US-20260124236-A1 - METHODS FOR TREATING EARLY ALZHEIMER’S DISEASE

Abstract

Provided herein are methods for treating early Alzheimer's Disease using hydroxypropyl β-cyclodextrin compositions.

Inventors

• SHARON H. HRYNKOW
• Jeffrey L. Tate
• N. SCOTT FINE

Assignees

• CYCLO THERAPEUTICS, INC.

Dates

Publication Date

20260507

Application Date

20230926

Claims (20)

1. 1 . A method of treating early Alzheimer's disease in a human patient in need thereof, the method comprising administering to the human patient an effective amount of a hydroxypropyl β-cyclodextrin composition.
2. 2 . The method of claim 1 , wherein the early Alzheimer's disease is Alzheimer's disease with mild cognitive impairment or mild Alzheimer's disease.
3. 3 . The method of claim 1 , wherein at the time of initiation of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition the human patient exhibits progressive cognitive decline.
4. 4 . The method of claim 1 , wherein at the time of initiation of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition the human patient has exhibited progressive cognitive decline for at least about 1 year.
5. 5 - 8 . (canceled)
6. 9 . The method of claim 1 , wherein the human patient has previously been administered a pro-cognitive drug and/or a symptomatic therapy for early Alzheimer's disease.
7. 10 . The method of claim 1 , wherein the human patient has previously been administered an acetylcholinesterase inhibitor and/or memantine.
8. 11 . The method of claim 1 , wherein the human patient is at least 50 years old.
9. 12 .- 14 . (canceled)
10. 15 . The method of claim 1 , wherein administering an effective amount of the hydroxypropyl β-cyclodextrin composition comprises administering to the human patient about 500 mg/kg to about 2000 mg/kg of the hydroxypropyl β-cyclodextrin composition.
11. 16 . (canceled)
12. 17 . The method of claim 1 , wherein administering an effective amount of the hydroxypropyl β-cyclodextrin composition comprises administering to the human patient by intravenous infusion about 500 mg/kg to about 2000 mg/kg of the hydroxypropyl β-cyclodextrin composition.
13. 18 . (canceled)
14. 19 . The method of claim 1 , wherein administering an effective amount of the hydroxypropyl β-cyclodextrin composition comprises administering to the human patient by intravenous infusion about 500 mg/kg to about 2000 mg/kg of the hydroxypropyl β-cyclodextrin composition, every 28 days.
15. 20 . (canceled)
16. 21 . The method of claim 1 , wherein administering an effective amount of the hydroxypropyl β-cyclodextrin composition comprises administering to the human patient by intravenous infusion about 500 mg/kg to about 2000 mg/kg of the hydroxypropyl β-cyclodextrin composition, every 28 days, for a period of at least about 24 weeks.
17. 22 . (canceled)
18. 23 . The method of claim 1 , wherein the hydroxypropyl β-cyclodextrin composition is administered to the human patient by intravenous infusion over a period of at least about 4 hours.
19. 24 . (canceled)
20. 25 . The method of claim 1 , wherein the hydroxypropyl β-cyclodextrin composition comprises about 25% (w/v) of a hydroxypropyl β-cyclodextrin.

Description

CROSS-REFERENCE This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63/411,935, filed Sep. 30, 2022, the content of which is incorporated herein by reference in its entirety. BACKGROUND Approximately 5.4 million Americans currently suffer from Alzheimer's disease, including early Alzheimer's disease, and this number is expected to rise to 13.8 million by 2050. In 2016, an estimated 700,000 Americans≥65 years old died with Alzheimer's disease. While United States (US) deaths from stroke, heart disease, and prostate cancer all decreased from 2000 to 2014, Alzheimer's disease-related deaths increased 89% over the same period. Total 2016 payments for health care, long-term care, and hospice services for people≥65 years old with dementia were estimated to be $236 billion. [Alzheimer's Association. 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 2016; 12:459-509.] More recently, with a better understanding of disease pathogenesis, drug development has shifted focus to limit, prevent, and mitigate amyloid-beta (Aβ) and tau accumulation. Numerous treatment strategies have been proposed for amyloid-based therapies that increase Aβ clearance or decrease Aβ aggregation, as well as targeted Aβ immunotherapy. To date, despite multiple attempts, these drugs have largely failed late-stage clinical trials, many of which enrolled patients in the later stages of dementia. Doubts concerning the risk/benefit profile of anti-amyloid antibody therapies remain as they have been associated with potentially dangerous, albeit manageable, adverse reactions such as cerebral edema and microscopic hemorrhages. Like Aβ therapies, to date, tau-based therapies have yielded early hope but are currently in early phase studies and will not yield efficacy data for several years. Cholesterol imbalance in Alzheimer's disease patients is well known, and significant research exists suggesting these imbalances are responsible for Aβ and tau accumulation. An increase in blood cholesterol is also associated with increased dementia risk, as plasma concentrations of cholesterol are significantly higher in Alzheimer's disease patients and patients with non-Alzheimer's-related dementia. Both the generation and clearance of Aβ are regulated by cholesterol. Tau toxicity also depends upon cellular cholesterol levels. High cholesterol diets increase tau hyperphosphorylation. As the cholesterol concentration increases, so does the susceptibility of neurons to Aβ-dependent calpain activation. [Ferreira A, Bigio E H. Calpain-mediated tau cleavage: a mechanism leading to neurodegeneration shared by multiple tauopathies. Mol Med. 2011; 17(7-8):676-685.] Calpain activation cleaves tau and generates toxic fragments. These cleaved tau forms induce neuronal death, synapse loss, and/or behavioral deficits. Young neurons that have measurably less cholesterol than aged neurons, also contain less phosphorylated tau. However, when these same young neurons are loaded with cholesterol, both increases in phosphorylated tau as well as susceptibility to death are observed. At present there are no approved therapies for treating early Alzheimer's disease through the modulation of cholesterol levels. As such, there is an unmet need to develop new therapies for the treatment of early Alzheimer's disease. SUMMARY In one aspect, provided herein is a method of treating early Alzheimer's disease in a human patient in need thereof, the method generally comprising administering to the human patient an effective amount of a hydroxypropyl β-cyclodextrin composition. In certain embodiments, the early Alzheimer's disease is Alzheimer's disease with mild cognitive impairment or mild Alzheimer's disease. In certain embodiments, at the time of initiation of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition the human patient exhibits progressive cognitive decline. In certain embodiments, at the time of initiation of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition the human patient has exhibited progressive cognitive decline for at least about 1 year. In certain embodiments, at the time of initiation of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition the human patient has a global Clinical Dementia Rating (CDR) scale score of about 0.5 and a CDR Memory Box score of about 0.5 or greater. In certain embodiments, at the time of initiation of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition the human patient has a global Clinical Dementia Rating (CDR) scale score of between about 0.5 and about 1.0 and a CDR Memory Box score of about 0.5 or greater. In certain embodiments, at the time of initiation of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition the human patient exhibits cerebral amyloid-beta (Aβ) pathology. In certain embodiments, at the time of ini