or citric acid. The pharmaceutically acceptable salts of the present invention also include those obtained by reacting the compound with a suitable base when the compound functions as an acid to form, for example, a salt of sodium, potassium, calcium, magnesium, ammonium or choline. While most salts of a given active ingredient are bioequivalent, some may have properties of, among others, enhanced solubility or bioavailability. Salt selection is now a common standard procedure in the drug development process, as taught by Stahl and Wermuth in their handbook (Stahl and Wermuth).

[0015] Examples of compounds that can be used to implement the combination of FENM and an acetylcholinesterase inhibitor according to the present invention are shown in Table 1 below. [Table 1]

[0016] A preferred donepezil salt is donepezil hydrochloride. A preferred galantamine salt is galantamine hydrobromide. A preferred rivastigmine salt is rivastigmine tartrate. A preferred FENM salt is FENM hydrochloride. A particularly preferred FENM salt is FENM hydrobromide.

[0017] The term "combination" in the sense of the present invention means a treatment in which at least FENM and at least one acetylcholinesterase inhibitor are co-administered to a subject to produce a biological effect. In a combination therapy according to the present invention, these at least two compounds can be administered together or separately, simultaneously or sequentially. In particular, FENM and said at least one acetylcholinesterase inhibitor may be administered according to different routes and / or administration protocols. Thus, although they may be formulated together, the compounds as elements of a combination in the sense of the present invention can also be formulated separately. For example, FENM may be administered orally and said at least one acetylcholinesterase inhibitor of the combination according to the present invention may be injected into said subject, for example, intravenously, subcutaneously or transdermally. In another embodiment, for example, FENM may be administered orally and said at least one acetylcholinesterase inhibitor may also be administered orally to said subject, simultaneously or at different times. Preferably, the order of administration of the active ingredients of the combination (FENM and said at least one acetylcholinesterase inhibitor) is such that said active ingredients or their active metabolites exert their biological effects simultaneously, so that the subject benefits from the maximum effect of said combination. Thus, in a particularly preferred manner, FENM and said at least one acetylcholinesterase inhibitor are administered simultaneously to reach their maximum concentrations in the plasma or cerebrospinal fluid, preferably in the cerebrospinal fluid.

[0018] The term synergy as applied to the combination according to the invention means a combination in which the observed or known memory-promoting or anti-amnesic effects of each active ingredient of said combination are additive or multiplicative when used such that their physiological effects interact. In particular, this synergy makes it possible to obtain a memory-promoting or anti-amnesic effect at doses where the active ingredients applied in monotherapy would have no or limited effect, which may allow to reduce side effects and / or to avoid or shorten the duration of dose escalation protocols. Furthermore, this synergy between the effects of the compounds of the combination according to the invention makes it possible to enhance these memory-promoting or anti-amnesic effects or to improve complex memory types, as shown in the experimental part. Methods for analyzing the interaction between two molecules and for determining the synergistic effect of a combination of compounds are well known to the skilled person. A non-limiting example is the analysis of isobolograms and the determination of combination indexes according to the principles described by Fraser (1872) and implemented, for example, by Martin et al. (2020). The presence of synergy can thus be detected by applying the mathematical methods described in the experimental part. Synergy can be demonstrated in vivo in animal models of pathology, for example by tests to assess cognitive performance or morphological dysfunction associated with the pathology. Synergy can be demonstrated in vitro, for example by measuring various parameters related to cell viability and, in the case of neuronal cells, neurite outgrowth, synapse formation, etc., in in vitro cell tests in models recognized by the scientific community, for example cytotoxicity tests. Descriptions of these tests for dementia and / or AD are given, for example, by Chumakov et al. (2015).

[0019] "Subject" should be understood herein to mean any member of the animal kingdom, preferably a mammal, and even more preferably a human. A subject in need of the combination treatment of the present invention is defined as a subject who is suffering from, suspected of suffering from, or believed to be at risk of suffering from a neurodegenerative pathology that leads to dementia and associated cognitive impairment. For example, these conditions are tauopathy, synucleinopathy, amyloidopathy, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, and amyotrophic lateral sclerosis. The compositions, combinations, and methods of the present invention are particularly suitable for treating cognitive impairment associated with Alzheimer's disease in its early, moderate, or advanced stages. Thus, in certain embodiments, the subject is suffering from, suspected of suffering from, or believed to be at risk of suffering from Alzheimer's disease in its early, moderate, or advanced stages. In another particular embodiment, the subject is thought to be suffering from, suspected of suffering from, or at risk of suffering from cognitive impairment associated with early, moderate, or advanced stage Alzheimer's disease, preferably cognitive impairment associated with early stage Alzheimer's disease.

[0020] As used herein, the term "treatment" includes the cure, prevention, prophylaxis, delay, or alleviation of symptoms or causes caused by the above diseases or disorders herein. In particular, the term treatment includes monitoring the progression of the disease and associated symptoms. In particular, the term treatment includes protection from the toxic effects caused by amyloid beta, or the reduction or delay of these effects in the treated subject. In particular, the term treatment refers to the improvement, halt, or delay of the cognitive symptoms of the aforementioned diseases. Combination of FENM with at least one acetylcholinesterase inhibitor As shown by the experimental data presented herein below, a synergistic interaction between the memory promoting or antiamnesic effects of FENM and an acetylcholinesterase inhibitor was discovered, which inhibits Aβ 25-35This resulted in improvement of cognitive symptoms in experimental animal models of toxicity induced by amyloid peptide Aβ. 25-35 The protective effect of this combination against cognitive decline caused by is observed on both short-term working memory and long-term memory. Thus, in a first aspect, the present invention relates to a synergistic combination of FENM or any one of its pharma- ceutically acceptable salts with at least one acetylcholinesterase inhibitor or any one of its pharma- ceutically acceptable salts.

[0021] In certain embodiments, said at least one acetylcholinesterase inhibitor is selected from donepezil, galantamine, rivastigmine or tacrine. Donepezil, galantamine and rivastigmine are particularly preferred because they have been approved for more than 20 years and their side effects and pharmacological properties are well known. Tacrine is less preferred due to its hepatotoxicity. However, the synergistic effect highlighted herein on protection from cognitive symptoms may allow the use of low doses where this hepatotoxicity is not observed. The synergistic combination of FENM and donepezil is particularly preferred. As mentioned above, the synergistic effects observed with the combinations of the present invention make it possible to consider using in humans the minimum doses of acetylcholinesterase inhibitors used in humans or doses lower than these minimum doses. Thus, in certain embodiments, in a synergistic combination according to the present invention, at least one acetylcholinesterase inhibitor is donepezil and is administered at a dose of 10 mg per day or less, 5 mg per day or less, 2.5 mg per day or less, yet sufficient to observe a beneficial effect of the combination on the cognitive performance of the subject.

[0022] In another specific embodiment, in a synergistic combination according to the invention, at least one acetylcholinesterase inhibitor is galantamine and is administered at a dose of 16 mg per day or less, 8 mg per day or less, 4 mg per day or less, or 2 mg per day or less, which is still sufficient to observe a beneficial effect of the combination on the cognitive performance of the subject. In another specific embodiment, in a synergistic combination according to the invention, at least one acetylcholinesterase inhibitor is rivastigmine and is administered at a dose of 3 mg or less per day, 1.5 mg or less per day, or 1 mg or less per day, which is still sufficient to observe a beneficial effect of the combination on the cognitive performance of the subject. In certain embodiments, FENM is used in a synergistic combination according to the present invention at a dose of 20 mg per day or less, 10 mg per day or less, or 5 mg per day or less, which is still sufficient to observe a beneficial effect of the combination on the cognitive performance of the subject.

[0023] The cognitive ability and its progress of human subjects can be measured by tests known to those skilled in the art.The tests commonly used for cognitive assessment of human subjects are, for example, Mini-Mental State Examination (MMSE or Folstein test), Revised Mini-Mental State Examination (i.e. 3MS scale), Abbreviated Mental Test Score (AMTS or Abbreviated Mental Test), Dementia Questionnaire for Mentally Retarded (i.e. DMR Questionnaire), Cognitive Abilities Screening Instrument (CASI), Trail Making Test, Clock Drawing Test, Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog), General Practitioner's Assessment of Cognition (GPCOG), Montreal Cognitive Assessment (MoCA), or Roland Universal Dementia Assessment Scale (RUDAS), or Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). More specifically, the MMSE allows screening of people with major neurocognitive disorders (dementia) without being tied to a specific pathology. The MMSE is also used to monitor the cognitive status of people and to measure the decline of cognitive function in people with neurocognitive disorders. The test evaluates orientation, recording, attention, and calculation, memory retention, language, and assembly practice. CERAD (acronym for Consortium to Establish a Registry for Alzheimer's Disease) has established a dementia severity scale related to the score obtained with the MMSE. A score of 19 to 24 is associated with mild dementia, 10 to 18 with moderate dementia, and a score of less than 10 with severe dementia, with a maximum score of 30. A change of 2 points in the score is generally considered to be clinically relevant.

[0024] The ADAS-Cog is the cognition subscale of the Alzheimer's Disease Scale and therefore concerns only the cognition-related aspects of dementia. It can therefore be used to assess (i.e. score) and monitor the progression of any type of dementia. The ADAS-Cog assesses orientation, memory, executive function, visuospatial ability, language, or praxis, with scores ranging from 0 to 70, with higher scores indicating greater deficits. The ADAS-Cog is considered to be more sensitive than the MMSE. It is one of the most commonly used tests for the clinical evaluation of compound candidates for marketing authorization in anti-dementia treatment, and also to measure the course of cognitive impairment. Thus, a combination having a beneficial effect of the combination on the cognitive ability of a subject will show a slowdown or stabilization of the deterioration of the cognitive ability of the subject with respect to the normal course established in untreated subjects at the same disease stage for a given period of time. In other words, for example, in the case of the ADAS-Cog, the beneficial effect on the cognitive ability of the subject will correspond to a decrease, stabilization, or a less intense increase in the ADAS-Cog score compared to the normal deterioration of the score observed in untreated subjects of the same age at the same stage. Although the deterioration of the score depends on the stage of the pathology and the age of the subject, an increase of 5.82 points in the ADAS-Cog score per year is commonly observed in subjects with untreated Alzheimer's disease (Zhang et al., 2020). With respect to the MMSE, for example, the beneficial effect on the cognitive ability of the subject will correspond to a lesser increase, stabilization, or a less intense decrease in the MMSE score compared to the normal deterioration of the MMSE score observed in untreated subjects. In subjects with untreated Alzheimer's disease, a yearly decline in MMSE scores of 2.28 points is commonly observed (Rossetti et al., 2010).

[0025] Surprisingly, synergy between FENM and at least one acetylcholinesterase inhibitor is observed at very low FENM / acetylcholinesterase inhibitor molar ratios. Indeed, the molar ratios tested for memantine and donepezil in the current situation are greater than 4, considering combinations based on memantine 20 mg and donepezil 10 mg, which is in particular the ratio included in the FDA-approved NAMZARIC®, based on donepezil hydrochloride and memantine hydrochloride. It should be noted that the Tmax values ​​in humans for donepezil and memantine upon oral administration are comparable, being 3-8 hours for memantine (Maekawa et al., 2019) and 4.1±1.5 hours for donepezil (Rogers & Friedoff, 1998). Experimental data show that the synergistic effect found in the combination of the present invention is obtained at much lower molar ratios, which can even be reversed, reflecting the specificity of the FENM-based synergistic combination.

[0026] Thus, in a particular embodiment of the synergistic combination of FENM and at least one acetylcholinesterase inhibitor according to the present invention, the molar ratio of FENM / acetylcholinesterase inhibitor is 4 or less, 3 or less, 2 or less, preferably 1 or less, 0.8 or less, or 0.5 or less. The molar ratio of FENM / acetylcholinesterase inhibitor is 0.1 or more. In a particularly preferred manner, the molar ratio of FENM / acetylcholinesterase inhibitor is less than 1 and 0.1 or more. In another particular embodiment, the acetylcholinesterase inhibitor is donepezil, and the molar ratio of FENM / donepezil is 4 or less, 3 or less, 2 or less, preferably 1 or less, 0.8 or less, or 0.5 or less. The molar ratio of FENM / acetylcholinesterase inhibitor is 0.1 or more. In a particularly preferred manner, the molar ratio of FENM / donepezil is less than 1 and 0.1 or more.

[0027] A composition according to the present invention comprising a synergistic combination of FENM and at least one acetylcholinesterase inhibitor. In another aspect, the present invention relates to a composition comprising a synergistic combination as described herein above. In this composition, FENM or any one of its pharma- ceutically acceptable salts and at least one acetylcholinesterase inhibitor or any one of its pharma- ceutically acceptable salts are formulated together or separately. In certain embodiments, FENM and at least one acetylcholinesterase inhibitor are the only active ingredients of the composition, in other words, FENM and at least one acetylcholinesterase inhibitor are the only compounds within the composition that have therapeutic or preventative activity. Preferably, the composition is administered to the subject in a pharmaceutical form, for example, but not limited to, orally, topically (cutaneously, orally, sublingually), or parenterally (subcutaneously, intramuscularly, or intravenously), with oral administration being particularly preferred.

[0028] The amount of active ingredients in this composition, i.e. at least FENM and at least one acetylcholinesterase inhibitor, conforms to the dosage determined herein above for the synergistic combination of the present invention. In other words, when the composition is in the form of a unit dose (pill, capsule, powder, emulsion, liquid), the dosage contains an amount of FENM or at least one acetylcholinesterase inhibitor that is a multiple or a division of the dosage determined for the synergistic combination of the present invention, thereby making it possible to obtain the appropriate dosage as defined above in one or more doses. In a specific embodiment, the composition according to the present invention contains 10 mg donepezil, 7.5 mg donepezil, 5 mg donepezil, or 2.5 mg donepezil. In another specific embodiment, the composition according to the present invention contains 16 mg galantamine, 8 mg galantamine, 4 mg galantamine, or 2 mg galantamine. In another specific embodiment, the composition according to the present invention contains 3 mg rivastigmine, 1.5 mg rivastigmine, or 1 mg rivastigmine.

[0029] In certain embodiments, compositions according to the present invention comprise 20 mg of FENM, 10 mg of FENM, 7.5 mg of FENM, 5 mg of FENM, or 2.5 mg of FENM. In another embodiment, the composition according to the invention comprises 20 mg FENM and 10 mg donepezil, 7.5 mg donepezil, 5 mg donepezil, or 2.5 mg donepezil. In another embodiment, the composition according to the invention comprises 10 mg FENM and 10 mg donepezil, 7.5 mg donepezil, 5 mg donepezil, or 2.5 mg donepezil. In another embodiment, the composition according to the invention comprises 7.5 mg FENM and 10 mg donepezil, 7.5 mg donepezil, 5 mg donepezil, or 2.5 mg donepezil. In another embodiment, the composition according to the invention comprises 5 mg FENM and 10 mg donepezil, 7.5 mg donepezil, 5 mg donepezil, or 2.5 mg donepezil. In another embodiment, the composition according to the invention comprises 2.5 mg FENM and 10 mg donepezil, 7.5 mg donepezil, 5 mg donepezil, or 2.5 mg donepezil.

[0030] In another embodiment, in the composition according to the invention, the molar ratio of FENM / acetylcholinesterase inhibitor is 4 or less, 3 or less, 2 or less, preferably 1 or less, 0.8 or less, or 0.5 or less. Said ratio is 0.1 or more. In a particularly preferred manner, said FENM / acetylcholinesterase inhibitor molar ratio is less than 1 and 0.1 or more. In another particular embodiment, said acetylcholinesterase inhibitor is donepezil, and said FENM / donepezil molar ratio is 4 or less, 3 or less, 2 or less, preferably 1 or less, 0.8 or less, or 0.5 or less, said ratio is 0.1 or more. In a particularly preferred manner, said FENM / donepezil molar ratio is less than 1 and 0.1 or more. The dose may be administered in multiple doses distributed throughout the day, the number of doses throughout the day allowing to obtain the desired daily dose.Thus, in certain embodiments, the dose considered may be administered in 1 to 4 daily doses, such as 1, such as 2, such as 3, or 4 doses.

[0031] In a preferred embodiment, in said composition, the FENM or combination of at least one acetylcholinesterase inhibitor is adjusted to provide a dose equivalent to one dose without the need for any manipulations, such as measuring the volume, weighing or dividing tablets, which is particularly advantageous in subjects with cognitive impairment, as it avoids any specific calculations or manipulations. For example, FENM or at least one acetylcholinesterase inhibitor may be formulated separately in the form of separate powders, microgranules, granules, or pills, and then combined into a capsule for ease of ingestion. The pharmaceutical composition may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (23rd ed.), ed. Adeboye Adejare, 2020) and the PK / PD properties of the active ingredients. Conventionally, in the compositions according to the invention, FENM and / or said at least one acetylcholinesterase inhibitor are mixed with pharma- ceutically acceptable excipients.

[0032] In one embodiment, the composition is in the form of a tablet or pill. The tablet or pill may be divisible into 1, 2, 3, or 4 pieces (multiple pieces), and 1, 2, or 3 pieces of the tablet may be used to provide the subject with the dose required for ingestion. This is of particular interest, for example, when a period of dose escalation is required for treatment, and the pieces may correspond to the increment steps and the whole tablet or pill may correspond to the target dose of treatment to reach the target daily dose. In one embodiment, in the composition, FENM and at least one acetylcholinesterase inhibitor are mixed with the same excipients in the same tablet or pill. In certain embodiments, FENM and at least one acetylcholinesterase inhibitor are present in different compartments of the tablet or pill with excipients specific thereto, depending on their physicochemical or pharmacokinetic properties. In another embodiment, which is of particular interest for molecules with different PK / PD profiles, FENM and at least one acetylcholinesterase inhibitor are present separately within the tablet. Thus, in certain embodiments, FENM and at least one acetylcholinesterase inhibitor are present in different compartments of the tablet or pill, for example, one compound is located on the outside and the other compound is located on the inside of the tablet or pill, which allows for separate, staggered administration of the compounds.

[0033] In one embodiment of the composition according to the invention, the FENM and / or at least one acetylcholinesterase inhibitor may be formulated to be released substantially immediately after administration, at any time, or at a predetermined time period after administration, i.e., in a controlled manner in the body. Controlled release formulations include (i) formulations that create a substantially constant concentration of the compound or its active derivative in the body over an extended period of time, (ii) formulations that create a substantially constant concentration of the compound or its active derivative in the body after a predetermined waiting period over an extended period of time, (iii) formulations that allow the action of the active compound or its derivative to be maintained for a predetermined period of time by maintaining a relatively constant and effective level of said compound or its active derivative in the body, while at the same time minimizing undesirable side effects associated with fluctuations in the plasma levels of said compound or its active derivative; (iv) formulations that localize the action of the compound or its active derivative, for example, near or in a diseased tissue or organ, or in a specific body compartment; and (v) formulations that direct the action of the compound or its active derivative to deliver the drug to a specific target cell type using a carrier or chemical derivative.

[0034] Administration of a compound in the form of a controlled release formulation is particularly preferred when the compound has (i) a narrow therapeutic index (i.e., a small difference between the plasma concentrations that lead to adverse effects, side effects, or toxic reactions and those that lead to a therapeutic effect; generally, the therapeutic index TI is defined as the ratio of the median lethal dose (DL50) to the median effective dose (DE50)); (ii) a narrow window of absorption in the gastrointestinal tract; or (iii) a very short biological half-life, requiring frequent administration to maintain plasma levels at effective therapeutic levels. Various strategies may be pursued to obtain a release with a release rate of the compound or its active derivatives that is adapted to the metabolism of the drug under consideration. Controlled release may be achieved by appropriate selection of various formulation parameters and components, including, for example, various types of controlled release compositions and coatings known to those skilled in the art. Thus, the compounds are formulated with suitable excipients into pharmaceutical compositions (unit or multiple compositions of pills or capsules, oily solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes) that release the compounds in a controlled manner upon administration. In even more specific embodiments, specific technological means such as a reservoir, a pump, or a transdermal patch (in other words, a self-adhesive patch that dispenses a substance transdermally) may contribute to the controlled release of at least FENM and / or at least one acetylcholinesterase inhibitor.

[0035] In another embodiment, the composition is formulated in liquid form, which may be packaged in unit dose form in a container such as an ampule, or in a container such as a bottle or vial in association with a device that allows sampling to obtain an appropriate dose and, optionally, delivery of a desired volume. Therapeutic uses of the synergistic combinations or compositions according to the present invention. The novel synergistic effects discovered by the inventors of the combination of FENM with at least one acetylcholinesterase inhibitor, as described in the experimental part, form a novel therapeutic solution. Thus, according to another aspect, the present invention relates in particular to a composition or synergistic combination as described above in all its embodiments, for its use as a medicament. In a preferred embodiment, the present invention relates to a synergistic combination of FENM and donepezil, or a composition comprising same, as described herein above in all its embodiments, for its use as a medicament. According to a further aspect, the present invention particularly relates to a composition or synergistic combination as described above for its use in the treatment of a condition selected from among tauopathies, synucleinopathies, amyloidopathies, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, amyotrophic lateral sclerosis. In a particular embodiment, said treatment relates to the treatment of Alzheimer's disease in its early, moderate or advanced stages, preferably in its early stages. In certain embodiments, said treatment relates to treatment of cognitive impairment associated with any one of the conditions selected from among tauopathies, synucleinopathies, amyloidopathies, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, amyotrophic lateral sclerosis.

[0036] Particular embodiments relate to the aforementioned compositions or synergistic combinations for their use in the treatment of cognitive impairments associated with early, moderate or advanced stages of Alzheimer's disease, preferably in the early stages. Indeed, experimental data show particularly important synergistic effects in the treatment of long-term contextual memory dysfunction, which is particularly advantageous for patients in the early stages of the disease. Another particular embodiment is associated with any one of the conditions selected from among tauopathy, synucleinopathy, amyloidopathy, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, and amyotrophic lateral sclerosis. - short-term memory, - Mid-term memory, - Spatial memory, or - Cognitive and / or learning ability The present invention relates to a composition or a synergistic combination as described above for its use for the alteration of short-term memory, medium-term memory, spatial memory, or cognitive and / or learning ability. In a particular embodiment, said impairment of short-term memory, medium-term memory, spatial memory, or cognitive and / or learning ability is associated with early, moderate or advanced stages of Alzheimer's disease, preferably early stage.

[0037] In another aspect, the present invention relates to a method for treating a condition selected from among tauopathies, synucleinopathies, amyloidopathies, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, amyotrophic lateral sclerosis, comprising administering to a subject in need thereof a synergistic combination of FENM or any one of its pharmaceutically acceptable salts and at least one acetylcholinesterase inhibitor or any one of its pharmaceutically acceptable salts. In said method, said synergistic combination is as described above in all embodiments. In one embodiment, said method may comprise administering a composition according to the invention as described herein above.

[0038] In certain embodiments, the method comprises administering FENM and at least one acetylcholinesterase inhibitor separately, simultaneously, or sequentially.In this embodiment, FENM and at least one acetylcholinesterase inhibitor can be administered separately to the subject via the same route, for example, oral, parenteral, or transdermal route.In alternative embodiments, FENM and at least one acetylcholinesterase inhibitor can be administered to the subject via different routes.For example, one is oral route and the other is transdermal or parenteral route.A specific example is the transdermal form of rivastigmine sold under the name Exelon® or donepezil (under investigation in the United States under the name Adlarity®). EXAMPLES

[0039] Abbreviation Aβ 25-35 : An 11 amino acid fragment of the APP peptide Nt-GSNKGAIIGLM-Ct sequence (SEQ ID NO: 1). FENM: 3(2-fluoroethyl)tricyclo[3.3.1.13,7]decane-1-amine bromohydrate (also fluoroethylnormemantine bromohydrate). DPZ: Donepezil hydrochloride. YMT: Spontaneous Alternation Test in the Y-maze, "Y-maze test." PAT: Passive Avoidance Test, or Step-Through Passive Avoidance Test. ICV: intraventricular. IP: Intraperitoneal. CI: combination index. iChE: acetylcholinesterase inhibitors. PP: percent protection. CNS: central nervous system. AD: Alzheimer's disease.

[0040] 1. Apparatus and method Animal experiments were performed according to the provisions of the European Union Directive 2010 / 63 and were duly approved by the French National Ethics Committee (CCNE) and the ARRIVE Directive (Kilkenny et al., 2010). 1.1.Animals In vivo experiments were performed in male Swiss OF-1 mice (January, St Berthevin, France) aged 7-9 weeks and mass 32 ± 2 g. Animals were housed in plastic cages in groups of 8-10 individuals in a controlled environment (12:00 day-night cycle, lights on at 7:00 AM, behavioral experiments performed 9:00 AM-5:00 PM), with controlled atmosphere and sound environment, and with free access to food and drink. 1.2. Test Compounds and Peptides DPZ and FENM stock solutions. DPZ was obtained from Eisai Co.Ltd (Tokyo, Japan). FENM was obtained from M2i Life Sciences (Saint-Cloud, France). Stock solutions of the compounds were obtained by dissolving them in NaCl buffer (0.9%, vehicle) at a concentration of 2 mg / mL, corresponding to a dose of 5 mg / Kg. These stock solutions are stored at 4°C for up to 2 weeks.

[0041] Stock solution of amyloid peptide [25-35]; formation of oligomers. Aβ 25-35 Amyloid peptide [25-35], designated as β-amyloid peptide (Eurogentec, Angers, France), was dissolved in sterile distilled water at a concentration of 3 mg / mL, and the stock solution thus formed was dispensed and stored at −20° C. until use. Aβ 25-35 Oligomers form as described by Maurice et al. (1996) when incubated at 37° C. for 4 days before injection into animals. Vehicle solution or control peptides are subjected to the same treatments before administration. Injection of vehicle solution (distilled water) reduces Aβ 25-35 It has already been demonstrated that injection of the control peptide Sc Aβ (control peptide), which contains the same amino acids as Aβ in random order and does not oligomerize, results in the same lack of effect. Animal Administration Compounds are administered IP in a volume of 100 μL per 20 g body weight. The administration of the FENM / DPZ combination is performed in a volume of 100 μL per 20 g body weight. The doses of compounds mentioned in the experimental section are the doses of the salts of the compounds used, not the mass equivalents of the compounds themselves. The administered doses, expressed in molar units, are shown in Table 2. For each compound, the administered doses are 0.01, 0.03, 0.1, 0.3, and 1 mg / kg. In the case of the combination, the co-administered doses of donepezil and FENM were 0.03 and 0.01 mg / kg, respectively.

[0042] The corresponding doses in mMol / Kg are given in Table 2 below. [Table 2] Aβ 25-35 The oligomer solution and vehicle (sterile distilled water) are administered to mice by ICV injection as described by Maurice et al. (1996).

[0043] 1.3.Cognitive / Behavioral Testing Aβ 25-35 The ICV injection model of oligomers is a well-known model at present. This model is considered to be a screening model related to the neuroprotective activity of compounds, and more specifically, a related first-line model of Alzheimer's disease. 25-35 The oligomers are known to be cytotoxic to neuronal cells in mice, inducing spatial and working memory impairments that are accompanied by the development of mitochondrial stress, oxidative stress, and cellular apoptosis, particularly in the hippocampus, as well as inflammation in the central nervous system. Aβ 25-35 The ability of compounds and combinations thereof to reduce the cognitive symptoms of neurodegeneration induced by oligomers is tested. To this end, administration of the test compounds reduces the Aβ 25-35 The same day as the oligomer injection, Aβ 25-35 The oligomer injections were continued daily until the 7th day after injection, and then Aβ 25-35 Eight days after injection of the oligomers, the mice are subjected to the YMT test or PAT.

[0044] Passive Avoidance Test (PAT) This test measures long-term non-spatial (contextual) memory. The apparatus used for this test is a box with two compartments (15 x 20 x 15 cm high), one illuminated with white PVC walls and the other dark with black PVC walls and a mesh floor. The compartments are separated by a guillotine door. A 60 W lamp is located 40 cm above the box and illuminates the white compartment. A generator (Lafayette Instruments, Lafayette, USA) allows the application of electric shocks (0.3 mA for 3 seconds) to the grid floor. The test consists of a learning session and a test session. The guillotine door is closed during the training session. Each mouse is placed in the white compartment. After 5 seconds, the door is raised. When the mouse enters the dark compartment and its four paws touch the mesh, the door closes and a discharge is applied for 3 seconds. The time it takes the mouse to enter the dark compartment (STL-Tg) and the level of shock sensitivity (0=no sign; 1=surge; surge and vocalization) are recorded. The test session is performed 24 hours after the learning session. Each mouse is placed back into the illuminated white compartment. After 5 seconds, the door is raised and the latency time (STL-R), i.e. the time it takes the mouse to go into the dark compartment, is measured. The maximum time is 300 seconds. Mice with STL-Tg and STL-R below 10 seconds and low sensitivity levels are not considered in the test. The attrition rate is usually 5%. Mice with impaired memory capacity will have a lower STL-R than mice with normal capacity. The results are shown as their median values ​​along with quartiles (25%-75%).

[0045] Y-maze spontaneous alternation test (YMT) The spontaneous alternation test is used to test the (very short-term) spatial working memory of rodents. The maze is made of opaque grey polyvinyl chloride (PVC). Each arm is 40 cm long, 13 cm high, and 3 cm wide at its base and 10 cm wide at its top. The arms converge to each other at a single point, with equal angles between the different arms. Briefly, each mouse is placed at the end of an arm and left to move freely during an 8-minute session. Entries of the mouse in each arm are recorded, including the arm in which the mouse was dropped. An alternation is defined as an animal entering three different arms consecutively. Thus, the maximum number of alternations is the total number of entries in each arm minus 2, and the percentage alternation is calculated according to the formula:

number

[0046] 1.4. Statistical analysis - Calculation of the combination index (CI) statistical analysis Analyses were performed using Prism v5.0 (GraphPad Software, San Diego, CA, USA). Data were analyzed using one-way analysis of variance (ANOVA, F value) followed by Dunnett's test or nonparametric Kruskal-Wallis ANOVA (H value) followed by Dunn's comparison test. Statistical significance levels were p < 0.05, p < 0.01, and p < 0.001. Combination Index The nature of the interaction of two compounds at a given effect level was evaluated by isobologram analysis (Martin et al., 2020; Mauritius, 2016). The representation of the isobologram follows the concept of Fraser (1872). The dose-response curve follows a biphasic effect, and only the ascending part of the curve was considered for the calculation. For compound A (ICx,A) and compound B (ICx,B), the concentrations required to produce a given effect (e.g., ICx=IC50) were determined and shown on the x and y axes of a two-coordinate plot, forming two points, (ICx,A,0) and (0,ICx,B). The line connecting these two points is the additivity line. In a mixture of drugs A+B, the concentrations of A and B in the combination that produce the same effect are represented by the coordinates (CA,x,CB,x).

[0047] The combination index (CI) is: IC=CA,x / ICx,A+CB,x / ICx,B where CA,x and CB,x are the concentrations of compounds A and B used in combination that produce x% of the maximal combined effect. CI is the combination index. ICx,A and ICx,B are the concentrations of compounds A and B required alone to produce x% of the maximal effect. CIs less than / equal to / greater than 1 indicate synergy / additivity / antagonism, respectively. To calculate CIs based on isobologram representations, the percentage of alternations and passive avoidance latency were expressed as percent protection (PP) for each treatment group, with PP(V / V) being 100% and PP(Aβ 25-35 / V) was set to 0% (Martin et al., 2020; Mauritius, 2016).

[0048] 2.Results 2.1. Synergistic effect of FENM-iChE combination on short-term working memory (YMT) in Aβ intoxication model. Aβ 25-35 The data confirm the antiamnesic effect of FENM and DPZ on the oligomer-induced impairment of short-term working memory. No effect doses, i.e., doses of compounds at which effects on FNEM-induced lesions are observed at the margin of significance when administered alone, or doses just below the initially significantly active dose, were investigated first.

[0049] Aβ 25-35 The performance of mice intoxicated with Aβ and administered FENM alone is significantly improved compared to controls at 0.03 mg / Kg (Figure 1). The improvement observed in mice administered the 0.01 mg / Kg dose is at the limit of statistical significance. At 0.03 mg / kg, FENM inhibits Aβ 25-35 DPZ significantly improved the percentage of alternations in mice intoxicated at 0.01 mg / Kg, and furthermore, these performances were not significantly different from those of non-intoxicated mice. The administration of donepezil alone also allows the improvement of the memory performance of animals measured in this test. However, no improvement was observed at 0.01 mg / Kg (not shown). When administered at 0.03 mg / Kg, DPZ does not provide a statistically significant improvement in the performance of intoxicated animals. When administered at 0.1 mg / kg, DPZ provides an improvement in memory symptoms, since the performances of intoxicated treated animals are not significantly different from those of non-intoxicated untreated animals; however, these performances are also not significantly different from those observed in untreated intoxicated mice. Co-treatment of intoxicated mice with FENM and DPZ at 0.01 and 0.03 mg / kg, respectively, resulted in an improvement in the percentage of alternation that was not significantly different from that in non-intoxicated mice. The molar ratio of FENM / DPZ in this co-treatment was 0.5.

[0050] Combination index data from these experiments are shown in Table 3 below. [Table 3] An IC of 0.3 (Table 3) is measured at an ineffective concentration of the FENM-DPZ combination. This IC reflects a strong synergistic interaction between FENM and DPZ, as shown by the percent protection scale depicted in FIG. 1. This strong synergistic interaction results in a percent protection not reached in mice administered the molecules alone, regardless of the dose. In the spontaneous alternation test, this translates into an improved memory performance of intoxicated animals treated with the FENM-DPZ combination compared to animals treated with the molecules alone (FIG. 1).

[0051] 2.2. Synergistic effect of FENM-iChE combination on long-term memory (PAT) in Aβ addiction model. Aβ 25-35 The data confirm the antiamnesic effect of FENM and DPZ on the oligomer-induced impairment of long-term working memory. Aβ 25-35 Mice intoxicated with 0.05 mg / kg and IP-treated with FENM at doses of 0.3 mg / kg or 1 mg / kg performed in a manner not significantly different from control, non-intoxicated, untreated mice (Figure 2); these performances were significantly different from untreated intoxicated mice. 25-35 DPZ does not protect against intoxication-induced memory impairment. Only the highest dose tested (1 mg / kg) of DPZ inhibited Aβ 25-35 This proved effective in counteracting the amnesic effects of intoxication with oligomers, with the latencies of the animals being significantly different from those of untreated intoxicated animals, however the improvement was not sufficient to fully restore the animals' performance, as these latencies were still significantly different from those of untreated non-intoxicated animals.

[0052] Coadministration of FENM and DPZ at the lowest and least effective doses of 0.01 and 0.03 mg / kg of FENM and DPZ, respectively, results in significant protection of the long-term memory performance of intoxicated mice compared to untreated intoxicated mice (Figure 2). In a particularly interesting manner, these doses are more than an order of magnitude lower than the first effective doses identified in this test, reflecting a particularly important synergistic effect of the compounds on long-term memory.

[0053] As shown in Table 4 below, such protection at low doses of the compounds is substantially lower, but can be explained by the particularly significant synergism of each compound, supported by the particularly low combination index, which reflects the particularly significant synergism. [Table 4]

[0054] 3. Conclusion These data show a synergistic protective effect of FENM in combination with that of iChE for both short-term and long-term working memory, and furthermore, this synergy is specific to the use of FENM, as it is not observed in combinations where FENM is substituted with memantine. These results make it possible to consider the use of the FENM-iChE combination in patients who currently have no approved therapeutic solutions for the treatment of memory symptoms of AD or related pathologies, such as those with early stage disease, and the observed synergy also makes it possible to obtain therapeutic effects at particularly low doses of the compounds, where little or no adverse effects are expected.

[0055] References TIFF2025500088000006.tif231170

Claims

1. A composition comprising a synergistic combination of 3-(2-fluoroethyl)adamantan-1-amine (FENM) or any one of its pharmaceutically acceptable salts, and at least one acetylcholinesterase inhibitor or any one of its pharmaceutically acceptable salts.

2. 2. The composition of claim 1, wherein the at least one acetylcholinesterase inhibitor is selected from the group consisting of donepezil, galantamine, rivastigmine, tacrine, or any one of their pharmaceutically acceptable salts.

3. 2. The composition of claim 1, wherein the FENM dose is compatible with a FENM dose of 20 mg / day or less.

4. 4. The composition according to any one of claims 1 to 3, wherein the at least one acetylcholinesterase inhibitor is donepezil, present in a dose compatible with a daily dosage of 10 mg or less.

5. The composition according to any one of claims 1 to 3, wherein the at least one acetylcholinesterase inhibitor is rivastigmine present in a dose compatible with a daily dosage of 3 mg or less.

6. 4. The composition of any one of claims 1 to 3, wherein the at least one acetylcholinesterase inhibitor is galantamine present in a dose compatible with a daily dosage of 16 mg or less.

7. The composition according to any one of claims 1 to 3, wherein the molar ratio of FENM / at least one acetylcholinesterase inhibitor is 4 or less, 3 or less, 2 or less, preferably 1 or less.

8. A composition according to any one of claims 1 to 3 for its use as a medicament.

9. 4. The composition of any one of claims 1 to 3 for its use in the treatment of a condition selected from among tauopathies, synucleinopathies, amyloidopathies, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, amyotrophic lateral sclerosis.

10. FENM or a pharmaceutically acceptable salt thereof, in synergistic combination with at least one acetylcholinesterase inhibitor selected from any one of donepezil, galantamine, rivastigmine, tacrine, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition selected from tauopathy, synucleinopathy, amyloidopathy, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, and amyotrophic lateral sclerosis.

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