Methods of treatment and prevention of alzheimer's disease

Abstract

This invention provides methods for reducing clinical decline in individuals with early-stage Alzheimer's disease; methods for converting amyloid-positive individuals with early-stage Alzheimer's disease to amyloid-negative; methods for reducing the amount of amyloid in an individual's brain; and methods for preventing Alzheimer's disease, the methods comprising administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the individual is ApoE4 positive. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

Description

[Technical Field] This invention relates to a method for the treatment and prevention of Alzheimer's disease. [Previous Technology] Alzheimer's disease (AD) is a progressive, neurodegenerative disease of unknown cause and the most common form of dementia in the elderly. In 2006, there were 26.6 million cases of AD worldwide (range: 11.4 million to 59.4 million) (Brookmeyer, R. et al., Forecasting the global burden of Alzheimer's Disease. Alzheimer Dement. 2007; 3:186-91), and it was reported that more than 5 million people in the United States had AD (Alzheimer's Association. Alzheimer's Association report. 2010 Alzheimer's disease facts and figures. Alzheimer Dement. 2010;6:158-94). By 2050, the global prevalence of AD is projected to reach 106.8 million (range: 47.2 million to 221.2 million), with an estimated prevalence of 11 million to 16 million in the United States alone. (Brookmeyer, see above, and 2010 Alzheimer's disease facts and figures, see above). Alzheimer's disease generally involves a general decline in cognitive function, which progresses slowly and often renders patients bedridden in the final stages. Patients with Alzheimer's disease typically survive only 3 to 10 years after symptom onset, although known extremes include 2 to 20 years. (Hebert, LE et al., Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003; 60:1119-1122.) Although deaths due to Alzheimer's disease are significantly underestimated because death certificates rarely attribute the cause of death to Alzheimer's, it remains the seventh leading cause of death in the United States and the fifth leading cause of death among Americans over the age of 65. (Alzheimer's Association. Alzheimer's Association report. 2010 Alzheimer's disease facts and figures. Alzheimer Dement. 2010; 6:158-94.) AD represents a heavy economic burden in industrialized countries, with significant impacts on healthcare systems and national treasuries, as well as on patients and their families. In the United States alone, the total cost in 2010 was estimated at $172 billion, including $123 billion spent on Medicare and Medicaid. To our knowledge, there is currently no cure for Alzheimer's disease (AD) and no method to slow its progression. Current treatments for AD include symptomatic agents such as acetylcholinesterase inhibitors (AChEIs), such as donepezil; and N-methyl-D-aspartic acid (NMDA) receptor antagonists, such as memantine. While these medications can improve AD symptoms, such as cognitive decline and impairment of daily living activities and behaviors, there have been no reports of them altering disease progression. Therefore, there remains an unmet need for methods to treat AD progression and / or prevent AD. [Summary of the Invention] In some embodiments, this document provides a method for reducing clinical decline in individuals with early-stage Alzheimer's disease, comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ fibrillary antibody. In some embodiments, the individual is an ApoE4 carrier. In some embodiments, the at least one anti-Aβ fibrillary antibody is BAN2401. In some embodiments, at least one anti-Aβ fibrillary antibody, such as BAN2401, prevents Aβ deposition before plaque formation begins in the brain. In some embodiments, at least one anti-Aβ fibrillary antibody, such as BAN2401, reduces fibrillary fibers and existing plaque in the brain. In some embodiments, at least one anti-Aβ fibrillary antibody, such as BAN2401, prevents Aβ deposition before plaque formation begins and reduces fibrillary fibers and existing plaque in the brain. In some embodiments, this document provides a method for converting an individual with amyloid-positive early Alzheimer's disease to an individual with amyloid-negative early Alzheimer's disease, comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ fibrillary antibody. In some embodiments, the individual is an ApoE4 carrier. In some embodiments, the at least one anti-Aβ fibrillary antibody is BAN2401. In some embodiments, this document provides a method for reducing the amount of amyloid protein in the brain of an individual with early-stage Alzheimer's disease, comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ fibrillary antibody. In some embodiments, the individual is an ApoE4 carrier. In some embodiments, the at least one anti-Aβ fibrillary antibody is BAN2401. In some embodiments, this document provides a method for preventing Alzheimer's disease in ApoE4-positive individuals. In some embodiments, the method includes determining the amount of amyloid protein in the individual's brain before drug administration, and if the individual's brain amyloid protein level is higher than a first predetermined amount, administering a therapeutically effective amount of at least one anti-Aβ fibrillary antibody. In some embodiments, the at least one anti-Aβ fibrillary antibody is BAN2401.

Implementation Method

Claims

1. Use of a composition comprising an anti-Aβ protofibril antibody for the preparation of a medicament for reducing clinical decline in an individual with early-stage Alzheimer's disease, wherein, after 18 months of administration of the medicament, the clinical decline is reduced by at least 21% relative to placebo, as determined by ADAS-Cog, wherein the medicament is formulated for intravenous administration of the anti-Aβ protofibril antibody at a dose of 10 mg / kg relative to the individual's body weight, and is administered to the individual every 2 weeks, wherein the individual is ApoE4 positive, and wherein the anti-Aβ protofibril antibody comprises the heavy chain of SEQ ID NO: 11 and the light chain of SEQ ID NO:

12.

2. For the purposes of claim 1, wherein the individual with early-stage Alzheimer's disease has been diagnosed with mild cognitive impairment due to moderate probability of Alzheimer's disease, and / or has been diagnosed with mild Alzheimer's dementia.

3. As claimed in claim 1, wherein, 18 months after administration of the drug, the clinical decline was reduced by at least 63% relative to placebo, as determined by ADCOMS.

4. As claimed in claim 1, wherein, 18 months after administration of the drug, the clinical decline was reduced by at least 84% relative to placebo, as measured by ADAS-Cog.

5. As claimed in claim 1, wherein, 18 months after administration of the drug, the clinical decline is reduced by at least 60% relative to placebo, as determined by CDR-SB.

6. For any of the uses of claims 1 to 5, the amounts of Aβ1-42, total t, phosphorylated t or neurogranin are measured.

7. As claimed in any of claims 1 to 5, wherein administering the drug to the individual causes a slowing of the increase in the amount of neurocilia light chains in the cerebrospinal fluid.

8. The use of any one of claims 1 to 5, wherein the system is simultaneously administered with an Alzheimer's drug other than the anti-Aβ fibrillary antibody comprising the heavy chain of SEQ ID NO: 11 and the light chain of SEQ ID NO:

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9. The use of any of claims 1 to 5, wherein the individual is not simultaneously given any Alzheimer's disease medication other than the anti-Aβ fibrillary antibody comprising the heavy chain of SEQ ID NO: 11 and the light chain of SEQ ID NO:

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10. For any of the uses of claims 1 to 5, wherein the individual has amyloid β pathology.

11. For any of the uses requested in items 1 to 5, wherein the intravenous infusion lasts for approximately 60 minutes.

12. The use of any of claims 1 to 5, wherein the drug contains sodium chloride.

13. For any of the uses of claims 1 to 5, wherein the individual is a heterozygous carrier of the lipoprotein E ε4 gene pair.

14. For any of the uses requested in items 1 to 5, wherein the individual’s ARIA-E and ARIA-H are monitored.

15. As requested in item 14, wherein the monitoring includes assessing the individual 3 months after administration of the drug.

16. Use of a composition comprising an anti-Aβ fibrillary antibody for the preparation of a medicament for reducing clinical decline in an individual with early Alzheimer's disease, wherein, after 18 months of administration of the medicament, the clinical decline is reduced by at least 21% relative to placebo, as determined by CDR-SB, wherein the medicament is formulated for intravenous administration of the anti-Aβ fibrillary antibody at a dose of 10 mg / kg relative to the individual's body weight, and is administered to the individual every 2 weeks, wherein the individual is ApoE4 positive, and wherein the anti-Aβ fibrillary antibody comprises the heavy chain of SEQ ID NO: 11 and the light chain of SEQ ID NO:

12.

17. As claimed in claim 16, wherein, 18 months after administration of the drug, the clinical decline is reduced by at least 60% relative to placebo, as determined by CDR-SB.

18. Use of a composition comprising an anti-Aβ fibrillary antibody for the preparation of a medicament for reducing clinical decline in an individual with early Alzheimer's disease, wherein, after 18 months of administration of the medicament, the clinical decline is reduced by at least 20% relative to placebo, as determined by ADCOMS, wherein the medicament is formulated for intravenous administration of the anti-Aβ fibrillary antibody at a dose of 10 mg / kg relative to the individual's body weight, and is administered to the individual every 2 weeks, wherein the individual is ApoE4 positive, and wherein the anti-Aβ fibrillary antibody comprises the heavy chain of SEQ ID NO: 11 and the light chain of SEQ ID NO:

12.

19. As claimed in claim 18, wherein, 18 months after administration of the drug, the clinical decline is reduced by at least 63% relative to placebo, as determined by ADCOMS.

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