WO2024165757A1 - Phénylbutyrate oral pour le traitement de tauopathies à 4 répétitions humaines - Google Patents

Phénylbutyrate oral pour le traitement de tauopathies à 4 répétitions humaines Download PDF

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WO2024165757A1
WO2024165757A1 PCT/EP2024/053388 EP2024053388W WO2024165757A1 WO 2024165757 A1 WO2024165757 A1 WO 2024165757A1 EP 2024053388 W EP2024053388 W EP 2024053388W WO 2024165757 A1 WO2024165757 A1 WO 2024165757A1
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phenylbutyrate
prodrug
pharmaceutically acceptable
acceptable salt
solvate
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English (en)
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Johannes LEVIN
Mikael Simons
Palleis CARLA
Lennart SCHLAPHOFF
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Ludwig-Maximilians-Universität München
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to the treatment or prevention of a 4-repeat tauopathy by orally administering phenylbutyrate or a pharmaceutically acceptable salt thereof or a prodrug thereof or a solvate thereof.
  • Tauopathies are a class of neurodegenerative diseases involving the aggregation of tau protein into neurofibrillary or gliofibrillary tangles (neurofibrillary tangle) in the human brain. Tau aggregates lead to neurofibrillary tangles (NFTs) associated with neurodegenerative disorders.
  • Tau protein refers to the protein product of the microtubule-associated protein tau gene (MAPT), and the number of spliced copies of the microtubule binding repeat (MTBR) domain determines whether the tau is a 3-repeat (3R) or a 4-repeat (4R) isoform.
  • MTT microtubule-associated protein tau gene
  • MTBR microtubule binding repeat
  • 4R-Tauopathies are a group of neurodegenerative diseases defined by cytoplasmic inclusions predominantly composed of 4R isoforms. Progressive supranuclear palsy (PSP), cortico-basal degeneration (CBD), argyrophilic grain disease (AGD), globular glial tauopathy (GGT), and frontotemporal lobar degeneration due to tau (FTLD-tau) due to MAPT mutation belong to the disease group of 4R-tauopathies (non-patent literature 1).
  • phenylbutyrate is an already clinically approved drug for the treatment of urea cycle disorders. Furthermore, it is known that phenylbutyrate crosses the blood-brain barrier. Phenylbutyrate and its use for the treatment of various clinical conditions and diseases such as benign prostate hyperplasia, cancer, cystic fibrosis, HIV, kidney and liver failure, thalassemia and urea cycle disorders are known (patent literature 1 to 5, non-patent literature 5).
  • phenylbutyrate has been shown to be neuroprotective in several animal studies, including models of Alzheimer's disease or Parkinson's disease, respectively (non-patent literature 2 and 3, and patent literature 6 to 8).
  • 4R-tauopathies are caused by toxic protein aggregates that are localized within cells (see non-patent literature 1). Intracellular protein aggregates are a target that is complex to address as demonstrated by multiple trials aiming at disease modification using intravenously applied antibodies such as Tilavonemab or Gosuranemab. In contrast, extracellular amyloid-beta aggregates have been successfully targeted leading to disease modification (non-patent literature 6).
  • Another toxic mechanism of neurodegenerative diseases is mitochondrial dysfunction.
  • 4R-tauopathies are characterized by the deposition of toxic aggregates of misfolded tau protein composed of the 4R splicing variant of said protein.
  • the diseases caused by 4R-tau aggregates are sporadic diseases such as PSP or CBD (see non-patent literature 1).
  • the pathology of 4R-tauopathies is limited to said aggregates composed of 4R-tau protein. This differentiates 4R-tauopathies from Alzheimer disease that is characterized by abeta pathology and mixed 3R- and 4R-tau protein in the tau deposits.
  • Non-patent literature 4 a model of tauopathy induced by low level expression of 35 kDa tau fragment (Tau35) in mice was investigated.
  • Non-patent literature 4 reported that animals treated intraperitoneally with phenylbutyrate over a 6-week period showed less tauopathy and cognitive changes.
  • the underlying mechanism is thought to be its function as a class-1 histone deacetylase inhibitor as a chemical chaperone, thus preventing misfolding of protein aggregates and reducing stress in the endoplasmic reticulum.
  • Patent Literature 1 WO 85/04805 Al
  • Patent Literature 2 DE 198 10383 Al
  • Patent Literature 3 WO 93/07866 Al
  • Patent Literature 4 WO 95/10271 Al
  • Patent Literature 5 WO 98/56370 Al
  • Patent Literature 6 WO 2009/112609 Al
  • Patent Literature 7 WO 2013/079205 Al
  • Patent Literature 8 WO 2013/149091 Al
  • Non-patent literature 1 VandeVrede, L. et al., Four-Repeat Tauopathies: Current Management and Future Treatments, Neurotherapeutics (2020) 17:1563-1581
  • Non-patent literature 2 Wiley J.C. et al., Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice, Aging cell (2011) 10:418-428
  • Non-patent literature 3 Ricobaraza, A., et aL, Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer's disease mouse model, Neuropsychopharmacology (2009) 34(7):1721-1732
  • Non-patent literature 4 Bondulich, M.K., et al., Tauopathy induced by low level expression of a human brain-derived tau fragment in mice is rescued by phenylbutyrate, Brain (2016) 139(Pt 8):2290-2306
  • Non-patent literature 5 McGuire, B. et al., Pharmacology and Safety of Glycerol Phenylbutyrate in Healthy Adults and Adults with Cirrhosis, Hepatology (2010) 51(6):2077-2085
  • Non-patent literature 6 Van Dyck, C. et al., Lecanemab in Early Alzheimer's Disease, New England Journal of Medicine (2023) 388( l):9-21
  • the present invention is directed to phenylbutyrate or a pharmaceutically acceptable salt thereof or a prodrug thereof or a solvate thereof for use in the treatment or prevention of a 4-repeat tauopathy, wherein phenylbutyrate or the pharmaceutically acceptable salt thereof or the prodrug thereof or a solvate thereof is to be administered orally.
  • composition comprising phenylbutyrate or a pharmaceutically acceptable salt thereof or a prodrug thereof or a solvate thereof for use in the treatment or prevention of a 4R-tauopathy, wherein phenylbutyrate or the pharmaceutically acceptable salt thereof or the prodrug thereof or the solvate thereof is to be administered orally.
  • the pharmaceutically acceptable salt of phenylbutyrate is sodium 4-phenylbutyrate.
  • the prodrug of phenylbutyrate is glycerol phenylbutyrate.
  • the 4-repeat tauopathy is selected from the group consisting of progressive supranuclear palsy (PSP), cortico-basal degeneration (CBD), argyrophilic grain disease (AGD), globular glial tauopathy (GGT), and frontotemporal lobar degeneration due to tau (FTLD-tau) due to MAPT mutation, preferably progressive supranuclear palsy (PSP), frontotemporal dementia or cortico-basal degeneration (CBD), more preferably cortico-basal degeneration (CBD).
  • the phenylbutyrate or a pharmaceutically acceptable salt thereof or a prodrug thereof or a solvate thereof is for use in the treatment or prevention of inflammation, preferably neuroinflammation, associated with the 4-repeat tauopathy.
  • the phenylbutyrate or the pharmaceutically acceptable salt thereof or the prodrug thereof or the solvate thereof or the pharmaceutical composition thereof is used in the treatment or prevention of motor dysfunction associated with the 4-repeat tauopathy.
  • the pharmaceutical composition is an oral dosage form in the form of a neat liquid, a tablet, a capsule, a lozenge, an aqueous solution, an oily solution, a suspension or an emulsion.
  • the phenylbutyrate or the pharmaceutically acceptable salt thereof or the prodrug thereof or the solvate thereof or the pharmaceutical composition thereof is to be administered once daily, two times daily, three times daily or four times daily.
  • the phenylbutyrate or the pharmaceutically acceptable salt thereof or the prodrug thereof or the solvate thereof or the pharmaceutical composition thereof is to be administered two times daily.
  • “Pharmaceutically acceptable salts” are defined as derivatives of phenylbutyrate which are modified by making a salt of the carboxylic acid residue of phenylbutyrate.
  • the pharmaceutically acceptable salts as mentioned herein comprise the therapeutically active non-toxic salt forms which phenylbutyrate is able to form.
  • the pharmaceutically acceptable salts can conveniently be obtained by treating the acid form of phenylbutyrate with such appropriate cations.
  • Appropriate basic salts comprise those formed with organic cations such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine; and those formed with metallic cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
  • salt forms can be converted by treatment with an appropriate acid into the free form.
  • suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 18 th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is hereby incorporated by reference.
  • a typical example is sodium phenylbutyrate which is, for instance, available under the trade names Buphenyl, Pheburane and Ammonaps.
  • Phenylbutyrate can also be provided as a hydrate or solvate that phenylbutyrate is able to form, including, e.g. the alcoholates such as methanolates or ethanolates.
  • solvate refers to those forms of phenylbutyrate that comprise either stoichiometric or non- stoichiometric amounts of solvent. Since water is a solvent, solvates also include hydrates.
  • Phenylbutyrate can also be provided in the form of a prodrug, i.e., a compound which is metabolized in vivo to phenylbutyrate.
  • prodrug means any covalently bonded compound which releases the active parent pharmaceutical phenylbutyrate due to in vivo biotransformation.
  • the prodrugs as mentioned herein are meant to comprise a pharmacologically substantially inactive derivative of phenylbutyrate that requires biotransformation, either spontaneous or enzymatic, within the organism to release phenylbutyrate.
  • Prodrugs may be variations or derivatives of the compounds that have groups cleavable under metabolic conditions.
  • prodrugs become compounds that are pharmaceutically active in vivo when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. Prodrugs may undergo a number of biotransformation steps to release the active drug within the organism. Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism.
  • Appropriate prodrugs are, but not limited to, esters prepared by reaction of the parent acids with a suitable alcohol such as diglycerol, triglycerol, or the like, or amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative.
  • Prodrugs also include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues that are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of the parent compounds.
  • the amino acid residues include, but not limited to, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine, methionine sulfone and the like.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters that are covalently bonded to the above substituents of a compound through the carbonyl carbon prodrug sidechain.
  • the Pharmacological Basis of Therapeutics, 8 th ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing prodrugs generally is hereby incorporated herein by reference.
  • a typical example of a prodrug is glycerol phenylbutyrate which is commercially available, e.g., under the trade name Ravicti.
  • “Pharmaceutically acceptable” is defined as those compounds, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
  • the terms “treating” and “method of treatment” as well as different forms thereof include curative, or palliative treatment.
  • the term “treating” includes alleviating or reducing at least one adverse or negative effect or symptom of a condition, disease or disorder.
  • the term “treating” covers reversing, stopping, or delaying progression of a 4R-tauopathy and/or ameliorating at least one symptom thereof.
  • prevention refers to the act of "preventing”, understood as avoiding the onset, existence or, alternatively, as delaying the onset or recurrence of a disease, disorder or condition to which the term is applied to, or of one or several of the symptoms associated to the disease, disorder or condition.
  • administering means providing to a patient the pharmaceutical composition or unit dose of the present invention.
  • terapéuticaally effective amount refers to the amount of a compound, e.g., phenylbutyrate or a pharmaceutically acceptable salt thereof or a prodrug thereof or a solvate thereof that, when administered, is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by a clinician.
  • subject and “patient” are used interchangeably herein, for example, to a mammalian subject, preferably a human.
  • Fig. 1A is a graph showing the longitudinal results of Rotarod analysis over the intervention period of 20 weeks of P301S Control, P301S Phenylbutyrate and Non-Carrier groups.
  • Fig. IB depicts the results of week 28. The results represent the mean duration of each group on the rotarod (error bars: 95% confidence interval).
  • Fig. 2 shows the results of neurofilament light chain (NfL) measurements from serum of P301S Control, P301S Phenylbutyrate and Non-Carrier groups at 28 weeks of age (error bars: 95% confidence interval).
  • Fig. 3 shows the immunohistological analysis of the Dentate Gyrus of the Hippocampus from P301S Control and P301S Phenylbutyrate.
  • Fig. 4 shows representative images from the analysis of Example 4 and Figure 3.
  • the immunofluorescent staining of GFAP, lb a 1 / and PHF (AT8) of the Dentate Gyrus of one animal each from the P3O1S Control and P301S Phenylbutyrate group are shown.
  • Fig. 5 shows the results of TSPO-PET scans at week 28 of the same animals as examined in Example 2. Areas of higher uptake are marked with arrows. While the Non Carrier Control shows no area of concentrated signal, the P3O1S mice treated with vehicle show slight concentration of signal in the brain stem, basal ganglia, and hippocampus. The P3O1S mice treated with sodium phenylbutyrate show strong concentration of signal in the brain stem, basal ganglia, and hippocampus.
  • Fig. 6 shows the results of the pharmacokinetic analysis of glycerol phenylbutyrate (GPBA) and sodium phenylbutyrate (Na-PBA).
  • Fig. 6A shows the plasma levels of PBA at different times after administration of either GPBA p.o. or Na-PBA i.p. at a dosage of Ig/kg/d per animal (error bars: standard deviation).
  • Fig. 6B shows the area under the curve (AUC) of both administrations from first to last measurement.
  • AUC area under the curve
  • the present invention relates to phenylbutyrate or a pharmaceutically acceptable salt thereof or a prodrug thereof or a solvate thereof for use in the treatment or prevention of a 4-repeat tauopathy, wherein phenylbutyrate or the pharmaceutically acceptable salt thereof or the prodrug thereof or a solvate thereof is to be administered orally.
  • the present invention also relates to a method of treating or preventing a 4-repeat tauopathy, wherein the method comprises orally administering a therapeutically effective amount of phenylbutyrate or a pharmaceutically acceptable salt thereof or a prodrug thereof or a solvate thereof to a subject in need thereof.
  • phenylbutyrate refers to 4-phenylbutyric acid (4-phenylbutyrate), a commercially available product that can be obtained from companies such as SIGMA-ALDRICH (Product No: P21005). It has a registry CAS number: 1821-12-1.
  • Phenylbutyrate is typically administered as a pharmaceutically acceptable salt or a prodrug.
  • a suitable pharmaceutically acceptable salt is sodium 4-phenylbutyrate, also a commercially available product that can be obtained, for instance, from BIOMOL International L.P. (Palatine House, Matford Court, Starbucks EX2 8NL, UK; Catalogue No.: EI320); registry CAS number 1716- 12-7. It is currently available under the trade names trade names Buphenyl, Pheburane and Ammonaps.
  • this compound can also be synthesized using known methods.
  • phenylbutyrate can be administered as a prodrug such as glycerol phenylbutyrate.
  • Glycerol phenylbutyrate is available as Ravicti® which is authorized by EMA for the treatment of urea cycle disorders.
  • Glycerol phenylbutyrate is a water-soluble prodrug of phenylbutyrate. It acts as a depot from which phenylbutyrate is slowly release upon metabolization, for instance, in the human digestive system by pancreatic lipase which is able to hydrolyse the triglyceride to produce glycerol and 4-phenylbutyrate.
  • Glycerol phenylbutyrate can be prepared by standard esterification procedures. Glycerol phenylbutyrate provides advantages over phenylbutyrate for human use in that glycerol phenylbutyrate is smell- and odorless and that glycerol phenylbutyrate is available in a liquid formulation that facilitates administration. For example, glycerol phenylbutyrate can be given orally via a syringe, through a feeding tube or mixed with food.
  • 4R-tauopathies are chronic progressive neurodegenerative diseases. Therefore, disease modifying treatments will be required to be taken long-term.
  • the observed high efficacy of phenylbutyrate given orally makes such use of phenylbutyrate in patients with 4R-tauopathies possible because a) oral treatment is not associated with a painful injection, b) local injection side reactions or c) even complications related to injections such as infections, d) no specific training for performing injections in a home setting is needed and e) no specific equipment for application such as syringes, disinfection and needles are needed. All factors a) to e) are challenges and cost drivers in a long-term application setting.
  • phenylbutyrate preferably sodium phenylbutyrate or glycerol phenylbutyrate
  • phenylbutyrate is present in the pharmaceutical composition, pharmaceutical formulation or medicament of the present invention, together with one or more pharmaceutically acceptable carriers, diluents and/or excipients.
  • the pharmaceutical composition, pharmaceutical formulation or medicament of the present invention can be of any form suitable for the application to humans and/or animals, preferably humans including infants, children and adults and can be produced by standard procedures known to those skilled in the art.
  • the pharmaceutical composition, pharmaceutical formulation or medicament can be produced by standard procedures known to those skilled in the art, e.g. from the table of contents of "Pharmaceutics: The Science of Dosage Forms", Second Edition, Aulton, M.E. (ED. Churchill Livingstone, Edinburgh (2002); “Encyclopedia of Pharmaceutical Technology", Second Edition, Swarbrick, J. and Boylan J.C. (Eds.), Marcel Dekker, Inc. New York (2002); "Modern Pharmaceutics", Fourth Edition, Banker G.S.
  • composition of the medicament may vary depending on the dosage form.
  • Carriers, diluents and excipients which are suitable for the preparation of a pharmaceutical composition, pharmaceutical formulation or medicament of the present invention are well known to those skilled in the art, e.g., from the "Handbook of Pharmaceutical Excipients” Sixth Edition, Raymond C. Rowe, Paul J. Sheskey and Marian E Quinn (Eds.), American Pharmaceutical Association (July 2009), which is hereby incorporated by reference and forms part of the disclosure.
  • the pharmaceutical composition, pharmaceutical formulation or medicament of the present invention may be formulated into orally administrable compositions containing one or more pharmaceutically acceptable carriers, diluents and/or excipients. These compositions may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents.
  • the compositions may suitably take the form of a neat liquid, tablets, capsules, such as, e.g., hard or soft gelatin capsules, lozenges, aqueous or oily solutions, suspensions or emulsions.
  • the pharmaceutical composition, pharmaceutical formulation or medicament of the present invention may also comprise an enteric coating, so that their dissolution is dependent on pH-value.
  • the pharmaceutical composition, pharmaceutical formulation or medicament may pass the stomach undissolved and the active agent will be liberated in the intestinal tract.
  • the enteric coating is soluble at a pH value of 5 to 7.5. Suitable materials and methods for the preparation are known from the prior art.
  • a physician will determine the actual dosage which will be most suitable for an individual subject.
  • the specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient as well as the severity of the condition to be treated. The precise dose and dosage form will ultimately be at the discretion of the attendant physician.
  • a proposed dose of phenylbutyrate (based on sodium phenylbutyrate) for administration to a human is at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg or at least about 700 mg of phenylbutyrate per unit dose.
  • the amount of phenylbutyrate in the pharmaceutical composition, pharmaceutical formulation or medicament is at most about 19 g, at most about 15 g, at most about 10 g, at most about 7 g, at most about 6 g, at most about 5 g or at most about 4 g of phenylbutyrate per unit dose.
  • Phenylbutyrate can be administered in one, two, three or more unit doses per day.
  • phenylbutyrate in the pharmaceutical composition, pharmaceutical formulation or medicament is to be administered to a subject in need thereof in a daily amount of about from 800 mg to 38 g per day, from 1 g to 20 g per day, from 1 g to 12 g per day, from 1 g to 10 g per day, from 1 g to 8 g per day.
  • phenylbutyrate sodium phenylbutyrate (Na-PBA) as such. If phenylbutyrate (PBA) is administered in the form of a different pharmaceutically acceptable salt thereof or a prodrug thereof or a solvate thereof then the amounts can be easily recalculated by taking the molecular weights of sodium phenylbutyrate and of the other pharmaceutically acceptable salt thereof or the prodrug thereof or the solvate thereof and its number of PBA molecules into account.
  • the amount of glycerol phenylbutyrate (GPBA) for instance can be obtained as follows:
  • the 4R-tauopathy is not particularly limited and can be, for instance, progressive supranuclear palsy (PSP), cortico-basal degeneration (CBD), argyrophilic grain disease (AGD), globular glial tauopathy (GGT), or frontotemporal lobar degeneration due to tau (FTLD-tau) due to MAPT mutation.
  • PSP progressive supranuclear palsy
  • CBD cortico-basal degeneration
  • ATD argyrophilic grain disease
  • GTT globular glial tauopathy
  • FTLD-tau frontotemporal lobar degeneration due to tau due to MAPT mutation.
  • the present invention is particularly applicable to 4R-tauopathies such as supranuclear palsy (PSP), frontotemporal dementia or cortico-basal degeneration (CBD), preferably supranuclear palsy (PSP) or cortico-basal degeneration (CBD), more preferably cortico-basal degeneration (CBD), which are associated with inflammation, more particularly neuroinflammation.
  • PSP supranuclear palsy
  • CBD cortico-basal degeneration
  • CBD cortico-basal degeneration
  • CBD cortico-basal degeneration
  • the present invention enables the effective treatment and prevention of inflammation, in particular neuroinflammation, which is associated with these 4R-tauopathies and thus provides a new approach for specifically treating these rapidly progressing types of 4R-tauopathies.
  • the motor dysfunction associated with the 4-repeat tauopathy is improved.
  • the phenylbutyrate or the pharmaceutically acceptable salt thereof or the prodrug thereof or the solvate thereof is for use in the treatment or prevention of 4R-tauopathies such as supranuclear palsy (PSP), frontotemporal dementia or cortico-basal degeneration (CBD), preferably supranuclear palsy (PSP) or cortico-basal degeneration (CBD), more preferably cortico-basal degeneration (CBD).
  • PSP supranuclear palsy
  • CBD cortico-basal degeneration
  • CBD cortico-basal degeneration
  • CBD cortico-basal degeneration
  • Example 4 As shown by histological examination in Example 4, in the context of 4R-tauopathy, dampening of inflammation in the brain by phenylbutyrate leads to less deposition of phospho-tau, which in turn leads to a less severe course of disease with better clinical outcome as evidenced by the motor performance assessment in Example 2.
  • the phenylbutyrate or the pharmaceutically acceptable salt thereof or the prodrug thereof or the solvate thereof is for use in the treatment or prevention of a motor dysfunction in a human 4R-tauopathy.
  • 4R-tauopathies such as CBD and PSP are clinically characterized by progressive signs of atypical parkinsonism that mostly manifest with a parkinsonian syndrome with little to no response to dopaminergic treatment. Key symptoms are: Slowness of movements, stiffness of muscles, problems with coordination of movements, gait disturbance, falls, unintelligible speech, swallowing disorders and finally dependence on others and reduced survival.
  • This phenotype can be associated by cognitive and/or behavioral disturbances. The progressive nature of the condition is significantly slowed by treatment with phenylbutyrate leading to a positive impact of this treatment on all aspects of 4R-tauopathies.
  • the phenylbutyrate or the pharmaceutically acceptable salt thereof or the prodrug thereof or the solvate thereof can be administered one or more times a day, such as, e.g., once, two times, three times, four times or five times.
  • the pharmaceutical composition, pharmaceutical formulation or medicament according to the invention is administered once a day.
  • the pharmaceutical composition, pharmaceutical formulation or medicament is administered twice a day.
  • the pharmaceutical composition, pharmaceutical formulation or medicament is administered once in the morning and once in the evening.
  • the phenylbutyrate or the pharmaceutically acceptable salt thereof or the prodrug thereof or the solvate thereof may be administered two times or more a day, such as, e.g., three times, four times or five times, wherein the administrations are 2 to 14 hours apart, such as, e.g., 4, 6, 8, 10 or 12 hours apart.
  • the phenylbutyrate or the pharmaceutically acceptable salt thereof or the prodrug thereof or the solvate thereof is administered twice a day, wherein the administrations are 8 to 12 hours apart.
  • once daily and “Q.D” refer to once a day dose administration, about once every 24 hours.
  • time daily and “BID” refer to twice a day dose administration, typically once in the morning and once in the evening.
  • combination therapy refers to the administration of two or more therapeutic agents to treat or prevent a 4R-tauopathy.
  • administration encompasses coadministration of these therapeutic agents in a substantially simultaneous manner, such as in a single dosage form having a fixed ratio of active ingredients or in multiple, separate dosage forms for each active ingredient.
  • administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the disorders described herein.
  • a non-limiting example is in the treatment of human 4-repeat tauopathies, wherein phenylbutyrate or a pharmaceutically acceptable salt thereof or a prodrug thereof or a solvate thereof may be administered in combination with, for example, an active pharmaceutical ingredient, which inhibits or promotes clearance of aggregated tau in the brain.
  • Such API may be chosen, for example, from antibodies binding to protein aggregates and/or diphenyl- pyrazoles and/or agents affecting expression of proteins involved in neurodegenerative diseases, and other.
  • Therapeutic compounds that may be administered with phenylbutyrate or a pharmaceutically acceptable salt thereof or a prodrug thereof or a solvate thereof include 5-(3-bromophenyl)-3-(3,4-methylenedioxyphenyl)-lH-pyrazole which is also known as anlel38b and the like.
  • the two components or active ingredients in the pharmaceutical combination of the present invention may be part of the same unitary pharmaceutical formulation; or part of separate pharmaceutical formulations for the coadministration of the two components or active ingredients as part of the same therapeutic regime.
  • the two components are administered in separate formulations, it is not necessary for them to be administered at the same time, although it could be done in this manner if so desired.
  • each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments.
  • the features recited in the composition embodiments can be used in the use embodiments described herein and vice versa.
  • P301S mice 20 adult (56 ⁇ 3 days) male and female heterozygous tau-P301S (P301S) transgenic (TG) mice (line PS19: B6; C3-Tg(Prnp-MAPT*P301S)PS19Vle/J; The Jackson Laboratory, Bar Harbor, ME) were investigated in the first part of the study with 10 age- and sex-matched non-carrier controls.
  • P301S mice express human P301S mutant 4R/0N tau (Thyl-hTau.P301S) in CBA.C57BL/6 background (Allen B, Ingram E, Takao M et al. (2002) Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein.
  • the phenotype manifests with learning deficits from 2 to 3 months of age, and onset of motor impairment at 4 months, leading to early death before 12 months of age (Xu H, Rosier TW, Carlsson T et al. (2014) Memory deficits correlate with tau and spine pathology in P301S MAPT transgenic mice. Neuropathology and Applied Neurobiology 40:833-843, and Yoshiyama Y, Higuchi M, Zhang B et al. (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337-351). The mice were randomly assigned into the different treatment groups.
  • mice were treated orally with phenylbutyrate (Enzo Life Sciences, Farmingdale, USA) dissolved in sterile water, and 10 control animals received standard water.
  • the dosage was approximately lg/kg body weight per day according to well-tolerated doses already tested in studies (Bonnemaison, M.L., E.S. Marks-Nelson, and E.l. Boesen, Sodium 4-phenylbutyrate treatment protects against renal injury in NZBWF1 mice. Clin Sci (Lond), 2019.
  • the animals received phenylbutyrate from the age of 8 weeks onwards and were monitored for feeding and drinking behavior and found to have no taste aversion to the PBA- treated water.
  • the control water and the PBA-treated water were changed twice a week on a 3 to 4 day rotating cycle until the end of the experiment.
  • the length of the observation period was 20 weeks until the age of 28 weeks.
  • the period of treatment was chosen until the appearance of the first motor symptoms.
  • 10 age- and sex-matched non-carrier mice on the same genetic background were included as non-carrier controls.
  • the mice of the first part of the study were analyzed for motor performance and neurofilament light chain biomarker levels in serum.
  • mice were treated orally with phenylbutyrate (Biosynth Ltd, United Kingdom) dissolved in sterile water, and 14 control animals received standard water.
  • the dosage was, as in the first part of the study, approximately lg/kg body weight per day.
  • the animals received phenylbutyrate from the age of 8 weeks onwards and were monitored for feeding and drinking behavior and found to have no taste aversion to the PBA-treated water.
  • the control water and PBA-treated water were changed twice a week on a 3 to 4-day rotating cycle until the end of the experiment. The length of the observation period was 20 weeks until the age of 28 weeks.
  • mice of the second part of the study were analyzed histologically for the expression of ionized calcium-binding adapter molecule 1 (IBA1), glial fibrillary acid protein (GFAP), and paired helical filament-tau (PHF-tau).
  • IBA1 ionized calcium-binding adapter molecule 1
  • GFAP glial fibrillary acid protein
  • PHF-tau paired helical filament-tau
  • mice For pharmacokinetic analysis, 30 adult (70 days) male C57BL/5J mice (Charles River Germany, Sulzfeld, Germany) were used.
  • animals were anaesthetized with an intraperitoneal injection of 10% ketamine and 2% xylazine and subsequently venous blood was sampled from the right ventricle and either left for 30 minutes at room temperature or treated with EDTA and placed on ice. After centrifugation at 1500xg for 10 min either serum or plasma were collected from the tubes. After collection of blood, animals were intracardially perfused with ice-cold phosphate- buffered saline (PBS).
  • PBS ice-cold phosphate- buffered saline
  • the brain was collected and fixed overnight in 4% paraformaldehyde (PFA) solution, cryoprotected in 30% sucrose in PBS, and frozen at -80°C until cryosectioning at 14 pm on a cryostat (CryoStar NX70, Thermo Scientific). Sections were mounted on superfrost slides and stored at -20°C until further processing.
  • PFA paraformaldehyde
  • Example 2 Motor performance assessment - Rotarod Analysis
  • mice For assessment of motor performance, a rotarod system for five mice (TSE Systems, Bad Homburg, Germany) with a diameter of 30mm per rod was used. All mice were tested regarding their rotarod performance every 4 weeks beginning at the age of 8 weeks (56 ⁇ 3 days of age). On the 3 days prior to the rotarod performance test, mice were trained in three trial runs each during which the rotarod rotated at a speed of 4 laps per minute over a period of 180 s. On the fourth day, the test consisted of three runs on a rod that accelerated continuously for 300 seconds from 4 to 40 laps per minute. The latency between each trial run was at least 40 s. This paradigm was designed in a way that all mice fell from the rod at some time point.
  • NfL neurofilament light chain
  • Plasma was diluted lOOx in sample diluent (Quanterix 102252) followed by addition of Simoa detector reagent and bead reagent (Quanterix 103159, 102246).
  • samples were incubated for 30 mins at 30°C with shaking at 800rpm. Following this, the sample plate was washed with Simoa Wash Buffer A (Quanterix 103078) using a Simoa Microplate Washer according to the Quanterix two step protocol. After addition of SBG reagent (Quanterix 102250) samples were again incubated at 30°C, 800rpm for another 10 min. The two-step washer protocol was continued with the sample beads being twice resuspended in Simoa Wash Buffer B (Quanterix 103079) before final aspiration of buffer.
  • Simoa Wash Buffer A Simoa Wash Buffer A
  • Example 1 For immunohistological analysis, the sections mounted in Example 1 were put at room temperature for 15 minutes and rehydrated in PBS. After heat induced antigen retrieval was performed, the sections were washed with PBS and blocked for 1 hour with blocking solution (2.5% bovine serum albumin, 2.5% fetal calf serum, and 2.5% fish gelatin in PBS). Primary antibodies (Anti-IBAl, 234308, Synaptic Systems; Anti-GFAP, 173006, Synaptic Systems; Anti- PHF (AT8), MN1020, ThermoFisher Scientific) were diluted in 25% blocking solution in PBS, applied to the sections, and incubated overnight at 4°C.
  • the dentate gyrus is one of the main areas of pathology in P301S transgenic animals and pathology is quite conserved, while also playing an important role in several crucial processes of the brain.
  • GFAP is an established marker of astrocytes
  • IBA1 is an established marker of microglia. Both cell types are very relevant in terms of inflammation of the brain. High expression of their respective marker is generally a sign of inflammatory cell states. Lower mean fluorescence ( Figures 3A, 3B and 4) upon treatment are indicative of successful dampening of the pathology-associated inflammation. The dampening of inflammation is most likely leading to better cell functionality and thus decreasing PHF deposition ( Figures 3C and 4) in P3O1S mice. PHF or phosphor-tau deposition and inflammation are one of the key pathological features of tauopathies. Dampening of inflammation and reduction of PHF in turn also have a clinical effect as shown by improved Rotarod performance ( Figure 1, Example 2).
  • Example 5 PET Imaging with 18 F-GE180 TSPO (18-kDa translocator protein)
  • PET imaging of TSPO (18-kDa translocator protein) is a well-described biomarker for changes in metabolic processes.
  • TSPO-PET tracer correlates with higher synaptic density and better clinical performance (Early and Longitudinal Microglial Activation but Not Amyloid Accumulation Predicts Cognitive Outcome in PS2APP Mice. Focke C. et al., J Nucl Med. 2019 Apr; 60(4):548-554).
  • Example 4 The higher uptake of TSPO-PET tracer in the PBA treated mice, showing a more active metabolism of cells, is indicative of an altered glial state which is also reflected by histological examination in Example 4. This alteration in metabolism of glial cells could allow them to function more efficiently and beneficial in the context of disease. As shown by histological examination in Example 4, in the context of 4R-tauopathy, the alteration in metabolism and reactivity of astrocytes and microglia leads to less inflammation and less deposition of PHF, which in turn leads to a less severe course of disease with better clinical outcome as evidenced by the motor performance assessment in Example 2
  • mice were administered with GPBA (Ravicti, Immedica Pharma AB, Sweden) per os at a dose of lg/kg/d in one administration, 10 mice were administered with Na-PBA (Biosynth Ltd, United Kingdom) intraperitoneal at 1 g/kg/d in one administration, and 10 mice were administered with Na-PBA (Biosynth Ltd, United Kingdom) via drinking water at lg/kg/d continuously for the day of measurement and four days prior to. At 1, 2, 4, 8, and 24 hours after administration, 2 mice per group were sacrificed and plasma was collected.
  • GPBA Ravicti, Immedica Pharma AB, Sweden
  • Phenylbutryric acid in mouse plasma was analyzed using UHPLC-MS/MS. Extraction was achieved by mixing 100 pL plasma with 500 pL MeOH with internal standards. After incubation, 50 pL aliquots of this extract were dried separately under a gentle stream of nitrogen and redissolved in 40 pL 20% acetonitrile (ACN). Analysis was performed using a Sciex ExionLC AD coupled to Sciex ZenoTOF 7600. Metabolites were separated using a Phenomenex Kinetex C18 column (100 mm x 2.1 mm ID, 1.7 pm particle size). Eluent A consisted of 100% H2O + 0.1% formic acid and eluent B consisted of 100% ACN + 0.1% formic acid. Analysis was performed in negative ionization mode using data-dependent acquisition.
  • Phenylbutyric acid was identified by comparison with an authentic standard and a calibration curve was constructed using sodium phenylbutyrate (Na-PBA) and dll-sodium phenylbutyrate (Dll-Na-PBA) as internal standard. Analysis was performed in Sciex OS 3.3. Extracted ion chromatograms were constructed for Na-PBA and Dll-Na-PBA and peak areas were used for quantitation.

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Abstract

La présente invention concerne le traitement ou la prévention d'une tauopathie à 4 répétitions par administration orale de phénylbutyrate ou d'un sel pharmaceutiquement acceptable de celui-ci ou d'un promédicament de celui-ci ou d'un solvate de celui-ci.
PCT/EP2024/053388 2023-02-10 2024-02-09 Phénylbutyrate oral pour le traitement de tauopathies à 4 répétitions humaines WO2024165757A1 (fr)

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