Methods for preventing or slowing the progression of cognitive decline or impairment in subjects
Administering levetiracetam, buvarrascartan, or celerastin addresses the inadequacy of current treatments by effectively delaying cognitive decline and atrophy in the medial temporal lobe subregion, entorhinal cortex, and trans-entorhinal cortex for APOE4 non-carriers.
Patent Information
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- AGENEBIO INC
- Filing Date
- 2026-05-15
- Publication Date
- 2026-07-10
AI Technical Summary
Current treatments are inadequate in preventing or delaying the progression of cognitive decline and cognitive impairment, particularly in APOE4 non-carriers, and there is a need for effective methods to slow the atrophy of specific brain regions such as the medial temporal lobe subregion, entorhinal cortex (ERC), and trans-entorhinal cortex (BA35).
Administering levetiracetam, buvarrascartan, or celerastin, or their pharmaceutically acceptable salts, or a pharmaceutical composition comprising these, to APOE4 non-carriers to delay cognitive decline and atrophy in brain regions like the medial temporal lobe subregion, entorhinal cortex, and trans-entorhinal cortex.
The administration of levetiracetam, buvarrascartan, or celerastin effectively delays cognitive decline and atrophy in the specified brain regions, providing a therapeutic approach for APOE4 non-carriers.
Smart Images
Figure 00000000_0000_ABST
Abstract
Description
Summary of Methods for Preventing or Delaying the Progression of Cognitive Decline or Impairment: Methods for preventing or delaying the progression of cognitive impairment or preventing the onset of cognitive decline or slowing the rate of cognitive decline. Methods for delaying atrophy or reduction in the volume of the medial temporal lobe subregion. Methods for delaying atrophy or reduction in the volume of the entorhinal cortex (ERC). Methods for delaying atrophy or reduction in the volume of the trans-entorhinal cortex (BA35). This method includes administering to APOE4 non-carrier subjects one or more of levetiracetam, buvarrascartan, or celerastin, or a pharmaceutically acceptable salt thereof, or administering a pharmaceutical composition comprising levetiracetam, buvarrascartan, or celerastin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Claims
WHAT IS CLAIMED1. A method of preventing or slowing the progression of cognitive impairment or preventing the development or reducing the rate of cognitive decline in an APOE4 noncarrier subject, the method comprising administering to the subject one or more of levetiracetam, brivaracetam or seletracetam, or a pharmaceutically acceptable salt thereof, wherein the levetiracetam, brivaracetam or seletracetam are administered at a daily dose of 0.7-350 mg, or comprising administering to the subject a pharmaceutical composition comprising the daily dose of the levetiracetam, brivaracetam or seletracetam, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
2. The method of claim 1, wherein the APOE4 non-carrier subjects carry a genetic risk factor for the development of cognitive impairment which is not APOE4.
3. The method of claim 1, wherein the subject presents or displays with cognitive performance below the normal range for their age.
4. The method of claim 1, wherein the subject presents or displays with volumetric atrophy of a subregion of the medial temporal lobe.
5. The method of claim 4, wherein the subregion of the medial temporal lobe is the entorhinal cortex (ERC).
6. The method of claim 5, wherein the entorhinal cortex (ERC) is the left ERC.
7. The method of claim 4, wherein the subregion of the medial temporal lobe is the transentorhinal cortex (BA35).
8. The method according to claim 7, wherein the transentorhinal cortex (BA35) is the right BA35.
9. The method of claims 1-8, wherein the subject is suffering from pre-mild cognitive impairment.
10. The method of claim 1 or 2, wherein the subject is suffering from mild cognitive impairment.
11. The method of any one of claims 1, 2 or 10, wherein the subject is suffering from mild cognitive impairment due to Alzheimer’s disease (AD) or prodromal AD.
12. The method of any one of claims 1, 2 or 10, wherein the subject is suffering from amnestic mild cognitive impairment (aMCI).
13. The method of any one of claims 1-12, wherein the daily dose of the levetiracetam or seletracetam is 7-350 mg.
14. The method of any one of claims 1-12, wherein the daily dose of the brivaracetam is 0.7-180 mg.
15. The method of any one of claims 1-12, wherein the daily dose of the levetiracetam or seletracetam is 125-250 mg.
16. The method of claim 13 or 15, wherein the daily dose of the levetiracetam or seletracetam is 220 mg.
17. The method of claim 13 or 15, wherein the daily dose of the levetiracetam or seletracetam is 190 mg.
18. The method of any one of claims 1-17, wherein the pharmaceutical composition is formulated in one or more of an oral form, an extended-release form, a single-unit-dosage form or a once-a-day form.
19. The method of claim 18, wherein the extended-release form is a controlled release form, a prolonged release form, a sustained release form, a delayed release form, or a slow release form.
20. The method of claim 18 or 19, wherein the extended-release form is a once-a-day extended-release form.
21. The method of any one of claims 1-13, 15, 16 or 18-20, wherein the daily dose of the levetiracetam in the pharmaceutical composition is 220 mg and wherein the pharmaceutical composition further comprises 280 mg-350 mg of hydroxypropyl methylcellulose, 1.2 mg- 1.4 mg of colloidal silicon dioxide, 92.8 mg-119.2 mg of silicified microcrystalline cellulose, and 6.0 mg-6.7 mg of magnesium stearate.
22. The method of claim 21, wherein the pharmaceutical composition comprises 280 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silicon dioxide, 92.8 mg of silicified microcrystalline cellulose, and 6.0 mg of magnesium stearate.
23. The method of claim 21, wherein the pharmaceutical composition comprises 347.5 mg of hydroxypropyl methylcellulose, 1.4 mg of colloidal silicon dioxide, 119.2 mg of silicified microcrystalline cellulose, and 6.7 mg of magnesium stearate.
24. The method of any one of claims 1-13, 15, or 17-20, wherein the daily dose of the levetiracetam in the pharmaceutical composition is 190 mg and wherein the pharmaceutical composition further comprises 300 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silicon dioxide, 102.8 mg of silicified microcrystalline cellulose or anhydrous dicalcium phosphate, and 6 mg of magnesium stearate.
25. The method of any one of claims 21-24, wherein the hydroxypropyl methylcellulose is hypromellose 2208.
26. The method of any one of claims 21-25, wherein the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90.
27. The method of any one of claims 1-13 or 15-20, wherein the pharmaceutical composition comprising the levetiracetam, or pharmaceutically acceptable salt thereof, is in a once-a-day extended release form and provides a steady state plasma concentration of levetiracetam in a subject of between 1.9 pg / mL and 4.4 pg / mL within 3 hours after administration and extending for at least 8 hours of a 24-hour period after said administration.
28. The method of claim 27, wherein the pharmaceutical composition provides a steady state plasma concentration of levetiracetam in a subject of between 1.9 pg / mL and 4.4 pg / mL within 2 hours after said administration and extending for at least 13 hours of a 24-hour period after said administration.
29. The method of claim 27, wherein the pharmaceutical composition provides a steady state plasma concentration of levetiracetam in a subject of between 1.9 pg / mL and 4.4 pg / mL within 1 hour after said administration and extending for at least 13 hours of a 24-hour period after said administration.
30. The method of claim 27, wherein the pharmaceutical composition provides a steady state plasma concentration of levetiracetam in a subject of between 1.9 pg / mL and 4.4 pg / mL within 1 hour after administration and extending for at least 13 to 16 hours of a 24-hour period after said administration.
31. The method of any of claims 1, 2, 4-8, or 13-30, wherein the subject displays or presents with cognitive performance within the normal range for the subject’s age.
32. The method of any one of claims 1-31, wherein the subject is a human.
33. A method for delaying or reducing the rate of volumetric atrophy of a subregion of the medial temporal lobe in an APOE4 non-carrier subject, the method comprising administering to the subject one or more of levetiracetam, brivaracetam or seletracetam, or a pharmaceutically acceptable salt thereof, wherein the levetiracetam, brivaracetam or seletracetam are administered at a daily dose of 0.7-350 mg, or comprising administering to the subject a pharmaceutical composition comprising the daily dose of the levetiracetam, brivaracetam or seletracetam, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
34. The method of claim 33, wherein the subregion of the medial temporal lobe is the entorhinal cortex (ERC).
35. The method of claim 34, wherein the ERC is the left ERC.
36. The method of claim 33, wherein the subregion of the medial temporal lobe is the transentorhinal cortex (BA35).
37. The method of claim 36, wherein the transentorhinal cortex (BA35) is the right BA35.
38. A method for delaying or reducing the rate of volumetric atrophy of the entorhinal cortex (ERC) in an APOE4 non-carrier subject, the method comprising administering to the subject one or more of levetiracetam, brivaracetam or seletracetam, or a pharmaceutically acceptable salt thereof, wherein the levetiracetam, brivaracetam or seletracetam are administered at a daily dose of 0.7-350 mg, or comprising administering to the subject a pharmaceutical composition comprising the daily dose of the levetiracetam, brivaracetam or seletracetam, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
39. The method of claim 38, wherein the entorhinal cortex (ERC) is the left ERC.
40. The method of any one of claims 33-39, wherein the APOE4 non-carrier subjects carry a genetic risk factor for the development of cognitive impairment which is not APOE4.
41. The method of any one of claims 33-39, wherein the subject presents or displays with cognitive performance below the normal range for their age.
42. The method according to any one of claim 33, wherein the subject presents or displays with volumetric atrophy of a subregion of the medial temporal lobe.
43. The method of claim 42, wherein the subregion of the medial temporal lobe is the transentorhinal cortex (BA35).
44. The method of claim 43, wherein the transentorhinal cortex (BA35) is the right BA35.
45. The method of claim 42, wherein the subregion of the medial temporal lobe is the entorhinal cortex (ERC).
46. The method of claim 38, wherein the subject presents with volumetric atrophy of the entorhinal cortex (ERC).
47. The method of claim 45 or 46, wherein the entorhinal cortex (ERC) is the left ERC.
48. The method of any one of claims 33-47, wherein the subject is suffering from pre- mild cognitive impairment.
49. The method of any one of claims 33-47, wherein the subject is suffering from mild cognitive impairment.
50. The method of any one of claims 33-40 and 49, wherein the subject is suffering from mild cognitive impairment due to Alzheimer’s disease (AD) or prodromal AD.
51. The method of any one of claims 33-40 and 49, wherein the subject is suffering from amnestic mild cognitive impairment (aMCI).
52. The method of any one of claims 33-51 wherein the daily dose of the levetiracetam or seletracetam is 7-350 mg.
53. The method of any one of claims 33-51, wherein the daily dose of the brivaracetam is 0.7-180 mg.
54. The method of any one of claims 33-52, wherein the daily dose of the levetiracetam or seletracetam is 125-250 mg.
55. The method of claim 52 or 54, wherein the daily dose of the levetiracetam or seletracetam is 220 mg.
56. The method of claim 52 or 54, wherein the daily dose of the levetiracetam or seletracetam is 190 mg.
57. The method of any one of claims 33-56, wherein the pharmaceutical composition is formulated in one or more of an oral form, an extended-release form, a single-unit-dosage form or a once-a-day form.
58. The method of claim 57, wherein the extended-release form is a controlled release form, a prolonged release form, a sustained release form, a delayed release form, or a slow release form.
59. The method of claim 57 or 58, wherein the extended-release form is a once-a-day extended-release form.
60. The method of any one of claims 33-52, 54, 55 or 57-59, wherein the daily dose of the levetiracetam in the pharmaceutical composition is 220 mg and wherein the pharmaceutical composition further comprises 280 mg-350 mg of hydroxypropyl methylcellulose, 1.2 mg- 1.4 mg of colloidal silicon dioxide, 92.8 mg-119.2 mg of silicified microcrystalline cellulose, and 6.0 mg-6.7 mg of magnesium stearate.
61. The method of claim 60, wherein the pharmaceutical composition comprises 280 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silicon dioxide, 92.8 mg of silicified microcrystalline cellulose, and 6.0 mg of magnesium stearate.
62. The method of claim 60, wherein the pharmaceutical composition comprises 347.5 mg of hydroxypropyl methylcellulose, 1.4 mg of colloidal silicon dioxide, 119.2 mg of silicified microcrystalline cellulose, and 6.7 mg of magnesium stearate.
63. The method of any one of claims 33-52, 54, or 56-59, wherein the daily dose of the levetiracetam in the pharmaceutical composition is 190 mg and wherein the pharmaceutical composition further comprises 300 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silicon dioxide, 102.8 mg of silicified microcrystalline cellulose or anhydrous dicalcium phosphate, and 6 mg of magnesium stearate.
64. The method of any one of claims 60-63, wherein the hydroxypropyl methylcellulose is hypromellose 2208.
65. The method according to any one of claims 60-64, wherein the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90.
66. The method according to any one of claims 33-52 or 54-65, wherein the pharmaceutical composition comprising the levetiracetam, or pharmaceutically acceptable salt thereof, is in a once-a-day extended release form and provides a steady state plasma concentration of levetiracetam in a subject of between 1.9 pg / mL and 4.4 pg / mL within 3 hours after administration and extending for at least 8 hours of a 24-hour period after said administration.
67. The method according to claim 66, wherein the pharmaceutical composition provides a steady state plasma concentration of levetiracetam in a subject of between 1.9 pg / mL and 4.4 pg / mL within 2 hours after said administration and extending for at least 13 hours of a 24-hour period after said administration.
68. The method of claim 66, wherein the pharmaceutical composition provides a steady state plasma concentration of levetiracetam in a subject of between 1.9 pg / mL and 4.4 pg / mL within 1 hour after said administration and extending for at least 13 hours of a 24-hour period after said administration.
69. The method of claim 66, wherein the pharmaceutical composition provides a steady state plasma concentration of levetiracetam in a subject of between 1.9 pg / mL and 4.4 pg / mL within 1 hour after administration and extending for at least 13 to 16 hours of a 24-hour period after said administration.
70. The method of any of claims 33-40, 42-47, or 52-69, wherein the subject displays or presents with cognitive performance within the normal range for the subject’s age.
71. The method of any one of claims 33-70, wherein the subject is a human.