EP-4739309-A1 - DANEGAPTIDE FOR USE IN TREATING SYNUCLEINOPATHIES

Abstract

There is provided a compound of formula I for use in a method for treating or preventing a synucleinopathy disease, the method comprising administering to a subject, a therapeutically effective amount of said compound (I): or a pharmaceutically acceptable salt or hydrate thereof.

Inventors

• RAHMAN, SAIFUR
• HASTINGS, Nataly

Assignees

• Cambridge Enterprise Limited

Dates

Publication Date

20260513

Application Date

20240703

Claims (17)

1. 1. A compound of formula I for use in the treatment or prevention of a synucleinopathy disease, wherein the compound of formula I is: or a pharmaceutically acceptable salt or hydrate thereof.
2. 2. A compound for use according to claim 1, wherein the use is treatment.
3. 3. A compound for use according to claim 1 or 2, wherein the synucleinopathy disease is selected from Parkinson's Disease, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).
4. 4. A compound for use according to claim 3, wherein the synucleinopathy disease is Parkinson's Disease.
5. 5. A compound for use according to any one of the preceding claims, wherein the compound is danegaptide (DG) hydrochloride.
6. 6. A compound for use according to any one of the preceding claims, wherein the compound is for administration via an invasive route, preferably via injection.
7. 7. A compound for use according to claim 6 wherein the injection is administered intraperitoneally, subcutaneously, intravenously or intramuscularly.
8. 8. A compound for use according to any one of claims 1 to 5, wherein the compound is for administration via a non-invasive route.
9. 9. A compound for use according to claim 8, wherein the non-invasive route is oral, intranasal, sublingual, inhalation, rectal or transdermal.
10. 10. A compound for use according to any of the preceding claims, wherein the dosage of the compound of formula (I) is (a) of from 10 to 350 mg, yet more preferably of from 50 to 200 mg, such as of from 75 to 150 mg and/or (b) 0.05 to 5 mg/kg, yet even more preferably of from 0.7 to 3.5 mg/kg, for example of from 1.1 to 2 mg/kg.
11. 11. A compound for use according to any of the preceding claims, wherein the patient is exhibiting one or more symptoms selected from motor symptoms (such as tremors, stiffness and slowness of movement), memory disorders, depression, psychotic symptoms (such as hallucinations and delusions), sleep disturbance, and dementia.
12. 12. A kit for treating or preventing a synucleinopathy disease, the kit comprising: a compound of formula I: (I); or a pharmaceutically acceptable salt or hydrate thereof.
13. 13. The kit according to claim 12, wherein the kit further comprises a delivery system.
14. 14. A kit according to claim 13, wherein the delivery system is configured to administer the drug non-invasively or invasively.
15. 15. A method of treating or preventing a synucleinopathy disease comprising administering a patient a therapeutically effective amount of a compound of formula I: or a pharmaceutically acceptable salt or hydrate thereof.
16. 16. Use of a compound of formula I for the manufacture of a medicament for treating or preventing a synucleinopathy disease, wherein the compound of formula I is: or a pharmaceutically acceptable salt or hydrate thereof.
17. 17. The kit, method or use according to any one of claims 12 to 16 having any one of the features of claims 1 to 11.

Description

THERAPIES TECHNICAL FIELD The present disclosure relates to therapies for treating a synucleinopathy disease. BACKGROUND Parkinson's Disease (PD), is an alpha-synucleinopathy and is an incurable neurodegenerative disorder with increasing prevalence. Reportedly, there are up to 10 million people suffering from PD worldwide, including arxound 150,000 people in the UK. Moreover, PD is likely to become more prevalent in ageing populations; PD is more frequently encountered by people over 65 years of age. Contemporarily, approved pharmacological treatments for PD are used to correct for dopamine deficiency in brains of PD sufferers, wherein dopamine is decreased following cell damage and subsequent death of brain cells, in particular dopaminergic neurones in a midbrain region of the human brain. However, these pharmacological treatments are not disease-modifying and often cause serious side effects including involuntary movements and hallucinations. Moreover, the underlying cause behind dopaminergic neurone death is not well-understood, wherein abnormal concentrations of calcium, alpha-synuclein (a-syn) aggregation, and an inflammatory environment are prominent examples of key proposed factors in PD pathogenicity. Therefore, in light of the foregoing discussion, there exists a need to provide improved methods and pharmaceutical compounds for treating synucleinopathy diseases, particularly PD, and further mitigating their symptoms. SUMMARY As demonstrated by the in vitro and in vivo data presented herein, the inventors have found that the compounds described herein have utility for treating and preventing synucleinopathy diseases, such as PD. In a first aspect, the present disclosure provides a compound for treating or preventing a synucleinopathy disease, according to claim 1. In a second aspect, the present disclosure provides a kit for treating or preventing a synucleinopathy disease, according to claim 12. In a third aspect, the present disclosure provides a method of treating or preventing a synucleinopathy disease, according to claim 15. In a fourth aspect, the present disclosure provides a use of a compound for treating or preventing a synucleinopathy disease, according to claim 16. Throughout the description and claims of this specification, the words "comprise" , "include", "have", and "contain" and variations of these words, for example "comprising" and "comprises" , mean "including but not limited to", and do not exclude other components, items, integers or steps not explicitly disclosed also to be present. Moreover, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise. BRIEF DESCRIPTION OF THE DRAWINGS FIGs. 1A-1C illustrate the HPLC and electrochemical detection analysis of striatal monoamines (dopamine metabolites: 3,4-Dihydroxyphenylacetic acid, DOPAC; and homovanillic acid, HVA); and tyrosine hydroxylase (TH, marker of dopaminergic neurones) immunostaining in the striatum from the in vivo study conducted in Example 1; FIGs. 2A-2B illustrate the Ibal immunostaining from the in vivo study conducted in Example 1; FIGs. 3A-3B illustrate the cerebrospinal fluid (CSF) cytokine I chemokine profile analysis from the in vivo study conducted in Example 1; FIGs. 4A-4C illustrate a reduction in a-syn aggregation and phosphorylation of a serine amino acid residue located at position 129 of the a-syn protein sequence, which is associated with pathological a-syn in human PD, in rat and human astrocytes grown in the presence of other cell types such as neurons due to treatment with 30nM DG; FIGs. 5A-D show 3 aspects of therapeutic action of 30nM DG in cell models of synucleinopathy; FIGs. 6A-6B illustrate a pharmacodynamic effect of DG in the rat brain, namely a preservation of astrocytic coupling; and a change, namely a decrease, in inflammatory cytokine and chemokine release in the rat CSF due to treatment with lOmg/kg DG under inflammatory challenge induced by LPS injection intraperitoneally; FIGs. 7A-D and 8A-B illustrate changes, namely the downregulation, in Cx43 puncta or Cx43 fluorescence intensity per astrocyte, or per cell, in cell culture models upon various challenges relevant to the pathogenesis of PD over a period ranging from two days to 2.5 weeks, in rat and human cells; FIGs. 9A-9E and 10A-10C illustrate changes, namely the downregulation, in 0x43 puncta or 0x43 fluorescence intensity per cell, in two rat models of a-syn aggregation relevant to human PD pathogenesis, in several brain regions relevant to the motor symptom development in PD, over a period of 12-18 months and 9 months, respectively; FIGs. 11A-11C illustrate functional changes in cortical rat astrocytes in cell culture showing decreased gap junctional (GJ) coupling in astrocytic networks upon inflammatory and a-syn challenges relev