Combination therapy of scyllinositol and vitamin d and / or other vitamins or active ingredients to treat cognitive disorders

Abstract

The present disclosure relates to a combination of active ingredients / adjuvants for use in the treatment of nervous system disorders and diseases such as Alzheimer's disease and mild cognitive impairment (MCI) and memory and cognitive impairments and disorders. In particular, scyllo-inositol and a combination for the treatment of Alzheimer's disease, such as Arcamikumab, and / or a combination with an essential fatty acid, such as a mixture of linolenic acid / linoleic acid, or vitamin D or a vitamin D compound, such as calcifediol, are useful. The combination may be in the form of a separate dosage form for each active ingredient, or may be in an oral dosage form with multiple active ingredients in a single capsule or tablet or oral solution. The present invention also relates to a method of treating a patient suffering from a mild cognitive disorder having an MMSE standard between 22 and 26 with a pharmaceutically effective amount of scyllo-inositol to treat said disease and slow progression to Alzheimer's disease.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This PCT application claims the benefit of U.S. Provisional Application No. 63 / 404,537, filed on September 7, 2022, U.S. Provisional Application No. 63 / 441,732, filed on January 27, 2023, and U.S. Provisional Application No. 63 / 453,583, filed on March 21, 2023, all of which are incorporated herein by reference in their entirety. Background Art

[0003] Alzheimer's disease (AD) is a neurodegenerative disorder or condition that progresses over time, leading to cognitive impairment and a variety of symptoms and disabilities that impact the daily lives of those afflicted. The number of people living with all stages of the disease is staggering, and the global figure is projected to exceed 115 million by 2050. Despite years of effort and billions of dollars invested in drug development research, effective treatments for the progression and / or treatment of AD remain elusive. Prior to this year, only three drugs were approved in the United States to treat the disease. These drugs include donepezil, rivastigmine, and galantamine—none of which are effective in halting disease progression. However, in a promising, albeit somewhat reserved, development, the FDA recently approved the monoclonal antibody drug aducanumab (BIIB037) for the treatment of mild cognitive impairment (MCI) and early-stage Alzheimer's disease.

[0004] In the elderly population, the prevalence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) has increased. The gradual loss of memory relevant to MCI is followed by the further degeneration of memory and the increase of functional loss. In the MCI late stage, the patient begins to develop into dementia and changes into mild AD. These patients may progress and develop into moderate and severe AD. The accumulation of beta amyloid in the brain occurs very early, and before there are symptoms, as the amyloid load in the brain continues to increase, the onset of early and late MCI occurs, and the severity continues to progress until the patient is diagnosed as AD. As is well known, clinical symptoms (such as memory loss) break out in early and late MCI, and subsequently as the patient develops into mild, moderate and final severe AD, memory and function decline faster. Patients suffering from moderate and severe Alzheimer's disease in the late stage show functional decline (needing the help of a caregiver) and may die.

[0005] Although the precise mechanisms that trigger AD pathology are not yet fully elucidated, it is known that the accumulation of amyloid-β fibrils, leading to the formation of plaques, is a hallmark of Alzheimer's disease. Furthermore, accumulation of amyloid-β fibrils in the brain begins approximately 10 to 15 years before the development of dementia and related clinical symptoms. The accumulation of fibrils and plaques increases with aging, with 30% to 40% of individuals over 55 years of age and over 70% of patients with MCI having a brain load of amyloid-β. The presence of amyloid-β fibrils and plaques leads to increased neurotoxicity and inflammation in the brain. Increased accumulation of these lesions is associated with more aggressive disease and memory and functional loss in patients with AD.

[0006] Over the past 20 years, a number of therapies targeting amyloid-β fibrils and plaques have shown promise in animal models of AD and have entered human clinical trials. These initial therapies involved antibodies that react with amyloid-β fibrils and plaques, resulting in reduced accumulation of amyloid-β in the brains of these animal models. Elan and Wyeth developed a humanized antibody, bapineuzamab, which showed promise in a Phase 2 study and has entered a Phase 3 clinical trial in patients with mild and moderate AD. Unfortunately, this study failed to demonstrate efficacy in patients with mild to moderate AD, a finding similar to that observed with antibody therapies developed by Lilly and others. The general consensus is that treating moderate AD with amyloid-β-targeted therapies is too late in the disease process to prevent neurotoxicity and the progression of dementia. Some evidence that amyloid-β-targeted therapies may be more effective in subpopulations of AD patients comes from clinical studies that showed modest efficacy in patients with APOE 4-positive mild AD, but this was overshadowed by the more rapid cognitive and functional decline observed in this moderate AD population.

[0007] Furthermore, oral small molecules (such as scyllo-inositol and homotaurine) have also shown promising data in disaggregating beta-amyloid fibrils in vitro and reducing plaques in AD animal models. Neurochem Pharma has launched an 18-month Phase 3 clinical trial in mild to moderate patients. The study failed to show improvement in cognition and function in AD patients. The data are not conclusive, with very high variability in data between patients and the fact that cognitive symptoms in patients with mild disease did not appear to progress sufficiently during the 18-month treatment period to measure efficacy. Two problems seem to arise in these trials. Beta-amyloid targeted drugs do not appear to affect AD cognition and function in moderate AD patients, suggesting that the lesions in the disease process are too advanced to be altered by beta-amyloid targeted therapies; and secondly, the cognitive and functional decline in mild AD patients is too slow to assess efficacy in the overall mild AD patient population, more specifically, to measure the reduction in decline in endpoints of cognition and function (such as ADASCog, NTB, CDR-SoB, ADCS-ADL, etc.).

[0008] Similarly, scyllo-inositol (an oral agent that destroys and prevents the formation of beta-amyloid fibrils) is effective in treating AD animal models. Following treatment of AD animal models with scyllo-inositol at doses of 3.3 mg / kg or higher, the prevalence and size of amyloid plaques were reduced, as well as improvements in memory and cognitive tests in different animal models suitable for evaluation. In a large Phase 2 trial, scyllo-inositol failed to show efficacy in mild and moderate AD patients across multiple endpoints (including NTB, CDR-SoB, ADCS-ADL, and ADAS-Cog). These data indicate that scyllo-inositol is ineffective in the overall mild and moderate AD population. Further, data examining mild AD patients with an MMSE of 20 to 26 or moderate AD patients with an MMSE of 16 to 20 also showed that the drug was ineffective for both AD populations. These data suggest that either the drug is generally ineffective for treating general mild and moderate AD patients, or that any efficacy produced 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 more advanced AD, the efficacy of scyllo-inositol was evaluated in patients with mild AD of varying disease severity, based on MMSE scores of 20 to 26. The data showed that the cognitive and functional effects of scyllo-inositol were more pronounced in patients with mild AD with MMSE scores of 22 to 26. The 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 with an MMSE score of 22 to 26. These clinical findings emphasize that selecting appropriate MCI and AD patient populations for amyloid-β-targeted therapies is crucial for observing efficacy.

[0009] Despite these advances and treatments, there remains a need for effective medications to treat patients with MCI and Alzheimer's disease and / or those who may be susceptible to treatment, including subpopulations across the full range of disease stages, from early onset to irreversible progression. This subpopulation includes patients with a genetic variant in the apolipoprotein E (APOE) gene (APOE ε4). It is believed that approximately 25% of people carry one copy of APOE ε4, while approximately 2% to 3% carry two copies of this allele. This gene is known to increase the risk of early onset of the disease. It is believed that the docking of Aβ fibrils to neuronal and glial cell membranes may be an early and interventional step during the progression of Alzheimer's disease. There is also a need for supplements or nutritional medications that can be provided to subjects who may be susceptible to early accumulation of amyloid β in the brain, which ultimately leads to progression to MCI, Alzheimer's disease, or other cognitive impairments. This need for supplemental interventions may arise in the early stages of MCI and Alzheimer's disease, long before any evidence of neurological symptoms is detected.

[0010] It is believed that scyllo-inositol has a direct effect on improving memory and cognition, which is detected within the first 6 months of treatment, based on the new findings of a subgroup of patients with a MMSE score of 22 to 26. In order to improve the direct effect of scyllo-inositol on cognition, a combination therapy with a more symptomatic treatment will be beneficial. Scyllo-inositol is combined with symptomatic drugs that improve synaptic transmission and memory through drugs such as donepezil, rivastigmine, galantamine and memantine. It has been shown that treatment with a mixture of linolenic acid and linoleic acid in a fixed ratio selected improves membrane fluidity and synaptic activity, thereby causing improvement in the cognition and function of AD patients. The combination of a mixture of linoleic acid and linolenic acid with scyllo-inositol can cause improvement in cognition in elderly patients with cognitive impairment. Furthermore, as described herein, it is believed that 25-hydroxyvitamin D3 and / or a combination of vitamin D and scyllo-inositol improves cognition in subjects who may be susceptible to neurological diseases or disorders, such as Alzheimer's disease or mild cognitive impairment or other conditions with beta-amyloid as a contributing factor to memory loss or cognition, and who also benefit from the elevated serum 25-hydroxyvitamin D3 and active hormonal levels of vitamin D produced therefrom.

[0011] It is speculated that glycolipids (such as gangliosides) may lead to the stabilization and prevention of Ab fibril formation, while phosphatidylinositol may lead to the acceleration of fibril formation. Scyllo-inositol (ELND005) has been disclosed as being useful for treating or preventing central or peripheral nervous system disorders, including Alzheimer's disease. See U.S. Patent No. 7,521,481, which is hereby incorporated by reference. Six clinical trials of the drug are shown on ClinicalTrials.gov. Completed Alzheimer's disease studies include a study titled ELND005 in patients with mild to moderate Alzheimer's disease and a long-term follow-up study in subjects with Alzheimer's disease.

[0012] To date, based on the results of such studies, scyllo-inositol has not made progress in the application of new drugs for the treatment of Alzheimer's disease. Although the results were not positive at the doses studied in the entire group of patients enrolled, the inventors found that scyllo-inositol alone or in combination with other active ingredients treated patients with MMSE scores of 22 to 26 and a subset of MCI patients with MMSE scores of 27 to 28 selected according to specific criteria for this group. In addition, the inventors found that the combination of scyllo-inositol and vitamin D and / or vitamin D prohormone (such as calcifediol) can be used to treat patients with vitamin D deficiency or insufficiency and any associated memory loss or cognitive impairment. It is believed that early intervention with the combination therapy can reduce the accumulation of beta-amyloid fibrils and restore serum 25(OH)D3 levels in the brain, thereby combining to alleviate and / or prevent the progression of memory loss, mild cognitive impairment and / or Alzheimer's disease in patients with MMSE scores of 22 to 26 and MCI patients and / or any subset of patients with MMSE scores or their equivalents of 27 to 28. The present invention also includes the use of scyllo-inositol alone at a daily dose of 250 mg BID to treat such Alzheimer's disease and / or MCI patients with such MMSE scores. Based on pharmacokinetic data showing scyllo-inositol levels in the brain and CSF of mild and moderate AD patients after treatment with 250 mg BID, it is suggested that a dose of 250 mg scyllo-inositol once daily or 125 mg BID will achieve the appropriate concentration range required for efficacy in the brain.

[0013] The inventors have also found that patients with MMSE scores within the above range and at least one APOEε4 allele are treated with a pharmaceutically effective amount of scyllo-inositol alone or in combination with other active ingredients described herein. No early studies or patents disclose the use of scyllo-inositol in Alzheimer's disease, disclosing treatment of specific subgroups or patient subpopulations as well as a broader group of Alzheimer's disease or MCI patients. In addition, no patents disclose the combination of scyllo-inositol with vitamin D compounds (such as 25-hydroxyvitamin D or vitamin B12).

[0014] In disclosed patents such as US 7,521,481, the inventors disclose that scyllo-inositol and other cyclohexane hexacols therein can treat Alzheimer's disease and illness of the central or peripheral nervous system selected from the following: presenile and senile forms of Alzheimer's disease, amyloid angiopathy, mild cognitive impairment; Alzheimer's disease-related dementia; Tau protein disease (taupathy) and many other diseases and illnesses. However, as mentioned above, clinical studies in human subjects have not yet proven the claims or propositions disclosed in early patents or studies. Therefore, the inventors have found a subgroup of patients within a wider range of Alzheimer's disease or MCI patient categories, and it is effective to treat it with a pharmaceutically effective amount of a single scyllo-inositol or with a combination of some other active ingredients. It is believed that the patient of this subset is comparable to or may be in a similar situation to a healthy subject with the initial stage of fibrillation and with some memory loss, dementia or mild cognitive impairment signs.

[0015] Scyllo-inositol and any other active 1,2,3,4,5,6-cyclohexanes (such as cis, epi, iso, visco, neo, D-chiral 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 (delayed release 25-hydroxyvitamin D3) can also be used to treat elderly patients with memory loss due to increased accumulation of beta-amyloid in the brain, optionally with an MMSE score of 22 to 26 and MCI patients susceptible to mild to moderate Alzheimer's disease with an MMSE score of 27 to 28. Vitamin B (such as vitamin B12) can be used instead of the vitamin D compound or as an additional vitamin in the combination or combination formulation. The dosage range of vitamin B12 can be about 20 micrograms to about 500 micrograms, and such amount will enable the subject to obtain sufficient vitamin B. These drug combinations will reduce the accumulation of amyloid in the brain, and reduce the inhibition of neuronal function by amyloid. In a preferred embodiment, the combination is a fixed dose combination in the same dosage form (such as tablets or capsules). It is believed that such a combination slows down the progress of cognitive and functional loss in these patient subgroups with the above-mentioned MMSE scores. Combination therapy also provides a more direct effect on cognitive and memory loss or other related symptoms. The combination can 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 to 3000 IU) or calcifediol (10 to 50 mcg). These amounts can vary depending on the specific subject. The combination can be in a separate dose or in a single dosage form or a combination of dosage forms with multiple active ingredients or vitamins. The present invention also includes aquaporin 4 (AQP4X) up-regulators, which include small molecules that mediate the removal of beta-amyloid by this astrocyte water channel. The compound that increases the readthrough of the aquaporin 4 gene includes apigenin (a flavonoid found in chamomile) and sulfaquinoxaline (antibiotic) (only for animals). Apigenin can be combined with scyllo-inositol to treat MCI and Alzheimer's patients, particularly those subjects whose MMSE scores are 22 to 26. Other suitable combination ingredients can include a compound that reduces soluble ST2 (sST2) levels in the brain, and this soluble ST2 is a protein known to have a negative impact on the removal of amyloid from the brain.

[0016] Depending on the dosage of the individual combinations of scyllo-inositol and another active ingredient (such as calcifediol in IR or ER form), the pharmaceutical combination can also be used as a supplement or nutraceutical, or as a fixed-dose combination with both scyllo-inositol and calcifediol in a single capsule or tablet. In a preferred embodiment, the vitamin D compound is calcifediol and is provided in a time-release dosage form. 25-hydroxyvitamin D3 alone or in combination with scyllo-inositol in a time-release dosage form can achieve higher and more sustained serum 25-hydroxyvitamin D3 levels in extrarenal tissues and organs (including the brain). This also leads to higher levels of vitamin D active hormone in the brain. Achieving serum calcifediol levels that are sufficient or between 30 and 90 ng / mL is particularly important for patients with inflammatory conditions that may be associated with neurological disorders and / or early stages of cognitive impairment. It is also believed that the combination of scyllo-inositol and vitamin B (such as vitamin B12) is effective in treating cognitive and memory disorders. Therefore, the present invention includes such a combination, either as a single combination in a single dosage form or as a single capsule or tablet with both scyllo-inositol and vitamin B. Also within the scope of the claimed invention are combinations of scyllo-inositol and donepezil for treating Alzheimer's disease subjects and / or MCI subjects. Summary of the Invention

[0017] 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 that can be used to treat a neurological disorder or 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 a vitamin D compound or a vitamin B compound. In such embodiments, the preferred vitamin D compound is vitamin D or 25-hydroxyvitamin D, and the preferred vitamin B compound is vitamin B12. In a preferred embodiment, the vitamin D compound is 25-hydroxyvitamin D3. The first compound and the second compound can be administered separately and provided in discrete dosage forms for co-administration. The first compound and the second compound can also be packaged as separate dosage forms in the form of a kit, which is provided to the patient in a suitable dosage form such as a capsule, tablet or ampoule for daily administration of the first compound and the second compound. Alternatively, the combination can be in the form of a single dosage form comprising (i) a first compound selected from an inositol and (ii) a second compound selected from a vitamin and / or an active pharmaceutical ingredient for treating a neurological disorder or symptom. 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 a vitamin D compound or a vitamin B compound. In a further preferred embodiment, the dosage form may be in the form of a capsule, tablet, or ampoule and contain 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 delayed release formulation. The present invention also includes a method for treating a subgroup of MCI and Alzheimer's patients or patients susceptible to cognitive impairment, dementia and / or memory loss or patients who progress to such diseases in such groups or subgroups of MCI and / or Alzheimer's patients with 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: a vitamin selected from the group consisting of vitamins A, B1, B2, B3, B5, B6, B7, B9, B12, C, D, E and K, or selected from the group consisting of linoleic acid or a combination of linolenic acid and / or linolenic acid. "Other active ingredients" can be selected from any known or previously approved drug for the treatment of Alzheimer's disease and / or memory loss or cognitive diseases. Such drugs include, for example, donepezil Or the monoclonal antibody aducanumab. Caffeine can also be selected as an ingredient. When donepezil is used herein, the dosage can range from about 5 mg to about 23 mg, twice daily or once in the evening.

[0018] A preferred subgroup of Alzheimer's patients is selected from patients with an MMSE score of 22 to 26 and / or from patients with such MMSE scores and at least one APOEε4 allele. Another preferred patient population is a patient with memory or cognitive problems but has not yet been diagnosed with Alzheimer's disease or MCI but has undergone at least one memory or cognitive test (such as an MMSE test or its equivalent). A preferred subgroup of MCI patients is a patient with an MMSE score of 27 to 28 or such MCI patients with at least one APOEε4 allele. The subject may have early mild AD. Thus, in an embodiment, the present invention includes treating a mild AD patient with an MMSE score of 22 to 26 with 250 mg BID scyllo-inositol, or treating a mild AD patient with an MMSE score of 22 to 26 and β-amyloid in the brain (for Aβ in plasma or brain PET scan of Aβ42 / 40 ratio) with 250 mg BID; or treating an MCI patient with an MMSE score of 26 to 30 and β-amyloid in the brain (for Aβ in plasma or brain PET scan of Aβ42 / 40 ratio) with 250 mg BID scyllo-inositol; or treating an MCI patient with an MMSE score of 26 to 30 and an ADAS score ≥8, FAQ ≥2, CDR ≥2 with 250 mg BID scyllo-inositol; or treating an MCI patient with an MMSE score of 26 to 30 and an ADAS score ≥8, FAQ ≥2, CDR ≥2 with 250 mg BID scyllo-inositol; BID scyllo-inositol is used to treat MCI patients with an MMSE score of 26 to 30, beta amyloid in the brain (brain PET scan for Aβ in plasma or Aβ42 / 40 ratio) and an ADAS score ≥8, FAQ ≥2, and CDR ≥2; or 250 mg BID scyllo-inositol is used to treat MCI patients with an MMSE score of 26 to 30 and an ADAS score ≥7, FAQ ≥1, and the total score of ADAS and FAQ must be ≥13; or 250 mg BID scyllo-inositol is used to treat MCI patients with an MMSE score of 26 to 30, beta amyloid in the brain (brain PET scan for Aβ in plasma or Aβ42 / 40 ratio) and an ADAS score ≥7, FAQ ≥1, and the total score of ADAS and FAQ must be ≥13. In some embodiments above and / or below, the treatment can be a combination therapy further comprising vitamins and / or other active ingredients as described herein.

[0019] In some embodiments, the present invention comprises,

[0020] 1) Use of scyllo-inositol in the treatment of mild AD with an MMSE score of 22 to 26 and MCI patients with an MMSE score of 26 to 30, using 250 mg of scyllo-inositol per day or BID or 500 mg of scyllo-inositol per day; or

[0021] 2) Use of scyllo-inositol in the treatment of mild AD with an MMSE score of 22 to 26 and MCI patients with an MMSE score of 26 to 30 and amyloid beta in the brain as measured by AlzaSure-Predict, using 250 mg of scyllo-inositol daily or BID; or

[0022] 2) Use of scyllo-inositol in the treatment of mild AD with an MMSE score of 22 to 26 and MCI patients with an MMSE score of 26 to 30, an ADAS score ≥8, a FAQ ≥2, and a CDR ≥2, using 250 mg of scyllo-inositol daily or BID or 500 mg of scyllo-inositol daily

[0023] 3) Use of scyllo-inositol in the treatment of mild AD with an MMSE score of 22 to 26 and MCI patients with an MMSE score of 26 to 30 and an ADAS score ≥7, FAQ ≥1, and the total score of ADAS and FAQ must be ≥13, with 250 mg of scyllo-inositol daily or BID or 500 mg of scyllo-inositol daily; or

[0024] 4) Use of scyllo-inositol in the treatment of mild AD with an MMSE score of 22 to 26 and MCI patients with an MMSE score of 26 to 30, ADAS ≥ 12, and CDR-SB ≥ 1.5, using 250 mg of scyllo-inositol daily or BID or 500 mg of scyllo-inositol daily; or

[0025] 5) Use of scyllo-inositol in the treatment of mild AD and MCI patients with an MMSE score of 22 to 30 and an ADAS score ≥8, FAQ ≥2, and CDR ≥2, using 250 mg BID of scyllo-inositol; or

[0026] 6) Use of scyllo-inositol in the treatment of mild AD and MCI patients with an MMSE score of 22 to 30 and an ADAS score ≥7, a FAQ ≥1, and the total ADAS and FAQ score must be ≥13, using 250 mg BID of scyllo-inositol; or

[0027] 7) Use of scyllo-inositol in the treatment of mild AD and MCI patients with an MMSE score of 22 to 30 and brain amyloid beta (brain PET scan for Aβ in plasma or Aβ42 / 40 ratio), ADAS ≥ 12 or CDR-SB ≥ 1.5; or

[0028] 8) Use of scyllo-inositol in the treatment of mild AD and MCI patients with MMSE scores of 22 to 30, ADAS scores ≥8, FAQ ≥2, and CDR ≥2, using 250 mg BID of scyllo-inositol; or

[0029] 9.) Use of scyllo-inositol in the treatment of mild AD and MCI patients with an MMSE score of 22 to 30, an ADAS score ≥7, a FAQ ≥1, and the total ADAS and FAQ score must be ≥13, using 250 mg BID of scyllo-inositol; or 11.) Use of scyllo-inositol in the treatment of mild AD and MCI patients with an MMSE score of 22 to 30, no assessment of beta-amyloid in the brain, an ADAS ≥12, and a CDR-SB ≥1.5.

[0030] Mild AD is different from MCI, so a particular subject may have an MMSE of 26, and whether they have MCI or mild AD depends on other parameters. MCI uses a CDR of 0.5, and mild AD uses a CDR of 1, and the designation is not based on the MMSE score. In those patients or subjects with mild AD or MCI and with the MMSE score range disclosed above, when used in combination with Aricept (donepezil), the preferred dose of donepezil used in combination with scyllo-inositol is about 5 to about 10 mg per day. It is preferred to titrate from a low dose of about 5 mg donepezil for four to six weeks to a higher dose of about 10 mg donepezil thereafter, once a day. In a preferred embodiment, donepezil (donepezil hydrochloride) is administered in tablet form or orally disintegrating tablets at a strength of 5 mg or 10 mg. The combination of scyllo-inositol (125 to 250 mg BID) and donepezil can be in the form of a combination of a kit or a separate dosage form, or can be administered to a subject in the form of a single capsule or tablet with both active ingredients. The 250 mg tablet having scyllo-inositol dispersed therein may be coated with an outer layer having 5 to 10 mg of donepezil in a pharmaceutically acceptable tablet excipient.

[0031] In those jurisdictions that do not allow medical use claims or method of treatment claims, such embodiments include pharmaceutical compositions or combinations of such scyllo-inositol and vitamins and / or other active ingredients, as a combination or single unit formulation for use in treating such subpopulations of Alzheimer's or MCI patients. Such combinations or compositions are novel and inventive in themselves. In any of the above uses or as further described herein, the dosage of scyllo-inositol may also include 250 mg once daily or 125 mg BID. 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 is a ratio of linolenic acid to linoleic fatty acids of 1:4. These fatty acids are known to affect serotonergic and catecholaminergic neurotransmission.

[0032] Combination products, particularly those comprising scyllo-inositol and aducanumab, enhance the efficacy of aducanumab (in treating cognition and function in patients with MCI and mild AD). Scyllo-inositol may also permit a reduction in aducanumab dosing for the treatment of MCI and mild AD while maintaining efficacy. In addition, scyllo-inositol reduces the prevalence of ARIA associated with aducanumab treatment at higher doses. Thus, the present invention includes a method for treating Alzheimer's disease in a human patient comprising administering a pharmaceutically effective amount of a recombinant, fully human, anti-beta amyloid monoclonal antibody selected from aducanumab and a pharmaceutically effective amount of scyllo-inositol.

[0033] The present invention also includes a method of treating Alzheimer's disease or MCI patients with MMSE scores of 22 to 26 or 27 to 28, respectively, with scyllo-inositol (250 mg once a day or BID or 500 mg QD) and optionally with a second compound (once a day or BID) comprising an active ingredient selected from a combination of linolenic acid and linoleic acid (1:4 molar ratio). An additional second compound may also be added to the composition as a third ingredient, and in a preferred embodiment, it may be a combination of any one of scyllo-inositol, 25-hydroxyvitamin D3, and the other active ingredients disclosed herein. The combination will reduce the amyloid load in the brain, reduce the long-term decline in memory and cognitive function associated with aging; will improve membrane fluidity, and enhance neuronal function, and improve both short-term and long-term memory and cognition. In a preferred embodiment, the combination is in the same dosage form, such as a capsule or tablet. In another preferred embodiment, the pharmaceutical combination comprises a combination of 250 mg to 500 mg BID of scyllo-inositol with 10 μg of calcifediol IR or with 30 to 90 μg of ER calcifediol Combinations. Any combination of drugs may be packaged together for use in a kit or dispenser.

[0034] In an embodiment, scyllo-inositol is administered orally in a dosage range of between 125 and 250 mg once daily or BID. In another embodiment, scyllo-inositol is administered in a dosage of 500 mg once daily.

[0035] In an embodiment, the invention includes a method of reducing brain beta amyloid plaques in an Alzheimer's disease patient comprising administering an effective amount of calcifediol in combination with an effective amount of scyllo-inositol.

[0036] In a further embodiment, the invention includes a method of treating an Alzheimer's disease patient in whom amyloid pathology is confirmed and the disease is at a mild cognitive impairment or mild dementia stage consistent with Alzheimer's disease stage 3 or stage 4, the method comprising administering between about 10 μg to 90 μg of calcifediol and comprising administering an effective amount of scyllo-inositol.

[0037] The present invention further includes a method for enhancing cognition in a subject having MCI or mild Alzheimer's disease and in need of treatment thereof, by: (1) pre-treating the subject with between 125 and 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 a pre-treatment period can extend for many years before the onset of full-blown Alzheimer's disease.

[0038] The present invention includes methods of treating a patient in need thereof, comprising treating the patient with a combination of scyllo-inositol and aducanumab, wherein following such treatment, ARIA aducanumab-related events are reduced with the combination treatment compared to treatment with aducanumab alone at the same infusion dose.

[0039] The present invention encompasses the use of scyllo-inositol as an adjuvant for modifying the amount of monoclonal antibody required to treat an Alzheimer's disease patient in need thereof.

[0040] In a preferred embodiment, the monoclonal antibody is selected from aducanumab.

[0041] In another preferred embodiment, the combination comprises scyllo-inositol and a 1:4 molar ratio (250 mg) of linolenic acid to linoleic acid per day or BID. In embodiments based on this embodiment, additional active ingredients may include a vitamin D compound such as calcifediol.

[0042] The present invention also includes a method of reducing ARIA in a patient receiving monoclonal antibody therapy, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of scyllo-inositol, wherein the reduction is compared to a patient receiving such monoclonal antibody therapy without scyllo-inositol.

[0043] In an embodiment, the invention further includes a method of reducing beta-amyloid load in the brain of a patient having mild Alzheimer's disease and being treated with a monoclonal antibody selected from aducanumab, the method comprising co-administering to the patient a pharmaceutically effective amount of scyllo-inositol.

[0044] In an embodiment, the invention includes a method of improving memory, cognition and / or brain function in an Alzheimer's disease patient in need thereof, wherein the patient is being treated with a monoclonal antibody, the method comprising co-administering a pharmaceutically effective amount of scyllo-inositol, wherein such co-administration results in improved memory, cognition and / or brain function relative to the patient being treated with the monoclonal antibody alone.

[0045] The invention further includes a method of improving positive biomarkers in the CSF of an Alzheimer's disease patient being treated with a monoclonal antibody, the method comprising co-administering a pharmaceutically effective amount of scyllo-inositol, wherein the improvement is relative to a control patient treated with the monoclonal antibody alone.

[0046] The present invention also encompasses the method according to any one of the above embodiments, wherein the patient is pretreated with scyllo-inositol at a daily dose of 125 to 250 mg scyllo-inositol once daily or BID prior to undergoing monoclonal antibody therapy.

[0047] The present invention includes a method in which the pre-treatment period is two weeks to several years. The combination of scyllo-inositol and calcifediol can advantageously be provided as a nutritional medicine. In a preferred embodiment, such a combination will be sold as a packet with a dosage form of 250mg BID or 500mg scyllo-inositol QD and 10 μg of calcifediol in immediate release form and / or 10 to 90 μg of ER calcifediol. In an additional preferred embodiment, the combination will be in the form of a single oral dosage form, in which the combination of active ingredients comprises scyllo-inositol, calcifediol and optionally linolenic acid / linoleic acid (1:4 ratio) and other pharmaceutically acceptable capsule or tablet excipients. An additional amount of the linolenic acid / linoleic acid combination exceeding 250mg can also be administered together with a combination capsule or tablet. Some dosages can be an additional 100mg to 1000mg oil mixture in such a 1:4 ratio. The oil can be purified or substantially pure in a mixture of additional essential fatty acids or nutrients. It is also possible to provide the subject with an isolated oil in a natural form from, for example, walnuts or other sources. The dosage of scyllo-inositol in such combinations is preferably 125 to 250 mg once daily or BID, but may also be provided QD at a dose of 250 mg to 500 mg. The size and type of capsule (hard capsule vs. soft capsule) may also vary depending on the amount of scyllo-inositol and the amount of the essential fatty acid oil combination. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 A to 1F show the effect of 250 mg scyllo-inositol treatment BID in patients with mild / moderate AD (MMSE 16-30) on the primary endpoints NTB, ADCS-ADL and CDR-SB

[0049] Figure 2 The efficacy of scyllo-inositol for 78 weeks in patients with early mild AD (MMSE 23 to 26) was demonstrated in the pre-specified overall and per-protocol populations.

[0050] Figure 3 A to 3I show the change from baseline to mild AD (PPS) in the NTB subscore in nine different subscores.

[0051] Figure 4 Shown are changes from baseline in ADCS-ADL in patients with early mild AD (MMSE 23 to 26) treated with scyllo-inositol and placebo for 78 weeks.

[0052] Figure 5 : Shown are the changes from baseline in CDR-SB in patients with early mild AD (MMSE 23 to 26) treated with scyllo-inositol and placebo for 78 weeks.

[0053] Figure 6 A to 6F: Shown are comparisons of the effects of scyllo-inositol and placebo treatment on the changes from baseline in the CDR-SB subitems of patients with early mild AD in the per-protocol population (PPS).

[0054] Figure 7 A to 7D show the observed changes from baseline in NTB scores of mild AD patients treated with scyllo-inositol with different MMSE scores ranging from 20 to 26, 21 to 26, 22 to 26, and 23 to 26, respectively.

[0055] Figure 8 A to 8D show bootstrap simulated data of the changes from baseline in NTB scores of different mild AD patient groups treated with scyllo-inositol with MMSE score ranges of 20-26, 21-26, 22-26, and 23-26, respectively.

[0056] Figure 9 A to 9D show observed data demonstrating changes from baseline in CDR-SB scores of different mild AD groups treated with scyllo-inositol having MMSE scores of 20 to 26, 21 to 26, 22 to 26, and 23 to 26, respectively.

[0057] Figure 10 A to 10D show bootstrapped simulated data demonstrating the changes from baseline in CDR-SB scores for different mild AD groups treated with scyllo-inositol, with MMSE scores ranging from 20 to 26, 21 to 26, 22 to 26, and 23 to 26, respectively.

[0058] Figure 11 A to 11D show comparisons of observed and bootstrapped simulated data for changes from baseline in NTB and CDR-SB scores in mild AD patients with MMSE scores of 22 to 26 treated with scyllo-inositol. DETAILED DESCRIPTION

[0059] In the elderly population, the prevalence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) has increased. The gradual loss of memory relevant to MCI is followed by the further degeneration of memory and the increase of functional loss. In the MCI late stage, the patient begins to develop into dementia and changes into mild AD. These patients may progress and develop into moderate and severe AD. As shown below, the accumulation of beta amyloid in the brain occurs very early, and is before the symptoms appear, along with the continuous increase of amyloid load in the brain, the outbreak of early and late MCI occurs, and the severity can continue to progress until the patient is diagnosed as AD. As is well known, clinical symptoms (such as memory loss) break out in early and late MCI, and subsequently along with the patient develops into mild, moderate and final severe AD, memory and function decline faster. Patients suffering from moderate and severe Alzheimer's disease in the late stage show functional decline (needing the help of a caregiver) and may die.

[0060] Although the precise mechanisms that trigger AD pathology are not yet fully elucidated, it is known that the accumulation of amyloid-β fibrils, leading to the formation of plaques, is a hallmark of Alzheimer's disease. Furthermore, accumulation of amyloid-β fibrils in the brain begins approximately 10 to 15 years before the development of dementia and related clinical symptoms. The accumulation of fibrils and plaques increases with aging, with 30% to 40% of individuals over 55 years of age and over 70% of patients with MCI having a brain load of amyloid-β. The presence of amyloid-β fibrils and plaques leads to increased neurotoxicity and inflammation in the brain. Increased accumulation of these lesions is associated with more aggressive disease and memory and functional loss in patients with AD.

[0061] Scyllo-inositol is an oral drug that crosses the blood-brain barrier to reach low mM levels in the blood. Scyllo-inositol has been reported to break down 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), and restored 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. See McLaurin J. et al., Nature Medicine (2006) 12:801-808. To date, a total of nine human trials have been conducted in Phase 1 studies. These studies have generally found that scyllo-inositol can be taken orally; provides a dose-proportional increase in plasma levels; crosses the blood-brain barrier; reaches levels in the brain and CSF fluid that have been shown to be effective in AD animal models; and provides an acceptable safety profile that allows entry into Phase 2 clinical studies. Patients taking placebo (82 subjects) were compared with patients taking 250 mg of scyllo-inositol over a 78-week treatment period. A phase 2 trial conducted in patients receiving scyllo-inositol BID showed no statistically significant differences between subjects in the complete analysis set for the primary endpoints of NTB and / or ADCS-ADL. According to the primary endpoints measured by NTB and ADCS-ADL, the patients in the per-protocol set (placebo = 47; scyllo-inositol-250 BID = 49) did not show a statistically significant difference in preventing decline at the end of the 78-week treatment period. The AD patient population in this study was mild to moderate Alzheimer's disease patients with an MMSE of 16 to 26. The publication reported a subgroup analysis of subjects with an MMSE between 23 and 26 in these studies (placebo: FAS 35 / PPS 22 vs. scyllo 250 Bid FAS 36 / PPS 24), and even this group did not reach statistical significance between the group receiving placebo and the group receiving scyllo-inositol. See Salloway et al. Neurology 2011; 77: 1253-1262.

[0062] While scyllo-inositol's properties in preventing Aβ fibril formation and its positive results in memory / cognitive tests in animal models of AD have been reported, published information regarding the actual treatment of Alzheimer's disease in subjects has been minimal to nonexistent, given the apparent failure of clinical studies to date. The present inventors have surprisingly and unexpectedly discovered a subgroup of patients susceptible to effective treatment with scyllo-inositol, to treat a subset of patients with Alzheimer's disease or with MCI, while meeting the primary endpoints in the clinical studies.

[0063] Glossary

[0064] The recitations of numerical ranges by endpoints herein include all numbers and fractions subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5, and numbers between these specific numbers).

[0065] The term "adjuvant" means a component that, when added to the dosing regimen of a single active ingredient or when added in combination with another active ingredient, adds or provides, in combination, an enhanced or beneficial and improved therapeutic or safety benefit to the other active ingredient in the combination, compared to the same properties of the single other active ingredient or component administered alone. An adjuvant by itself may not have clinically significant properties in the target patient population, but in combination with such other active ingredients does provide additional therapeutic or safety clinically significant properties to such other active ingredients in the target patient population.

[0066] The terms "administering" and "administration" refer to the process of preventing and / or treating a condition or disease by delivering a therapeutically effective amount of a compound or composition encompassed herein to a patient.

[0067] The term "treating" refers to reversing, alleviating or suppressing the disease or one or more symptoms of the disease to which the term applies. Depending on the condition of the patient or subject, the term also refers to preventing the disease and includes, depending on the particular disease or condition, preventing the onset of such disease.

[0068] The terms "subject" or "patient" are used interchangeably herein and include mammalian subjects, including humans or animals such as horses, dogs, cows, cats, or other mammals.

[0069] 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 non-toxic to the subject to which it is administered. Excipients may include diluents, binders, adhesives, lubricants, disintegrants, bulking agents, wetting agents or emulsifiers, pH buffers, and other known pharmaceutically effective excipients.

[0070] The term "combination therapy" or "co-administration" means that the active ingredients are administered to the patient being treated simultaneously. When administered simultaneously, the components can be administered simultaneously or sequentially in any order at different time points. The term includes pre-treatment with one active ingredient and then treatment with both active ingredients and / or either active ingredient at the same or different time points - all in order to achieve the desired therapeutic and / or beneficial effect. Beneficial effects include, for example, a reduction in side effects of one or both active ingredients due to the presence of the other active ingredient.

[0071] The term "beneficial effect" refers to an effect of a compound or adjuvant or composition or combination that includes a favorable pharmacological and / or therapeutic effect, and / or improved biological activity, and that includes or can include a reduction in side effects. The term "beneficial effect" includes effects such as improved cognitive function, reduced vascular load, reduced astrogliosis, reduced amyloid load, reduced microgliosis, and / or improved survival. Beneficial effects may also include enhanced stability, longer half-life, and / or enhanced uptake and transport of one active ingredient or adjuvant across the blood-brain barrier to achieve an overall benefit for another active ingredient.

[0072] Immunotherapy for Alzheimer's disease is a promising approach to reducing beta-amyloid fibrils and plaques in the brain. Previous clinical trials investigating active or passive immunotherapy approaches to reduce beta-amyloid burden in the brain have shown some benefit in reducing beta-amyloid and improving cognition. 1 – 4 However, the doses of antibody therapies used are limited by the appearance of treatment-related abnormalities on brain imaging. Although these imaging abnormalities may be clinically asymptomatic, their long-term safety impact is uncertain and potentially dangerous.

[0073] Imaging abnormalities associated with immunotherapy have been observed in several humanized monoclonal antibody therapies targeting amyloid β, including the phase 2 study of bapineuzumab. 1 , 2 These MRI abnormalities were originally termed "vasogenic edema" 4 As the number of studies and findings were identified in subsequent trials of most other immunotherapies, it became clear that there was a spectrum of imaging changes associated with amyloid-modifying therapies. Amyloid-associated imaging abnormalities (ARIAs), 5 These include abnormalities in FLAIR signal thought to represent parenchymal vasogenic edema and sulcal effusion (ARIA-E) and abnormalities detectable on GRE / T2* sequences thought to represent microbleeds and hemosiderosis (ARIA-H).

[0074] The prevalence and severity of ARIA correlates strongly with increasing doses of antibodies targeting beta-amyloid, thereby hindering the full efficacy of immunotherapy by limiting the administration of the high levels of antibodies needed to optimize brain amyloid reduction and improve cognition in Alzheimer's disease. In most cases, immunotherapy treatment has been administered with suboptimal doses of beta-amyloid antibodies to prevent patients from developing ARIA.

[0075] Recently, an immunotherapy against beta-amyloid (aducanumab) has recently shown that higher doses of the antibody are effective in patients with MCI and mild AD relative to lower doses. In order to reduce the ARIA associated with the higher doses required for optimal efficacy, a dose escalation regimen is used to reduce the prevalence and severity of ARIA. Aducanumab is first administered to patients at a low dose (such as 1 mg / kg) and then slowly increased to 3, 6, and then 10 mg / kg over a period of time. Studies have found that by slowly increasing the dose, higher doses of therapy can be administered, resulting in efficacy with an acceptable safety profile.

[0076] However, there is a significant unmet medical need for agents, drugs, or adjuvants with specific properties that would permit / allow increased doses / dosing schedules of immunotherapeutics, such as aducanumab and other potent monoclonal antibodies, by reducing / mitigating safety concerns associated with ARIA, while allowing / enabling a significant increase in the dose and efficacy of such immunotherapies in patients with MCI and mild AD who are in need of their treatment.

[0077] This need has been met by the surprising discovery that small molecules such as scyllo-inositol can effectively act together with monoclonal antibodies against Aβ to effectively treat Alzheimer's patients, even better than aducanumab alone, or the final titration intensity can be reduced and / or the intensity and dose of aducanumab can be increased to achieve the same or reduced ARIA levels. It is also believed that triple combinations of such monoclonal antibodies with a combination of scyllo-inositol and linolenic acid / linoleic acid can provide effective relief to cognitively impaired patients, including those with mild Alzheimer's disease and MCI.

[0078] Although the exact mechanism of action of immunotherapy in the development of ARIA is unclear, it is possible that increased antibody binding to large amyloid-β aggregates in perivascular cuffs and palpable plaques in the brain leads to localized inflammation and leakage. High doses of amyloid-β antibodies are required to disaggregate these aggregates and increase clearance of amyloid-β from the brain to the CSF and blood. As the antibody dose increases, the likelihood of generating pockets of antibodies that react with amyloid aggregates and plaques also increases, leading to the symptoms associated with ARIA. Therefore, agents that can interact with and disaggregate amyloid aggregates may have the potential to reduce these pockets of antibody complexes in the brain.

[0079] Scyllo-inositol (a stereoisomer of inositol) has been found to decompose and prevent the formation of beta-amyloid fibrils in vitro. In vivo, daily administration of 0.3 to 30 mg / kg scyllo-inositol to an AD transgenic mouse model showed a reduction in beta-amyloid load in the brain and improvements in cognitive and functional tests. In addition, treatment with scyllo-inositol showed a reduction in neurotoxicity and brain inflammation. The ability of scyllo-inositol to cross the blood-brain barrier through the inositol transporter enables the drug to reach sufficient levels to reduce large amyloid aggregates and plaques to small oligomers of beta-amyloid. The improvement in cognition can reflect a reduction in amyloid load and a reduction in large aggregates and plaques.

[0080] Preclinical studies were conducted as disclosed, for example, in US2007 / 0197452, using methods for testing mouse models of Alzheimer's disease, such as TgCRND8 mice. Tests performed included behavioral tests such as the Morris water maze test; brain amyloid burden; plasma and brain Aβ content; quantification of gliosis; survival screening; brain APP analysis; soluble Aβ oligomer analysis; long-term potentiation; and synaptophysin immunohistochemical staining. The results obtained in these studies demonstrated the effectiveness of scyllo-inositol in treating TgCRND8 mice, which have amyloid plaque morphology, density, and distribution similar to those seen in the brains of human patients with Alzheimer's disease.

[0081] The focus of the present disclosure is multifaceted: pre-treatment with scyllo-inositol in combination with vitamins, particularly vitamin D and / or vitamin D prohormones such as calcifediol, as well as continued treatment, can be used to treat memory loss, mild cognitive impairment, and early Alzheimer's disease in a subset of patients with certain MMSE scores. In addition, such drug combinations can also be used to treat Alzheimer's disease and certain side effects associated with treatment with monoclonal antibodies such as aducanumab or other known monoclonal antibodies for the treatment of Alzheimer's disease. It is believed that the combination of scyllo-inositol (alone or in combination with vitamin D compounds), further combined with aducanumab, will reduce the prevalence and severity of ARIA caused by aducanumab treatment. The combination allows for an increase in the dose of antibodies administered to patients with MCI and mild AD, leading to improvements in cognition and function; secondly, relative to antibody therapy alone, the co-administration of scyllo-inositol with vitamin supplements, alone or in combination with antibody therapy for amyloid-β, will increase the clearance of amyloid-β from the brain to the CSF and blood, leading to a reduction in the amyloid load in the brain, leading to improvements in cognition, and finally; compared to the administration of scyllo-inositol alone, the co-administration of scyllo-inositol and vitamins, particularly vitamin D compounds selected from, for example, calcifediol, will enhance the efficacy on cognition and function through synergistic or combined effects to prevent the accumulation of amyloid-β in the brain, while also increasing serum levels of 25-hydroxyvitamin D3. In a preferred embodiment, calcifediol is the preferred vitamin D metabolite that is administered directly in combination with scyllo-inositol. Calcifediol is available in immediate release form or delayed release form and is sold around the world under various brand names. The drug in delayed release form is called Prescription drug products in immediate-release form are sold under the brand name Sold as soft gel capsules. DSM produces a ten microgram immediate-release tablet, which is available in some countries under the trade name Ampli-D.

[0082] The present invention also includes a method for treating Alzheimer's disease patients, which comprises pre-treating with scyllo-inositol for 2 weeks, followed by co-administration of scyllo-inositol in combination with anti-β-amyloid antibody therapy to patients with MCI and mild AD to reduce safety issues associated with ARIA and enhance the reduction of β-amyloid load in the brain, thereby resulting in improvements in efficacy and safety. Alternatively, patients already using aducanumab can be co-administered with scyllo-inositol to treat MCI and mild AD. However, the initial clinical protocol required a two-week course of pre-treatment. Patients with MCI and mild AD were divided into 3 cohorts and treated as follows:

[0083] a. Cohort 1: Patients will be treated with 250mg BID or 500mg QD scyllo-inositol alone for 54 weeks. Patients will be examined for amyloid burden, memory, cognitive and functional tests, and ARIA testing.

[0084] b. Cohort 2: Patients will be treated with 250 mg BID or 500 mg QD scyllo-inositol alone for two weeks, followed by a combination of 250 mg BID or 500 mg QD scyllo-inositol and escalating doses of aducanumab starting at 1 mg / kg (4 weeks), then 3 mg / kg (4 weeks), then 6 mg / kg (4 weeks), and then a final dose of 10 mg / kg for the remainder of the study (40 weeks). Patients will be evaluated for ARIA, beta-amyloid burden, memory, cognition and function, and safety parameters.

[0085] c. Cohort 3: Patients will be treated with escalating doses of aducanumab alone, starting at 1 mg / kg (4 weeks), 3 mg / kg (4 weeks), 6 mg / kg (4 weeks), and 10 mg / kg for the remainder of the study (40 weeks). Patients will be evaluated for ARIA, beta-amyloid burden, memory, cognition, function, and safety parameters.

[0086] Treatment with scyllo-inositol and aducanumab over a 52-week period resulted in:

[0087] ARIA was reduced compared with treatment with aducanumab alone.

[0088] The burden of beta-amyloid in the brain was reduced compared with treatment with aducanumab alone.

[0089] Memory, cognition, and function improved compared with aducanumab treatment alone.

[0090] Improvement of beta-amyloid biomarkers in CSF, such as beta-amyloid 42 / 40 ratio, Tau, and phosphorylated Tau.

[0091] The combination will also allow for greater flexibility in the dosing schedule of aducanumab by allowing modification of the intensity of the dose and by allowing modification of the titration schedule of the currently approved course of treatment.

[0092] In another embodiment, the present invention includes a drug combination for treating cognitive impairment and / or memory loss. Therefore, the present invention relates to a combination of (i) a first compound selected from a combination of scyllo-inositol and / or a similar cyclohexanol or such inositol or a pharmaceutically acceptable salt thereof and (ii) a second compound selected from the group consisting of 25-hydroxyvitamin D (such as 25-hydroxyvitamin D3 or D2). Such a combination can be in the form of a kit comprising a dosage form with the first compound and a dosage form with the second compound. Alternatively, the present invention relates to a single capsule, tablet or dosage form comprising both a first compound selected from scyllo-inositol and a second compound selected from 25-hydroxyvitamin D3 or D2. Such capsules, tablets or dosage forms can be in any suitable formulation and comprise additional pharmaceutically acceptable excipients. The capsule or tablet can comprise a combination of an immediate release form of scyllo-inositol, and it can further comprise a layer of an immediate release amount of calcifediol surrounding the immediate release tablet core or a layer of a delayed release formulation of calcifediol.

[0093] Scyllo-inositol

[0094] Scyllo-inositol can be obtained from methods disclosed in many 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 preventing, treating and diagnosing protein aggregation disorders is disclosed in, for example, EP1608350B1 or 8859628 or 7,521,481, which are incorporated herein by reference. The data shown therein demonstrate that treatment with scyllo-inositol significantly reduced amyloid burden and gliosis in mice. Scyllo-inositol is described as having the property of inhibiting amyloid deposition already established in the living brain. Therefore, the data indicate that scyllo-inositol has the property of reducing amyloid plaque burden and improving cognition in mammals in need of its treatment. Diseases that can be treated with scyllo-inositol include disorders of the central or peripheral nervous system or systemic organs, and it has deposition of proteins or protein fragments and peptides in β-pleated sheets and / or fibrils or aggregates as a disorder. In patients being treated with or prescribed monoclonal antibodies for such diseases, such deposits and / or tissues already harboring such sheets can be disrupted by co-administration or combination of scyllo-inositol and a suitable dosage form of such monoclonal antibodies.

[0095] Over the past 25 years, scientific and clinical data have shown that the accumulation of amyloid-β fibrils in the brain plays a significant role in the progressive loss of memory and cognition during aging, and can ultimately lead to dementia even if Alzheimer's disease never develops. It is well known that amyloid-β oligomers and fibrils accumulate in the brain for 5 to 15 years before significant effects on memory, cognition, and potentially Alzheimer's disease are observed. It is also known that 30% to 40% of people over the age of 55 show accumulation of amyloid-β in the brain, which may lead to an increased risk of memory loss or mild cognitive impairment. Among patients with signs or symptoms of mild cognitive impairment, approximately 60% to 70% of such subjects have amyloid oligomers and fibrils in the brain. Administering scyllo-inositol at clinically proven safe levels (such as 250 mg twice daily) can reduce amyloid burden in the brain. Co-administration of such doses of scyllo-inositol with a vitamin D compound that effectively increases serum levels of 25-hydroxyvitamin D3 in the brain can treat or alleviate memory loss or cognitive impairment.

[0096] Scyllo-inositol offers advantages including: (i) the ability to cross the blood-brain barrier to disassemble amyloid fibrils and reduce the amyloid burden in the brain; and (2) improvement of related 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 that overexpress beta-amyloid, thereby leading to cognitive improvements—see McLaurin J. et al. Nature Medicine 2006; 12(7): 801-8. In addition, as claimed herein, unpublished Phase 2 clinical trial results indicate that scyllo-inositol alone can treat certain previously undisclosed Alzheimer's disease and MCI patients with a range of MMSE scores. The combination of human and animal data suggests that scyllo-inositol alone can both reduce fibril burden and treat or alleviate cognitive impairment in subjects. It is reasonable to believe that very early intervention with a pharmaceutically effective amount or nutraceutical effective amount of scyllo-inositol, alone or in combination with a vitamin D compound and optionally other active ingredients or other vitamin compounds, can treat such subjects to reduce fibril formation. Scyllo-inositol can also prevent Aβ aggregation, reduce Aβ load, and improve 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.

[0097] Oral administration of 250 mg scyllo-inositol BID in humans showed a trend toward improved cognition and function in elderly individuals with mild AD over a period of 78 weeks.

[0098] Specific diseases and conditions that can be treated with such combination therapies include Alzheimer's disease, both early-onset and senile 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 having polyglutamine, polyalanine, or other repeat sequences resulting from pathological expansion of trinucleotide or tetranucleotide elements within the corresponding genes, and other diseases and conditions disclosed, for example, in U.S. Pat. No. 7,521,481, which is incorporated herein by reference.

[0099] Scyllo-inositol can be formulated into any suitable pharmaceutical formulation. The compound can be delivered orally or by other suitable means. Oral formulations can be in the form of tablets or capsules, comprising pharmaceutically acceptable excipients selected from adhesives, fillers, surfactants, preservatives, lubricants, etc. The dosage of the drug varies, but in combination therapy, the range is on the higher strength side and between 125 and 250 mg BID or 500 mg QD. The prescribing physician can modify the dosage according to the specific disease condition or state of the patient treated with the combination regimen, and the adjuvant dose can be reduced to between 50 and 150 mg BID. Tablets and / or capsules can be manufactured by methods known to those skilled in the art. The administration of scyllo-inositol can also be achieved by using oral liquids or suspensions, intravenous administration, intramuscular administration or other modes (such as intraperitoneal, intradermal, transdermal, subcutaneous, intranasal, sublingual, inhalation or other modes).

[0100] Aducanumab

[0101] Aducanumab-avwa is described as a recombinant human immunoglobulin gamma 1 (IgG1) monoclonal antibody that is directed against soluble and insoluble forms of aggregated beta-amyloid. The immunoglobulin is expressed in a Chinese hamster ovary cell line and has a molecular weight of 146 kDa. The pre-diluted injection formulation is preservative-free and contains 100 mg of aducanumab-avwa and 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 per mL of solution at a pH of approximately 5.5. Clinical studies have demonstrated that ADUHELM reduces beta-amyloid plaques as described in such studies. The drug reduced beta-amyloid plaques in a dose- and time-dependent manner compared to placebo. Using PET imaging ( 18 F-Flubetapyr ( 18 The drug's effect on the levels of such plaques was assessed using a PET tracer (F-florbetapir). PET signal was quantified using the standardized uptake value ratio (SUVR) method to estimate brain levels of beta-amyloid plaques in a composite of brain regions expected to be affected by Alzheimer's disease pathology. See the prescribing information for ADUHELM. These regions were the frontal, parietal, lateral, temporal, sensorimotor, and anterior and posterior cingulate cortices, compared to a brain region expected to be free of such pathology (cerebellum).

[0102] Substudies of these clinical studies of aducanumab showed reductions in brain beta-amyloid plaque levels at both the low and high dose levels compared with placebo at both weeks 26 and 78. The magnitude of these reductions was again described as dose- and time-dependent.

[0103] In the third clinical study, ADUHELM demonstrated statistically significant dose- and time-dependent reductions in amyloid plaque levels at week 26 in the 3 mg / kg, 6 mg / kg, and 10 mg / kg treatment groups and at week 54 in all treatment groups compared to placebo.

[0104] The effect of ADUHELM on Tau pathophysiology (marker levels) was also studied. Studies have shown that ADUHELM reduces markers of tau pathophysiology (CSF p-Tau and Tau PET) and markers of neurodegeneration (CSF t-Tau) (Studies 1 and 2). In substudies conducted in Studies 1 and 2, the immunotherapy drug also reduced CSF levels of p-Tau. At Week 78 of Study 1, the adjusted mean change from baseline in CSF p-Tau levels favored the low-dose and high-dose ADUHELM groups relative to placebo. In the substudies conducted in Study 1, the drug also reduced CSF t-Tau levels in the low-dose and high-dose groups compared to placebo.

[0105] Substudies were also conducted in Study 1 and Study 2 to investigate the effects of PET imaging ( 18 F-MK6240 tracer) to observe the effect of aducanumab on neurofibrillary tangles composed of tau protein. 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 lobe, frontal lobe, cingulate, parietal lobe, and occipital cortex) compared to brain regions expected to be unaffected (such as the cerebellum). Clinical data showed that the adjusted mean change from baseline in tau PET SUVR at follow-up favored the administration of aducanumab at a high dose and in the medial temporal lobe, temporal lobe, and frontal lobe regions of the brain relative to placebo.

[0106] Finally, additional data were collected on the exposure-response relationship after taking aducanumab compared with placebo. The data demonstrated that higher exposure to aducanumab was associated with greater reductions in clinical decline (as measured by CDR-SB, ADAS-Cog 13, and ADCS-ADL-MCI) and greater reductions in beta-amyloid plaques in subjects.

[0107] Clinical studies of the combination products described herein will use the same methodology utilized in the ADUHELM study to show efficacy, marker reductions, and improvements in AIRA-related events following combination treatment and pre-treatment with scyllo-inositol.

[0108] As described in U.S. Patent No. 10,842,871 (which is incorporated herein by reference), during the development of drugs to treat Alzheimer's disease, the U.S. Food and Drug Administration ("FDA") expressed concern in 2010 about the development of abnormalities that appeared on MRI scans after treatment in clinical trials. These abnormalities were identified and / or believed to represent vasogenic edema (VE) and microhemorrhages (mH) and were first observed in clinical trials of monoclonal antibodies against beta-amyloid. Since then, developers of such drugs (including the developers of the recently approved monoclonal antibody therapy aducanumab) have focused on efficacy and safety, as well as new questions about VE or mH arising from monoclonal antibody treatment. The root cause of the abnormal increases in VE and mH is not fully understood. The presence of the apolipoprotein E ε4 allele, ApoE ε4, has been found to be a significant risk factor for the development of ARIA-E (VE-associated MRI abnormalities). On the other hand, mH has not been found to be associated with any specific allele, but is generally attributed to one of two causes: small vessel angiopathy and cerebral amyloid angiopathy (CAA). It has also been suggested that a local inflammatory component induced by drug therapy may lead to ARIA-E and / or ARIA-H.

[0109] In any case, Biogen-IDEC received FDA approval for ADUHELM to treat both MCI and mild Alzheimer's disease and to mitigate ARIA caused by such treatments. TMAducanumab was approved with a treatment regimen that requires titration to reduce ARIA. The drug is a beta-amyloid-directed antibody indicated for the treatment of Alzheimer's disease and was approved under accelerated approval based on the reduction in beta-amyloid plaques observed in patients treated with ADUHELM. The Dosing and Administration section of the approved label states: (1) titration is required when initiating treatment; (2) the recommended maintenance dose is 10 mg / kg administered as an intravenous infusion over approximately one hour every four weeks; (3) a recent (within one year) brain MRI prior to initiating treatment; (4) an MRI obtained before the 7th and 12th infusions. If radiographically severe ARIA-H is observed, treatment should be continued with caution only after clinical evaluation and subsequent MRI demonstrate radiographic stability (i.e., no increase in the size or number of ARIA-H); (5) dilute with 100 mL of 0.9% Sodium Chloride Injection, USP, prior to administration; and (6) administer as an intravenous infusion over approximately one hour through a 0.2 or 0.22 micron inline filter. The approved dosage forms and strengths are 170 mg / 1.7 mL (100 mg / mL) solution for injection in a single-dose vial and 300 mg / 3 mL (100 mg / mL) solution in a single-dose vial. The Warnings and Precautions section of the label warns that amyloid-related imaging abnormalities (ARIAs) require increased clinical vigilance for such ARIAs during the first 8 doses of treatment, especially during the titration period. The period between IV infusions is every four weeks. The dosing or titration schedule for infusions 1 and 2 is 1 mg / kg aducanumab; for infusions 3 and 4, 3 mg / kg; for infusions 5 and 6, 6 mg / kg; and for infusions 7 and above, 10 mg / kg. The Adverse Reactions section of the label states that the most common adverse reactions (incidence of at least 10% and greater compared to placebo) are ARIA-edema, headache, ARIA-H microhemorrhages, ARIA-H superficial siderosis, and falls.

[0110] The ARIA monitoring section states that if 10 or more new microhemorrhages or greater than 2 focal areas of superficial siderosis (radiologically severe ARIA-H) are observed, it is prudent to continue treatment only after clinical evaluation and follow-up MRI demonstrate radiological stability (i.e., no increase in size or number of ARIA-H).

[0111] In clinical studies of ADUHELM and the combinations described herein, the severity of ARIA was classified according to the radiographic criteria provided in Table 1 below:

[0112] Table 1

[0113]

[0114] In clinical studies of aducanumab alone versus placebo, ARIA E and / or H were observed in 41% of patients treated with the planned 10 mg / kg dose of the drug (454 of 1105) and in 10% of patients taking placebo (111 of 1087). ARIA-E was observed in 35% of patients treated with aducanumab 10 mg / kg and in 3% of patients taking placebo. As previously discussed, the incidence of ARIA-E was higher in apolipoprotein E ε4 (ApoE ε4) carriers than in ApoE ε4 non-carriers (42% and 20%, respectively). Clinical studies have demonstrated that most ARIA-E radiological events occurred early in treatment (within the first 8 doses), but also indicate that such ARIAs may occur at any time. 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%. 68% of patients with ARIA-E achieved remission within 12 weeks of detection, 91% achieved remission within 20 weeks, and the overall remission rate was 98%. 10% of all patients receiving aducanumab 10 mg / kg experienced more than one ARIA-E episode. In the setting of ARIA-E associated with the use of ADUHELM 10 mg / kg, ARIA-H was observed in 21% of patients treated with the drug and in 1% of patients taking placebo.

[0115] ADUHELM is administered in a titration-based regimen because it is desirable to reduce ARIA-related events that occur or are more likely to occur in a fixed-dose regimen. It is believed that titration will slow the rate of initial amyloid removal and thereby allow for slower removal throughout the patient's treatment period. It is believed that pretreatment with a non-monoclonal antibody regimen, for example, a drug such as scyllo-inositol, will promote plaque removal and reduce plaque burden without causing ARIA-related events, such that subsequent co-administration of scyllo-inositol and aducanumab will reduce ARIA-related or related events due to antibody treatment, and thus allow titration with a higher dose of aducanumab and / or promote a fixed-dose regimen of aducanumab / scyllo-inositol without ARIA-related events or fewer such events in the treated patient. In combination, the rate of plaque removal can therefore be accelerated without slowing down the removal of amyloid.

[0116] Aducanumab (BIIBO37) is an IgG1 monoclonal antibody composed of two heavy chains and two kappa light chains linked by interchain disulfide bonds. The antibody recognizes a conformational epitope found in Aβ aggregates. A murine IgG2a chimeric version of this antibody (chl 2F6A) has been shown to reduce or decrease plaque burden in aged Tg2576 mice, a mouse model of Alzheimer's disease. See Wilcock and Colton 2009. The humanized version of the antibody, 12F6A, has the same amino acid sequence as BIIBO37, which is produced in a different Chinese hamster ovary cell line.

[0117] Aducanumab has a V H and / or V L The antigen binding domains of the variable regions are shown in Table 2.

[0118] Table 2

[0119]

[0120]

[0121] Aducanumab (BIIB037) has the following CDR protein sequence names:

[0122] Table 3

[0123]

[0124] The heavy chain of the anti-Aβ antibody BIIB037 has the following sequence:

[0125] QVQLVESGGG VVQPGRSLRL SCAASGFAFS SYGMH WVRQA

[0126] PGKGLEWVA V IWFDGTKKYY TDSVKG RFTI SRDNSKNTLY

[0127] LQMNTLRAED TAVYYCAR DR GIGARRGPYY MDV WGKGTTV

[0128] TVSSASTKGPSVFPLAPSSK STSGGTAALG CLVKDYFPEP

[0129] VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL

[0130] GTQTYICNVN HKPSNTKVDK RVEPKSCDKT HTCPPCPAPE

[0131] LLGGPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV

[0132] KFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDW

[0133] LNGKEYKCKV SNKALPAPIE KTISKAKGQP REPQVYTLPP

[0134] SREEMTKNQV SLTCLVKGRY PSDIAVEWES NGQPENNYKT

[0135] TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH

[0136] NHYTQKSLSL SPG (SEQ ID NO: 9)

[0137] The heavy chain CDRs are underlined.

[0138] The light chain of the anti-Aβ antibody BIIB037 has the following sequence:

[0139] DIQMTWSPSS LSASVGDRVT ITC RASQSIS SYLN WYQQK

[0140] GKAPKLLIYA ASSLQS GVPS RFSGSGSGTD FTLTISSLQP

[0141] EDFATYYC QQ SYSTPLT FGG GTKVEIKRTV AAPSVFIFPP

[0142] SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ

[0143] ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG

[0144] LSSPVTKSFN RGEC (SEQ ID NO: 10).

[0145] Light chain CDRs are underlined.

[0146] Antibodies can be produced using the methods described in, for example, US2021018895 (this U.S. Patent is incorporated herein by reference). As described therein, they can be produced in eukaryotic cells 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 cells and eukaryotic cells, yeast cells can also be used to produce antibodies or their scFv. The general process includes constructing a polynucleotide encoding an antibody, introducing it into an expression vector and expressing the antibody in a suitable host cell. Molecular biotechnology is well known to those skilled in the art. If the antibody is expressed in CHO, COS or NIH3T3 cells, a promoter such as SV40, MMLV-LTR or EF1α or CMV promoter is required. Additional sequences (such as regulatory sequences) can be added, and these sequences can promote replication and selection, and can confer resistance to drugs introduced into the vector. Suitable vectors include pMAM, pDR2 and other vectors described in US2021188954. To illustrate the production of BIIB037, recombinant expression vectors encoding antibody heavy and light chains were 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 any one of SV40, CMV, etc. (CMV enhancer / AdML: promoter regulatory elements or SV40 enhancers in such systems) to promote high-level transcription of the gene. The vector was also made to contain the DHFR gene, which allows the use of methotrexate selection / amplification to select CHO cells that have been transfected with the vector. The selected transformed cells were cultured to provide expression of the antibody light and heavy chains, and then the antibodies were recovered from the culture medium and used in the compositions described herein for the treatment of Alzheimer's patients. Purification methods are known in the art, and such antibodies can be separated and purified to the level 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.

[0147] The composition of the antibody can be prepared according to the method and composition described in U.S. Patent No. 10,842,871 (this U.S. Patent is incorporated herein by reference). The composition can include a pharmaceutically acceptable excipient, such as a phosphate buffered saline solution, water, an emulsion including an oil-in-water emulsion, etc. A wetting agent can be added and such a composition can be delivered as a sterile solution. The administration of the antibody and pharmaceutical composition can be, for example, intravenous, intraperitoneal, subcutaneous, intramuscular, topical or transdermal administration. Various concentrations of antibodies can be prepared and used for combination therapy. As a high concentration antibody composition, such a concentration can be in the range of 50 mg / mL to more than 300 mg / mL. Sterile injectable solutions of such antibodies are prepared and need to be filtered and sterilized. It may be necessary to coat such antibodies with lecithin to ensure the appropriate fluidity of the sample. Additional ingredients that can, for example, reduce the risk of aggregation and / or ensure appropriate viscosity can be added. Excipients can include, for example, L-arginine hydrochloride in various concentration ranges (40 to 260 nM and the range therebetween). Sucrose can be added in a concentration ranging from about 0.5% to about 5%. Methionine can also be included in the composition in a concentration range of 5mM to about 150mM. Other excipients that facilitate formulation and processing can include polysorbates in a concentration range of 0.01% to 0.03%. Buffers can also be added to achieve a pH range of about 5.0 to 6.5 or levels therebetween. Histidine can be used as a buffer in a concentration range of about 5mM to 50mM or values ​​therebetween. Antioxidants such as glutathione CSH, cysteine, and cystine can be utilized in a concentration range of about 0.02mM to 4mM.

[0148] The method for measuring clinical efficacy and results is determined on a per-patient basis and involves measuring and determining the presence, severity, and progression of Alzheimer's disease over a period of time. This involves clinically determining the patient's overall functional level; daily living behaviors and life skills or behavioral deficits; using technology such as beta-amyloid PET imaging to perform volumetric analysis of brain structure and measure the deposition of abnormal proteins associated with the disease in the brain in vivo. In addition, blood, body fluid, or CSF markers are measured as indicators of disease presence or disease progression, and include measuring tau protein and other biomarkers (such as pyroglutamate-Aβ, Aβ40, and Aβ42) in the blood and total Tau, phosphorus Tau, pyroglutamate-Aβ, Aβ40, and Aβ42 in the CSF. ApoE isotype and hippocampal volume (HCV) MRI can also be used to define and / or stage disease progression. The measurement of such markers and methods for determining the levels of such markers are known in the art. In addition, it is well known that such markers can predict the pathogenesis of Alzheimer's disease. See, for example, Duyckaerts (2011) Lancet Neurol. 10, 774-775 and Craak et al. (2013), Acta Neuropath., 126: 631-41.

[0149] Amyloid plaque burden is measured using 18F-AV-45 PET. 18F-AV-45 is a known amyloid ligand marketed and developed by Avid Radiopharmaceuticals. A skilled PET imaging specialist can review acquired PET images to determine the average uptake of 18F-AV-45 in patients with AD and between AD patients and age-matched controls. PET measurements of regional glucose metabolism and morphometric MRI measurements can also be used to assess AD status or progression. MRI can also be used to monitor ARIA-related events.

[0150] Linolenic acid :

[0151] Linoleic acid is (Z,Z)-9,12-octadecadienoic acid (mol.wt 280.44), and is an essential fatty acid, a major component of vegetable oils. This fatty acid is a colorless oil. Linolenic acid has two main forms—alpha and gamma. Alpha-linolenic acid is (Z,Z,Z)-9,12,15-octadecatrienoic acid, and is also an essential fatty acid and a colorless liquid. Gamma-linolenic acid is (6Z,9Z12Z)-6,9,12-octadecatrienoic acid and is produced in the body as a metabolite of linoleic acid. These fatty acids are commercially available. In 1993, Yehuda and colleagues published an article on the discovery of the optimal ratio of these fatty acids and the benefits of the optimized ratio on neuronal membrane function and neuronal transmission (expressed as a "membrane fluidity" index). See Proc. Natl. Acad. Sci. USA, Vol. 90, pp. 10345-10349, November 1993 Neurobiology. Yehuda found that the ratio of alpha-linolenic acid to linoleic acid is the key variable that enhances cognitive function and other neurological characteristics. Yehuda found that, under the ratio of the purified free alpha-linolenic acid and linoleic acid (about 25mg / kg body weight every day) of the ratio between 1:3.5 and 1:5 (for example, preferably 1:4), animals (rats) were treated for four weeks, and the thermoregulatory control of the hypothermia caused by learning performance, pain threshold and d-amphetamine produced a significant beneficial effect. Additionaly, these essential fatty acids have also been clinically studied in the wide range of diseases including ADHD and other nervous system disorders. The essential oils of these combinations and with these specific ratios are commercially available. As described, the combination with scyllo-inositol can be a combination of " mixture " of scyllo-inositol and essential fatty acids in a single dosage form (for example scyllo-inositol tablets and fatty acid mixture capsules), or active ingredients can be formulated into a single oral formulation together and produced in the form of capsules or oral solutions. Tablets can be formed by compression and can be produced from crystalline, powdered or granular materials together with other pharmaceutically acceptable excipients (such as binders, disintegrants, lubricants, diluents and colorants). Diluents can be selected from, for example, dicalcium phosphate, lactose, cellulose, mannitol, dry starch, powdered sugar and / or sodium chloride. Binders can be selected from starch, gelatin and sugars such as sucrose, glucose, dextrose or lactose. Natural and / or synthetic gums can also be used. Lubricants such as magnesium stearate can also be incorporated into tablets or capsules. Flavoring agents can also be used. When the 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 can be selected from a hard capsule or a soft capsule. The capsule can be a gelatin-based capsule or any known suitable form of hard or soft capsule. Preferred capsules contain 250 mg of scyllo-inositol and 250 mg of free α-linolenic acid and linoleic acid in a molar ratio of 1:4. These capsules are administered to subjects twice daily. The dose can be increased and can also be provided to subjects QD.Any pharmaceutically effective amount of scyllo-inositol can be utilized. This amount ranges from 100 mg to more than 500 mg. The 1:4 ratio of linolenic acid / linoleic acid of any suitable amount of mixing can be utilized, and can also be provided BID or QD. The amount of the oil blend can be 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850 and up to about 1000 mg or between or above such amounts (mg / gram). In some cases, the subject can take a few grams (1 to 12 grams) of the oil blend, but this will be provided in a separate oral dose. This combination oral dosage form or other combinations of such active ingredients can also be combined with aducanumab.

[0152] Additional active ingredients and / or essential nutrients and vitamins may also be combined with the combination of scyllo-inositol and the "mixture" of linolenic and linoleic acids. Vitamins that may be utilized in the combination include vitamins E, K, D, B, and C. 25-hydroxyvitamin D may also be combined with the combination. The formulation may also be administered as an immediate release dosage form or as a controlled release dosage form.

[0153] Calcifediol.

[0154] Many patents and patent publications as well as scientific publications disclose the use and administration of calcifediol in both immediate release and delayed release forms. U.S. Patent No. 8,207,149 discloses a controlled release formulation of a vitamin D compound for oral administration, which incorporates a vitamin D compound as defined therein into a solid or semisolid mixture of a waxy material to form a delayed release formulation. Such formulations are described as being filled into gelatin capsules. Prohormone 25-hydroxyvitamin D3 is described as a preferred compound. In the present invention comprising a combination of scyllo-inositol and a vitamin D compound (such as 25-hydroxyvitamin D3), the vitamin D compound can be provided as an immediate release formulation comprising calcifediol in a suitable tablet formulation or capsule formulation or liquid formulation, or it can comprise a delayed release formulation comprising a waxy controlled release carrier, a lipid agent, and an oily solvent for the vitamin D compound. The carrier can be selected from waxes, such as synthetic waxes, microcrystalline waxes, paraffin wax, carnauba wax, or beeswax. Additional excipients may include polyethoxylated castor oil derivatives, hydrogenated vegetable oils, glyceryl monobehenate, glyceryl dibehenate, or glyceryl tribehenate; long chain alcohols such as stearyl alcohol, cetyl alcohol, and the like, and mixtures thereof, wherein the formulation is blended into a time-release formulation. Other patents disclose additional, stable formulations, such as those disclosed in U.S. Patent No. 10,357,502, which, along with U.S. Patent No. 8,207,149, is hereby incorporated by reference in its entirety. Capsule formulations containing the following: 25-hydroxyvitamin D3 (30, 60 or 90 μg); paraffin (20 wt %); mineral oil (35.36%); hydroxypropyl methylcellulose K100MCR (10.0%); glyceryl monostearate (22.5%); lauroyl polyoxyethylene glyceride and polyoxyglycerol esters (GELUCIRE 44 / 14) 9.75%; anhydrous alcohol (2.32%) and BHT 0.02% or its variants can be formulated into soft or hard capsules and used in combination with tablets of scyllo-inositol (250 mg).

[0155] U.S. Publication No. 2021 / 0401752 (hereby incorporated herein by reference) discloses a dosage form of calcifediol dispersed in a polymer composition, and which can be a delayed release formulation. Embodiments include vitamin D compounds, such as calcifediol, embedded in a polymer network. The specification discloses a spheronized pellet formulation comprising 25-hydroxyvitamin D and a pharmaceutically acceptable excipient. In certain embodiments, the spheronized pellet comprises a delayed release component selected from a polymer and / or a lipid component. The polymer can be a water-insoluble polymer and can include or be a water-soluble polymer. The formulation can be a nano / micron particle formulation made by an emulsion followed by spray drying and freeze drying technology, as described in the '752 publication. The formulation can also be a powder formulation made by spray congealing. The formulation can include delayed release coated seeds or active coated particles. The formulation can be wax-free and / or wax-containing.

[0156] As further described in U.S. Patent Publication No. US20210308151, it is believed that increasing serum total 25-hydroxyvitamin D to a sufficiently high level can solve the state of immunodeficiency of the human host and avoid worsening the progression of infection and related complications. It is believed that the inference of this effect in humans is also applicable to nervous system diseases or disorders associated with inflammatory signaling or any type of inflammation. Therefore, the combination treatment of vitamin D compounds, particularly calcifediol, and more particularly ER calcifediol will cause the treatment or alleviation of such nervous system disorders and / or symptoms associated with any level of inflammation. In particular, the combination administration of the active vitamin D receptors produced or delivered to the brain outside the kidney of calcitriol together with the inositol selected from scyllo-inositol can achieve both fibril destruction and high levels of 25-hydroxyvitamin D3, which is then converted into calcitriol (active vitamin D) in vivo to avoid the worsening of any inflammation-related progression of such nervous system diseases or disorders or their associated symptoms.

[0157] An immediate release calcifediol dosage form can be prepared according to, for example, AU 2021100513, which discloses an immediate release tablet formulation of calcifediol. The spray-dried powder prepared from the emulsion is added to tablet excipients and formed into tablets having 10 micrograms of calcifediol.

[0158] It is believed that based on the weight and BMI of patients with cognitive impairment, increasing or safely increasing the levels of 25-hydroxyvitamin D3 to sufficient levels (e.g., greater than 30 to 100 ng / mL) together with scyllo-inositol combined treatment will further enhance cognition and memory by safely maintaining sufficient levels of 25-hydroxyvitamin D3. A corollary of this is that inadequate levels of vitamin D in patients or subjects with cognitive decline or memory loss, regardless of whether they are susceptible to Alzheimer's disease or mild cognitive impairment, will lead to a more rapid onset of memory loss and cognitive problems, and if these patients are susceptible to Alzheimer's disease, the onset of such disease will be more rapid, while subjects with adequate serum 25-hydroxyvitamin D3 levels will either be less susceptible to such disease or the development of such disease will be more "mild" compared to patients with serum calcifediol deficiency or insufficiency.

[0159] B vitamins

[0160] The B vitamins that can be used in the combination comprising a single dosage form or a single dosage form with scyllo-inositol (125 to 250 mg QD or BID) and vitamins and / or other active ingredients are selected from the group consisting of: vitamin B9 (folic acid) at a dose of about 30 to 1500 μg / day; vitamin B12 (cobalamin or cyanocobalamin) in an amount of about 0.1 to about 300 μg / day; vitamin B1 (thiamine, thiamine); vitamin B2 (riboflavin); vitamin B3 (niacin or nicotinic acid) or similar compounds, such as nicotinamide, including nicotinamide riboside; vitamin B5 (pantothenic acid); vitamin B6 and vitamin B7 (biotin). The dosage in the combination in a single dosage form or the dosage in the single dosage form of the combination with scyllo-inositol is selected from the dosage of each vitamin that is suitable for correcting the deficiency or insufficiency of such vitamins in the subject in need thereof.

[0161] In the case of nicotinamide riboside, a precursor of nicotinamide adenine dinucleotide (NAD+), the dosage is selected to treat cognitive impairment associated with brain inflammation. The dosage range is 30 to 500 mg / day. In a preferred embodiment, the dosage is about 300 mg / day. Therefore, the present invention further includes a combination of a first compound selected from scyllo-inositol and a second compound selected from vitamin B or a nicotinamide adenine dinucleotide precursor (such as nicotinamide riboside). In a preferred embodiment, the second compound is selected from nicotinamide riboside. NAD+ depletion is a recognized hallmark of Alzheimer's disease (AD), and nicotinamide riboside has been shown to provide beneficial effects on oxidative stress and DNA repair in AD mouse models by increasing NAD+ levels. In addition, nicotinamide riboside has been shown to reduce Aβ levels in mouse AD animal models. The combination can be provided as a separate dosage form, or as a single tablet or capsule or formulation with both scyllo-inositol and nicotinamide riboside. Any form of the combination can be administered to a subject in need of treatment thereof, including an Alzheimer's disease subject, an MCI subject, or a subject with cognitive impairment or memory loss or any acute brain injury or chronic neurodegenerative disease with or with signs of axonal degeneration. In addition, the combination of scyllo-inositol and nicotinamide riboside can be used to treat ophthalmic disorders such as retinal degeneration, age-related dysfunction, diabetic retinopathy, or light-induced degeneration or photoreceptor degeneration. Other diseases or conditions that can be treated with such a combination include neuromuscular diseases, including progressive wasting syndrome; Duchenne muscular dystrophy (DMD) and any other neurological disease or condition in which it is desired to reduce ribosylation (PARylation) levels, including AD patients and MCI patients. In addition to the first and second compounds discussed directly above, the present invention further includes a combination having calcifediol as the third compound. In alternative embodiments, the combination of calcifediol and nicotinamide riboside can be used alone as two separate dosage forms or in a single dosage form with both active agents to treat NAD+ deficiency or insufficiency and to treat vitamin D deficiency or insufficiency in Alzheimer's disease subjects or MCI subjects or subjects with neurological disorders associated with cognitive or memory impairment. In preferred embodiments, when calcifediol is present as a separate active substance in a single dosage form in such a combination in a single tablet or capsule, it is a delayed release formulation that also has a dosage form of nicotinamide riboside. In an embodiment, the combination can be in the form of a single dosage form with both calcifediol and nicotinamide riboside. These combinations or compositions can optionally be administered alone or in combination with scyllo-inositol in a separate dosage form or in a capsule or tablet with all three active agents. A kit with two or three active substances in separate dosage forms can be prepared in suitable packaging. In a preferred embodiment, one of the capsules contains 30, 60 or 90 μg of (ER calcifediol), and wherein the capsule can be a soft capsule or a hard capsule. In another embodiment, calcifediol can be an immediate release dosage form with 10 or 20 μg of calcifediol in a tablet or capsule. In another embodiment, calcifediol can be a soft capsule with 266 μg, wherein calcifediol is in an oil-based formulation and is administered once a month in conjunction with a nicotinamide riboside and scyllo-inositol dosage form.

[0162] Other supplements or active ingredients may also be used in combination with scyllo-inositol. Doses range from about 10 mg to about 500 mg of the flavonoid apigenin (C 15 H 10 The combination of apigenin (0.25) and scyllo-inositol (100 to 500 mg) can be used in a separate dosage form or in a single dosage form with two ingredients. In a preferred embodiment, the dosage form is a single dosage form, such as a tablet or capsule with about 150 mg of each active substance. The combination, together with other pharmaceutically acceptable excipients, comprises a drug or nutraceutical composition that can be used to treat cognitive impairment, mild cognitive impairment, and Alzheimer's disease in those patient subsets with an MMSE score of about 22 to 26. Apigenin is commercially available and sold as a nutritional supplement in multiple doses.

[0163] Clinical assessments for determining the stage and overall progression of Alzheimer's disease and / or halting or improving disease progression use CDR, FCSRT, Neuropsychiatric Inventor Questionnaire (NPI-Q) and a battery of neurological tests, including the Rey Auditory Verbal Learning Test (RA VLT), immediate and delayed recall, the Wechsler Memory Scale (WMS) Verbal Paired Learning Test's immediate and delayed recall, the Delis-Kaplan Executive Function System Verbal Fluency Disorders 1 and 2, and the Wechsler Adult Intelligence Scale-4 Symbol Search and Encoding Subsets and the Cognitive Drug Research Battery. The Mini-Mental Exam Scale (MMSE) and the Neuropsychiatric Barth Test (NTB) and sub-items can also be used to test cognition. While these assessments are typically used for subjects suspected of having MCI or Alzheimer's disease, such tests can also be used in healthy subjects long before a physician diagnoses cognitive impairment. It is believed that in some dosage forms and at some doses, and relative to the individual active ingredients with sufficient safety and efficacy data, the combination of scyllo-inositol and calcifediol can be safely administered to subjects outside the prescribed range.

[0164] Examples

[0165] Example 1 - Phase 2 clinical trial of scyllo-inositol in patients with mild to moderate AD for 18 months.

[0166] 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 were enrolled. Patients aged 50 to 85 years with probable AD, a Mini-Mental State Examination (MMSE) score of 16 to 26, an MRI scan consistent with AD without other pathological findings, a Rosen modified Hachinski 17 score of 4, and no significant neurological, psychiatric, or medical illness. No medications with potential cognitive effects were permitted, except for a stable dose of an acetylcholinesterase inhibitor or memantine. Patients were randomly assigned to the placebo group and treated with 250 mg twice daily. Randomization was stratified by MMSE score (16 to 21 vs. 22 to 26), APOE 4 carrier status (1 or 2 alleles vs. none), and use of approved symptomatic AD medications (yes vs. no). Cognitive, functional, and MRI assessments were performed at baseline and at weeks 12 (no MRI), 24, 48, and 78. Safety assessments included adverse event (AE) monitoring, clinical laboratory tests, and electrocardiograms. Co-primary efficacy endpoints were changes 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 endpoints were the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), the Clinical Dementia Rating Scale-SB total score (CDR-SB), and the Neuropsychiatric Inventory (NPI) score. The 12-item ADAS Cog version was used. An 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 levels of scyllo-inositol and myo-inositol. Lumbar puncture was performed in another subset of patients to determine CSF Abeta-40, Abeta-42, total tau, phosphor-tau181 (p-tau), 30, and ELND005 concentrations at baseline, Week 24 (primary CSF biomarker endpoint), and Week 78. A repeated measures model was used to compare changes from baseline in all continuous efficacy and biomarker endpoints between the 250 mg group and the placebo group.

[0167] In a Phase 2 study examining a 250 mg BID dose for 18 months in patients with mild to moderate AD (MMSE 16 to 26), data ( Figure 1 、 Figure 1A, 1B, 1C, 1D, 1E and 1F) showed that scyllo-inositol did not improve the two primary endpoints (NTB and ADCS-ADL) measuring cognition and function in the overall population of patients with mild to moderate AD. Throughout the 18 months of treatment, no substantial differences were observed between the placebo group and scyllo-inositol-treated patients in the complete analysis data (FAS-all patients who received at least one dose) and the per-protocol analysis (PPS-all patients who completed the study) of the NTB, ADCS-ADL and CDR-SoB cognitive and functional tests. The NTB test in the per-protocol group (patients who completed the study) was numerically slightly improved, indicating that scyllo-inositol can improve cognition, enough to be detected in the overall mild and moderate AD population. The data observed with scyllo-inositol are consistent with previous trials with other amyloid-beta targeted therapies.

[0168] However, in the pre-specified subgroup of patients with mild AD with an MMSE score of 23 to 26, there were trends toward improvement across various cognitive and functional endpoints; NTB scores, CDR-SB scores, and ADCS-ADL scores were present in both the FAS and PPS patient populations, but these trends were not statistically significant. In the FAS and PPS populations treated with scyllo-inositol versus placebo, NTB scores improved by 72% and over 100%, respectively. Similarly, improvements of 31% to 44% in CDR-SB scores and ADCS-ADL scores were observed over 78 weeks in patients treated with scyllo-inositol versus placebo. These data suggest that scyllo-inositol has the potential to improve cognition and function in patients with mild AD with an MMSE score of 23 to 26. Treatment with scyllo-inositol for 18 months achieved or exceeded the target 30% improvement in all three cognitive and functional tests. While these data suggest that such patients may improve, they are not conclusive and only after examining unpublished data from the study did the inventors focus on the subpopulation of patients with an MMSE score of 22, which is even more severely affected than the milder patients with an MMSE score of 23 to 26. Therefore, these combined data suggest and provide evidence that patients with an MMSE score of 22 to 26 are effectively treated with scyllo-inositol at the BID dose provided in this pivotal study.

[0169] Table 4. Summary of clinical outcomes in mild AD (placebo and ELND005 250 mg BID)

[0170]

[0171] Figure 2The present study describes the change from baseline in the NTB score for mild AD patients with an MMSE score of 23 to 26 over 78 weeks in the placebo and scyllo-inositol treatment groups. The change from baseline in the NTB score was most pronounced after 12 and 18 months of treatment, indicating that scyllo-inositol has disease-modifying properties. Although scyllo-inositol treatment induced improvements in NTB scores during the first 6 months, suggesting a potential direct effect on AD symptoms, a smaller effect was also detected with placebo. The FAS and PPS populations; statistics and NTB scores, along with other clinical outcomes, are shown in Table 4. ELND005 is scyllo-inositol.

[0172] The change from baseline in the NTB subscores was examined for the mild AD patient population (MMSE 23 to 26) over the duration of the study (78 weeks). Figure 3 、 Figure 3 Data from A to 3J show that scyllo-inositol treatment improved eight of nine NTB sub-items over 78 weeks. These data suggest that scyllo-inositol has the potential to improve multiple cognitive-related symptoms, but this post hoc analysis was not powered to demonstrate efficacy in this group of patients or in a larger cohort of patients in the Phase 2 clinical trial.

[0173] Figure 4 and Figure 5 The changes of ADCS-ADL and CDR-SB scores from baseline in the mild AD patient population (MMSE 23 to 26) are shown respectively. Compared with placebo, scyllo-inositol improved both ADCS-ADL and CDR-SB scores. In addition, the placebo mild AD patient group in the study showed a decrease in CDR-SB score during the duration of the study, similar to the mild AD patients with MMSE 23 to 26 selected from the ADNI database. These data will show that the CDR-SB score decline rate of mild AD patients in the scyllo-inositol Phase 2 trial is similar to the larger mild AD population derived from the ADNI database. Table 5 shows the population; statistics and ACCS-ADLΔ; drug effect % and p value of mild AD (MMSE 23 to 26) in the FAS and PPS populations. Table 6 shows the population; statistics and CDR-SB changes from baseline (mild AD (MMSE 23 to 26)).

[0174] Table 5

[0175]

[0176] Table 6

[0177]

[0178] Figure 6 、 Figure 6A to 6F show the change from baseline in the CDR-SB sub-item scores of a mild AD patient population (PPS) treated with scyllo-inositol compared to placebo. Eight of the nine CDR-SB sub-item scores improved with scyllo-inositol treatment, indicating a broad positive effect on items representing both cognition and function.

[0179] Patients with mild AD have an MMSE score of 20 to 26, and patients with an MMSE score of 23 to 26 will be considered as very mild AD patients. The clinical data were further analyzed to determine a specific MMSE cutoff that demonstrated efficacy of treatment with scyllo-inositol for the overall mild AD patient population (MMSE 20 to 26).

[0180] The data in Table 7 below show that only patients with an MMSE score of 22 and above responded to scyllo-inositol treatment. This data has not been made public and is provided here for the first time. Therefore, the inventors have discovered a new subgroup of Alzheimer's patients that can be effectively treated with scyllo-inositol. Similar efficacy was observed in all three cognitive and functional endpoints (such as NTB, CDR-SB and ADCS-ADL). These data determine the selection of appropriate patient populations that will benefit from scyllo-inositol treatment and can be used to select patients for clinical studies. In short, scyllo-inositol is effective in mild AD patients with 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 its equivalent to distinguish between available drug therapy treatment or unresponsive to such therapy.

[0181] Table 7. Endpoint results for mild subgroups defined by various baseline MMSE cutoffs in AD201

[0182]

[0183] More than 70% of patients with MCI (MMSE 26 to 30) are thought to have beta-amyloid fibrils and plaques in the brain. This is consistent with data showing that accumulation of beta-amyloid in the brain occurs long before memory loss and AD-like symptoms appear. However, the progression of MCI pathology and symptoms that leads to the transition of an MCI patient to mild AD is variable and difficult to predict for an individual MCI patient. In general, a large proportion of patients with MCI progress slowly, making it difficult to enroll MCI patients in clinical studies to evaluate the efficacy of beta-amyloid targeted therapies. Furthermore, if a patient has not progressed sufficiently, then amyloid-targeted drugs are less useful in slowing progression.

[0184] Recently, the FDA approved an immunotherapy targeting beta-amyloid (aducanumab). It showed efficacy in only one of two phase 3 trials that enrolled patients with mild AD and MCI. The data suggested that aducanumab appeared to be effective, but the results were highly variable. In contrast, another immunotherapy (donezumab) demonstrated efficacy in a phase 2 study in patients with MCI and mild AD who were biomarker- and clinically selected. In this setting, the donezumab study was considered highly successful, suggesting that it may be necessary to select patients to test clinical efficacy in patients with MCI and mild AD.

[0185] Developing screening tests to select MCI patients with more rapid symptom progression is crucial for assessing cognitive and functional improvement in MCI patients over 12 to 18 months. Furthermore, it is believed that MCI patients with milder amyloid-β-related pathology will be a preferred patient population for amyloid-β-targeted therapies.

[0186] It is critical to develop criteria for selecting patients with mild cognitive impairment who have beta-amyloid in the brain and who are progressing at a detectable rate within a reasonable amount of time. PET scans are used to detect beta-amyloid in the brain. Other approaches include measuring the level of beta-amyloid in the CSF, such that patients with beta-amyloid levels below 192 pg / ml have a very high likelihood of having amyloid in the brain of AD patients. The MCI patient population is more complex, with patients having beta-amyloid levels less than the 192 pg / ml cutoff as well as those with greater than 192 pg / ml in the CSF. Because the amount of beta-amyloid in the brain may not indicate the severity or rate of memory and cognitive loss, selection criteria should include parameters at baseline to identify patients who are progressing more quickly and who may benefit from beta-amyloid therapy.

[0187] A comprehensive analysis of the ADNI database of all 507 MCI patients (MMSE=26 to 30) (as shown in Table 8 below) was evaluated to select different clinical cognitive and functional tests for screening MCI patients who will progress faster to mild AD. Data show that the patient population of cognitive and functional decline measured by MMSE, ADAS-Cog-11, CRD-SB and FAQ tests was selected by combining three different cognitive and functional tests using different cutoff values ​​(i.e., ADAS≥8 and FAQ≥2 or ADAS≥8 and CDR≥2 at baseline). The data were based on the baseline scores of the above parameters, comparing the key clinical endpoints of the overall MCI patient population that was not enriched in the time period of 12 months and 18 months with the enriched population. As shown below, compared with the overall MCI population, the selection / enrichment MCI patients with ADAS, FAQ and CDR specific cutoff values ​​showed a significant increase in the loss of cognitive and functional symptoms. Compared with 12 months, the disease progressed faster from baseline at 18 months. Because the delta between baseline and 12 or 18 months was larger and, secondarily, the standard deviation was similar or lower, the selected patient population was expected to respond better to scyllo-inositol in clinical trials. Furthermore, if the severity of baseline cognitive and functional parameters used to select MCI patients were increased, the MCI patient population would have a further increase in disease progression over time and would likely be more sensitive to scyllo-inositol or other amyloid-β-targeting drugs.

[0188] The selection criteria for MCI patients will also select patients who also have beta-amyloid in the brain, thereby enriching patients who are most likely to respond to beta-amyloid targeted drugs. Studies have also shown that selecting MCI patients with ADAS score = / >8+FAQ score = / >2 or CDR = / >2 at baseline will select a patient population of 58% that converts to mild AD, and 88.5% have beta-amyloid levels below 192 mg / ml in CSF (consistent with accumulation of beta-amyloid in the brain). As more stringent clinical criteria are applied to these parameters, the enrichment of patients with more rapid cognitive and functional decline increases. The patient population selected according to these key criteria at baseline is effective in selecting MCI patients with beta-amyloid in the brain, more rapid cognitive and functional decline, and conversion to mild AD.

[0189] Table 8. Enrichment of MCI patients with MMSE 26 to 30 by scyllo-inositol treatment

[0190]

[0191]

[0192] By analyzing the ADNI database, a second set of enrichment criteria was developed to select MCI patients with more rapid cognitive and functional loss. These patients were selected based on their combined ADAS and FAQ scores at baseline, as shown in Table 9. Selecting MCI patients with an ADAS score of >7 and FAQ score of >1, and a baseline combined score of 13 or greater, showed increased decline in CDR-SB, MMSE, ADAS-Cog11, and FAQ scores relative to the overall MCI patient population over 12 and 18 months. Similar increases in disease progression were observed with subsequent cognitive and functional tests over the same timeframe. By increasing the stringency of the combined test total score criterion to 14, or by raising the baseline ADAS score to 8 and the combined score to 14, the selection of patients with rapidly progressive MCI was enriched. Compared to the overall patient population over the 18-month period, this enriched group of MCI patients was more likely to have amyloid-β in their brains and to transition to a milder AD state. These criteria will provide a useful tool for selecting MCI patients for clinical studies evaluating amyloid-β-targeted drugs and for those who would benefit from scyllo-inositol treatment.

[0193] Table 9. Enrichment of MCI patients with MMSE scores of 26 to 30 by scyllo-inositol treatment

[0194]

[0195]

[0196] The same selection criteria based on baseline parameters can be applied to mild AD patients and MCI patients with MMSE scores of 23 to 30. Table 10 shows the same analysis performed above on all mild AD and MCI subjects with MMSE scores of 23 to 30 (N=753) who provided baseline data for MMSE, FAQ, ADAS-Cog (11) and CDR-SB. Of these, 664 and 316 subjects provided complete data for key cognitive and functional scores at 12 and 18 months, respectively. Similarly, this approach selected enriched populations that had a faster progression of cognitive and functional decline at 12 and 18 months compared to the overall population. These data support the hypothesis that selected patient populations will benefit from beta-amyloid-targeted drugs, such as scyllo-inositol.

[0197] Table 10: Enrichment of patients with mild Alzheimer's disease and MCI with MMSE 23 to 30 by treatment with scyllo-inositol

[0198]

[0199]

[0200]

[0201] A second approach was used to select and enrich mild AD and MCI patients with MMSE of 23 to 30 treated with scyllo-inositol, as shown in Table 11. Similar findings to those described above were obtained. These data show that based on key cognitive and functional endpoints (such as MMSE, ADAS-Cog 11, CDR-SB, and FAQ), patients enriched with baseline ADAS≥7 and FAQ≥1 and ADAS+FAQ≥13 showed a significant increase in disease progression within 12 and 18 months. By increasing the severity / severity of patients at baseline, we can enrich patients with a greater rate of progression.

[0202] Table 11. Enrichment of patients with mild Alzheimer's disease and MCI with MMSE 23 to 30 by scyllo-inositol treatment

[0203]

[0204]

[0205] Example 2 Clinical study of the treatment of selected mild AD subpopulation with MMSE 22 to 26 and MCI patient population with MMSE 26 to 30 with scyllo-inositol.

[0206] Mild AD patients with MMSE scores of 22 to 26 and MCI patients with the following baseline characteristics (MMSE 26 to 30); ADAS ≥ 8 and FAQ ≥ 2 or / and ADAS ≥ 8 and CDR ≥ 2 will be selected and combined to participate in the study. The selected patients will be divided into two groups; placebo and scyllo-inositol treatment. Patients will be treated with placebo or 250mg scyllo-inositol BID for a period of up to 18 months. Patients will be tracked for safety and efficacy. Key efficacy endpoints (NTB, ADAS-cog 11 and CDR-SB) will be measured at baseline and after 3, 6, 12 and 18 months of treatment with placebo or 250mg BID scyllo-inositol. Safety will be analyzed at similar time points.

[0207] Example 3 - Clinical study of the combination of scyllo-inositol and aducanumab

[0208] The clinical study was conducted in patients with mild cognitive impairment (MCI) and / or mild Alzheimer's disease. Enrolled patients with MCI and / or mild Alzheimer's disease were pretreated with scyllo-inositol for 2 weeks and then co-administered scyllo-inositol (250 mg BID) in combination with an anti-beta amyloid antibody therapy (aducanumab) for MCI and mild AD to alleviate concerns about ARIA associated with monoclonal therapy alone. This clinical study will measure the effectiveness of the drug combination in enhancing the reduction of beta amyloid load in the brain, thereby improving efficacy and safety relative to treatment with either drug alone. Patients with MCI and mild AD were assigned to 3 cohorts and treated as follows:

[0209] a. Cohort #1: Patients will be treated with 250 mg scyllo-inositol BID alone for two weeks, followed by 250 mg BID scyllo-inositol for an additional 52 weeks. Patients will be examined for amyloid burden, memory, cognitive and functional tests, and ARIA testing.

[0210] b. Cohort #2: Patients will be treated with 250 mg scyllo-inositol BID alone for two weeks, followed by a combination of 250 mg BID scyllo-inositol and escalating doses of aducanumab starting at 1 mg / kg (4 weeks), then 3 mg / kg (4 weeks), then 6 mg / kg (4 weeks), and then a final dose of 10 mg / kg for the remainder of the study (40 weeks). Patients will be evaluated for ARIA, beta-amyloid burden, memory, cognition and function, and safety parameters.

[0211] c. Cohort #3: Patients will be treated with escalating doses of aducanumab alone, starting from 1

[0212] The patients will be evaluated for ARIA, beta-amyloid burden, memory, cognition and function, and safety parameters starting at 1 mg / kg (4 weeks), 3 mg / kg (4 weeks), 6 mg / kg (4 weeks), and 10 mg / kg for the remainder of the study (40 weeks).

[0213] Results will demonstrate that treatment with a combination of scyllo-inositol and aducanumab over a 52-week period will result in:

[0214] ARIA was reduced compared with treatment with aducanumab alone at each treatment dose.

[0215] Beta-amyloid burden in the brain was reduced compared with treatment with aducanumab alone at each treatment dose.

[0216] Memory, cognition, and function improved compared with aducanumab treatment alone.

[0217] Improvement of beta-amyloid biomarkers in CSF, such as beta-amyloid 42 / 40 ratio, Tau, and phosphorylated Tau.

[0218] The specific clinical protocol followed the same protocol used in the ADUHELM clinical study for measuring each of plaque levels, ARIA effects, Tau protein in CSF, and exposure-response relationships.

[0219] Example 4 - Studies on the combination of scyllo-inositol and linolenic / linoleic acid.

[0220] The clinical study is carried out in patients with mild cognitive impairment (MCI) with an MMSE of 26 to 30 and / or mild Alzheimer's disease with an MMSE of 22 to 26. The patients with MCI and / or mild Alzheimer's disease enrolled were treated with placebo or scyllo-inositol (250 mg BID) and 250 mg BID in combination with linoleic acid and linolenic acid at a ratio of 4: 1 to determine the efficacy of scyllo-inositol and linolenic acid mixture combination therapy on memory, cognition and function. The clinical study will measure the effectiveness of scyllo-inositol and linolenic acid mixture combination therapy at a ratio of 4: 1 relative to placebo. The patient will be treated for 6, 12 and 18 months and memory and cognition will be assessed using standard tests (such as MMSE, NTB and ADAS-cog11 and the sub-items of these tests) that focus on different types of memory and cognition. MCI and mild AD patients will be assigned to 3 cohorts and treated as described below:

[0221] a. Cohort #1: Patients with MCI and / or mild Alzheimer's disease will be treated with placebo BID for up to 18 months. Patients will be examined for memory, cognitive and functional tests, as well as safety.

[0222] b. Cohort #2: Patients will be treated with 250 mg BID scyllo-inositol and 250 mg BID of a 4:1 ratio mixture of linoleic and linolenic acids for a period of up to 18 months. Patients will be evaluated for memory, cognition, and function, as well as safety parameters.

[0223] Clinical studies will demonstrate the efficacy of scyllo-inositol combined with a mixture of linoleic and linolenic acids on memory and cognition. The combination therapy will also demonstrate the short-term and long-term benefits of the fatty acid mixture, as well as the long-term effects of scyllo-inositol on disease progression due to the expected reduction in beta-amyloid protein load.

[0224] Example 5: Synergistic effect of scyllo-inositol and a mixture of linoleic acid and linolenic acid in an AD animal model.

[0225] Mice with Alzheimer's disease were divided into four groups, and the effects of scyllo-inositol alone or in combination with a mixture of linoleic and linolenic acids were analyzed compared to either the mixture alone or a placebo. The doses selected were designed to enhance synergy between the two therapies, potentially increasing their effects on pathology and cognition in the animal studies. The combination of scyllo-inositol and a mixture of linoleic and linolenic acids is expected to show improvements in memory and cognition.

[0226] Example 6. Clinical study of the combination of scyllo-inositol and calcifediol.

[0227] The study aims to evaluate the effect of scyllo-inositol combined with either vitamin D3 or calcifediol (ER and IR) to slow the progression of cognitive and functional loss in patients with mild AD and MCI over a 12- to 18-month period. Additionally, we will examine the more immediate effects of scyllo-inositol and vitamin D3 or calcifediol on cognition and function at 6 months, which may represent and assess the symptomatic effects of treatment.

[0228] Patient population:

[0229] Patients with mild AD with an MMSE score of 22 to 26 alone or in combination with patients with MCI with an MMSE score of 27 to 28, who are predicted to experience a more rapid decline in cognition and function based on specific inclusion criteria described below;

[0230] 1. Mild AD patients with MMSE scores of 22 to 26

[0231] 2. MCI patients with an MMSE score of 27 to 28 who meet the following criteria:

[0232] √ADAS ≥ 8, FAQ ≥ 2, CDR ≥ 2 or

[0233] √ADAS ≥ 7, FAQ ≥ 1, and the total score of ADAS and FAQ must be ≥ 13

[0234] 3. Methods for beta-amyloid-positive brain

[0235] 4. Stratification of patients based on mild AD, Apo e4 genotype, and MMSE score in patients with MCI

[0236] Treatment groups studied:

[0237] 1) Placebo (patients are treated twice daily with exactly the same conditions as the treatment but without active drug),

[0238] 2) scyllo-inositol (patients were treated with 150 to 250 mg scyllo-inositol once or twice daily (BID),

[0239] 3) scyllo-inositol (patients were treated with 250 mg scyllo-inositol once or twice daily plus 1000 units of vitamin D3 once or twice daily (BID) or 10 to 90 μg ml IR calcifediol once daily); and

[0240] 4) Scyllo-inositol (patients were treated with 250 mg of scyllo-inositol once or twice daily plus 30 to 90 μg of calcifediol ER once daily).

[0241] Number of patients in each group: 210 patients

[0242] 1) Placebo – 70

[0243] 2) Scyllo-Inositol – 70

[0244] 3) Scyllo-inositol and vitamin D3 or calcifediol – 70

[0245] Treatment Period: Patients will be treated for up to 18 months. A blinded, independent team will conduct an interim analysis at 6 months to assess safety and efficacy, and the trial design may be expanded to increase the number of patients in each group.

[0246] Primary and key endpoints for analysis:

[0247] NTB, ADAS-Cog 11, CDR-SB, and IADRS have been used as primary endpoints in phase 2 and 3 studies and have recently been accepted by the FDA as primary endpoints. Specific endpoints can be examined based on the patient population, as well as potential additional memory and cognitive endpoints.

[0248] Safety and further analysis:

[0249] Typical safety parameters required for mild AD and MCI indications will be examined similarly to those outlined in our previous Phase 2 trials. Additional testing may include biomarkers and beta-amyloid scans, pharmacokinetic data, and the like. Additional studies may be conducted using additional vitamins such as B12, with dosages that allow patients to achieve sufficiency and escape deficiency or deficiency. In a protocol such as the one directly above, vitamin B12 may be administered in a group at a dose of 2000 μg per day together with 250 mg BID of scyllo-inositol. The combination will treat cognitive impairment, memory loss, and mild Alzheimer's and MCI patients as described herein.

[0250] Example 7 - Simulated Clinical Study Results in Selected Patient Populations

[0251] Phase 2 data evaluating the change from baseline in NTB and CDR-SB scores in patients with mild AD treated with scyllo-inositol over an 18-month period were further analyzed using bootstrap simulations to determine the reproducibility of the data using a larger population of patients with mild AD. The observed data represent data obtained from 43 placebo-treated and 42 scyllo-inositol-treated patients in the mild AD study. The simulated data using bootstrap analysis represent 100 subjects per group, generated from each mild AD group, and were simulated 1000 times to generate the final data. Figure 7 A to 7D show the changes from baseline in NTB scores observed at weeks 12, 24, 48, and 78. Scyllo-inositol treatment showed improvements in NTB scores across all MMSE groups with an MMSE score of 20 to 26. However, the best effect of scyllo-inositol was observed in the patient population with an MMSE score of 22 to 26. Although not statistically significant, the p value of 0.08 for MMSE 22 to 26 showed a strong efficacy signal compared to the other patient groups with an MMSE score of 20 to 26 (p value of 0.23).

[0252] Figure 8 A to 8D show bootstrap simulation data of NTB scores in different mild AD patient groups with MMSE 20 to 26. The simulated data are similar to the observed data of NTB changes from baseline. However, the simulated data show that the NTB scores of AD patient groups with MMSE of 21 to 26, 22 to 26, and 23 to 26 treated with scyllo-inositol are statistically improved from baseline. When analyzed using bootstrap simulations, the improvement in cognitive efficacy measured by the NTB test gives people confidence that the benefits of scyllo-inositol treatment are reproducible and the statistical significance increases with the number of patients.

[0253] Phases 9A to 9D show the observed data showing the change from baseline in CDR-SB scores in different mild AD groups with MMSE of 20 to 26 at 12, 24, 48 and 78 months after scyllo-inositol treatment. Treatment with scyllo-inositol had no significant effect on the change in CDR-SB scores in mild AD patients with MMSE of 20 to 26. The improvement in the scyllo-inositol group increased in the mild AD patient groups with MMSE of 21 to 26, 22 to 26 and 23 to 26. The mild AD group that showed the best effect of scyllo-inositol had an MMSE of 22 to 26. Simulated data based on the CDR-SB scores of the same patient population with MMSE scores ( Figure 10A to 10D). However, as measured by the CDR-SB test, cognitive and functional efficacy was statistically significant and more pronounced in the patient groups with MMSE 22 to 26 (p value 0.0034) and 23 to 26 (p value .0027). Further, the increase in reproducibility and statistical significance observed in the simulated data strengthens the confidence in the efficacy data of the mild AD patient population with scyllo-inositol treated at a dose of 250 mgs / day BID with MMSE of 22 to 26. In addition, depending on the severity of the subject's illness and progression, these doses can be adjusted downward to about 125 mg / day BID or once a day at 250 mg or 500 mg / day.

[0254] Figure 11 A to 11D summarize and compare the observed and simulated changes in NTB and CDR-SB scores from baseline in patients with mild AD with MMSE 22 to 26 after 78 weeks of scyllo-inositol treatment. The simulated data showed that scyllo-inositol treatment for 78 weeks statistically improved cognition and function, as measured by both NTB and CDR-SB tests, with p values ​​of 0.009 and 0.034, respectively. The overall data indicate that scyllo-inositol does not improve cognition and function in the overall mild AD population with MMSE 20 to 26, but when the simulation represents a sample of 100 patients, it does show strong and significant improvements in the group of mild AD patients with MMSE scores of 22 to 26. This is particularly surprising and unexpected considering previous data from analyses of subgroups of patients with MMSE scores of 23 to 26, who generally have milder disease than subgroups of patients with MMSE scores in the 22 to 26 range.

[0255] Preclinical and clinical studies related to scyllo-inositol have been published and demonstrate its safety and activity. See Clinicaltrials.gov and the patent publications cited herein, all of which are incorporated by reference. In addition, unpublished analyses have been conducted and have yielded findings regarding the use of scyllo-inositol in a subgroup of patients with mild AD and / or MCI who have MMSE scores between 22 and 26.

[0256] all in all, Figure 1 A to 1F show the effect of 250 mg scyllo-inositol treatment BID on the primary endpoints NTB, ADCS-ADL and CDR-SB in mild / moderate AD patients (MMSE 16 to 30). The data demonstrate that 78 weeks of treatment with scyllo-inositol in mild and moderate AD patients did not improve NTB, ADCS-ADL and CDR-SB scores as a measure of cognition and function. Although a small signal was observed in the NTB score of the per-protocol population.

[0257] Figure 2The results show that scyllo-inositol has an effect on the treatment of early mild AD patients (MMSE 23 to 26) in a pre-specified complete and in accordance with the protocol population for 78 weeks. After scyllo-inositol treatment, analysis of the entire population showed that the NTB score increased by 72% relative to the placebo population. Similarly, data from the in accordance with the protocol population showed that the NTB score increased by 100% relative to the placebo. These data show a strong signal that scyllo-inositol treatment improves cognition in patients with early mild AD.

[0258] Figure 3 A to 3I show the change from baseline in the NTB sub-item scores of the mild AD patient population (MMSE 23 to 26) treated with scyllo-inositol and placebo over the duration of the study (78 weeks). The data demonstrate that 8 of the 9 NTB sub-items improved with scyllo-inositol treatment over 78 weeks. These data demonstrate that scyllo-inositol improves multiple cognition-related symptoms.

[0259] Figure 4 The ADCS-ADL changes from baseline for 78 weeks of scyllo-inositol and placebo treatment of early mild AD patients (MMSE 23 to 26) are shown. The data show that scyllo-inositol treatment improved ADCS-ADL scores throughout the 78-week study period compared to placebo. Scyllo-inositol treatment resulted in 35% and 31% improvement in ADCS-ADL scores in the full analysis and protocol-compliant populations, respectively. These data suggest that scyllo-inositol improves the function of patients with early mild AD.

[0260] Figure 5 :Shows the change from baseline in the CDR-SB of patients with early mild AD (MMSE 23 to 26) treated with scyllo-inositol and placebo for 78 weeks. The data show that compared with placebo, scyllo-inositol treatment improved the CDR-SB score over the duration of the 78-week study. For the full analysis and per-protocol populations, scyllo-inositol treatment increased the CDR-SB score by 40% and 44% relative to placebo, respectively. These data demonstrate that scyllo-inositol improves cognition and function, as measured by the CDR-SB test.

[0261] Figure 6 A to 6F: The effects of scyllo-inositol and placebo treatment on the changes from baseline in the CDR-SB subitems in patients with early mild AD in the per-protocol population (PPS) were compared. These data showed that scyllo-inositol improved 5 of the 6 subitems in the CDR-SB test that measure both cognition and function.

[0262] Figure 7A to 7D show the observed changes from baseline in NTB scores in mild AD patients treated with scyllo-inositol with varying MMSE scores ranging from 20 to 26. The data show that scyllo-inositol is more effective in improving NTB scores in the patient population whose MMSE scores increase to 23. Ideally, the drug would be more effective in patients with MMSE scores of 22 or higher.

[0263] Figure 8 Figures A to 8D show bootstrapped simulation data for the change from baseline in NTB scores in different groups of mild AD patients with MMSE scores ranging from 20 to 26 treated with scyllo-inositol. Analysis of the data using the Bootstrapp simulation method, by increasing N = 30 to N = 100, revealed a pattern similar to the observed data. These data show that the change in NTB was more pronounced in the scyllo-inositol-treated group when bootstrapped, further suggesting that the analysis would be strengthened by increasing the number of patients.

[0264] Figure 9 A to 9D show observed data demonstrating changes from baseline in CDR-SB scores with scyllo-inositol treatment in different mild AD groups with MMSE scores ranging from 20 to 26. Similarly, scyllo-inositol treatment was more effective in early mild AD patients with an MMSE of 22 or higher.

[0265] Figure 10 A to 10D show bootstrapped simulation data demonstrating the change from baseline in CDR-SB scores for different mild AD groups treated with scyllo-inositol, with MMSE scores ranging from 20 to 26. When bootstrapped simulation analysis was performed, the data showed a similar pattern of treatment effect of scyllo-inositol on the CDR-SB test. In the simulation analysis, when N was increased from 30 to 100 patients, the change in CDR-SB scores was more pronounced in the scyllo-inositol-treated group compared to placebo.

[0266] Figure 11 A to 11D show the comparison of observed data and simulated data on changes in NTB and CDR-SB scores in mild AD patients with MMSE scores of 22 to 26 treated with scyllo-inositol. Figure 1 A shows AD201 observed value (NTB). Figure 1 B shows simulated bootstrapping (NTB). Figure 1 C shows AD201 observations (CDR-SB). Figure 1 D shows the simulated bootstrap (CDR-SB). The bootstrap simulation used N = 100, while the observation set used N = 30. In the simulated comparison of the two endpoints, NTB and CDR-SB, the treatment group achieved statistical significance relative to the placebo group. These data demonstrate that scyllo-inositol shows a strong efficacy signal in improving cognition and function in patients with early mild AD with an MMSE of 22 or higher.

[0267] Thus, the data support the use of a single agent to treat patient populations of subjects with such MMSE scores or their equivalents, and further support the combination of scyllo-inositol in a dose range of about 125 mg to about 500 mg once daily, or BID, with other vitamins and / or active ingredient combinations that can be used to treat cognitive impairment and / or to increase vitamin levels to levels that treat such vitamin deficiencies or insufficiencies. In particular, vitamin D (including prohormones of vitamin D such as calcifediol or B vitamins such as vitamin B12) in combination with scyllo-inositol is particularly suitable for treating subjects with early-stage Alzheimer's disease or MCI or with Aβ fibrils together with any evidence of such 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. The combination according to claim 1, wherein the first compound is selected from scyllo-inositol or other active 1,2,3,4,5,6-cyclohexanehexasols, 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 a small molecule.

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

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

5. The combination according to claim 4, wherein the dosage of scyllo-inositol for treating a neurological disorder or condition is about 150 to 250 mg once or twice a day (BID), and the total dosage of calcifediol is about 10 to 90 μg per day, and the dosage of vitamin B12 ranges from about 20 to 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 vitamin compounds and / or active pharmaceutical ingredients.

7. The dosage form according to claim 6, wherein the first compound is selected from scyllo-inositol or other active 1,2,3,4,5,6-cyclohexanehexasol, 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 or nicotinamide riboside, and the active pharmaceutical ingredient is selected from a monoclonal antibody or a small molecule.

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

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

10. The dosage form of claim 9, wherein the dosage of scyllo-inositol for treating a nervous system disorder or condition is about 150 to 250 mg once or twice daily (BID) and the dosage of calcifediol is about 10 to 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. The dosage form according to claim 11, which is in the form of a tablet comprising an immediate release formulation of scyllo-inositol and an immediate release formulation of calcifediol.

13. The dosage form according to claim 11, which is in the form of a tablet comprising an immediate release formulation of scyllo-inositol and a delayed release formulation of calcifediol.

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

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

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

17. A method of treating a subject suffering from cognitive impairment, memory loss, and vitamin D deficiency or insufficiency, the method 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. The method of claim 17, wherein the effective amount of scyllo-inositol is about 150 to 250 mg BID, and the effective amount of vitamin D is about 400 to 5000 IU per day, and the effective amount of 25-hydroxyvitamin D is about 10 to 90 μg / day, and the effective amount of a vitamin B compound is about 20 to about 500 μg / day, and the effective amount of nicotinamide riboside is about 300 mg / day.

19. A method of treating a subject susceptible to a neurological disease or disorder, the method 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. A method of treating a patient suffering from Alzheimer's disease, the method comprising administering a pharmaceutically effective amount of scyllo-inositol in combination with aducanumab.

21. The method of claim 20, wherein side effects of aducanumab are reduced.

22. A method for treating a subject having at least one APOEε4 allele, the method comprising administering 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 vitamin compounds and optionally (iii) an additional active pharmaceutical ingredient for treating such a subject having said allele.

23. Use of scyllo-inositol at a dose of 125 mg to 250 mg once daily or twice daily in combination with a vitamin combination selected from the group consisting of vitamin D, calcifediol or vitamin B12 for treating 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. A combination according to claim 24, wherein each active ingredient is in a separate dosage form.

26. The combination according to claim 24, wherein the combination is in a single dosage form.

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

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

29. The combination according to claim 28, wherein the dosage of scyllo-inositol is about 150 mg; the dosage of vitamin B12 is about 500 mcg, the dosage of B9 is about 500 mcg, the dosage of B6 is about 3 mg, and the dosage of vitamin D3 is about 1,000 to 3000 IU, and the dosage of calcifediol is about 10 to 50 mcg.

30. A combination comprising scyllo-inositol and apigenin.

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

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