Combination therapy of SCYLLO-INOSITOL with vitamin D and / or other vitamins or active ingredients for treating cognitive impairment

Abstract

This disclosure relates to active ingredient / adjuvant combinations for the treatment of neurological disorders and diseases, such as Alzheimer's disease and mild cognitive impairment (MCI), as well as memory and cognitive impairment and conditions. In particular, combinations of scyllo-inositol with Alzheimer's disease treatments (e.g., aducanumab) and / or essential fatty acids (e.g., linolenic acid / linoleic acid mixtures) or vitamin D or vitamin D compounds (e.g., calcifediol) are disclosed as useful. The combinations may be in the form of separate dosage forms for each active ingredient, or may be oral dosage forms with multiple active ingredients in a single capsule, tablet, or oral solution. The present invention also relates to methods for treating patients with mild cognitive impairment (MMSE) scores of 22-26 with a pharmaceutically effective amount of scyllo-inositol to treat the disease and slow the progression of Alzheimer's disease.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This PCT application claims the benefit of U.S. Provisional Application No. 63 / 404,537, filed September 7, 2022, U.S. Provisional Application No. 63 / 441,732, filed January 27, 2023, and U.S. Provisional Application No. 63 / 453,583, filed March 21, 2023, all of which are incorporated herein by reference. [Background technology]

[0002] Alzheimer's disease (AD) is a neurodegenerative disorder that progresses over time, causing cognitive impairment and a variety of symptoms or disabilities that affect the daily lives of those affected. The number of people affected by the disease at various stages is enormous, estimated to increase to more than 115 million worldwide by 2050. Despite years of effort and billions of dollars invested in drug development research, no effective treatment has yet been found to address the progression and / or treatment of AD. Until this year, only three drugs had been approved in the United States to treat the disease. These include donepezil, rivastigmine, and galantamine, but none of them are effective in halting disease progression. However, in a promising new development, the FDA recently approved the monoclonal antibody drug aducanumab (BIIB037) for the treatment of mild cognitive impairment (MCI) and early-stage AD, albeit with some reservations.

[0003] In an aging society, the prevalence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) increases. The gradual memory decline associated with MCI is followed by further memory decline and increasing functional loss. In the later stages of MCI, patients begin to develop dementia and mild AD. These patients may progress to moderate to severe AD. Amyloid-β accumulation in the brain occurs early, before symptoms appear. As the amyloid burden in the brain continues to increase, the onset of early and late MCI appears, and the severity continues to progress until the patient is diagnosed with AD. It is well documented that the onset of clinical symptoms, such as memory loss, begins in early and late stages of MCI, followed by a more rapid decline in memory and function as patients progress to mild, moderate, and finally severe AD. Patients in the later stages of moderate and severe AD exhibit functional decline requiring caregiver assistance and may even die.

[0004] Although the exact mechanisms underlying AD pathology remain unclear, it is well established that the accumulation of amyloid-β fibrils resulting in the formation of plaques is a hallmark of Alzheimer's disease. Furthermore, the accumulation of amyloid-β fibrils in the brain begins approximately 10–15 years before the onset of dementia and related clinical symptoms. The accumulation of fibrils and plaques increases with age, with 30–40% of people over the age of 55 and over 70% of patients with mild cognitive impairment (MCI) harboring amyloid-β accumulation in the brain. The presence of amyloid-β fibrils and plaques leads to increased neurotoxicity and the emergence of inflammation in the brain. These cumulative pathologies are associated with the emergence of more aggressive disease and loss of memory and function in AD patients.

[0005] Over the past two decades, numerous therapies targeting amyloid-β fibrils and plaques have shown promise in animal models of AD and advanced to human clinical trials. These initial treatments involved antibodies reactive with amyloid-β fibrils and plaques, reducing amyloid-β accumulation in the brains of AD animal models. Elan and Wyeth developed the humanized antibody bapineuzamab, which showed promising results in a phase 2 study and advanced to a phase 3 clinical trial in patients with mild and moderate AD. Unfortunately, this study did not demonstrate efficacy in patients with mild to moderate AD, although similar results have been observed with antibody therapies from Lilly and others. The general consensus was that treating moderate AD disease with amyloid-targeted therapies occurs too late in the disease progression to prevent neurotoxicity and dementia progression. Some of the evidence that amyloid-β-targeted therapies may be more effective in subpopulations of AD patients comes from clinical studies showing modest benefits in APOE 4-positive patients with mild AD, but these benefits were masked by the rapid decline in cognition and function observed in the moderate AD patient population.

[0006] Additionally, orally available small molecules such as scyllo-inositol and tramiprosate have shown promising data in disassembling amyloid-β fibrils in vitro and reducing plaques in animal models of AD. Neurochem Pharma has initiated an 18-month Phase 3 clinical trial in patients with mild to moderate AD. The study did not demonstrate improvements in cognition and function in patients with AD. The data were inconclusive, with significant interpatient variability, and cognitive symptoms in milder patients did not appear to have progressed sufficiently over the 18-month treatment period to allow for measurable efficacy. These trials appear to have encountered two problems: Aβ-targeted drugs did not appear to affect AD cognition or function in patients with moderate AD, indicating that the disease process was too advanced for Aβ-targeted therapy to alter its progression; and second, the decline in cognition and function in patients with mild AD was too gradual over the 18-month treatment period to assess efficacy in patients with mild AD overall, more specifically, reduction in decline in outcomes measuring cognition and function such as the ADASCog, NTB, CDR-SoB, and ADCS-ADL.

[0007] Similarly, scyllo-inositol, an oral agent that disrupts and prevents the formation of amyloid-β fibrils, has been effective in treating AD animal models. Administration of scyllo-inositol at doses of 3.3 mg / kg or higher to AD animal models reduced the incidence and size of amyloid plaques and improved memory and cognitive tests across a variety of animal models. In a large-scale phase 2 trial, scyllo-inositol failed to demonstrate efficacy in patients with mild and moderate AD on several assessment measures, including NTB, CDR-SoB, ADCS-ADL, and ADAS-Cog. These data indicated that scyllo-inositol was ineffective in patients with mild and moderate AD overall. Furthermore, data examining patients with mild AD (MMSE scores of 20-26) or moderate AD (MMSE scores of 16-20) also indicated that this drug was ineffective in both AD patient groups. These data suggested that the drug is generally ineffective in treating patients with mild and moderate AD, or that efficacy observed in subpopulations of AD patients is masked by data from the overall population. Based on clinical evidence that amyloid-β-targeted drugs may be ineffective in patients with advanced AD, the efficacy of scyllo-inositol was evaluated in patients with mild AD, whose disease severity varied based on MMSE scores of 20 to 26. The data showed that the effects of scyllo-inositol on cognition and function were more pronounced in patients with mild AD who had MMSE scores of 22 to 26. Inclusion of patients with mild AD with MMSE scores of 20 and 21 was sufficient to mask the efficacy observed in patients with mild AD who had MMSE scores of 22 to 26. These clinical findings emphasize the importance of selecting appropriate MCI and AD patient populations for amyloid-β-targeted therapy to observe efficacy.

[0008] Despite these advances and treatments, there remains a need for effective drugs to treat potentially treatable patients, including those with MCI and Alzheimer's disease and / or subpopulations across the full spectrum of disease stages, from early onset to irreversible progression. This subpopulation includes patients with APOEε4, a genetic mutation in the apolipoprotein E (APOE) gene. Approximately twenty-five percent (25%) of people are thought to have one copy of APOEε4, and approximately 2-3% have two copies of this allele. This gene is known to increase the risk of early onset of disease. The docking of Aβ fibrils to neuronal and glial membranes is thought to be an early and potentially intervenible step in the progression of Alzheimer's disease. There is also a need for supplements or nutritional aids that can be provided to subjects who may be susceptible to early amyloid-β accumulation in the brain, which ultimately leads to the progression of MCI, Alzheimer's disease, or other cognitive disorders. The need for this supplemental intervention may occur in the early stages of MCI and Alzheimer's disease, long before evidence of neurological symptoms is detected.

[0009] The newly identified subpopulation of patients with MMSE scores of 22-26 suggests that scyllo-inositol may have rapid effects on memory and cognition, with detectable effects within 6 months of treatment initiation. To enhance the immediate cognitive benefits of scyllo-inositol, combination therapy with more symptomatic treatments may be beneficial. The combination of symptomatic medications with scyllo-inositol improves synaptic transmission and memory with drugs such as donepezil, rivastigmine, galantamine, and memantine. Treatment with a selected mixture of linoleic acid and linoleic acid in a fixed ratio has been shown to improve membrane fluidity and synaptic activity, resulting in improved cognition and function in patients with AD. The combination of a linoleic acid and linolenic acid mixture and scyllo-inositol can improve cognition in elderly patients with cognitive impairment. Additionally, as described herein, the combination of 25-hydroxyvitamin D3 and / or vitamin D with scyllo-inositol is believed to improve cognition in subjects who are prone to neurological diseases or disorders, such as Alzheimer's disease or mild cognitive impairment, or other conditions that have beta-amyloid as a contributing factor to memory loss or cognition, and who would also benefit from increased serum levels of 25-hydroxyvitamin D3 and the active hormone vitamin D produced therefrom.

[0010] It has been speculated that glycolipids, such as gangliosides, may stabilize and prevent Ab fibrillogenesis, while phosphatidylinositol may promote fibrillogenesis. Scyllo-inositol (ELND005) has been shown to be useful for treating or preventing diseases of the central or peripheral nervous system, including Alzheimer's disease. See U.S. Patent No. 7,521,481, which is incorporated herein by reference. ClinicalTrials.gov lists six clinical trials for this drug. Completed studies of Alzheimer's disease include a study titled "Long-Term Follow-Up of ELND005 and Alzheimer's Disease in Patients with Mild to Moderate Alzheimer's Disease."

[0011] To date, these study results have not led to the filing of a new drug application for the treatment of Alzheimer's disease. While results were not positive at the doses studied in the entire enrolled patient population, the inventors have discovered that scyllo-inositol alone or in combination with other active ingredients treats subsets of patients with MCI, selected based on specific criteria for this population: patients with MMSE scores of 22-26 and those with MMSE scores of 27-28. Furthermore, the inventors have discovered that the combination of scyllo-inositol with vitamin D and / or a vitamin D prohormone, such as calcifediol, is effective in treating patients with vitamin D deficiency or insufficiency and associated memory loss or cognitive impairment. Early intervention with combination therapy is believed to reduce amyloid-beta fibril accumulation, restore serum 25(OH)D3 levels in the brain, and alleviate and / or prevent the progression of memory loss, mild cognitive impairment, and / or Alzheimer's disease in some patients with MMSE scores of 22-26, MCI patients, and / or patients with MMSE scores of 27-28 or equivalent. The present invention also encompasses the use of scyllo-inositol alone at a dose of 250 mg twice daily to treat Alzheimer's disease and / or MCI patients with such MMSE scores. Based on pharmacokinetic data demonstrating scyllo-inositol levels in the brain and CSF of patients with mild and moderate AD after 250 mg twice daily treatment, it is suggested that administration of 250 mg twice daily or 125 mg scyllo-inositol achieves the appropriate concentration range required for efficacy in the brain.

[0012] The present inventors have also discovered that patients with MMSE scores within the above range and at least one APOE ε4 allele can be administered a pharmaceutically effective amount of scyllo-inositol alone or in combination with other active ingredients described herein. Previous studies or patents disclosing the use of scyllo-inositol for Alzheimer's disease have not disclosed the treatment of specific subgroups or patient subpopulations within the broader group of patients with Alzheimer's disease or MCI. Furthermore, no patents have disclosed the combination of scyllo-inositol with vitamin D compounds such as 25-hydroxyvitamin D or vitamin B12.

[0013] In published patents, such as U.S. Patent No. 7,521,481, the inventors have demonstrated that scyllo-inositol and other cyclohexanehexols can treat Alzheimer's disease and other central or peripheral nervous system conditions, including Alzheimer's disease, presenile and senile forms, amyloid angiopathy, mild cognitive impairment, Alzheimer's disease-related dementia, taupathies, and numerous other diseases and conditions. However, as previously discussed, no human clinical studies have substantiated the claims or assertions disclosed in earlier patents or studies. Accordingly, the inventors have discovered a subpopulation of patients within the broader class of patients with Alzheimer's disease or mild cognitive impairment who are effectively treated with pharmaceutically effective amounts of scyllo-inositol, alone or in combination with other active ingredients. This subset of patients is believed to be in the early stages of fibrillogenesis and to be comparable to or similar to healthy subjects with signs of memory loss, dementia, or mild cognitive impairment.

[0014] Scyllo-inositol and any of the other active 1,2,3,4,5,6-cyclohexenehexols, such as cis-, epi-, allo-, muco-, neo-, D-chiro-, and L-chiro-inositol, in combination with an active ingredient selected from the group consisting of donepezil, rivastigmine, galantamine, aducanumab, linolenic acid and linoleic acid, or a vitamin D compound selected from vitamin D (cholecalciferol or ergocalciferol), calcifediol (25-hydroxyvitamin D3), or ER-calcifediol (sustained-release 25-hydroxyvitamin D3), are also useful for treating elderly patients (optionally with an MMSE score of 22-26) with memory loss due to increased amyloid beta accumulation in the brain, as well as mild to moderate MCI patients (with an MMSE score of 27-28) who are prone to Alzheimer's disease. Vitamin B, such as vitamin B12, can be used in place of vitamin D compounds or as an additional vitamin in combination or complex formulations. The dosage of vitamin B12 ranges from about 20 micrograms to about 500 micrograms, providing a sufficient intake of vitamin B in a subject. Combining these drugs reduces amyloid accumulation in the brain and alleviates amyloid-mediated inhibition of neuronal function. In a preferred embodiment, the combination is a fixed-dose combination in the same dosage form, such as a tablet or capsule. Such a combination is believed to slow cognitive and functional decline in a subgroup of patients with the above-mentioned MMSE scores. Combination therapy also provides more immediate benefits for cognitive and memory loss and other related symptoms. The combination may also include a combination selected from scyllo-inositol (150 mg), vitamin B12 (500 mcg), B9 (folic acid) (500 mcg), B6 ​​(3 mg), and vitamin D3 (1,000-3,000 IU) or calcifediol (10-50 mcg). These amounts may vary depending on the specific subject. The combination may be in separate dosages, a single dosage form, or a combination of dosage forms with multiple active ingredients or vitamins.The present invention also includes aquaporin 4 (AQP4X) upregulators, including small molecules that mediate amyloid-β clearance through this astrocytic water channel. Compounds that increase aquaporin 4 gene readthrough include apigenin, a flavone found in chamomile, and sulfaquinoxaline (animals only), an antibiotic. Apigenin can be combined with scyllo-inositol to treat patients with MCI and Alzheimer's disease, particularly those with MMSE scores of 22-26. Other suitable combination components may include compounds that reduce levels of soluble ST2 (sST2) in the brain, a protein known to adversely affect amyloid clearance from the brain.

[0015] Drug combinations may also be useful as supplements or dietary supplements, depending on the dosage, such as a separate combination of scyllo-inositol with another active ingredient, such as calcifediol in IR or ER form, or a fixed-dose combination containing both scyllo-inositol and calcifediol in a single capsule or tablet. In a preferred embodiment, the vitamin D compound is calcifediol, provided in a sustained-release dosage form. The use of sustained-release forms of 25-hydroxyvitamin D3, alone or in combination with scyllo-inositol, can result in higher and more sustained increases in serum 25-hydroxyvitamin D3 concentrations in tissues and organs other than the kidney, including the brain. This also leads to the formation of higher levels of the active hormone vitamin D in the brain. Achieving adequate serum calcifediol concentrations, or concentrations in the range of 30-90 ng / mL, is particularly important for patients with inflammatory diseases associated with the early stages of neurological and / or cognitive impairment. Combinations of scyllo-inositol with B vitamins, such as vitamin B12, are also believed to be effective in treating cognitive and memory disorders. Accordingly, the present invention includes such combinations, either as separate combinations in individual dosage forms or as a single capsule or tablet containing both scyllo-inositol and vitamin B. The combination of scyllo-inositol with donepezil for treating subjects with Alzheimer's disease and / or MCI is also within the scope of the claimed invention. Summary of the Invention [Means for solving the problem]

[0016] In a first embodiment, the present invention comprises a combination of (i) a first compound selected from an inositol compound or a pharmaceutically acceptable salt thereof and (ii) a second compound selected from an additional active ingredient, wherein the additional active ingredient is selected from the group consisting of vitamins and / or active pharmaceutical ingredients useful for treating neurological disorders, cognitive impairment, or memory loss in a subject in need thereof. In a preferred embodiment, the first compound is selected from scyllo-inositol, and the second compound is selected from vitamin D compounds or vitamin B compounds. In such an embodiment, a preferred vitamin D compound is vitamin D or 25-hydroxyvitamin D, and a preferred vitamin B compound is vitamin B12. In a preferred embodiment, the vitamin D compound is 25-hydroxyvitamin D3. The first and second compounds may be administered separately or provided in separate dosage forms for co-administration. The first and second compounds may also be packaged as separate dosage forms in the form of a kit provided to a patient for daily administration of the first and second compounds in appropriate dosage forms, such as capsules, tablets, or ampoules. Alternatively, the combination may be in the form of a single dosage form containing (i) a first compound selected from inositol and (ii) a second compound selected from vitamins and / or active pharmaceutical ingredients used in the treatment of neurological disorders or conditions. In a preferred embodiment of such a single dosage form, the first compound is selected from scyllo-inositol, and the second compound is selected from vitamin D compounds or vitamin B compounds. In a further preferred embodiment, the dosage form may be in the form of a capsule, tablet, or ampoule, and contains scyllo-inositol as the first compound and a vitamin D compound as the second compound. In such an embodiment, the preferred vitamin D compound is 25-hydroxyvitamin D. In such an embodiment, 25-hydroxyvitamin D may be formulated as an immediate-release formulation or a sustained-release formulation.The present invention also includes methods for treating subpopulations of MCI and Alzheimer's disease patients, or patients susceptible to cognitive impairment, dementia, and / or memory loss, or patients in such populations or subpopulations of MCI and / or Alzheimer's disease patients where such disease has progressed, using a pharmaceutically effective amount of scyllo-inositol and / or other active 1,2,3,4,5,6-cyclohexanehexol, alone or in combination with an active ingredient or vitamin supplement selected from the group consisting of vitamins A, B1, B2, B3, B5, B6, B7, B9, B12, C, D, E, and K, or lineolic acid, or a combination of linolenic acid and / or linoleic acid. The "other active ingredient" may be selected from known or previously approved drugs for treating Alzheimer's disease and / or memory loss or cognitive disorders. Such drugs include, for example, donepezil (Aricept®) or the monoclonal antibody aducanumab. Caffeine may also be selected as an ingredient. When donepezil is used herein, the dosage ranges from about 5 mg to about 23 mg and can be administered twice daily or once in the evening.

[0017] A preferred subpopulation of Alzheimer's disease patients is selected from patients with an MMSE score of 22-26 and / or patients with such an MMSE score and at least one APOE ε4 allele. Another preferred patient population is patients with memory or cognitive problems who have not yet been diagnosed with Alzheimer's disease or MCI, but who have undergone at least one MMSE test or equivalent memory or cognitive test. A preferred subpopulation of MCI patients is patients with an MMSE score of 27-28 or MCI patients with at least one APOE ε4 allele. The subject may have early, mild AD. Thus, in one embodiment, the present invention provides for treating mild AD patients with an MMSE score of 22-26 with 250 mg BID of scyllo-inositol, or treating such mild AD patients with an MMSE score of 22-26 and amyloid beta in the brain (Aβ in plasma or Aβ42 / 40 ratio by brain PET scan) with 250 mg BID of scyllo-inositol, or treating MCI patients with an MMSE score of 26-30 and amyloid beta in the brain (Aβ in plasma or Aβ42 / 40 ratio by brain PET scan) with 250 mg BID of scyllo-inositol, or treating MCI patients with an MMSE score of 26-30, ADAS score ≥ 8, FAQ ≥ 2, CDR ≥ 2 with 250 mg BID of scyllo-inositol. Treatment of MCI patients with an MMSE score of 26-30, brain amyloid beta (plasma Aβ or Aβ42 / 40 ratio by brain PET scan), ADAS score ≥ 8, FAQ ≥ 2, and CDR ≥ 2 with 250 mg BID scyllo-inositol; or treatment of MCI patients with an MMSE score of 26-30, ADAS score ≥ 7, FAQ ≥ 1, and a combined ADAS and FAQ score ≥ 13 with 250 mg BID scyllo-inositol; or treatment of MCI patients with an MMSE score of 26-30, brain amyloid beta (plasma Aβ or Aβ42 / 40 ratio by brain PET scan), ADAS score ≥ 7, FAQ ≥ 1, and a combined ADAS and FAQ score ≥ 13 with 250 mg BID scyllo-inositol.In some embodiments above and / or below, the treatment may be a combination therapy further comprising vitamins and / or other active ingredients as described herein.

[0018] In some embodiments, the present invention provides 1) Use of scyllo-inositol in the treatment of patients with mild AD with an MMSE score of 22-26 and MCI with an MMSE score of 26-30 (250 mg scyllo-inositol per day or 250 mg scyllo-inositol BID, or 500 mg scyllo-inositol per day); or 2) Use of scyllo-inositol in the treatment of patients with mild AD with an MMSE score of 22-26 and MCI with an MMSE score of 26-30 and predicted brain amyloid beta as measured by AlzaSure (250 mg scyllo-inositol per day or 250 mg scyllo-inositol BID). 2) Use of scyllo-inositol in the treatment of patients with mild AD (MMSE score 22-26) and MCI (MMSE score 26-30, ADAS score ≥8, FAQ ≥2, CDR ≥2) (250 mg scyllo-inositol per day or 250 mg scyllo-inositol BID, or 500 mg scyllo-inositol per day) 3) Use of scyllo-inositol (250 mg scyllo-inositol per day or 250 mg scyllo-inositol BID, or 500 mg scyllo-inositol per day) in the treatment of patients with mild AD with an MMSE score of 22-26 and MCI who require an MMSE score of 26-30, an ADAS score ≥7, a FAQ ≥1, and a combined ADAS and FAQ score ≥13; or 4) Use of scyllo-inositol (250 mg scyllo-inositol per day or 250 mg scyllo-inositol BID, or 500 mg scyllo-inositol per day) in the treatment of patients with mild AD with an MMSE score of 22-26 and patients with MCI with an MMSE score of 26-30, ADAS ≥ 12, and CDR-SB ≥ 1.5; or 5) Use of scyllo-inositol (250 mg BID scyllo-inositol) in the treatment of patients with mild AD and MCI with an MMSE score of 22-30 and an ADAS score of ≥8, FAQ ≥2, and CDR ≥2; or 6) Use of scyllo-inositol (250 mg BID scyllo-inositol) in the treatment of patients with mild AD and MCI with an MMSE score of 22-30, an ADAS score ≥7, a FAQ ≥1, and a combined ADAS and FAQ score ≥13; or 7) Use of scyllo-inositol in the treatment of patients with mild AD and MCI with an MMSE score of 22-30, brain amyloid beta (plasma Aβ or Aβ 42 / 40 ratio by brain PET scan), ADAS ≥ 12, or CDR-SB ≥ 1.5; or 8) Use of scyllo-inositol (250 mg BID scyllo-inositol) in the treatment of patients with mild AD and MCI with an MMSE score of 22-30, an ADAS score of ≥8, an FAQ of ≥2, and a CDR of ≥2; or 9) Use of scyllo-inositol (250 mg BID scyllo-inositol) in the treatment of patients with mild AD and MCI with an MMSE score of 22-30, an ADAS score of ≥7, FAQ ≥1, and a combined ADAS and FAQ score of ≥13; or 11) Use of scyllo-inositol in the treatment of patients with mild AD and MCI with an MMSE score of 22-30, brain amyloid beta not assessed, an ADAS ≥12, and a CDR-SB ≥1.5.

[0019] Mild AD differs from mild cognitive impairment (MCI), so a subject may have an MMSE score of 26 and be diagnosed with either mild cognitive impairment (MCI) or mild AD, depending on other parameters. MCI uses a CDR of 0.5, and mild AD uses a CDR of 1; the designation is not based on the MMSE score. For patients or subjects with mild AD or MCI and the MMSE score ranges disclosed above, when combined with Aricept (donepezil), the preferred dose of donepezil in combination with scyllo-inositol is about 5 to about 10 mg per day. A low dose of about 5 mg of donepezil is preferably administered for 4 to 6 weeks, followed by a gradual increase to a high dose of about 10 mg of donepezil once daily. In a preferred embodiment, donepezil (donepezil hydrochloride) is administered in tablet or orally disintegrating tablet form at a concentration of 5 mg or 10 mg. The combination of scyllo-inositol (125-250 mg BID) and donepezil can be administered to a subject in the form of a kit or a combination of separate dosage forms, or in the form of a single capsule or tablet containing both active ingredients. A 250 mg tablet with dispersed scyllo-inositol can be coated with an outer layer containing 5-10 mg of donepezil in a pharmaceutically acceptable tablet excipient.

[0020] In jurisdictions that do not permit medical use claims or method of treatment claims, such embodiments include pharmaceutical compositions or combinations of such scyllo-inositol with vitamins and / or other active ingredients as combined or single-unit formulations for use in treating such subpopulations of patients with Alzheimer's disease or MCI. Such combinations or compositions are novel and inventive in themselves. In any of the uses described above, or as further described herein, the dosage of scyllo-inositol also includes 250 mg once daily, or 125 mg twice daily. In some embodiments, the present invention includes a second compound selected from an active pharmaceutical ingredient selected from a monoclonal antibody. A preferred monoclonal antibody is aducanumab. In some embodiments, the active pharmaceutical ingredient is selected from a mixture of linolenic acid and linoleic acid. A preferred mixture of linolenic acid and linoleic acid has a 1:4 linolenic acid to linoleic acid ratio. These fatty acids are known to affect serotonin and catecholine neurotransmission.

[0021] Combination products, particularly those containing scyllo-inositol and aducanumab, enhance the efficacy, cognition, and function of aducanumab in treating patients with mild cognitive impairment (MCI) and mild AD. Scyllo-inositol also allows for lower aducanumab dosages and maintain efficacy in treating MCI and mild AD. Furthermore, scyllo-inositol reduces the prevalence of anti-amyloid associated with aducanumab treatment at high doses. Accordingly, the present invention includes methods for treating Alzheimer's disease in a human patient, comprising administering a pharmaceutically effective amount of a recombinant, fully human anti-amyloid beta monoclonal antibody selected from aducanumab and a pharmaceutically effective amount of scyllo-inositol.

[0022] The present invention also includes a method for treating patients with Alzheimer's disease or MCI with an MMSE score of 22-26 or 27-28, respectively, with scyllo-inositol (250 mg once daily or BID, or 500 mg QD) and, optionally, a second compound containing an active ingredient selected from a combination of linolenic acid and linoleic acid (1:4 molar ratio). The additional second compound can be added to the composition as a third component, and in preferred embodiments, it can be a combination of scyllo-inositol, 25-hydroxyvitamin D3, and any one of the other active ingredients disclosed herein. This combination(s) reduces amyloid burden in the brain, attenuates age-related long-term decline in memory and cognitive function, improves membrane fluidity, enhances neuronal function, and enhances short- and long-term memory and cognition. In preferred embodiments, the combination is in the same dosage form, such as a capsule or tablet. In another preferred embodiment, the pharmaceutical combination comprises 250 mg to 500 mg BID scyllo-inositol in combination with 10 μg of calcifediol IR, or 30 to 90 μg of ER calcifediol (RAYALDEE®). Any pharmaceutical combination can be packaged together in a kit or dispenser for ease of use.

[0023] In one embodiment, scyllo-inositol is administered orally in the range of 125-250 mg once daily or BID, hi another embodiment, scyllo-inositol is administered at a dosage of 500 mg once daily.

[0024] In one embodiment, the invention includes a method for reducing brain amyloid-β plaques in a patient with Alzheimer's disease, comprising administering an effective amount of calcifediol in combination with an effective amount of scyllo-inositol.

[0025] In a further embodiment, the invention includes a method of treating an Alzheimer's disease patient with confirmed amyloid pathology and mild cognitive impairment or mild dementia consistent with stage 3 or 4 Alzheimer's disease, comprising administering about 10 μg to 90 μg of calcifediol and administering an effective amount of scyllo-inositol.

[0026] The present invention further includes a method of enhancing cognition in a subject with mild cognitive impairment (MCI) or mild Alzheimer's disease in need of treatment by (1) pretreating the subject with 125-250 mg of scyllo-inositol and / or calcifediol once daily or BID, and (2) administering to the subject a pharmaceutically effective amount of scyllo-inositol in combination with calcifediol to enhance cognition in the subject. Such pretreatment period can extend for years, until Alzheimer's disease is fully developed.

[0027] The invention includes treating the patient with a combination of scyllo-inositol and aducanumab, where after such treatment, the combination therapy reduces ARIA aducanumab-related events compared to treatment with aducanumab alone at the same infusion volume.

[0028] The present invention involves the use of scyllo-inositol as an adjuvant to modify the amount of monoclonal antibody required to treat an Alzheimer's disease patient in need of treatment.

[0029] In a preferred embodiment, the monoclonal antibody is selected from aducanumab.

[0030] In another preferred embodiment, the combination includes scyllo-inositol and linolenic acid in a molar ratio of 1:4 (250 mg) (daily, or BID). In one embodiment dependent on this embodiment, the additional active ingredient may include a vitamin D compound, such as calcifediol.

[0031] The present invention also includes a method for alleviating ARIA in a patient undergoing monoclonal antibody therapy, comprising administering to the patient in need of treatment a pharmaceutically effective amount of scyllo-inositol, said alleviation being compared to a patient undergoing such monoclonal antibody therapy without scyllo-inositol.

[0032] In one embodiment, the invention further includes a method of reducing amyloid beta accumulation in the brain of a patient having mild Alzheimer's disease and being treated with a monoclonal antibody selected from aducanumab, comprising co-administering to the patient a pharmaceutically effective amount of scyllo-inositol.

[0033] In one embodiment, the invention includes a method of improving memory, cognition, and / or brain function in an Alzheimer's disease patient in need of treatment, wherein the patient is treated with a monoclonal antibody with co-administration of a pharmaceutically effective amount of scyllo-inositol, wherein such co-administration improves memory, cognition, and / or brain function compared to a patient treated with the monoclonal antibody alone.

[0034] The present invention includes a method for improving positive biomarkers in the CSF of Alzheimer's disease patients treated with a monoclonal antibody, the improvement being compared to a control patient treated with the monoclonal antibody alone, comprising the co-administration of a pharmaceutically effective amount of scyllo-inositol.

[0035] The invention also includes methods according to any one of the above embodiments, wherein the patient is pre-treated with scyllo-inositol at a daily dosage of 125-250 mg scyllo-inositol once daily or BID prior to receiving monoclonal antibody therapy.

[0036] The present invention encompasses methods in which the pretreatment period ranges from two weeks to several years. The combination of scyllo-inositol and calcifediol can be advantageously provided as a dietary supplement. In a preferred embodiment, such a combination is sold in packets containing 250 mg BID or 500 mg QD of scyllo-inositol and 10 μg of immediate-release calcifediol and / or 10-90 μg of ER calcifediol. In a further preferred embodiment, the combination is in the form of a single oral dosage form containing active ingredients including scyllo-inositol, calcifediol, and, optionally, linolenic acid / linoleic acid (1:4 ratio) in combination with other pharmaceutically acceptable capsule or tablet excipients. Additional amounts of linolenic acid / linoleic acid beyond the 250 mg of the combination can also be administered with the combined capsule or tablet. In some dosages, an additional 100 mg to 1000 mg of such 1:4 ratio oil mixture can also be added. The oil may be refined or substantially purified with additional essential fatty acids or nutrients. For example, oil isolated from walnuts or other sources may be provided to the subject in crude form. The scyllo-inositol in such combinations is preferably administered once daily or twice daily at a dose of 125-250 mg, but can also be provided in QDs at doses of 250 mg-500 mg. The size and type of capsule (hard vs. soft) also vary depending on the amount of scyllo-inositol and the amount of essential fatty acid oil combination. [Brief explanation of the drawings]

[0037] [Figure 1] A–F show the effect of 250 mg BID scyllo-inositol treatment in patients with mild / moderate AD (MMSE 16–30) on primary endpoints (NTB, ADCS-ADL, and CDR-SB). [Figure 2] We demonstrate the effects of 78 weeks of scyllo-inositol treatment in patients with early, mild AD (MMSE 23-26) in a pre-specified overall population and in a protocol-adherent population. [Figure 3]A-I show the change in NTB sub-items from baseline to mild AD (PPS) across nine different sub-items. [Figure 4] Figure 1 shows the change in ADCS-ADL from baseline in patients with early to mild AD (MMSE 23-26) treated with scyllo-inositol and placebo for 78 weeks. [Figure 5] Figure 1 shows the change in CDR-SB from baseline in patients with early to mild AD (MMSE 23-26) treated with scyllo-inositol and placebo for 78 weeks. [Figure 6] A–F show a comparison of the effects of scyllo-inositol and placebo treatment on the change from baseline in the CDR-SB subscale in patients with early mild AD from the Per-Protocol Population (PPS). [Figure 7] A–D show the observed change from baseline in NTB scores with scyllo-inositol treatment for patients with different mild AD with MMSE score ranges of 20–26, 21–26, 22–26, and 23–26, respectively. [Figure 8] Panels A–D show bootstrap simulation data for the change from baseline in NTB scores with scyllo-inositol treatment in different groups of patients with mild AD, with MMSE scores of 20–26, 21–26, 22–26, and 23–26, respectively. [Figure 9] Panels A to D show observational data showing the change from baseline in CDR-SB scores with scyllo-inositol treatment in different mild AD groups with MMSE scores of 20–26, 21–26, 22–26, and 23–26, respectively. [Figure 10] Panels A–D show bootstrap simulation data showing the change from baseline in CDR-SB scores with scyllo-inositol treatment in different mild AD groups with MMSE score ranges of 20–26, 21–26, 22–26, and 23–26, respectively. [Figure 11]A–D show a comparison of observed and bootstrap simulation data for the change from baseline in NTB and CDR-SB scores in patients with mild AD with MMSE scores of 22–26 treated with scyllo-inositol. DETAILED DESCRIPTION OF THE INVENTION

[0038] In an aging society, the prevalence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) increases. The gradual memory decline associated with MCI is followed by further memory decline and increasing functional loss. In the later stages of MCI, patients begin to develop dementia and mild AD. These patients may progress to moderate to severe AD. As shown below, amyloid-β accumulation in the brain occurs early, before symptoms appear. As the amyloid burden in the brain continues to increase, the onset of early and late MCI appears, and the severity continues to progress until the patient is diagnosed with AD. It is well documented that the onset of clinical symptoms, such as memory loss, begins in early and late stages of MCI, followed by a more rapid decline in memory and function as patients progress to mild, moderate, and finally severe AD. Patients in the later stages of moderate and severe AD exhibit functional decline requiring caregiver assistance and may even die.

[0039] Although the exact mechanisms underlying AD pathology remain unclear, it is well established that the accumulation of amyloid-β fibrils resulting in the formation of plaques is a hallmark of Alzheimer's disease. Furthermore, the accumulation of amyloid-β fibrils in the brain begins approximately 10–15 years before the onset of dementia and related clinical symptoms. The accumulation of fibrils and plaques increases with age, with 30–40% of people over the age of 55 and over 70% of patients with mild cognitive impairment (MCI) harboring amyloid-β accumulation in the brain. The presence of amyloid-β fibrils and plaques leads to increased neurotoxicity and the emergence of inflammation in the brain. These cumulative pathologies are associated with the emergence of more aggressive disease and loss of memory and function in AD patients.

[0040] Scyllo-inositol is an oral drug that crosses the blood-brain barrier to maintain low mM levels in the blood. Scyllo-inositol has been reported to degrade Aβ fibrils and prevent Aβ from binding to fibrils. See McLaurin, J. et al., J Mol. Biol. (1998):183-194. Scyllo-inositol has been reported to inhibit Aβ binding to neuronal membranes in in vitro studies. (McLaurin J., et al., J Biol Chem 2000 24:18495) It has also been reported to restore long-term potentiation in hippocampal slices (Townsend M., et al. Annals of Neurology 2006 Dec.;60(6):668-76). Scyllo-inositol has been reported to reduce Aβ burden in transgenic AD animal models and improve cognitive function in such animals. McLaurin J., et al., Nature See Medicine (2006) 12:801-808. To date, a total of nine Phase 1 studies have been conducted in humans. These studies have essentially demonstrated that scyllo-inositol can be taken orally, increases plasma levels in a dose-proportional manner, crosses the blood-brain barrier, reaches brain and CSF levels shown to be effective in animal models of AD, and provides an acceptable safety profile that allows it to proceed to Phase 2 clinical studies. A Phase 2 study comparing patients receiving placebo (82 subjects) with patients receiving 250 mg BID scyllo-inositol over a 78-week treatment period showed no statistically significant differences between subjects in the full analysis set in the primary endpoints of NTB and / or ADCS-ADL. The adherence population of patients (placebo = 47, scyllo-inositol = 250 mg BID) showed no statistically significant differences in the primary endpoints of NTB and / or ADCS-ADL. In a BID=49 study, no statistically significant differences were found in the prevention of functional decline at the end of the 78-week treatment period for the primary endpoints measured by NTB and ADCS-ADL. The AD patient population in this study consisted of patients with mild to moderate Alzheimer's disease with MMSE scores of 16-26.One publication reported a subgroup analysis of subjects with MMSE scores of 23-26 in these studies (placebo: FAS 35 / PPS 22 vs. scyllo 250 Bid FAS 36 / PPS 24), but again no statistical significance was achieved between the placebo and scyllo-inositol groups. See Salloway, et al. Neurology 2011;77:1253-1262.

[0041] Although scyllo-inositol has been reported to have properties related to the prevention of Aβ fibril formation, along with positive results in memory / cognitive tests in AD animal models, there has been little or no published information regarding the actual treatment of Alzheimer's disease in subjects, given the clear failure of clinical studies to date. The present inventors have surprisingly and unexpectedly discovered a subgroup of patients for which scyllo-inositol can be effectively treated to treat a subset of patients with Alzheimer's disease or MCI, while meeting the primary endpoint in clinical studies.

[0042] Glossary As used herein, numerical ranges recited by endpoints include all numbers and fractions within that range (e.g., 1-5 includes 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, and numbers between those particular numbers).

[0043] The term "adjuvant" means a component that, when added to the dosing regimen of a single active ingredient or in combination with another active ingredient, in combination adds or provides an enhanced or beneficial modified therapeutic effect or safety advantage to the other active ingredient(s) in the combination compared to the same property of the single other active ingredient or ingredients administered alone. An adjuvant may not itself have clinically significant properties in the target patient population, but in combination with such other active ingredient(s) provides an additional clinically significant therapeutic or safety property to such other active ingredient(s) in the target patient population.

[0044] The terms "administer" and "administration" refer to the process of delivering a therapeutically effective amount of a compound or composition contemplated herein to a patient for the prevention and / or treatment of the described condition or disease.

[0045] The term "treatment" refers to reversing, alleviating, or inhibiting the progression of a disease or one or more symptoms of such a disease to which such term applies. Depending on the condition of the patient or subject, the term may also refer to preventing a disease, and depending on the particular disease or condition, may also include preventing the onset of such a disease.

[0046] The terms "subject" or "patient" are used interchangeably herein and include mammalian subjects, including humans or animals such as horses, dogs, cows, cats, and other mammals.

[0047] The term "pharmaceutically acceptable excipient or carrier" refers to a medium that does not interfere with the effectiveness or activity of the active ingredient and is not toxic to the subject to which it is administered. Excipients include diluents, binders, adhesives, lubricants, disintegrants, fillers, wetting or emulsifying agents, pH buffers, and other known pharmaceutically effective excipients.

[0048] The term "combination therapy" or "coadministration" means that active ingredients are administered simultaneously to a patient being treated. In the case of coadministration, the ingredients can be administered simultaneously or sequentially at different times and in any order. This term includes pretreatment with one active ingredient followed by treatment with both active ingredients and / or any active ingredients simultaneously or at different times to achieve a desired therapeutic and / or beneficial effect. A beneficial effect includes, for example, a reduction in the side effects of one or both active ingredients due to the presence of the other active ingredient.

[0049] The term "beneficial effect" refers to an effect of a compound, adjuvant, composition, or combination that includes a favorable pharmaceutical and / or therapeutic effect and / or improved biological activity, and may include reduced side effects. The term "beneficial effect" includes effects such as improved cognitive function, reduced vascular load, reduced astrogliosis, reduced amyloid load, reduced microglia, and / or improved survival. A beneficial effect may also include improved stability, increased half-life, and / or improved uptake and transport across the blood-brain barrier by one active ingredient or adjuvant to the overall benefit of the other active ingredient.

[0050] Immunotherapy for Alzheimer's disease is a promising approach to reduce amyloid-β fibrils and plaques in the brain. Previous clinical trials investigating active or passive immunotherapy approaches to reduce the amyloid-β burden in the brain have shown some efficacy in reducing amyloid-β and improving cognition. 1-4 However, the dosage of antibody therapy used was limited by the appearance of treatment-related abnormalities on brain imaging. Although these imaging abnormalities may be clinically silent, their long-term impact on safety is unknown and potentially dangerous.

[0051] Imaging abnormalities associated with immunotherapy have been observed with several humanized monoclonal antibody therapies directed against beta-amyloid, including a phase 2 study of bapineuzumab. 1,2 These MRI abnormalities were initially diagnosed as "vasogenic edema." 4 As more research and discoveries emerged in most other immunotherapy trials, it became clear that there were a variety of imaging changes associated with amyloid-modifying treatments. 5 include FLAIR signal abnormalities thought to represent parenchymal vasogenic edema and crevicular effusion (ARIA-E), and abnormalities detectable on GRE / T2* sequences thought to represent microhemorrhages and hemosiderosis (ARIA-H).

[0052] The prevalence and severity of ARIA are closely correlated with increasing doses of antibodies against amyloid-β, thus preventing the full efficacy of immunotherapy treatment by limiting the administration of high levels of antibodies necessary to optimize brain amyloid reduction and improve cognition in Alzheimer's disease. In most cases, immunotherapy treatments have been administered with suboptimal doses of amyloid-β antibodies to prevent patients from developing ARIA.

[0053] More recently, immunotherapy against amyloid beta (aducanumab) has been shown to be more effective at higher doses of the antibody than at lower doses when administered to patients with mild cognitive impairment (MCI) and mild AD. To mitigate ARIA associated with the high doses required for optimal efficacy, a dose-escalation regimen was used to reduce the prevalence and severity of ARIA. Aducanumab was initially administered to patients at low doses, such as 1 mg / kg, and then slowly increased over time to higher doses of 3, 6, and then 10 mg / kg. The discovery that higher doses of treatment could be administered by gradually increasing the dose provided efficacy with an acceptable safety profile.

[0054] However, there remains a significant unmet medical need for agents, drugs, or adjuvants with specific properties that can mitigate / alleviate the safety issues associated with ARIA, thereby enabling / tolerating increased doses / administration regimens of immunotherapeutic agents such as aducanumab and other effective monoclonal antibodies, and enabling / achieving significant increases in the dosing and efficacy of such immunotherapeutic agents in patients with MCI and mild AD who require such treatment.

[0055] This need has been met by the surprising discovery that small molecules such as scyllo-inositol can effectively partner with monoclonal antibodies to attack Aβ and treat patients with Alzheimer's disease more effectively than aducanumab alone, or can achieve similar or reduced levels of ARIA with lower final titers and / or increased aducanumab concentrations and doses. It is also believed that triple combinations of such monoclonal antibodies, scyllo-inositol, and linolenic acid / linoleic acid can provide effective relief to patients with cognitive impairment, including those with mild Alzheimer's disease and mild cognitive impairment (MCI).

[0056] Although the exact mechanism of immunotherapy's role in the development of ARIA is unclear, increased antibody binding to large amyloid-β aggregates in perivascular cuffs and accessible plaques in the brain can lead to local inflammation and leakage. Large doses of antibodies against amyloid-β are required to break down these aggregates and promote clearance of amyloid-β from the brain to the CSF and blood. Increasing antibody doses increase the likelihood of forming pockets of antibodies that react with amyloid aggregates and plaques, resulting in the development of symptoms associated with ARIA. Therefore, drugs that can interact with and disperse amyloid aggregates may reduce pockets of antibody complexes in the brain.

[0057] Scyllo-inositol, a stereoisomer of myo-inositol, has been shown to disassemble amyloid-β fibrils and prevent their formation in vitro. In vivo, daily administration of 0.3–30 mg / kg of scyllo-inositol to transgenic mouse models of AD reduced brain amyloid-β burden and improved cognitive and functional tests. Furthermore, treatment with scyllo-inositol has been shown to reduce neurotoxicity and brain inflammation. Because scyllo-inositol can cross the blood-brain barrier via the myo-inositol transporter, the drug can achieve levels sufficient to reduce large amyloid aggregates and plaques to small amyloid-β oligomers. Cognitive improvement may reflect a reduction in amyloid burden and a reduction in large aggregates and plaques.

[0058] Preclinical studies have been conducted using methods to test mouse models of Alzheimer's disease, such as TgCRND8 mice, as disclosed in US2007 / 0197452. Tests performed include behavioral tests such as the Morris water maze, quantification of brain amyloid burden, plasma and brain Aβ content, gliosis, survival studies, analysis of APP in the brain, analysis of soluble Aβ oligomers, long-term potentiation, and synaptophysin immunohistochemical staining. The results of these studies demonstrated the efficacy of scyllo-inositol in treating TgCRND8 mice, which have amyloid plaque morphology, density, and distribution similar to those found in the brains of human patients with Alzheimer's disease.

[0059] The focus of this disclosure is broad: pre- and follow-up treatment with scyllo-inositol in combination with vitamins, particularly vitamin D and / or vitamin D prohormones such as calcifediol, is effective in treating memory loss, mild cognitive impairment, and early Alzheimer's disease in subsets of patients with certain MMSE scores. Furthermore, such drug combinations may also be effective in treating Alzheimer's disease and certain side effects associated with treatment with monoclonal antibodies, such as aducanumab and other monoclonal antibodies known to treat Alzheimer's disease. Scyllo-inositol, alone or in combination with vitamin D compounds, and in combination with aducanumab, is believed to reduce the prevalence and severity of ARIA associated with aducanumab treatment. This combination can increase the dose of antibodies administered to patients with mild cognitive impairment (MCI) and mild AD, improving cognition and function. Second, administration of scyllo-inositol as a vitamin supplement alone or coadministered with antibody therapy against amyloid beta increases clearance of amyloid beta from the brain to the CSF and blood, reducing amyloid burden in the brain and improving cognition compared to antibody therapy alone. Finally, coadministration of scyllo-inositol with vitamins, particularly vitamin D compounds selected from the group consisting of calcifediol, enhances cognitive and functional efficacy by synergistic or combinatorial actions that prevent amyloid beta accumulation in the brain compared to administration of scyllo-inositol alone, while simultaneously increasing serum levels of 25-hydroxyvitamin D3. In a preferred embodiment, calcifediol is the preferred vitamin D metabolite administered directly in combination with scyllo-inositol. Calcifediol is available in immediate-release or sustained-release forms and is sold under various brand names worldwide. In sustained-release form, the drug is known as RAYALDEE®. An immediate-release prescription form of the product is sold as softgels under the brand name Hidroferol®. DSM manufactures 10 microgram immediate-release tablets, which are sold in certain countries under the brand name Ampli-D.

[0060] The present invention also includes a method for treating patients with Alzheimer's disease, which involves pre-treatment with scyllo-inositol for two weeks, followed by co-administration of scyllo-inositol with anti-amyloid beta antibody therapy in patients with mild to moderate-grade Alzheimer's disease (MCI) and mild AD, to mitigate safety concerns associated with ARIA and promote reduction of amyloid beta burden in the brain, thereby improving efficacy and safety. Alternatively, patients already receiving aducanumab can be co-administered with scyllo-inositol for the treatment of MCI and mild AD. However, initial clinical protocols require a two-week pre-treatment course. Patients with MCI and mild AD will be divided into three cohorts and treated as follows: a. Cohort 1, patients are treated with Scyllo-inositol alone at 250 mg BID or 500 mg QD for 54 weeks. Patients are assessed for amyloid burden, memory, cognitive and functional tests, and ARIA. b. Cohort 2: Patients were treated with 250 mg BID or 500 mg QD scyllo-inositol alone for 2 weeks, followed by 250 mg BID or 500 mg QD scyllo-inositol in combination with aducanumab, initially at 1 mg / kg (4 weeks), then 3 mg / kg (4 weeks), 6 mg / kg (4 weeks), and finally at a final dose of 10 mg / kg for the remainder of the study (40 weeks). Patients were evaluated for ARIA, amyloid-beta burden, memory, cognition and function, and safety parameters. c. Cohort 3, patients are treated with escalating doses of aducanumab alone, initially at 1 mg / kg (4 weeks), then 3 mg / kg (4 weeks), 6 mg / kg (4 weeks), and 10 mg / kg for the remainder of the study (40 weeks). Patients are evaluated for ARIA, amyloid-beta burden, memory, cognition and function, and safety parameters.

[0061] Combination treatment with Scyllo-inositol and aducanumab for 52 weeks yields the following results:

[0062] ARIA was reduced compared with aducanumab treatment alone.

[0063] Amyloid-beta burden in the brain was reduced compared with treatment with aducanumab alone.

[0064] Memory, cognition, and function improved compared with aducanumab treatment alone.

[0065] CSF amyloid beta biomarkers such as amyloid beta 42 / 40 ratio, tau, and phosphorylated tau improved.

[0066] This combination also provides greater flexibility in aducanumab dosing regimens by allowing for modified dose concentrations and alterations to the currently approved course of treatment.

[0067] In another embodiment, the present invention includes a combination of drugs for the treatment of cognitive impairment and / or memory loss. Accordingly, the present invention relates to a combination of (i) a first compound selected from scyllo-inositol and / or a similar cyclohexanol, or a combination of such inositols, or a pharmaceutically acceptable salt thereof, with (ii) a second compound selected from the group consisting of 25-hydroxyvitamin D, such as 25-hydroxyvitamin D3 or D2. Such a combination may be in the form of a kit containing a dosage form containing the first compound and a dosage form containing the second compound. Alternatively, the present invention relates to a single capsule, tablet, or dosage form containing both a first compound selected from scyllo-inositol and a second compound selected from 25-hydroxyvitamin D3 or D2. Such a capsule, tablet, or dosage form may be in any suitable formulation and may include additional pharmaceutically acceptable excipients. The capsule or tablet may contain a combination of an immediate release form of scyllo-inositol and may further contain a layer of an immediate release amount of calcifediol or a layer of a sustained release formulation of calcifediol surrounding an immediate release tablet core.

[0068] Scyllo-inositol Scyllo-inositol can be obtained through processes disclosed in numerous patents and applications. See U.S. Patent Nos. 8,409,833 and / or 7,745,671, both of which are incorporated herein by reference. Its use in the prevention, treatment, and diagnosis of protein accumulation disorders is disclosed, for example, in EP 1608350B1, EP 8859628, or EP 7,521,481, both of which are incorporated herein by reference. The data presented herein demonstrate that scyllo-inositol treatment in mice significantly reduced amyloid burden and gliosis. Scyllo-inositol is said to have properties that inhibit established amyloid deposition in the brain in vivo. Thus, the data suggest that scyllo-inositol has properties that reduce amyloid plaque burden and improve cognition in mammals in need of such treatment. Diseases treatable with scyllo-inositol include conditions of the central nervous system, peripheral nervous system, or systemic organs that are characterized by the deposition of proteins or protein fragments and peptides in beta-pleated sheets and / or fibrils or aggregates. In patients undergoing or prescribed monoclonal antibody therapy for such diseases, the deposition and / or tissues already containing such sheets can be disrupted by the co-administration or combination of an appropriate formulation of scyllo-inositol and such monoclonal antibody.

[0069] Scientific and clinical data from the past 25 years support the idea that the accumulation of amyloid-β fibrils in the brain plays a key role in the progressive decline in memory and cognition with age and may ultimately lead to dementia, even in the absence of Alzheimer's disease. Amyloid-β oligomers and fibrils are known to accumulate in the brain 5 to 15 years before significant effects on memory, cognition, and potential age-related dementia are observed. Furthermore, 30 to 40% of people aged 55 and older have accumulated amyloid-β in their brains, potentially increasing their risk of memory loss or mild cognitive impairment (MCI). Approximately 60 to 70% of patients who exhibit signs or symptoms of mild cognitive impairment (MCI) have amyloid oligomers and fibrils in their brains. Scyllo-inositol, administered at clinically proven safe levels, such as 250 mg twice daily, can reduce the amyloid burden in the brain. Co-administration of such doses of scyllo-inositol with vitamin D compounds that effectively increase serum levels of 25-hydroxyvitamin D3 in the brain can treat or reduce memory loss or cognitive impairment.

[0070] Scyllo-inositol offers benefits including (i) the ability to cross the blood-brain barrier and degrade amyloid fibrils, reducing amyloid burden in the brain, and (2) the ability to improve associated neurological conditions or symptoms, such as memory loss or cognitive impairment. Scyllo-inositol has been shown to prevent and reverse amyloid burden in the brain of animal models overexpressing amyloid beta, resulting in improved cognition (see McLaurin J., et al. Nature Medicine 2006;12(7):801-8). Furthermore, as claimed herein, unpublished results from a phase 2 clinical trial demonstrate that scyllo-inositol alone can treat certain Alzheimer's disease and MCI patients with previously unpublished MMSE score ranges. Combined human and animal data demonstrate that scyllo-inositol alone can reduce fibril burden and treat or alleviate cognitive impairment in subjects. There is reason to believe that very early intervention with a pharmaceutically or nutraceutical effective amount of scyllo-inositol, alone or in combination with vitamin D compounds and, if necessary, other active ingredients or other vitamin compounds, can treat such subjects and reduce fibrillogenesis. Scyllo-inositol prevents Aβ accumulation, reduces Aβ burden, and improves cognitive function in transgenic animal models of Alzheimer's disease. See McLaurin J, et al. J Biol Chem 2000 24:18495; McLaurin J., et al., Nature Medicine 2006 Jul;12(7):801-8; and Townsend M., et al., Annals of Neurology 2006 Dec;60(6):668-76.

[0071] Oral administration of 250 mg BID scyllo-inositol to humans showed a trend toward improved cognition and function in older adults with mild AD over 78 weeks.

[0072] Specific diseases and conditions treatable with such combination therapies include Alzheimer's disease, presenile and geriatric forms, amyloid angiopathy, mild cognitive impairment (MCI), Alzheimer's disease-related dementia, tauopathies, alpha-synucleinopathies, Parkinson's disease, amyotrophic lateral sclerosis, motor neuron disease, spastic paraplegia, Huntington's disease, spinocerebellar ataxia, Friedrich's ataxia, neurodegenerative diseases associated with intracellular and / or intraneuronal aggregates of proteins containing polyglutamine, polyalanine or other repeats resulting from pathological expansion of tri- or tetranucleotide elements within the corresponding genes, and other diseases and disorders disclosed, for example, in U.S. Pat. No. 7,521,481, incorporated herein by reference.

[0073] Scyllo-inositol can be formulated into any suitable pharmaceutical formulation. The compound can be administered orally or by other suitable means. Oral formulations can be in the form of tablets or capsules containing pharmaceutically acceptable excipients selected from binders, fillers, surfactants, preservatives, lubricants, etc. The amount of drug varies, but in combination therapy, it is typically in the high end of the range, typically 125-250 mg BID, or 500 mg QD. The prescribing physician can modify this dosage depending on the patient's specific condition or condition, reducing the supplemental dose to 50-150 mg BID. Tablets and / or capsules can be prepared by means known to those skilled in the art. Scyllo-inositol can also be administered via oral solution or suspension, intravenous administration, intramuscular administration, or other means, such as intraperitoneal, intradermal, transdermal, subcutaneous, intranasal, sublingual, or inhalation.

[0074] Aducanumab Aducanumab-abauwa is described as a recombinant human immunoglobulin gamma 1 (IgG1) monoclonal antibody that targets accumulated soluble and insoluble amyloid-beta. The immunoglobulin is expressed in a Chinese hamster ovary cell line and has a molecular weight of 146 kDa. The pre-diluted injection contains no preservatives and contains 100 mg of aducanumab-abauwa, L-arginine hydrochloride (31.50 mg), L-histidine (0.60 mg), L-histidine hydrochloride monohydrate (3.39 mg), L-methionine (1.49 mg), polysorbate 80 (0.50 mg), and water for injection with a pH of approximately 5.5 per mL. Clinical studies have demonstrated and documented that ADUHELM reduces amyloid-beta plaques. The drug reduced amyloid-β plaques in a dose- and time-dependent manner compared with placebo. The drug's effect on plaque levels was assessed using PET imaging (18-florbetapir tracer). PET signals were quantified using the standardized uptake value ratio (SUVR) method to estimate brain levels of amyloid-β plaques in a complex of brain regions predicted to be affected by Alzheimer's disease pathology. See the ADUHELM prescribing information. These regions include the frontal, parietal, lateral, temporal, sensorimotor, and anterior and posterior cingulate cortices, compared with a brain region predicted to be less affected by such pathology (the cerebellum).

[0075] A substudy of this clinical trial of aducanumab demonstrated a reduction in brain levels of amyloid-beta plaques at both low and high dose levels compared with placebo at weeks 26 and 78. The extent of these reductions was again described as both dose- and time-dependent.

[0076] A third clinical study of ADUHELM demonstrated statistically significant dose- and time-dependent reductions in amyloid plaque levels at 26 weeks in the 3 mg / kg, 6 mg / kg, and 10 mg / kg treatment groups and at 54 weeks in all treatment groups compared to placebo treatment.

[0077] ADUHELM was also studied for its effect on tau pathophysiology (marker levels). Studies demonstrated that ADUHELM reduced tau pathophysiology markers (CSF p-tau and tau PET) and neurodegeneration markers (CSF t-tau) (Studies 1 and 2). The immunotherapy drug also reduced CSF p-tau levels in substudies conducted in Studies 1 and 2. At week 78 in Study 1, the adjusted mean change from baseline in CSF p-tau levels compared with placebo was favorable for the low- and high-dose ADUHELM groups. The drug also reduced CSF t-tau levels compared with placebo in the low- and high-dose ADUHELM groups in a substudy conducted in Study 1.

[0078] In studies 1 and 2, PET imaging ( 18 A substudy was also conducted to confirm the effect of aducanumab on neurofibrillary tangles composed of tau protein using the F-MK6240 tracer. PET signals were quantified using the SUVR method to estimate brain levels of tau in brain regions expected to be affected by Alzheimer's disease pathology (medial temporal lobe, temporal cortex, frontal cortex, cingulate cortex, parietal cortex, and occipital cortex) compared with brain regions expected not to be affected (e.g., cerebellum). Clinical data showed that adjusted mean changes from baseline in tau PET SUVR compared with placebo at follow-up were superior for aducanumab administered at high doses to the medial temporal lobe, temporal region, and frontal regions of the brain.

[0079] Finally, additional data were collected on the exposure-response relationship after receiving aducanumab versus placebo. The data showed that increased exposure to aducanumab was associated with greater reductions in subjects' clinical decline, as measured by CDR-SB, ADAS-Cog13, and ADCS-ADL-MCI, as well as greater reductions in amyloid-beta plaques.

[0080] Clinical studies conducted on the combination products described herein will use the same methods used in the ADUHELM study to demonstrate efficacy, reduction in markers, and improvement in AIRA-related events following combination therapy and pretreatment with scyllo-inositol.

[0081] As set forth in U.S. Patent No. 10,842,871, incorporated herein by reference, during the development of drugs for the treatment of Alzheimer's disease, the Food and Drug Administration (FDA) expressed concerns in 2010 regarding the occurrence of abnormalities evident on MRI scans following treatment in clinical trials. These abnormalities, identified and / or believed to represent vasogenic edema (VE) and microhemorrhages (mH), were first observed in clinical trials of monoclonal antibodies directed against amyloid beta. Subsequently, developers of these drugs, including those of the recently approved monoclonal antibody treatment aducanumab, have focused on efficacy and safety, as well as emerging concerns regarding VE or mH arising from monoclonal antibody treatment. The underlying reasons for the increase in VE and mH abnormalities are not fully understood. The presence of the apolipoprotein E ε4 allele, ApoEε4, has been found to be a significant risk factor for the development of ARIA-E (VE-associated MRI abnormalities). On the other hand, mH is not associated with specific alleles and is generally thought to result from one of two etiologies: small vessel angiopathy and cerebral amyloid angiopathy (CAA). It has also been suggested that a local inflammatory component caused by drug treatment may trigger both ARIA-E and / or ARIA-H.

[0082] In all cases, to treat mild cognitive impairment (MCI) and mild Alzheimer's disease and reduce ARIA resulting from such treatment, Biogen-IDEC received FDA approval for ADUHELM™ aducanumab, with a treatment regimen requiring titration to reduce ARIA. The agent is an amyloid-beta-targeting antibody indicated for the treatment of Alzheimer's disease and was granted accelerated approval based on the reduction in amyloid-beta plaques observed in patients treated with ADUHELM. The dosage and administration section of the approval labeling states that (1) titration is required to initiate treatment, (2) the recommended maintenance dose is 10 mg / kg administered by intravenous infusion over approximately one hour every four weeks, (3) a recent (within one year) brain MRI should be performed prior to initiating treatment, and (4) an MRI should be obtained before the seventh and twelfth infusions. If severe ARIA-H is observed radiologically, treatment can be continued cautiously only after radiological stability (no increase in the size or number of ARIA-H) is demonstrated by clinical evaluation and follow-up MRI. (5) Diluted in 100 mL of 0.9% Sodium Chloride Injection, USP, prior to administration, (6) administered as an intravenous infusion over approximately 1 hour through a 0.2 or 0.22 micron in-line filter. Approved dosage forms and strengths are 170 mg / 1.7 mL (100 mg / mL) for injection in single-dose vials and 300 mg / 3 mL (100 mg / mL) for injection in single-dose vials. The label's warnings and precautions section warns of the need for increased clinical vigilance for amyloid-related imaging abnormalities (ARIA), particularly during the titration period and the first eight doses of treatment. IV infusion intervals are every four weeks. The dosing or titration schedule is 1 mg / kg aducanumab for infusions 1 and 2, 3 mg / kg for infusions 3 and 4, 6 mg / kg for infusions 5 and 6, and 10 mg / kg for infusions 7 and beyond. The side effects section of the label states that the most common side effects (incidence of at least 10% or greater compared with placebo) are ARIA-edema, headache, ARIA-H microhemorrhages, ARIA-H superficial hemosiderosis, and falls.

[0083] The section on monitoring ARIA states that if 10 or more new microbleeds or more than two focal superficial hemosiderosis (radiologically severe ARIA-H) are observed, treatment can be continued cautiously only after clinical evaluation and follow-up MRI demonstrate radiological stability (no increase in size or number of ARIA-H).

[0084] In the ADUHELM clinical study and the clinical study of the combination therapy described in this specification, the severity of ARIA will be classified by the radiological criteria shown in Table 1 below. [Table 1]

[0085] In a clinical study comparing aducanumab monotherapy with placebo, ARIA-E and / or ARIA-H were observed in 41% (454 of 1105) of patients treated with the planned dose of 10 mg / kg, compared with 10% (111 of 1087) of patients receiving placebo. ARIA-E was observed in 35% of patients receiving aducanumab 10 mg / kg, compared with 3% of patients receiving placebo. As previously mentioned, the incidence of ARIA-E was higher in apolipoprotein E ε4 (ApoEε4) carriers than in ApoEε4 non-carriers (42% and 20%, respectively). Clinical trials have demonstrated that ARIA can occur at any time, but the majority of ARIA-E radiological events occurred early in treatment (within the first eight doses). Among patients treated with aducanumab (10 mg / kg) who experienced an ARIA-E event, the maximum radiographic severity was mild in 30% of patients, moderate in 58%, and severe in 13%. Sixty-eight percent of patients with ARIA-E experienced resolution by 12 weeks after detection, 91% by 20 weeks, and overall, 98% experienced resolution of symptoms. Ten percent of all patients receiving aducanumab 10 mg / kg experienced one or more ARIA-E episodes. ARIA-H in the setting of ARIA-E associated with the use of ADUHELM 10 mg / kg was observed in 21% of patients receiving the drug compared with 1% of patients receiving placebo.

[0086] ADUHELM is administered in a titration-based regimen, driven by the need to reduce ARIA-related events that occur or are likely to occur with a fixed-dose regimen. Titration is believed to slow the pace of amyloid clearance initially, allowing for slower clearance throughout a patient's overall treatment. Pretreatment with a non-monoclonal antibody regimen, for example with agents such as scyllo-inositol, is believed to accelerate plaque clearance and reduce plaque burden without causing ARIA-related events. As a result, subsequent coadministration of scyllo-inositol and aducanumab reduces ARIA-related or related events associated with antibody treatment, thereby allowing titration to higher doses of aducanumab and / or facilitating a fixed-dose regimen of aducanumab / scyllo-inositol without causing or reducing ARIA-related events in treated patients. This combination accelerates the rate of plaque clearance without slowing amyloid clearance.

[0087] Aducanumab (BIIBO37) is an IgG1 monoclonal antibody consisting of two heavy chains and two kappa light chains linked by interchain disulfide bonds. This antibody recognizes a conformational epitope found in Aβ aggregates. A murine IgG2a chimeric version of this antibody (chl 2F6A) has been shown to attenuate or reduce plaque burden in aged Tg2576 mice, a mouse model of Alzheimer's disease. See Wilcock and Colton 2009. A human version of antibody 12F6A has an amino acid sequence identical to BIIBO37, produced in a different Chinese hamster ovary cell line.

[0088] Aducanumab has been shown to be effective against V H and / or V L It has an antigen-binding domain that includes a variable region. [Table 2]

[0089] Aducanumab (BIIB037) has the following named CDR protein sequences: [Table 3]

[0090] The sequence of the heavy chain of the anti-Aβ antibody BIIB037 is as follows: QVQLVESGGG VVQPGRSLRL SCAASGFAFS SYGMH WVRQA PGKGLEWVA V IWFDGTKKYY TDSVKG RFTI SRDNSKNTLY LQMNTLRAED TAVYYCAR DR GIGARRGPYY MDV WGKGTTV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK RVEPKSCDKT HTCPPCPAPE LLGGPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE KTISKAKGQP REPQVYTLPP SREEMTKNQV SLTCLVKGRY PSDIAVEWES NGQPENNYKT TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SPG (SEQ ID NO: 9)

[0091] The heavy chain CDRs are underlined.

[0092] The sequence of the light chain of the anti-Aβ antibody BIIB037 is as follows: DIQMTWSPSS LSASVGDRVT ITC RASQSIS SYLN WYQQKP GKAPKLLIYA ASSLQS GVPS RFSGSGSGTD FTLTISSLQP EDFATYYC QQ SYSTPLT FGG GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 10).

[0093] The light chain CDRs are underlined.

[0094] Antibodies can be prepared using, for example, the process described in US2021018895, which is incorporated herein by reference. As described herein, they can be prepared in eukaryotic or bacterial cells. In a preferred embodiment, they are produced in transformed eukaryotic cell lines such as CHO, 292E, and COS. In addition to bacterial and eukaryotic cells, yeast cells can also be used to produce antibodies or their scFvs. The general process involves constructing a polynucleotide encoding the antibody, introducing it into an expression vector, and expressing the antibody in a suitable host cell. Molecular biology techniques are known to those skilled in the art. When antibodies are expressed in CHO, COS, or NIH3T3 cells, a promoter such as the SV40, MMLV-LTR, EF1α, or CMV promoter is required. Additional sequences, such as regulatory sequences, can be added to facilitate replication and selection or to confer resistance to drugs into which the vector has been introduced. Suitable vectors include pMAM, pDR2, and the like, described in US2021188954. To demonstrate the preparation of BIIB037, a recombinant expression vector encoding the antibody heavy and light chains was introduced into dhfr-CHO cells by calcium phosphate-mediated transfection. The antibody heavy and light chains were operably linked to enhancer / promoter regulatory elements derived from either SV40, CMV, or other vectors, such as the CMV enhancer / AdML:promoter regulatory element or the SV40 enhancer, in a system that drives high levels of gene transcription. The vector also contained a DHFR gene, allowing for the selection of CHO cells transfected with the vector using methotrexate selection / amplification. Selected transformants were cultured to express the antibody light and heavy chains, after which the antibody was recovered from the culture medium and used in the compositions described herein for the treatment of Alzheimer's disease patients. Purification methods are known in the art, and such antibodies can be isolated and purified to levels required for human administration. Purification methods include column chromatography, filtration, ultrafiltration, salting out, solvent extraction, solvent precipitation, immunoprecipitation, and other means including SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, and recrystallization.

[0095] Antibody compositions can be formulated according to the methods and compositions described in U.S. Patent No. 10,842,871, incorporated herein by reference. Compositions can include pharmaceutically acceptable excipients, such as phosphate-buffered saline, water, and emulsions, including oil-in-water emulsions. Wetting agents can be added, and such compositions can be delivered as sterile solutions. Antibodies and pharmaceutical compositions can be administered, for example, intravenously, intraperitoneally, subcutaneously, intramuscularly, topically, or transdermally. Various concentrations of antibodies can be prepared and utilized for combination therapy. Such concentrations can range from 50 mg / mL to over 300 mg / mL for highly concentrated antibody compositions. Sterile injections of such antibodies are made and require filtration sterilization. Coating of such antibodies with lecithin may be necessary to ensure proper sample flow. Additional components can be added to reduce the risk of accumulation and / or ensure appropriate viscosity. Excipients include, for example, L-arginine hydrochloride in various concentrations (40-260 nM and ranges therebetween). Sucrose may be further added at a concentration of about 0.5% to about 5%. Methionine may also be included in the composition at a concentration range of 5 mM to about 150 mM. Other excipients for ease of formulation and handling may include polysorbate at a concentration range of 0.01% to 0.03%. A buffering agent may also be added to achieve a pH range of about 5.0 to 6.5 or any level therebetween. Histidine may be used as a buffering agent at a concentration range of about 5 mM to 50 mM or any value therebetween. Antioxidants such as glutathione CSH, cysteine, and cystine may be used at a concentration range of about 0.02 mM to 4 mM.

[0096] Methods used to measure clinical efficacy and outcomes are determined for each patient and include measuring and determining the presence, severity, and progression of Alzheimer's disease over a period of time. This includes clinically determining the patient's overall level of function, deficits in daily living activities and abilities, volumetric analysis of brain structure using techniques such as PET imaging of beta-amyloid protein, and in vivo measurement of disease-related deposition of abnormal proteins in the brain. Additionally, blood, body fluid, or CSF markers are also measured as indicators of disease presence or progression, including measurement of tau protein and other biomarkers, such as pyroglutamate-Aβ, Aβ40, and Aβ42, in blood, and total tau, phosphorylated tau, pyroglutamate-Aβ, Aβ40, and Aβ42 in CSF. ApoE isotype and hippocampal volumetric (HCV) MRI also help define and / or stage disease progression. Measurement of such markers and methods for determining their levels are known in the art. Furthermore, such markers are known to predict the onset of Alzheimer's disease. See, for example, Duyckaerts (2011) Lancet Neurol. 10, 774-775, and Craak, et al., (2013), Acta Neuropath., 126:631-41.

[0097] Amyloid plaque burden is measured by 18F-AV-45 PET. 18F-AV-45 is a known amyloid ligand developed and marketed by Avid Radiopharmaceuticals. A trained PET imaging specialist can review acquired PET images to determine the mean 18F-AV-45 uptake between AD patients and age-matched controls. PET and morphometric MRI measurements of regional glucose metabolism are also utilized to assess AD status or progression. MRI monitors ARIA-related events.

[0098] Linolenic / Linoleic Acid: Linoleic acid, (Z,Z)-9,12-octadecadienoic acid (molecular weight 280.44), is an essential fatty acid found as the main component of vegetable oils. This fatty acid is a colorless oil. Linolenic acid is found in two major forms: alpha and gamma. alpha-linolenic acid is (Z,Z,Z)-9,12,15-octadecatrienoic acid, an essential fatty acid and a colorless liquid. gamma-linolenic acid is (6Z,9Z12Z)-6,9,12-octadecatrienoic acid, produced in the body as a metabolite of linoleic acid. These fatty acids are commercially available. In 1993, Yehuda and colleagues published a paper on the discovery of the optimal ratio of these fatty acids and the benefits it had on nerve membrane function and neurotransmission levels, expressed as a "membrane fluidity" index. See Proc. Natl. Acad. Sci. USA, vol. 90, pp. 10345-10349, Nov. 1993, Neurobiology. Yehuda discovered that the ratio of α-linolenic acid to linoleic acid is an important variable in improving cognitive function and other neurological characteristics. Yehuda treated animals (rats) with purified free α-linolenic acid to linoleic acid (approximately 25 mg per kg of body weight daily) for four weeks and found that a ratio of 1:3.5 to 1:5 (e.g., 1:4 is preferable) produced significant positive effects on learning performance, pain threshold, and thermoregulatory control of d-amphetamine-induced hypothermia. Furthermore, these essential fatty acids are being studied clinically across a wide range of disorders, including ADHD and other neurological disorders. These essential oils are commercially available in combination with these specific ratios. The combination with scyllo-inositol can be, as described above, a combination of both the scyllo-inositol and the essential fatty acid "mixture" in separate dosage forms (e.g., a scyllo-inositol tablet and a fatty acid mixture capsule), or the active ingredients can be formulated together in a single oral dosage form, prepared in the form of a capsule or oral liquid. Tablets can be formed by compression and can be prepared from crystalline, powdered, or granular material together with other pharmaceutically acceptable excipients such as binders, disintegrants, lubricants, diluents, and colorants.The diluent may be selected from, for example, dicalcium phosphate, lactose, cellulose, mannitol, dry starch, powdered sugar, and / or sodium chloride. The binder may be selected from starch, gelatin, and sugars such as sucrose, glucose, dextrose, and lactose. Natural and / or synthetic gums may also be used. Lubricants such as magnesium stearate may also be incorporated into tablets or capsules. Flavoring ingredients may also be used. When a mixture of scyllo-inositol and essential fatty acid oil is formulated into a single pharmaceutical composition, the preferred dosage form is a capsule. The capsule may be selected from hard or soft capsules. The capsule may be a gelatin-based capsule or a known suitable hard or soft capsule. A preferred capsule contains 250 mg of scyllo-inositol and 250 mg of free α-linolenic acid and linoleic acid (molar ratio 1:4). These capsules are administered to a subject twice daily. The dosage may be increased and provided to a subject in a QD format. A pharmaceutically effective amount of scyllo-inositol can be utilized. This amount can range from 100 mg to over 500 mg. A suitable amount of mixed linolenic acid / linoleic acid (1:4 ratio) can be used and can be provided BID or QD. The amount of oil mixture can be 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, up to about 1000 mg, or any amount between or greater than these amounts (mg / gram). In some cases, a subject can ingest several grams (1-12 grams) of the oil mixture, but this is provided in a separate oral administration. This combined oral dosage form or other combinations of such active ingredients can also be combined with aducanumab.

[0099] Additional active ingredients and / or essential nutrients and vitamins can also be combined with the "mix" combination of scyllo-inositol and linolenic and linoleic acids. Vitamins available in this combination include vitamins E, K, D, B, and C. 25-hydroxyvitamin D can also be combined with this combination. The formulation can also be administered as an immediate-release or controlled-release dosage form.

[0100] Calcifediol Numerous patents, patent publications, and scientific publications disclose the use and administration of calcifediol in both immediate-release and sustained-release forms. U.S. Patent No. 8,207,149 discloses a controlled-release formulation of a vitamin D compound for oral administration, in which the vitamin D compound as defined therein is incorporated into a solid or semi-solid mixture of a waxy substance to form a sustained-release formulation. Such formulations are described as being filled into gelatin capsules. The prohormone 25-hydroxyvitamin D3 is described as a preferred compound. The present invention involves a combination of scyllo-inositol and a vitamin D compound, such as 25-hydroxyvitamin D3, in a suitable tablet, capsule, or liquid formulation. The vitamin D compound may be provided as an immediate-release formulation containing calcifediol, or as a sustained-release formulation containing a waxy controlled-release carrier agent for the vitamin D compound, a lipid agent, and an oily vehicle. The carrier may be selected from waxes such as synthetic waxes, microcrystalline waxes, paraffin waxes, carnauba waxes, or beeswax. Additional excipients include polyethoxylated castor oil derivatives, hydrogenated vegetable oils, glyceryl mono-, di-, or tribehenate, long-chain alcohols such as stearyl alcohol, cetyl alcohol, and mixtures thereof, which are incorporated into sustained-release formulations. Other patents disclose additional stable formulations, such as those disclosed in U.S. Patent No. 10,357,502, which is incorporated herein by reference in its entirety, along with U.S. Patent No. 8,207,149. A capsule formulation containing 25-hydroxyvitamin D3 (30, 60, or 90 μg), paraffin wax (20% by weight), mineral oil (35.36%), hydroxypropyl methylcellulose K100 MCR 10.0%, glycerol monostearate (22.5%), lauroyl macrogol glycerides and polyoxylglycerides (GELUCIRE 44 / 14) 9.75%, absolute alcohol (2.32%), and BHT 0.02% or variations thereof may be formulated into a soft or hard capsule and used in combination with a scyllo-inositol (250 mg) tablet.

[0101] U.S. Publication No. 2021 / 0401752, incorporated herein by reference, discloses a dosage form of calcifediol dispersed in a polymer composition, which may be a sustained-release formulation. An embodiment includes a vitamin D compound, such as calcifediol, embedded in a polymer network. This specification discloses a spheronized pellet formulation containing 25-hydroxyvitamin D and a pharmaceutically acceptable excipient. In certain embodiments, the spheronized pellet contains a sustained-release component selected from a polymer and / or a lipid component. The polymer may be a water-insoluble polymer, may include a water-soluble polymer, or may be a water-soluble polymer. The formulation may be a nano / microparticle formulation made by emulsion followed by freeze-drying of spray drying, as described in the '752 publication. The formulation may be a powder formulation made by spray congealing. The formulation may include sustained-release coated seeds or active-coated granules. The formulation may be wax-free and / or wax-containing.

[0102] As further described in U.S. Patent Publication No. US20210308151, it is believed that raising serum total 25-hydroxyvitamin D to sufficiently high levels can reverse the immunodeficiency state of a human host and prevent the progression of infectious diseases and associated complications. The consequences of this effect in humans are also believed to apply to neurological diseases or disorders associated with inflammatory signaling or any type of inflammation. Therefore, combined therapy with vitamin D compounds, particularly calcifediol, and more specifically, ER-calcifediol, may result in the treatment or alleviation of such neurological disorders and / or symptoms associated with any level of inflammation. In particular, the extrarenal generation or delivery of calcitriol to active vitamin D receptors in the brain, combined with the administration of an inositol selected from scyllo-inositol, can achieve both fibril disruption and high levels of 25-hydroxyvitamin D3, which is then converted to calcitriol (active vitamin D) in vivo, thereby preventing the inflammation-related progression of such neurological diseases or disorders or the worsening of their associated symptoms.

[0103] Immediate-release calcifediol dosage forms can be prepared, for example, according to AU2021100513, which discloses an immediate-release tablet formulation of calcifediol, in which spray-dried powder prepared from an emulsion is added to tablet excipients and formed into a tablet containing 10 micrograms of calcifediol.

[0104] It is believed that cognition and memory can be further enhanced by safely raising 25-hydroxyvitamin D3 levels (e.g., 30-100 ng / mL or higher) in patients with cognitive impairment based on their weight and BMI, and safely maintaining sufficient 25-hydroxyvitamin D3 levels through combination therapy with scyllo-inositol. These results suggest that, regardless of whether a patient or subject with cognitive decline or memory loss has a predisposition to developing Alzheimer's disease or mild cognitive impairment, memory loss and cognitive problems develop more rapidly when vitamin D levels are insufficient, and if such patients have a predisposition to Alzheimer's disease, the onset of such disease will be more rapid. Meanwhile, subjects with sufficient serum 25-hydroxyvitamin D3 levels are less likely to develop such disorders or experience a milder onset of such disease than patients with deficient or insufficient serum calcifediol.

[0105] Vitamin B Useful B vitamins, either in separate dosage forms or in a single dosage form containing scyllo-inositol (125-250 mg QD or BIQ) and vitamins and / or other active ingredients, are selected from the group consisting of vitamin B9 (folic acid) in a dose of about 30-1500 μg / day, vitamin B12 (cobalamin or cyanocobalamin) in a dose of about 0.1 to about 300 μg / day, vitamin B1 (thiamine, thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin or nicotinic acid) or analogs such as nicotinamide, including nicotinamide riboside, vitamin B5 (pantothenic acid), vitamin B6, and vitamin B7 (biotin). The dosages in the separate dosage forms or in the single dosage form containing the scyllo-inositol combination are selected from the dosages of each vitamin appropriate to correct a deficiency or insufficiency of such vitamin in a subject in need of treatment.

[0106] In the case of nicotinamide riboside, a precursor of nicotinamide adenine dinucleotide (NAD+), the dosage is selected to treat cognitive impairment correlated with brain inflammation. The dosage range is 30-500 mg / day. In a preferred embodiment, the dosage is approximately 300 mg / day. Accordingly, the present invention further includes a combination of a first compound selected from scyllo-inositol and a second compound selected from a precursor of nicotinamide adenine dinucleotide, such as vitamin B or nicotinamide riboside. In a preferred embodiment, the second compound is selected from nicotinamide riboside. NAD+ depletion is a known marker of Alzheimer's disease (AD), and nicotinamide riboside has been shown to have beneficial effects on oxidative stress and DNA repair in AD mouse models by increasing NAD+ levels. Furthermore, nicotinamide riboside has been shown to reduce Aβ levels in mouse AD animal models. This combination can be provided as separate dosage forms or as a single tablet, capsule, or formulation containing both scyllo-inositol and nicotinamide riboside. Either form of the combination can be administered to patients in need of treatment, including those with Alzheimer's disease, MCI, or acute brain injury or chronic neurodegenerative disease accompanied by or accompanied by signs of cognitive impairment or memory loss, or axonal degeneration. Furthermore, the combination of scyllo-inositol and nicotinamide riboside is useful for treating ophthalmic disorders such as retinal degeneration, age-related dysfunction, diabetic retinopathy, light-induced degeneration, or photoreceptor degeneration. Other diseases or conditions that can be treated with such a combination include neuromuscular diseases, including progressive wasting syndromes, Duchenne muscular dystrophy (DMD), and other neurological diseases or conditions in which reduced PARylation levels are desired, including those in AD and MCI patients. The present invention also encompasses additional combinations that include calcifediol as a third compound in addition to the first and second compounds described above.In an alternative embodiment, the combination of calcifediol and nicotinamide riboside can be used separately as two separate dosage forms or as a single dosage form containing both active ingredients to treat NAD+ deficiency or insufficiency and vitamin D insufficiency or insufficiency in patients with Alzheimer's disease, MCI, or neurological disorders associated with cognitive or memory impairment. In a preferred embodiment, calcifediol is a sustained-release formulation when contained in a single tablet or capsule as another active ingredient in a separate dosage form, in a combination that also contains a dosage form of nicotinamide riboside. In one embodiment, the combination can be in the form of a single dosage form containing both calcifediol and nicotinamide riboside. These combinations or compositions can be administered, optionally alone or in combination with scyllo-inositol, in separate dosage forms or in a single capsule or tablet containing all three active ingredients. Kits containing two or three active ingredients in separate dosage forms can be prepared in suitable packaging. In a preferred embodiment, one of the capsules contains a 30, 60, or 90 μg dose of RAYALDEE® (ER calcifediol), and the capsule can be a softgel or hardgel. In another embodiment, calcifediol is in an immediate-release form containing 10 or 20 μg of calcifediol in a tablet or capsule. In another embodiment, calcifediol is a 266 μg softgel, an oil-based formulation, and is administered once a month along with a dosage form of nicotinamide riboside and scyllo-inositol.

[0107] Other supplements or active ingredients may also be used in combination with scyllo-inositol. 15 H 10The combination of apigenin (O5) and scyllo-inositol (100-500 mg) may be utilized in separate dosage forms or in a single dosage form containing both ingredients. In a preferred embodiment, the dosage form is a single dosage form, such as a tablet or capsule, containing approximately 150 mg of each active ingredient. This combination, together with other pharmaceutically acceptable excipients, comprises a pharmaceutical or dietary supplement composition useful for the treatment of cognitive impairment, mild cognitive impairment, and Alzheimer's disease in a subset of patients with an MMSE score of approximately 22-26. Apigenin is commercially available and sold as a dietary supplement in various dosages.

[0108] Clinical evaluations used to determine the stage and overall progression of Alzheimer's disease and / or to prevent or ameliorate disease progression include the CDR, FCSRT, Neuropsychiatric Inventory-Questionnaire (NPI-Q), and the Rey Auditory Verbal Learning Test (RA-VLT), a neurological test battery including immediate and delayed memory, the Wechsler Memory Scale (WMS), the Verbal Paired Associate Learning Test (VLT), the DeLis-Kaplan Executive Function Test (VLT), Verbal Fluency Criteria 1 and 2, and the Wechsler Adult Intelligence Scale-Fourth Edition, Symbol Search and Encoding subsets, as well as the Cognitive Drug Research test battery. The Mini-Mental State Examination (MMSE) and the Neuropsychological Test Battery (NTB) and their subitems may also be used to assess cognition. While these assessments are often used in subjects suspected of MCI or Alzheimer's disease, such tests may also be used in healthy subjects long before a physician has diagnosed cognitive impairment. In some dosage forms and at some dosage amounts, the combination of scyllo-inositol and calcifediol is believed to be safely administered to subjects outside of the prescription range for single active ingredients with sufficient safety and efficacy data. [Example]

[0109] Example 1 - Phase 2 clinical trial of 18 months of scyllo-inositol treatment in patients with mild to moderate AD. A double-blind, parallel-group, randomized, placebo-controlled, multicenter safety and efficacy study was conducted at 58 sites in North America between December 2007 and May 2010. Patients aged 50–85 years were enrolled. They were suspected of having AD, had a Mini-Mental State Examination (MMSE) score of 16–26, MRI scans consistent with AD, no other pathological findings, a Rosen-Modified Hachinski score of 17 or 4, and no significant neurological, psychiatric, or medical illness. Medications that could affect cognition were not permitted, except for stable administration of acetylcholinesterase inhibitors or memantine. Patients were randomly assigned to either a placebo group or a 250 mg BID treatment group. Randomization was stratified by MMSE score (16–21 vs. 22–26), APOE4 carrier status (1 or 2 alleles vs. none), and use of approved AD symptomatic medications (yes vs. no). Cognitive, functional, and MRI assessments were performed at baseline and at weeks 12 (without MRI), 24, 48, and 78. Safety evaluations included adverse event (AE) monitoring, clinical laboratory tests, and electrocardiograms. The primary efficacy outcome measures were the change from baseline to week 78 in the Neuropsychological Test Battery (NTB) 19z score and the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score. Secondary clinical outcome measures were the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Clinical Dementia Rating-Summary of Boxes (CDR-SB), and Neuropsychiatric Inventory (NPI) score. The 12-item version of the ADASCog was used. The exploratory clinical outcome was the change in MMSE score from baseline to week 78. A subset of patients underwent magnetic resonance spectroscopy (MRS) to assess brain scyllo-inositol and myo-inositol levels. In another subset of patients, lumbar punctures were performed to determine CSF concentrations of Aβ-40, Aβ-42, total tau, phosphorylated tau 181 (p-tau), 30, and ELND005 at baseline, week 24 (primary CSF biomarker endpoint), and week 78. Repeated-measures models were used to compare changes from baseline between the 250 mg and placebo groups for all continuous efficacy and biomarker endpoints.

[0110] In a phase 2 study examining a 250 mg BID dose for 18 months in patients with mild to moderate AD (MMSE 16-26), data (Figure 1, Figure 1A, Figure 1B, Figure 1C, Figure 1D, Figure 1E, Figure 1F) showed that scyllo-inositol did not improve the two primary endpoints, NTB and ADCS-ADL, measuring overall cognition and function in patients with mild to moderate AD. Throughout the 18-month treatment period, no substantial differences were observed between placebo-treated and scyllo-inositol-treated patients in the full analysis (FAS - all patients who received at least one dose) and per protocol analysis (PPS - all patients who completed the study) of the NTB, ADCS-ADL, and CDR-SoB cognitive and functional tests. Small numerical improvements were observed in the NTB tests in the per protocol group (patients who completed the study), suggesting that scyllo-inositol can detectably improve cognition in patients with mild and moderate AD overall. The data observed with Scyllo-inositol were consistent with previous trials of other amyloid-beta-targeted therapies.

[0111] However, in a prespecified subgroup of mild AD patients with MMSE scores of 23-26, trends toward improvement in various cognitive function assessments—NTB, CDR-SB, and ADCS-ADL—were observed in both the FAS and PPS patient populations, but the results were not statistically significant. In the FAS and PPS populations receiving scyllo-inositol, NTB scores improved by 72% and over 100%, respectively, compared with placebo. Similarly, CDR-SB and ADCS-ADL scores improved by 31-44% over 78 weeks in patients receiving scyllo-inositol versus placebo. These data demonstrate the potential for scyllo-inositol to improve both cognition and function in patients with mild AD with MMSE scores of 23-26. The targeted 30% improvement in all three cognitive and functional tests was achieved or exceeded by 18 months of scyllo-inositol treatment. While this data suggested that such patients may have improvement, it was not conclusive, and it was only after reviewing the study's unpublished data that the inventors were able to focus on the subgroup of patients with an MMSE score of 22, who are more severely affected than the mildly affected patients with an MMSE score of 23 to 26. Thus, this combined data suggests and provides evidence that patients with an MMSE score of 22 to 26 can be effectively treated with scyllo-inositol at the BID dose provided in this important study. [Table 4]

[0112] Figure 2 shows the change from baseline in NTB scores over 78 weeks in patients with mild AD who had MMSE scores of 23-26 in the placebo and scyllo-inositol treatment groups. The change from baseline in NTB scores was most pronounced after 12 and 18 months of treatment, demonstrating the disease-modifying properties of scyllo-inositol. Scyllo-inositol treatment improved NTB scores within the first 6 months, suggesting a potential immediate effect on AD symptoms, although a similar effect was detected to a lesser extent with placebo. The FAS and PPS populations, demographics, NTB scores, and other clinical outcomes are shown in Table 4. ELND005 is scyllo-inositol.

[0113] Changes from baseline in NTB subscale scores were examined in a mild AD patient population (MMSE 23-26) over the course of the study (78 weeks). Data presented in Figure 3 (Figure 3A-J) indicate that eight of the nine NTB subscales improved over 78 weeks with scyllo-inositol treatment. While these data indicate that scyllo-inositol may improve various symptoms related to cognition, this post-hoc analysis is insufficient to demonstrate the efficacy of the drug in this patient population or in a larger patient population for a phase 2 clinical trial.

[0114] Figures 4 and 5 show the change from baseline in ADCS-ADL and CDR-SB scores, respectively, for the mild AD patient population (MMSE 23-26). Scyllo-inositol improved both ADCS-ADL and CDR-SB scores compared with placebo. Furthermore, the placebo-treated mild AD patient group in this study showed a decline in CDR-SB scores over the study period, similar to mild AD patients with MMSE 23-26 selected from the ADNI database. These data suggest that the rate of decline in CDR-SB scores for mild AD patients in the scyllo-inositol phase 2 trial was similar to that of the larger mild AD population obtained from the ADNI database. Table 5 shows the population, statistics, ACCS-ADL delta, drug effect % and p-value for mild AD (MMSE 23-26) in the FAS and PPS populations. Table 6 shows the population, statistics, and change in CDR-SB scores from baseline for mild AD (MMSE 23-26). [Table 5] [Table 6]

[0115] Figure 6 (Figure 6A-F) shows the change from baseline in CDR-SB subitem scores for the mild AD patient population (PPS) treated with scyllo-inositol compared to placebo. Eight of nine CDR-SB subitem scores improved with scyllo-inositol treatment, demonstrating broad positive effects on both cognition and function.

[0116] Mild AD patients have an MMSE score of 20-26, and patients with an MMSE score of 23-26 are considered to have very mild AD. Clinical data were further analyzed to identify a specific MMSE cutoff that demonstrates the efficacy of scyllo-inositol treatment in all mild AD patients (MMSE 20-26).

[0117] The data in Table 7 below show that only patients with an MMSE score of 22 or higher responded to scyllo-inositol treatment. This data has not been published and is provided here for the first time. Thus, the inventors have discovered a new subgroup of Alzheimer's disease patients who can be effectively treated with scyllo-inositol. Similar efficacy was observed across all three cognitive and functional assessments: NTB, CDR-SB, and ADCS-ADL. These data can be used to identify appropriate patient populations who will benefit from scyllo-inositol treatment and to select patients for clinical studies. In summary, scyllo-inositol is effective in patients with mild AD who have an MMSE score of 22 to 26. Therefore, the present invention also includes a method for selecting patients with a specific MMSE score range or equivalent to distinguish between those who can be treated with drug therapy and those who do not respond to such therapy. [Table 7]

[0118] More than 70% of MCI patients (MMSE 26-30) are believed to have amyloid-β fibrils and plaques in their brains. This is consistent with data showing that amyloid-β accumulation in the brain occurs well before memory loss and AD-like symptoms appear. However, the progression of MCI pathology and symptoms that causes MCI patients to transform into mild AD patients is variable and difficult to predict for individual MCI patients. In general, the majority of MCI patients progress slowly, making it very difficult to enroll MCI patients in clinical studies to evaluate the efficacy of amyloid-β-targeted therapies. Furthermore, if patients do not progress sufficiently, the effectiveness of amyloid-targeted drugs in slowing progression is reduced.

[0119] Recently, the FDA approved aducanumab, an immunotherapy targeting amyloid beta. It demonstrated efficacy in only one of two phase 3 trials in patients with mild AD and mild cognitive impairment (MCI). Data suggest that aducanumab appears to be effective, but with considerable variability. In comparison, donanemab, another immunotherapy, demonstrated efficacy in biomarker- and clinically selected patients with MCI and mild AD in a phase 2 study. In this case, the study with donenemab was considered highly successful, suggesting that patient selection may be necessary to detect clinical benefit in patients with MCI and mild AD.

[0120] The development of screening tests to select for MCI patient populations with more rapidly progressing symptoms is essential for assessing cognitive and functional improvement in MCI patients over a 12-18 month period. Furthermore, treatment of MCI patients with mild amyloid-β-related pathology is considered a preferred patient population for amyloid-β-targeted therapies.

[0121] It is important to develop criteria for selecting patients with amyloid-β in the brain who are progressing to mild cognitive impairment at a detectable rate within a reasonable time frame. PET scans are used to detect amyloid-β in the brain. Other methods include measuring amyloid-β levels in the CSF, and patients with amyloid-β levels below 192 pg / ml are highly likely to have amyloid in the brains of patients with AD. The MCI patient population is more complex, with some patients having CSF amyloid-β levels below the 192 pg / ml cutoff value and others exceeding it. Because the amount of amyloid-β in the brain may not be indicative of the severity or rate of memory and cognitive loss, selection criteria should include parameters that identify patients who progress more rapidly at baseline and who may benefit from amyloid-β therapy.

[0122] As shown in Table 8 below, the ADNI database for all 507 MCI patients (MMSE = 26-30) was thoroughly analyzed and evaluated to select various clinical cognitive and functional tests to be used to screen for MCI patients who will rapidly progress to mild AD. The data showed that using three different cognitive and functional test combinations with different cutoff values—ADAS ≥ 8 and FAQ ≥ 2 or ADAS ≥ 8 and CDR ≥ 2 at baseline—selected patient populations for cognitive and functional decline as measured by the MMSE, ADAS-Cog-11, CRD-SB, and FAQ tests. The data also compared key clinical endpoints over 12 and 18 months between the overall unenhanced and enhanced MCI patient populations based on baseline scores for the above parameters. As shown below, selected / enhanced MCI patients with specific cutoff values ​​for the ADAS, FAQ, and CDR demonstrated significantly increased cognitive and functional symptom loss compared to the overall MCI population. Disease progression from baseline to 18 months was more rapid compared to 12 months. This selected patient population is expected to respond well to scyllo-inositol in clinical trials because of the large difference and similar or lower standard deviation between baseline and 12 or 18 months. Furthermore, as the severity of baseline cognitive and functional parameters used to select patients with MCI increases, disease progression in this population increases over time, making them more likely to respond to scyllo-inositol or other Aβ-targeting agents.

[0123] The selection criteria for MCI patients also select for those with amyloid-beta in the brain, narrowing the pool of patients most likely to respond to amyloid-beta-targeting drugs. Furthermore, selecting MCI patients with an ADAS score >8 and an FAQ score >2 or CDR >2 at baseline has been shown to select a population of patients in which 58% will progress to mild AD and 88.5% will have CSF amyloid-beta levels below 192 mg / mL (consistent with amyloid-beta accumulation in the brain). Applying more stringent clinical criteria to these parameters increases the proportion of patients who demonstrate more rapid cognitive and functional decline. This patient population, selected by these key criteria at baseline, is effective in selecting MCI patients with amyloid-beta in the brain who will demonstrate more rapid cognitive and functional decline and progression to mild AD. [Table 8]

[0124] A second set of enhanced criteria was developed to select MCI patients with more rapid cognitive and functional loss by analyzing the ADNI database. Patients were selected based on the combined ADAS and FAQ scores at baseline, as shown in Table 9. MCI patients with baseline ADAS scores >7 and FAQ scores >1, resulting in a combined score of 13 or greater, demonstrated increased decline in both CDR-SB, MMSE, ADAS-Cog11, and FAQ scores over 12 and 18 months compared with the overall MCI patient population. Similar increases in disease progression were observed across various cognitive and functional tests administered over the same time period. Selection of rapidly progressing MCI patients was enhanced by increasing the stringency of the criteria to a combined score of 14 or by increasing the ADAS score from 8 to a combined score of 14 at baseline. The enhanced MCI patient population was more likely to accumulate amyloid-beta in the brain and progress to a mild AD state over 18 months compared with the overall MCI population. These criteria provide a useful tool for selecting patients with MCI eligible for clinical studies evaluating Aβ-targeting drugs and who may also benefit from scyllo-inositol treatment. [Table 9]

[0125] The same selection criteria based on baseline parameters can also be applied to mild AD patients and MCI patients with MMSE scores of 23–30. Table 10 shows the same analysis performed above for all mild AD and MCI subjects (N = 753) with MMSE scores of 23–30 who provided baseline data on the MMSE, FAQ, ADAS-Cog (11), and CDR-SB. Of these, 664 and 316 subjects provided complete data at 12 and 18 months for key cognitive and functional scores, respectively. Similarly, this approach selected an enriched population with more rapid progression of cognitive and functional decline over the 12 and 18 months compared with the overall population. These data support the hypothesis that the selected patient population would benefit from amyloid-β-targeting agents, such as scyllo-inositol. [Table 10]

[0126] Using the second approach, we selected patients with mild AD and MCI with MMSE scores of 23–30 and intensified treatment with scyllo-inositol (see Table 11). Similar results to those shown above were achieved. These data indicate that patients with ADAS scores ≥ 7, FAQ scores ≥ 1, and ADAS+FAQ scores ≥ 13 at baseline experienced significantly increased disease progression over 12 and 18 months based on key cognitive and functional endpoints, including MMSE, ADAS-Cog 11, CDR-SB, and FAQ. Increasing the severity of patients' disease at baseline may increase the likelihood of progression. [Table 11]

[0127] Example 2 Clinical study of a selected population of mild AD (MMSE 22-26 subpopulation) and MCI patients with MMSE 26-30 treated with scyllo-inositol. Patients with mild AD (MMSE score 22-26) and MCI patients (MMSE score 26-30) with baseline characteristics of ADAS ≥ 8 and FAQ ≥ 2 or / and ADAS ≥ 8 and CDR ≥ 2 will be selected and combined for enrollment in the study. Selected patients will be divided into two groups: a placebo group and a scyllo-inositol treatment group. Patients will receive placebo or 250 mg twice daily scyllo-inositol for up to 18 months. Patients will be followed for safety and efficacy. Primary efficacy endpoints (NTB, ADAS-cognitive score 11, CDR-SB) will be measured at baseline and after 3, 6, 12, and 18 months of treatment with placebo or scyllo-inositol 250 mg twice daily. Safety will be analyzed at similar time points.

[0128] Example 3 - Clinical Study of Scyllo-inositol in Combination with Aducanumab The clinical study will be conducted in patients with mild cognitive impairment (MCI) and / or mild Alzheimer's disease. Enrolled patients with MCI and / or mild Alzheimer's disease will be pretreated with scyllo-inositol for two weeks, followed by co-administration of scyllo-inositol (250 mg BID) with an anti-amyloid beta antibody therapy (aducanumab) for MCI and mild AD to mitigate concerns associated with ARIA with monoclonal therapy alone. This clinical study will measure the efficacy of the drug combination in enhancing reduction of amyloid beta burden in the brain and demonstrate improved efficacy and safety compared to treatment with either drug alone. MCI and mild AD patients will be divided into three cohorts and treated as follows: a. Cohort #1, patients are treated with 250 mg BID scyllo-inositol alone for 2 weeks, followed by an additional 52 weeks of treatment with 250 mg BID scyllo-inositol. Patients are evaluated for amyloid burden, memory, cognitive and functional tests, and ARIA. b. Cohort #2, patients are treated with either 250 mg BID scyllo-inositol alone for 2 weeks, followed by either 250 mg BID scyllo-inositol in combination with aducanumab, initially at 1 mg / kg (4 weeks), then 3 mg / kg (4 weeks), 6 mg / kg (4 weeks), and a final dose of 10 mg / kg for the remainder of the study (40 weeks). Patients are evaluated for ARIA, amyloid-beta burden, memory, cognition and function, and safety parameters. c. Cohort #3, patients are treated with escalating doses of aducanumab alone, initially at 1 mg / kg (4 weeks), then 3 mg / kg (4 weeks), 6 mg / kg (4 weeks), and 10 mg / kg for the remainder of the study (40 weeks). Patients are evaluated for ARIA, amyloid-beta burden, memory, cognition and function, and safety parameters.

[0129] Results demonstrate that 52 weeks of combined treatment with scyllo-inositol and aducanumab results in:

[0130] Each treatment dose reduced ARIA compared with aducanumab alone.

[0131] Each treatment dose reduced amyloid-beta burden in the brain compared with aducanumab treatment alone.

[0132] Memory, cognition, and function improved compared with aducanumab treatment alone.

[0133] CSF amyloid beta biomarkers such as amyloid beta 42 / 40 ratio, tau, and phosphorylated tau improved.

[0134] The specific clinical protocol will follow the same protocols used in the ADUHELM clinical study to measure plaque levels, ARIA impact, tau protein in the CSF, and exposure-response relationships, respectively.

[0135] Example 4 - Studies carried out with a combination of scyllo-inositol and linolenic acid / linoleic acid. The clinical study will be conducted in patients with mild cognitive impairment (MCI) (MMSE 26-30) and / or mild Alzheimer's disease (MMSE 22-26). Enrolled patients with MCI and / or mild Alzheimer's disease will be treated with either placebo or scyllo-inositol (250 mg BID) in combination with 250 mg BID of linoleic and linolenic acid (4:1 ratio) to determine the efficacy of scyllo-inositol in combination with a linoleic and linolenic acid mixture on memory, cognition, and function. This clinical study will measure the efficacy of combination treatment with scyllo-inositol and a linoleic and linolenic acid mixture (4:1 ratio) compared with placebo. Patients will undergo treatment for 6, 12, and 18 months, and memory and cognition will be assessed using standardized tests, including the MMSE, NTB, and ADAS-Cog11, as well as sub-items of these tests focusing on various types of memory and cognition. Patients with MCI and mild AD will be divided into three cohorts and treated as follows: Cohort #1: Patients with MCI and / or mild Alzheimer's disease are treated with placebo BID for up to 18 months. Patients are evaluated for memory, cognitive and functional tests, and safety. b. Cohort #2: Patients are treated with 250 mg BID scyllo-inositol and 250 mg BID of a mixture of linoleic and linolenic acid (4:1 ratio) for up to 18 months. Patients are evaluated for memory, cognition and function, and safety parameters.

[0136] Clinical studies have demonstrated the effects of treatment with scyllo-inositol in combination with a mixture of linoleic and linolenic acids on memory and cognition. This combination demonstrates the short- and long-term benefits of the fatty acid mixture, as well as the long-term effects of scyllo-inositol on disease progression resulting from the expected reduction in amyloid-beta burden.

[0137] Example 5: Synergistic effect of scyllo-inositol and a mixture of linoleic and linolenic acids in an AD animal model. Mice with AD-like disease will be divided into four groups and the effects of scyllo-inositol alone or in combination with a mixture of linoleic and linolenic acids will be analyzed compared to the mixture of linoleic and linolenic acids alone or a placebo. The selected dosage will be used to enhance synergy between both treatments on pathology and cognition in animal studies. Combining scyllo-inositol with a mixture of linoleic and linolenic acids is expected to improve memory and cognition.

[0138] Example 6. Clinical study with a combination of scyllo-inositol and calcifediol. The aim of this study was to evaluate the effect of scyllo-inositol in combination with vitamin D3 or calcifediol (ER and IR) treatment to slow the progression of cognitive and functional loss in patients with mild AD and MCI over a 12-18 month period. We also investigated the more immediate effects of scyllo-inositol and vitamin D3 or calcifediol on cognition and function after 6 months, which may indicate a symptomatic effect of treatment.

[0139] Patient population: Mild AD patients alone with MMSE scores of 22–26, or combined with MCI patients with MMSE scores of 27–28 who were predicted to experience more rapid decline in cognition and function based on the specific inclusion criteria described below. 1. Mild AD patients with an MMSE score of 22-26 2. MCI patients with an MMSE score of 27-28 who meet the following criteria: -ADAS≥8, FAQ≥2, CDR≥2 or ADAS ≥ 7, FAQ ≥ 1, total score of ADAS and FAQ ≥ 13 3. Testing positive for amyloid beta in the brain 4. Patients with mild AD, Apo e4 genotype, and MCI stratified based on MMSE score

[0140] Treatment arms of the study: 1) placebo (patients treated twice daily under identical conditions to the treatment but without active drug); 2) Patients treated with scyllo-inositol (150–250 mg scyllo-inositol once daily or twice daily (BID) 3) Patients treated with scyllo-inositol (250 mg scyllo-inositol once or twice daily, plus 1000 units vitamin D3 once or twice daily (BID) or IR calcifediol 10-90 μg once daily, and 4) Scyllo-inositol (patients treated with 250 mg of scyllo-inositol once or twice daily and 30–90 μg of calcifediol ER once daily).

[0141] Number of patients per group: 210 patients 1) Placebo 70 people 2) Scyllo-inositol 70 people 3) Scyllo-inositol and vitamin D3 or calcifediol (70 people)

[0142] Treatment duration: Patients will receive treatment for up to 18 months. A blinded, independent study will conduct an interim analysis at 6 months to evaluate safety and efficacy, and the study design may be expanded to increase the number of patients per group.

[0143] Key primary endpoints for the analysis: The NTB, ADAS-Cog 11, CDR-SB, and IADRS have been used as primary endpoints in phase 2 and 3 studies and were recently approved as primary endpoints by the FDA. Depending on the patient population, specific endpoints, and possibly other memory and cognition endpoints, may be tested.

[0144] Safety and further analysis: General safety parameters required for the mild AD and MCI indications will be considered, similar to those outlined in the previous Phase 2 study. Additional testing may include biological markers, amyloid-beta scans, pharmacokinetic data, etc. Additional studies may be conducted using additional vitamins, such as B12, at doses that ensure sufficient patient sufficiency and eliminate deficiency or insufficiency. In the protocol described above, vitamin B12 may be administered to the group at a dose of 2000 μg per day along with 250 mg twice daily of scyllo-inositol. This combination therapy has been shown to treat patients with cognitive impairment, memory loss, mild AD, and MCI, as described herein.

[0145] Example 7 - Results of a Simulation Clinical Study in Selected Patient Populations Phase 2 data evaluating changes from baseline in NTB and CDR-SB scores in mild AD patients treated with scyllo-inositol over an 18-month period were further analyzed with bootstrap simulations to determine data reproducibility using a larger, generated population of mild AD patients. Observed data represent data obtained from 43 patients treated with placebo and 42 patients treated with scyllo-inositol in the mild AD study. Simulated data using bootstrap analysis represented 100 subjects per group generated from each mild AD group and were simulated with 1,000 runs to generate the final data. Figure 7A-D shows the observed changes from baseline in NTB scores at weeks 12, 24, 48, and 78. Scyllo-inositol treatment demonstrated improvements in NTB scores across all MMSE groups, ranging from 20 to 26. However, the optimal effect of scyllo-inositol was observed in the patient population with MMSE scores of 22 to 26. Although not statistically significant, the p-value of 0.08 for MMSE 22-26 indicated a strong signal of efficacy compared with the other patient group with MMSE 20-26 (p-value 0.23).

[0146] Figures 8A–D show bootstrap simulation data for NTB scores for various mild AD patient groups (MMSE 20–26). The simulation data are similar to the observed data for change in NTB from baseline. However, the simulation data showed that the NTB scores of AD patient groups (MMSE 21–26, 22–26, and 23–26) treated with scyllo-inositol statistically improved from baseline. When analyzed by bootstrap simulation, the improved efficacy of cognition measured by the NTB test provides confidence that the benefits of scyllo-inositol treatment are reproducible, and statistical significance strengthens with increasing patient numbers.

[0147] Figure 9A-D shows observed data showing the change from baseline in CDR-SB scores in various mild AD groups with MMSE scores of 20-26 at 12, 24, 48, and 78 months after scyllo-inositol treatment. No clear effect was observed in the change in CDR-SB scores for mild AD patients (MMSE scores of 20-26) treated with scyllo-inositol. Improvement with scyllo-inositol was increased in mild AD patient groups with MMSE scores of 21-26, 22-26, and 23-26. The optimal mild AD group showing a scyllo-inositol effect was an MMSE score of 22-26. Similar data were observed in simulated data (Figure 10A-D) for CDR-SB scores for the same patient population based on MMSE scores. However, the cognitive and functional efficacy measured by the CDR-SB test was statistically significant and was more pronounced in the patient groups with MMSE scores of 22-26 (p-value 0.0034) and 23-26 (p-value 0.0027). Furthermore, the increased reproducibility and statistical significance observed in the simulated data reinforces the reliability of the efficacy data when treating mild AD patient populations with MMSE scores of 22-26 with scyllo-inositol at a dose of 250 mg / day twice daily. Furthermore, depending on the severity of symptoms and patient progression, these doses can be lowered to approximately 125 mg / day twice daily or 250 mg or 500 mg / day twice daily.

[0148] Figures 11A–D summarize and compare the observed and simulated changes from baseline in NTB and CDR-SB scores after 78 weeks of scyllo-inositol treatment in mild AD patients with MMSE scores of 22–26. The simulated data show that 78 weeks of scyllo-inositol treatment statistically improved cognition and function as measured by both the NTB and CDR-SB tests, with p-values ​​of 0.009 and 0.034, respectively. Overall, the data indicate that scyllo-inositol does not improve cognition and function in the overall population of mild AD patients with MMSE scores of 20–26, but does show strong and significant improvements in the subset of mild AD patients with MMSE scores of 22–26 when simulated to represent a sample of 100 patients. This is particularly surprising and unexpected given previous data analyzed on the subpopulation of patients with MMSE scores of 23-26, who, overall, have lower disease severity than the subset of patients in the MMSE 22-26 range.

[0149] Preclinical and clinical studies related to scyllo-inositol have been published, demonstrating its safety and activity. See Clinicaltrials.gov and the patent publications cited herein, all of which are incorporated by reference. Additionally, an unpublished analysis has been conducted, providing findings regarding the use of scyllo-inositol in a subset of patients with mild AD and / or MCI, with MMSE scores of 22-26.

[0150] In summary, Figure 1A-F shows the effect of 250 mg BID scyllo-inositol treatment in mild / moderate AD patients (MMSE 16-30) on the primary endpoints (NTB, ADCS-ADL, and CDR-SB). The data demonstrate that treating mild and moderate AD patients with scyllo-inositol for 78 weeks did not improve the NTB, ADCS-ADL, and CDR-SB scores as indicators of cognition and function. However, a small signal was observed in the NTB score in the protocol-compliant population.

[0151] Figure 2 shows the effect of 78 weeks of scyllo-inositol treatment in patients with early, mild AD (MMSE 23-26) in the pre-specified overall and per-protocol populations. After scyllo-inositol treatment, analysis of the overall population showed a 72% improvement in NTB scores compared to the placebo population. Similarly, data from the per-protocol population showed a 100% improvement in NTB scores compared to placebo. These data provide a strong signal that scyllo-inositol treatment improves cognition in patients with early, mild AD.

[0152] Figures 3A-I show the change from baseline in NTB subscale scores for a population of mild AD patients (MMSE23-26) treated with scyllo-inositol and placebo over the study period (78 weeks). The data show that eight of the nine NTB subscales improved over 78 weeks with scyllo-inositol treatment. These data indicate that scyllo-inositol improves a variety of symptoms related to cognition.

[0153] Figure 4 shows the change in ADCS-ADL scores from baseline in patients with early to mild AD (MMSE 23-26) treated with scyllo-inositol and placebo for 78 weeks. The data show that compared with placebo, scyllo-inositol treatment improved ADCS-ADL scores throughout the 78-week study period. Scyllo-inositol treatment improved ADCS-ADL scores by 35% and 31% in the complete analysis and protocol-compliant populations, respectively. These data suggest that scyllo-inositol improves function in patients with early to mild AD.

[0154] Figure 5 shows the change from baseline in CDR-SB scores in patients with early-to-mild AD (MMSE 23-26) treated with scyllo-inositol and placebo for 78 weeks. The data show that scyllo-inositol treatment improved CDR-SB scores over the 78-week study period compared to placebo. Scyllo-inositol treatment resulted in 40% and 44% improvements in CDR-SB scores compared to placebo in the complete analysis and protocol-compliant populations, respectively. These data demonstrate that scyllo-inositol improves cognition and function as measured by the CDR-SB test.

[0155] Figures 6A-F show the effects of scyllo-inositol versus placebo treatment on change from baseline in the CDR-SB subscales in patients with early mild AD from the Per-Protocol Population (PPS). These data show that scyllo-inositol improved five of the six subscales of the CDR-SB test, which measures both cognition and function.

[0156] Figures 7A-D show the observed change from baseline in NTB scores with scyllo-inositol treatment in patients with mild AD who had MMSE scores of 20-26. The data show that scyllo-inositol was more effective in improving NTB scores in the patient population whose MMSE scores increased up to 23. Ideally, this agent would be effective in patients with MMSE scores of 22 or higher.

[0157] Figures 8A–D show bootstrap simulation data for the change from baseline in NTB scores with scyllo-inositol treatment in various groups of mild AD patients with MMSE scores ranging from 20 to 26. Analyzing the data using the bootstrap simulation method, increasing N from 30 to 100, showed a pattern similar to the observed data. These data indicate that the change in NTB was more pronounced in the scyllo-inositol-treated group when bootstrap analysis was performed, suggesting that further increasing the number of patients would strengthen the analysis.

[0158] Figures 9A-D show observational data showing the change from baseline in CDR-SB scores with scyllo-inositol treatment in different mild AD groups with MMSE scores of 20 to 26. Similarly, scyllo-inositol treatment was effective in patients with early mild AD with an MMSE score of 22 or higher.

[0159] Figures 10A-D show bootstrap simulation data showing the change from baseline in CDR-SB scores with scyllo-inositol treatment in various mild AD groups with MMSE score ranges of 20-26. The data show a similar pattern of scyllo-inositol treatment effects on CDR-SB tests when bootstrap simulation analyses were performed. When the number of patients in the simulation analysis was increased from 30 to 100, the change in CDR-SB scores in the scyllo-inositol-treated group compared to placebo was more pronounced.

[0160] Figures 11A–D show a comparison of observed and simulated data for changes in NTB and CDR-SB scores with scyllo-inositol treatment in patients with mild AD with MMSE scores of 22–26. Figure 1A shows the AD201 observed values ​​(NTB). Figure 1B shows the simulated bootstrap (NTB). Figure 1C shows the AD201 observed values ​​(CDR-SB). Figure 1D shows the simulated bootstrap (CDR-SB). For the bootstrap simulation, N = 100 was used, whereas N = 30 for the observed set. For both NTB and CDR-SB endpoints, statistical significance was achieved in the treatment group compared with the placebo group in the simulated comparisons. These data demonstrate that scyllo-inositol exhibits strong efficacy in improving cognition and function in patients with early mild AD with MMSE scores of 22 or higher.

[0161] Therefore, the data support the use of a single agent to treat target patient populations with such MMSE scores or equivalent, and further support the combination of scyllo-inositol in a dosage range of about 125 mg to about 500 mg (once daily or BID) in combination with other vitamins and / or active ingredients that are useful in treating cognitive impairment and / or helping to raise vitamin levels to levels that treat vitamin deficiencies or insufficiencies. In particular, combining scyllo-inositol with vitamin D, including the vitamin D prohormone calcifediol, or B vitamins such as vitamin B12, is particularly suitable for treating subjects in the early stages of Alzheimer's disease or mild cognitive impairment (MCI), or who have evidence of Aβ fibrils along with vitamin deficiencies or insufficiencies.

Claims

1. A combination of (i) a first compound selected from inositol or a pharmaceutically acceptable isomer or salt thereof, and (ii) a second compound selected from a vitamin compound or an active pharmaceutical ingredient.

2. 2. The combination of claim 1, wherein the first compound is selected from scyllo-inositol or other active 1,2,3,4,5,6-cyclohexanehexol and the second compound is selected from the group consisting of vitamins A, B1, B2, B3, B5, B6, B7, B9, B12, C, D, E and K, nicotinamide riboside, or an active pharmaceutical ingredient selected from a monoclonal antibody or small molecule.

3. 3. The combination of claim 2, wherein the first compound is selected from scyllo-inositol, the second compound is selected from a vitamin D3 compound selected from the group consisting of cholecalciferol or calcifediol, and the B vitamin is vitamin B12.

4. 4. The combination of claim 3, wherein the vitamin D3 compound is calcifediol.

5. 5. The combination of claim 4, wherein the dosage of scyllo-inositol used to treat a neurological disorder or condition is about 150-250 mg once or twice daily (BID), the total dosage of the calcifediol is about 10-90 μg per day, and the dosage range of the vitamin B12 is about 20-500 μg / day.

6. A dosage form comprising a combination of (i) a first compound selected from inositol or a pharmaceutically acceptable isomer or salt thereof, and (ii) a second compound selected from a vitamin compound and / or an active pharmaceutical ingredient.

7. 7. The dosage form of claim 6, wherein the first compound is selected from scyllo-inositol or other active 1,2,3,4,5,6-cyclohexanehexol, the second compound is selected from the group consisting of vitamins A, B1, B2, B3, B5, B6, B7, B9, B12, C, D, E and K, or nicotinamide riboside, and the active pharmaceutical ingredient is selected from a monoclonal antibody or a small molecule.

8. 8. The dosage form of claim 7, wherein the first compound is selected from scyllo-inositol, the second compound is selected from a vitamin D3 compound selected from the group consisting of cholecalciferol or calcifediol, vitamin B12, or nicotinamide riboside, the small molecule is selected from the group consisting of donepezil, rivastigmine, caffeine, and galantamine, and the monoclonal antibody is selected from aducanumab.

9. 9. The dosage form of claim 8, wherein the vitamin D3 compound is calcifediol.

10. 10. The dosage form of claim 9, wherein the dosage of scyllo-inositol used to treat a neurological disorder or condition is about 150-250 mg once or twice daily (BID) and the dosage of calcifediol is about 10-90 μg per day.

11. The dosage form according to claims 6 to 10, wherein the dosage form is in the form of a capsule or a tablet.

12. 12. The dosage form of claim 11 in the form of a tablet comprising an immediate release formulation of scyllo-inositol and an immediate release formulation of calcifediol.

13. 12. The dosage form of claim 11 in the form of a tablet comprising an immediate release formulation of scyllo-inositol and a sustained release formulation of calcifediol.

14. A method of treating a subject with an MMSE score in the range of 22-26 with a pharmaceutically effective amount of scyllo-inositol.

15. 15. The method of claim 14, wherein the subject has Alzheimer's disease.

16. 16. The method of claim 14 or claim 15, wherein the pharmaceutically effective amount of scyllo-inositol is about 250 mg BID per day.

17. 1. A method of treating a subject having cognitive impairment, memory loss, and vitamin D deficiency or insufficiency, comprising administering an effective amount of scyllo-inositol in combination with (i) a vitamin D compound selected from the group consisting of vitamin D or 25-hydroxyvitamin D, or (ii) a vitamin B compound selected from the group consisting of vitamin B12, or (iii) nicotinamide riboside.

18. 18. The method of claim 17, wherein the effective amount of the scyllo-inositol is about 150-250 mg BID, the effective amount of the vitamin D is about 400-5000 IU per day, the effective amount of the 25-hydroxyvitamin D is about 10-90 μg / day, the effective amount of the B vitamin compound is about 20 to about 500 μg / day, and the effective amount of the nicotinamide riboside is about 300 mg / day.

19. 1. A method for treating a subject susceptible to a neurological disease or condition, comprising administering to the subject in need thereof an effective amount of a combination of (i) a first compound selected from inositol or a pharmaceutically acceptable isomer or salt thereof, and (ii) a second compound selected from a vitamin compound or an active pharmaceutical ingredient.

20. 1. A method of treating a patient with Alzheimer's disease, comprising administering a pharmaceutically effective amount of scyllo-inositol in combination with aducanumab.

21. 21. The method of claim 20, wherein a side effect of aducanumab is reduced.

22. 1. A method of treating a subject having at least one APOE ε4 allele, comprising administering a combination of (i) a first compound selected from inositol or a pharmaceutically acceptable isomer or salt thereof, (ii) a second compound selected from a vitamin compound, and optionally (iii) an additional active pharmaceutical ingredient for use in treating such a subject having said allele.

23. 1. Use of a combination of scyllo-inositol at a dose of 125 mg to 250 mg once daily or twice daily and a vitamin selected from the group consisting of vitamin D, calcifediol, or vitamin B12 to treat a subject with MCI or Alzheimer's disease.

24. A combination comprising a first compound selected from scyllo-inositol and a second compound selected from the group consisting of calcifediol, vitamin D, vitamin B12, donepezil, rivastigmine, galantamine and aducanumab.

25. 25. The combination of claim 24, wherein each active ingredient is in a separate dosage form.

26. 25. The combination of claim 24, wherein the combination is in a single dosage form.

27. 26. The combination of claim 24 or 25, wherein the dosage of donepezil is about 5 mg to 10 mg.

28. A combination comprising a single dosage form or multiple dosage forms having at least two compounds having scyllo-inositol as a first compound and an additional compound selected from the group consisting of vitamins B12, B9, B6 and vitamin D3, or calcifediol.

29. 29. The combination of claim 28, wherein the scyllo-inositol dosage is about 150 mg, the vitamin B12 dosage is about 500 mcg, the vitamin B9 dosage is about 500 mcg, the vitamin B6 dosage is about 3 mg, the vitamin D3 dosage is about 1,000-3,000 IU, and the calcifediol dosage is about 10-50 mcg.

30. A combination comprising scyllo-inositol and apigenin.

31. 31. The combination of claim 30, in a single oral dosage form having about 150 mg of said scyllo-inositol and about 150 mg of apigenin and pharmaceutically acceptable excipients.

Images