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US-20260124278-A1 - COMPOSITIONS AND METHODS FOR TREATMENT OF NEUROLOGICAL DISORDERS

US20260124278A1US 20260124278 A1US20260124278 A1US 20260124278A1US-20260124278-A1

Abstract

Long-acting glucagon like peptide 1 receptor agonists (GLP-1r agonists) reduce and inhibit pathological processes that give rise to long-term neurological impairment. A biotinylated and/or lipidated GLP-1r agonist analogs with enhanced enzymatic stability needed for gastrointestinal absorption, improved bioavailability and pharmacokinetics are described. In preferred embodiments, the GLP-1r agonist analogs have the amino acid sequence of any one of SEQ ID NOs: 9-35. The compositions are typically administered via oral or parenteral routes. The compositions are particularly suited for treating, alleviating, and/or preventing one or more neurological diseases or disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Methods of treating a human subject having AD or PD or at risk of AD or PD are provided.

Inventors

  • Eun Ji PARK
  • Jong-Sung Park

Assignees

  • D&D PHARMATECH INC.

Dates

Publication Date
20260507
Application Date
20230526

Claims (20)

  1. 1 . A method of treating or preventing a neurodegenerative disease or disorder in a subject suffering from or at risk of developing a neurodegenerative disease or disorder, comprising administering a pharmaceutically effective amount of a composition comprising a long-acting GLP-1r agonist to treat or alleviate one or more symptom of the neurodegenerative disease or disorder.
  2. 2 . The method of claim 1 , wherein the long-acting GLP-1r agonist comprises (i) a polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 1-8; and (ii) one or more biotin moieties and/or one or more fatty acids, or derivatives thereof, wherein the one or more biotin moieties and/or one or more fatty acids, or derivatives thereof are conjugated to the polypeptide.
  3. 3 . The method of claim 1 , wherein the one or more biotin moieties and/or one or more fatty acids, or derivative thereof, are conjugated to the polypeptide via one or more amino acid residues selected from the group consisting of cysteine and lysine.
  4. 4 . The method of claim 1 , wherein the one or more biotin moieties and/or one or more fatty acids, or derivative thereof, are conjugated to the polypeptide via one or more amino acid residues selected from the group consisting of lysine at position 12, lysine at position 27, and a C-terminal residue.
  5. 5 . The method of claim 1 , wherein the long-acting GLP-1r agonist comprises the amino acid sequence of any one of SEQ ID NOs: 9-35.
  6. 6 . The method of claim 1 , wherein the composition is administered in an amount effective to inhibit the secretion of inflammatory and/or neurotoxic mediators secreted from activated microglial cells, as compared to an appropriate control.
  7. 7 . The method of claim 1 , wherein the composition is administered in amount effective to inhibit or reduce the secretion of inflammatory and/or neurotoxic mediators secreted from astrocytes, as compared to an appropriate control.
  8. 8 . The method of claim 1 , wherein the composition is administered in an effective amount to reduce one or more inflammatory or neurotoxic mediators in the subject as compared to an appropriate control, wherein the inflammatory or neurotoxic mediators are selected from the group consisting of TNF-α, IL-1α, IL-1β, IFN-γ, IL-6, and C1q.
  9. 9 . The method of claim 1 , wherein the composition is administered in an effective amount to reduce the number of activated microglial cells in the brain of the subject.
  10. 10 . The method of claim 1 , wherein the composition is administered in an effective amount to reduce abnormally aggregated proteins through upregulation of GLP-1r.
  11. 11 . The method of claim 10 , wherein the abnormally aggregated proteins are α-synuclein, β-amyloid or tau.
  12. 12 . The method of claim 1 , wherein the neurodegenerative disease or disorder is Parkinson's disease.
  13. 13 . The method of claim 1 , wherein the neurodegenerative disease or disorder is Alzheimer's disease.
  14. 14 . The method of claim 1 , wherein the composition is administered via a route selected from the group consisting of enteral administration and parenteral administration.
  15. 15 . The method of claim 1 , wherein the composition is administered via oral administration or subcutaneous administration.
  16. 16 . The method of claim 1 , wherein the composition is administered in a form selected from the group consisting of pills, capsules, tablets, liquids, and suspensions.
  17. 17 . The method of claim 1 , wherein the composition is administered at an interval selected from the group consisting of once a month, once every two weeks, once a week, once every three days, once every two days, once daily, and twice daily.
  18. 18 . The method of claim 1 , wherein the composition is administered to the subject once a week for up to 6 months.
  19. 19 . The method of claim 1 , wherein the composition is administered to the subject for a duration of between one and ten days, weeks, months, or years, inclusive.
  20. 20 . The method of claim 1 , wherein the composition is administered to a human subject at a dose of between about 0.001 mg/kg body weight of the subject and about 100 mg/kg body weight of the subject, inclusive.

Description

CROSS-REFERENCE TO RELATED APPLICATION This application is a National Phase application under 35 U.S.C. 371 of PCT/IB2023/055432, filed May 26, 2023, which claims the benefit of and priority to U.S. Ser. No. 63/346,502 filed May 27, 2022, and which are incorporated by reference herein in their entirety. REFERENCE TO SEQUENCE LISTING The Sequence Listing submitted as an XML file named “DDP_106_PCT_ST26.xml” created on Nov. 4, 2025, and having a size of 74,340 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.834 (c) (1). FIELD OF THE INVENTION The invention is generally in the field of treatment for neurological disorders, and in particular, methods and compositions for treating Parkinson's disease and Alzheimer's disease. BACKGROUND OF THE INVENTION Neurodegenerative disease encompasses a range of conditions induced by the progressive loss of structure or function of neurons, including death of neurons. Diverse neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) occur because of neurodegenerative processes. Parkinson's disease (PD) is a late onset, progressive neurodegenerative disorder that affects about one million Americans and 7 to 10 million people worldwide. Although dopamine replacement alleviates the symptomatic motor dysfunction, its effectiveness is reduced as the disease progresses, leading to unacceptable side effects such as severe motor fluctuations and dyskinesias. Moreover, this palliative therapeutic approach does not address the underlying mechanisms of the disease. Alzheimer's disease (AD) is one of the most common neurodegenerative disease and accounts for more than 80% of dementia cases worldwide. It leads to the progressive loss of mental, behavioral, functional decline and ability to learn. In 2020, an estimated 5.8 million Americans aged 65 years or older had Alzheimer's disease. This number is projected to nearly triple to 14 million people by 2060 (Matthews, K. A. et al., Alzheimer's & Dementia (2018)). Currently approved treatments, e.g., acetylcholinesterase inhibitors, only provide symptomatic improvement but do not modify the disease process. The number of new strategies including the amyloid and tau-based therapeutics are in clinical development, however, no drugs have proven to show clear efficacy in humans. Thus, despite significant efforts, no effective therapeutic agents or treatment methods have been approved to repair, or counteract, the neuronal damage of these neurodegenerative diseases, or the associated cognitive decline or impairment. New disease modifying treatments are sorely needed. Therefore, it is an object of the invention to provide compositions and methods to reduce or prevent the pathological processes associated with the development and progression of neurological diseases such as Parkinson's disease and Alzheimer's disease, and methods of making and using thereof. It is also an object of the invention to provide compositions and methods for the treatment or prevention of neuronal damage associated with Parkinson's disease and Alzheimer's disease and the associated motor and cognitive decline or impairment. It is yet a further object of the invention to provide compositions and methods for blocking or reducing microglial activation and/or reactive astrocytes in neurodegenerative diseases with minimal off-target toxicity. SUMMARY OF THE INVENTION It has been established that long-acting glucagon like peptide 1 receptor agonists (long-acting GLP-1r agonists) reduce and/or inhibit pathological processes such as microglial activation caused by abnormally aggregated proteins such as α-synuclein, β-amyloid or tau. While GLP-1r agonists are effective in neurodegenerative disease through inhibition of microglial activation, currently available GLP-1r agonists delivery are suboptimal; subcutaneous injection lowers patient compliance and oral administration has lower bioavailability due to enzymatic instability and insufficient gastrointestinal absorption because of peptide's inherent properties. Modified GLP-1r agonists show improved enzymatic stability, higher oral bioavailability and increased blood brain barrier (BBB) permeation. Modified GLP-1r agonists with improved pharmacokinetic properties share the same target receptor and should have the same effects on microglia, though their clinical efficacy may not be the same and may differ depending on tissue distribution, blood brain barrier access, receptor kinetics, and exposure at well-tolerated doses. Compositions and methods for treating or preventing a neurodegenerative disease or disorder in a subject suffering from or at risk of developing a neurodegenerative disease or disorder are provided. A composition including a long-acting GLP-1r agonist is administered in an amount effective to alleviate or treat one or more symptoms of the neurodegenerative disease or disorder. In some embodiment