ALZ-801 Used to Treat Alzheimer's Disease

Abstract

Provided herein are methods of treating Alzheimer's disease using increased doses of ALZ-801.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 287,552, filed December 9, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Alzheimer's disease (AD) currently ranks as the sixth leading cause of death in the United States. AD symptoms worsen over time, but the rate at which the disease progresses can vary. The stages of AD are divided into three categories: early, intermediate, and late AD (also commonly referred to as mild, moderate, and severe AD). Because Alzheimer's disease affects different people differently, the way symptoms manifest or the disease progresses can also vary from person to person.

[0003] ALZ-801 is a promising novel treatment for AD and is currently being studied in clinical trials in subjects with early AD (MMSE>22). Initial data using 265 mg of ALZ-801 administered orally twice daily (BID) showed approximately 125% efficacy in cognition (ADAS-cog) and 81% efficacy in function (CDR-SB) compared to placebo. See, e.g., Tolar, et al., Int. J. Mol. Sci. 2021, 22, 6355. ALZ-801 has good blood-brain barrier permeability and the ability to target toxic soluble amyloid oligomers.

[0004] Despite these benefits, there remains a need to treat patients with moderate to severe AD (MMSE<22). Summary of the Invention

[0005] It has now been found that doses of ALZ-801 greater than 530 mg / day (e.g., 265 mg BID) can induce disease-modifying effects in subjects with moderate to more severe AD. Evidence of this newly discovered effect was observed in a recent compassionate use study conducted under an Expanded Access IND. See, for example, the following compassionate use study: A 73-year-old female subject diagnosed with severe neurocognitive disorder of the Alzheimer's type (i.e., considered based on symptoms to have an MMSE<22) initially showed improvement and stabilization of symptoms after treatment with 265 mg ALZ-801 BID, but showed cognitive improvement and / or regression of associated symptoms after or at the end of a 14-month treatment period. Notably, when the subject's ALZ-801 dose was increased from 265 mg BID to 265 mg TID, the subject's motivation, speech, physical activity, activities of daily living (i.e., cooperative interactions with caregivers, ability to perform light tasks, etc.), mood, and gait rapidly and clearly improved. The higher dose was also well tolerated. This initial period of clinical improvement lasted for approximately one year, after which the subject began to show decline characterized by cognitive deterioration, apathy, and overall decreased activity. After a total of approximately 15 months of taking ALZ-801 265 mg TID, the subject's dosage was increased to 265 mg QID (four times a day). The subject has been taking this QID medication for the past six months. As with the TID dosing, the QID dosing was well tolerated, and the subject improved during the later stages of the TID dosing regimen, showing increased alertness, increased responsiveness, and a more positive attitude.

[0006] Thus, in one embodiment, a method is provided for treating AD in a subject by administering to a subject having moderate to more severe Alzheimer's disease (e.g., an MMSE score of less than 22) at least about 700 mg / day of ALZ-801.

[0007] In other aspects, methods are provided for treating Alzheimer's disease by a) administering to a subject a first dose of ALZ-801 over a period of about 50 weeks or more, or until the subject shows a diminished therapeutic response to the first dose of ALZ-801 of about 400 mg / day to about 600 mg / day (e.g., about 530 mg / day), and b) subsequently administering a second dose of ALZ-801 that is at least 1.5 times the first dose (e.g., at least about 700 mg / day).

[0008] In certain embodiments, if the subject exhibits a decreased therapeutic response to the second dose, the subject is administered a third dose that is at least twice the first dose (e.g., at least about 1000 mg / day).

[0009] Additionally, methods are provided for treating Alzheimer's disease in a subject using at least about 700 mg / day, such as about 265 mg TID, or at least about 1000 mg / day, such as about 265 mg QID, of ALZ-801.

[0010] In certain embodiments, subjects treated by the subject methods have an MMSE score below a particular threshold or within a particular range.

[0011] In certain embodiments, the subject treated by the subject method has moderate to severe AD. In other embodiments, the subject treated by the subject method has mild AD and has progressed to a worsening mild AD, or to moderate or severe AD (e.g., as determined by one or more cognitive tests or other methods). In other embodiments, the subject treated by the subject method has moderate AD and has progressed to severe AD.

[0012] In certain embodiments, the subject treated by the subject methods is APOE4 positive. [Brief description of the drawings]

[0013] [Figure 1A]1 is a graph showing steady-state tramiprosate plasma AUC at different ALZ-801 dosing frequencies. [Figure 1B] 1 is a graph showing Cmax at different dosing frequencies of ALZ-801. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] As part of a first embodiment, provided herein is a method of treating Alzheimer's disease in a subject, comprising administering to the subject at least about 700 mg / day (e.g., about 795 mg / day) of ALZ-801.

[0015] ALZ-801 has the following structure: [ka] It refers to valyl-3-amino-1-propanesulfonic acid, represented by:

[0016] The terms "subject" and "patient" are used interchangeably. In one embodiment, the subject is a human. In some embodiments, the subject is a human under 100 years of age, under 95 years of age, under 90 years of age, or under 85 years of age. In other embodiments, the subject is a human between 65 and 100 years of age, between 65 and 95 years of age, between 65 and 90 years of age, or between 65 and 85 years of age. In yet other embodiments, the subject is a human over 58 years of age. In still other embodiments, the human is in need of treatment.

[0017] As used herein, the terms "treat," "treating," or "treatment" refer to reversing, ameliorating, inhibiting, or slowing the progression of Alzheimer's Disease (AD), including cognitive decline or one or more symptoms associated therewith.

[0018] As part of a second embodiment, provided herein is a method of treating Alzheimer's disease in a subject, the method comprising: a) administering to the subject about 400 mg / day to about 600 mg / day (e.g., about 530 mg / day) of ALZ-801 for a period of about 50 weeks or more; and b) thereafter administering at least about 700 mg / day (e.g., about 795 mg / day) of ALZ-801. Alternatively, as part a) of the second embodiment, the subject is administered about 400 mg / day to about 600 mg / day (e.g., about 530 mg / day) of ALZ-801 for a period of about 52 weeks or more. In another alternative, as part a) of the second embodiment, the subject is administered about 400 mg / day to about 600 mg / day (e.g., about 530 mg / day) of ALZ-801 for a period of about 55 weeks or more, about 60 weeks or more, about 65 weeks or more, about 70 weeks or more, about 75 weeks or more, or about 80 weeks or more. In another alternative, as part a) of the second embodiment, the subject is administered about 400 mg / day to about 600 mg / day (e.g., about 530 mg / day) of ALZ-801 for a period of about 50 weeks to about 80 weeks, about 50 weeks to about 75 weeks, about 50 weeks to about 70 weeks, about 50 weeks to about 65 weeks, about 52 weeks to about 80 weeks, about 52 weeks to about 75 weeks, about 52 weeks to about 70 weeks, or about 52 weeks to about 65 weeks.

[0019] As part of a third embodiment, provided herein is a method of treating Alzheimer's disease in a subject, the method comprising: a) administering to the subject about 400 mg / day to about 600 mg / day (e.g., about 530 mg / day) of ALZ-801 until the subject shows a decreased therapeutic response to such administration; and b) thereafter administering at least about 700 mg / day (e.g., about 795 mg / day) of ALZ-801.

[0020] In some aspects of the first, second, and third embodiments, at least about 700 mg / day of ALZ-801 administered to a subject refers to an amount of at least about 750 mg / day of ALZ-801, about 750 mg / day of ALZ-801, about 700 mg / day to about 1.0 g / day, about 795 mg / day of ALZ-801, or about 265 mg of ALZ-801 TID.

[0021] As part of a fourth embodiment, provided herein is a method of treating Alzheimer's disease in a subject, the method comprising: a) administering to the subject about 400 mg / day to about 600 mg / day (e.g., about 530 mg / day) of ALZ-801 for a first period of about 50 weeks or more; b) administering at least about 700 mg / day (e.g., about 795 mg / day) of ALZ-801 for a second period of 35 weeks or more; and c) thereafter administering at least about 1.0 g / day (e.g., about 1.06 g / day) of ALZ-801.

[0022] In some aspects of the fourth embodiment, the first period of time is about 52 weeks or more, about 55 weeks or more, about 60 weeks or more, about 65 weeks or more, about 70 weeks or more, about 75 weeks or more, about 80 weeks or more, 50 weeks to about 80 weeks, 50 weeks to about 75 weeks, 50 weeks to about 70 weeks, 50 weeks to about 65 weeks, about 52 weeks to about 80 weeks, about 52 weeks to about 75 weeks, about 52 weeks to about 70 weeks, or about 52 weeks to about 65 weeks.

[0023] In some aspects of the fourth embodiment, the second period is about 40 weeks or more, about 50 weeks or more, about 52 weeks or more, about 55 weeks or more, about 60 weeks or more, about 65 weeks or more, about 70 weeks or more, about 75 weeks or more, about 80 weeks or more, 35 weeks to about 40 weeks, 35 weeks to about 50 weeks, 35 weeks to about 52 weeks, 35 weeks to about 55 weeks, 35 weeks to about 60 weeks, about 40 weeks to about 50 weeks, about 40 weeks to about 52 weeks, about 40 weeks to about 55 weeks, about 40 weeks to about 50 weeks, about 45 weeks to about 50 weeks, about 45 weeks to about 52 weeks, about 45 weeks to about 55 weeks, about 45 weeks to about 60 weeks, or about 50 weeks to about 55 weeks, or about 50 weeks to about 60 weeks.

[0024] As part of a fifth embodiment, provided herein is a method of treating Alzheimer's disease in a subject, the method comprising: a) administering a first dose to the subject for a first period of time until the subject exhibits a diminished therapeutic response to the first dose of about 400 mg / day to about 600 mg / day of ALZ-801; and b) administering a second dose for a second period of time that is at least 1.5 times the first dose. In some aspects of the fifth embodiment, the second dose is less than 1.5 times to 2 times the first dose.

[0025] As part of a sixth embodiment, provided herein is a method of treating Alzheimer's disease in a subject, the method comprising: a) administering a first dose to the subject for a first period of time until the subject exhibits a diminished therapeutic response to a first dose of ALZ-801 of about 400 mg / day to about 600 mg / day; b) administering a second dose for a second period of time until the subject exhibits a diminished therapeutic response to a second dose that is 1.5 to less than 2 times the first dose; and c) administering a third dose that is at least twice the first dose for a third period of time. In some aspects of the sixth embodiment, the third dose is 2 to less than 2.5 times the first dose.

[0026] As part of a seventh embodiment, provided herein is a method of treating Alzheimer's disease in a subject, the method comprising: a) administering a first dose to the subject for a first period of time until the subject exhibits a decreased therapeutic response to a first dose of ALZ-801 of about 400 mg / day to about 600 mg / day; b) administering a second dose for a second period of time until the subject exhibits a decreased therapeutic response to a second dose that is 1.5 to less than 2 times the first dose; c) administering a third dose for a third period of time until the subject exhibits a decreased therapeutic response to a third dose that is 2 to less than 2.5 times the first dose; and d) administering a fourth dose that is 2.5 times or more the first dose. In some aspects of the seventh embodiment, the fourth dose is 2.5 to less than 3 times the first dose.

[0027] As used herein, "decreased therapeutic response" refers to an observed or measured decrease in a subject's previously observed or measured therapeutic response to ALZ-801 over a period of time. For example, if a subject shows a reversal or cessation of cognitive decline (as compared to before such treatment) during treatment with 400 mg / day to about 600 mg / day (e.g., about 530 mg / day) of ALZ-801, then a decreased therapeutic response would be an observed or measured increase in cognitive decline from the level that was reversed or halted. If a subject shows a slowing of cognitive decline (as compared to before such treatment) during treatment with 400 mg / day to about 600 mg / day (e.g., about 530 mg / day) of ALZ-801, then an increase in the rate of cognitive decline would indicate a decreased therapeutic response.

[0028] As part of the eighth embodiment, the reduction in therapeutic response described herein (including any one of the fourth to sixth embodiments) is exhibited over a period of at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 12 months, or at least about 1 year. Alternatively, as part of the fourth embodiment, the reduction in therapeutic response described herein (including the fourth embodiment) is exhibited over a period of about 1 week to about 1 year, about 1 month to about 1 year, about 3 months to about 1 year, about 6 months to about 1 year, about 1 week to about 6 weeks, about 1 week to about 5 weeks, about 1 week to about 4 weeks, about 1 week to about 3 weeks, about 2 weeks to about 6 weeks, about 2 weeks to about 4 weeks, or about 2 weeks to about 3 weeks.

[0029] As part of the ninth embodiment, the reduction in therapeutic response described herein (including any one of the third to eighth embodiments) is indicated by an observable decline in one or more daily living activities, such as reduced motor skills, reduced verbalization, reduced conversation, reduced comprehension, reduced self-feeding ability, reduced food intake, reduced mobility, reduced cooperation with caregivers, increased depression, increased agitation, increased abnormal motor behavior, or increased repetitive movements. Usually, the observable decline in one or more daily living activities is made by one or more people who interact with the subject frequently enough and have sufficient detailed knowledge of the subject's daily activities to be able to make a reasonable assessment of the decline. Such a person is usually the subject's caregiver or family member (such as a parent, spouse, child, nurse, or other professional caregiver). Such a person may also be a physician who is familiar with the subject's daily activities (e.g., as reported by the caregiver or family member).

[0030] As part of a tenth embodiment, the reduced therapeutic response described herein (including any one of the third through eighth embodiments) is indicated by one or more cognitive tests (e.g., the Mini-Mental State Examination (MMSE), the Mini-Cog test, or the Clinical Dementia Rating scale-sum of boxes (CDR-SB), improved or modified versions of any of the foregoing, any newly developed cognitive tests, or any combination of the foregoing).

[0031] In one aspect of the tenth embodiment, the reduction in therapeutic response described herein is indicated by an MMSE reduction of at least 2 points, at least 3 points, at least 4 points, or at least 5 points over a period of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or at least 1 year. Alternatively, in another aspect of the tenth embodiment, the rate of cognitive decline in the subject is indicated by an MMSE reduction of at least 2 points, at least 3 points, at least 4 points, or at least 5 points over a period of about 3 months to about 1 year or about 6 months to about 1 year. In another alternative aspect of the tenth embodiment, the rate of cognitive decline in the subject is indicated by an MMSE reduction in the range of 2-5 points, 2-4 points, 2-3 points, 3-5 points, 3-4 points, or 4-5 points over a period of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or at least 1 year. In yet another alternative aspect of the tenth embodiment, the subject's rate of cognitive decline is indicated by an MMSE decline in the range of 2-5 points, 2-4 points, 2-3 points, 3-5 points, 3-4 points, or 4-5 points over a period of about 3 months to about 1 year or about 6 months to about 1 year.

[0032] In yet another aspect of the tenth embodiment, the reduced therapeutic response described herein is indicated by a CDR-SB increase of 0.5 to 1 over a period of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or at least 1 year. In yet another aspect of the tenth embodiment, the rate of cognitive decline in the subject is indicated by a CDR-SB increase of 0.5 to 1 over a period of about 3 months to about 1 year or about 6 months to about 1 year.

[0033] In certain aspects of the ninth and tenth embodiments, the observation of decline in one or more daily living activities may be combined with cognitive testing to determine and confirm that the subject is experiencing a reduced therapeutic response. It should be understood that in certain circumstances, conflicting results may be obtained when comparing the results of one or more cognitive tests with the observation of one or more daily living activities. In other words, cognitive testing may not show a gradual decline, but the observation of daily living activities may indicate that such a decline is occurring. Similarly, cognitive testing may suggest a gradual decline when the observation of daily living activities shows some decline. In such circumstances, the doctor treating the subject, possibly in collaboration with the subject's caregivers and family, may decide to increase the dosage of ALZ-801.

[0034] As part of the eleventh embodiment, the second dose of ALZ-801 described in the fifth, sixth, and seventh embodiments is at least about 700 mg / day, at least about 750 mg / day, at least about 795 mg / day, about 700 mg / day to about 1000 mg / day, about 750 mg / day to about 1000 mg / day, about 750 mg / day to about 800 mg / day, or about 795 mg / day. In some aspects of the eleventh embodiment, the second dose of ALZ-801 described in the fifth, sixth, and seventh embodiments is administered TID. In some aspects of the eleventh embodiment, the second dose of ALZ-801 described in the fifth, sixth, and seventh embodiments is administered TID of about 265 mg of ALZ-801.

[0035] In some aspects of the eleventh embodiment, the third dose of ALZ-801 described in the sixth and seventh embodiments is at least about 1000 mg / day, at least about 1050 mg / day, about 1000 mg / day to less than about 1300 mg / day, about 1000 mg / day to about 1100 mg / day, about 1050 mg / day to less than about 1300 mg / day, about 1050 mg / day to about 1100 mg / day, or about 1060 mg / day. In some aspects of the eleventh embodiment, the third dose of ALZ-801 described in the sixth and seventh embodiments is administered TID. In other aspects of the eleventh embodiment, the third dose of ALZ-801 described in the sixth and seventh embodiments is administered QID. In another aspect of the eleventh embodiment, the third dose of ALZ-801 described in the sixth and seventh embodiments is 265 mg of ALZ-801 administered QID.

[0036] In some aspects of the eleventh embodiment, the fourth dose of ALZ-801 described in the seventh embodiment is at least about 1300 mg / day, at least about 1325 mg / day, at least about 1400 mg / day, at least about 1450 mg / day, at least about 1500 mg / day, at least about 1550 mg / day, at least about 1590 mg / day, about 1300 mg / day to about 1600 mg / day, about 1325 mg / day to about 1600 mg / day, about 1325 mg / day to about 1590 mg / day, about 1325 mg / day, or about 1590 mg / day. In some aspects of the eleventh embodiment, the fourth dose of ALZ-801 described in the seventh embodiment is administered TID. In other aspects of the eleventh embodiment, the fourth dose of ALZ-801 described in the seventh embodiment is administered QID. In yet another aspect of the eleventh embodiment, the fourth dose of ALZ-801 described in the seventh embodiment is administered five or six times daily. In yet another aspect of the eleventh embodiment, the fourth dose of ALZ-801 described in the seventh embodiment is 265 mg of ALZ-801 administered five times daily. In yet another aspect of the eleventh embodiment, the fourth dose of ALZ-801 described in the seventh embodiment is 265 mg of ALZ-801 administered six times daily.

[0037] As part of the twelfth embodiment, the subject treated by the subject methods (including any one of the first to eleventh embodiments) has mild to moderate AD. Alternatively, as part of the twelfth embodiment, the subject treated by the subject methods (including any one of the first to eleventh embodiments) has moderate to severe AD. In another alternative, as part of the twelfth embodiment, the subject treated by the subject methods (including any one of the first to eleventh embodiments) has an MMSE score of 21 or less, 20 or less, 19 or less, 18 or less, 17 or less, 16 or less, or 15 or less.

[0038] In some aspects of the twelfth embodiment, a subject treated by the subject methods (including any one of the first through eleventh embodiments) has an MMSE score in the range of 15-21, 16-21, 17-21, 18-21, 19-21, 15-20, 16-20, 17-20, 18-20, 15-19, 16-19, 17-19, 15-18, or 16-18. In still other aspects of the twelfth embodiment, a subject treated by the subject methods (including any one of the first through eleventh embodiments) has an MMSE score of 15, 16, 17, 18, 19, 20, or 21.

[0039] As part of the thirteenth embodiment, the subject treated by the subject method (including any one of the first through twelfth embodiments) is one that has at least one APOE4 allele, i.e., APOE4 positive or APOE4 + In some aspects of the twelfth embodiment, the subject treated by the subject methods (including any one of the first through eleventh embodiments) is an APOE4 homozygous, i.e., APOE4 / 4 subject.

[0040] As part of the fourteenth embodiment, ALZ-801 as defined herein (including any one of the first through thirteenth embodiments) is orally administered to a subject.

[0041] As part of the fifteenth embodiment, ALZ-801 as defined herein (including any one of the first through fourteenth embodiments) is formulated in a tablet, capsule, liquid, orally dissolving tablet, sachet, or sprinkle. In some aspects of the fifteenth embodiment, ALZ-801 is formulated in a capsule. In some aspects of the fifteenth embodiment, ALZ-801 is formulated in an immediate release capsule. In other aspects of the fifteenth embodiment, ALZ-801 is formulated in a sustained release capsule. In still other aspects of the fifteenth embodiment, each capsule contains about 265 mg of ALZ-801.

[0042] As part of the sixteenth embodiment, if a subject receiving an increased dose of at least about 700 mg / day of ALZ-801 (including any one of the first to fifteenth embodiments) exhibits undesirable side effects, such as stomach discomfort or nausea, the dose can be reduced for a period of time to a dose that does not result in such side effects, e.g., an amount higher than the previous dosage level administered to the subject and lower than the dosage that caused the undesirable side effects, e.g., an amount higher than about 530 mg / day and lower than about 795 mg / day. Once the subject is able to tolerate the reduced dose of ALZ-801, the dose can be increased again to at least about 700 mg / day. In some aspects of this twenty-third embodiment, the increase in the dose again to at least about 700 mg / day can be done stepwise over a period of weeks, e.g., the daily dose can be increased by about 50, about 75, about 100, about 150, about 200, or about 250 mg every week, every two weeks, or every three weeks until the desired dose is reached. In this way, increased dosages are better tolerated by the subject.

[0043] As part of the seventeenth embodiment (including any one of the first and twelfth through fifteenth embodiments), ALZ-801-naive subjects will be given or titrated to a dose of at least about 700 mg / day (e.g., at least about 795 mg / day) of ALZ-801. In other words, subjects not currently receiving ALZ-801 will be initially administered a lower daily dose, e.g., about 200-300 mg / day of ALZ-801, for a period of time to determine whether the subject experiences undesirable side effects. Once it is established that the lower dose is tolerated, the daily dose is incrementally increased (e.g., by about 50, about 75, about 100, about 125, about 150, about 175, about 200, about 250, or about 265 mg increments) over a period of time (e.g., 1 week, 2 weeks, or 3 weeks) until the incrementally increased dose is tolerated, and the incremental increase process is repeated until the desired daily dose is reached.

[0044] As part of an eighteenth embodiment, provided herein is a pharmaceutical kit for use in any of the aforementioned methods. The kit contains separate dosage forms of ALZ-801 according to any of the above embodiments, to be taken by a subject at a time, in separate compartments, such as foil-packaged or blister-packaged unit doses, separated from each other. For example, if the dose to be taken is 265 mg of ALZ-801 three times a day, each 265 mg dose is in a separate compartment. The separate compartments can be labeled with the time of day to take the dose (e.g., morning, afternoon, and nighttime, if the subject takes ALZ-801 three times a day) and / or the day of the week to take the dose. The kit can further include instructions for taking the dose. The kit can include sufficient doses in total for one week, two weeks, three weeks, four weeks, one month, two months, three months, six months, nine months, one year, or longer.

[0045] In some aspects of the eighteenth embodiment, the dosage forms of ALZ-801 in the kit are present in multiples of 3. Such kits are useful for subjects in whom administration of ALZ-801 is TID. In some aspects of the eighteenth embodiment, the dosage forms of ALZ-801 in the kit are present in multiples of 4. Such kits are useful for subjects in whom administration of ALZ-801 is QID. EXAMPLES

[0046] Compassionate Use Testing A 72-year-old female subject diagnosed with severe neurocognitive impairment of the Alzheimer's type was treated with ALZ-801 as part of a compassionate use trial. The subject was APOE4 homozygous, was receiving standard cognitive enhancing medication, and had enrolled in a clinical trial of an amyloid immunotherapy agent for which she was unresponsive and had no treatment options.

[0047] The subject was administered ALZ-801 orally at a dose of 265 mg BID for approximately 14 months (61 weeks and 2 days). By the end of the first 13 months of treatment (approximately 58 weeks), the woman's condition was significantly improved and stabilized. For example, the woman's motor skills improved as she made efforts to brush her teeth, dress, and bathe herself. She was also able to hold a phone to her ear, and her walking and eating improved, which she was not able or willing to do before treatment with ALZ-801 at 265 mg BID. In addition, the woman's mood was significantly brighter, she felt more content, and her verbal communication improved. However, by the end of the first 12 months of treatment, the subject's improvement in condition stagnated and her cognitive status declined. She became apathetic, spoke less, and was unable to follow instructions. She also showed decreased physical activity and worsening gait.

[0048] On the sixth day of the 62nd week of treatment, the ALZ-801 dose was increased from 265mg BID to 265mg TID. Notably, the woman's cognitive stagnation and decline ceased once she began the 265mg TID dosing regimen. She became more verbal, felt happier, and not only completed tasks that she had achieved while taking 265mg BID ALZ-801, but improved beyond them. She understood the context of conversations and behaved in a more "normal" or "natural" manner. Overall, there was a clear improvement in the woman's motivation, speech, activities of daily living (i.e., cooperative interactions with caregivers, ability to perform light tasks, etc.), physical activity, mood, and gait. The subject has been taking 265mg TID ALZ-801 for at least nine months with no significant side effects. A plateau or decline in cognitive status similar to that observed with the 265 mg BID ALZ-801 dose began approximately 12 months after the initiation of 265 mg TID ALZ-801 dosing. The subject continued on 265 mg TID ALZ-801 for approximately another 3 months (total of 15 months), after which the dose was increased to ALZ-801 265 mg QID (4 times daily), which has been maintained for the past 7 months. The woman's caregivers reported that the new (QID) dosing regimen was well tolerated, with no associated nausea or significant side effects. More importantly, the subject's cognitive status and other quality of life indicators appeared to improve and remain stable over the 7 months on QID. Caregivers noted improved attitude and alertness, increased responsiveness, increased cooperation, and improved interactions with caregivers.

[0049] The steady-state pharmacokinetics of TID and QID dosing regimens in patients was evaluated using the area under the curve (AUC) and maximum concentration (C max) and compared to BID dosing values ​​in the patient population in the Phase 2 human clinical trial of ALZ-801. Once the patient reached steady state on a particular dosing regimen (any time after day 7 of a particular dosing regimen), blood samples were drawn immediately prior to administration of a dose of AZL-801 and then again 1, 2, and 4 hours after administration of that dose. Plasma was isolated from the samples by centrifugation, the plasma samples were frozen, and the tramiprosate concentrations (the active moiety of ALZ-801) were determined, as well as the AUC and C max The values ​​obtained from the plasma were then used to calculate the predicted brain AUC. The results are shown in Table 1 below and in Figure 1. These results demonstrate the dose-proportional plasma AUC and C based on dosing frequency. max This indicates an increase in [Table 1]

[0050] Having described a number of embodiments of the invention, it will be apparent that our basic examples may be modified to provide other embodiments that utilize the compounds and methods of the invention. It will therefore be understood that the scope of the invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

[0051] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) that may be cited in this application are expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one of ordinary skill in the art.

Claims

1. 1. A pharmaceutical composition for use in a method for treating Alzheimer's disease in a subject having an MMSE score of 21 or less, the pharmaceutical composition comprising ALZ-801, the method comprising administering to the subject at least about 700 mg / day of ALZ-801.

2. The pharmaceutical composition of claim 1, wherein in the method, the subject is administered about 700 mg / day to about 1.0 g / day of ALZ-801.

3. The pharmaceutical composition of claim 1, wherein the subject is administered approximately 795 mg / day of ALZ-801.

4. The pharmaceutical composition of claim 1, wherein the subject is administered approximately 265 mg of ALZ-801 TID in the method.

5. 1. A pharmaceutical composition for use in a method of treating Alzheimer's disease in a subject, the pharmaceutical composition comprising ALZ-801, the method comprising: a. administering to the subject about 400 mg / day to about 600 mg / day of ALZ-801 for a first period of 50 weeks or more; b. thereafter administering at least about 700 mg / day of ALZ-801; The pharmaceutical composition comprising:

6. 6. The pharmaceutical composition of claim 5, wherein the first period is from about 52 weeks to about 65 weeks.

7. The pharmaceutical composition of claim 5, wherein the subject is administered approximately 530 mg / day of ALZ-801 over the first period.

8. The pharmaceutical composition of claim 7, wherein the subject is administered approximately 265 mg of ALZ-801 BID over the first period.

9. The pharmaceutical composition of claim 5, wherein the subject is subsequently administered approximately 795 mg / day of ALZ-801.

10. The pharmaceutical composition of claim 9, wherein the subject is subsequently administered approximately 265 mg of ALZ-801 TID.

11. 10. The pharmaceutical composition of claim 1 or 5, wherein the subject has an MMSE score of 21 or less.

12. 12. The pharmaceutical composition of claim 11, wherein the subject has an MMSE score of 16 or less.

13. The pharmaceutical composition of claim 11, wherein the subject has an MMSE score of 16-21.

14. 11. The pharmaceutical composition of any one of claims 5-10, wherein the subject has an MMSE score of 16 or less prior to the subsequent administration of at least about 700 mg / day of ALZ-801.

15. 1. A pharmaceutical composition for use in a method of treating Alzheimer's disease in a subject, the pharmaceutical composition comprising ALZ-801, the method comprising: administering a first dose of about 400 mg / day to about 600 mg / day of ALZ-801 to the subject for a first period of time until the subject exhibits a decreased therapeutic response to the first dose; b. administering a second dose that is at least 1.5 times the first dose over a second period of time; The pharmaceutical composition comprising:

16. 16. The pharmaceutical composition of claim 15, wherein the second dose is 1.5 to less than 2 times the first dose.

17. 17. The pharmaceutical composition of claim 16, wherein the second period of time is until the subject exhibits a decreased therapeutic response to the second dose, and the method further comprises administering a third dose that is at least twice the first dose for a third period of time.

18. 18. The pharmaceutical composition of claim 17, wherein the third dose is 2 to less than 2.5 times the first dose.

19. 19. The pharmaceutical composition of claim 18, wherein the third period of time is until the subject exhibits a decreased therapeutic response to the third dose, and the method further comprises administering a fourth dose that is 2.5 times or greater than the first dose.

20. 20. The pharmaceutical composition of claim 19, wherein the fourth dose is 2.5 to less than 3 times the first dose.

21. 21. The pharmaceutical composition of any one of claims 15 to 20, wherein the second dose of ALZ-801 is at least about 700 mg / day.

22. 22. The pharmaceutical composition of claim 21, wherein the second dose of ALZ-801 is about 795 mg / day.

23. 22. The pharmaceutical composition of claim 21, wherein the second dose of ALZ-801 is administered TID.

24. 18. The pharmaceutical composition of claim 17, wherein the third dose of ALZ-801 is at least about 1000 mg / day.

25. 25. The pharmaceutical composition of claim 24, wherein the third dose of ALZ-801 is about 1060 mg / day.

26. 25. The pharmaceutical composition of claim 24, wherein the third dose of ALZ-801 is administered TID or QID.

27. 27. The pharmaceutical composition of claim 26, wherein the third dose of ALZ-801 is administered QID.

28. 20. The pharmaceutical composition of claim 19, wherein the fourth dose is at least about 1300 mg / day.

29. 29. The pharmaceutical composition of claim 28, wherein the fourth dose is from about 1325 mg / day to about 1590 mg / day.

30. 30. The pharmaceutical composition of claim 29, wherein the fourth dose of ALZ-801 described in the seventh embodiment is administered TID, QID, five times a day, or six times a day.

31. 16. The pharmaceutical composition of claim 15, wherein the reduced therapeutic response is demonstrated over a period of at least about 2 weeks, about 2 to about 3 weeks, at least about 6 months, or about 6 months to about 1 year.

32. 16. The pharmaceutical composition of claim 15, wherein the decreased response to treatment is indicated by one or more of: decreased motor skills, decreased verbalization, decreased speech, decreased comprehension, decreased ability to feed oneself, decreased food intake, decreased mobility, decreased cooperation with caregiver, increased depression, increased agitation, increased abnormal motor behavior, or increased repetitive movements.

33. 16. The pharmaceutical composition of claim 15, wherein the reduced therapeutic response is indicated by one or more cognitive tests.

34. 34. The pharmaceutical composition of claim 33, wherein the one or more cognitive tests are selected from the Mini-Mental State Examination (MMSE), the Mini-Cog test, and the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), or a combination thereof.

35. The reduced therapeutic response may be a. A decrease in MMSE score of 4 to 5 over a period of about 6 months to about 1 year, or b. A CDR-SB increase of 0.5 to 1 over a period of about 6 months to about 1 year 35. The pharmaceutical composition of claim 34, wherein the composition is represented by one or more of:

36. The subject is APOE4 ＋ 16. The pharmaceutical composition of any one of claims 1, 5, and 15, wherein

37. 37. The pharmaceutical composition of claim 36, wherein the subject is APOE4 homozygous.

38. 16. The pharmaceutical composition of any one of claims 1, 5, and 15, wherein the ALZ-801 is formulated into a tablet, capsule, liquid, orally dissolving tablet, sachet, or sprinkle.

39. 39. The pharmaceutical composition of claim 38, wherein the ALZ-801 is formulated in a capsule.

40. A pharmaceutical kit comprising individual dosage forms of ALZ-801 separated from one another, wherein the dosage forms of ALZ-801 in the kit are present in multiples of three or multiples of four.

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