Methods for preventing or slowing the progression of cognitive decline or impairment in a subject

Abstract

Methods for preventing or slowing the progression of cognitive impairment or preventing the onset of or reducing the rate of cognitive decline. Methods for slowing volumetric atrophy or the reduction of subregions of the medial temporal lobe. Methods for slowing volumetric atrophy or the reduction of the entorhinal cortex (ERC). Methods for slowing volumetric atrophy or the reduction of the perirhinal cortex (BA35). The methods include administering to an APOE4 non-carrier subject one or more of levetiracetam, brivaracetam, or seletracetam, or a pharmaceutically acceptable salt thereof, or administering a pharmaceutical composition comprising levetiracetam, brivaracetam, or seletracetam, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Description

[Technical Field]

[0001] Statement of government support The subject matter of this disclosure was made with government support under Grant No. R01AG061091 awarded by the National Institutes of Health (NIH), an agency of the United States Government, and specifically by its Division of the National Institute on Aging (NIA). The United States Government has certain rights in the subject matter of this disclosure.

[0002] Related Applications This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 439,035, filed January 13, 2023, and U.S. Provisional Patent Application No. 63 / 545,348, filed October 23, 2023, each of which is incorporated by reference herein in its entirety.

[0003] Field of Disclosure The present disclosure relates to methods for preventing or slowing the progression of cognitive impairment or preventing the onset or reducing the rate of cognitive decline in subjects who are APOE4 non-carriers (e.g., neither homozygous nor heterozygous for APOE4). In some aspects, the present disclosure relates to methods for reducing the volume, thickness, or slowing the atrophy of a subregion of the medial temporal lobe (e.g., the entorhinal cortex (ERC) or the perirhinal cortex (BA35)), wherein the volume reduction, reduction, or atrophy is characteristic of and a biomarker for the progression of cognitive impairment. In some aspects, the present disclosure relates to methods for reducing the volume, thickness, or rate of atrophy of a subregion of the medial temporal lobe (e.g., the entorhinal cortex (ERC) or the perirhinal cortex (BA35)), wherein the volume reduction, reduction, or atrophy is characteristic of and a biomarker for the progression of cognitive impairment.

[0004] In some aspects of the present disclosure, the APOE4 non-carrier can show or present cognitive performance within the normal range for the age of the subject.In other aspects, the APOE4 non-carrier can show pre-symptomatic cognitive impairment (i.e., show or present cognitive performance somewhat below the normal range for the age of the subject, early mild cognitive impairment (early MCI), mild cognitive impairment, mild cognitive impairment (MCI) due to Alzheimer's disease (AD), prodromal stage AD or amnesic MCI (aMCI).In some aspects of the present disclosure, the APOE4 non-carrier can have the risk of developing or presenting cognitive impairment associated with various other CNS disorders. In some aspects of the present disclosure, the APOE4 non-carrier presents reduced volume, shrinkage or atrophy of medial temporal lobe subregions (such as entorhinal cortex (ERC) or perirhinal cortex (BA35)), and the non-carrier is selected from the group of subjects who present or exhibit subregional volume of the medial temporal lobe that is below normal, and subjects who present or exhibit cognitive performance that is within the normal range for the age of the subject, or in some aspects, slightly below this normal range.The method of the present disclosure comprises administering to the subject one or more of levetiracetam, brivaracetam or seletracetam or their pharmaceutically acceptable salts, or a pharmaceutical composition comprising levetiracetam, brivaracetam or seletracetam or their pharmaceutical salts and a pharmaceutically acceptable carrier.

[0005] In some aspects of the present disclosure, the APOE4 non-carrier has one or more risks that are predicted or associated with the occurrence of cognitive decline or cognitive impairment or the progression of said decline or impairment.Some of these risks are associated with aging.Others are genetic risks that are associated with genomic variants, mutations, or polymorphisms, or associated with changes in the expression of genes associated with cognitive decline or impairment.In some aspects of the present disclosure, the genetic risk factor is not APOE4.In some aspects, the risk is the volume reduction, shrinkage, or atrophy of a subregion of the medial temporal lobe (for example, the entorhinal cortex (ERC) or the perirhinal cortex (BA35)). [Background technology]

[0006] Background to the disclosure Cognitive ability may decline as a normal and inevitable consequence of aging, or may be associated with genomic variations, mutations, or polymorphisms, with the development of cognitive impairment or decline in the context of CNS diseases and disorders (e.g., Alzheimer's disease (AD)), or with changes in the volume, shrinkage, or atrophy of subregions of the medial temporal lobe (e.g., the entorhinal cortex (ERC) or perirhinal cortex (BA35)), associated with changes in hippocampal activity (e.g., hyperactivity). Subjects may exhibit or demonstrate cognitive performance within the normal range for their age, but may still be at risk of developing cognitive impairment or decline.

[0007] Postmortem studies of patients with AD dementia have provided insight into the spatial and temporal progression of AD pathology in the brain, revealing that the formation of neurofibrillary tangles (NFTs) in the early stages of AD pathology occurs in the entorhinal cortex (ERC), specifically in the perirhinal cortex (TEC or BA35), which serves as a transition between the lateral part of the ERC and the perirhinal area (Braak et al., Acta Neuropathologica, 112(4), 389-404 (2006); Braak & Braak, Acta Neuropathologica, 80(5), 479-486 (1990); Kaufman et al., Acta Neuropathologica, 136(1), 57-67 (2018)). Tau accumulation in TECs is also common by age 60, even among cognitively normal older adults (Maass et al., Journal of Neuroscience, 38(3), 530-543 (2018)). Tau pathology then spreads to areas beyond the medial temporal lobe (MTL; Braak et al., 2006), which plays a role in episodic memory function (Dickerson & Eichenbaum, Neuropsychopharmacology, 35(1), Article 1 (2010)). Tau localization and spread co-occur temporally and spatially as neurodegeneration progresses.

[0008] The entorhinal cortex has shown disease-related declines in cortical volume in cross-sectional and longitudinal studies. For example, Fan et al. reported atrophy of the left entorhinal cortex in cognitively normal patients with subjective memory decline (Fan et al., Hum Brain Mapp., 39(6):2549-2562 (2018)). Tran et al. reported significantly reduced volume localized to bilateral subregions of the entorhinal cortex consistent with the TEC in patients with mild cognitive impairment (Tran et al., Neurobiol Aging, 112:151-160 (2022)). Tward et al. reported significant atrophy localized to the perirhinal cortex in patients with mild cognitive impairment, and Kulason et al. showed that changes in the volume and thickness of the entorhinal cortex and TEC could be observed in participants 8–11 and 9–14 years before a diagnosis of mild cognitive impairment was made (Tward et al., Alzheimers Dement (Amst), 14(9):41–50 (2017); Kulason et al. Front Neurosci., 14:804 (2020)).

[0009] Although APOE4 is one of the more prominent genetic risk factors for the occurrence of cognitive decline, including AD, it is neither necessary nor sufficient.Therefore, individuals with one or two copies of APOE4 polymorphism (i.e., APOE4 carriers) may not experience cognitive decline or suffer from AD or other dementia, while individuals who are APOE4 non-carriers may suffer from cognitive decline and its related diseases and disorders.However, the focus of many treatment studies is on APOE4 carriers, that is, the subjects who have one of both APOE4 alleles.

[0010] In fact, there is no FDA-approved treatment for APOE4 non-carriers who exhibit or display cognitive performance within the normal range for their age, but who may be at risk due to aging, shrinkage or atrophy of small areas of the medial temporal lobe (e.g., the entorhinal cortex (ERC) or perirhinal cortex (BA35)), or various genetic risk factors for CNS disorders related to the development or progression of cognitive impairment or cognitive decline. Furthermore, other than amyloid-targeting biologics, there are no treatments that specifically prevent or slow the progression of cognitive impairment or prevent or reduce the rate of cognitive decline in subjects with aMCI or MCI due to AD. Such biologics are also expensive, are administered intravenously, and require careful monitoring for potential side effects, such as cerebral hemorrhage. Therefore, there is a need for effective clinical and therapeutic measures to (1) prevent or slow the progression of cognitive impairment; (2) prevent the occurrence of cognitive decline or reduce its speed; or (3) delay or reduce the volume atrophy or shrinkage of the medial temporal lobe subregion (for example, entorhinal cortex (ERC)) in APOE4 non-carriers who exhibit or present cognitive performance within the normal range for the age of the subject, but may be at risk of developing or progressing to cognitive impairment or cognitive decline, and APOE4 non-carriers who show early stage cognitive impairment and decline (for example, subjects who present symptoms related to early MCI, aMCI or MCI caused by AD, whether or not MCI is related to aging).There is also a need for less expensive and safer therapeutic options for reducing and delaying the progression of such cognitive impairment. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Braak et al., Acta Neuropathologica, 112(4), 389-404 (2006) [Non-patent document 2] Braak & Braak, Acta Neuropathologica, 80(5), 479-486 (1990) [Non-patent document 3] Kaufman et al., Acta Neuropathologica, 136(1), 57-67 (2018) [Non-patent document 4] Maass et al., Journal of Neuroscience, 38(3), 530-543 (2018) [Non-Patent Document 5] Dickerson & Eichenbaum, Neuropsychopharmacology, 35(1), Article 1 (2010) [Non-patent document 6] Fan et al., Hum Brain Mapp., 39(6):2549-2562 (2018) [Non-Patent Document 7] Tran et al., Neurobiol Aging, 112:151-160 (2022) [Non-patent document 8] Tward et al., Alzheimers Dement (Amst), 14(9):41-50 (2017) [Non-Patent Document 9] Kulason et al. Front Neurosci., 14:804 (2020) Summary of the Invention [Means for solving the problem]

[0012] A brief summary of the disclosure The present disclosure relates to methods for preventing or slowing the progression of cognitive impairment or preventing or reducing the rate of cognitive decline in non-APOE4 carriers who exhibit or display cognitive performance within the normal range for the subject's age. In another aspect, the present disclosure relates to methods for preventing or slowing the progression of cognitive impairment or preventing or reducing the rate of cognitive decline in non-APOE4 carriers who exhibit or display cognitive performance below the normal range for the subject's age.

[0013] In other aspects, the APOE4 non-carrier may exhibit pre-symptomatic cognitive impairment, i.e., cognitive performance somewhat below the normal range for the subject's age, early mild cognitive impairment (early MCI), mild cognitive impairment, mild cognitive impairment (MCI) due to Alzheimer's disease (AD), prodromal AD, or amnesic MCI (aMCI). In other aspects, the present disclosure relates to methods for preventing or slowing the progression of cognitive impairment, or preventing or reducing the rate of cognitive decline, in APOE4 non-carriers at risk of developing or exhibiting cognitive impairment associated with various other CNS disorders. In another aspect, the present disclosure relates to a method for slowing or reducing the rate of volume atrophy or shrinkage of subregions of the medial temporal lobe in non-APOE4 carrier subjects selected from the group of subjects who exhibit or present a volume in a subregion of the medial temporal lobe that is below normal, and subjects who exhibit or present cognitive performance that is within, or in some aspects somewhat below, the normal range for the age of the subject.In another aspect, the present disclosure relates to a method for slowing or reducing the rate of volume atrophy or shrinkage of the entorhinal cortex in non-APOE4 carrier subjects.The method comprises administering to the subject one or more of levetiracetam, brivaracetam, or seletracetam, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising levetiracetam, brivaracetam, or seletracetam, or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier. In some embodiments of the present disclosure, the method includes administering to the subject levetiracetam or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0014] In some aspects of the present disclosure, the APOE4 non-carrier exhibits one or more risk factors that predict or are associated with the occurrence of cognitive decline or cognitive impairment or the progression of said decline or impairment.Some of these risks are associated with aging.Others are genetic risks that are associated with genomic variants, mutations, or polymorphisms, or are associated with changes in the expression of genes associated with cognitive decline or impairment.In some aspects of the present disclosure, the inherited risk factor is not APOE4.In some aspects, the risk is the volume reduction, shrinkage, or atrophy of a subregion of the medial temporal lobe (for example, the entorhinal cortex (ERC) or the perirhinal cortex (BA35)).

[0015] In some embodiments, the disclosed method includes administering to the subject one or more of levetiracetam, brivaracetam, or seletracetam, or a pharmaceutically acceptable salt thereof, at a daily dose of 0.7 to 350 mg. In other aspects, the disclosed method includes administering to the subject a pharmaceutical composition comprising one or more of levetiracetam, brivaracetam, or seletracetam, or a pharmaceutically acceptable salt thereof, at a daily dose of 0.7 to 350 mg, and a pharmaceutically acceptable carrier. In some embodiments, the disclosed method includes administering to the subject levetiracetam or a pharmaceutically acceptable salt thereof, at a daily dose of 0.7 to 350 mg.

[0016] In some embodiments, the daily dose of levetiracetam or seletracetam, or a pharmaceutically acceptable salt thereof, by itself or as part of a pharmaceutical composition, is 7 to 350 mg. In some embodiments, the daily dose of brivaracetam or a pharmaceutically acceptable salt thereof, by itself or as part of a pharmaceutical composition, is 0.7 to 180 mg. In other embodiments, the daily dose of levetiracetam or seletracetam, or a pharmaceutically acceptable salt thereof, by itself or as part of a pharmaceutical composition, is 125 to 250 mg. In some embodiments, the daily dose of levetiracetam or seletracetam, or a pharmaceutically acceptable salt thereof, by itself or as part of a pharmaceutical composition, is 220 mg. In some embodiments, the daily dose of levetiracetam or seletracetam, or a pharmaceutically acceptable salt thereof, by itself or as part of a pharmaceutical composition, is 190 mg.

[0017] In some embodiments, the levetiracetam, brivaracetam, or seletracetam, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition comprising one or more thereof, is formulated into one or more of an oral form, a sustained-release form, a single-unit dosage form, or a once-daily dosage form. In some embodiments, the sustained-release form is a controlled-release form, a long-term release form, a sustained-release form, a delayed-release form, or a slow-release form. In some aspects of the present disclosure, the sustained-release form, the single-unit dosage form, and the once-daily form are for oral administration. In some embodiments, the levetiracetam, brivaracetam, or seletracetam, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition comprising one or more thereof, is administered once a day. In some embodiments, the levetiracetam, brivaracetam or seletracetam, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition comprising one or more thereof, is administered twice daily.

[0018] In some embodiments of the present disclosure, the method comprises administering to the APOE4 non-carrier an oral, single-daily dosage form of a pharmaceutical sustained-release composition comprising 220 mg of levetiracetam or a pharmaceutically acceptable salt thereof, 280 mg to 350 mg of hydroxypropyl methylcellulose, 1.2 mg to 1.4 mg of colloidal silicon dioxide, 92.8 mg to 119.2 mg of silicified microcrystalline cellulose, and 6.0 mg to 6.7 mg of magnesium stearate. In other embodiments, the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof in the pharmaceutical sustained-release composition is 220 mg, and the pharmaceutical composition further 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. In another embodiment, the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is 220 mg in the pharmaceutical sustained-release composition, which further 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. In another embodiment of the sustained-release composition useful in the method of the present disclosure, the hydroxypropyl methylcellulose is hypromellose 2208. In another embodiment, the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90.

[0019] In some embodiments of the present disclosure, the method comprises administering to the APOE4 non-carrier an oral daily, in some embodiments, once-daily, single-use dosage form of a pharmaceutical sustained-release composition comprising 220 mg of levetiracetam, 280 mg to 350 mg of hydroxypropyl methylcellulose, 1.2 mg to 1.4 mg of colloidal silicon dioxide, 92.8 mg to 119.2 mg of silicified microcrystalline cellulose, and 6.0 mg to 6.7 mg of magnesium stearate. In other embodiments, the daily or once-daily dose of levetiracetam in the pharmaceutical sustained-release composition is 220 mg, and the pharmaceutical composition further 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. In another embodiment, the daily or once-daily dose of levetiracetam in the pharmaceutical sustained-release composition is 220 mg, and the pharmaceutical composition further 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. In another embodiment of the sustained-release composition useful in the methods of the present disclosure, the hydroxypropyl methylcellulose is hypromellose 2208. In another embodiment, the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90.

[0020] In some embodiments of the present disclosure, the method comprises administering to the subject a daily dose of a pharmaceutical composition comprising 190 mg of levetiracetam, 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. In other embodiments, the hydroxypropyl methylcellulose is hypromellose 2208. In other embodiments, the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90.

[0021] In some embodiments of the present disclosure, the method comprises administering to the subject a daily or once-daily dose of a pharmaceutical composition comprising 190 mg of levetiracetam, 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. In other embodiments, the hydroxypropyl methylcellulose is hypromellose 2208. In other embodiments, the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90.

[0022] In some embodiments of the present disclosure, the method comprises administering a pharmaceutical composition comprising an oral, single-use daily dosage form of a sustained-release composition comprising levetiracetam or a pharmaceutically acceptable salt thereof, wherein the administration provides, in the APOE4 non-carrier, a steady-state plasma concentration of levetiracetam between 1.9 μg / mL and 4.4 μg / mL within 3 hours after administration and a sustained concentration of at least 8 hours within a 24-hour period after the administration. In some embodiments of the present disclosure, the method comprises administering a pharmaceutical composition comprising an oral, single-use daily dosage form of a sustained-release composition comprising levetiracetam or a pharmaceutically acceptable salt thereof, wherein the administration provides, in the APOE4 non-carrier, a steady-state plasma concentration of levetiracetam between 1.9 μg / mL and 4.4 μg / mL within 3 hours after administration and a sustained concentration of at least 8 hours within a 24-hour period after the administration. In some embodiments of the present disclosure, the method comprises administering a pharmaceutical composition comprising an oral, once-daily, single-use dosage form of a sustained-release composition comprising levetiracetam, wherein the administration provides, in the APOE4 non-carrier, a steady-state plasma concentration of levetiracetam between 1.9 μg / mL and 4.4 μg / mL within 3 hours of administration and a duration of at least 8 hours within a 24-hour period after administration. In some embodiments, the pharmaceutical sustained-release composition provides, in the APOE4 non-carrier, a steady-state plasma concentration of levetiracetam between 1.9 μg / mL and 4.4 μg / mL within 2 hours of administration and a duration of at least 13 hours within a 24-hour period after administration. In some embodiments, the pharmaceutical sustained-release composition provides, in the APOE4 non-carrier, a steady-state plasma concentration of levetiracetam between 1.9 μg / mL and 4.4 μg / mL within 1 hour of administration and a duration of at least 13 hours within a 24-hour period after administration.In other embodiments, the pharmaceutical sustained release composition provides a steady-state plasma concentration of levetiracetam of between 1.9 μg / mL and 4.4 μg / mL within 1 hour post-administration and a duration of at least 13-16 hours within a 24 hour period post-administration in the APOE4 non-carrier (see FIG. 2 and WO2016191288, which is incorporated by reference in its entirety).

[0023] In some embodiments of the present disclosure, the APOE4 non-carrier to be treated is at risk of developing cognitive decline or cognitive impairment, and the risk is associated with aging.In some embodiments, the risk is associated with the reduction or shrinkage of the volume of the medial temporal lobe subregion (for example, the entorhinal cortex (ERC) or the perirhinal cortex (BA35)).In other aspects, the present disclosure relates to a method for preventing or slowing the progression of cognitive impairment, or preventing or reducing the rate of cognitive decline in APOE4 non-carriers who exhibit or display cognitive performance below the normal range for the age of the subject.In some embodiments of the present disclosure, the APOE4 non-carrier may display pre-symptomatic mild cognitive impairment, i.e., exhibit or display cognitive performance somewhat below the normal range for the age of the subject. In another aspect, the present disclosure relates to a method for slowing or reducing the volumetric atrophy or shrinkage of subregions of the medial temporal lobe (for example, entorhinal cortex (ERC) or perirhinal cortex (BA35)) in APOE4 non-carrier subjects, wherein the APOE4 non-carrier subjects are selected from the group of subjects who show or exhibit smaller than normal volumes in subregions of the medial temporal lobe, and subjects who show or exhibit cognitive performance that is within the normal range for the age of the subject, or in some aspects, slightly below this range. In another aspect, the present disclosure relates to a method for slowing or reducing the volumetric atrophy of the entorhinal cortex (ERC) in APOE4 non-carrier subjects. In some embodiments of the present disclosure, the APOE4 non-carrier to be treated is at risk of developing volumetric atrophy of subregions of the medial temporal lobe (for example, entorhinal cortex (ERC) or perirhinal cortex (BA35)). In some embodiments of the present disclosure, the APOE4 non-carrier to be treated is at risk of developing the volume atrophy of the entorhinal cortex (ERC).In some embodiments of the present disclosure, the APOE4 non-carrier to be treated is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with genomic variants, mutations or polymorphisms, or associated with the altered expression of genes associated with cognitive decline or impairment.In some embodiments of the present disclosure, the APOE4 non-carrier to be treated is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with early MCI. In some embodiments of the present disclosure, the APOE4 non-carrier to be treated is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with aMCI. In some embodiments of the present disclosure, the APOE4 non-carrier to be treated is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with MCI. In some embodiments of the present disclosure, the APOE4 non-carrier to be treated is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with MCI due to Alzheimer's disease (AD) or prodromal stage AD.

[0024] One aspect of the present disclosure relates to the use of levetiracetam, brivaracetam or seletracetam, or a pharmaceutical composition of any of them, in the manufacture of a medicament for preventing or slowing the progression of cognitive impairment or preventing the onset of or reducing the rate of cognitive decline in APOE4 non-carriers who have pre-symptomatic cognitive impairment, i.e., who demonstrate or exhibit cognitive performance somewhat below the normal range for the subject's age. In another aspect, the present disclosure relates to the use of one or more of levetiracetam, brivaracetam or seletracetam or a pharmaceutical composition of any of them in the manufacture of a medicament for slowing or reducing the rate of volumetric atrophy of a medial temporal lobe subregion (e.g., the entorhinal cortex (ERC) or perirhinal cortex (BA35)) in an APOE4 non-carrier subject, wherein the non-APOE4 non-carrier subject is selected from the group of subjects who exhibit or display a smaller than normal volume in a medial temporal lobe subregion, and subjects who exhibit or display cognitive performance that is within, or in some aspects somewhat below, the normal range for the subject's age. In another aspect, the present disclosure relates to the use of one or more of levetiracetam, brivaracetam or seletracetam, or a pharmaceutical composition of any of them, in the manufacture of a medicament for slowing or reducing the rate of volumetric atrophy or reduction of the entorhinal cortex (ERC) in an APOE4 non-carrier subject.

[0025] In some embodiments, as described above, the APOE4 non-carrier is at risk of developing cognitive impairment or decline, or the progression of said impairment or decline. In some embodiments, as described above, the APOE4 non-carrier is at risk of developing cognitive decline as a necessary consequence of the progression of volumetric atrophy of a subregion of the medial temporal lobe (e.g., the entorhinal cortex (ERC) or the perirhinal cortex (BA35)). In some embodiments, as described above, the APOE4 non-carrier is at risk of developing volumetric atrophy of the entorhinal cortex (ERC). In some embodiments of the present disclosure, the APOE4 non-carrier to be treated is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with genomic variants, mutations, or polymorphisms, or is associated with changes in the expression of genes associated with cognitive decline or impairment. In some embodiments of the present disclosure, as described above, the risk is associated with one or more of early MCI, MCI, aMCI, AD, prodromal AD, or MCI due to other CNS disorders.

[0026] In other embodiments, the present disclosure relates to the use of levetiracetam, brivaracetam or seletracetam, or a pharmaceutical composition of any of them, to prevent or slow the progression of cognitive impairment or prevent the occurrence of or reduce the rate of cognitive decline in said APOE4 non-carriers who show or exhibit cognitive performance within the normal range for the subject's age. In another aspect, the present disclosure relates to the use of levetiracetam, brivaracetam or seletracetam or any of their pharmaceutical compositions for slowing or reducing the volumetric atrophy or shrinkage of subregions of the medial temporal lobe (for example, entorhinal cortex (ERC) or perirhinal cortex (BA35)) in APOE4 non-carrier subjects, wherein the APOE4 non-carrier subjects are selected from subjects who show or exhibit subregions of the medial temporal lobe that are below normal, and subjects who show or exhibit cognitive performance that is within the normal range for the age of the subject, or in some aspects, slightly below this range.In another aspect, the present disclosure relates to the use of one or more of levetiracetam, brivaracetam or seletracetam or any of their pharmaceutical compositions for slowing or reducing the volumetric atrophy of entorhinal cortex (ERC) in APOE4 non-carrier subjects. In some embodiments, as described above, the APOE4 non-carrier is at risk of developing cognitive impairment or decline, or the progression of said impairment or decline. In some embodiments, the APOE4 non-carrier is at risk of developing cognitive decline or cognitive impairment, wherein said risk is associated with the progression of volumetric atrophy of a subregion of the medial temporal lobe (for example, the entorhinal cortex (ERC) or the perirhinal cortex (BA35)). In some embodiments, as described above, the APOE4 non-carrier is at risk of developing volumetric atrophy of the entorhinal cortex (ERC). In some embodiments of the present disclosure, the APOE4 non-carrier to be treated is at risk of developing cognitive decline or cognitive impairment, wherein said risk is associated with genomic variants, mutations, or polymorphisms, or associated with changes in the expression of genes associated with cognitive decline or impairment.In some embodiments, as described above, the APOE4 non-carrier is at risk of developing cognitive impairment or decline, or the progression of said impairment or decline.In some embodiments of the present disclosure, as described above, said risk is associated with one or more of early MCI, MCI, aMCI, AD, prodromal AD or MCI caused by other CNS disorders. [Brief explanation of the drawings]

[0027] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] Figure 1 depicts plasma concentrations of levetiracetam effective for treating cognitive impairment based on aged-impaired rat studies and a Phase II study in patients with aMCI. In one aspect of the present disclosure, the effective plasma concentration is between 1.9 and 4.4 μg / mL. In another aspect, the effective plasma concentration is between 2.9 and 4.4 μg / mL. In another aspect, the effective plasma concentration is between 1.9 and 3.9 μg / mL.

[0028] [Figure 2] Figure 2 shows steady-state modeling of the PK profile of 190 mg tablet A from Table 1, demonstrating that this tablet provides plasma concentrations of levetiracetam between 1.9 and 4.4 μg / mL.

[0029] [Figure 3] Figure 3 shows steady-state modeling of the PK profile of 220 mg tablet D from Table 2, demonstrating that this tablet provides plasma concentrations of levetiracetam between 2.9 and 4.4 μg / mL.

[0030] [Figure 4] FIG. 4 is a flow diagram of one embodiment of a process for manufacturing sustained release compositions of levetiracetam (eg, the 190 mg and 220 mg tablets listed in Tables 1 and 2).

[0031] [Figure 5]Figure 5 provides the study design for a multicenter, randomized, double-blind, placebo-controlled, 78-week, fixed-dose study evaluating low-dose levetiracetam, 220 mg, extended-release tablets versus placebo as a treatment for slowing the progression of mild cognitive impairment (MCI) due to Alzheimer's disease (AD).

[0032] [Figure 6] Figure 6 provides a graphical representation of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) results over 78 weeks. CDR-SB scores were obtained at baseline, 26 weeks, 52 weeks, and 78 weeks after levetiracetam (LEV) or placebo treatment, including differences between the two groups over time.

[0033] [Figure 7] Figure 7 provides a graphical representation of the results of Functional Activities Questionnaire (FAQ) scores over 78 weeks. CDR-SB scores were obtained at baseline, 26 weeks, 52 weeks, and 78 weeks after levetiracetam (LEV) or placebo treatment, including differences between the two groups over time.

[0034] [Figure 8] FIG. 8 provides a graphical representation of entorhinal cortex (ERC) volume at baseline and change in ERC volume after 78 weeks of levetiracetam (LEV) or placebo administration to APOE4 non-carriers.

[0035] [Figure 9] FIG. 9 provides a graphical representation of Brodmann area 35 (BA35) volume at baseline and the change in BA35 volume after 78 weeks of levetiracetam (LEV) or placebo administration to APOE4 non-carriers. DETAILED DESCRIPTION OF THE INVENTION

[0036] Detailed Description of Disclosure Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature used in connection with and techniques of cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art. See, e.g., "Principles of Neural Science," McGraw-Hill Medical, New York, NY (2000); Motulsky, "Intuitive Biostatistics," Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th Edition," W.H. Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th Edition," W.H. Freeman & Co., NY (1999); Gilbert et al., "Developmental Biology, 6th Edition," Sinauer Associates, Inc., Sunderland, MA (2000).

[0037] Chemical terms used herein are used in accordance with conventional usage in the art, as exemplified by "The McGraw-Hill Dictionary of Chemical Terms," ​​Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0038] All publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference in their entirety. In case of conflict, the present specification, including specific definitions thereof, will control.

[0039] Throughout this specification, the wording "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer (or component) or group of integers (or components), but not the exclusion of any other integer (or component) or group of integers (or components).

[0040] The singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0041] "Including" is used to mean "including but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0042] "Patient," "subject," or "individual" are used interchangeably and refer to either a human or a non-human animal. Patients, subjects, or individuals can include mammals, such as humans, primates, livestock (including cows, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats). In some embodiments, the patient, subject, or individual is human.

[0043] "Preventing" the onset or progression of cognitive decline or impairment refers to affecting cognitive performance so that cognitive performance does not decline or fall below that observed in the subject at first presentation or diagnosis, or slowing such decline in performance.

[0044] "Slowing" the onset or progression of cognitive decline refers to slowing the progression of cognitive decline in a subject, which can be determined by a physician using a known assessment of cognition or function (e.g., the AD Composite Score (ADCOMS), the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the Alzheimer's Disease Cooperative Study-Activities of Daily Living-MCI (ADCS-ADL-MCI) or one or more of the assessments mentioned below), or by comparison with an untreated population.

[0045] "Cognitive impairment" or "cognitive decline" refers to cognitive performance in a subject that is less robust than the normal range expected in a subject of similar age. In some cases, cognitive performance is reduced by about 5%, about 10%, about 30%, or more compared to the normal range of cognitive performance expected in a subject of similar age. In some cases, "cognitive impairment" in a subject can refer to cognitive performance in a subject that is less robust than the normal range expected in age-matched subjects, or the performance of a young adult subject (e.g., a subject who has an average score for a given age on a test of cognitive performance).

[0046] "Pre-MCI" or "pre-clinical MCI" refers to a subject who exhibits features of MCI on clinical examination but lacks impairment on neuropsychological testing. Subjects may exhibit biomarkers other than APOE4 that identify risk of progression.

[0047] An "APOE4 carrier" or "APOE4 positive subject" refers to a subject who has one or both copies of the apolipoprotein E4 (APOE4) allele. APOE is a protein involved in fat metabolism in the mammalian body and is polymorphic. There are three major alleles: APOE2, APOE3, and APOE4; 25% of the general population has one copy of the APOE4 allele, and 2-3% has both alleles. APOE4 carriers can be identified by a variety of methods, including restriction fragment length polymorphism identification (RFLPI) of genomic DNA (see, e.g., Dai, S., Long, Y. (2015). In: Batley, J. (eds) Plant Genotyping. Methods in Molecular Biology, vol 1245. Humana Press, New York, NY.), random amplified polymorphism detection (RAPD) of genomic DNA (see, e.g., Williams JG, Kubelik AR, Livak KJ, Rafalski JA, Tingey SV. Nucleic Acids Res. 1990 Nov 25;18(22):6531-5), amplified fragment length polymorphism detection (AFLPD) (see, e.g., Paun O, Schoenswetter P. Methods Mol Biol. 2012;862:75-87), and polymerase chain reaction (PCR) (see, e.g., Waters DL, Shapter FM. Methods Mol Biol. 2014;1099:65-75), DNA sequencing, allele-specific oligonucleotide (ASO) probes (see, e.g., Stavljenic-Rukavina A, Sertic J, Salzer B, Dumic M, Radica A, Fumic K, Krajina A. Clin Chim Acta. 1993 Jul 16;216(1-2):191-8), and hybridization to DNA microarrays or beads.An "APOE4 non-carrier" or "APOE negative subject" refers to a subject who does not have an APOE4 allele. An APOE4 non-carrier may be a carrier of other polymorphisms of APOE in their genome, including, but not limited to, APOE2 or APOE3.

[0048] "Cognitive performance" refers to a measurable cognitive behavior or ability in a subject. Various art-recognized tests for assessing cognitive performance in humans, including, but not limited to, the Clinical Global Impression of Change Scale (CIBIC-Plus Scale); Mini-Mental State Examination (MMSE); Neuropsychiatric Inventory (NPI); Clinical Dementia Rating Scale (CDR); Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB); Cambridge Neuropsychological Test Automated Battery (CANTAB); Sandoz Clinical Assessment-Geriatric (SCAG), Buschke Selective Reminding Test (Buschke and Fuld, 1974); Verbal Paired Associates subtest; Logical Memory subtest; Visual Reproduction subtest of the Wechsler Memory Scale-Revised The Workplace Mental Health Scale-Revised (WMS-R) (Wechsler, 1997); the Benton Visual Retention Test; or the MATRICS Consensus Neuropsychological Test Battery, which includes tests of working memory, processing speed, attention, verbal learning, visual learning, reasoning, and problem-solving and social cognition.Folstein et al., J Psychiatric Res 12: 189-98, (1975); Robbins et al., Dementia 5: 266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168-79, (1999); See Marquis et al., 2002 and Masur et al., 1994. See also Buchanan, RW, Keefe, RSE, Umbricht, D., Green, MF, Laughren, T., and Marder, SR (2011), The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later? Schizophr. Bull. 37, 1209-1217. Another example of a cognitive test in humans is the explicit 3-alternative forced choice task. In this test, subjects are presented with color photographs of common objects consisting of three types of image pairs: similar pairs, identical pairs, and a mixture of unrelated foils. The second of the similar object pairs is called the "lure." These image pairs are completely randomized and presented individually as a series of images. Subjects are instructed to determine whether the perceived object is new, old, or similar. A "similar" response to presentation of the lure stimulus indicates successful memory retrieval by the subject. In contrast, calling the lure stimulus "old" or "new" indicates that accurate memory retrieval did not occur.

[0049] In addition to assessing cognitive performance, the progression of cognitive impairment and dementia can be monitored by assessing surrogate changes in the subject's brain. Surrogate changes include, but are not limited to, changes in regional brain volume, perforant path degeneration, and changes in brain function observed through resting-state functional magnetic resonance imaging (R-fMRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), fluorodeoxyglucose positron emission tomography (FDG-PET), or any other imaging technique that allows for the measurement of brain function. Examples of regional brain volumes useful for monitoring the progression of cognitive impairment and dementia include a decrease in hippocampal volume and a decrease in the volume or thickness of the entorhinal cortex. These volumes can be measured in subjects, for example, by MRI. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010). Perforant path degeneration has been found to be associated with age and reduced cognitive performance. For example, older adults with more perforant path degeneration tend to perform worse in hippocampal-dependent memory tests. Perforant path degeneration can be monitored in subjects through ultra-high-resolution diffusion tensor imaging (DTI). Yassa et al., PNAS 107:12687-12691 (2010). Resting-state fMRI (R-fMRI) involves imaging the brain while at rest and recording large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in the fMRI signal that are temporally correlated across functionally relevant regions. Seed-based functional connectivity, independent component analysis, and / or frequency domain analysis of the signal are used to reveal functional connectivity between brain regions, particularly those regions whose connectivity increases or decreases with age, and the degree of cognitive impairment and / or dementia. FDG-PET uses FDG uptake as a measure of regional metabolic activity in the brain. Decreased FDG uptake in areas such as the posterior cingulated cortex, temporoparietal cortex, and frontal association cortex has been shown to be associated with cognitive decline and severity of dementia.Aisen et al., Alzheimer's & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 (2002).

[0050] "Pharmaceutically acceptable salt" Examples of "salts" include, but are not limited to, water soluble and water insoluble salts (e.g., acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, ethanesulfonate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, Sethionate, Lactate, Lactobionate, Laurate, Magnesium, Malate, Maleate, Mandelate, Mesylate, Methyl Bromide, Methyl Nitrate, Methyl Sulfate, Mucate, Napsylate, Nitrate, N-Methylglucamine Ammonium Salt, 3-Hydroxy-2-naphthoate, Oleate, Oxalate, Palmitate, Pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate) thoate, einbonate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0051] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. A "pharmaceutically acceptable acid addition salt" is a salt that retains the biological effectiveness and properties of its free base, which is not biologically or otherwise undesirable, and is a salt of an acid selected from the group consisting of inorganic acids (e.g., hydrohalic acids, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (e.g., acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, and the like). acid), gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydroxyacetic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0052] Conversely, said salt forms can be converted into the free base by treatment with an appropriate base or acid.

[0053] Compositions and medicaments useful in the methods of the present disclosure The compositions and medicaments useful in the methods and uses of the present disclosure are characterized by one or more of levetiracetam, brivaracetam, or seletracetam, or pharmaceutically acceptable salts thereof. In some embodiments, the compositions and medicaments are characterized by levetiracetam or a pharmaceutically acceptable salt thereof.

[0054] Levetiracetam refers to the compound (2S)-2-(2-oxopyrrolidin-1-yl)butanamide (International Union of Pure and Applied Chemistry (IUPAC) name). Levetiracetam is a widely used antiepileptic drug. It has also been shown to directly inhibit synaptic activity and neurotransmission by binding to a specific site in the CNS: synaptic vesicle protein 2A (SV2A) (see, for example, Noyer et al. 1995; Fuks et al. 2003; Lynch et al. 2004; Gillard et al. 2006), thereby inhibiting presynaptic neurotransmitter release (Yang et al., 2007). Levetiracetam is sold as Keppra®, an FDA-approved antiepileptic drug. Typically, therapeutically effective doses of levetiracetam (Keppra®) are in the range of 1000-3000 mg / day.

[0055] Levetiracetam is rapidly and almost completely absorbed after oral administration, and its bioavailability is not affected by food. The plasma half-life of levetiracetam is approximately 7 ± 1 hour (predicted to be 9-10 hours in elderly patients due to decreased renal function). Absorption is rapid, with peak plasma concentrations occurring approximately 1 hour after oral administration. Steady state can be achieved after 2 consecutive days of twice-daily dosing.

[0056] A typical starting dose of levetiracetam for treating epilepsy in humans is 500 mg twice daily, after which the dosage is increased to 3000 mg daily until optimal efficacy is achieved.

[0057] Brivaracetam refers to the compound (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide (IUPAC name). It has anticonvulsant activity and binds to SV2A in the brain. It is approved under the name Briviact®. A typical starting dose is 50 mg orally twice daily, and the maintenance dose is 25-100 mg orally twice daily.

[0058] Seletracetam refers to the compound (2S)-2-[(4S)-4-(2,2-difluoroethenyl)-2-oxopyrrolidin-1-yl]butanamide (IUPAC name). It is an antiepileptic drug that binds to SV2A in the brain.

[0059] In some embodiments, the administration interval of the levetiracetam, brivaracetam, or seletracetam, or their pharmaceutically acceptable salts, or the pharmaceutical composition comprising any of the above, is once every 12 hours (twice a day) or once every 24 hours (once a day).In some embodiments, once a day administration is used.Administration at shorter intervals (for example, once every 6 hours) may also be used.

[0060] In some embodiments, the levetiracetam or a pharmaceutically acceptable salt thereof, by itself or as part of a pharmaceutical composition, is administered in a daily dose of 70 mg to 140 mg, or 7 mg to 180 mg, or 25 mg to 180 mg, or 40 mg to 130 mg, or 140 mg to 300 mg, or 200 mg to 300 mg, or 140 mg to 200 mg, or 7 mg to 350 mg, 70 mg to 350 mg, 100 mg to 300 mg, or 125 mg to 250 mg. In some embodiments, the levetiracetam or a pharmaceutically acceptable salt thereof, by itself or as part of a pharmaceutical composition, is administered in a daily dose of 190 mg to 220 mg. In some embodiments, the levetiracetam or a pharmaceutically acceptable salt thereof, by itself or as part of a pharmaceutical composition, is administered in a daily dose of 190 mg to 240 mg. In some embodiments, the levetiracetam or a pharmaceutically acceptable salt thereof, by itself or as part of a pharmaceutical composition, is administered in a daily dose of 220 mg. In some embodiments, the levetiracetam or a pharmaceutically acceptable salt thereof, by itself or as part of a pharmaceutical composition, is administered in a daily dose of 190 mg.

[0061] In some embodiments of the method of the present disclosure, the levetiracetam or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising levetiracetam or a pharmaceutically acceptable salt thereof, is administered in an oral form, a sustained release form (e.g., a controlled release form, an extended release form, a sustained release form, a delayed release form, or a slow release form), or a unit dosage form or a form for once-daily administration. In some embodiments, the pharmaceutical sustained release composition is in the form of a tablet or capsule. In some embodiments, the levetiracetam or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising levetiracetam or a pharmaceutically acceptable salt thereof, is administered once or twice a day. In some embodiments, the levetiracetam or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising levetiracetam or a pharmaceutically acceptable salt thereof, is administered once a day. In some embodiments, the levetiracetam or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising levetiracetam or a pharmaceutically acceptable salt thereof, is administered once a day. In some embodiments, the administration is in an oral single unit dose, sustained-release form. In some embodiments, the pharmaceutical sustained-release composition of levetiracetam or a pharmaceutically acceptable salt thereof is in solid form.

[0062] In some embodiments of the present disclosure, the brivaracetam or a pharmaceutically acceptable salt thereof, by itself or as part of a pharmaceutical composition, is administered in a daily dose of 7 to 15 mg, or 0.7 to 180 mg, or 2.5 to 180 mg, or 4.0 to 130 mg, or 14 to 30 mg. In other embodiments, the brivaracetam or a pharmaceutically acceptable salt thereof, by itself or as part of a pharmaceutical composition, is administered in a daily dose of 0.7 to 50 mg, 0.7 to 75 mg, 0.7 to 100 mg, 0.7 to 150 mg, 0.7 to 180 mg, 1.8 to 50 mg, 1.8 to 75 mg, 1.8 to 100 mg, 1.8 to 150 mg, 1.8 to 180 mg, 3.5 to 50 mg, 3.5 to 75 mg, 3.5 to 100 mg, 3.5 to 1 It is administered in daily doses of 50 mg, 3.5 to 180 mg, 5 to 50 mg, 5 to 75 mg, 5 to 100 mg, 5 to 150 mg, 5 to 180 mg, 7 to 50 mg, 7 to 75 mg, 7 to 100 mg, 7 to 150 mg, 7 to 180 mg, 15 to 50 mg, 15 to 75 mg, 15 to 100 mg, 15 to 150 mg, 15 to 180 mg, 35 to 50 mg, 35 to 75 mg, 35 to 100 mg, 35 to 150 mg, and 35 to 180 mg.

[0063] In some embodiments, the brivaracetam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising brivaracetam or a pharmaceutically acceptable salt thereof, is administered in an oral form, a sustained-release form (e.g., a controlled-release form, a long-term release form, a sustained-release form, a delayed-release form, or a slow-release form), or in a unit dosage form or a form for once-daily administration. In some embodiments, the pharmaceutical sustained-release composition is in the form of a tablet or capsule. In some embodiments, the brivaracetam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising brivaracetam or a pharmaceutically acceptable salt thereof, is administered once or twice daily. In some embodiments, the brivaracetam or a pharmaceutical composition thereof is administered once daily in a single-use sustained-release form. In some embodiments, the pharmaceutical sustained-release composition is in a solid form. In some embodiments, the pharmaceutical sustained-release composition is in the form of a tablet or capsule. In some embodiments, the brivaracetam or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising brivaracetam or its pharmaceutically acceptable salt, is administered once a day. In some embodiments, the brivaracetam or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising brivaracetam or its pharmaceutically acceptable salt, is administered once a day. In some embodiments, the administration is in an oral single-unit sustained-release form. In some embodiments, the pharmaceutical sustained-release composition of brivaracetam or its pharmaceutically acceptable salt is in solid form.

[0064] In some embodiments, the seletracetam or a pharmaceutically acceptable salt thereof, by itself or as part of a pharmaceutical composition, is administered in a daily dose of 70 mg to 140 mg, or 7 mg to 180 mg, or 25 mg to 180 mg, or 40 mg to 130 mg, or 140 mg to 300 mg, or 200 mg to 300 mg, or 140 mg to 200 mg, or 7 mg to 350 mg, 70 mg to 350 mg, 100 mg to 300 mg, or 125 mg to 250 mg. In some embodiments, the seletracetam or a pharmaceutically acceptable salt thereof, by itself or as part of a pharmaceutical composition, is administered in a daily dose of 190 mg to 220 mg. In some embodiments, the seletracetam or a pharmaceutically acceptable salt thereof, by itself or as part of a pharmaceutical composition, is administered in a daily dose of 190 mg to 240 mg. In some embodiments, the seletracetam or a pharmaceutically acceptable salt thereof is administered by itself or as part of a pharmaceutical composition at a daily dose of 220 mg. In some embodiments, the seletracetam or a pharmaceutically acceptable salt thereof is administered by itself or as part of a pharmaceutical composition at a daily dose of 190 mg.

[0065] In some embodiments of the method of the present disclosure, the seletracetam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising seletracetam or a pharmaceutically acceptable salt thereof, is administered in an oral form, a sustained-release form (e.g., a controlled-release form, a long-term release form, a sustained-release form, a delayed-release form, or a slow-release form), or in a unit dosage form or a form for once-daily administration. In some embodiments, the pharmaceutical sustained-release composition is in the form of a tablet or capsule. In some embodiments, the seletracetam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising seletracetam or a pharmaceutically acceptable salt thereof, is administered once or twice a day. In some embodiments, the seletracetam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising seletracetam or a pharmaceutically acceptable salt thereof, is administered once a day. In some embodiments, the seletracetam or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising seletracetam or its pharmaceutically acceptable salt, is administered once a day.In some embodiments, the administration is in an oral single-unit sustained-release form.In some embodiments, the pharmaceutical sustained-release composition of seletracetam or its pharmaceutically acceptable salt is in solid form.

[0066] In some embodiments of the methods and uses of the present disclosure, the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 220 mg, and the pharmaceutical composition further comprises 280 mg to 350 mg of hydroxypropyl methylcellulose, 1.2 mg to 1.4 mg of colloidal silicon dioxide, 92.8 mg to 119.2 mg of silicified microcrystalline cellulose, and 6.0 mg to 6.7 mg of magnesium stearate. In other embodiments, the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 220 mg, and the pharmaceutical composition further 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. In other embodiments, the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 220 mg, and the pharmaceutical composition further 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. In some embodiments, the hydroxypropyl methylcellulose is hypromellose 2208. In some embodiments, the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90. In some embodiments, the composition is in a unit dosage form for once-daily administration. In some embodiments, the composition is in an oral sustained-release form. In some embodiments, the pharmaceutical sustained-release composition is in a solid form. In some embodiments, the pharmaceutical sustained-release composition is in the form of a tablet or capsule. In some embodiments, the oral sustained-release form is 220 mg in a unit dosage form for once-daily administration.

[0067] In some embodiments of the methods and uses of the present disclosure, the daily dose of levetiracetam in the pharmaceutical composition is 220 mg, and the pharmaceutical composition further comprises 280 mg to 350 mg of hydroxypropyl methylcellulose, 1.2 mg to 1.4 mg of colloidal silicon dioxide, 92.8 mg to 119.2 mg of silicified microcrystalline cellulose, and 6.0 mg to 6.7 mg of magnesium stearate. In other embodiments, the daily dose of levetiracetam in the pharmaceutical composition is 220 mg, and the pharmaceutical composition further 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. In other embodiments, the daily dose of levetiracetam in the pharmaceutical composition is 220 mg, and the pharmaceutical composition further 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. In some embodiments, the hydroxypropyl methylcellulose is hypromellose 2208.

[0068] In some embodiments of the methods and uses of the present disclosure, the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 190 mg, and 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. In some embodiments of the methods and uses of the present disclosure, the daily dose of levetiracetam in the pharmaceutical composition is 190 mg, and 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. In some embodiments, the hydroxypropyl methylcellulose is hypromellose 2208. In some embodiments, the hydroxypropyl methylcellulose is hypromellose 2208. In some embodiments, the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90. In some embodiments, the composition is in a unit dosage form for once-daily administration. In some embodiments, the composition is in an oral sustained release form. In some embodiments, the pharmaceutical sustained release composition is in a solid form. In some embodiments, the pharmaceutical sustained release composition is in the form of a tablet or capsule. In some embodiments, the oral sustained release form is 190 mg in a unit dosage form for once-daily administration.

[0069] In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is in sustained release form and provides in the subject a steady-state plasma concentration of levetiracetam of between 1.9 μg / mL and 4.4 μg / mL within 3 hours after administration and a duration of at least 8 hours within a 24-hour period after administration. In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is in sustained release form and provides in the subject a steady-state plasma concentration of levetiracetam of between 1.9 μg / mL and 4.4 μg / mL within 2 hours after administration and a duration of at least 13 hours within a 24-hour period after administration. In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is in sustained release form and provides in the subject a steady-state plasma concentration of levetiracetam of between 1.9 μg / mL and 4.4 μg / mL within 1 hour after administration and a duration of at least 13 hours within a 24-hour period after administration. In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam is in sustained release form and provides in the subject a steady-state plasma concentration of levetiracetam of between 1.9 μg / mL and 4.4 μg / mL within 3 hours after administration and a duration of at least 8 hours within a 24-hour period after administration. In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam is in sustained release form and provides in the subject a steady-state plasma concentration of levetiracetam of between 1.9 μg / mL and 4.4 μg / mL within 2 hours after administration and a duration of at least 13 hours within a 24-hour period after administration. In some embodiments, the pharmaceutical composition comprising the daily dose of levetiracetam is in sustained release form and provides in the subject a steady-state plasma concentration of levetiracetam of between 1.9 μg / mL and 4.4 μg / mL within 1 hour after administration and sustained for at least 13 hours within a 24 hour period after administration.In other embodiments, the pharmaceutical composition provides a steady-state plasma concentration of levetiracetam in the subject of between 1.9 μg / mL and 4.4 μg / mL within 1 hour after administration and for at least 13 to 16 hours within a 24-hour period after administration. See, e.g., WO2016191288.

[0070] In some embodiments, the pharmaceutical composition comprising the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is formulated in one or more of an oral form, a sustained release form, a single unit dosage form, or a form for once-daily administration. In some embodiments, the pharmaceutical composition comprising the daily dose of levetiracetam is formulated in one or more of an oral form, a sustained release form, a single unit dosage form, or a form for once-daily administration. In other embodiments, the sustained release form is a controlled release form, a long-term release form, a sustained release form, a delayed release form, or a slow release form. In some embodiments, the pharmaceutical sustained release composition of levetiracetam or a pharmaceutically acceptable salt thereof is in a solid form. In some embodiments, the pharmaceutical sustained release composition of levetiracetam or a pharmaceutically acceptable salt thereof is in the form of a tablet or capsule.

[0071] Table 1 provides a description of three sustained release oral formulations of levetiracetam (190 mg Tablets A, B, and C). In some embodiments, a pharmaceutical composition useful in the methods and uses of the present disclosure is selected from the group of formulations in Table 1. In one embodiment of the methods and uses of the present disclosure, the pharmaceutical composition is 190 mg Tablet A formulation. [Table 1]

[0072] Table 2 provides a description of two extended release formulations of levetiracetam (220 mg tablets D and E). In some embodiments of the methods and uses of the present disclosure, the pharmaceutical composition is selected from the group of formulations in Table 2. In one embodiment, the pharmaceutical composition is the 220 mg tablet D formulation. [Table 2]

[0073] In addition to oral delivery, the pharmaceutical compositions and medicaments useful in the methods and uses of the present disclosure can also be formulated for respiratory delivery (pulmonary and nasal delivery).In this form, they can be delivered by device and in the form of, but not limited to, various pressurized metered dose inhalers, dry powder inhalers, nebulizers, aqueous mist inhalers, drops, liquids, suspensions, sprays, powders, gels, ointments, and special systems such as liposomes and microspheres (see, for example, Owens DR, Zinman B, Bolli G. Alternative routes of insulin delivery. Diabet Med. 2003 Nov;20(11):886-98 and Martini G, Ciani L. Electron spin resonance spectroscopy in drug delivery. Phys Chem Phys. 2009).

[0074] Pharmaceutical compositions and medicaments useful in the methods and uses of the present disclosure may also be formulated for transdermal delivery using formats including, but not limited to, colloids, patches, and microemulsions.

[0075] Pharmaceutical compositions and medicaments useful in the methods and uses of the present disclosure may also contain auxiliary substances (e.g., preservatives, wetting agents, emulsifying agents, and dispersing agents). Prevention of microbial activity can be achieved by including various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol sorbic acid, etc.). It may also be desirable to include isotonic agents (e.g., sugars, sodium chloride, etc.) in pharmaceutical compositions.

[0076] Pharmaceutical compositions and medicaments useful in the methods and uses of the present disclosure may be prepared by methods well known in the pharmaceutical arts (see, for example, Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed., eds. JG Hardman, LE Limbird, and AG Gilman. McGraw Hill, New York. 2001; Ansel et al., Pharmaceutical Calculations, The Pharmacist's Handbook 2004, Lippincott Williams & Wilkins; Stoklosa et al., 2001 Pharmaceutical Calculations 11th ed. (9780781731720) - Textbooks.com; and Bustamante et al., "A Modification of the Extended Hildebrand Approach to Predict the Solubility of Structurally Related Drugs in Solvent Mixtures", Journal of Pharmacy and Pharmacology, 45:253-257 (1993)). [Example]

[0077] Example Example 1: Composition of Levetiracetam Compositions containing levetiracetam may be made via the process illustrated in the flow diagram of Figure 4. Briefly, silicified microcrystalline cellulose ProSolv TM SMCC HD90 (or Encompress, anhydrous dicalcium phosphate) is sieved through a deagglomerate #30 US mesh sieve and then blended with colloidal silicon dioxide (16 qt V-shell blender; 75 rpm ± 5 rpm). The blended sample is then passed through a Round 1601 Impeller (2A024R screen). 220 mg of levetiracetam and hypromellose 2208 (Methocel TM K15M Premium CR) (or Methocel TM K100M Premium CR) was also sieved through a deagglomeration #30 US mesh sieve and then sieved through a 1 ft. 3 Milled silicified microcrystalline cellulose ProSolv in a Slant Cone Blender (250 rpm ± 5 rpm) TM The blended sample is then passed through a Round 1601 Impeller (2A024R screen) and then through a 1 ft. 3 Blend with sieved magnesium stearate (HyQual®) (sieved through a deagglomerated #30 US mesh sieve) in a Slant Cone Blender (125 rpm ± 5 rpm). Compress the blended sample into tablets. Optionally, film coat the tablets with a hypromellose-based (HPMC-based) coating (e.g., Opadry® complete film coating system). A similar process can be used for a composition containing 190 mg of levetiracetam.

[0078] Example 2: Evaluation of levetiracetam plasma levels The effective steady-state levetiracetam plasma concentration range for treating cognitive impairment was previously established using the aMCI clinical trial and the aging rat study disclosed in WO2016191288 (which is incorporated herein by reference in its entirety). In one embodiment, the levetiracetam concentration range is between 2.9 and 4.4 μg / mL. In another embodiment, the levetiracetam concentration range is between 1.9 and 4.4 μg / mL. In another aspect, the effective plasma concentration is between 1.9 and 3.9 μg / mL. See Figure 1.

[0079] This example further describes a two-arm, single-dose, two-period, two-way crossover, food-effect study of two extended-release levetiracetam formulations: 190 mg Tablet A of Table 1 and 220 mg Tablet D of Table 2.

[0080] Test Design This is an open-label, randomized, two-arm, single-dose, two-period crossover, food-effect study. Fifty-six (56) healthy subjects will be enrolled. Subjects who successfully complete the above screening process will check into the study site the night before their first dose. Subjects who continue to meet the inclusion / exclusion criteria on the morning of dosing will be assigned a subject number based on the order in which they successfully complete the required screening process and procedures. Dosing days will be separated by a washout period of at least 7 days. Subjects will be randomly assigned to one of two groups: [Table 4-1] [Table 4-2]

[0081] Clinical Procedure Overview During each study period, 6 mL blood samples will be obtained before each dose and at selected times throughout the 24-hour post-dose period after each dose. A total of 34 pharmacokinetic blood samples will be collected from each subject, with 17 samples collected during each study period. Additionally, blood and urine will be drawn for clinical laboratory tests at screening and end of study.

[0082] For each study period, subjects will be admitted to the study unit the night before their scheduled dosing. Subjects will be confined to the study facility for the duration of each study period until completion of 24-hour blood draws and other study procedures.

[0083] Procedure for sample collection for pharmacokinetic analysis Blood samples (1 x 6 mL) are collected into vacutainer tubes containing K2-EDTA as a preservative at pre-dose (0) and 1.0, 2.0, 3.0, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10, 12, 18, and 24 hours post-dose.

[0084] Overview of Bioanalysis Plasma samples are analyzed for levetiracetam using a validated LC-MS procedure. The method is validated for levetiracetam over a range of 0.0500 to 30.0 μg / mL based on the analysis of 0.200 mL of human EDTA plasma. Data are stored in the Watson Laboratory Information Management System (LIMS; Version 7.2.0.03, Thermo Fisher Scientific).

[0085] Pharmacokinetic analysis Data are analyzed by noncompartmental analysis in WinNonlin. Concentration-time data below the limit of quantitation (BLQ) are treated as zero in data summaries and descriptive statistics. In pharmacokinetic analyses, BLQ concentrations are treated as zero from time zero until the time the first quantifiable concentration is observed; implant and / or terminal BLQ concentrations are treated as "missing." Actual sample times are used for all pharmacokinetic and statistical analyses.

[0086] The following pharmacokinetic parameters are calculated: peak plasma concentration (C max ), time to peak concentration (T max ), elimination rate constant (λz), terminal half-life (T 1 / 2 ), the area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC last ), and the area under the plasma concentration-time curve extrapolated from time zero to infinity (AUC inf ). Furthermore, C max , AUC last , and AUC inf Dose-normalized.

[0087] Steady-State Modeling Steady-state modeling of the PK profile for 190 mg Tablet A showed that plasma concentrations of levetiracetam were between 1.9 and 4.4 μg / mL over a substantial portion of the 24-hour post-dose period. See Figure 2.

[0088] Steady-state modeling of the PK profile for 220 mg tablet D showed that plasma concentrations of levetiracetam were between 2.9 and 4.4 μg / mL over a substantial portion of the 24-hour post-dose period. See Figure 3.

[0089] Example 3: Evaluation of 220 mg Levetiracetam Extended-Release Tablets for Slowing the Progression of Mild Cognitive Impairment (MCI) Due to Alzheimer's Disease (AD) This example describes a Phase IIb multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of low-dose levetiracetam, 220 mg, extended-release tablets, in slowing the progression of mild cognitive impairment (MCI) due to Alzheimer's disease (prodromal Alzheimer's disease). Outcomes are assessed using the well-recognized and accepted Clinical Dementia Rating Scale-Sum of the Box (CDR-SB) score.

[0090] Subject Subjects for this study were between 55 and 85 years of age (inclusive), in good health, willing and able to consent and participate for the duration of the study, had sufficient educational attainment (equivalent to an eighth-grade level) or a good employment history to rule out mental retardation, had sufficient vision and hearing for neuropsychological testing, and were fluent in the local language to participate in all neuropsychological testing assessments. Clinical evaluations of 63 participants were used for analysis.

[0091] APOE4 carrier status determination Blood samples were collected from each subject to determine APOE4 carrier status. Genomic DNA was prepared from the blood samples according to standard procedures. The quality of the genomic DNA samples was quantified using optical density, and DNA purity was calculated. Using the extracted genomic DNA as a template, locus-specific DNA fragments were amplified by polymerase chain reaction (PCR). The purified PCR products were used as templates for sequencing reactions. According to the chain termination methodology of Sanger et al. (Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463-7), DNA sequence analysis was based on the termination of growing DNA chains due to the incorporation of dye-labeled ddNTPs by DNA polymerase. The resulting dye-labeled products were detected using an automated sequencing platform. Data were analyzed using SEQPATIENT software from JSI-medical systems®.

[0092] research design The study included a screening period of up to 5 weeks consisting of three visits and a 78-week treatment period consisting of 10 visits (one baseline visit, three telephone visits, and six clinic visits). See Figure 5. The primary endpoint of the study was analysis of the change in CDR-SB score from baseline to 78 weeks. Secondary endpoints included analysis of the change in Functional Activities Questionnaire (FAQ) score from baseline to 78 weeks. Subjects received a low-dose of levetiracetam, 220 mg, extended-release tablets or placebo in the morning in identical-appearing extended-release single-unit oral dosage forms.

[0093] Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) The CDR-SB test was performed using standard methods. Briefly, subjects were tested using the following six categories or "boxes": memory, orientation, judgment and problem-solving, social activities, home life and hobbies, and personal care. CDR-SB scores were calculated by adding the box scores. Total scores ranged from 0 to 18, with higher scores indicating greater impairment. Absolute CDR-SB scores and changes from baseline were summarized using descriptive statistics and indicated by APOE4 non-carrier status. Table 3 summarizes the statistical analyses, where each cell contains a point estimate followed by a 95% confidence interval (CI). Figure 6 shows a graphical representation of CDR-SB scores at baseline and 26, 52, and 78 weeks after levetiracetam (LEV) or placebo treatment. Briefly, APOE4 non-carriers demonstrated a surprising and unexpected 36.8% reduction in CDR-SB change scores after 78 weeks of treatment with low-dose levetiracetam, 220 mg, extended-release tablets, compared with placebo-treated APOE4 non-carriers, with the maximal effect demonstrated between 52 and 78 weeks of treatment. [Table 3]

[0094] Although exemplary methods and materials are described, methods and materials similar or equivalent to those described herein can also be used in the practice or testing of various aspects and embodiments. The above materials, methods, and examples are illustrative only and not intended to be limiting.

[0095] Analysis of the primary efficacy endpoint revealed that for the entire study population, the mean CDR-SB change score at week 78 was 1.12 for the levetiracetam group and 1.22 for the placebo group, yielding a predicted mean treatment effect of -0.10 (p=0.71). For the APOE-4 carrier subgroup, the mean CDR-SB change score at week 78 was 0.95 for the levetiracetam group (n=54) and 1.05 for the placebo group (n=45), yielding a predicted mean treatment effect of -0.10. However, for the APOE-4 non-carrier subgroup, the mean change from baseline at week 78 was 0.68 for the levetiracetam group (n=26) and 1.13 for the placebo group (n=37), yielding a predicted mean treatment effect of -0.45.

[0096] Secondary outcome - Functional Activities Questionnaire (FAQ) score FAQ scores were obtained to measure an individual's functional ability over time. Briefly, the FAQ measures instrumental activities of daily living (e.g., preparing a meal and balancing a checkbook) because these functional changes are found earlier in the dementia process compared to more basic activities. The questionnaire includes 10 questions answered using a 0-3 scoring system (0 being normal and 3 being dependent on someone else to complete the task) for each question. The total score thus ranges from 0 to 30, with higher scores associated with greater impairment. Figure 7 shows a graphical representation of FAQ scores at baseline and 26, 52, and 78 weeks after levetiracetam (LEV) or placebo treatment. Briefly, APOE4 non-carriers showed a surprising and unexpected decrease in FAQ scores after 78 weeks of treatment with low-dose levetiracetam, 220 mg, extended-release tablets, compared with placebo-treated APOE4 non-carriers, with maximal effects shown between 26 and 52 weeks of treatment.

[0097] Although exemplary methods and materials are described, methods and materials similar or equivalent to those described herein can also be used in the practice or testing of various aspects and embodiments. The above materials, methods, and examples are illustrative only and not intended to be limiting.

[0098] Analysis of secondary efficacy endpoints revealed that for the entire study population, the predicted mean FAQ score from baseline at week 78 was 3.82 (95% CI: 2.10, 5.17) for the levetiracetam group and 3.81 (95% CI: 2.38, 5.59) for the placebo group. For the APOE-4 carrier subgroup, the mean FAQ total score change from baseline to week 78 was 5 for the levetiracetam group (n=54) and 3.3 for the placebo group (n=45). However, for the APOE-4 non-carrier subgroup, the mean FAQ total score change from baseline to week 78 was 1.8 for the levetiracetam group (n=26) and 4.1 for the placebo group (n=37).

[0099] Volumetric MRI of a small area of ​​the medial temporal lobe To examine whether treatment with levetiracetam had an effect on cortical brain atrophy in APOE-4 noncarriers (same subjects and groups as above) in addition to the observed effect on CDR-SB scores, we performed an analysis of cortical volume as a function of treatment status. Brain regions of interest were selected a priori before local examination based on the location of postmortem tau accumulation in early stages of AD (Braak et al., Acta Neuropathologica, 112(4): 389-404 (2006); Braak & Braak, Acta Neuropathologica, 80(5): 479-486 (1990)) and robust atrophy of the entorhinal cortex in AD. For this purpose, we used Automated Segmentation of Hippocampal Subfields (ASHS) software (Xie et al., Hum Brain Mapp. 40:3431-3451 (2019)). The regions provided by this software include the left and right entorhinal cortex (ERC), Brodmann area 35 (BA35) (which largely corresponds to TEC (Braak et al., Acta Neuropathologica, 112(4): 389-404 (2006); Braak & Braak, Acta Neuropathologica, 80(5): 479-486 (1990))), part of the perirhinal area, and BA36 (which primarily includes the perirhinal area) (Xie et al., 2019).

[0100] High-resolution T1-weighted MRI images of the subjects' brains were collected at baseline and 78 weeks using an MRI scanner.

[0101] Automatic Segmentation using ASHS Automated segmentation was performed using T1-weighted MRI images using ASHS-T1 open source software. See also Xie et al., Hum Brain Mapp. 40:3431-3451 (2019).

[0102] The T1-weighted MRI images were analyzed using ASHS-T1 open-source software. See also Xie et al., Hum Brain Mapp. 40:3431-3451 (2019). Volumetric and thickness measurements of the ERC and BA35 were extracted for each subject. The quality of all automated segmentations generated by ASHS was visually checked. The pipeline labeled the baseline and week 78 T1-weighted MRI scans of all subjects.

[0103] All statistical analyses were two-sided, with a significance level of p = 0.05.

[0104] result For APOE4 non-carrier subjects, baseline ERC volume did not differ between those assigned to the placebo group (n=37) or the levetiracetam treatment group (n=26). At the end of the 78-week study visit, left ERC volume change showed a significant reduction in atrophy in the levetiracetam treatment group compared to the placebo group (LEV treatment group: -1.878% mean volume change in volume; placebo group: -6.185% mean volume change in volume (p=0.048)) (Figure 8). Baseline volume at BA35 in APOE-4 non-carriers also did not differ between groups at baseline. At the end of the 78-week study visit, right BA35 volume change showed some atrophy reduction in the levetiracetam treatment group compared to the placebo group (LEV treatment group: -0.789% mean volume change in volume; placebo group: -4.758% mean volume change in volume (p=0.094)) (FIG. 9).

Claims

1. 1. A method of preventing or slowing the progression of cognitive impairment or preventing the onset of or reducing the rate of cognitive decline 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 is administered in a daily dose of 0.7 to 350 mg, or alternatively, administering to the subject a pharmaceutical composition comprising a daily dose of 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 subject has a genetic risk factor for the development of cognitive impairment that is not APOE4.

3. 10. The method of claim 1, wherein the subject presents or exhibits cognitive performance below the normal range for their age.

4. 10. The method of claim 1, wherein the subject exhibits or shows volumetric atrophy of a small region of the medial temporal lobe.

5. 5. The method of claim 4, wherein the subregion of the medial temporal lobe is the entorhinal cortex (ERC).

6. 6. The method of claim 5, wherein the entorhinal cortex (ERC) is the left ERC.

7. 5. The method of claim 4, wherein the subregion of the medial temporal lobe is the perirhinal cortex (BA35).

8. 8. The method of claim 7, wherein the perirhinal cortex (BA35) is the right BA35.

9. The method of claims 1 to 8, wherein the subject is suffering from early mild cognitive impairment.

10. 3. The method of claim 1 or 2, wherein the subject is suffering from mild cognitive impairment.

11. 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 stage AD.

12. 11. The method of any one of claims 1, 2 or 10, wherein the subject suffers from amnesic mild cognitive impairment (aMCI).

13. 13. The method of any one of claims 1 to 12, wherein the daily dose of levetiracetam or seletracetam is 7 to 350 mg.

14. 13. The method according to any one of claims 1 to 12, wherein the daily dose of brivaracetam is 0.7 to 180 mg.

15. 13. The method of any one of claims 1 to 12, wherein the daily dose of levetiracetam or seletracetam is 125 to 250 mg.

16. 16. The method of claim 13 or 15, wherein the daily dose of levetiracetam or seletracetam is 220 mg.

17. 16. The method of claim 13 or 15, wherein the daily dose of levetiracetam or seletracetam is 190 mg.

18. 18. The method of any one of claims 1 to 17, wherein the pharmaceutical composition is formulated in one or more of an oral form, a sustained release form, a unit dosage form, or a once-daily form.

19. 20. The method of claim 18, wherein the sustained release form is a controlled release form, an extended release form, a sustained release form, a delayed release form, or a slow release form.

20. 20. The method of claim 18 or 19, wherein the sustained release form is a once-daily sustained release form.

21. 21. The method of any one of claims 1-13, 15, 16 or 18-20, wherein the daily dose of levetiracetam in the pharmaceutical composition is 220 mg, and the pharmaceutical composition further comprises 280 mg to 350 mg of hydroxypropyl methylcellulose, 1.2 mg to 1.4 mg of colloidal silicon dioxide, 92.8 mg to 119.2 mg of silicified microcrystalline cellulose, and 6.0 mg to 6.7 mg of magnesium stearate.

22. 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. 22. 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. 21. The method of any one of claims 1-13, 15, or 17-20, wherein the daily dose of levetiracetam in the pharmaceutical composition is 190 mg, and 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. 25. The method of any one of claims 21 to 24, wherein the hydroxypropyl methylcellulose is hypromellose 2208.

26. 26. The method of any one of claims 21 to 25, wherein the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90.

27. 21. The method of any one of claims 1 to 13 or 15 to 20, wherein the pharmaceutical composition comprising levetiracetam or a pharmaceutically acceptable salt thereof is in a once-daily sustained release form and provides in a subject a steady-state plasma concentration of levetiracetam of between 1.9 μg / mL and 4.4 μg / mL within 3 hours after administration and sustained for at least 8 hours within a 24 hour period after said administration.

28. 28. The method of claim 27, wherein the pharmaceutical composition provides in a subject a steady-state plasma concentration of levetiracetam of between 1.9 μg / mL and 4.4 μg / mL within 2 hours after the administration and sustained for at least 13 hours within a 24 hour period after the administration.

29. 28. The method of claim 27, wherein the pharmaceutical composition provides in a subject a steady-state plasma concentration of levetiracetam of between 1.9 μg / mL and 4.4 μg / mL within 1 hour after said administration and sustained for at least 13 hours within a 24 hour period after said administration.

30. 28. The method of claim 27, wherein the pharmaceutical composition provides in a subject a steady-state plasma concentration of levetiracetam of between 1.9 μg / mL and 4.4 μg / mL within 1 hour after administration and sustained for at least 13-16 hours within a 24 hour period after said administration.

31. 31. The method of any of claims 1, 2, 4-8, or 13-30, wherein the subject exhibits or displays cognitive performance within the normal range for the subject's age.

32. The method of any one of claims 1 to 31, wherein the subject is a human.

33. 1. A method for slowing 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 is administered in a daily dose of 0.7 to 350 mg, or administering to the subject a pharmaceutical composition comprising a daily dose of levetiracetam, brivaracetam or seletracetam, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

34. 34. The method of claim 33, wherein the subregion of the medial temporal lobe is the entorhinal cortex (ERC).

35. 35. The method of claim 34, wherein the ERC is a left ERC.

36. 34. The method of claim 33, wherein the subregion of the medial temporal lobe is the perirhinal cortex (BA35).

37. 37. The method of claim 36, wherein the perirhinal cortex (BA35) is the right BA35.

38. 1. A method for slowing 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 is administered in a daily dose of 0.7 to 350 mg, or administering to the subject a pharmaceutical composition comprising a daily dose of levetiracetam, brivaracetam or seletracetam, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

39. 39. The method of claim 38, wherein the entorhinal cortex (ERC) is the left ERC.

40. The method of any one of claims 33 to 39, wherein the APOE4 non-carrier subject has a genetic risk factor for the development of cognitive impairment that is not APOE4.

41. 40. The method of any one of claims 33 to 39, wherein the subject presents or exhibits cognitive performance below the normal range for their age.

42. 34. The method of any one of claims 33, wherein the subject exhibits or shows volumetric atrophy of a subregion of the medial temporal lobe.

43. 43. The method of claim 42, wherein the subregion of the medial temporal lobe is the perirhinal cortex (BA35).

44. 44. The method of claim 43, wherein the perirhinal cortex (BA35) is the right BA35.

45. 43. The method of claim 42, wherein the subregion of the medial temporal lobe is the entorhinal cortex (ERC).

46. 39. The method of claim 38, wherein the subject exhibits volumetric atrophy of the entorhinal cortex (ERC).

47. 47. The method of claim 45 or 46, wherein the entorhinal cortex (ERC) is the left ERC.

48. 48. The method of any one of claims 33 to 47, wherein the subject is suffering from early mild cognitive impairment.

49. 48. The method of any one of claims 33 to 47, wherein the subject suffers from mild cognitive impairment.

50. 50. The method of any one of claims 33 to 40 and 49, wherein the subject is suffering from mild cognitive impairment due to Alzheimer's disease (AD) or prodromal stage AD.

51. 50. The method of any one of claims 33 to 40 and 49, wherein the subject suffers from amnesic mild cognitive impairment (aMCI).

52. 52. The method of any one of claims 33 to 51, wherein the daily dose of levetiracetam or seletracetam is 7 to 350 mg.

53. 52. The method according to any one of claims 33 to 51, wherein the daily dose of brivaracetam is 0.7 to 180 mg.

54. 53. The method of any one of claims 33 to 52, wherein the daily dose of levetiracetam or seletracetam is 125 to 250 mg.

55. 55. The method of claim 52 or 54, wherein the daily dose of levetiracetam or seletracetam is 220 mg.

56. 55. The method of claim 52 or 54, wherein the daily dose of levetiracetam or seletracetam is 190 mg.

57. 57. The method of any one of claims 33 to 56, wherein the pharmaceutical composition is formulated in one or more of an oral form, a sustained release form, a unit dosage form, or a once-daily form.

58. 58. The method of claim 57, wherein the sustained release form is a controlled release form, an extended release form, a sustained release form, a delayed release form, or a slow release form.

59. 59. The method of claim 57 or 58, wherein the sustained release form is a once-daily sustained release form.

60. 60. The method of any one of claims 33-52, 54, 55 or 57-59, wherein the daily dose of levetiracetam in the pharmaceutical composition is 220 mg, and the pharmaceutical composition further comprises 280 mg to 350 mg of hydroxypropyl methylcellulose, 1.2 mg to 1.4 mg of colloidal silicon dioxide, 92.8 mg to 119.2 mg of silicified microcrystalline cellulose, and 6.0 mg to 6.7 mg of magnesium stearate.

61. 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. 61. 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. 60. The method of any one of claims 33-52, 54, or 56-59, wherein the daily dose of levetiracetam in the pharmaceutical composition is 190 mg, and 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. 64. The method of any one of claims 60 to 63, wherein the hydroxypropyl methylcellulose is hypromellose 2208.

65. 65. The method of any one of claims 60 to 64, wherein the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90.

66. 66. The method of any one of claims 33-52 or 54-65, wherein the pharmaceutical composition comprising levetiracetam, or a pharmaceutically acceptable salt thereof, is in a once-daily sustained release form and provides in a subject a steady-state plasma concentration of levetiracetam of between 1.9 μg / mL and 4.4 μg / mL within 3 hours after administration and sustained for at least 8 hours within a 24 hour period after said administration.

67. 67. The method of claim 66, wherein the pharmaceutical composition provides in a subject a steady-state plasma concentration of levetiracetam of between 1.9 μg / mL and 4.4 μg / mL within 2 hours after the administration and sustained for at least 13 hours within a 24 hour period after the administration.

68. 67. The method of claim 66, wherein the pharmaceutical composition provides in a subject a steady-state plasma concentration of levetiracetam of between 1.9 μg / mL and 4.4 μg / mL within 1 hour after said administration and sustained for at least 13 hours within a 24 hour period after said administration.

69. 67. The method of claim 66, wherein the pharmaceutical composition provides in a subject a steady-state plasma concentration of levetiracetam of between 1.9 μg / mL and 4.4 μg / mL within 1 hour after administration and sustained for at least 13-16 hours within a 24 hour period after said administration.

70. 70. The method of any of claims 33-40, 42-47, or 52-69, wherein the subject exhibits or displays cognitive performance within the normal range for the subject's age.

71. The method of any one of claims 33 to 70, wherein the subject is a human.

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