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EP-4429648-B1 - NOVEL SYNERGISTIC COMBINATIONS BASED ON FLUOROETHYLNOREMMANTINE (FENM) AND AN ACETYLCHOLINESTERASE INHIBITOR FOR USE IN THE TREATMENT OF NEURODEGEATIVE DISEASES

EP4429648B1EP 4429648 B1EP4429648 B1EP 4429648B1EP-4429648-B1

Inventors

  • RUBINSTENN, GILLES
  • MAURICE, TANGUI
  • FREYSSIN, Aline

Dates

Publication Date
20260513
Application Date
20221108

Claims (10)

  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. The composition according to claim 1, wherein said at least one acetylcholine esterase inhibitor is selected from among donepezil, galantamine, rivastigmine, tacrine, or any one of their pharmaceutically-acceptable salts.
  3. The composition according to any one of claims 1 to 2, wherein the FENM dose is compatible with a FENM dose less than or equal to 20 mg/day.
  4. The composition according to any one of claims 1 to 3, wherein said at least one acetylcholinesterase inhibitor is donepezil which is present at a dose compatible with a dosage less than or equal to 10 mg/day.
  5. The composition according to any one of claims 1 to 4, wherein said at least one acetylcholinesterase inhibitor is the rivastigmine which is present at a dose compatible with a dosage less than or equal to 3 mg/day.
  6. The composition according to any one of claims 1 to 5, wherein said at least one acetylcholinesterase inhibitor is galantamine which is present at a dose compatible with a dosage less than or equal to 16 mg/day.
  7. The composition according to any one of claims 1 to 6, wherein the FENM/at least one acetylcholine esterase inhibitor molar ratio is less than or equal to 4, less than or equal to 3, less than or equal to 2, preferably less than or equal to 1.
  8. The composition according to any one of claims 1 to 7 for use thereof as a drug.
  9. The composition according to any one of claims 1 to 8 for use thereof in the treatment of a pathology 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 among donepezil, galantamine, rivastigmine, tacrine, or any one of their pharmaceutically-acceptable salts, for use in the treatment of a pathology selected from among tauopathies, synucleinopathies, amyloidopathies, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, amyotrophic lateral sclerosis.

Description

The invention focuses on the field of neurodegenerative diseases. The invention relates more particularly to compositions comprising a synergistic combination of 3(2-Fluoroethyl)tricyclo[3.3.1.13,7]decan-1-amine (Fluoroethylnormemantine, FENM) with at least one acetylcholinesterase inhibitor. The invention also relates to these combinations or compositions comprising them for their use in the treatment of neurodegenerative diseases and, more particularly, in the prevention and/or treatment of cognitive disorders of these diseases. Previous art The World Health Organization (WHO) estimates that by 2050 the number of people over 60 will reach two billion. This unprecedented aging of the global population suggests that chronic age-related diseases will place significant pressure on healthcare systems. Dementia is one such disease. The WHO estimates that the total number of people living with dementia will exceed 150 million by 2050. Dementia is characterized by a decline in cognitive functions, particularly memory and reasoning, which impacts the patient's behavior and their ability to perform everyday tasks. Dementia is a syndrome encompassing pathologies with highly diverse etiologies that affect different areas of the brain and/or other regions of the central nervous system, notably involving neurodegeneration and the death of neuronal cells. Directly linked to aging, mitochondrial dysfunction and oxidative stress play a crucial role in the pathogenesis of neurodegenerative diseases. These pathologies and syndromes are also often associated with an abnormal accumulation of certain proteins and/or the accumulation of mutated and/or abnormally folded proteins, as observed in Aβ amyloidosis, tauopathies, synucleinopathies, and the aggregation of superoxide dismutase-1 (SOD1), polyglutamine, and TDP-43 protein. Alzheimer's disease is the most common cause of dementia and is thought to be responsible for 60-70% of cases (source WHO). Today, several molecules are authorized for the symptomatic treatment of Alzheimer's disease. These include anticholinesterases such as donepezil, rivastigmine, and galantamine, which have marketing authorizations for use as monotherapy in the mild, moderate, or moderately severe stages of the disease. Memantine, a voltage-gated antagonist, is also approved. Non-competitive NMDA receptor antagonists are authorized for use in moderate and severe stages of the disease but not in mild stages. These compounds are not recommended in the early stages of the disease due to a lack of clinical efficacy. Furthermore, their effects are symptomatic and limited, and have only been demonstrated in the short term (on average 6 months) in nearly two-thirds of patients included in clinical trials (source: French National Authority for Health). A combination treatment of donepezil and memantine, under the brand name Acrescent® , had its marketing authorization refused by the European Medicines Agency (EMA) due to the limited benefits of this combination (20 mg memantine/10 mg donepezil) compared to the compounds used alone (EMA, 18, October 2012). The only advantage would be limited to taking a single tablet instead of two, in patients with cognitive impairment. This treatment was nevertheless approved in the United States by the FDA. Furthermore, the supposed efficacy of cholinesterase inhibitors in the early stages of the disease rests on a single study conducted specifically on patients at this stage, in which a modest benefit was observed only in patients who tolerated doses of 10 mg per day of donepezil. Health authorities in France consider that this study does not support the conclusion that there is any benefit in initiating this treatment in the early stages of the disease (Source: French National Authority for Health, 2012). Acetylcholinesterase inhibitors are also associated with a risk of serious adverse effects that may impair quality of life and/or necessitate discontinuation of treatment. These may include digestive disorders (diarrhea, vomiting), cardiovascular disorders (bradycardia, syncope), or even neuropsychiatric disorders (dizziness, mental confusion), which are counterproductive in the case of dementia treatment. The increased risk of adverse effects with longer treatment duration, coupled with the lack of benefit beyond six months, strongly limits their long-term use. In practice, these treatments are administered to patients with already impaired cognitive abilities, in the moderate to advanced stages of the disease. The demand WO 2014/191424 describes 18F -labeled FENM for labeling NMDA receptors and visualizing them by positron emission tomography to study the distribution of these receptors and their response to drug treatments. The application WO 2019/115833 describes FENM in the treatment of anxiety and depression-related disorders. The demand WO 2013/064579 describes a combination of a connexin blocking agent (such as meclofenamic acid) with an acetylcholine esterase