Combination of SCYLLO-inositol and Flavone

Abstract

The present invention relates to the use of scyllo-inositol alone or in combination with other active ingredients, including the flavone apigenin, to support cognitive health in subjects taking the product or combination product. The present invention relates to compositions comprising scyllo-inositol alone or in combination with other agents, including, but not limited to, flavones or other substances that prevent the upregulation or downregulation of aquaporin 4 channels. The compositions, including oral dosage forms such as tablets or capsules, are provided to subjects, including humans or other mammals such as dogs or cats, or other animals, in need of cognitive improvement. The combination product(s) degrade amyloid-β aggregates and promote the clearance of amyloid-β fibrils from the glymphatic system.

Description

[Technical Field]

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

[0002] Alzheimer's disease (AD) is a neurodegenerative disorder that progresses over time, causing cognitive impairment and a variety of symptoms or disabilities that affect the daily lives of those affected. The number of people affected by this disease at various stages is enormous, estimated to increase to more than 115 million worldwide by 2050. Despite years of effort and billions of dollars invested in drug development research, no effective treatment has yet been found to address the progression and / or treatment of AD. Prior to the recent approval of monoclonal antibody therapy, only three small-molecule drugs were approved in the United States for the treatment of this disease. These include donepezil, rivastigmine, and galantamine, but none are effective in halting disease progression. In an aging society, the prevalence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) increases. The gradual memory decline associated with MCI is followed by further memory decline and increasing functional loss. In the later stages of MCI, patients begin to develop dementia and mild AD. These patients may progress to moderate to severe AD. Amyloid-β accumulation in the brain occurs early, before symptoms appear. As the amyloid burden in the brain continues to increase, early and late MCI develop, progressing in severity until the patient is diagnosed with AD. It is well documented that the onset of clinical symptoms, such as memory loss, begins in early and late MCI, followed by a more rapid decline in memory and function as patients progress to mild, moderate, and finally severe AD. Patients in the later stages of moderate and severe AD exhibit functional decline requiring caregiver assistance and may even die. While the exact mechanisms underlying AD pathology are not fully understood, it is well documented that plaque formation due to the accumulation of amyloid-β fibrils is a hallmark of AD. Furthermore, the accumulation of amyloid-β fibrils in the brain begins approximately 10–15 years before the onset of dementia and its associated clinical symptoms. The accumulation of amyloid-β fibrils and plaques increases with age, and 30-40% of people over the age of 55 and over 70% of patients with MCI have amyloid-β accumulation in the brain. The presence of amyloid-β fibrils and plaques leads to increased neurotoxicity and the appearance of inflammation in the brain.These cumulative pathologies are associated with the emergence of more aggressive disease and loss of memory and function in AD patients.

[0003] The aging population is rapidly increasing worldwide, resulting in an increasing number of individuals predisposed to or diagnosed with neurological disorders, such as mild cognitive impairment (MCI) and Alzheimer's disease (AD). The development of these neurodegenerative conditions is characterized by a clinical progression from memory loss to more severe cognitive and functional loss. The presence of amyloid-β aggregates and plaques, as well as secondary pathologies such as inflammation and neuronal death, are hallmarks of AD.

[0004] Increased amyloid-β accumulation in the aging brain is thought to be due to the accumulation and formation of amyloid-β oligomers and fibrils, which are trapped within the brain and are not readily released into the CSF or digested by cells or enzymes. Once the amyloid-β precursor protein is synthesized and appears on the neuronal surface, it is cleaved by α- and β-secretases to generate free amyloid-β peptides. Aging, cerebrovascular disease, previous traumatic brain injury, and sleep disorders are established or emerging risk factors for the development of neurodegenerative diseases, including Alzheimer's disease. Glymphatic function is impaired in each animal model. Given the role of perivascular glymphatic exchange in the clearance of amyloid-β and tau, it is now proposed that impaired glymphatic pathway function is important in the development of these diseases. Imaging of glymphatic function using dynamic contrast-enhanced MRI (DCE-MRI) has only recently begun, but early studies have demonstrated that glymphatic function in humans is impaired in the presence of normal pressure hydrocephalus and small vessel disease.

[0005] Although the role of glymphatic dysfunction in the pathogenesis of other neurodegenerative diseases has not yet been directly evaluated, emerging data from human population studies suggest a role for aquaporin 4 ("AQP4") in these diseases. In a postmortem case series, decreased perivascular AQP4 loading was observed in the frontal cortex of subjects diagnosed with Alzheimer's disease, whereas preserved perivascular AQP4 loading was observed in cognitively normal subjects over the age of 85. Decreased perivascular AQP4 loading was further associated with increased amyloid-β and tau pathology, as well as general indicators of cognitive decline. Three recent genetic studies conducted in different human populations showed that single nucleotide polymorphisms in the human AQP4 gene were associated with variations in cognitive decline, amyloid burden, and clinical status, as well as an association between sleep disturbance and amyloid burden. Recent human transcriptome studies have further demonstrated that, in addition to AQP4 expression, differential expression of genes that determine perivascular AQP4 localization (specifically, genes encoding elements of DAC, SNTA1, DTNA, DMD, and DAG1) is associated with dementia status and temporal cortical tau pathology. These findings suggest that alterations in AQP4 expression and localization may contribute to the onset and progression of neurodegenerative diseases, including Alzheimer's disease, in human populations. Understanding the novel role of dynamic AQP4 subcellular relocalization provides a new framework for understanding waste clearance in the healthy brain and paves the way for novel therapeutic approaches to slow the progression of neurodegenerative diseases.

[0006] Over the past two decades, numerous therapies targeting amyloid-β fibrils and plaques have shown promise in animal models of AD and advanced to human clinical trials. These initial treatments involved antibodies reactive with amyloid-β fibrils and plaques, reducing amyloid-β accumulation in the brains of AD animal models. Elan and Wyeth developed the humanized antibody bapineuzamab, which showed promising results in a phase 2 study and advanced to a phase 3 clinical trial in patients with mild and moderate AD. Unfortunately, this study did not demonstrate efficacy in patients with mild to moderate AD, although similar results have been observed with antibody therapies from Lilly and others. The general consensus was that treating moderate AD disease with amyloid-targeted therapies occurs too late in the disease progression to prevent neurotoxicity and dementia progression. Some of the evidence that amyloid-β-targeted therapies may be more effective in subpopulations of AD patients comes from clinical studies showing modest benefits in APOE 4-positive patients with mild AD, but these benefits were masked by the rapid decline in cognition and function observed in the moderate AD patient population.

[0007] Additionally, orally available small molecules such as scyllo-inositol and tramiprosate have shown promising data in disassembling amyloid-β fibrils in vitro and reducing plaques in animal models of AD. Neurochem Pharma has initiated an 18-month Phase 3 clinical trial in patients with mild to moderate AD. The study did not demonstrate improvements in cognition and function in patients with AD. The data were inconclusive, with significant interpatient variability, and cognitive symptoms in milder patients did not appear to have progressed sufficiently over the 18-month treatment period to allow for measurable efficacy. Two problems appear to have arisen in these trials: Aβ-targeted drugs do not appear to affect AD cognition or function in patients with moderate AD, indicating that the disease process is too advanced for Aβ-targeted therapy to alter its progression; and second, the cognitive and functional decline in patients with mild AD is too gradual over the 18-month treatment period to assess efficacy in patients with mild AD overall, more specifically, reduction in decline in endpoints measuring cognition and function such as the ADASCog, NTB, CDR-SoB, and ADCS-ADL.

[0008] Similarly, scyllo-inositol, an oral agent that disrupts and prevents the formation of amyloid-β fibrils, has been effective in treating AD animal models. Administration of scyllo-inositol at doses of 3.3 mg / kg or higher to AD animal models reduced the incidence and size of amyloid plaques and improved memory and cognitive tests across a variety of animal models. In a large-scale phase 2 trial, scyllo-inositol failed to demonstrate efficacy in patients with mild and moderate AD on several endpoints, including NTB, CDR-SoB, ADCS-ADL, and ADAS-Cog. These data across the entire study treated population suggest that scyllo-inositol may not be effective in treating Alzheimer's disease across the entire mild and moderate AD population. Furthermore, data examining patients with mild AD (MMSE scores of 20–26) or moderate AD (MMSE scores of 16–20) also indicated that the drug was ineffective in both AD patient populations under the specific study conditions of treating Alzheimer's disease. These data suggested that the drug is generally ineffective in treating patients with mild and moderate AD, or that efficacy observed in subpopulations of AD patients is masked by data from the overall population. Based on clinical evidence that amyloid-β-targeting drugs may be ineffective in patients with advanced AD, the efficacy of scyllo-inositol was evaluated in patients with mild AD who differed in disease severity based on MMSE scores of 20–26. The data showed that the effects of scyllo-inositol on cognition and function were more pronounced in patients with mild AD (MMSE scores of 22–26). Inclusion of patients with mild AD (MMSE scores of 20 and 21) was sufficient to mask the efficacy observed in patients with mild AD (MMSE scores of 22–26).

[0009] These clinical findings emphasize the importance of selecting appropriate MCI and AD patient populations for amyloid-β-targeted therapy to observe efficacy. In one embodiment, the present invention involves treating mild AD patients with MMSE scores of 22-26 with a pharmaceutically effective dose of scyllo-inositol. New data evaluated in this patient subset also suggest that scyllo-inositol may be effective in delaying or attenuating any further cognitive or memory loss in subjects with mild cognitive impairment and / or memory loss, prior to or well before the actual onset of disease. These data suggest that the use of safe doses of scyllo-inositol, alone or in combination with appropriate dietary supplements or functional foods, such as apigenin, may be particularly beneficial for young, healthy populations prone to developing more severe cognitive or memory impairment later in life.

[0010] Therefore, there is a need for effective nutritional or dietary supplement ingredients, including scyllo-inositol alone or a combination product containing scyllo-inositol and a nutritional or functional ingredient, that are useful for improving memory or cognitive function in populations prone to memory loss or mild cognitive impairment. In a preferred embodiment, the combination is a composition containing a first component selected from scyllo-inositol and a second component containing a flavone such as apigenin. There is also a need for combination products containing scyllo-inositol and another active ingredient selected from pharmaceuticals, dietary supplements, or dietary supplements that can be provided to subjects who may be predisposed to early amyloid-beta accumulation in the brain and ultimately progress to MCI, Alzheimer's disease, or other cognitive disorders. The need for this intervention may occur in the early stages of MCI and Alzheimer's disease, long before evidence of neurological symptoms is detected.

[0011] The newly identified subpopulation of patients with MMSE scores of 22-26 suggests that scyllo-inositol may have a rapid effect on improving memory and cognition, with effects detectable within 6 months of treatment initiation.

[0012] It has been speculated that glycolipids such as gangliosides may stabilize and prevent Ab fibrillogenesis, while phosphatidylinositol may promote fibrillogenesis. Scyllo-inositol (ELND005) has been shown to be useful for treating or preventing diseases of the central or peripheral nervous system, including Alzheimer's disease. See U.S. Patent No. 7,521,481, which is incorporated herein by reference. Completed studies on Alzheimer's disease include a study titled "Long-Term Follow-Up of ELND005 and Alzheimer's Disease in Patients with Mild to Moderate Alzheimer's Disease."

[0013] Thus, the inventors have discovered a subpopulation of patients within the broader class of Alzheimer's disease or MCI patients who are effectively treated with pharmaceutically effective amounts of scyllo-inositol, alone or in combination with other active ingredients, who are believed to be in the early stages of fibrillogenesis and comparable or similar to healthy subjects with signs of memory loss, dementia, or mild cognitive impairment.

[0014] The use of scyllo-inositol and other active 1,2,3,4,5,6-cyclohexyl inositols, such as cis-, epi-, allo-, muco-, neo-, D-chiro-, and L-chiro-inositols, in combination with apigenin, is also useful for treating elderly patients (optionally with an MMSE score of 22-26) with memory loss due to increased amyloid-β accumulation in the brain, as well as patients with mild to moderate Alzheimer's disease (MCI) (with an MMSE score of 27-28). This drug combination reduces amyloid accumulation in the brain and also alleviates amyloid-related inhibition of neuronal function. In a preferred embodiment, the combination is a fixed-dose combination in the same dosage form, such as a tablet or capsule. It is believed that such a combination slows the progression of cognitive and functional loss in subgroups of patients with the above MMSE scores, and improves memory and cognition or delays memory or cognitive loss in healthy populations prone to amyloid-β accumulation.

[0015] Combination therapy also provides more immediate relief from cognitive and memory loss and other related symptoms. This combination may also include a combination selected from scyllo-inositol (minimum 70-500 mg) and apigenin (minimum 60-150 mg). These amounts may vary depending on the specific subject. The combination may be in separate doses, a single dosage form, or a combination of dosage forms with additional ingredients such as vitamins.

[0016] The present invention also encompasses any other aquaporin 4 (AQP4X) upregulators, including small molecules or nucleotides such as oligonucleotides that upregulate AQP4X expression and promote amyloid-β clearance through this astrocytic water channel. Compounds that increase aquaporin 4 gene readthrough include apigenin, a flavone found in chamomile, and sulfaquinoxaline (animals only), an antibiotic. Apigenin can also be combined with scyllo-inositol to treat MCI and Alzheimer's disease patients, particularly those with an MMSE score of 22. Other suitable combination components may include compounds that reduce levels of soluble ST2 (sST2) in the brain, a protein known to adversely affect amyloid clearance from the brain.

[0017] The pharmaceutical combination may also be useful as a supplement or dietary supplement, depending on the dosage of the separate combination of scyllo-inositol and another active ingredient, such as apigenin. Summary of the Invention

[0018] In one embodiment, the present invention includes a composition comprising 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 aquaporin 4 (AQP4X) upregulator and fibrous astrocytosis relocalization to the podocyte. In one embodiment, the composition is useful for treating a neurological disorder or cognitive impairment or memory loss in a subject in need of such treatment.

[0019] In a preferred embodiment, the first compound is selected from scyllo-inositol, and the second compound is selected from flavones such as apigenin or any agent that upregulates the expression of aquaporin channels. The first and second compounds can be administered separately or provided in separate dosage forms for simultaneous administration. The first and second compounds can also be packaged as separate dosage forms in the form of a kit provided to patients for daily administration of the first and second compounds in appropriate dosage forms such as capsules, tablets, or ampoules. Alternatively, the combination can be in the form of a single dosage form containing (i) a first compound selected from inositol and (ii) a second compound selected from aquaporin 4 upregulators and relocalization. In such a single dosage form, the first compound is selected from scyllo-inositol, and the second compound is selected from apigenin. In a further preferred embodiment, the dosage form may be in the form of a capsule, tablet, or ampoule and may comprise scyllo-inositol as the first compound and apigenin as the second compound.

[0020] In jurisdictions that do not permit medical use claims or method of treatment claims, such embodiments include pharmaceutical compositions or combinations of such scyllo-inositol and aquaporin 4 upregulator / relocalizer as a combination or single-unit formulation for use in treating such subpopulations of Alzheimer's disease or MCI patients, or to provide a combined dietary supplement or novel food substance useful as a supplement in healthy subjects. Such combinations or compositions are themselves novel and inventive. In any of the above uses, or as further described herein, the dosage of scyllo-inositol also includes 70-250 mg once daily, or 35-125 mg BID.

[0021] In one embodiment, the present invention includes a method for reducing amyloid-beta levels and plaque formation in the brain of a healthy subject, comprising administering an effective amount of apigenin in combination with an effective amount of scyllo-inositol.

[0022] In a further embodiment, the present invention includes a method of treating an Alzheimer's disease patient with confirmed amyloid pathology and mild cognitive impairment or mild dementia consistent with stage 3 or 4 Alzheimer's disease, comprising administering about 50-250 mg of apigenin and administering an effective amount of scyllo-inositol.

[0023] In one embodiment, the present invention includes a method for improving memory, cognition, and / or brain function in a subject, comprising co-administering a nutraceutical effective amount of scyllo-inositol and a nutraceutical effective amount of apigenin, where such co-administration results in improved memory, cognition, and / or brain function compared to patients treated with scyllo-inositol or apigenin alone. In such embodiments, co-administration may include administration of a composition comprising a fixed-dose combination of scyllo-inositol and apigenin in a single dosage form, such as a tablet or capsule. In one embodiment, a combination composition comprising scyllo-inositol and apigenin in an appropriate dosage form is provided to subjects aged 50 or older who are at risk for amyloid-beta accumulation. Such subjects may exhibit early signs of memory loss, and early intervention in the form of a supplement would be beneficial.

[0024] The present invention includes the following. 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 molecule that upregulates aquaporin 4. 2. The combination of claim 1, wherein the first compound is selected from scyllo-inositol or other active 1,2,3,4,5,6-cyclohexanehexols and the second compound is selected from the group consisting of molecules flavones. 3. The combination of claim 2, wherein the first compound is selected from scyllo-inositol and the second compound is selected from apigenin. 4. A composition comprising a flavone and scyllo-inositol. 5. The composition of claim 4, wherein the composition is a dietary supplement composition comprising apigenin and scyllo-inositol. 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 flavones. 7. The dosage form of claim 6, wherein the first compound is selected from scyllo-inositol or other active 1,2,3,4,5,6-cyclohexanehexol and the second compound is selected from apigenin. 8. The dosage form of claim 7, wherein the first compound is selected from scyllo-inositol. 9. The dosage form of claim 8, which is a solid oral dosage form. 10. The dosage form of claim 9, wherein the scyllo-inositol dosage is about 75-150 mg once or twice daily (BID) and the apigenin dosage is about 60-150 mg per day. 11. The dosage form according to claims 6 to 10, wherein the dosage form is in the form of a capsule or tablet. 12. The dosage form of claim 11 in the form of a tablet comprising the immediate release formulation of scyllo-inositol and the immediate release formulation of apigenin. 13. The dosage form of claim 11 in the form of a tablet comprising an immediate release formulation of scyllo-inositol and a sustained release formulation of apigenin. 14. A method comprising treating a subject having an MMSE score in the range of 22-26 with a pharmaceutically effective amount of scyllo-inositol. 15. The method of claim 14, wherein the subject has 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 per day. 17. A method for treating a subject having cognitive impairment, memory loss, comprising administering an effective amount of scyllo-inositol in combination with a flavone. 18. The method of claim 17, wherein the flavone is selected from apigenin. 19. A method of providing a nutritional supplement to a subject susceptible to a neurological disease or condition, comprising obtaining 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 flavones, and providing said combination to said subject in need of treatment thereof. 20. A method for improving memory loss, comprising administering an oral dosage form comprising scyllo-inositol, apigenin, and a nutraceutically acceptable excipient. 21. The method of claim 20, wherein the oral dosage form is in the form of a tablet, which comprises a nutraceutical acceptable excipient selected from at least one of a binder, a filler, and a disintegrant. 22. A scored tablet comprising a combination of scyllo-inositol and apigenin, and a nutraceutically acceptable excipient. 23. Use of a combination of scyllo-inositol in a dosage of 75 mg to 250 mg once daily or twice daily and a flavone in the manufacture of a dietary supplement for consumption by a subject. 24. A combination comprising a first compound selected from scyllo-inositol and a second compound selected from the group consisting of flavones or other small molecules, or oligonucleotides that modulate the expression of aquaporin 4 channels. 25. The combination of claim 24, wherein each compound is in a separate dosage form. 26. The combination of claim 24, wherein the combination is in a single dosage form. 27. The combination of claim 24 or 25, wherein the scyllo-inositol is administered in an amount of 70 to 125 mg and the apigenin is administered in an amount of 70 to 125 mg. 28. The combination of claim 27, further comprising a vitamin or additional supplement that supports cognitive health. 29. A combination comprising scyllo-inositol and apigenin. 30. The combination of claim 30, in a single oral dosage form having about 150 mg of said scyllo-inositol and about 150 mg of apigenin and pharmaceutically acceptable excipients. 31. A method for supporting cognitive health, comprising administering a nutraceutical effective amount of a composition comprising scyllo-inositol and apigenin. [Brief explanation of the drawings]

[0025] [Figure 1] A–F show the effect of 250 mg BID scyllo-inositol treatment in patients with mild / moderate AD (MMSE 16–30) on primary endpoints (NTB, ADCS-ADL, and CDR-SB). [Figure 2] We demonstrate the effect of 78 weeks of scyllo-inositol treatment in early mildly affected patients (MMSE 23-26) in a pre-specified overall population and a protocol-compliant population. [Figure 3] A-I show the change in NTB sub-items from baseline to mild AD (PPS) across nine different sub-items. [Figure 4] Figure 1 shows the change in ADCS-ADL from baseline in patients with early to mild AD (MMSE 23-26) treated with scyllo-inositol and placebo for 78 weeks. [Figure 5] Figure 1 shows the change in CDR-SB from baseline in patients with early to mild AD (MMSE 23-26) treated with scyllo-inositol and placebo for 78 weeks. [Figure 6] A–F show a comparison of the effects of scyllo-inositol and placebo treatment on the change from baseline in the CDR-SB subscale in patients with early mild AD from the Per-Protocol Population (PPS). [Figure 7] A–D show the observed change from baseline in NTB scores with scyllo-inositol treatment for patients with different mild AD with MMSE score ranges of 20–26, 21–26, 22–26, and 23–26, respectively. [Figure 8] Panels A–D show bootstrap simulation data for the change from baseline in NTB scores with scyllo-inositol treatment in different groups of patients with mild AD, with MMSE scores of 20–26, 21–26, 22–26, and 23–26, respectively. [Figure 9] Panels A to D show observational data showing the change from baseline in CDR-SB scores with scyllo-inositol treatment in different mild AD groups with MMSE scores of 20–26, 21–26, 22–26, and 23–26, respectively. [Figure 10] Panels A–D show bootstrap simulation data showing the change from baseline in CDR-SB scores with scyllo-inositol treatment in different mild AD groups with MMSE score ranges of 20–26, 21–26, 22–26, and 23–26, respectively. [Figure 11] A–D show a comparison of observed and bootstrap simulation data for the change from baseline in NTB and CDR-SB scores in patients with mild AD with MMSE scores of 22–26 treated with scyllo-inositol. DETAILED DESCRIPTION OF THE INVENTION

[0026] In an aging society, the prevalence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) increases. The gradual memory decline associated with MCI is followed by further memory decline and increasing functional loss. In the later stages of MCI, patients begin to develop dementia and mild AD. These patients may progress to moderate to severe AD. As shown below, amyloid-β accumulation in the brain occurs early, before symptoms appear. As the amyloid burden in the brain continues to increase, the onset of early and late MCI appears, and the severity continues to progress until the patient is diagnosed with AD. It is well documented that the onset of clinical symptoms, such as memory loss, begins in early and late stages of MCI, followed by a more rapid decline in memory and function as patients progress to mild, moderate, and finally severe AD. Patients in the later stages of moderate and severe AD exhibit functional decline requiring caregiver assistance and may even die.

[0027] Although the exact mechanisms underlying AD pathology remain unclear, it is well established that the accumulation of amyloid-β fibrils resulting in the formation of plaques is a hallmark of Alzheimer's disease. Furthermore, the accumulation of amyloid-β fibrils in the brain begins approximately 10–15 years before the onset of dementia and related clinical symptoms. The accumulation of fibrils and plaques increases with age, with 30–40% of people over the age of 55 and over 70% of patients with mild cognitive impairment (MCI) harboring amyloid-β accumulation in the brain. The presence of amyloid-β fibrils and plaques leads to increased neurotoxicity and the emergence of inflammation in the brain. These cumulative pathologies are associated with the emergence of more aggressive disease and loss of memory and function in AD patients.

[0028] Scyllo-inositol is an oral drug that crosses the blood-brain barrier to maintain low mM levels in the blood. Scyllo-inositol has been reported to disassemble Aβ fibrils and prevent Aβ from binding to fibrils. See McLaurin, J. et al., J Mol. Biol. (1998):183-194. Scyllo-inositol has been reported to inhibit Aβ binding to neuronal membranes in in vitro studies. (McLaurin J., et al., J Biol Chem 2000 24:18495) It has also been reported to restore long-term potentiation in hippocampal slices (Townsend M., et al. Annals of Neurology 2006 Dec.;60(6):668-76). Scyllo-inositol has been reported to reduce Aβ burden in transgenic AD animal models and improve cognitive function in such animals. McLaurin J., et al., Nature See Medicine (2006) 12:801-808. To date, a total of nine Phase 1 studies have been conducted in humans. These studies have essentially demonstrated that scyllo-inositol can be taken orally, increases plasma levels in a dose-proportional manner, crosses the blood-brain barrier, reaches brain and CSF levels shown to be effective in animal models of AD, and provides an acceptable safety profile that allows it to proceed to Phase 2 clinical studies. A Phase 2 study comparing patients receiving placebo (82 subjects) with patients receiving 250 mg BID scyllo-inositol over a 78-week treatment period showed no statistically significant differences between subjects in the full analysis set in the primary endpoints of NTB and / or ADCS-ADL. The adherence population of patients (placebo = 47, scyllo-inositol = 250 mg BID) showed no statistically significant differences in the primary endpoints of NTB and / or ADCS-ADL. In a BID=49 study, no statistically significant differences were found in the prevention of functional decline at the end of the 78-week treatment period for the primary endpoints measured by NTB and ADCS-ADL. The AD patient population in this study consisted of patients with mild to moderate Alzheimer's disease with MMSE scores of 16-26.One publication reported a subgroup analysis of subjects with MMSE scores of 23-26 in these studies (placebo: FAS 35 / PPS 22 vs. scyllo 250 Bid FAS 36 / PPS 24), but again no statistical significance was achieved between the placebo and scyllo-inositol groups. See Salloway, et al. Neurology 2011;77:1253-1262.

[0029] Although scyllo-inositol has been reported to have properties related to the prevention of Aβ fibril formation, along with positive results in memory / cognitive tests in AD animal models, there has been little or no published information regarding the actual treatment of Alzheimer's disease in subjects, given the clear failure of previous clinical studies. The present inventors have surprisingly and unexpectedly discovered a subgroup of patients for whom scyllo-inositol can be effectively treated to treat a subset of patients with Alzheimer's disease or MCI, while meeting the primary endpoint in clinical studies. Therefore, the present invention includes the use of scyllo-inositol alone to treat this subpopulation and / or to provide it to healthy subjects in the form of a dietary supplement, which in a preferred embodiment includes a composition comprising a first component selected from scyllo-inositol and a second component selected from aquaporin 4 upregulators.

[0030] Glossary As used herein, numerical ranges recited by endpoints include all numbers and fractions within that range (e.g., 1-5 includes 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, and numbers between those particular numbers).

[0031] The term "adjuvant" refers to a component that, when added to the administration regimen of a single active ingredient or in combination with another active ingredient, in combination adds or provides an enhanced or beneficial modified therapeutic or safety advantage to the other active ingredient(s) in the combination compared to the same property of the single other active ingredient or ingredient administered alone. An adjuvant may not have properties of clinical importance in its own right in the target patient population, but in combination with such other active ingredient(s), provides additional clinically important therapeutic or safety properties to such other active ingredient(s) in the target patient population. The adjuvant may be an oil known to those skilled in the art.

[0032] The terms "administer" and "administration" refer to the process of delivering a therapeutically effective amount of a compound or composition contemplated herein to a patient for the prevention and / or treatment of a described condition or disease. The term can also refer to administering a dietary supplement to a subject for the supplementation of such an ingredient.

[0033] The term "treatment" refers to reversing, alleviating, or inhibiting the progression of a disease or one or more symptoms of such a disease to which such term applies. Depending on the condition of the patient or subject, the term may also refer to preventing a disease, and depending on the particular disease or condition, may also include preventing the onset of such a disease.

[0034] The terms "subject" or "patient" are used interchangeably herein and include mammalian subjects, including humans or animals such as horses, dogs, cows, cats, and other mammals.

[0035] The term "supports cognitive health" refers to the purpose of the dosage form as described on the label or promotional materials of the dietary supplement of the claimed invention.

[0036] The term "pharmaceutically acceptable excipient or carrier" or "nutraceutically acceptable excipient or carrier" refers to a vehicle that does not interfere with the effectiveness or activity of the active ingredient or dietary supplement and is not toxic to the subject to which it is administered. Excipients include diluents, binders, adhesives, lubricants, disintegrants, fillers, wetting or emulsifying agents, pH buffers, and other known pharmaceutically effective excipients.

[0037] The term "pharmaceutically effective amount" or "nutraceutical effective amount" refers to the amount of pharmaceutically active ingredient(s) or "active agent(s)" present in a dietary supplement in each dosage form, as distinguished from other ingredients or excipients in the dosage form that are present in the formulation for purposes other than pharmaceutical or biological activity.

[0038] The term "combination therapy" or "coadministration" means that active ingredients are administered simultaneously to a patient being treated. In the case of coadministration, the ingredients can be administered simultaneously or sequentially at different times and in any order. This term includes pre-treatment with one active ingredient followed by treatment with both active ingredients and / or any active ingredients simultaneously or at different times to achieve a desired therapeutic effect and / or beneficial effect or complementary benefit. A beneficial effect includes, for example, a reduction in the side effects of one or both active ingredients due to the presence of the other active ingredient.

[0039] The term "beneficial effect" refers to an effect of a compound, adjuvant, composition, or combination that includes a favorable pharmaceutical and / or therapeutic effect and / or improved biological activity, and may include reduced side effects. The term "beneficial effect" includes effects such as improved cognitive function, reduced vascular load, reduced astrogliosis, reduced amyloid load, reduced microglia, and / or improved survival. A beneficial effect may also include improved stability, increased half-life, and / or improved uptake and transport across the blood-brain barrier by one active ingredient or adjuvant to the overall benefit of the other active ingredient.

[0040] Scyllo-inositol, a stereoisomer of myo-inositol, has been shown to disassemble amyloid-β fibrils and prevent their formation in vitro. In vivo, daily administration of 0.3–30 mg / kg of scyllo-inositol to transgenic mouse models of AD reduced brain amyloid-β burden and improved cognitive and functional tests. Furthermore, treatment with scyllo-inositol has been shown to reduce neurotoxicity and brain inflammation. Because scyllo-inositol can cross the blood-brain barrier via the myo-inositol transporter, the drug can achieve levels sufficient to reduce large amyloid aggregates and plaques to small amyloid-β oligomers. Improvements in cognition may reflect a reduction in amyloid burden and a reduction in large aggregates and plaques.

[0041] Preclinical studies have been conducted using methods to test mouse models of Alzheimer's disease, such as TgCRND8 mice, as disclosed in US2007 / 0197452. Tests performed include behavioral tests such as the Morris water maze, quantification of brain amyloid burden, plasma and brain Aβ content, gliosis, survival studies, analysis of APP in the brain, analysis of soluble Aβ oligomers, long-term potentiation, and synaptophysin immunohistochemical staining. The results of these studies demonstrated the efficacy of scyllo-inositol in treating TgCRND8 mice, which have amyloid plaque morphology, density, and distribution similar to those found in the brains of human patients with Alzheimer's disease.

[0042] Scyllo-inositol Scyllo-inositol can be obtained from processes disclosed in numerous patents and applications. See U.S. Patent Nos. 8,409,833 and / or 7,745,671, both of which are incorporated herein by reference. Its use in the prevention, treatment, and diagnosis of protein accumulation disorders is disclosed, for example, in EP 1608350B1, EP 8859628, or EP 7,521,481, both of which are incorporated herein by reference. Data presented herein demonstrate that scyllo-inositol treatment in mice significantly reduced amyloid burden and gliosis. Scyllo-inositol is said to have properties that inhibit established amyloid deposition in the brain in vivo. Thus, the data suggest that scyllo-inositol has properties that reduce amyloid plaque burden and improve cognition in mammals in need of such treatment. Diseases treatable with scyllo-inositol include conditions of the central nervous system, peripheral nervous system, or systemic organs that involve the deposition of proteins or protein fragments and peptides in beta-pleated sheets and / or fibrils or aggregates. Scyllo-inositol offers benefits such as (1) the ability to cross the blood-brain barrier and degrade amyloid fibrils, reducing the amyloid burden in the brain, and (2) a reduction in Aβ accumulation.

[0043] There is reason to believe that very early intervention in subjects with a pharmaceutically or nutraceutical-effective amount of scyllo-inositol, alone or in combination with an aquaporin-4 upregulator, can reduce fibril formation. Scyllo-inositol prevents Aβ accumulation, reduces Aβ burden, and improves cognitive function in transgenic animal models of Alzheimer's disease. See McLaurin J., et al. J Biol Chem 2000 24:18495; McLaurin J., et al., Nature Medicine 2006 Jul;12(7):801-8; and Townsend M., et al., Annals of Neurology 2006 Dec;60(6):668-76.

[0044] Scyllo-inositol can be formulated into any suitable pharmaceutical formulation. The compound can be administered orally or by other suitable means. Oral formulations can be in the form of tablets or capsules containing pharmaceutically acceptable excipients selected from binders, fillers, surfactants, preservatives, lubricants, etc. The amount of drug varies, but is typically between 75 and 250 mg twice daily for combination therapy, or 500 mg daily. This dosage may vary depending on the specific combination product and, for example, the dietary supplement composition or product to which it is being provided. Tablets and / or capsules can be prepared by means known to those skilled in the art. Administration of scyllo-inositol can also be via oral solution or suspension, intravenous administration, intramuscular administration, or other means, such as intraperitoneal, intradermal, transdermal, subcutaneous, intranasal, sublingual, or inhalation. Adjuvants can be added to enhance delivery of the adjuvant. In one embodiment, the present invention includes a composition comprising scyllo-inositol, apigenin, and an adjuvant.

[0045] A preferred combination product is an oral dosage form. Solid oral dosage forms contain an active substance, such as scyllo-inositol or apigenin, along with a suitable diluent. Dosage forms can be prepared by compression or molding. Tablets can be prepared from powdered, granular, or crystalline materials alone or in combination with pharmaceutically or nutraceutical acceptable excipients, such as binders, disintegrants, lubricants, diluents, colorants, and flavorings. Diluents can be selected from, for example, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. In some cases, and in some formulations, disintegrating tablets can be formed, while in other cases, non-rapidly disintegrating tablets can be formed. Microcrystalline cellulose can be used in direct compression formulations. Binders can be selected from the group consisting of starch, gelatin, or sugars selected from sucrose, glucose, dextrose, molasses, and lactose. Natural and synthetic gums selected from sodium alginate, acacia, panwar gum, methylcellulose, and polyvinylpyrrolidone may be used as binders. Lubricants include talc, magnesium stearate, and the like. Glidants may be selected from silicon dioxide, and the like. Disintegrants may be selected from starch, clay, cellulose, algin, gum, and cross-linked polymers.

[0046] Powder compression or wet granulation can be used to form tablets. The active ingredient, diluent, and disintegrant are mixed, dried, sieved, lubricated, and compressed. Dry granulation can also be used to form tablets. Other methods include spray drying and spheronization.

[0047] Other suitable oral dosage forms include capsules. Capsules include hard gelatin capsules, soft gelatin capsules, or soft capsules containing gelatin substitutes. Capsule filling methods are known in the art. Hard gelatin capsules are easy to fill and are particularly useful for the combination of scyllo-inositol and apigenin. The two active ingredients can be mixed with pharmaceutically or nutraceutical acceptable excipients to form a fine, uniform powder. The two active ingredients can be formed into two separate capsules, for example, having two different colors, and packaged in a kit or capsule container containing both dosage forms. Combining the two ingredients into a single dosage form offers numerous advantages, including ease of use and formulation benefits.

[0048] Tablets or capsules containing either or both scyllo-inositol and apigenin can also be coated for taste masking purposes or to create functional embodiments such as delayed release capsules or tablets.

[0049] For the compositions and methods described herein, it is contemplated that optional features, including but not limited to components, compositional ranges thereof, substituents, conditions, and steps, may be selected from the various aspects, embodiments, and examples described herein.

[0050] Further aspects and advantages will become apparent to those skilled in the art upon review of the following detailed description in conjunction with the drawings. While the compositions and methods are capable of embodiment in a variety of forms, the following description includes specific embodiments, with the understanding that the disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein.

[0051] In one embodiment, the composite formulation comprises scyllo-inositol and a flavone component. In another embodiment, such a formulation is in the form of a spheronized pellet or multiparticulates. In one embodiment, the formulation comprises a spheronized pellet containing an excipient selected from the group consisting of binders, surfactants, diluents, lubricants, gums, waxes, polymers, etc. The polymer may be selected from water-insoluble polymers and may optionally include a water-soluble polymer. In one embodiment, the formulation may be a nano / microparticle formulation produced by emulsion and spray drying, such as the emulsion diffusion spray drying / freeze drying techniques described herein. In another embodiment, the formulation may be a powder formulation produced by, for example, hot melt cooling / spray agglomeration. In another embodiment, the formulation may be a coated seed. In another embodiment, the formulation may be a granule containing the active substance.

[0052] Spheronized pellets produced from an aqueous wet granulation process may also have other ingredients in the granulation mixture, such as absorption enhancers, diluents, spheronization aids, pore formers, binders, binding aids, fillers, water, etc.

[0053] Formulations and dosage forms, and their associated methods of manufacture, are contemplated to include embodiments that include any combination of one or more of the additional optional elements, features, and steps further described below, unless otherwise indicated. Oral suspension formulations containing scyllo-inositol and apigenin, or other agents that increase aquaporin 4 expression or increase channel number or clearance through such channels, may also be produced.

[0054] As used herein, the term % by weight refers to parts by weight based on the total weight of what is being described, e.g., by default based on the total weight of the vitamin D-containing region, and, where appropriate by context and explicitly stated, based on the total weight of the formulation.

[0055] One aspect of the present disclosure is a formulation in the form of a hard capsule, comprising an active pharmaceutical ingredient selected from scyllo-inositol and apigenin dispersed in an immediate-release pharmaceutical composition. In an embodiment, the formulation is an immediate-release formulation for oral administration.

[0056] Another aspect of the present disclosure is a nano / microparticle formulation comprising a combination of scyllo-inositol and apigenin, and optionally an additional active pharmaceutical ingredient, and a pharmaceutically or nutraceutical acceptable excipient. In embodiments, the nano / microparticle formulation can provide immediate release of the combination of scyllo-inositol and apigenin at a dosage of about 70-125 mg, or at a weight ratio of about 1:1, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2, for example, by using a mixture of excipients.

[0057] Another aspect of the present disclosure is a nonpareil seed formulation containing an active pharmaceutical ingredient, preferably scyllo-inositol, alone or in combination with apigenin and a pharmaceutically acceptable excipient. In embodiments, the formulation may be, for example, an immediate-release formulation for oral administration. In embodiments, any one of the hard capsules may contain an additional polymer coating. Such a coating may be applied to pellets, granules, or seeds within the capsule, or the capsule may be coated externally.

[0058] In one aspect, extrusion-spheronization is utilized to produce pellets with excellent physical strength, uniform diameter, and good porosity. The main advantage that pellets produced by extrusion-spheronization have over other methods is the ability to incorporate high drug loads, particularly high drug loads of scyllo-inositol and optionally apigenin, without producing excessively large particles.

[0059] Thus, extrusion-spheronization can produce multiparticulates combining active ingredients with numerous other excipients that aid in the formulation's wettability, release profile, and ability to create extrudates and spheroids suitable for oral delivery of such ingredients. For appropriate drug concentrations in these pellets or multiparticulates, the drug load achieved comprises at least about 50-90% of the total weight of the formulation, excluding the capsule. The surface of the multiparticulates can also be coated with an optional coating system, allowing for safe handling of the exposed active multiparticulates and easy filling into capsules, stick packs, or containers suitable for bulk delivery. A preferred active combination is scyllo-inositol and apigenin.

[0060] Another aspect of the present disclosure is a method for producing pharmaceutical formulations and dosage forms. In embodiments, the method can be a method for producing an immediate-release pharmaceutical formulation, comprising combining an active pharmaceutical ingredient, such as scyllo-inositol, and optionally apigenin, with at least one excipient selected from the group consisting of a spheronization aid (diluent), a humectant, a stabilizer, a binder, a superdisintegrant, a lubricant, a solvent, and an optional coating.

[0061] The present invention includes a process comprising blending an API, a diluent / spheronization aid, and a superdisintegrant, dispensing such materials, adding a binder, an optional humectant, granulating / wet massing under certain conditions and endpoints, extruding the wet mass, spheronizing the sieved extrudate, drying, dividing, lubricating, and optionally coating to form a formulation having a uniform size and shape suitable for filling into capsules, sachets, and / or stick packs. In a preferred embodiment, the API is selected from a combination of scyllo-inositol and apigenin.

[0062] Another aspect of the present disclosure is a method of treating a disease or condition comprising administering a formulation or dosage form according to the present disclosure to a subject in need thereof. In a preferred embodiment, the subject is a mammal, including animals such as humans and dogs.

[0063] Another aspect of the present invention is a method for supporting the cognitive health of a subject in need thereof, comprising administering to the subject a specific amount of a combination of scyllo-inositol and apigenin in a suitable dosage form. The dosage, concentration, and relative ratio of the active ingredients will vary depending on the subject's cognitive impairment or condition. In some instances, and in some cases, a nutritional supplement combination may be preferred, provided to the subject years before the subject exhibits signs or evidence of cognitive impairment, such as memory loss. Providing such products or supplements may help prevent subsequent accumulation of beta-amyloid, and such products are believed to promote fibril clearance by the glymphatic system. Pharmaceuticals and clinically effective products are also within the scope of the disclosed claims.

[0064] Methods utilized to measure clinical efficacy and outcomes are determined for each patient and include measuring and determining the presence, severity, and progression of Alzheimer's disease over a period of time. This includes clinically determining the patient's overall level of function, deficits in activities and abilities of daily living, volumetric analysis of brain structure using techniques such as PET imaging of beta-amyloid protein, and in vivo measurement of disease-related deposition of abnormal proteins in the brain. Additionally, blood, body fluid, or CSF markers are also measured as indicators of disease presence or progression, including measurement of tau protein and other biomarkers, such as pyroglutamate-Aβ, Aβ40, and Aβ42, in blood, and total tau, phosphorylated tau, pyroglutamate-Aβ, Aβ40, and Aβ42 in CSF. ApoE isotype and hippocampal volumetric (HCV) MRI also help define and / or stage disease progression. Measurement of such markers and methods for determining their levels are known in the art. Furthermore, such markers are known to be predictive of the onset of Alzheimer's disease. See, for example, Duyckaerts (2011) Lancet Neurol. 10, 774-775, and Craak, et al., (2013), Acta Neuropath., 126:631-41.

[0065] Amyloid plaque burden is measured by 18F-AV-45 PET. 18F-AV-45 is a known amyloid ligand developed and marketed by Avid Radiopharmaceuticals. A trained PET imaging specialist can review acquired PET images to determine the mean 18F-AV-45 uptake between AD patients and age-matched controls. PET and morphometric MRI measurements of regional glucose metabolism are also utilized to assess AD status or progression. MRI monitors ARIA-related events.

[0066] U.S. Publication No. 2021 / 0401752, incorporated herein by reference, discloses a dosage form of calcifediol dispersed in a polymer composition, which may be a sustained-release formulation. An embodiment includes a vitamin D compound, such as calcifediol, embedded in a polymer network. This specification discloses a spheronized pellet formulation containing 25-hydroxyvitamin D and a pharmaceutically acceptable excipient. In certain embodiments, the spheronized pellet contains a sustained-release component selected from a polymer and / or a lipid component. The polymer may be a water-insoluble polymer, may include a water-soluble polymer, or may be a water-soluble polymer. The formulation may be a nano / microparticle formulation made by emulsion followed by freeze-drying of spray drying, as described in the '752 publication. The formulation may be a powder formulation made by spray congealing. The formulation may include sustained-release coated seeds or active-coated granules. The formulation may be wax-free and / or wax-containing.

[0067] Immediate-release dosage forms can be prepared, for example, according to AU2021100513, which discloses an immediate-release tablet formulation of the active substance disclosed herein. There, spray-dried powder prepared from the emulsion is added to tablet excipients and formed into a tablet containing 10 micrograms of the active ingredient. This process can be applied to the production of dosage forms containing scyllo-inositol combined with apigenin.

[0068] The flavone apigenin (C) in doses ranging from about 10 mg to about 500 mg 15 H 10 The combination of apigenin (O5) and scyllo-inositol (100-500 mg) may be utilized in separate dosage forms or in a single dosage form containing both ingredients. In a preferred embodiment, the dosage form is a single dosage form, such as a tablet or capsule, containing approximately 150 mg of each active ingredient. This combination, together with other pharmaceutically acceptable excipients, comprises a pharmaceutical or dietary supplement composition useful for the treatment of cognitive impairment, mild cognitive impairment, and Alzheimer's disease in a subset of patients with an MMSE score of approximately 22-26. Apigenin is commercially available and sold as a dietary supplement in various dosages.

[0069] The combination of scyllo-inositol and apigenin reduces amyloid-β aggregate formation and increases amyloid-β clearance more than either agent administered alone at the same dose or concentration. This combination is effective in improving memory and cognitive decline seen in elderly patients with early to mild Alzheimer's disease. The combination of reduced accumulation and increased or accelerated clearance minimizes and reduces amyloid accumulation in the brain, helping to improve memory decline and cognitive impairment in treated populations. Scyllo-inositol inhibits amyloid fibril formation and degrades amyloid-β oligomers and fibrils, promoting amyloid clearance and reduction in the brain's amyloid burden. Apigenin increases the expression and localization of aquaporin-4 channels on perivascular astrocytes, which are responsible for waste clearance, including amyloid-β clearance. This combination reduces amyloid-beta accumulation in the brain, reduces the risk of progression to cognitive impairment and dementia, and improves memory and cognition in the elderly population.

[0070] Aquaporin-4 channels are involved in the clearance of amyloid beta in the brain, and deletion of these channels increases memory impairment in mouse AD models. Xu, et al. Mol Neurodeneneration 2015; Sapkora, et al. Brain 2022. Apigenin shortens the half-life of amyloid beta in brain interstitial fluid, increases amyloid beta clearance, and improves cognition in mouse AD models. Zhao, et al. 2013.

[0071] The prevalence of amyloid-β accumulation increases with age and can occur 10–15 years before the onset of memory loss, mild cognitive impairment, and Alzheimer's disease. Thirty to 40% of subjects aged 55 years and older have amyloid-β accumulation in their brains, and more than 70% suffer from mild cognitive impairment. Increased amyloid-β accumulation in the aging brain is thought to be due to the accumulation and formation of amyloid-β oligomers and fibrils. These oligomers and fibrils are trapped within the brain and are not readily released into the CSF or digested by brain cells or enzymes. Once amyloid-β precursor protein is synthesized and appears on the neuronal surface, it is cleaved by α- and β-secretases to generate free amyloid-β peptides. Free amyloid-β peptides are then excreted into the cerebrospinal fluid via the glymphatic system of perivascular astrocytes. Furthermore, microglia can ingest and digest free amyloid-β. The combined clearance mechanisms maintain low concentrations of Aβ in the brain interstitial fluid and prevent the formation of Aβ aggregates and fibrils. Increased Aβ synthesis combined with an imbalance in either of these clearance mechanisms can lead to Aβ accumulation and increased memory and cognitive decline.

[0072] Aging, cerebrovascular disease, multiple previous concussions or other traumatic brain injuries, sleep disorders, and genetic predisposition are emerging risk factors for the development of neurodegenerative diseases such as mild cognitive impairment and Alzheimer's disease. Glymphatic function in the brain, which is responsible for the clearance of waste products such as amyloid-β, may be impaired in animal models and human Alzheimer's disease. Patients with Alzheimer's disease have been shown to have reduced perivascular astrocyte aquaporin channels involved in the glymphatic exchange for the removal of amyloid-β and tau. Reduced clearance of amyloid-β may play an important role in the accumulation of amyloid burden and the associated development of these diseases. In a postmortem case series, perivascular AQP-4 channels were observed to be reduced in the frontal regions of patients with AD, whereas channels were preserved in elderly patients aged 85 years or older with normal cognitive impairment. Therefore, reduced aquaporin-4 channels may impair the clearance of amyloid-β, tau, and other waste products in the brain through the CSF. These findings suggest that alterations in the expression and localization of aquaporin channels may contribute to the onset and progression of neurodegenerative diseases. Therefore, the combination of amyloid fibril degradation in the brain and increased expression and localization of aquaporin channels in perivascular astrocytes may be beneficial for the clearance of amyloid beta and tau via the cerebrospinal fluid (CSF).

[0073] In a postmortem case series, decreased perivascular AQP4 load was observed in the frontal cortex of subjects diagnosed with Alzheimer's disease, whereas maintained perivascular AQP4 load was observed in cognitively normal subjects over the age of 85. Decreased perivascular AQP4 levels were further associated with increased amyloid-β and tau pathology, as well as general indicators of cognitive decline. Three recent genetic studies conducted in different human populations demonstrated that single nucleotide polymorphisms in the human AQP4 gene are associated with variations in cognitive decline, amyloid burden, and clinical status, as well as the association between sleep disturbance and amyloid burden. A recent human transcriptome study further demonstrated that, in addition to AQP4 expression, differential expression of genes that determine perivascular AQP4 localization (specifically, genes encoding elements of DAC, SNTA1, DTNA, DMD, and DAG1) is associated with dementia status and temporal cortical tau pathology. These findings suggest that changes in AQP4 expression and localization may contribute to the onset and progression of neurodegenerative diseases, including Alzheimer's disease, in human populations. Understanding the novel role of dynamic AQP4 subcellular relocalization provides a new framework for understanding waste clearance in the healthy brain and opens up new therapeutic avenues for slowing the progression of neurodegenerative diseases.

[0074] The combination of scyllo-inositol and apigenin is designed for elderly individuals at risk of amyloid-β accumulation in the brain, which can lead to memory loss and cognitive impairment. Scyllo-inositol prevents the formation of amyloid-β aggregates in the brain and degrades existing aggregates to generate amyloid-β monomers, which are then ingested and digested by microglia and excreted into the cerebrospinal fluid (CSF) via aquaporin-4 channels in perivascular astrocytes. In comparison, apigenin increases the clearance of amyloid-β in the brain by increasing the expression and localization of aquaporin-4 channels on perivascular astrocytes, which are responsible for the clearance of amyloid-β, tau, and other waste products through the cerebrospinal fluid (CSF). This combination product is based on combining both natural products. This combination product promotes the clearance of amyloid-β in the brain and helps prevent the onset and progression of memory loss and cognitive impairment.

[0075] Benefits of combining scyllo-inositol with apigenin include: - Reduces the accumulation of amyloid beta and plaque formation in the brain - Improved memory and cognition - Reduces the risk of age-related cognitive impairment and dementia progression - Scyllo-inositol and apigenin therapy has a good safety profile.

[0076] Scyllo-inositol is a naturally occurring sugar found in many nutrients, including coconut, carrots, grapes, and citrus fruits. It has been well established that scyllo-inositol prevents the formation of amyloid-beta aggregates and fibrils in vitro in a concentration-dependent manner. Scyllo-inositol at concentrations of 0.1 μM to 5 μM prevents amyloid-beta monomers from binding to amyloid-beta oligomers, preventing the formation of oligomers and fibrils. Furthermore, similar concentrations of scyllo-inositol also break down existing amyloid-beta fibrils into soluble monomers.

[0077] When amyloid beta binds to neurons, it reduces synaptic activity and causes neurotoxicity. Scyllo-inositol has been shown to prevent amyloid beta from binding to neurons and reduce neurotoxicity (Maclaruin, et al.). Furthermore, Townsend, et al. showed that injecting scyllo-inositol into rat brains rescues long-term potentiation induced by toxic amyloid beta oligomers in hippocampal slices and reverses amyloid beta-induced memory loss in a rat model.

[0078] McLaurin et al. investigated the efficacy of scyllo-inositol in vivo in a transgenic mouse model of Alzheimer's disease. Animals were orally administered 0, 3, 10, or 30 mg of scyllo-inositol per kilogram for four months after the development of amyloid-beta fibrils and plaques. Brains from each group were examined for amyloid-beta fibrils and plaques, amyloid-beta burden, and cognitive performance. Administration of scyllo-inositol at a low dose of 3 mg / kg demonstrated a reduction in amyloid-beta fibril and plaque staining and amyloid-beta burden. Assessment of cognitive performance using the Morris water maze test showed that untreated transgenic AD animals exhibited cognitive decline due to the accumulation of amyloid-beta in the brain. However, oral administration of scyllo-inositol sufficiently reduced amyloid-beta burden and improved cognitive performance to levels comparable to that of normal animals.

[0079] In summary, AD model studies have shown that orally administered scyllo-inositol inhibits Alzheimer's-like behavioral deficits, neuropathology, and accelerated mortality in transgenic mouse models of Alzheimer's disease. These effects were observed regardless of whether scyllo-inositol was administered at disease onset or during the manifest phase of the AD-like disease.

[0080] The phase 2 study will investigate the effects of scyllo-inositol on patients with mild and moderate AD.

[0081] A randomized, double-blind, placebo-controlled phase 2 study examined the safety and efficacy of 250 mg BID over 78 weeks in patients with mild and moderate AD. One of the primary endpoints used to measure cognitive change was a neuropsychological test battery (NTB) and measurement of biomarker levels, such as amyloid-β42 and phosphorylated tau, in cerebrospinal fluid (CSF). The primary analysis compared 250 mg BID (n=84) with placebo (n=82) in patients with mild to moderate AD, with additional prespecified analyses conducted in patients with mild AD who received placebo versus those who received treatment. The cognitive change in the mild to moderate patient population was not statistically significant. However, mild AD patients treated with 250 mg BID showed very strong signs of improvement in NTB scores (see Figure xxx). Interestingly, scyllo-inositol demonstrated improvement in seven of the nine parameters measured by the NTB. Similar trends were observed in other cognitive and functional tests, including the CSR-SoB and ADCS-ADL. The effect of scyllo-inoistol was more pronounced in the adherent population, who received at least 80% of the medication over 78 weeks.

[0082] The glymphatic system plays a key role in the clearance of waste products in the brain, such as amyloid-β and tau. More specifically, aquaporin-4 channels are important for the continuous clearance of amyloid-β from the brain interstitial fluid to the CSF via perivascular astrocytes. The most compelling evidence comes from transgenic mouse models lacking the aquaporin-4 gene. Deletion of the aquaporin-4 gene in transgenic AD mouse models significantly increases the percentage of plaques in both the cortex and hippocampus compared with transgenic mouse models. Furthermore, deletion of the aquaporin-4 channel gene in both wild-type and transgenic AD mice resulted in detrimental effects on cognition. These data clearly demonstrate that aquaporin channels are essential for clearing amyloid-β and maintaining normal cognition in both normal and AD brains in mouse models. The effects of reduced aquaporin-4 channel levels have a more pronounced effect on cognition in AD brains.

[0083] More recently, it has been shown that the brains of patients with AD exhibit reduced localization of aquaporin-4 channels located in perivascular astrocytes, which are responsible for the clearance of amyloid-β. Impaired localization of aquaporin channels on perivascular astrocytes, rather than the expression of aquaporin-4 channels, may be responsible for the reduced clearance and accumulation of amyloid-β in the brain. Patients with reduced localization of aquaporin channels on perivascular astrocytes correlated with increased amyloid burden compared with cognitively normal elderly subjects. These data suggest that drugs that increase the expression and localization of aquaporin channels in perivascular astrocytes may be beneficial in reducing the amyloid burden in the brains of elderly patients at risk for amyloid-β accumulation.

[0084] demonstrated that apigenin treatment reduced amyloid-β accumulation and restored cognitive decline to normal levels in transgenic AD mice. The question is what is the mechanism of action of apigenin in reducing amyloid-β accumulation?

[0085] More recently, Sapkota et al. demonstrated that apigenin treatment in transgenic AD mice significantly shortened the half-life of amyloid-β and increased amyloid-β clearance in the AD brain. These effects were not observed in transgenic AD mice lacking the aquaporin 4 gene, suggesting that apigenin's effect on clearance may be mediated by aquaporin channels. Furthermore, this paper demonstrated that apigenin treatment in transgenic AD mice increased the expression and localization of aquaporin channels on perivascular astrocytes. These findings suggest that apigenin can increase the clearance of amyloid-β and tau via the glymphatic system and reduce amyloid-β accumulation in the brains of elderly individuals at risk for cognitive impairment.

[0086] Administration of a combination product containing scyllo-inositol and apigenin degrades amyloid-β oligomers and increases their clearance in the brain. A composition containing scyllo-inositol and apigenin at appropriate doses, selected from a dose-ranging study in mice, has the potential to prevent cognitive impairment and neurodegenerative diseases associated with amyloid-β burden in elderly populations, 5 to 10 years before the onset of cognitive deficits.

[0087] Both scyllo-inositol and apigenin have been administered to animals and humans, with acceptable safety profiles even with long-term use.

[0088] Scylloinositol: preclinical A full preclinical safety program for scyllo-inositol has been completed. Data indicate that scyllo-inositol is safe in rats at doses up to 2500 mg / kg / day for 6 months, with no pathology observed. Additionally, dogs receiving 300 mg / kg / day for 12 months were safe and no pathology observed. Mild adverse events, including dermatitis, gingivitis, and pneumonia, were observed at 2000 mg / kg / day for 12 months.

[0089] Scyllo-inositol: clinical studies The ELND005 clinical development program to date includes a total of 18 studies, six of which are currently ongoing and one of which was recently initiated.

[0090] Completed Research A total of 13 clinical studies have been completed with ELND005, including nine Phase 1 studies, two Phase 2 studies in patients with mild to moderate AD dementia, one Phase 2 study in agitation and aggression in patients with moderate to severe AD, and one Phase 1 / 2 study in Down syndrome.

[0091] In completed studies, more than 470 subjects received at least one dose of ELND005 (161 healthy subjects in the phase 1 study and 306 patients in the phase 2 study). 306 patients with mild and moderate AD were treated with ELND005 at doses up to 2000 mg BID. In completed phase 2 studies, treatment duration was up to 2.5 years at the 250-mg BID dose. Phase 2 AD studies provided a total of 370.2 patient-years of exposure at any dose. At the 250-mg BID dose, exposure in AD patients totaled 154.8 patient-years. In a phase 2 study of agitation and aggression in patients with moderate to severe AD, more than 150 patients were treated with 1000 mg BID for 4 weeks, followed by maintenance treatment with 250 mg BID scyllo-inositol for 12 weeks.

[0092] Of the 161 healthy subjects who received ELND005 in the Phase 1 study, 87 were aged 18 to 54 years (inclusive) and 74 were aged 55 to 81 years (inclusive). The dose range was 70 to 7000 mg for single-dose studies and 200 to 3000 mg BID for multiple-dose studies of up to 10 days. Patients with AD were treated with 250 mg BID to 2000 mg BID.

[0093] Based on review of clinical studies by a Clinical Monitoring Committee for up to 2.5 years and agreement with the FDA and EMA to conduct additional clinical trials, scyllo-inositol 250 mg BID appears safe for long-term use.

[0094] Apigenin Apigenin (4',5,7-trihydroxyflavone or 7-trihydroxyflavone) is available in a variety of foods, including parsley, chamomile, celery, morning glory, artichoke, and oregano. The most abundant source is in the dried form; for example, dried parsley has been reported to have up to 45 mg / g of dried parsley. Therefore, subjects are exposed to high concentrations of apigenin in their daily diet. Apigenin is currently available as a dietary supplement in capsules of 50–300 mg taken daily. Apigenin has been described as a flavonoid with low toxicity and numerous bioactive properties. In addition to its effects on the aquaporin 4 receptor, it can prevent cell migration, stimulate the immune system, and maintain the cell cycle. It has also been described as having anti-inflammatory properties. See Abid et al., Molecules 2022, 27, 4304. Apigenin is poorly water-soluble and lipophilic. Its chemical structure is shown below. [ka] Apigenin has been described for its ability to protect neurites and cell survival by promoting the downregulation of cytokine and nitric oxide (NO) release in inflammatory cells. In addition to its beneficial properties on aquaporin 4 expression, it also exerts neuroprotective effects in mammalian and human induced pluripotent stem cell (iPSC) models of familial and sporadic Alzheimer's disease through various mechanisms. See Balez, et al., Scientific Reports 6:31450 or www.nature.com / scientificreports, August 12, 2016. Even apigenin levels as low as 3.5–4.5 mg per day can increase glutathione reductase and superoxide desmutase levels over a period of days to weeks. While individuals who consume vegetables or plants containing large amounts of flavones, such as apigenin, may choose scyllo-inositol combination products with lower apigenin content, individuals who consume fewer plant-based foods may choose combination products with higher apigenin content. Thus, in one embodiment, the present invention includes tablets or capsules containing approximately 75-150 mg of scyllo-inositol and approximately 4-50 mg of apigenin. Table 1 provides a range of combination products from which consumers can select ratios based on their diet. [Table 1]

[0095] In another embodiment, a dosage form containing both scyllo-inositol and apigenin can be selected from a dosage form containing higher concentrations of scyllo-inositol, such as 150 mg, in the same 4-25 mg variation in 5 mg increments, or from another higher concentration apigenin line with apigenin increments of 10, 15, 25, 50, and 75 mg. Similarly, a dosage form with 75 mg scyllo-inositol can have a higher concentration range of apigenin depending on the subject's dietary intake.

[0096] Other flavones or flavonoids can also be combined with scyllo-inositol to provide beneficial effects. Additional flavones or flavonoids include plant polyphenols selected from the group consisting of kaempferol, quercetin, myricetin, and luteolin. These plant polyphenols are widely available. These additional polyphenols can also be combined with compositions containing scyllo-inositol and apigenin.

[0097] Preclinical animal studies used doses of 20–40 mg / kg / day over a 3–4 month treatment period. No adverse events were observed or reported.

[0098] Safety has been evaluated in clinical studies using either encapsulated apigenin or various food sources. No signs of adverse events have been observed.

[0099] In vitro studies have demonstrated that 2-5uM, or approximately 2-5ugms / ml, of scyllo-inositol is sufficient to prevent oligomer formation and disassemble amyloid-beta aggregates and fibrils. Therefore, the target concentration in CSF (which is assumed to resemble the interstitial fluid in the brain) is approximately 2-5ugm / ml.

[0100] Dosing patients with AD with 250mg BID scyllo-inositol results in an average concentration of 15µg / ml of scyllo-inositol in the CSF. If our target dose is approximately 2-5µg / ml of scyllo-inositol, the dose would be approximately 75mg of scyllo-inositol per day up to 250mg BID, which has previously been shown to improve cognition in patients with mild AD.

[0101] Furthermore, the effective dose of scyllo-inositol in transgenic AD mice was approximately 3–30 mg / kg / day. Taking into account the differences in sensitivity between humans and mice (9;1), this corresponds to approximately 20–200 mg of scyllo-inositol per day for a 60 kg subject.

[0102] Therefore, a daily dose of 75 to 250 mg of scyllo-inositol is considered sufficient to ensure efficacy and safety as described above.

[0103] The observed efficacy of apigenin in animal models is approximately 20-40 mg / kg / day. Assuming a 9-fold increase in sensitivity relative to body weight in mice, approximately 2-4 mg / kg of apigenin appears to be adequate for efficacy. Therefore, the appropriate dosage of apigenin for adult subjects is approximately 120-240 mg / day.

[0104] In one embodiment, the claimed invention comprises a pharmaceutical composition comprising a first active ingredient selected from scyllo-inositol and a second active ingredient selected from apigenin.

[0105] Clinical evaluations used to determine the stage and overall progression of Alzheimer's disease and / or to prevent or ameliorate disease progression include the CDR, FCSRT, Neuropsychiatric Inventory-Questionnaire (NPI-Q), and the Rey Auditory Verbal Learning Test (RA-VLT), a neurological test battery including immediate and delayed memory, the Wechsler Memory Scale (WMS), the Verbal Paired Associate Learning Test (VLT), the DeLis-Kaplan Executive Function Test (VLT), Verbal Fluency Criteria 1 and 2, and the Wechsler Adult Intelligence Scale-Fourth Edition, Symbol Search and Encoding subsets, as well as the Cognitive Drug Research test battery. The Mini-Mental State Examination (MMSE) and the Neuropsychological Test Battery (NTB) and their subitems may also be used to assess cognition. While these assessments are often used in subjects suspected of MCI or Alzheimer's disease, such tests may also be used in healthy subjects long before a physician has diagnosed cognitive impairment. In some dosage forms and at some dosage amounts, the combination of scyllo-inositol and calcifediol is believed to be safely administered to subjects outside of the prescription range for single active ingredients with sufficient safety and efficacy data. [Example]

[0106] Example 1 A clinical study in which a selected population of patients with mild AD (subpopulation with MMSE 22-26) and MCI with MMSE 26-30 were treated with scyllo-inositol.

[0107] Patients with mild AD (MMSE score 22-26) and MCI patients (MMSE score 26-30) with baseline characteristics of ADAS ≥ 8 and FAQ ≥ 2 or / and ADAS ≥ 8 and CDR ≥ 2 will be selected and combined for enrollment in the study. Selected patients will be divided into two groups: a placebo group and a scyllo-inositol treatment group. Patients will receive placebo or 250 mg twice daily scyllo-inositol for up to 18 months. Patients will be followed for safety and efficacy. Primary efficacy endpoints (NTB, ADAS-cognitive score 11, CDR-SB) will be measured at baseline and after 3, 6, 12, and 18 months of treatment with placebo or scyllo-inositol 250 mg twice daily. Safety will be analyzed at similar time points.

[0108] Example 2. Mouse study of a combination of scyllo-inositol and apigenin

[0109] Effect of scyllo-inositol and apigenin treatment in the 5XFAD transgenic AD mouse model.

[0110] To investigate the effects of scyllo-inositol and apigenin alone or in combination on amyloid-β accumulation, the number and size of plaques in the brain, and inflammation, 5XFAD transgenic AD mice were administered various concentrations of scyllo-inositol and apigenin daily. Eight 5XFAD mice (3 months old) per group were administered different doses of scyllo-inositol and apigenin daily, as shown below. The drugs were dissolved in water as a suspension and administered orally daily. The animals' weight and clinical appearance were observed at least once a week.

[0111] After 3 months of treatment, animals were sacrificed moribund, their brains removed, and one hemisphere fixed in 4% paraformaldehyde embedded in paraffin wax. 50 μm sections were analyzed for amyloid-β42 and plaques using an anti-amyloid-β antibody and visualized with DAB. Fibrillar astrocytes were analyzed using an antibody against GFAP. The amount of amyloid-β staining, number of plaques, plaque size, and number of fibrous astrocytes were quantified.

[0112] The other hemisphere was homogenized and prepared for analysis of amyloid-beta 40 and 42, and GFAP levels. The levels of these proteins in the brain homogenate were measured by immunoblotting and / or radioimmunoassay using antibodies specific for each protein. The groups were as follows: Group 1: Control - non-transgenic mice - parental strain (for control histological staining of amyloid-β and GFAP levels and preparation of homogenates for quantification of amyloid-β and GFAP levels) Group 2 Control - 5XFAD mice (untreated) sacrificed moribund at 3 months (baseline for transgenic mice) Group 3: Control-5XFAD mice (no drug treatment) and sacrificed moribund after 6 months Group 4 Treatment - 15 mg / kg scyllo-inositol (treatment for 3 months) and sacrificed moribund after 6 months Group 5 Treatment - 40 mg / kg scyllo-inositol (treatment for 3 months) and sacrificed moribund after 6 months Group 6 Treatment - 15 mg / kg apigenin (treated for 3 months) and sacrificed moribund after 6 months Group 7 Treatment - 40 mg / kg apigenin inositol (treatment for 3 months) and sacrificed moribund after 6 months Group 8 Treatment - 15 mg / kg scyllo-inositol + 15 mg / kg apigenin (treatment for 3 months) and sacrificed moribund after 6 months Group 9 Treatment - 15 mg / kg scyllo-inositol + 40 mg / kg apigenin (3 months treatment) and sacrificed moribund after 6 months Group 10 Treatment - 40 mg / kg scyllo-inositol + 15 mg / kg apigenin (treatment for 3 months) and sacrificed moribund after 6 months Group 11 Treatment - 40 mg / kg scyllo-inositol + 40 mg / kg apigenin (treatment for 3 months) and sacrificed moribund after 6 months

[0113] Previous studies have shown that 10 mg / kg and 30 mg / kg scyllo-inositol can reduce brain amyloid-β42 by 20–30% and plaque counts by 25–50% (Nature of Medicine publication). These changes were sufficient to improve memory and cognition in transgenic AD models. Apigenin has been shown to increase brain amyloid-β clearance by 30–40% and reduce amyloid-β42 burden by 20–30% in transgenic mouse models. Because the mechanisms of action of the two active ingredients are very different, there is no way to predict in advance whether a combination will have a greater or additive effect than either drug alone. Therefore, this study is designed to determine whether adding apigenin to scyllo-inositol administration actually reduces amyloid-β and plaque counts in the brains of mice in an AD mouse model more than either drug administered alone.

[0114] When the drugs are administered at their maximum known efficacy without confounding factors, treatment with the combination product may result in a statistically significant additional 10-20% reduction in brain amyloid-beta compared to either drug alone. Overall amyloid-beta reduction after treatment with the combination of scyllo-inositol and apigenin may range from 30-50%, depending on the dosage of both drugs. Regarding plaque counts, combination therapy with scyllo-inositol and apigenin may result in a 35-70% reduction in plaque counts.

[0115] For clinical trials and / or products marketed as dietary supplements for humans or animals, preferred dosage forms include capsules or tablets containing various dosage amounts of both scyllo-inositol and apigenin. These amounts may include various ratios of scyllo-inositol by weight, molar concentration, or mg / kg dose relative to the apigenin drug. Combination products can also be administered as separate dosage forms in which each active ingredient is administered simultaneously in a once-daily or twice-daily formulation. In some embodiments, tablets can be in the form of a tablet having an inner core of scyllo-inositol and an outer layer of apigenin mixed with pharmaceutically acceptable tablet excipients, such as a lubricant or filler. Tablets can additionally or optionally be enteric coated, for example, with Eudragit L / S or other suitable enteric coating polymers. The outer layer of apigenin rapidly dissolves and subsequently increases the expression of aquaporin 4 channels, whereas the inner core of scyllo-inositol is later released and enters the interstitial fluid in the brain, inhibiting and / or halting the formation of β-amyloid plaques and promoting the clearance of fibrils through expressed aquaporin channels and other catabolic pathways.

[0116] Example 3. Clinical studies of scyllo-inositol and apigenin

[0117] Patient population: Mild AD patients alone with MMSE scores of 22–26, or combined with MCI patients with MMSE scores of 27–28 who were predicted to experience more rapid decline in cognition and function based on the specific inclusion criteria described below. 1. Mild AD patients with an MMSE score of 22-26 2. MCI patients with an MMSE score of 27-28 who meet the following criteria: -ADAS≥8, FAQ≥2, CDR≥2 or ADAS ≥ 7, FAQ ≥ 1, total score of ADAS and FAQ ≥ 13 3. Testing positive for amyloid beta in the brain 4. Patients with mild AD, Apoe4 genotype, and MCI stratified based on MMSE score

[0118] Treatment arms of the study: Group #1: Placebo (patients treated under the exact same conditions as the treated patients described below, but without taking the active agent (placebo tablets or capsules)). Group #2: Patients will be treated daily for 6 months with tablets or capsules containing 75 mg of scyllo-inositol and 75 mg of apigenin. Patients will continue treatment in an open-label extension study and be followed for up to an additional 12 months. Patients will be analyzed for efficacy using specific memory tests, the NTB test and its sub-items, at 3 and 6 months, and at 12 and 18 months in an OLE study. Safety will be monitored at the same time points used for efficacy confirmation above.

[0119] Group #3: Patients will be treated daily for 6 months with tablets or capsules containing 225 mg of scyllo-inositol and 150 mg of apigenin. Patients will continue treatment in an open-label extension study and be followed for up to an additional 12 months. Patients will be analyzed for efficacy at 3 and 6 months using specific memory tests, the NTB test and its subtests, and at 12 and 18 months in an OLE study. Safety will be monitored at the same time points used for efficacy studies above.

[0120] Number of patients per group: 210 patients 1) Placebo 70 people 2) Treatment group #1: scyllo-inositol (75 mg) and apigenin (75 mg) 70 people 3) Treatment group #2: scyllo-inositol (225 mg) and apigenin (150 mg) 70 patients

[0121] Treatment duration: Patients will be treated for 6 months, followed by up to an additional 12 months in an open-label extension study. A blinded, independent group will perform efficacy and safety analyses at 3 and 6 months for evaluation in the primary study. Similarly, efficacy and safety will be analyzed at 12 and 18 months in the open-label extension study.

[0122] Key primary endpoints for the analysis: Memory testing will be the primary endpoint, including NTB tests and individual sub-items. Depending on the patient population, specific endpoints, and potentially other memory and cognitive endpoints, may be tested.

[0123] Safety and further analysis: General safety parameters required for the mild AD and MCI indications will be examined. Results of the study demonstrate clinical benefit for subjects receiving a combination product containing different doses of scyllo-inositol and apigenin compared to a placebo group. Data are designed to detect significant changes in specific memory tests and potentially NTB tests.

[0124] Preclinical animal and clinical studies of scyllo-inositol and apigenin have demonstrated that this combination is useful for treating and / or providing to subjects to reduce the accumulation of beta-amyloid fibrils. Early intervention and provision of such a combination is believed to improve cognitive health, particularly in subjects aged 50 years or older who have not yet shown signs of cognitive impairment, including memory loss and cognitive impairment associated with the earliest or ongoing formation of beta-amyloid aggregates. The combination of fibril disruption and fibril clearance, along with the additional important properties of flavones, particularly apigenin, on inflammation and aquaporin 4 expression, provides enhanced and unexpected properties demonstrated in mouse studies and clinical trials of subjects treated in the studies disclosed herein.

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 molecule that upregulates aquaporin 4.

2. 2. The combination of claim 1, wherein said first compound is selected from scyllo-inositol or other active 1,2,3,4,5,6-cyclohexanehexol and said second compound is selected from the group consisting of molecules flavones.

3. 3. The combination of claim 2, wherein the first compound is selected from scyllo-inositol and the second compound is selected from apigenin.

4. A composition comprising a flavone and a scyllo-inositol.

5. 5. The composition of claim 4, wherein the composition is a dietary supplement composition comprising apigenin and scyllo-inositol.

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 flavones.

7. 7. The dosage form of claim 6, wherein the first compound is selected from scyllo-inositol or other active 1,2,3,4,5,6-cyclohexanehexol and the second compound is selected from apigenin.

8. 8. The dosage form of claim 7, wherein the first compound is selected from scyllo-inositol.

9. 9. The dosage form of claim 8, which is a solid oral dosage form.

10. 10. The dosage form of claim 9, wherein the scyllo-inositol dosage is about 75-150 mg once or twice daily (BID) and the apigenin dosage is about 60-150 mg per day.

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

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

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

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

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

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

17. A method for treating a subject having cognitive impairment, memory loss, comprising administering an effective amount of scyllo-inositol in combination with a flavone.

18. 18. The method of claim 17, wherein the flavone is selected from apigenin.

19. 1. A method for providing a nutritional supplement to a subject susceptible to a neurological disease or condition, comprising obtaining 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 flavones, and providing said combination to said subject in need of treatment thereof.

20. A method of ameliorating memory loss, comprising administering an oral dosage form comprising scyllo-inositol, apigenin, and a nutraceutically acceptable excipient.

21. 21. The method of claim 20, wherein the oral dosage form is in the form of a tablet, which comprises a nutraceutical acceptable excipient selected from at least one of a binder, a filler, and a disintegrant.

22. A scored tablet comprising a combination of scyllo-inositol and apigenin, and a nutraceutically acceptable excipient.

23. Use of a combination of scyllo-inositol in a dosage of 75 mg to 250 mg once daily or twice daily and a flavone in the manufacture of a dietary supplement for consumption by a subject.

24. A combination comprising a first compound selected from scyllo-inositol and a second compound selected from the group consisting of flavones or other small molecules, or oligonucleotides that modulate the expression of aquaporin 4 channels.

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

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

27. 26. The combination of claim 24 or 25, wherein the dosage of scyllo-inositol is 70 to 125 mg and the dosage of apigenin is 70 to 125 mg.

28. 28. The combination of claim 27, further comprising a vitamin or additional supplement that supports cognitive health.

29. A combination comprising scyllo-inositol and apigenin.

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

31. A method for supporting cognitive health, comprising administering a nutraceutical effective amount of a composition comprising scyllo-inositol and apigenin.

32. 32. The method of claim 31, wherein a composition comprising scyllo-inositol and apigenin is provided to a subject aged 50 or older who is at risk of amyloid-β accumulation.

33. 33. The method of claim 31 or 32, wherein the subject exhibits early signs of memory loss.

34. A composition comprising scyllo-inositol, apigenin and an adjuvant.

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