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

Abstract

Methods for preventing or slowing the progression of cognitive impairment or preventing the occurrence of or reducing the rate of cognitive competence decline. A method for slowing volume atrophy or reduction in a medial temporal lobe subregion. Methods for slowing volumetric atrophy or reduction of the endometrial cortex (ERC). A method for slowing volume atrophy or reduction across the endometrial cortex (BA35). The methods comprise administering to an APOE4 non-carrier subject one or more of levetiracetam, brivaracetam, or cetriracetam, or a pharmaceutically acceptable salt thereof, or administering a pharmaceutical composition comprising levetiracetam, brivaracetam, or cetriracetam, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Description

[0001] Government-supported statement

[0002] The subject matter of this disclosure was completed with government support under grant number R01AG061091 granted by the National Institutes of Health (NIH), and particularly its National Institute on Aging (NIA) division (an agency of the U.S. government). The U.S. government retains certain rights to the subject matter of this disclosure.

[0003] Related applications

[0004] This application claims the benefits and priorities of U.S. Provisional Application No. 63 / 439,035, filed January 13, 2023, and U.S. Provisional Application No. 63 / 545,348, filed October 23, 2023, each of which is incorporated herein by reference in its entirety. Invention Field

[0005] This disclosure relates to methods for preventing or slowing the progression of cognitive impairment in subjects who are APOE4 non-carriers, e.g., not homozygous or heterozygous for APOE4, or for preventing the onset of cognitive decline or reducing the rate of cognitive decline. In some aspects, this disclosure relates to methods for delaying volume reduction, thickness contraction, or atrophy in a subregion of the medial temporal lobe (e.g., the entorhinal cortex (ERC) or transentorhinal cortex (BA35)), wherein said volume reduction, contraction, or atrophy is a characteristic and biomarker of cognitive impairment progression. In some aspects, this disclosure relates to methods for reducing the rate of volume reduction, thickness contraction, or atrophy in a subregion of the medial temporal lobe (e.g., the entorhinal cortex (ERC) or transentorhinal cortex (BA35)), wherein said rate of volume reduction, contraction, or atrophy is a characteristic and biomarker of cognitive impairment progression.

[0006] In some aspects of this disclosure, the APOE4 non-carriers may show or exhibit cognitive performance within the normal range for the subject's age. In other aspects, the APOE4 non-carriers may exhibit preclinical cognitive impairment (i.e., showing or exhibiting cognitive performance slightly below the normal range for the subject's age), pre-MCI (pre-MCI), mild cognitive impairment, mild cognitive impairment due to Alzheimer's disease (AD) (MCI), prodromal AD, or amnestic MCI (aMCI). In some aspects of this disclosure, the APOE4 non-carriers may be at risk of developing or exhibiting cognitive impairment associated with various other CNS disorders. In some aspects of this disclosure, the APOE4 non-carriers exhibit reduced, contracted, or atrophied volume of the medial temporal lobe subregion (e.g., the entorhinal cortex (ERC) or trans-entorhinal cortex (BA35)), and the non-carriers are selected from subjects showing or exhibiting below-normal medial temporal lobe subregion volume and subjects showing or exhibiting cognitive performance within the normal range for the subject's age or slightly below the normal range for the subject's age in some respects. The methods disclosed herein include administering to the subject one or more of the following: levetiracetam, buvascarbamazetam, or seletracetam, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising levetiracetam, buvascarbamazetam, or seletracetam, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0007] In some aspects of this disclosure, APOE4 noncarriers have one or more predictable risks or risks associated with the occurrence of cognitive decline or impairment, or the progression of said decline or impairment. Some of these risks are related to aging. Other risks are genetic risks associated with genomic variants, mutations, or polymorphisms, or with changes in the expression of genes associated with cognitive decline or impairment. In some aspects of this disclosure, the genetic risk factor is not APOE4. In some aspects, the risk is a reduction in volume, shrinkage, or atrophy of the medial temporal lobe subregion (e.g., the entorhinal cortex (ERC) or transentorhinal cortex (BA35)). Background of the Invention

[0009] Cognitive abilities can decline as a normal consequence of aging, or they can be associated with changes in hippocampal activity (e.g., hyperactivity), genomic variants, mutations, or polymorphisms, the occurrence of cognitive impairment or decline in the context of CNS diseases and disorders such as Alzheimer's disease (AD), or changes in volume, contraction, or atrophy of the medial temporal lobe subregions (e.g., the entorhinal cortex (ERC) or transentorhinal cortex (BA35)). Although subjects may exhibit or demonstrate cognitive performance within the normal range for their age, they may still be at risk of developing cognitive impairment or decline.

[0010] Postmortem studies of patients with Alzheimer's disease (AD) have provided insights into the spatial and temporal progression of AD pathology in the brain, revealing that the formation of neurofibrillary tangles (NFTs) in the initial stages of AD pathology occurs in the entorhinal cortex (ERC), particularly in the transentorhinal cortex (TEC or BA35), which acts as a transition between the lateral portion of the ERC and the periolfactory cortex (Braak et al., Acta Neuropathologica, 112(4), 389-404 (2006); Braak and Braak, Acta Neuropathologica, 80(5), 479-486 (1990); Kaufman et al., Acta Neuropathologica, 136(1), 57-67 (2018)). Even in cognitively normal older adults, the accumulation of tau in the TEC is common by age 60 (Maass et al., Journal of Neuroscience, 38(3), 530-543 (2018)). The tau pathology then spreads through other medial temporal lobe regions (MTL; Braak et al., 2006), which play a role in episodic memory function (Dickerson and Eichenbaum, Neuropsychopharmacology, 35(1), Article 1(2010)). The localization and spread of tau occur temporally and spatially in conjunction with the progression of neurodegeneration.

[0011] In both cross-sectional and longitudinal studies, the entorhinal cortex has shown disease-associated reductions in cortical volume. For example, Fan et al. reported left-sided entorhinal cortex atrophy in patients with normal cognition but subjective memory decline (Fan et al., HumBrain Mapp., 39(6):2549-2562 (2018)). Tran et al. reported significant reductions in the volume of bilateral subregions of the entorhinal cortex in patients with mild cognitive impairment, which are consistent with the TEC (Tran et al., Neurobiol Aging, 112:151-160 (2022)). Tward et al. reported significant atrophy of the trans-entorhinal cortex in patients with mild cognitive impairment, and Kulason et al. showed that changes in the volume and thickness of the entorhinal and TEC could be observed in participants 8–11 years and 9–14 years prior to the diagnosis of mild cognitive impairment (Tward et al., Alzheimers Dement (Amst), 14(9):41–50 (2017); Kulason et al., Front Neurosci., 14:804 (2020)).

[0012] Although APOE4 is one of the more prominent genetic risk factors for cognitive decline, including Alzheimer's disease (AD), it is neither a necessary nor a sufficient factor. Therefore, individuals with one or two polymorphic copies of APOE4 (i.e., APOE4 carriers) may never experience cognitive decline or develop AD or other dementias, while conversely, non-carriers of APOE4 may develop cognitive decline and related illnesses and disorders. However, much of the focus of treatment research has been on subjects who are APOE4 carriers (i.e., those with one of the two APOE4 alleles).

[0013] In fact, there are no FDA-approved therapies for APOE4 noncarriers who show or exhibit cognitive performance within the normal range for their age, but may be at risk of developing or progressing to cognitive impairment or decline due to aging, contraction or atrophy of medial temporal lobe subregions (e.g., the entorhinal cortex (ERC) or transentorhinal cortex (BA35)), various genetic risk factors, or CNS disorders. Apart from biologics targeting amyloid, no therapy is claimed to specifically prevent or slow the progression of cognitive impairment in subjects with aMCI or AD-induced MCI, or to prevent the onset of or reduce the rate of cognitive decline. Such biologics are also expensive, administered intravenously, and require close monitoring for potential side effects, such as cerebral hemorrhage.

[0014] Therefore, effective clinical and therapeutic measures are needed to (1) prevent or slow the progression of cognitive impairment; (2) prevent the onset of or reduce the rate of cognitive decline; or (3) delay or reduce the volume atrophy or contraction of the medial temporal lobe subregion (e.g., the entorhinal cortex (ERC)) in APOE4 non-carriers who show or exhibit cognitive performance within the normal range for their age but may be at risk of developing or progressing to cognitive impairment or decline, and in APOE4 non-carriers who show early stages of cognitive impairment and decline (e.g., subjects exhibiting symptoms associated with pre-MCI, aMCI, or AD-related MCI, regardless of whether pre-MCI, aMCI, or MCI is age-related) in the early stages of cognitive impairment and decline. More affordable and safer treatment options are also needed to reduce and delay the progression of such cognitive impairment.

[0015] Brief Overview of the Invention

[0016] This disclosure relates to methods for preventing or slowing the progression of cognitive impairment or preventing the occurrence of cognitive decline or reducing the rate of cognitive decline in APOE4 non-carriers who exhibit or demonstrate cognitive performance within the normal range for the subject's age. In other aspects, this disclosure relates to methods for preventing or slowing the progression of cognitive impairment or preventing the occurrence of cognitive decline or reducing the rate of cognitive decline in APOE4 non-carriers who exhibit or demonstrate cognitive performance below the normal range for the subject's age.

[0017] In other respects, the APOE4 non-carriers may exhibit preclinical cognitive impairment, i.e., showing or exhibiting cognitive performance slightly below the normal range for the subject's age, pre-MCI, mild cognitive impairment, mild cognitive impairment due to Alzheimer's disease (AD), prodromal AD, or amnestic MCI (aMCI). In other respects, this disclosure relates to methods for preventing or slowing the progression of cognitive impairment or preventing the occurrence of cognitive decline or reducing the rate of cognitive decline in APOE4 non-carriers who are at risk of developing or exhibiting cognitive impairment associated with various other CNS disorders. In other respects, this disclosure relates to methods for delaying or reducing the rate of atrophy or shrinkage of the medial temporal lobe subregion in APOE4 non-carrier subjects selected from subjects showing or exhibiting below-normal medial temporal lobe subregion volume and subjects showing or exhibiting cognitive performance within the normal range for the subject's age or slightly below the normal range in some respects. In other respects, this disclosure relates to methods for delaying or reducing the volume atrophy or contraction of the entorhinal cortex or decreasing its rate in APOE4 non-carrier subjects. The methods include administering to the subject one or more of levetiracetam, buvaseritam, or cetracetam, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising levetiracetam, buvaseritam, or cetracetam, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments of this disclosure, the method includes administering to the subject levetiracetam, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0018] In some aspects of this disclosure, APOE4 noncarriers exhibit one or more risk factors that are predictable or associated with the occurrence or progression of cognitive decline or impairment. Some of these risks are related to aging. Other risks are genetic risks associated with genomic variants, mutations, or polymorphisms, or with changes in the expression of genes associated with cognitive decline or impairment. In some aspects of this disclosure, the genetic risk factor is not APOE4. In some aspects, the risk is a reduction, contraction, or atrophy of the volume of a subregion of the medial temporal lobe (e.g., the entorhinal cortex (ERC) or trans-entorhinal cortex (BA35)).

[0019] In some embodiments, the method of this disclosure includes administering to the subject one or more of levetiracetam, brivaracetam, or cetracetam, or a pharmaceutically acceptable salt thereof, at a daily dose of 0.7-350 mg. In other aspects, the method of this disclosure includes administering to the subject a pharmaceutical composition comprising one or more of levetiracetam, brivaracetam, or cetracetam, or a pharmaceutically acceptable salt thereof, at a daily dose of 0.7-350 mg, and a pharmaceutically acceptable carrier. In some embodiments, the method of this disclosure includes administering to the subject levetiracetam, or a pharmaceutically acceptable salt thereof, at a daily dose of 0.7-350 mg.

[0020] In some embodiments, the daily dose of levetiracetam or cetracetam, or a pharmaceutically acceptable salt thereof (either alone or as part of a pharmaceutical composition), is 7-350 mg. In some embodiments, the daily dose of brivaracetam, or a pharmaceutically acceptable salt thereof (either alone or as part of a pharmaceutical composition), is 0.7-180 mg. In other embodiments, the daily dose of levetiracetam or cetracetam, or a pharmaceutically acceptable salt thereof (either alone or as part of a pharmaceutical composition), is 125-250 mg. In some embodiments, the daily dose of levetiracetam or cetracetam, or a pharmaceutically acceptable salt thereof (either alone or as part of a pharmaceutical composition), is 220 mg. In some embodiments, the daily dose of levetiracetam or cetracetam, or a pharmaceutically acceptable salt thereof (either alone or as part of a pharmaceutical composition), is 190 mg.

[0021] In some embodiments, the levetiracetam, brivaracetam, or cetracetam, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition comprising one or more of these, is formulated as an oral form, a delayed-release form, a single-unit dosage form, or a once-daily administration form. In some embodiments, the delayed-release form is a controlled-release form, an extended-release form, a sustained-release form, a delayed-release form, or a slow-release form. In some aspects of this disclosure, the delayed-release form, the single-unit dosage form, and the once-daily form are for oral administration. In some embodiments, the levetiracetam, brivaracetam, or cetracetam, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition comprising one or more of these, is administered once daily. In some embodiments, the levetiracetam, brivaracetam, or cetracetam, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition comprising one or more of these, is administered twice daily.

[0022] In some embodiments of this disclosure, the method includes administering an oral, daily, single-dose, delayed-release pharmaceutical composition to a non-APOE4 carrier, comprising 220 mg of levetiracetam or a pharmaceutically acceptable salt thereof, 280 mg-350 mg of hydroxypropyl methylcellulose, 1.2 mg-1.4 mg of colloidal silica, 92.8 mg-119.2 mg of silanized microcrystalline cellulose, and 6.0 mg-6.7 mg of magnesium stearate. In other embodiments, the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof in the delayed-release pharmaceutical composition is 220 mg, and the pharmaceutical composition further comprises 280 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silica, 92.8 mg of silanized 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 delayed-release pharmaceutical composition is 220 mg, and the pharmaceutical composition further comprises 347.5 mg hydroxypropyl methylcellulose, 1.4 mg colloidal silica, 119.2 mg silanized microcrystalline cellulose, and 6.7 mg magnesium stearate. In other embodiments of the delayed-release composition that can be used in the methods of this disclosure, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208. In other embodiments, the silanized microcrystalline cellulose is silanized microcrystalline cellulose SMCC 90.

[0023] In some embodiments of this disclosure, the method includes administering to a non-APOE4 carrier an oral, daily (in some embodiments, once daily), single-dose delayed-release pharmaceutical composition comprising 220 mg levetiracetam, 280 mg-350 mg hydroxypropyl methylcellulose, 1.2 mg-1.4 mg colloidal silica, 92.8 mg-119.2 mg silanized microcrystalline cellulose, and 6.0 mg-6.7 mg magnesium stearate. In other embodiments, the daily or once-daily dose of levetiracetam in the delayed-release pharmaceutical composition is 220 mg, and the pharmaceutical composition further comprises 280 mg hydroxypropyl methylcellulose, 1.2 mg colloidal silica, 92.8 mg silanized microcrystalline cellulose, and 6.0 mg magnesium stearate. In other embodiments, the delayed-release pharmaceutical composition contains 220 mg of levetiracetam daily or once-daily, and the composition further comprises 347.5 mg of hydroxypropyl methylcellulose, 1.4 mg of colloidal silica, 119.2 mg of silanized microcrystalline cellulose, and 6.7 mg of magnesium stearate. In other embodiments of the delayed-release composition that can be used in the methods of this disclosure, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208. In other embodiments, the silanized microcrystalline cellulose is silanized microcrystalline cellulose SMCC 90.

[0024] In some embodiments of this disclosure, the method includes administering a daily dose of a pharmaceutical composition to the subject, comprising 190 mg levetiracetam, 300 mg hydroxypropyl methylcellulose, 1.2 mg colloidal silica, 102.8 mg silanized microcrystalline cellulose or anhydrous dicalcium phosphate, and 6 mg magnesium stearate. In other embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208. In other embodiments, the silanized microcrystalline cellulose is silanized microcrystalline cellulose SMCC 90.

[0025] In some embodiments of this disclosure, the method includes administering to the subject a daily or once-daily dose of a pharmaceutical composition comprising 190 mg levetiracetam, 300 mg hydroxypropyl methylcellulose, 1.2 mg colloidal silica, 102.8 mg silanized microcrystalline cellulose or anhydrous dicalcium phosphate, and 6 mg magnesium stearate. In other embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208. In other embodiments, the silanized microcrystalline cellulose is silanized microcrystalline cellulose SMCC 90.

[0026] In some embodiments of this disclosure, the method includes administering a pharmaceutical composition comprising an oral, daily, single-dose, delayed-release composition comprising levetiracetam or a pharmaceutically acceptable salt thereof, wherein the administration, occurring within 3 hours of administration and continuing for at least 8 hours over a 24-hour period following administration, provides a steady-state plasma concentration of levetiracetam in APOE4 non-carriers between 1.9 μg / mL and 4.4 μg / mL. In some embodiments of this disclosure, the method includes administering a pharmaceutical composition comprising an oral, once-daily, single-dose, delayed-release composition comprising levetiracetam or a pharmaceutically acceptable salt thereof, wherein the administration, occurring within 3 hours of administration and continuing for at least 8 hours over a 24-hour period following administration, provides a steady-state plasma concentration of levetiracetam in APOE4 non-carriers between 1.9 μg / mL and 4.4 μg / mL. In some embodiments of this disclosure, the method includes administering a pharmaceutical composition comprising an oral, once-daily, single-use, delayed-release composition containing levetiracetam, wherein the administration, occurring within 3 hours of administration and continuing for at least 8 hours over a 24-hour period following administration, provides a steady-state plasma concentration of levetiracetam in APOE4 non-carriers between 1.9 μg / mL and 4.4 μg / mL. In some embodiments, the delayed-release pharmaceutical composition provides a steady-state plasma concentration of levetiracetam in APOE4 non-carriers between 1.9 μg / mL and 4.4 μg / mL within 2 hours of administration and continuing for at least 13 hours over a 24-hour period following administration. In some embodiments, the delayed-release pharmaceutical composition provides a steady-state plasma concentration of levetiracetam in APOE4 non-carriers between 1.9 μg / mL and 4.4 μg / mL within 1 hour of administration and continuing for at least 13 hours over a 24-hour period following administration. In other embodiments, the delayed-release pharmaceutical composition provides steady-state plasma concentrations of levetiracetam in APOE4 non-carriers between 1.9 μg / mL and 4.4 μg / mL for at least 13 to 16 hours over a 24-hour period following administration (see [link to original text]). Figure 2 (and WO2016191288, which is incorporated herein by reference in its entirety).

[0027] In some embodiments of this disclosure, the APOE4 non-carrier to be treated is at risk of developing cognitive decline or impairment, said risk being age-related. In some embodiments, said risk is associated with a decrease or contraction in the volume of a subregion of the medial temporal lobe (e.g., the entorhinal cortex (ERC) or trans-entorhinal cortex (BA35)). In other aspects, this disclosure relates to methods for preventing or slowing the progression of cognitive impairment or preventing the occurrence of or reducing the rate of cognitive decline in APOE4 non-carriers who exhibit or demonstrate cognitive performance below the normal range for the subject's age. In some embodiments of this disclosure, the APOE4 non-carrier may exhibit mild preclinical cognitive impairment, i.e., exhibit or demonstrate cognitive performance slightly below the normal range for the subject's age. In other aspects, this disclosure relates to methods for delaying or reducing the rate of atrophy or contraction of the medial temporal lobe subregion (e.g., the entorhinal cortex (ERC) or trans-entorhinal cortex (BA35)) in APOE4 non-carrier subjects selected from subjects showing or exhibiting below-normal medial temporal lobe subregion volume and subjects showing or exhibiting cognitive performance within the normal range for their age or slightly below the normal range for their age in some respects. In other aspects, this disclosure relates to methods for delaying or reducing the rate of atrophy of the entorhinal cortex (ERC) in APOE4 non-carrier subjects. In some embodiments of this disclosure, the APOE4 non-carrier to be treated is at risk of atrophy of the medial temporal lobe subregion (e.g., the entorhinal cortex (ERC) or trans-entorhinal cortex (BA35)). In some embodiments of this disclosure, the APOE4 non-carrier to be treated is at risk of atrophy of the entorhinal cortex (ERC). In some embodiments of this disclosure, the APOE4 non-carrier to be treated is at risk of developing cognitive decline or impairment, wherein said risk is associated with genomic variants, mutations, or polymorphisms, or with changes in the expression of genes associated with cognitive decline or impairment. In some embodiments of this disclosure, the APOE4 non-carrier to be treated is at risk of developing cognitive decline or impairment, wherein said risk is associated with pre-MCI. In some embodiments of this disclosure, the APOE4 non-carrier to be treated is at risk of developing cognitive decline or impairment, wherein said risk is associated with aMCI. In some embodiments of this disclosure, the APOE4 non-carrier to be treated is at risk of developing cognitive decline or impairment, wherein said risk is associated with MCI. In some embodiments of this disclosure, the APOE4 non-carrier to be treated is at risk of developing cognitive decline or impairment, wherein said risk is associated with MCI caused by Alzheimer's disease (AD) or prodromal AD.

[0028] One aspect of this disclosure relates to the use in the preparation of a pharmaceutical composition of one or more of levetiracetam, buvaracetam, or cetracetam, or any of these, for the purpose of preventing or slowing the progression of cognitive impairment or preventing or reducing the rate of cognitive decline in APOE4 non-carriers who have preclinical cognitive impairment, i.e., showing or exhibiting cognitive performance slightly below the normal range for the subject's age. In other aspects, this disclosure relates to the use in the preparation of a pharmaceutical composition of one or more of levetiracetam, buvaracetam, or cetracetam, or any of these, for the purpose of delaying or reducing the rate of atrophy of the medial temporal lobe subregion (e.g., the entorhinal cortex (ERC) or transentorhinal cortex (BA35)) in APOE4 non-carrier subjects selected from subjects showing or exhibiting below-normal medial temporal lobe subregion volume and subjects showing or exhibiting cognitive performance within the normal range for the subject's age or slightly below the normal range in some respects for the subject's age. In other respects, this disclosure relates to the use of one or more of levetiracetam, buvaracetam, or cetracetam, or any of these pharmaceutical compositions, in the preparation of a medicament for delaying or reducing the volume shrinkage or contraction of the entorhinal cortex (ERC) or decreasing its rate in APOE4 non-carrier subjects.

[0029] 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 cognitive decline as a consequence of progressive atrophy of the medial temporal lobe subregion (e.g., the entorhinal cortex (ERC) or trans-entorhinal cortex (BA35)). In some embodiments, as described above, the APOE4 non-carrier is at risk of developing entorhinal cortex (ERC) atrophy. In some embodiments of this disclosure, the APOE4 non-carrier to be treated is at risk of developing cognitive decline or impairment, wherein said risk is associated with genomic variants, mutations, or polymorphisms, or with changes in the expression of genes associated with cognitive decline or impairment. In some embodiments of this disclosure, as described above, said risk is associated with one or more of pre-MCI, MCI, aMCI, AD-related MCI, prodromal AD, or other CNS disorders.

[0030] In other embodiments, this disclosure relates to the use of a pharmaceutical composition of levetiracetam, buvaracetam, or cetracetam, or any one thereof, for the prevention or slowing of the progression of cognitive impairment or the prevention of or reduction of the rate of cognitive decline in APOE4 non-carriers who exhibit or demonstrate cognitive performance within the normal range for the subject's age. In other aspects, this disclosure relates to the use of a pharmaceutical composition of levetiracetam, buvaracetam, or cetracetam, or any one thereof, for the delay or reduction of the rate of atrophy or contraction of the medial temporal lobe subregion (e.g., the entorhinal cortex (ERC) or transentorhinal cortex (BA35)) in APOE4 non-carrier subjects selected from subjects exhibiting or demonstrating below-normal medial temporal lobe subregion volume and subjects exhibiting or demonstrating cognitive performance within the normal range for the subject's age or, in some respects, slightly below the normal range for the subject's age. In other aspects, this disclosure relates to the use of one or more pharmaceutical compositions of levetiracetam, buvascarbamazetam, or cetracetam, or any of these, for delaying or reducing the rate of atrophy of the 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 cognitive decline, or the progression of said impairment or cognitive 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 atrophy of the medial temporal lobe subregion (e.g., the entorhinal cortex (ERC) or trans-entorhinal cortex (BA35)). In some embodiments, as described above, the APOE4 non-carrier is at risk of developing atrophy of the entorhinal cortex (ERC). In some embodiments of this 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 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 this disclosure, as described above, said risk is associated with one or more of pre-MCI, MCI, aMCI, AD-related MCI, prodromal AD, or other CNS disorders. Brief description of the attached diagram

[0032] Figure 1Plasma concentrations of levetiracetam, an effective treatment for cognitive impairment, based on studies in aged impaired rats and a phase II study in patients with aMCI, are described. In one aspect of this 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 yet another aspect, the effective plasma concentration is between 1.9 and 3.9 μg / mL.

[0033] Figure 2 Steady-state modeling of the PK curve for 190 mg tablet A in Table 1 is shown, indicating that the tablet provides plasma concentrations of levetiracetam between 1.9 and 4.4 μg / mL.

[0034] Figure 3 Steady-state modeling of the PK curves for 220 mg tablet D in Table 2 is shown, indicating that the tablet provides plasma concentrations of levetiracetam between 2.9 and 4.4 μg / mL.

[0035] Figure 4 This is a flowchart of one embodiment of a process for preparing levetiracetam delayed-release compositions (e.g., 190 mg and 220 mg tablets listed in Tables 1 and 2).

[0036] Figure 5 This study provides a multicenter, randomized, double-blind, placebo-controlled 78-week fixed-dose study design that evaluates low-dose levetiracetam 220 mg delayed-release tablets compared to placebo as a treatment for slowing the progression of mild cognitive impairment (MCI) in Alzheimer's disease (AD).

[0037] Figure 6 A graphical representation of the Clinical Dementia Score-Sum (CDR-SB) results over 78 weeks is provided. CDR-SB scores were assessed at baseline, and at 26, 52, and 78 weeks after treatment with levetiracetam (LEV) or placebo, including differences between the two groups over time.

[0038] Figure 7 Graphical representations of the Functional Activities Questionnaire (FAQ) scores over 78 weeks are provided. CDR-SB scores were assessed at baseline, and at 26, 52, and 78 weeks after treatment with levetiracetam (LEV) or placebo, including differences between the two groups over time.

[0039] Figure 8 A graphical representation of the changes in entorhinal cortex (ERC) volume at baseline and after 78 weeks of administration of levetiracetam (LEV) or placebo to APOE4 non-carriers is provided.

[0040] Figure 9Graphical representations of the Broadman region 35 (BA35) volume at baseline and the changes in BA35 volume after 78 weeks of administration of levetiracetam (LEV) or placebo to APOE4 noncarriers are provided. Invention Details

[0042] Unless otherwise defined herein, the scientific and technical terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art. Generally, the nomenclature and techniques used in the associations 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, for example, “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,” WH Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th Edition,” WH Freeman & Co., NY (1999); Gilbert et al., “Developmental Biology, 6th Edition,” Sinauer Associates, Inc., Sunderland, MA (2000).

[0043] Use the chemical terms used herein in accordance with the usual usage in the art, as illustrated in “The McGraw-Hill Dictionary of Chemical Terms,” Parker S., ed., McGraw-Hill, San Francisco, CA (1985).

[0044] All publications, patents, and published patent applications mentioned in this application are incorporated herein by reference in their entirety. In case of conflict, this specification (including its specific definitions) shall prevail.

[0045] In this specification, the word “comprise” or variations such as “comprises” or “comprising” should be understood to mean that the said integer (or component) or group of integers (or components) is included, but does not exclude any other integer (or component) or group of integers (or components).

[0046] Unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include the plural forms.

[0047] "Including" is used to mean "including, but not limited to". "Including" and "including, but not limited to" are used interchangeably.

[0048] The terms "patient," "subject," or "individual" are used interchangeably and refer to human or non-human animals. Patients, subjects, or individuals may include mammals such as humans, primates, livestock (including cattle, 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 a human.

[0049] "Prevention" of the occurrence or progression of cognitive decline or impairment refers to influencing cognitive performance so as not to decline or fall below the cognitive performance observed in the subject at the time of initial consultation or diagnosis, or delaying such decline or impairment.

[0050] “Slowing down” the onset or progression of cognitive decline refers to delaying the progression of cognitive decline in a subject. This can be determined by a physician using well-known cognitive or functional assessments (e.g., the Alzheimer’s Disease Comprehensive Score (ADCOMS), the Alzheimer’s Disease Rating Scale-Cognitive Subscale (ADAS-Cog), the Alzheimer’s Disease Collaborative 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.

[0051] “Cognitive impairment” or “cognitive decline” refers to a subject’s cognitive performance being less than the expected normal range among subjects of similar age. In some cases, cognitive performance is reduced by approximately 5%, 10%, 30%, or more compared to the expected normal range of cognitive performance among subjects of similar age. In some cases, a subject’s “cognitive impairment” can refer to a subject’s cognitive performance being less than the expected normal range among age-matched subjects or less than that of younger adult subjects (e.g., subjects with average scores for a given age on cognitive performance tests).

[0052] "Pre-MCI" or "preclinical MCI" refers to subjects who show characteristics of MCI on clinical examination but lack impairment on neuropsychological examination. Subjects may exhibit biomarkers other than APOE4 that indicate a risk of progression.

[0053] "APOE4 carrier" or "APOE4 positive subject" refers to a subject who carries one or two copies of the apolipoprotein E4 (APOE4) allele. APOE is a protein involved in lipid metabolism in mammals and is polymorphic, with three major alleles: APOE2, APOE3, and APOE4. About 25% of the general population carries one copy of the APOE4 allele, and 2-3% of the general population carries two alleles. Genotyping techniques can be used to identify APOE4 carriers, including, but not limited to, restriction fragment length polymorphism (RFLPI) of genomic DNA (see, e.g., Dai, S., Long, Y. (2015). See: Batley, J. (ed.) Plant Genotyping. Methods in Molecular Biology, Vol. 1245. Humana Press, New York, NY.), random amplified polymorphism (RAPD) of genomic DNA (see, e.g., Williams JG, Kubelik AR, Livak KJ, Rafalski JA, Tingey SV. Nucleic Acids Res. 25 Nov 1990; 18(22): 6531-5.), and amplified fragment length polymorphism (AFLPD) (see, e.g., Paun O, P. Methods Mol Biol. 2012; 862:75-87.), polymerase chain reaction (PCR) (see, e.g., Waters DL, Shaper 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. 16 July 1993; 216(1-2):191-8), and hybridization with DNA microarrays or beads. "APOE4 non-carrier" or "APOE-negative subject" refers to a subject who does not carry the APOE4 allele. An APOE4 non-carrier can be a carrier of other APOE polymorphisms (including, but not limited to, APOE2 or APOE3) in their genome.

[0054] “Cognitive performance” refers to a subject’s measurable cognitive behavior or cognitive ability. There are several widely accepted tests in this field for assessing human cognitive performance, such as, but not limited to, the Clinical Changes Global Impression Scale (CIBIC-plus); the Mini-Mental State Examination (MMSE); the Neuropsychiatric Questionnaire (NPI); the Clinical Dementia Rating Scale (CDR); the Clinical Dementia Score Total (CDR-SB); the Cambridge Automated Neuropsychological Suite (CANTAB); the Sandoz Clinical Assessment of Geriatrics (SCAG); the Buschke Selective Reminder Test (Buschke and Fuld, 1974); the Verbal Matching Association Test; the Logical Memory Test; the Wechsler Memory Scale Visual Reproduction Subtest-Revised (WMS-R) (Wechsler, 1997); the Benton Visual Retention Test; or the MATRICS Consensus Neuropsychological Suite, which includes tests of working memory, processing speed, attention, verbal learning, visual learning, reasoning and problem-solving, and social cognition. See Folstein et al., J Psychiatric Res 12:189-98, (1975); Robbins et al., Dementia 5:266-81, (1994); Rey, L'examen clinique enpsychologie, (1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168-79, (1999); 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 cognitive testing in humans is the explicit three-point forced selection task. In this test, subjects are presented with colored photographs of common objects, consisting of a mixture of three types of image pairs: similar pairs, identical pairs, and irrelevant foils. The second of the similar object pairs is called a "decoy." These image pairs are completely randomized and presented individually as a series of images. Subjects are instructed to make judgments about whether the objects they see are new, old, or similar. A "similar" response to the presented decoy stimulus indicates successful memory retrieval by the subject.In contrast, referring to the bait stimulus as "old" or "new" indicates that the correct memory retrieval did not occur.

[0055] In addition to assessing cognitive performance, the progression of cognitive impairment and dementia can be monitored by evaluating alternative changes in the subject's brain. Alternative changes include, but are not limited to, changes in regional brain volume, degeneration of the anterior perforator pathway, and changes in brain function seen via resting-state fMRI (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 that can be used to monitor 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)). Degeneration of the anterior perforator pathway has been shown to be associated with age and reduced cognitive performance. For example, older adults with more anterior perforator pathway degeneration tend to perform worse on hippocampus-dependent memory tests. Degeneration of the anterior perforated pathway can be monitored in subjects using ultra-high resolution diffusion tensor imaging (DTI). Yassa et al., PNAS 107:12687-12691 (2010). Resting-state fMRI (R-fMRI) involves imaging the brain during rest and recording large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in temporally correlated fMRI signals between functionally related regions. Seed-based functional connectivity, independent component analysis, and / or frequency domain analysis of the signals are used to reveal functional connectivity between brain regions, particularly those 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 regions such as the posterior cingulate cortex, temporoparietal cortex, and prefrontal association cortex has been shown to be associated with cognitive decline and the degree of dementia. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 (2002).

[0056] "Pharmaceutically acceptable salts" include, but are not limited to, water-soluble and water-insoluble salts such as acetates, 4,4-diaminostilbene-2,2-disulfonates, benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, calcium salts, calcium ethylenediaminetetraacetate, camphorsulfonates, carbonates, chlorides, citrates, clavulariate, dihydrochlorides, ethylenediaminetetraacetate, ethanedisulfonates, estolates, esylates, fiunarates, gluconate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, and hydrobromide. Salts, hydrochlorides, hydroxynaphthylcarboxylate, iodides, hydroxyethyl sulfonate, lactates, lactobionates, laurates, magnesium salts, malates, maleates, mandelates, methanesulfonates, methyl bromide, methyl nitrates, methyl sulfates, mucilages, naphthalene sulfonates, nitrates, N-methylglucosamine ammonium salts, 3-hydroxy-2-naphthylcarboxylate, oleates, oxalates, palmitates, 1,1-methylene-bis-2-hydroxy-3-naphthylcarboxylate (einbonate), pantothenates, phosphates / bisphosphonates, picrates, polygalacturonic acids, propionates, p-toluenesulfonates, salicylates, stearates, hypoacetates, succinates, sulfates, sulfosalicylates, suramates, tannates, tartrates, 8-chlorotheophylline salts, toluenesulfonates, triethyl iodide, and valerates.

[0057] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" can refer to salts that retain the biological effectiveness and properties of a free base, are not biologically or otherwise undesirable, and are formed from: inorganic acids such as, but not limited to, hydrohalic acids, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexane, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethyl... Sulfonic acid, formic acid, fumaric acid, galactosic acid, gentic acid, glucoheponic acid, gluconic acid, glucuronic acid, glutamic acid, glutamate, 2-oxoglutamate, glycerophosphate, glycolic acid, hippuric acid, glycolic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoic 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, dihydroxynaphthalic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanate, p-toluenesulfonic acid, trifluoroacetic acid, undecenoic acid, etc.

[0058] Conversely, the salt form can be converted into the free form by treatment with a suitable base or acid.

[0059] Compositions and pharmaceuticals that can be used in the methods described in this disclosure

[0060] The compositions and pharmaceuticals that can be used in the methods and uses described in this disclosure are characterized by one or more of levetiracetam, buvascarbamazetam, or cetracetam, or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions and pharmaceuticals are characterized by levetiracetam, or a pharmaceutically acceptable salt thereof.

[0061] Levetiracetam refers to the compound (2S)-2-(2-oxopyrrolidone-1-yl)butyramide (IUPAC name). Levetiracetam is a widely used antiepileptic drug. Levetiracetam binds to a specific site in the CNS: synaptic vesicle protein 2A (SV2A) (see, e.g., Noyer et al. 1995; Fuks et al. 2003; Lynch et al. 2004; Gillard et al. 2006), and has been further shown to directly inhibit synaptic activity and neurotransmission by inhibiting the release of presynaptic neurotransmitters (Yang et al. 2007). Levetiracetam is an FDA-approved antiepileptic drug. For Sale. Levetiracetam is typically used. The effective therapeutic dose is in the range of 1000-3000 mg / day.

[0062] Levetiracetam is rapidly and almost completely absorbed after oral administration, and its bioavailability is unaffected by food. The plasma half-life of levetiracetam is approximately 7 ± 1 hours (expected to be 9–10 hours in older adults 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 two days of repeated twice-daily dosing.

[0063] The usual starting dose of levetiracetam for treating human epilepsy is 500 mg twice daily. The dose is then increased until optimal efficacy is achieved, up to a maximum of 3000 mg daily.

[0064] Brivaceran refers to the compound (2S)-2-[(4R)-2-oxo-4-propylpyrrolidine-1-yl]butyramide (IUPAC name). It possesses anticonvulsant activity and binds to SV2A in the brain. It is named after... Approved. The usual starting dose is 50 mg orally twice daily, with a maintenance dose of 25-100 mg orally twice daily.

[0065] Cetracetan refers to the compound (2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxopyrrolidine-1-yl]butyramide (IUPAC name). It is an antiepileptic drug that binds to SV2A in the brain.

[0066] In some embodiments, levetiracetam, buvaracetam, or cetracetam, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing, is administered every 12 hours (twice daily) or every 24 hours (once daily). In some embodiments, once daily administration is used. Administration at lower frequency intervals, such as every 6 hours, may also be used.

[0067] In some embodiments, levetiracetam or a pharmaceutically acceptable salt thereof (alone or as part of a pharmaceutical composition) is administered at 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 to 300 mg, or 200 to 300 mg, or 140 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, levetiracetam or a pharmaceutically acceptable salt thereof (alone or as part of a pharmaceutical composition) is administered at a daily dose of 190 mg to 220 mg. In some embodiments, levetiracetam or a pharmaceutically acceptable salt thereof (alone or as part of a pharmaceutical composition) is administered at a daily dose of 190 mg to 240 mg. In some embodiments, levetiracetam or a pharmaceutically acceptable salt thereof (alone or as part of a pharmaceutical composition) is administered at a daily dose of 220 mg. In some implementations, levetiracetam or a pharmaceutically acceptable salt thereof (either on its own or as part of a pharmaceutical composition) is administered at a daily dose of 190 mg.

[0068] In some embodiments of the methods disclosed herein, levetiracetam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing levetiracetam or a pharmaceutically acceptable salt thereof, is administered orally, in a delayed-release form (e.g., controlled-release, extended-release, sustained-release, delayed-release, or slow-release form), or in a single-unit dosage form or for once-daily administration. In some embodiments, the delayed-release pharmaceutical composition is in the form of tablets or capsules. In some embodiments, levetiracetam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing levetiracetam or a pharmaceutically acceptable salt thereof, is administered once or twice daily. In some embodiments, levetiracetam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing levetiracetam or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, levetiracetam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing levetiracetam or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, the administration is oral, in a single-unit dose, delayed-release form. In some embodiments, a delayed-release pharmaceutical composition of levetiracetam or a pharmaceutically acceptable salt thereof is in solid form.

[0069] In some embodiments of this disclosure, brivaceran or a pharmaceutically acceptable salt thereof (either alone or as part of a pharmaceutical composition) is administered at daily doses 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, 0.7-50 mg, 0.7-75 mg, 0.7-100 mg, 0.7-150 mg, 0.7-180 mg, 1.8-50 mg, 1.8-75 mg, 1.8-100 mg, 1.8-150 mg, 1.8-180 mg, 3.5-50 mg, 3.5-75 mg, 3.5-100 mg, 3.5-150 mg, 3.5-180 mg, 5-50 mg, 5-75 mg, 5-100 mg, Administer brivaceran or a pharmaceutically acceptable salt thereof (either on its own or as part of a pharmaceutical composition) at daily doses of 5-150 mg, 5-180 mg, 7-50 mg, 7-75 mg, 7-100 mg, 7-150 mg, 7-180 mg, 15-50 mg, 15-75 mg, 15-100 mg, 15-150 mg, 15-180 mg, 35-50 mg, 35-75 mg, 35-100 mg, 35-150 mg, or 35-180 mg.

[0070] In some embodiments, brivasertan or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing brivasertan or a pharmaceutically acceptable salt thereof, is administered orally, in a delayed-release form (e.g., controlled-release, extended-release, sustained-release, delayed-release, or slow-release form), or in a single-unit dosage form or for once-daily administration. In some embodiments, the delayed-release pharmaceutical composition is in the form of tablets or capsules. In some embodiments, brivasertan or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing brivasertan or a pharmaceutically acceptable salt thereof, is administered once or twice daily. In some embodiments, brivasertan or a pharmaceutical composition thereof is administered once daily in a single-use delayed-release form. In some embodiments, the delayed-release pharmaceutical composition is in a solid form. In some embodiments, the delayed-release pharmaceutical composition is in the form of tablets or capsules. In some embodiments, brivasertan or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing brivasertan or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, brivacertan or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising brivacertan or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, the administration is in the form of an oral, single-unit dose, delayed-release formulation. In some embodiments, the delayed-release pharmaceutical composition of brivacertan or a pharmaceutically acceptable salt thereof is in solid form.

[0071] In some embodiments, cetracetan or a pharmaceutically acceptable salt thereof (alone or as part of a pharmaceutical composition) is administered at 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 to 300 mg, or 200 to 300 mg, or 140 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, cetracetan or a pharmaceutically acceptable salt thereof (alone or as part of a pharmaceutical composition) is administered at a daily dose of 190 mg to 220 mg. In some embodiments, cetracetan or a pharmaceutically acceptable salt thereof (alone or as part of a pharmaceutical composition) is administered at a daily dose of 190 mg to 240 mg. In some embodiments, cetracetan or a pharmaceutically acceptable salt thereof (alone or as part of a pharmaceutical composition) is administered at a daily dose of 220 mg. In some implementations, cetracetan or a pharmaceutically acceptable salt thereof (either on its own or as part of a pharmaceutical composition) is administered at a daily dose of 190 mg.

[0072] In some embodiments of the methods disclosed herein, cetrachecillin or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing cetrachecillin or a pharmaceutically acceptable salt thereof, is administered orally, in a delayed-release form (e.g., controlled-release, extended-release, sustained-release, delayed-release, or slow-release form), or as a single-unit dosage form or for once-daily administration. In some embodiments, the delayed-release pharmaceutical composition is in the form of tablets or capsules. In some embodiments, cetrachecillin or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing cetrachecillin or a pharmaceutically acceptable salt thereof, is administered once or twice daily. In some embodiments, cetrachecillin or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing cetrachecillin or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, cetrachecillin or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing cetrachecillin or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, the administration is oral, in a single-unit dose, delayed-release form. In some embodiments, the delayed-release pharmaceutical composition of cetrachecillin or a pharmaceutically acceptable salt thereof is in solid form.

[0073] In some embodiments of the methods and uses disclosed herein, 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-350 mg of hydroxypropyl methylcellulose, 1.2 mg-1.4 mg of colloidal silica, 92.8 mg-119.2 mg of silanized microcrystalline cellulose, and 6.0 mg-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 silica, 92.8 mg of silanized 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 silica, 119.2 mg of silanized microcrystalline cellulose, and 6.7 mg of magnesium stearate. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208. In some embodiments, the silanized microcrystalline cellulose is silanized 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, delayed-release form. In some embodiments, the delayed-release pharmaceutical composition is in solid form. In some embodiments, the delayed-release pharmaceutical composition is in the form of tablets or capsules. In some embodiments, the oral, delayed-release form is in a 220 mg unit dosage form for once-daily administration.

[0074] In some embodiments of the methods and uses disclosed herein, the daily dose of levetiracetam in the pharmaceutical composition is 220 mg, and the pharmaceutical composition further comprises 280 mg-350 mg of hydroxypropyl methylcellulose, 1.2 mg-1.4 mg of colloidal silica, 92.8 mg-119.2 mg of silanized microcrystalline cellulose, and 6.0 mg-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 silica, 92.8 mg of silanized 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 silica, 119.2 mg of silanized microcrystalline cellulose, and 6.7 mg of magnesium stearate. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208.

[0075] In some embodiments of the methods and uses of this 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 hydroxypropyl methylcellulose, 1.2 mg colloidal silica, 102.8 mg silanized microcrystalline cellulose or anhydrous dicalcium phosphate, and 6 mg magnesium stearate. In some embodiments of the methods and uses of this disclosure, the daily dose of levetiracetam in the pharmaceutical composition is 190 mg, and the pharmaceutical composition further comprises 300 mg hydroxypropyl methylcellulose, 1.2 mg colloidal silica, 102.8 mg silanized microcrystalline cellulose or anhydrous dicalcium phosphate, and 6 mg magnesium stearate. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208. In some embodiments, the silanized microcrystalline cellulose is silanized 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, delayed-release form. In some embodiments, the delayed-release pharmaceutical composition is in a solid form. In some embodiments, the delayed-release pharmaceutical composition is in the form of tablets or capsules. In some embodiments, the oral, delayed-release form is a 190 mg unit dosage form for once-daily administration.

[0076] In some embodiments, a pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is in a delayed-release form, providing a steady-state plasma concentration of levetiracetam in the subject between 1.9 μg / mL and 4.4 μg / mL over a period of at least 8 hours following administration and within a 24-hour period after administration. In some embodiments, a pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is in a delayed-release form, providing a steady-state plasma concentration of levetiracetam in the subject between 1.9 μg / mL and 4.4 μg / mL over a period of at least 13 hours following administration and within a 24-hour period after administration. In some embodiments, a pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is in a delayed-release form, providing a steady-state plasma concentration of levetiracetam in the subject between 1.9 μg / mL and 4.4 μg / mL over a period of at least 13 hours following administration and within a 24-hour period after administration. In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam is in a delayed-release form, providing a steady-state plasma concentration of levetiracetam in the subject between 1.9 μg / mL and 4.4 μg / mL for at least 8 hours within a 24-hour period following administration. In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam is in a delayed-release form, providing a steady-state plasma concentration of levetiracetam in the subject between 1.9 μg / mL and 4.4 μg / mL for at least 13 hours within a 24-hour period following administration. In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam is in a delayed-release form, providing a steady-state plasma concentration of levetiracetam in the subject between 1.9 μg / mL and 4.4 μg / mL for at least 13 hours within a 24-hour period following administration. In other embodiments, the pharmaceutical composition provides the steady-state plasma concentration of levetiracetam in the subject between 1.9 μg / mL and 4.4 μg / mL within 1 hour after administration and for at least 13 to 16 hours over a 24-hour period following administration. See, for example, WO2016191288.

[0077] In some embodiments, a pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is formulated as an oral form, a delayed-release form, a single-unit dosage form, or for once-daily administration, or one or more thereof. In some embodiments, the delayed-release form is a controlled-release form, an extended-release form, a sustained-release form, a delayed-release form, or a slow-release form. In some embodiments, the delayed-release pharmaceutical composition of levetiracetam or a pharmaceutically acceptable salt thereof is in solid form. In some embodiments, the delayed-release pharmaceutical composition of levetiracetam or a pharmaceutically acceptable salt thereof is in tablet or capsule form.

[0078] Table 1 provides a description of three delayed-release oral formulations of levetiracetam (190 mg tablets A, B, and C). In some embodiments, the pharmaceutical composition used in the methods and uses of this disclosure is selected from the group of formulations in Table 1. In one embodiment of the methods and uses of this disclosure, the pharmaceutical composition is 190 mg tablet formulation A.

[0079] Table 1: Methods for preparing a delayed-release composition containing 190 mg levetiracetam

[0080]

[0081] Table 2 provides descriptions of two delayed-release formulations of levetiracetam (220 mg tablets D and E). In some embodiments of the methods and uses described in this disclosure, the pharmaceutical composition is selected from the group of formulations in Table 2. In one embodiment, the pharmaceutical composition is 220 mg tablet D.

[0082] Table 2: Method for preparing a delayed-release composition containing 220 mg levetiracetam

[0083]

[0084]

[0085] In addition to oral delivery, pharmaceutical compositions and drugs that can be used in the methods and uses described in this disclosure may also be formulated for inhalation delivery (lung and nasal delivery). In such a form, they may be delivered by means of devices and in forms including, but not limited to, a variety of pressurized metered inhalers, dry powder inhalers, nebulizers, water mist inhalers, drops, solutions, suspensions, sprays, powders, gels, ointments and specialized 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).

[0086] Pharmaceutical compositions and drugs that can be used in the methods and uses described in this disclosure may also be formulated for transdermal delivery, in forms including, but not limited to, colloids, patches and microemulsions.

[0087] Pharmaceutical compositions and pharmaceuticals that can be used in the methods and uses described in this disclosure may also include excipients such as preservatives, wetting agents, emulsifiers, and dispersants. Antimicrobial activity can be provided by including various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenolic sorbic acid, etc.). It may also be necessary to include isotonic agents such as sugars and sodium chloride in the pharmaceutical compositions.

[0088] Pharmaceutical compositions and medicaments that can be used in the methods and uses described herein can be prepared using methods well known in the pharmaceutical field, see, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics, 10th edition, J.G. Hardman, L.E. Limbird, and A.G. Gilman, eds., McGraw Hill, New York, 2001; Ansel et al., Pharmaceutical Calculations, The Pharmacist's Handbook, 2004, Lippincott Williams & Wilkins; Stoklosa et al., Pharmaceutical Calculations, 11th edition, 2001 (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

[0089] Example 1: Levetiracetam Composition

[0090] It can be done Figure 4 The flowchart illustrates the method for preparing compositions containing levetiracetam. In short, silanized microcrystalline cellulose ProSolv... TM SMCC HD90 (or Encompress, anhydrous dicalcium phosphate) was depolymerized and sieved through a US #30 mesh sieve, and then blended with colloidal silica (16-quart V-shell mixer; 75 rpm ± 5 rpm). The blended sample was then passed through a round 1601 impeller (2A024R sieve). 220 mg levetiracetam and hydroxypropyl methylcellulose 2208 (Methocel) TM K15M Premium CR (or Methocel) TM K100M Premium CR was also depolymerized and sieved through a US #30 mesh sieve, and then mixed with milled siliconized microcrystalline cellulose ProSolv in a 1 cubic foot inclined cone mixer (250 rpm ± 5 rpm). TMHD90 and colloidal silica were blended. The blended sample was then passed through a circular 1601 impeller (2A024R sieve) and then mixed with sieved magnesium stearate in a 1 cubic foot inclined cone mixer (125 rpm ± 5 rpm). (Sieved through a US #30 mesh sieve) Blend. Compress the blended sample into tablets. Optionally, coat the tablets with a hydroxypropyl methylcellulose-based (HPMC-based) coating (such as... A complete film coating system is used for film coating. A similar method can be used for compositions containing 190 mg of levetiracetam.

[0091] Example 2: Evaluation of levetiracetam plasma levels

[0092] Previously, aMCI clinical trials and aged rat studies disclosed in WO2016191288 (which is incorporated herein by reference in its entirety) determined the range of steady-state levetiracetam plasma concentrations effective for treating cognitive impairment. In one embodiment, the concentration range of levetiracetam is between 2.9 and 4.4 μg / mL. In another embodiment, the concentration range of levetiracetam is between 1.9 and 4.4 μg / mL. In yet another, the effective plasma concentration is between 1.9 and 3.9 μg / mL. See also Figure 1 .

[0093] This example further describes a two-group, single-dose, two-period, bidirectional crossover food effect study of two delayed-release levetiracetam formulations (i.e., 190 mg tablet A in Table 1 and 220 mg tablet D in Table 2).

[0094] Research Design

[0095] This was an open-label, randomized, two-group, single-dose, two-period crossover study of food effects. Fifty-six (56) healthy participants were recruited. Participants who successfully completed the screening process were enrolled at the research center the night before the first dose. Participants who continued to meet the inclusion / exclusion criteria on the morning of the dose were assigned participant numbers based on the order in which they successfully completed the required screening process and procedures. Dosing days were separated by a washout period of at least 7 days. Participants were randomly assigned to one of the following two groups:

[0096] Group 1: Subjects (n=28) received the delayed-release tablet A (190mg) in Table 1.

[0097] Treatment A: Tablet A

[0098] Dosage = 1 x 190 mg tablets, administered orally under fasting conditions.

[0099] Treatment B: Tablet A

[0100] Dosage = 1 x 190 mg tablet, administered orally with food.

[0101] Group 2: Subjects (n=28) received the delayed-release tablet D (220mg) as shown in Table 2.

[0102] Treatment A: Tablet D

[0103] Dosage = 1 x 220 mg tablet, administered orally under fasting conditions.

[0104] Treatment B: Tablet D

[0105] Dosage = 1 x 220 mg tablet, administered orally with food.

[0106] Clinical Procedure Overview

[0107] During each study cycle, a 6 mL blood sample was obtained before each dose and after each dose at selected times up to 24 hours post-dose. A total of 34 pharmacokinetic blood samples were collected from each subject, with 17 samples per study cycle. In addition, blood and urine were drawn for clinical laboratory testing at screening and study exit.

[0108] During each study cycle, subjects were allowed to enter the study unit the night before the scheduled dose. During each study cycle, subjects were confined to the research center until 24-hour blood collection and other study procedures were completed.

[0109] Procedure for collecting samples for pharmacokinetic analysis

[0110] Blood samples (1 x 6 mL) were collected in vacuum blood collection tubes containing K2-EDTA as a preservative before (0) and at 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 after administration.

[0111] Overview of Bioanalysis

[0112] Levetiracetam in plasma samples was analyzed using a validated LC-MS procedure. The method was validated for levetiracetam in the range of 0.0500 to 30.0 μg / mL based on the analysis of 0.200 mL of human EDTA-treated plasma. Data was stored in the Watson Laboratory Information Management System (LIMS; version 7.2.0.03, Thermo Fisher Scientific).

[0113] Pharmacokinetic analysis

[0114] Data were analyzed using non-compartmental methods in WinNonlin. Concentration-time data below the limit of quantitation (BLQ) were treated as zero in data summaries and descriptive statistics. In pharmacokinetic analyses, BLQ concentrations from time zero until the first quantifiable concentration was observed were treated as zero; embedded and / or terminal BLQ concentrations were treated as "missing". Actual sample times were used for all pharmacokinetic and statistical analyses.

[0115] Calculate the following pharmacokinetic parameters: peak plasma concentration (C0). max ), time to reach peak concentration (T) max ), elimination rate constant (λz), and final half-life (T) 1 / 2 The area under the concentration-time curve (AUC) from time zero to the final quantifiable concentration. last ) and the area under the plasma concentration-time curve extrapolated from time zero to infinity (AUC) inf Additionally, C max AUC last and AUC inf Dosage normalization.

[0116] Steady-state modeling

[0117] Based on steady-state modeling of the PK curve for 190 mg tablet A, plasma concentrations of levetiracetam ranged from 1.9 to 4.4 μg / mL for most of the 24-hour post-administration period. See also Figure 2 .

[0118] Steady-state modeling of the PK curve for 220 mg tablet D showed that plasma concentrations of levetiracetam ranged from 2.9 to 4.4 μg / mL for most of the 24-hour post-administration period. See also... Figure 3 .

[0119] Example 3: 220mg levetiracetam delayed-release tablets for slowing the progression of mild cognitive impairment caused by Alzheimer's disease (AD). Evaluation of the progression of Known Injury (MCI)

[0120] This example describes a phase IIb multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of low-dose levetiracetam 220 mg delayed-release tablets in slowing the progression of MCI in Alzheimer's disease (prodromal Alzheimer's disease). The results were evaluated using the recognized and accepted Clinical Dementia Score-Sum (CDR-SB).

[0121] Subjects

[0122] The participants in this study were aged 55 to 85 years (inclusive), in good general health, willing and able to consent to and participate in the duration of the study, had an eighth-grade education or a good work history sufficient to exclude intellectual disability, sufficient visual and auditory sensitivity to undergo neuropsychological testing, and fluency in their native language to participate in all neuropsychological assessments. Clinical assessments of 63 participants were used for analysis.

[0123] APOE4 carrier status confirmed.

[0124] Blood samples were taken from each subject to determine APOE4 carrier status. Genomic DNA was prepared from the blood samples according to standard procedures. The mass 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. DNA sequencing analysis was based on the termination of elongated DNA chains due to the incorporation of dye-labeled ddNTPs by DNA polymerase, according to the chain termination method of Sanger et al. (Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. Dec 1977; 74(12):5463-7). The obtained dye-labeled products were detected using an automated sequencing platform. The DNA sequence was obtained from JSI-medical The data was analyzed using SEQPATIENT software.

[0125] Research Design

[0126] The study included a 5-week screening period (consisting of 3 visits) and a 78-week treatment period (consisting of 10 visits: 1 baseline visit, 3 telephone visits, and 6 outpatient visits). See also Figure 5 The primary endpoint of the study was to analyze the change in CDR-SB score from baseline to week 78. Secondary endpoints included analyzing the change in Functional Activities Questionnaire (FAQ) score from baseline to week 78. Subjects received a low-dose levetiracetam 220 mg delayed-release tablet or placebo in the morning, which were identical in appearance and were a one-unit oral dosage form.

[0127] Clinical Dementia Rating Scale-Sum (CDR-SB)

[0128] The CDR-SB test was performed using a standard methodology. In short, subjects were tested using six categories, or “boxes,” including memory, orientation, judgment and problem-solving, social affairs, family and hobbies, and personal care. The CDR-SB score was calculated by summing the box scores. The total score ranged from 0 to 18, with higher scores indicating greater impairment. Descriptive statistics were used to summarize the absolute values ​​and changes relative to baseline in the CDR-SB, presented in the APOE4 non-carrier status. Table 3 summarizes the statistical analysis, where each cell contains a point estimate followed by a 95% confidence interval (CI). Figure 6 The graph shows a representation of CDR-SB scores at baseline, and at 26, 52, and 78 weeks after treatment with levetiracetam (LEV) or placebo. In summary, APOE4 non-carriers showed a surprising and unexpected 36.8% decrease in CDR-SB scores after 78 weeks of treatment with low-dose levetiracetam 220 mg delayed-release tablets compared to placebo-treated non-carriers, with the greatest effect observed between weeks 52 and 78 of treatment.

[0129] Table 3: CDR-SB change score as an estimate of treatment effect and mean value

[0130] APOE4 non-carriers (n=63) LEV Change Rating 0.96 (CI: 0.08, 2.01) Placebo Change Score 1.52 (CI: 0.85, 2.62) Treatment efficacy (differences) -0.56 (CI: -1.90, 0.47)

[0131] Exemplary methods and materials have been described, but similar or equivalent methods and materials may also be used in the practice or testing of various aspects and embodiments. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0132] Analysis of the primary efficacy endpoint revealed that, for the entire study population, at week 78, the mean CDR-SB change score was 1.12 in the levetiracetam group and 1.22 in the placebo group, with an estimated mean treatment effect of -0.10 (p = 0.71). In the APOE-4 carrier subgroup, at week 78, the mean CDR-SB change score was 0.95 in the levetiracetam group (n = 54) and 1.05 in the placebo group (n = 45), with an estimated mean treatment effect of -0.10. However, in the APOE-4 non-carrier subgroup, at week 78, the mean change from baseline was 0.68 in the levetiracetam group (n = 26) and 1.13 in the placebo group (n = 37), with an estimated mean treatment effect of -0.45.

[0133] Secondary Outcomes - Functional Activities Questionnaire (FAQ) Scoring

[0134] FAQ scores are obtained to measure an individual's functional abilities over time. In short, the FAQ measures instrumental activities of daily life, such as preparing meals and balancing a checkbook, because these functional changes are detected earlier in the course of dementia compared to more basic activities. The questionnaire contains 10 questions, each answered using a 0-3 rating system, where 0 represents normal function and 3 represents dependence on others to complete tasks. Therefore, the total score ranges from 0 to 30, with higher scores associated with greater impairment. Figure 7 Graphical representations of FAQ scores at baseline, and at 26, 52, and 78 weeks after treatment with levetiracetam (LEV) or placebo are shown. In summary, APOE4 non-carriers showed a surprising and unexpected decrease in FAQ scores after 78 weeks of treatment with low-dose levetiracetam 220 mg delayed-release tablets compared to placebo-treated non-carriers, with the greatest effect observed between weeks 26 and 52 of treatment.

[0135] Exemplary methods and materials have been described, but similar or equivalent methods and materials may also be used in the practice or testing of various aspects and embodiments. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0136] Analysis of secondary efficacy endpoints revealed that, for the entire study population, the estimated mean FAQ score at week 78 was 3.82 (95% CI: 2.10, 5.17) relative to baseline in the levetiracetam group and 3.81 (95% CI: 2.38, 5.59) in the placebo group. In the APOE-4 carrier subgroup, the mean change in total FAQ score from baseline to week 78 was 5 in the levetiracetam group (n=54) and 3.3 in the placebo group (n=45). However, in the APOE-4 non-carrier subgroup, the mean change in total FAQ score from baseline to week 78 was 1.8 in the levetiracetam group (n=26) and 4.1 in the placebo group (n=37).

[0137] Volumetric MRI of the medial temporal lobe subregion

[0138] To examine whether levetiracetam treatment, in addition to its observed effect on CDR-SB scores, also showed an effect on cortical atrophy in APOE-4 non-carriers (the same subjects and groups as described above), an analysis of cortical volume changes with treatment status was performed. Prior to the trial, target brain regions were selected a priori based on the location of post-mortem tau accumulation in the early stages of AD (Braak et al., Acta Neuropathologica, 112(4):389-404(2006); Braak and Braak, Acta Neuropathologica, 80(5):479-486(1990)) and the significant atrophy of entorhinal cortex volume in AD. For this purpose, the Automatic Hippocampal Subregion Segmentation (ASHS) software (Xie et al., Hum Brain Mapp. 40:3431-3451(2019)) was used. The software provides coverage areas including the left and right entorhinal cortex (ERC), the Broadman area 35 (BA35) which largely overlaps with the TEC (Braak et al., Acta Neuropathologica, 112(4):389-404(2006); Braak and Braak, Acta Neuropathologica, 80(5):479-486(1990)), and portions of the periaristal cortex and BA36, which primarily covers the periaristal cortex (Xie et al., 2019).

[0139] High-resolution T1-weighted MRI images of the subjects' brains were collected at baseline and at 78 weeks using an MRI scanner.

[0140] Automatic segmentation using ASHS

[0141] Automatic segmentation of T1-weighted MRI images using the ASHS-T1 open-source software, and see also Xie et al., Hum Brain Mapp. 40:3431-3451 (2019).

[0142] T1-weighted MRI images were analyzed using the ASHS-T1 open-source software, and see also Xie et al., Hum BrainMapp. 40:3431-3451 (2019). Volume and thickness measurements of ERC and BA35 were extracted for each subject. The quality of all automatically segmented data generated by ASHS was visually examined. The procedure was based on baseline and week 78 T1-weighted MRI scans for all subjects.

[0143] All statistical analyses were two-tailed analyses, with a significance level of p = 0.05.

[0144] result

[0145] For APOE-4 non-carrier subjects, there was no difference in ERC volume at baseline between subjects assigned to the placebo group (n=37) or the levetiracetam treatment group (n=26). At the end of week 78 of the trial visit, the levetiracetam treatment group showed a significantly reduced reduction in left-sided ERC volume compared to the placebo group (LEV treatment group: -1.878% mean volume change, placebo group: -6.185% mean volume change (p=0.048)). Figure 8 The baseline volume of BA35 in APOE-4 non-carriers did not differ between groups at baseline. At the end of week 78 of the trial visit, the levetiracetam treatment group showed a reduction in right-sided BA35 volume compared to the placebo group (LEV treatment group: -0.789% mean volume change, placebo group: -4.758% mean volume change (p = 0.094)). Figure 9 ).

Claims

1. A method for preventing or slowing the progression of cognitive impairment in a non-APOE4 carrier subject or preventing the occurrence of cognitive decline or reducing the rate of cognitive decline, the method comprising administering to the subject one or more of levetiracetam, brivaracetam, or cetracetam or a pharmaceutically acceptable salt thereof, wherein levetiracetam, brivaracetam, or cetracetam is administered at a daily dose of 0.7-350 mg, or the method comprising administering to the subject a pharmaceutical composition comprising a daily dose of levetiracetam, brivaracetam, or cetracetam or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

2. The method of claim 1, wherein the APOE4 non-carrier subject carries a non-APOE4 genetic risk factor for cognitive impairment.

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

4. The method of claim 1, wherein the subject exhibits or displays volume atrophy in the medial temporal lobe subregion.

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

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

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

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

9. The method of claims 1-8, wherein the subject suffers from mild precognitive impairment.

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

11. The method of any one of claims 1, 2 or 10, wherein the subject suffers from Alzheimer's disease (AD) or mild cognitive impairment due to prodromal AD.

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

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

14. The method of any one of claims 1-12, wherein the daily dose of brovacertan is 0.7-180 mg.

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

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

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

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

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

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

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 wherein the pharmaceutical composition further comprises 280 mg-350 mg of hydroxypropyl methylcellulose, 1.2 mg-1.4 mg of colloidal silica, 92.8 mg-119.2 mg of silanized microcrystalline cellulose and 6.0 mg-6.7 mg of magnesium stearate.

22. The method of claim 21, wherein the pharmaceutical composition comprises 280 mg hydroxypropyl methylcellulose, 1.2 mg colloidal silica, 92.8 mg silanized microcrystalline cellulose and 6.0 mg magnesium stearate.

23. The method of claim 21, wherein the pharmaceutical composition comprises 347.5 mg hydroxypropyl methylcellulose, 1.4 mg colloidal silica, 119.2 mg silanized microcrystalline cellulose and 6.7 mg magnesium stearate.

24. 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 wherein the pharmaceutical composition further comprises 300 mg hydroxypropyl methylcellulose, 1.2 mg colloidal silica, 102.8 mg silanized microcrystalline cellulose or anhydrous dicalcium phosphate and 6 mg magnesium stearate.

25. The method of any one of claims 21-24, wherein the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208.

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

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

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

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

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

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

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

33. A method for delaying or reducing the rate of volume atrophy in the medial temporal lobe subregion of a non-APOE4 carrier subject, the method comprising administering to the subject one or more of levetiracetam, brivaracetam, or cetracetam, or a pharmaceutically acceptable salt thereof, wherein levetiracetam, brivaracetam, or cetracetam is administered at a daily dose of 0.7-350 mg, or the method comprising administering to the subject a pharmaceutical composition comprising a daily dose of levetiracetam, brivaracetam, or cetracetam, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

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

36. The method of claim 33, wherein the medial temporal lobe subregion is the trans-entorhinal cortex (BA35).

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

38. A method for delaying or reducing the rate of atrophy of the entorhinal cortex (ERC) in a non-APOE4 carrier subject, the method comprising administering to the subject one or more of levetiracetam, brivaracetam, or cetracetam, or a pharmaceutically acceptable salt thereof, wherein levetiracetam, brivaracetam, or cetracetam is administered at a daily dose of 0.7-350 mg, or the method comprising administering to the subject a pharmaceutical composition comprising a daily dose of levetiracetam, brivaracetam, or cetracetam, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

40. The method of any one of claims 33-39, wherein the APOE4 non-carrier subject carries a non-APOE4 genetic risk factor for cognitive impairment.

41. The method of any one of claims 33-39, wherein the subject exhibits or displays cognitive performance below the normal range for his age.

42. The method of any one of claims 33, wherein the subject exhibits or displays volume atrophy in the medial temporal lobe subregion.

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

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

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

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

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

48. The method of any one of claims 33-47, wherein the subject suffers from mild precognitive impairment.

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

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

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

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

53. The method of any one of claims 33-51, wherein the daily dose of brovacertan is 0.7-180 mg.

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

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

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

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

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

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

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 wherein the pharmaceutical composition further comprises 280 mg-350 mg of hydroxypropyl methylcellulose, 1.2 mg-1.4 mg of colloidal silica, 92.8 mg-119.2 mg of silanized microcrystalline cellulose and 6.0 mg-6.7 mg of magnesium stearate.

61. The method of claim 60, wherein the pharmaceutical composition comprises 280 mg hydroxypropyl methylcellulose, 1.2 mg colloidal silica, 92.8 mg silanized microcrystalline cellulose and 6.0 mg magnesium stearate.

62. The method of claim 60, wherein the pharmaceutical composition comprises 347.5 mg hydroxypropyl methylcellulose, 1.4 mg colloidal silica, 119.2 mg silanized microcrystalline cellulose and 6.7 mg magnesium stearate.

63. 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 wherein the pharmaceutical composition further comprises 300 mg hydroxypropyl methylcellulose, 1.2 mg colloidal silica, 102.8 mg silanized microcrystalline cellulose or anhydrous dicalcium phosphate and 6 mg magnesium stearate.

64. The method of any one of claims 60-63, wherein the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208.

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

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

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

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

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

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

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

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