Combining immunotherapy with SCYLLO-inositol for the treatment of Alzheimer's disease

Abstract

The present disclosure relates to active ingredient / adjuvant combinations for the treatment of neurological disorders and diseases, such as Alzheimer's disease and mild cognitive impairment (MCI), as well as memory and cognitive impairment and conditions. In particular, combinations with Alzheimer's disease therapies such as scyllo-inositol and lecanemab are disclosed to be useful.

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 disease or disorder that progresses over time, causing cognitive impairment and a variety of symptoms or disabilities that affect the daily lives of those affected. The number of people affected by the disease at various stages is enormous, estimated to increase to more than 115 million worldwide by 2050. Despite years of effort and billions of dollars invested in drug development research, no effective treatment has yet been found to address the progression and / or treatment of AD. Until this year, only three medications had been approved in the United States to treat the disease. These include donepezil, rivastigmine, and galantamine, but none of them are effective in halting the disease's progression.

[0003] However, in a new development, the FDA recently approved the monoclonal antibody drugs aducanumab (BIIB037) and lecanemab for the treatment of mild cognitive impairment (MCI) and early Alzheimer's disease, albeit with some reservations. Aducanumab and lecanemab are recombinant, fully human anti-amyloid beta monoclonal antibodies. See U.S. Patent No. 10,842,871, which is incorporated herein by reference. See also Sevigny J., et al. Nature, 537, 50-56 (2016). In the overall development of monoclonal antibodies for the treatment of AD, the FDA focused on MRI abnormalities potentially associated with Alzheimer's disease treatment. MRI signal changes were thought to reflect possible vasogenic edema (VE) and microhemorrhages (mH). These MRI signal changes have been observed in several clinical trials, including Salloway 2009, Sperling 2009, and Black 2010.

[0004] LEQEMBI (lecanemab) (BAN2401) is an intravenously administered amyloid beta-targeting antibody for the treatment of Alzheimer's disease. Treatment with this agent should begin in patients with mild cognitive impairment or mild dementia. The warnings and precautions section of the prescribing information highlights amyloid-related imaging abnormalities (ARIA) and recommends increased clinical vigilance for ARIA during the first 14 weeks of treatment with LEQEMBI. The risk of ARIA, including symptomatic ARIA, is increased in apolipoprotein E ε4 homozygotes compared with heterozygotes and non-carriers. Lecanemab-irmb is a recombinant humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody that targets accumulated soluble and insoluble amyloid beta. It is expressed in a CHO cell line and has a molecular weight of approximately 150 kDa. It is commercially available in single-dose vials at concentrations of 500 mg / 5 mL (100 mg / mL) or 200 mg / 2 mL (100 mg / mL). This solution contains histidine hydrochloride monohydrate, polysorbate, histidine, arginine hydrochloride, and water at pH 5.0.

[0005] A working group collaborating with the FDA has dubbed the set of imaging abnormalities that occur during disease progression and its treatment amyloid-related imaging abnormalities (ARIA). The terminology has evolved, with ARIA-E referring to MRI signal changes thought to represent VE and related extravascular fluid leakage, and ARIA-H referring to signal changes associated with mH and hemosiderosis. By focusing on the underlying pathology seen on MRI, aducanumab and lecanemab have been developed as drugs to reduce the incidence of ARIA in susceptible patients with Alzheimer's disease. Furthermore, aducanumab and lecanemab are approved for the treatment of mild Alzheimer's disease and are administered to patients in increasing doses over time. Currently, lecanemab is the preferred and approved drug for the treatment of Alzheimer's disease. Clinical trials of lecanemab demonstrated that the monoclonal antibody targets soluble accumulated amyloid beta and demonstrated activity across oligomers, prefibrils, and insoluble fibrils. Swanson, et al., Alzheimer's & Therapy (2021) 13:80.

[0006] The phase 2 trial of lecanemab aimed to establish the minimum dose achieving a maximal therapeutic response of ≥90%. The primary endpoint of the study was described as a Bayesian analysis of clinical change over 12 months in the Alzheimer's Disease Composite Score (ADCOMS) at the 90th dose (ED90). The endpoint required subjects to have an 80% probability of achieving a ≥25% reduction in functional decline compared with placebo. Secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography, clinical worsening on the ADCOMS Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14), and changes in CSF core biomarkers and total hippocampal volume (HV) using volumetric magnetic resonance imaging. In addition to data showing a 64% chance of 25% superiority over placebo in ADCOMS at 12 months and some positive secondary results at 18 months, the trial found that lecanemab was well tolerated, with an incidence of ARIA (edema / exudate) of only 9.9% when administered at 10 mg / kg every two weeks.

[0007] Aducanumab, another approved monoclonal antibody, is administered to these patients at multiple doses of at least 1 mg / kg at regular intervals. Over the course of this treatment, the dose can be increased to 3 mg / kg, then 6 mg / kg, and then 10 mg / kg. The dosing protocol for aducanumab or lecanemab is determined based on the patient's ApoE4 status, and the dose intervals can be approximately 4 weeks. A typical aducanumab treatment regimen involves first administering 1 mg / kg to the patient 1 to 5 times at regular intervals, then administering 3 mg / kg to the patient 1 to 5 times at regular intervals, and finally administering 6 mg / kg to the patient 1 to 5 times at regular intervals. Treatment with aducanumab or lecanemab reduces the amyloid burden in the brain and also reduces the patient's susceptibility to ARIA. Methods for determining drug efficacy include MRI plus time-specific positron emission tomography (PET) combined standard uptake value ratio (SUVR) determined by PET scan. The Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Mini-Mental State Examination (MMSE) were used to assess patients' progress on aducanumab. Clinical data from studies on aducanumab and lecanemab showed a reduction in amyloid plaques after drug treatment.

[0008] For LEQEMBI (lecanemab), once the presence of amyloid-β is confirmed, the recommended dose is 10 mg / kg, which should be diluted and administered as an intravenous infusion over approximately one hour once every two weeks. MRI is required to assess ARIA before starting treatment and before the fifth, seventh, and fourteenth infusions. Monoclonal antibodies targeting accumulated forms of beta amyloid, including LEQEMBI, are known to cause ARIA characterized as ARIA with edema detectable on MRI scans as cerebral edema or gingival crevicular fluid (ARIA-E), as described in the prescribing information. Reduction or elimination of clusters or accumulated forms of beta amyloid will alleviate ARIA caused by monoclonal antibody treatment.

[0009] Donanemab is another monoclonal antibody currently undergoing clinical trials. This drug specifically targets a specific modified form of amyloid-β, namely N-terminally truncated pyroglutamate-modified amyloid-β. A phase 2 clinical trial demonstrated a significant reduction in Alzheimer's disease-associated brain amyloid plaque levels measured by positron emission tomography (PET) compared with placebo-treated subjects. See Lancet, Comment Vol 2 (7), E395-E396, July 2021. Also see New England Journal of Medicine 2021;384:1691-1704. These clinical trials also reported that the incidence of ARIA-E was significantly higher in subjects treated with medication (26.7%) than in subjects treated with placebo (0-8%). Therefore, this particular antibody treatment regimen requires a concomitant medication, such as scyllo-inositol, to reduce amyloid plaque burden and potentially mitigate ARIA-related events. Other known monoclonal antibodies for the treatment of Alzheimer's disease include bapinezumab, gantenerumab, GSK933776, solanezumab, crenezumab, and ponezumab, any of which can be combined with scyllo-inositol as described herein.

[0010] The docking of Aβ fibrils to neuronal and glial cell membranes is thought to be an early and potentially intervenible step in the progression of Alzheimer's disease. It has also been speculated that glycolipids, such as gangliosides, may stabilize and prevent Ab fibril formation, while phosphatidylinositol may promote fibril formation. Scyllo-inositol (ELND005) has been shown to be useful for the treatment or prevention of central or peripheral nervous system diseases, including Alzheimer's disease. See U.S. Patent No. 7,521,481, which is incorporated herein by reference.

[0011] While patent publications generally disclose combination therapy of scyllo-inositol with other nervous system-focused drugs or therapies, they do not disclose the combination of scyllo-inositol with monoclonal antibodies selected from aducanumab or lecanemab, nor the use of scyllo-inositol to reduce ARIA events when combined with or used as a pretreatment for patients receiving monoclonal antibodies for the treatment of Alzheimer's disease or related cognitive disorders. ClinicalTrials.gov lists six clinical trials involving scyllo-inositol. Completed studies in Alzheimer's disease include one titled "Long-Term Follow-Up of ELND005 in Patients with Mild to Moderate Alzheimer's Disease and Alzheimer's Disease." The efficacy and safety of ELND005 as a treatment for agitation and aggression in Alzheimer's disease have also been completed. A 36-week safety extension study of ELND005 as a treatment for agitation and aggression in Alzheimer's disease has been completed. The clinical trial included patients receiving scyllo-inositol 250 mg / day versus placebo. The primary outcome in the Alzheimer's disease study was the change from baseline to week 78 in the ADCS-ADL score. The ADCS-ADL test is a 23-item scale measuring a subject's functional ability as assessed by their caregiver. The scale ranges from 0 to 78, with lower scores indicating greater functional impairment. Secondary outcomes included the change from baseline to week 78 in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) score. This test measures cognitive ability and consists of 12 items with a score ranging from 0 to 75. Higher scores indicate greater cognitive impairment. To date, these study results have not led to the filing of a new drug application for scyllo-inositol for the treatment of Alzheimer's disease.Although results were not favorable at the doses studied in the broad range of subjects studied, the inventors have discovered dosing regimens in combination with the monoclonal antibodies aducanumab or lecanemab that surprisingly and unexpectedly improve the clinical endpoints of these monoclonal antibodies in the treatment of mild cognitive impairment (MCI) and mild to moderate Alzheimer's disease, primarily related to a reduction in ARIA-related events in subjects receiving such monoclonal antibodies.

[0012] The basis for these improvements is thought to be the fact that scyllo-inositol is an oral drug that crosses the blood-brain barrier at low mM levels and disassembles amyloid beta (Aβ) fibrils at low (0.1–5) nM levels. Scyllo-inositol prevents soluble Aβ binding and reduces neurotoxicity. This drug has also been shown to improve memory and cognition in AD animal models. Combining it with aducanumab or lecanemab, or other monoclonal antibodies used to treat Alzheimer's disease, improves the side effect profile of monoclonal antibodies such as aducanumab or lecanemab, allowing for the use of higher doses of monoclonal antibodies to more effectively treat MCI and Alzheimer's disease.

[0013] The use of scyllo-inositol in combination with monoclonal antibodies may also be effective in treating elderly patients with memory loss due to increased amyloid-beta accumulation in the brain, and in patients with mild to moderate cognitive impairment (MCI), who are prone to developing mild to moderate Alzheimer's disease. The combination of these drugs reduces amyloid accumulation in the brain and alleviates the amyloid-related impairment of neuronal function. Pretreatment of patients receiving aducanumab or lecanemab with scyllo-inositol reduces the level of accumulated amyloid plaques, alleviates monoclonal antibody-associated ARIA, and allows for higher doses of the monoclonal antibody, further enhancing the efficacy of the treatment for Alzheimer's disease. Summary of the Invention

[0014] The present invention includes a method for treating MCI and Alzheimer's disease using a combination of scyllo-inositol and a monoclonal antibody. The preferred monoclonal antibody is lecanemab, but other options include aducanumab, donanemab, or any monoclonal antibody developed for the treatment of Alzheimer's disease that has associated ARIA-related events with monoclonal antibody treatment. Combination products, particularly those containing scyllo-inositol and aducanumab or lecanemab, enhance the efficacy of aducanumab or lecanemab in treating patients with MCI and mild AD. Scyllo-inositol also allows for reduced dosages of aducanumab or lecanemab in the treatment of MCI and mild AD while maintaining efficacy similar to that achieved without scyllo-inositol. Furthermore, scyllo-inositol reduces the prevalence of ARIA associated with aducanumab or lecanemab treatment at high doses. Accordingly, the present invention includes a method of treating Alzheimer's disease in a human patient comprising administering a pharmaceutically effective amount of a recombinant fully human anti-amyloid beta monoclonal antibody and a pharmaceutically effective amount of scyllo-inositol.

[0015] The present invention also includes a method of treating Alzheimer's disease or MCI with a recombinant monoclonal antibody selected from aducanumab or lecanemab (BAN2401) in combination with scyllo-inositol (250 mg once daily or BID, or 500 mg QD). This combination reduces amyloid burden in the brain, attenuates age-related long-term decline in memory and cognition, improves membrane fluidity, enhances neuronal function, and enhances short- and long-term memory and cognition.

[0016] In one embodiment, aducanumab comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a complementarity determining region 1 (VHCDR1) having the amino acid sequence set forth in SEQ ID NO:3, a VHCDR2 having the amino acid sequence set forth in SEQ ID NO:4, and a VHCDR3 having the amino acid sequence set forth in SEQ ID NO:5, and the VL comprises a VLCDR1 having the amino acid sequence set forth in SEQ ID NO:6, a VLCDR2 having the amino acid sequence set forth in SEQ ID NO:7, and a VLCDR3 having the amino acid sequence set forth in SEQ ID NO:8.

[0017] In another embodiment, lecanemab comprises a sequence selected from the group consisting of subunit 1 (SEQ ID NO: 9), subunit 2 (SEQ ID NO: 9), subunit 3 (SEQ ID NO: 10), subunit 4 (SEQ ID NO: 10).

[0018] In one embodiment, scyllo-inositol, optionally in combination with an immunotherapeutic agent, is administered orally in the range of 100-250 mg once daily or BID. In another embodiment, scyllo-inositol is administered at a dosage of 500 mg once daily.

[0019] In one embodiment, the invention includes a method of reducing brain amyloid-beta plaques in a patient with Alzheimer's disease, comprising administering an effective amount of aducanumab or lecanemab (lecanemab-IRMB) in combination with an effective amount of scyllo-inositol.

[0020] In a further embodiment, the invention includes a method of treating Alzheimer's disease patients with confirmed amyloid pathology and a disease stage of mild cognitive impairment or mild dementia consistent with Stage 3 or Stage 4 of Alzheimer's disease, the method comprising administering about 1 mg / kg to about 10 mg / kg of aducanumab as an IV infusion over a 1 hour every 4 weeks separated by at least 21 days, and administering an effective amount of scyllo-inositol.

[0021] In a further embodiment, the invention includes a method of treating Alzheimer's disease patients with confirmed amyloid pathology and a disease stage of mild cognitive impairment or mild dementia consistent with stage 3 or 4 Alzheimer's disease, the method comprising administering about 1 mg / kg to about 10 mg / kg of lecanemab as an IV infusion over a one-hour period once every two weeks, and further comprising administering an effective amount of scyllo-inositol.

[0022] In another embodiment, the invention includes a method according to the above embodiment, wherein the scyllo-inositol is administered once daily or BID in an oral dosage form at a concentration of about 125-250 mg.

[0023] In one embodiment, once the presence of amyloid-β pathology is confirmed in a subject, the method includes: (i) pre-treating the patient with a pharmaceutically effective amount of scyllo-inositol; (ii) obtaining a brain MRI of the subject to assess for pre-existing amyloid-related imaging abnormalities (ARIA) within one year of initiating treatment with a monoclonal antibody selected from lecanemab; and (ii) administering lecanemab in a diluted formulation at a dose of about 10 mg / kg, and administering the diluted lecanemab formulation as an intravenous infusion over about one hour once every two weeks.

[0024] In one embodiment involving subsequent infusions of lecanemab, the invention includes continuing treatment with scyllo-inositol at a dose of about 250-500 mg BID or QD daily from the start of prior treatment, and obtaining an MRI prior to the 5th, 7th, and 14th infusions of lecanemab.

[0025] In a further embodiment, the diluted lecanemab formulation comprises lecanemab diluted in about 250 mL of 0.9% Sodium Chloride Injection, USP, and is administered by infusion through a distal, low protein binding 0.2 micron in-line filter.

[0026] In another embodiment, the invention includes a method wherein scyllo-inositol increases the efficacy of aducanumab or lecanemab by increasing the dosage of aducanumab or lecanemab from about 10 mg / kg per infusion to about 12-15 mg / kg per infusion.

[0027] The present invention includes methods for enhancing cognitive ability in a subject with MCI or mild Alzheimer's disease and in need of treatment thereof by (1) pre-treating the subject with 125-250 mg of scyllo-inositol once daily or BID, and (2) co-administering a pharmaceutically effective amount of scyllo-inositol in combination with aducanumab or lecanemab to the subject, thereby enhancing cognitive ability in the subject.

[0028] The invention includes treating such patients with a combination of scyllo-inositol and aducanumab or lectunemab, where after such treatment, the combination therapy reduces ARIA aducanumab- or lectunemab-related events compared to treatment with aducanumab or lectunemab alone at the same infusion volume.

[0029] The present invention involves the use of scyllo-inositol as an adjuvant to modify the amount of monoclonal antibody required to treat an Alzheimer's disease patient in need of treatment.

[0030] In a preferred embodiment, the monoclonal antibody is selected from lectunemab.

[0031] In another preferred embodiment, the combination comprises scyllo-inositol and a pharmaceutically effective amount of lecanemab.

[0032] The present invention also includes a method for alleviating ARIA in a patient undergoing monoclonal antibody therapy, comprising administering to the patient in need of treatment a pharmaceutically effective amount of scyllo-inositol, said alleviation being compared to a patient undergoing such monoclonal antibody therapy without scyllo-inositol.

[0033] In one embodiment, the invention further includes a method of reducing amyloid-beta accumulation in the brain of a patient having mild Alzheimer's disease and being treated with a monoclonal antibody selected from aducanumab or lecanemab, comprising co-administering to the patient a pharmaceutically effective amount of scyllo-inositol.

[0034] In one embodiment, the invention includes a method of improving memory, cognition, and / or brain function in an Alzheimer's disease patient in need of treatment, wherein the patient is treated with a monoclonal antibody with co-administration of a pharmaceutically effective amount of scyllo-inositol, wherein such co-administration improves memory, cognition, and / or brain function compared to a patient treated with the monoclonal antibody alone.

[0035] The present invention includes a method for improving positive biomarkers in the CSF of Alzheimer's disease patients treated with a monoclonal antibody, the improvement being compared to a control patient treated with the monoclonal antibody alone, comprising the co-administration of a pharmaceutically effective amount of scyllo-inositol.

[0036] The invention also includes a method according to any one of the above embodiments, wherein the patient is pre-treated with scyllo-inositol at a daily dosage of 125-250 mg BID prior to receiving monoclonal antibody therapy.

[0037] The present invention encompasses methods in which the pretreatment period is up to two weeks. In a preferred embodiment, such combinations are sold as packets containing 250 mg twice daily or 500 mg of QD scyllo-inositol and 10 mg / kg per injection of a monoclonal antibody selected from aducanamab or lecanemab. The scyllo-inositol in such combinations is preferably provided in a dose of 125-250 mg twice daily, but can also be provided in a dose of 250 mg-500 mg QD. Capsule size and type (hard vs. soft) may also vary depending on the amount of scyllo-inositol and inactive ingredients. [Brief explanation of the drawings]

[0038] [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

[0039] 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).

[0040] The term "adjuvant" means a component that, when added to the dosing regimen of a single active ingredient or in combination with another active ingredient, in combination adds or provides an enhanced or beneficial modified therapeutic effect or safety advantage to the other active ingredient(s) in the combination compared to the same property of the single other active ingredient or ingredients administered alone. An adjuvant may not itself have clinically significant properties in the target patient population, but in combination with such other active ingredient(s) provides an additional clinically significant therapeutic or safety property to such other active ingredient(s) in the target patient population.

[0041] The terms "administer" and "administration" refer to the process of delivering a therapeutically effective amount of a compound or composition contemplated herein to a patient for the prevention and / or treatment of the described condition or disease.

[0042] 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.

[0043] 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.

[0044] The term "pharmaceutically acceptable excipient or carrier" refers to a medium that does not interfere with the effectiveness or activity of the active ingredient and is not toxic to the subject to which it is administered. Excipients include diluents, binders, adhesives, lubricants, disintegrants, fillers, wetting or emulsifying agents, pH buffers, and other known pharmaceutically effective excipients.

[0045] The term "combination therapy" or "coadministration" means that active ingredients are administered simultaneously to a patient being treated. In the case of coadministration, the ingredients can be administered simultaneously or sequentially at different times and in any order. This term includes pretreatment with one active ingredient followed by treatment with both active ingredients and / or any active ingredients simultaneously or at different times to achieve a desired therapeutic and / or beneficial effect. A beneficial effect includes, for example, a reduction in the side effects of one or both active ingredients due to the presence of the other active ingredient.

[0046] 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. Reduction of ARIA is considered a beneficial effect.

[0047] Immunotherapy for Alzheimer's disease is a promising approach to reduce amyloid-β fibrils and plaques in the brain. Previous clinical trials investigating active or passive immunotherapy approaches to reduce the amyloid-β burden in the brain have shown some efficacy in reducing amyloid-β and improving cognition. 1-4 However, the dosage of antibody therapy used was limited by the appearance of treatment-related abnormalities on brain imaging. Although these imaging abnormalities may be clinically silent, their long-term impact on safety is unknown and potentially dangerous.

[0048] Imaging abnormalities associated with immunotherapy have been observed with several humanized monoclonal antibody therapies directed against beta-amyloid, including a phase 2 study of bapineuzumab. 1,2 These MRI abnormalities were initially diagnosed as "vasogenic edema." 4 As more research and discoveries emerged in most other immunotherapy trials since then, it became clear that there are a variety of imaging changes associated with amyloid-modifying treatments. 5 include FLAIR signal abnormalities thought to represent parenchymal vasogenic edema and crevicular exudate (ARIA-E), and abnormalities detectable on GRE / T2* sequences thought to represent microhemorrhages and hemosiderosis (ARIA-H).

[0049] The prevalence and severity of ARIA are closely correlated with increasing doses of antibodies against amyloid-β, thus preventing the full efficacy of immunotherapy treatment by limiting the administration of high levels of antibodies necessary to optimize brain amyloid reduction and improve cognition in Alzheimer's disease. In most cases, immunotherapy treatments have been administered with suboptimal doses of amyloid-β antibodies to prevent patients from developing ARIA.

[0050] More recently, immunotherapy against amyloid beta (aducanumab) has been shown to be more effective at higher doses of the antibody than at lower doses when administered to patients with mild cognitive impairment (MCI) and mild AD. To mitigate ARIA associated with the high doses required for optimal efficacy, a dose-escalation regimen was used to reduce the prevalence and severity of ARIA. Aducanumab was initially administered to patients at low doses, such as 1 mg / kg, and then slowly increased over time to higher doses of 3, 6, and then 10 mg / kg. The discovery that higher doses of treatment could be administered by gradually increasing the dose provided efficacy with an acceptable safety profile.

[0051] Another recently approved monoclonal antibody, lecanemab, has also been shown to be effective in treating patients with Alzheimer's disease, but its prescribing information and package insert mandate that patients receiving treatment be monitored for ARIA-related events using MRI both before and during the multi-week course of treatment.

[0052] Thus, there is a significant unmet medical need for agents, drugs, or adjuvants with specific properties that can reduce / mitigate safety issues associated with ARIA, thereby enabling / tolerating increased doses / administration regimens of immunotherapeutic agents such as aducanumab or lectunemab and other effective monoclonal antibodies, and enabling / achieving significant increases in the dosing and efficacy of such immunotherapies in patients with MCI and mild AD who require such treatment. Similarly, there is a need for adjuvants or agents that can treat mild Alzheimer's disease patients or subjects with MCI concurrently with the treatment provided by immunotherapeutic agents, while minimizing or mitigating ARIA-related events at either low doses of the immunotherapeutic agent or high doses of the immunotherapeutic agent.

[0053] This need has been met by the surprising discovery that small molecules such as scyllo-inositol can effectively partner with monoclonal antibodies to attack Aβ and treat Alzheimer's disease patients more effectively than aducanumab or lekunemab alone, or can achieve similar or reduced levels of ARIA with lower final titers and / or increased concentrations and doses of aducanumab or lekunemab.

[0054] Combination treatment with scyllo-inositol and immunotherapy appears to be particularly effective in a subgroup of patients with mild AD, with MMSE scores between 22 and 26. Comparison of observed and simulated data for changes in NTB and CDR-SB scores in mild AD patients treated with scyllo-inositol showed statistically significant improvements in NTB and CDR-SB scores. See Figure 11.

[0055] Although the exact mechanism of immunotherapy's role in the development of ARIA is unclear, increased antibody binding to large amyloid-β aggregates in perivascular cuffs and accessible plaques in the brain can lead to local inflammation and leakage. Large doses of antibodies against amyloid-β are required to break down these aggregates and promote clearance of amyloid-β from the brain to the CSF and blood. Increasing antibody doses increase the likelihood of forming pockets of antibodies that react with amyloid aggregates and plaques, resulting in the development of symptoms associated with ARIA. Therefore, drugs that can interact with and disperse amyloid aggregates may reduce pockets of antibody complexes in the brain.

[0056] 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.

[0057] 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. Results from these studies demonstrated the effectiveness of scyllo-inositol in treating TgCRND8 mice, which have amyloid plaque morphology, density, and distribution similar to those seen in the brains of human patients with Alzheimer's disease. At a dose of 250 mg BID, CSF scyllo-inositol levels ranged from approximately 10 to 20 μg / ml, while plasma scyllo-inositol levels at the same dose ranged from approximately 5 to 8 μg / ml, meeting the target dose required to disassemble Aβ aggregates.

[0058] The focus of this disclosure is threefold: first, pre-treatment and continuation treatment with scyllo-inositol in combination with amyloid-beta antibody therapy, such as aducanumab or lecanemab, reduces the prevalence and severity of ARIA, allowing for higher antibody doses in patients with MCI and mild AD, and improving cognition and function; second, co-administration of scyllo-inositol with antibody therapy directed against amyloid-beta increases the clearance of amyloid-beta from the brain to CSF ​​and blood, reducing amyloid burden in the brain and improving cognition compared to antibody therapy alone; and third, co-administration of scyllo-inositol with anti-amyloid-beta antibodies acts synergistically or in combination to prevent amyloid-beta accumulation in the brain and improves cognitive efficacy compared to antibody therapy alone.

[0059] Table 1 shows a comparison of the phase 2 efficacy data for scyllo-inositol with the phase 2 or 3 data for donanemab, aducanamab, and lecanemab. [Table 1]

[0060] This table shows the difference between active drug and placebo (% drug effect). The data show that scyllo-inositol demonstrated equivalent or improved efficacy compared to the three individual immunotherapies on the CDR-SB test, which includes both cognitive and functional domains. Scyllo-inositol also demonstrated equivalent or improved efficacy on the ADCS-ADL (functional test) and MMSE when compared to donanemab data. No ARIA E or H was observed with scyllo-inositol, whereas ARIAs of 22-40 were observed with the immunotherapies.

[0061] The present invention includes the use of scyllo-inositol in combination with an immunotherapeutic agent, wherein the scyllo-inositol performs at least one of the following: (i) disassembles Aβ fibrils; (ii) prevents Aβ binding to fibrils; (iii) increases soluble Aβ levels in brain interstitial fluid; and (iv) increases Aβ uptake by microglia; and (v) reduces Aβ burden and increases Aβ clearance in a subject in need of treatment at an effective concentration of about 5-10 μM.

[0062] The present invention includes a combination of scyllo-inositol and an immunotherapeutic agent selected from the group consisting of donanemab, aducanumab, or lecanemab to improve cognitive function in a subject in need of treatment. Such a combination is believed to be surprisingly additive, as well as beneficial in terms of reducing ARIA-related events. The beneficial effects of Aβ fibril disruption and clearance, combined with the mutual therapeutic effects of scyllo-inositol and the immunotherapeutic agent with reduced ARIA side effects, provide a synergistic effect in the treatment of Alzheimer's disease, particularly mild disease and / or mild cognitive impairment in subjects with an MMSE score of 22-26.

[0063] The present invention includes a combination therapy comprising scyllo-inositol and an immunotherapeutic agent, which enhances Aβ clearance compared to either agent administered alone, while simultaneously alleviating ARIA and improving cognitive function in patients in need of treatment. This synergistic improvement is achieved through the ability of scyllo-inositol to cross the blood-brain barrier and degrade Aβ aggregates, generating soluble Aβ that is cleared via microglia and the CSF, while the immunotherapeutic agent simultaneously extracts and sequesters soluble Aβ from the brain into the CSF, thereby reducing Aβ levels in the brain. This combination enhances clearance and improves cognition and function in subjects treated with the combination(s). Furthermore, scyllo-inositol can solubilize Aβ aggregates in vascular drainage pathways and basement membranes, thereby reducing the formation of immune complexes and associated ARIA.

[0064] The present invention includes a method of reducing the severity and / or prevalence of ARIA in a subject being treated with an immunotherapeutic agent by administering a pharmaceutically effective amount of scyllo-inositol to the subject prior to and concurrently with administration of the immunotherapeutic agent. In a further embodiment, the present invention includes a method of inhibiting the accumulation and formation of Aβ deposits in the vascular drainage pathway in a subject in need of treatment, comprising administering a combination of scyllo-inositol and an immunotherapeutic agent selected from the group consisting of donanemab, aducanumab, or lecanemab.

[0065] The present invention includes a method of reducing cerebral arterial amyloid angiopathy in a subject, comprising administering to the subject a pharmaceutically effective amount of scyllo-inositol in combination with an immunotherapeutic agent, wherein said reduction in cerebral arterial amyloid angiopathy is compared to treatment with the immunotherapeutic agent alone in said subject.

[0066] The present invention involves pre-treatment with scyllo-inositol for two weeks, followed by co-administration of scyllo-inositol with anti-amyloid beta antibody therapy in patients with MCI and mild AD, to mitigate safety concerns associated with ARIA and promote reduction of amyloid beta burden in the brain, improving efficacy and safety. Alternatively, patients already receiving monoclonal antibody therapy can be co-administered with scyllo-inositol for the treatment of MCI and mild AD. However, initial clinical protocols require a two-week pre-treatment course. Patients with MCI and mild AD will be divided into three cohorts and treated as follows: a. Cohort 1, patients are treated with scyllo-inositol alone at 250 mg BID or 500 mg QD for 54 weeks. Patients are assessed for amyloid burden, memory, cognitive and functional tests, and ARI. b. Cohort 2: Patients were treated with 250 mg BID or 500 mg QD scyllo-inositol alone for 2 weeks, followed by 250 mg BID or 500 mg QD scyllo-inositol in combination with the monoclonal antibody, initially at 1 mg / kg, then 3 mg / kg (4 weeks), 6 mg / kg (4 weeks), and a final dose of 10 mg / kg for the remainder of the study (40 weeks). Patients were evaluated for ARIA, amyloid-beta burden, memory, cognition and function, and safety parameters. c. Cohort 3, patients are treated with escalating doses of monoclonal antibody alone, initially at 1 mg / kg (4 weeks), then at 3 mg / kg (4 weeks), 6 mg / kg (4 weeks), and 10 mg / kg for the remainder of the study (40 weeks). Patients are evaluated for ARIA, amyloid-beta burden, memory, cognition and function, and safety parameters.

[0067] After 52 weeks of combined treatment with scyllo-inositol and immunotherapy drugs, the following results were observed:

[0068] ARIA was reduced compared with immunotherapy alone.

[0069] The amyloid-beta burden in the brain was reduced compared with treatment with the immunotherapy drug alone.

[0070] Memory, cognition, and function improved compared with treatment with the immunotherapy drug alone.

[0071] CSF amyloid beta biomarkers such as amyloid beta 42 / 40 ratio, tau, and phosphorylated tau improved.

[0072] This combination also allows for greater flexibility in immunotherapy dosing regimens by allowing for variations in dosage strength and titration of currently approved treatment courses.

[0073] An alternative phase 2 study combining scyllo-inositol with immunotherapy for the treatment of MCI and early mild AD may also be conducted. Subsets of patients with mild AD who have MMSE scores of 22-26 or 23-26 will be recruited for the clinical trial. Each group will include at least 45-50 patients. The three groups included: (1) patients treated with placebo for 4 weeks followed by 16 (16) weeks of treatment with the selected immunotherapy; (2) patients treated with 250 mg scyllo-inositol twice daily for 4 weeks followed by 16 (16) weeks of treatment with 250 mg scyllo-inositol twice daily plus the selected immunotherapy at the prescribed dose and frequency; and (3) patients treated with 500 mg scyllo-inositol twice daily for 4 weeks followed by 16 (16) weeks of treatment with 250 mg scyllo-inositol twice daily plus the selected immunotherapy at the prescribed dose and frequency. The primary endpoints were the incidence of ARIA E and H at weeks 0, 4, 12, and 20. Secondary endpoints included measurement of Aβ burden (PET scan) at weeks 0, 12, and 20. Other endpoints included NTB, cDR-SB, and MMSE. Biomarkers such as tau and P-tau may also be measured. The incidence or prevalence of ARIA in patients receiving immunotherapy drugs is estimated to be approximately 22-30% for ARIA E and H.

[0074] 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. In patients undergoing or prescribed monoclonal antibody therapy for such diseases, this deposition and / or tissues already containing such sheets can be disrupted by the co-administration or combination of an appropriate formulation of scyllo-inositol and such monoclonal antibody.

[0075] Specific diseases and conditions treatable with such combination therapies include Alzheimer's disease, presenile and geriatric forms, amyloid angiopathy, mild cognitive impairment (MCI), Alzheimer's disease-related dementia, taoupathies, alpha-synucleinopathies, Parkinson's disease, amyotrophic lateral sclerosis, motor neuron disease, spastic paraplegia, Huntington's disease, spinocerebellar ataxia, Friedrich's ataxia, neurodegenerative diseases associated with intracellular and / or intraneuronal aggregates of proteins containing polyglutamine, polyalanine or other repeats resulting from pathological expansion of tri- or tetranucleotide elements within the corresponding genes, and other diseases and disorders disclosed, for example, in U.S. Pat. No. 7,521,481, incorporated herein by reference.

[0076] Scyllo-inositol can be formulated into any suitable pharmaceutical formulation. The compound can be administered orally or by other suitable means. Oral formulations can be in the form of tablets or capsules containing pharmaceutically acceptable excipients selected from binders, fillers, surfactants, preservatives, lubricants, etc. The amount of drug varies, but in combination therapy, it is typically in the high end of the range, typically 125-250 mg BID, or 500 mg QD. The prescribing physician can modify this dosage depending on the patient's specific condition or condition, reducing the supplemental dose to 50-150 mg BID. Tablets and / or capsules can be prepared by methods known to those skilled in the art. Scyllo-inositol can also be administered via oral solutions or suspensions, intravenously, intramuscularly, or by other means, such as intraperitoneally, intradermally, transdermally, subcutaneously, intranasally, sublingually, or by inhalation.

[0077] Scyllo-inositol can be formulated as oral tablets or capsules. Tablets can be formed by compression and can be prepared from crystalline, powdered, or granular materials with other pharmaceutically acceptable excipients, such as binders, disintegrants, lubricants, diluents, and colorants. Diluents can be selected from, for example, dicalcium phosphate, lactose, cellulose, mannitol, dry starch, powdered sugar, and / or sodium chloride. Binders can be selected from starch, gelatin, and sugars such as sucrose, glucose, dextrose, and milk sugar. Natural and / or synthetic gums can also be used. Lubricants, such as magnesium stearate, can also be incorporated into tablets or capsules. Flavoring ingredients can also be used.

[0078] Aducanumab Aducanumab is described as a recombinant human immunoglobulin gamma 1 (IgG1) monoclonal antibody that targets accumulated soluble and insoluble amyloid beta. This immunoglobulin is expressed in a Chinese hamster ovary cell line and has a molecular weight of 146 kDa. The prediluted injection contains no preservatives and contains 100 mg of aducanumab, L-arginine hydrochloride (31.50 mg), L-histidine (0.60 mg), L-histidine hydrochloride monohydrate (3.39 mg), L-methionine (1.49 mg), polysorbate 80 (0.50 mg), and water for injection with a pH of approximately 5.5 per mL. Clinical studies have demonstrated and documented that ADUHELM reduces amyloid beta plaques. This agent reduced amyloid beta plaques in a dose- and time-dependent manner compared to placebo. The effect of drugs on these plaque levels was assessed using PET imaging ( 18The PET signal was assessed using a F-florbetapir tracer. The PET signal was quantified using the standard uptake value ratio (SUVR) method, which is described as estimating brain levels of amyloid-beta plaques in a complex of brain regions predicted to be affected by Alzheimer's disease pathology. See the ADUHELM prescribing information. These regions include the frontal, parietal, lateral, temporal, sensorimotor, and anterior and posterior cingulate cortices, compared with a brain region predicted to be less affected by such pathology (the cerebellum).

[0079] A substudy of this clinical trial of aducanumab demonstrated a reduction in brain levels of amyloid-beta plaques at both low and high dose levels compared with placebo at weeks 26 and 78. The extent of these reductions was again described as both dose- and time-dependent.

[0080] A third clinical study of ADUHELM demonstrated statistically significant dose- and time-dependent reductions in amyloid plaque levels at 26 weeks in the 3 mg / kg, 6 mg / kg, and 10 mg / kg treatment groups and at 54 weeks in all treatment groups compared to placebo treatment.

[0081] ADUHELM was also studied for its effect on tau pathophysiology (marker levels). Studies demonstrated that ADUHELM reduced tau pathophysiology markers (CSF p-tau and tau PET) and neurodegeneration markers (CSF t-tau) (Studies 1 and 2). The immunotherapy drug also reduced CSF p-tau levels in substudies conducted in Studies 1 and 2. At week 78 in Study 1, the adjusted mean change from baseline in CSF p-tau levels compared with placebo was favorable for the low- and high-dose ADUHELM groups. The drug also reduced CSF t-tau levels in the low- and high-dose groups compared with placebo in a substudy conducted in Study 1.

[0082] In studies 1 and 2, PET imaging ( 18A substudy was also conducted to confirm the effects of aducanumab on neurofibrillary tangles composed of tau protein using the F-MK6240 tracer. PET signals were quantified using the SUVR method to estimate brain levels of tau in brain regions expected to be affected by Alzheimer's disease pathology (medial temporal lobe, temporal cortex, frontal cortex, cingulate cortex, parietal cortex, and occipital cortex) compared with brain regions expected not to be affected (e.g., cerebellum). Clinical data showed that adjusted mean changes from baseline in tau PET SUVR compared with placebo at follow-up were superior for aducanumab administered at high doses to the medial temporal lobe, temporal region, and frontal regions of the brain.

[0083] Finally, additional data were collected on the exposure-response relationship after receiving aducanumab versus placebo. The data showed that increased exposure to aducanumab was associated with greater reductions in subjects' clinical decline, as measured by CDR-SB, ADAS-Cog13, and ADCS-ADL-MCI, as well as greater reductions in amyloid-beta plaques.

[0084] Clinical studies conducted on the combination products described herein will use the same methods used in the ADUHELM study to demonstrate efficacy, reduction in markers, and improvement in AIRA-related events following combination therapy and pretreatment with scyllo-inositol.

[0085] As set forth in U.S. Patent No. 10,842,871, incorporated herein by reference, during the development of drugs for the treatment of Alzheimer's disease, the Food and Drug Administration (FDA) expressed concerns in 2010 about the occurrence of abnormalities evident on MRI scans following treatment in clinical trials. These abnormalities, identified and / or believed to represent vasogenic edema (VE) and microhemorrhages (mH), were first observed in clinical trials of monoclonal antibodies against amyloid beta. Subsequently, developers of these drugs, including those of the recently approved monoclonal antibody treatment aducanumab, have focused on efficacy and safety, as well as emerging concerns regarding VE or mH arising from monoclonal antibody treatment. The underlying reasons for the increase in VE and mH abnormalities are not fully understood. The presence of the apolipoprotein E ε4 allele, ApoEε4, has been found to be a significant risk factor for the development of ARIA-E (VE-associated MRI abnormalities). On the other hand, mH is not associated with specific alleles and is generally thought to result from one of two etiologies: small vessel angiopathy and cerebral amyloid angiopathy (CAA). It has also been suggested that a local inflammatory component caused by drug treatment may trigger both ARIA-E and / or ARIA-H.

[0086] In all cases, to treat mild cognitive impairment (MCI) and mild Alzheimer's disease and reduce ARIA resulting from such treatment, Biogen-IDEC received FDA approval for ADUHELM™ aducanumab, with a treatment regimen requiring titration to reduce ARIA. The agent is an amyloid-beta-targeting antibody indicated for the treatment of Alzheimer's disease and was granted accelerated approval based on the reduction in amyloid-beta plaques observed in patients treated with ADUHELM. The dosage and administration section of the approval labeling states that (1) titration is required to initiate treatment, (2) the recommended maintenance dose is 10 mg / kg administered by intravenous infusion over approximately one hour every four weeks, (3) a recent (within one year) brain MRI should be performed prior to initiating treatment, and (4) an MRI should be obtained before the seventh and twelfth infusions. If severe ARIA-H is observed radiologically, treatment can be continued cautiously only after radiological stability (no increase in the size or number of ARIA-H) is demonstrated by clinical evaluation and follow-up MRI. (5) Diluted in 100 mL of 0.9% Sodium Chloride Injection, USP, prior to administration, (6) administered as an intravenous infusion over approximately 1 hour through a 0.2 or 0.22 micron in-line filter. Approved dosage forms and strengths are 170 mg / 1.7 mL (100 mg / mL) for injection in single-dose vials and 300 mg / 3 mL (100 mg / mL) for injection in single-dose vials. The label's warnings and precautions section warns of the need for increased clinical vigilance for amyloid-related imaging abnormalities (ARIA), particularly during the titration period and the first eight doses of treatment. IV infusion intervals are every four weeks. The dosing or titration schedule is 1 mg / kg aducanumab for infusions 1 and 2, 3 mg / kg for infusions 3 and 4, 6 mg / kg for infusions 5 and 6, and 10 mg / kg for infusions 7 and beyond. The side effects section of the label states that the most common side effects (incidence of at least 10% or greater compared with placebo) are ARIA-edema, headache, ARIA-H microhemorrhages, ARIA-H superficial hemosiderosis, and falls.

[0087] The section on monitoring ARIA states that if 10 or more new microbleeds or more than two focal superficial hemosiderosis (radiologically severe ARIA-H) are observed, treatment can be continued cautiously only after clinical evaluation and follow-up MRI demonstrate radiological stability (no increase in size or number of ARIA-H).

[0088] In the ADUHELM clinical study and the clinical study of the combination therapy described in this specification, the severity of ARIA will be classified by the radiological criteria shown in Table 2 below. [Table 2]

[0089] In a clinical study comparing aducanumab monotherapy with placebo, ARIA-E and / or ARIA-H were observed in 41% (454 of 1105) of patients treated with the planned dose of 10 mg / kg, compared with 10% (111 of 1087) of patients receiving placebo. ARIA-E was observed in 35% of patients receiving aducanumab 10 mg / kg, compared with 3% of patients receiving placebo. As previously mentioned, the incidence of ARIA-E was higher in apolipoprotein E ε4 (ApoEε4) carriers than in ApoEε4 non-carriers (42% and 20%, respectively). Clinical trials have demonstrated that ARIA can occur at any time, but the majority of ARIA-E radiological events occurred early in treatment (within the first eight doses). Among patients treated with aducanumab (10 mg / kg) who experienced an ARIA-E event, the maximum radiographic severity was mild in 30% of patients, moderate in 58%, and severe in 13%. Sixty-eight percent of patients with ARIA-E experienced resolution by 12 weeks after detection, 91% by 20 weeks, and overall, 98% experienced resolution of symptoms. Ten percent of all patients receiving aducanumab 10 mg / kg experienced one or more ARIA-E episodes. ARIA-H in the setting of ARIA-E associated with the use of ADUHELM 10 mg / kg was observed in 21% of patients receiving the drug compared with 1% of patients receiving placebo.

[0090] ADUHELM is administered in a titration-based regimen, driven by the need to reduce ARIA-related events that occur or are likely to occur with a fixed-dose regimen. Titration is believed to slow the pace of amyloid clearance initially, allowing for slower clearance throughout a patient's overall treatment. Pretreatment with a non-monoclonal antibody regimen, for example with agents such as scyllo-inositol, is believed to accelerate plaque clearance and reduce plaque burden without causing ARIA-related events. As a result, subsequent coadministration of scyllo-inositol and aducanumab reduces ARIA-related or related events associated with antibody treatment, thereby allowing titration to higher doses of aducanumab and / or facilitating a fixed-dose regimen of aducanumab / scyllo-inositol without causing or reducing ARIA-related events in treated patients. This combination accelerates the rate of plaque clearance without slowing amyloid clearance.

[0091] Aducanumab (BIIBO37) is an IgG1 monoclonal antibody consisting of two heavy chains and two kappa light chains linked by interchain disulfide bonds. This antibody recognizes a conformational epitope found in Aβ aggregates. A murine IgG2a chimeric version of this antibody (chl 2F6A) has been shown to attenuate or reduce plaque burden in aged Tg2576 mice, a mouse model of Alzheimer's disease. See Wilcock and Colton 2009. A human version of antibody 12F6A has an amino acid sequence identical to BIIBO37, produced in a different Chinese hamster ovary cell line.

[0092] Aducanumab has an antigen-binding domain comprising VH and / or VL variable regions as shown in Table 3. [Table 3]

[0093] Aducanumab (BIIB037) has the following named CDR protein sequences: [Table 4]

[0094] The sequence of the heavy chain of the anti-Aβ antibody BIIB037 has the following sequence: QVQLVESGGG VVQPGRSLRL SCAASGFAFS SYGMH WVRQA PGKGLEWVA V IWFDGTKKYY TDSVKG RFTI SRDNSKNTLY LQMNTLRAED TAVYYCAR DR GIGARRGPYY MDV WGKGTTV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK RVEPKSCDKT HTCPPCPAPE LLGGPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE KTISKAKGQP REPQVYTLPP SREEMTKNQV SLTCLVKGRY PSDIAVEWES NGQPENNYKT TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SPG (SEQ ID NO: 11)

[0095] The heavy chain CDRs are underlined.

[0096] The sequence of the light chain of the anti-Aβ antibody BIIB037 has the following sequence: DIQMTWSPSS LSASVGDRVT ITC RASQSIS SYLN WYQQKP GKAPKLLIYA ASSLQS GVPS RFSGSGSGTD FTLTISSLQP EDFATYYC QQ SYSTPLT FGG GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 12).

[0097] The light chain CDRs are underlined.

[0098] Antibodies can be prepared using, for example, the process described in US2021018895, which is incorporated herein by reference. As described herein, they can be prepared in eukaryotic or bacterial cells. In a preferred embodiment, they are produced in transformed eukaryotic cell lines such as CHO, 292E, and COS. In addition to bacterial and eukaryotic cells, yeast cells can also be used to produce antibodies or their scFvs. The general process involves constructing a polynucleotide encoding the antibody, introducing it into an expression vector, and expressing the antibody in a suitable host cell. Molecular biology techniques are known to those skilled in the art. When antibodies are expressed in CHO, COS, or NIH3T3 cells, a promoter such as the SV40, MMLV-LTR, EF1α, or CMV promoter is required. Additional sequences, such as regulatory sequences, can be added to facilitate replication and selection or to confer resistance to drugs into which the vector has been introduced. Suitable vectors include pMAM, pDR2, and the like, described in US2021188954. To demonstrate the preparation of BIIB037, a recombinant expression vector encoding the antibody heavy and light chains was introduced into dhfr-CHO cells by calcium phosphate-mediated transfection. The antibody heavy and light chains were operably linked to enhancer / promoter regulatory elements derived from either SV40, CMV, or other vectors, such as the CMV enhancer / AdML:promoter regulatory element or the SV40 enhancer, in a system that drives high levels of gene transcription. The vector also contained a DHFR gene, allowing for the selection of CHO cells transfected with the vector using methotrexate selection / amplification. Selected transformants were cultured to express the antibody light and heavy chains, after which the antibody was recovered from the culture medium and used in the compositions described herein for the treatment of Alzheimer's disease patients. Purification methods are known in the art, and such antibodies can be isolated and purified to levels required for human administration. Purification methods include column chromatography, filtration, ultrafiltration, salting out, solvent extraction, solvent precipitation, immunoprecipitation, and other means including SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, and recrystallization.

[0099] Antibody compositions can be formulated according to the methods and compositions described in U.S. Patent No. 10,842,871, incorporated herein by reference. Compositions can include pharmaceutically acceptable excipients, such as phosphate-buffered saline, water, and emulsions, including oil-in-water emulsions. Wetting agents can be added, and such compositions can be delivered as sterile solutions. Antibodies and pharmaceutical compositions can be administered, for example, intravenously, intraperitoneally, subcutaneously, intramuscularly, topically, or transdermally. Various concentrations of antibodies can be prepared and utilized for combination therapy. Such concentrations can range from 50 mg / mL to over 300 mg / mL for highly concentrated antibody compositions. Sterile injections of such antibodies are made and require filtration sterilization. Coating of such antibodies with lecithin may be necessary to ensure proper sample flow. Additional components can be added to reduce the risk of accumulation and / or ensure appropriate viscosity. Excipients include, for example, L-arginine hydrochloride in various concentrations (40-260 nM and ranges therebetween). Sucrose may be further added at a concentration of about 0.5% to about 5%. Methionine may also be included in the composition at a concentration range of 5 mM to about 150 mM. Other excipients for ease of formulation and handling may include polysorbate at a concentration range of 0.01% to 0.03%. A buffering agent may also be added to achieve a pH range of about 5.0 to 6.5 or any level therebetween. Histidine may be used as a buffering agent at a concentration range of about 5 mM to 50 mM or any value therebetween. Antioxidants such as glutathione CSH, cysteine, and cystine may be used at a concentration range of about 0.02 mM to 4 mM.

[0100] Leknemab LEQEMBI (lecanemab) (BAN2401) is an intravenously administered amyloid beta-targeting antibody for the treatment of Alzheimer's disease. Treatment with this agent should begin in patients with mild cognitive impairment or mild dementia. The warnings and precautions section of the prescribing information highlights amyloid-related imaging abnormalities (ARIA) and recommends increased clinical vigilance for ARIA during the first 14 weeks of treatment with LEQEMBI. The risk of ARIA, including symptomatic ARIA, is increased in apolipoprotein E ε4 homozygotes compared with heterozygotes and non-carriers. Lecanemab-irmb is a recombinant humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody that targets accumulated soluble and insoluble amyloid beta. It is expressed in a CHO cell line and has a molecular weight of approximately 150 kDa. It is commercially available in single-dose vials at concentrations of 500 mg / 5 mL (100 mg / mL) or 200 mg / 2 mL (100 mg / mL). This solution contains histidine hydrochloride monohydrate, polysorbate, histidine, arginine hydrochloride, and water at pH 5.0.

[0101] For LEQEMBI (lecanemab), once the presence of amyloid-β is confirmed, the recommended dose is 10 mg / kg, which should be diluted and administered as an intravenous infusion over approximately one hour once every two weeks. MRI is required to assess ARIA before starting treatment and before the fifth, seventh, and fourteenth infusions. Monoclonal antibodies targeting accumulated forms of beta amyloid, including LEQEMBI, are known to cause ARIA characterized as ARIA with edema detectable on MRI scans as cerebral edema or gingival crevicular fluid (ARIA-E), as described in the prescribing information. Reduction or elimination of clusters or accumulated forms of beta amyloid will alleviate ARIA caused by monoclonal antibody treatment.

[0102] Lecanemab comprises a sequence selected from the group consisting of: Subunit 1 (SEQ ID NO: 9) EVQLVESGGG LVQPGGSLRL SCSASGFTFS SFGMHWVRQA PGKGLEWVAY ISSGSSTIYY GDTVKGRFTI SRDNAKNSLF LQMSSLRAED TAVYYCAREG GYYYGRSYYT MDYWGQGTTV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK RVEPKSCDKT HTCPPCPAPE LLGGPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE KTISKAKGQP REPQVYTLPP SREEMTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SPGK Subunit 2 (SEQ ID NO: 9) EVQLVESGGG LVQPGGSLRL SCSASGFTFS SFGMHWVRQA PGKGLEWVAY ISSGSSTIYY GDTVKGRFTI SRDNAKNSLF LQMSSLRAED TAVYYCAREG GYYYGRSYYT MDYWGQGTTV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK RVEPKSCDKT HTCPPCPAPE LLGGPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE KTISKAKGQP REPQVYTLPP SREEMTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SPGK Subunit 3 (SEQ ID NO: 10) DVVMTQSPLS LPVTPGAPAS ISCRSSQSIV HSNGNTYLEW YLQKPGQSPK LLIYKVSNRF SGVPDRFSGS GSGTDFTLRI SRVEAEDVGI YYCFQGSHVP PTFGPGTKLE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC Subunit 4 (SEQ ID NO: 10) DVVMTQSPLS LPVTPGAPAS ISCRSSQSIV HSNGNTYLEW YLQKPGQSPK LLIYKVSNRF SGVPDRFSGS GSGTDFTLRI SRVEAEDVGI YYCFQGSHVP PTFGPGTKLE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC

[0103] Logovinsky, et al. reported on the safety and tolerability of BAN2401 in a clinical study of Alzheimer's disease using a prefibril-selective Aβ antibody. See Logovinsky, et al. Alzheimer's Research & Therapy (2016) 8:14. Prefibrils are soluble Aβ aggregates larger than approximately 100 kDa. The article noted that there is growing evidence that soluble oligomers and prefibrils are more toxic than insoluble prefibrils. Safety and tolerability were evaluated in subjects with mild to moderate Alzheimer's disease. In this study, BAN2401 was administered in parallel at stepwise escalation doses ranging from a single dose of 0.1 mg / kg to 10 mg / kg every other week for 4 months. The presence of ARIA (ARIA-E and ARIA-H) was measured using MRI and cerebrospinal fluid (CSF), and plasma samples were also analyzed to determine the pharmacokinetics of biomarkers and the drug's potential effect on such markers. Data essentially showed that BAN2401 was well tolerated and the incidence of ARIA-E / H as measured by MRI was comparable to placebo. These results allowed progression to a Phase 2b efficacy study.

[0104] BAN2401 is described as a humanized IgG1 monoclonal version of the murine monoclonal antibody mAb158, which selectively binds to Aβ prefibrils. U.S. Patent No. 8,025,878 discloses an isolated antibody or fragment thereof having selective and high affinity for human Aβ prefibrils, wherein the six CDR regions of the antibody or fragment thereof comprise a consensus sequence selected from the following: VH-CDR-1 SFGMH SEQ ID NO: 13 VH-CDR2 YISSGSSTIYYGDTVKG SEQ ID NO: 14 VH-CDR3 EGGYYYGRSYYTMDY SEQ ID NO: 15 VL-CDR1 RSSQSIVHSNGNTYLE SEQ ID NO: 16 VL-CDR2 KVSNRFS SEQ ID NO: 17 VL-CDR3 FQGSHVPPT SEQ ID NO: 18.

[0105] U.S. Pat. No. 9,573,994 discloses an antibody or antigen-binding fragment thereof having affinity for Aβ protofibrils, the antibody or antigen-binding fragment thereof comprising a variable light chain set forth in SEQ ID NO: 8 (herein SEQ ID NO: 19), x1 (X at position 17 of SEQ ID NO: 19) is selected from A, D, E, and Q, or functional analogs thereof; x2 (X at position 79 of SEQ ID NO: 19) is selected from R, T, K, A, and G, or functional analogs thereof; x3 (X at position 82 of SEQ ID NO: 19) is selected from R, S, C, g, and N, or a functional analog thereof; y1 (X at position 13 of SEQ ID NO: 19) is selected from V and A; y2 (X at position 21 of SEQ ID NO: 19) is selected from I and V; y3 (X at position 81 of SEQ ID NO: 19) is selected from S and Q; y4 (X at position 84 of SEQ ID NO: 19) is a variable light chain selected from E and D, and optionally A variable heavy chain according to SEQ ID NO: 14 (herein SEQ ID NO: 20), z1 (X at position 37 of SEQ ID NO: 20) is selected from V and I; z2 (X at position 38 of SEQ ID NO: 20) is selected from R and Q; z3 (X at position 40 of SEQ ID NO: 20) has a variable heavy chain selected from R and Q; However, the combinations x1=A, x2=R, and x3=R are exceptions.

[0106] SEQ ID NO: 19: DVVMTQSPLSLPXTPGXPAS XSCRSSQSIVHSNGNTYLEW YLQKPGQSPKLLIYKVSNRF SGVPDRFSGSGSGTDFTLXI XXVXAEDVGIYYCFQGSHVP PTFGPGTKLEIK SEQ ID NO: 20 EVQLVESGGGLVQPGGSLRL SCSASGFTFSSFGMHWXXQX PGKGLEWVAYISSGSSTIYY GDTVKGRFTISRDNAKNSLF LQMSSLRAEDTAVYYCAREG GYYYGRSYYTMDYWGQGTTV TVSS

[0107] SEQ ID NO:12 (light chain) and SEQ ID NO:16 (heavy chain) disclosed in U.S. Pat. No. 9,573,994 (SEQ ID NOs:21 and 22 herein) are nearly identical to or identical to SEQ ID NO:10 and SEQ ID NO:9, respectively, disclosed herein.

[0108] SEQ ID NO: 21 DVVMTQSPLSLPATPGDPAS ISCRSSQSIVHSNGNTYLEW YLQKPGQSPKLLIYKVSNRF SGVPDRFSGSGSGTDFTLTI SRVDAEDVGIYYCFQGSHVP PTFGPGTKLEIK SEQ ID NO:22: EVQLVESGGGLVQPGGSLRL SCSASGFTFSSFGMHWVRQT PGKGLEWVAYISSGSSTIYY GDTVKGRFTISRDNAKNSLF LQMSSLRAEDTAVYYCAREG GYYYGRSYYTMDYWGQGTTV TVSS

[0109] Swanson et al. reported a randomized, double-blind, phase 2b, proof-of-concept clinical trial of lecanemab in early Alzheimer's disease. See Swanson et al. Alzheimer's Research and Therapy (2021) 13:80. Lecanemab (BAN2401) is described as having activity across oligomers, protofibrils, and insoluble protofibrils, preferentially targeting soluble accumulated amyloid beta (Aβ). The primary endpoint of this study was described as a Bayesian analysis of 12-month clinical change in the Alzheimer's Disease Composite Score (ADCOMS) at the ED90 dose, requiring an 80% probability of a ≥25% reduction in functional decline compared to placebo. Secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography, clinical deterioration on the ADCOMS Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Alzheimer's Disease Rating Scale Cognitive Subscale (ADS-Cog14), and changes in CSF core biomarkers and total hippocampal volume (HV) using volumetric magnetic resonance imaging. Although the study results did not meet the primary endpoint, promising results from this phase 2b study led to the initiation of a phase 3 study. In this study, a prespecified 18-month Bayesian and frequentist analyses demonstrated that lecanemab at 10 mg / kg every 2 weeks resulted in consistent reductions in clinical deterioration across several clinical and biomarker endpoints, along with reductions in brain amyloid, and a low incidence (9.9%) of amyloid-related imaging abnormalities (edema / effusion). The analysis results for ApoE4-positive and ApoE4-negative patients with ARIA-E were 14.3% and 8.0%, respectively, with a mean of 9.9%.

[0110] Lecanemab was approved for use in 2023. Notably, patients enrolled in a clinical study conducted prior to approval (i.e., Study 1) had a Clinical Dementia Rating (CDR) global score of 0.5 or 1.0 and a Memory Box score of 0.5 or greater. Additionally, all patients had a Mini-Mental State Examination (MMSE) score of ≤22. Combining scyllo-inositol with lecanemab in the same patient population appears to significantly improve the primary endpoints of these studies and significantly reduce ARIA-E events in both ApoEE4-positive and -negative subjects.

[0111] U.S. Patent No. 8,025,878 discloses a mouse antibody or humanized monoclonal antibody that is the lead mouse antibody for lecanemab, both of which are selective for the prefibrillar structure of amyloid beta protein (Aβ) and are of the IgG class and IgG1 or IgG4 subclass, or a combination thereof. The patent's figures and detailed examples provide characterization data, i.e., therapeutic efficacy in transgenic mouse models, as well as the reactivity of mAb158 with Aβ prefibrils, Aβ fibrils, medin fibrils, iset amyloid polypeptide (IAPP) fibrils, and α-synuclein fibrils in dot blot assays. The patent also provides immunoprecipitation data from HEK cell culture medium, along with data showing the results of a sandwich ELISA using mAb158 as both the capture and detection antibodies. Figure 8 in the disclosure provides the levels of Aβ prefibrils in APP Arc-Swe and APP Swe transgenic mice after four months of treatment with mAb158 or placebo. U.S. Patent No. 8,025,878 also discloses the binding activity of the humanized antibody BAN2401 (lecanemab), and the results showed that it has the same binding characteristics as mAb158. Example 11 describes a manufacturing method for the chimeric antibody BAN2401. Example 8 provides a method used to demonstrate in vivo activity in transgenic mice. mAb158 (12 mg / kg) was intraperitoneally injected into 9-10 month-old APP-swearc mice once weekly for 18 weeks. Upon completion of the study, mouse brains were isolated, homogenized in TBS, and centrifuged to precipitate insoluble material. The insoluble material was then dissolved in formic acid. Two fractions were obtained from the mouse brains: a TBS fraction and a formic acid fraction. The levels of Aβ profibrils in the TBS fraction were determined using ELISA. This example showed that the levels of Aβ prefibrils were significantly reduced in mice treated with mAb158 compared to the placebo group. Figure 8 of this patent shows the results. Total Aβ in the formic acid fraction was also determined by ELISA, confirming that formic acid is used to solubilize all Aβ forms, making all such forms detectable.Figure 9 of this patent shows results demonstrating a significant reduction in total Aβ in drug-treated mice compared to the control group. These same studies can be performed using any monoclonal antibody combination, but more specifically, in mouse studies, antibodies that exhibit selective affinity for Aβ prefibrils, such as lecanemab or mAb158, can be combined with scyllo-inositol to determine the effect of the combination therapy(ies) in transgenic mice. Studies can include mice pretreated with scyllo-inositol for a period of time and / or can be performed with scyllo-inositol and monoclonal antibody treatment at the same time points and over the same treatment period.

[0112] U.S. Patent No. 9,573,994 discloses and claims Aβ prefibril-binding antibodies, including BAN2401 (lecanemab). The patent reveals that a humanized form of mAb158, known as BAN2401, exhibits enhanced properties, such as increased half-life, when specific mutations are introduced into specific positions in the variable light chain of BAN2401. These include Kabat positions 17, 74, and 77 in the variable light chain. This mutated version is now known as lecanemab. The A, R, and R at each position on the BAN2401 variable light chain are altered as described in this patent, which is incorporated herein by reference in its entirety. Example 5 shows an in vitro whole protein T-cell assay of BAN2401 compared to the variants A17D, A17D / R79T, and A17D / R79T / R82S. The results showed that the risk of immunogenicity was low for BAN2401, with A17D showing a low risk near the lower limit, while A17D / R79T and A17D / R79T / R82S showed an unexpectedly high immunogenicity risk.

[0113] The '994 patent discloses these antibodies for use in treating or preventing Alzheimer's disease and other diseases associated with the accumulation of Aβ protein. Specific such uses include traumatic brain injury (TBI), Lewy body dementia (LBD), Down's syndrome, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, tauopathies, systemic amyloidosis, atherosclerosis, and Parkinson's disease dementia. The methods involve the use of the antibodies and antibody-binding fragments thereof.

[0114] Donanemab Donanemab is a humanized IgG1 antibody that targets the N-terminal pyroglutamic acid Aβ epitope, known to be located on established plaques. The monoclonal antibody does not exhibit off-target binding to other Aβ species. A phase 2 study reported in the New England Journal of Medicine and other journals included subjects with early-onset Alzheimer's disease, defined as prodromal Alzheimer's disease characterized by mild cognitive impairment, or mild Alzheimer's disease accompanied by dementia. The study included subjects with MMSE scores of 20-28. This clinical trial is known as the TRAILBLAZER-ALZ trial. U.S. Patent No. 8,679,498 discloses and claims donanemab and is incorporated herein by reference in its entirety. This patent describes and discloses an in vitro target binding study that describes immunohistochemistry of exogenously added Aβ antibodies to brain sections from fixed PDAPP transgenic mouse brains (24 months old) to determine in vitro target binding. This mouse model is said to develop much of the pathology of, or associated with, Alzheimer's disease. In this example, a biotin tag was used on the mouse antibody, which was performed on mouse tissue. In these studies, the biotinylated 3D6 N-terminal (1-5) antibody was shown to strongly label the bulk of Aβ deposited in the PDAPP hippocampus. Similarly, examples in this patent disclosure demonstrate in vivo target binding in a mouse model and also describe plaque reduction studies of therapeutics in 23-month-old PDAPP mice.

[0115] A plaque reduction study of these therapeutics was conducted as follows: A negative control antibody (IgG2a) was administered subcutaneously at a dose of 12.5 mg / kg weekly for three months, along with 3D6, mE8 (IgG1), and mE8c (IgG2a). At the beginning of the study (time point zero), groups of mice were sacrificed, and initial plaque burden at 23 months of age was determined. At the end of the study, plasma was obtained, and brains were processed (one brain per group) for biochemical and histological results. Next, hippocampal and cortical regions were homogenized in 5 M guanidine, and Aβ content was measured using acid urea gel, followed by Western blotting. The patented data showed no significant increase in deposited Aβ plaque burden in the control group, thus confirming that the mice were in a state where plaque progression had ceased. Treatment with the comparative antibody 3D6 was ineffective in reducing plaques. Treatment with the N3pGlu antibodies mE8 or mE8c significantly reduced plaques compared to the IgG2a negative control antibody. mE8 and mE8c reduced hippocampal Aβ1-42 levels by approximately 38% and 53%, respectively.

[0116] Similar studies can be performed using either the monoclonal antibodies described herein or their murine versions to determine the plaque-lowering efficacy of therapeutics that combine monoclonal antibodies with scyllo-inositol.

[0117] 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.

[0118] 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.

[0119] Clinical evaluations used to determine the stage and overall progression of Alzheimer's disease and / or to prevent or reverse disease progression include the CDR, FCSRT, Neuropsychiatric Inventory-Questionnaire (NPI-Q), and neurological test batteries, including the Rey Auditory Verbal Learning Test (RA-VLT), immediate and delayed memory, the Wechsler Memory Scale (WMS), the Verbal Paired Associate Learning Test (VLT), Verbal Fluency Test (VLT), Conditions 1 and 2 of the DeLis-Kaplan Executive Function Test, and the Wechsler Adult Intelligence Scale-Fourth Edition, Symbol Retrieval 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 subitems may also be used to assess cognition. [Example]

[0120] Example 1 - Preclinical and clinical studies demonstrating that scyllo-inositol interacts with and disassembles amyloid aggregates Preclinical and clinical studies related to scyllo-inositol have been published, demonstrating its safety and activity. See Clinicaltrials.gov and the patent publications cited herein, all of which are incorporated by reference. Additionally, unpublished analyses have been conducted that have yielded findings regarding the use of scyllo-inositol in a subset of patients with mild AD and / or MCI, with MMSE scores of 22-26.

[0121] Figure 1A-F shows the effect of 250 mg BID scyllo-inositol treatment in mild / moderate AD patients (MMSE 16-30) on the primary endpoints (NTB, ADCS-ADL, and CDR-SB). The data demonstrate that treating mild and moderate AD patients with scyllo-inositol for 78 weeks did not improve NTB, ADCS-ADL, or CDR-SB scores as measures of cognition and function. However, a small signal was observed in NTB scores in the protocol-compliant population.

[0122] Figure 2 shows the effect of 78 weeks of scyllo-inositol treatment in patients with early, mild AD (MMSE 23-26) in the pre-specified overall and per-protocol populations. After scyllo-inositol treatment, analysis of the overall population showed a 72% improvement in NTB scores compared to the placebo population. Similarly, data from the per-protocol population showed a 100% improvement in NTB scores compared to placebo. These data provide a strong signal that scyllo-inositol treatment improves cognition in patients with early, mild AD.

[0123] Figures 3A-I show the change from baseline in NTB subscale scores for a population of mild AD patients (MMSE23-26) treated with scyllo-inositol and placebo over the study period (78 weeks). The data show that eight of the nine NTB subscales improved over 78 weeks with scyllo-inositol treatment. These data indicate that scyllo-inositol improves a variety of symptoms related to cognition.

[0124] Figure 4 shows the change from baseline in ADCS-ADL scores for patients with early to mild AD (MMSE 23-26) treated with scyllo-inositol and placebo for 78 weeks. The data show that, compared with placebo, scyllo-inositol treatment improved ADCS-ADL scores throughout the 78-week study period. Scyllo-inositol treatment improved ADCS-ADL scores by 35% and 31% in the complete analysis and protocol-compliant populations, respectively. These data suggest that scyllo-inositol improves function in patients with early to mild AD.

[0125] Figure 5 shows the change in CDR-SB score from baseline in patients with early-to-mild AD (MMSE 23-26) treated with scyllo-inositol and placebo for 78 weeks. The data show that scyllo-inositol treatment improved CDR-SB scores over the 78-week study period compared to placebo. Scyllo-inositol treatment resulted in a 40% and 44% improvement in CDR-SB scores compared to placebo in the complete analysis and protocol-compliant populations, respectively. These data demonstrate that scyllo-inositol improves cognition and function as measured by the CDR-SB test.

[0126] Figures 6A-F show the effects of scyllo-inositol versus placebo treatment on change from baseline in the CDR-SB subscales in patients with early mild AD from the Per-Protocol Population (PPS). These data show that scyllo-inositol improved five of the six subscales of the CDR-SB test, which measures both cognition and function.

[0127] Figures 7A-D show the observed change from baseline in NTB scores with scyllo-inositol treatment in patients with mild AD who had MMSE scores of 20-26. The data show that scyllo-inositol was more effective in improving NTB scores in the patient population whose MMSE scores increased up to 23. Ideally, this agent would be effective in patients with MMSE scores of 22 or higher.

[0128] Figures 8A–D show bootstrap simulation data for the change from baseline in NTB scores with scyllo-inositol treatment in various groups of mild AD patients with MMSE scores ranging from 20 to 26. Analyzing the data using the bootstrap simulation method, increasing N from 30 to 100, showed a pattern similar to the observed data. These data indicate that the change in NTB was more pronounced in the scyllo-inositol-treated group when bootstrap analysis was performed, suggesting that further increasing the number of patients would strengthen the analysis.

[0129] 9A-D show observational data showing the change from baseline in CDR-SB scores with scyllo-inositol treatment in different mild AD groups with MMSE scores of 20-26. Similarly, scyllo-inositol treatment was effective in patients with early, mild AD who had an MMSE score of 22 or higher.

[0130] Figures 10A-D show bootstrap simulation data showing the change from baseline in CDR-SB scores with scyllo-inositol treatment in various mild AD groups with MMSE score ranges of 20-26. The data show a similar pattern of scyllo-inositol treatment effects on CDR-SB tests when bootstrap simulation analyses were performed. When the number of patients in the simulation analysis was increased from 30 to 100, the change in CDR-SB scores in the scyllo-inositol-treated group compared to placebo was more pronounced.

[0131] Figures 11A–D show a comparison of observed and simulated data for changes in NTB and CDR-SB scores with scyllo-inositol treatment in patients with mild AD with MMSE scores of 22–26. Figure 1A shows the AD201 observed values ​​(NTB). Figure 1B shows the simulated bootstrap (NTB). Figure 1C shows the AD201 observed values ​​(CDR-SB). Figure 1D shows the simulated bootstrap (CDR-SB). In the bootstrap simulation, an N = 100 was used, whereas in the observed set, N = 30. For both NTB and CDR-SB endpoints, statistical significance was achieved in the treatment group compared with the placebo group in the simulated comparisons. These data demonstrate that scyllo-inositol exhibits strong efficacy in improving cognition and function in patients with early mild AD with an MMSE score of 22 or higher.

[0132] Example 2 - Clinical Study of Scyllo-inositol in Combination with Aducanumab The clinical study will be conducted in patients with mild cognitive impairment (MCI) and / or mild Alzheimer's disease. Enrolled patients with MCI and / or mild Alzheimer's disease will be pretreated with scyllo-inositol for 4 weeks, followed by co-administration of scyllo-inositol (250 mg or 500 mg BID) with anti-amyloid beta antibody therapy for MCI and mild AD to mitigate concerns associated with ARIA with monoclonal therapy alone. This clinical study will measure the efficacy of the drug combination in enhancing reduction of amyloid beta burden in the brain and demonstrate improved efficacy and safety compared to treatment with either drug alone. MCI and mild AD patients will be divided into three cohorts and treated as follows: a. Cohort #1, patients will be treated with placebo for 4 weeks, followed by a combination of placebo and ascending doses of aducanamab alone, initially at 1 mg / kg (4 weeks), 3 mg / kg (4 weeks), 6 mg / kg (4 weeks), and 10 mg / kg for the remainder of the study (24 weeks). Patients will be evaluated for ARIA, amyloid-beta burden, memory, cognition and function, and safety parameters. b. Cohort #2, patients are treated with either 250 mg BID scyllo-inositol alone for 4 weeks, followed by either 250 mg BID scyllo-inositol in combination with aducanamab, initially at 1 mg / kg, then 3 mg / kg (4 weeks), 6 mg / kg (4 weeks), and a final dose of 10 mg / kg for the remainder of the study (24 weeks). Patients are evaluated for ARIA, amyloid beta burden, memory, cognition and function, and safety parameters. c. Cohort #3, patients were treated with 500 mg BID scyllo-inositol alone for 4 weeks, followed by 250 mg BID scyllo-inositol in combination with aducan, initially at 1 mg / kg (4 weeks), 3 mg / kg (4 weeks), 6 mg / kg (4 weeks), and then escalating to 10 mg / kg for the remainder of the study (24 weeks). Patients were evaluated for ARIA, amyloid beta burden, memory, cognition and function, and safety parameters.

[0133] Results demonstrate that 36 weeks of combined treatment with scyllo-inositol and aducanumab results in:

[0134] ARIA was reduced compared with aducanumab treatment alone.

[0135] Amyloid-beta burden in the brain was reduced compared with treatment with aducanumab alone.

[0136] Memory, cognition, and function improved compared with aducanumab treatment.

[0137] CSF amyloid beta biomarkers such as amyloid beta 42 / 40 ratio, tau, and phosphorylated tau improved.

[0138] The specific clinical protocol will follow the same protocols used in the ADUHELM clinical study to measure plaque levels, ARIA impact, tau protein in the CSF, and exposure-response relationships, respectively.

[0139] Example 3 - Studies conducted with the combination of scyllo-inositol and lecanemab The clinical study will be conducted in patients with mild cognitive impairment (MCI) with an MMSE score of 26-30 and / or mild Alzheimer's disease with an MMSE score of 22-26. Enrolled patients with MCI and / or mild Alzheimer's disease will be treated with either placebo or scyllo-inositol in combination with lecanemab.

[0140] A subset of patients with mild AD with MMSE scores of 22-26 or 23-26 will be recruited for the clinical trial. Each group will include at least 45-50 patients. The three groups include: (1) patients treated with placebo for 4 weeks followed by treatment with the selected immunotherapy agent for 36 weeks; (2) patients treated with scyllo-inositol 250 mg BID for 4 weeks followed by treatment with scyllo-inositol 250 mg BID plus the selected immunotherapy agent at the prescribed dose and frequency for 36 weeks; and (3) patients treated with scyllo-inositol 500 mg BID for 4 weeks followed by treatment with scyllo-inositol 250 mg BID plus the selected immunotherapy agent at the prescribed dose and frequency for 36 weeks. The primary endpoints are the incidence of ARIA E and H at weeks -4, 0, 14, 26, and 36. Secondary endpoints include measurement of Aβ burden (PET scan) at weeks -4 and 36; other endpoints include NTB, cDR-SB, and MMSE. Biomarkers such as tau and p-tau may also be measured. The incidence or prevalence of ARIA in patients treated with immunotherapy drugs is estimated to be approximately 22-30% for ARIA E and H, based on and compared to data obtained for ARIA in reported clinical trials of lecanemab in both Apo E4-negative and -positive subjects.

[0141] Clinical studies of combinations of decanemab with other known monoclonal antibodies for treating Alzheimer's disease and scyllo-inositol can also be conducted following protocols similar to those described above for lecanemab and aducanumab.

Claims

1. A method of treating MCI and Alzheimer's disease in a human patient comprising administering a pharmaceutically effective amount of a recombinant fully human anti-amyloid beta monoclonal antibody and a pharmaceutically effective amount of scyllo-inositol.

2. 2. The method of claim 1, wherein the monoclonal antibody is selected from aducanumab, lecanemab, or donanemab.

3. 3. The method of claim 2, wherein the aducanumab comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a complementarity determining region 1 (VHCDR1) having the amino acid sequence set forth in SEQ ID NO: 3, a VHCDR2 having the amino acid sequence set forth in SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence set forth in SEQ ID NO: 5, and the VL comprises a VLCDR1 having the amino acid sequence set forth in SEQ ID NO: 6, a VLCDR2 having the amino acid sequence set forth in SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence set forth in SEQ ID NO:

8.

4. 3. The method of claim 2, wherein the lecanemab comprises a heavy chain and a light chain selected from sequences having at least 90% identity to SEQ ID NOs: 9 and 10.

5. 10. The method of claim 1, wherein the scyllo-inositol is administered orally in a dosage range of 125-250 mg BID, or 250 mg QD or 500 mg QD.

6. 1. A method for reducing brain amyloid-β plaques in a patient with Alzheimer's disease, comprising administering an effective amount of aducanumab in combination with an effective amount of scyllo-inositol.

7. 1. A method of treating Alzheimer's disease patients with confirmed amyloid pathology and a disease stage of mild cognitive impairment or mild dementia consistent with stage 3 or stage 4 of Alzheimer's disease, comprising administering about 1 mg / kg to about 10 mg / kg of aducanumab as an IV infusion over one hour every four weeks separated by at least 21 days, and administering an effective amount of scyllo-inositol.

8. 8. The method of claim 7, wherein infusions 1 and 2 are 1 mg / kg, infusions 3 and 4 are 3 mg / kg, infusions 5 and 6 are 6 mg / kg, and infusions 7 and beyond are 10 mg / kg, injections are given at 4 week intervals, and the scyllo-inositol is administered at a concentration of 100 mg BID, or 125-250 mg BID or 250 mg QD or 500 mg QD.

9. 8. The method of claim 7, wherein the scyllo-inositol enhances the efficacy of aducanumab as measured by NTB, CDR-SoB, MMSE, and related cognitive and functional sub-items.

10. 8. The method of claim 7, wherein the scyllo-inositol enhances cognition in a subject receiving the combination therapy compared to treatment with aducanumab alone.

11. 8. The method of claim 7, wherein the scyllo-inositol reduces the dosage requirement of the aducanumab, with seventh and subsequent infusions being 6 mg / kg.

12. 8. The method of claim 7, wherein the combination therapy reduces ARIA aducanumab-related events compared to treatment with aducanumab alone at the same infusion volume.

13. The use of scyllo-inositol as an adjuvant to reduce the amount of monoclonal antibody required to treat an Alzheimer's disease patient in need of treatment.

14. 14. The use of claim 13, wherein the monoclonal antibody is selected from aducanumab, lecanemab, or decanemab.

15. 1. A method of alleviating ARIA in a patient receiving monoclonal antibody therapy, comprising administering to a patient in need of treatment a pharmaceutically effective amount of scyllo-inositol, wherein said reduction is compared to a patient receiving such monoclonal antibody therapy without scyllo-inositol.

16. 1. A method for reducing the amount of amyloid beta accumulation in the brain of a patient with mild Alzheimer's disease, comprising administering to said patient a pharmaceutically effective amount of scyllo-inositol in combination with a pharmaceutically effective amount of a monoclonal antibody, wherein said mild Alzheimer's disease includes patients with an MMSE score of 22-26.

17. 1. A method of improving memory, cognition and / or brain function in an Alzheimer's disease patient in need of treatment, wherein said patient is treated with a monoclonal antibody with co-administration of a pharmaceutically effective amount of scyllo-inositol, such co-administration improving memory, cognition and / or brain function compared to a patient treated with said monoclonal antibody alone.

18. 18. The method of claim 17, wherein the monoclonal antibody is selected from the group consisting of aducanumab, lecanemab, or decanemab.

19. 1. A method for improving positive biomarkers in the CSF of Alzheimer's disease patients treated with a monoclonal antibody, comprising co-administration of a pharmaceutically effective amount of scyllo-inositol, wherein the improvement is compared to a control patient treated with the monoclonal antibody alone.

20. 20. The method of any one of claims 15-19, wherein the patient is pretreated with scyllo-inositol at a dosage of 125-250 mg BID, or 250 mg QD or 500 mg QD at a time, prior to receiving the monoclonal antibody therapy.

21. 21. The method of claim 20, wherein the pretreatment period is about 2 to 6 weeks.

22. 22. The method of claim 21, wherein the duration of the combination therapy is at least 6 months, or the entire duration of the antibody treatment.

23. A pharmaceutical combination comprising a scyllo-inositol and a humanized monoclonal antibody or binding fragment thereof, wherein said antibody is selected from the group consisting of aducanumab, decanemab, or lecanemab.

24. 24. The method of claim 23, wherein the scyllo-inositol is administered at a dosage of 250 mg BID and the monoclonal antibody is administered at a dosage of about 1-10 mg / kg by intravenous infusion over 1 hour once every two weeks.

25. 25. The combination of claim 24, wherein the monoclonal antibody is selected from lecanemab.

26. A method of treating cognitive decline in a subject in need thereof, comprising administering to said subject a pharmaceutically effective amount of a combination of scyllo-inositol and a humanized monoclonal antibody.

27. 27. The method of claim 26, wherein the humanized monoclonal antibody is selected from aducanumab, lecanemab, or decanemab.

28. Use of a combination of a pharmaceutically effective amount of scyllo-inositol and a pharmaceutically effective amount of a humanized monoclonal antibody targeting at least one Aβ oligomer, prefibril, protofibril, or version thereof in the manufacture of a medicament for treating Alzheimer's disease and related cognitive disorders.

29. 1. A method of treating a patient in need thereof, comprising administering a pharmaceutically effective amount of scyllo-inositol in combination with an immunotherapeutic agent, wherein the scyllo-inositol performs at least one of the following functions: (i) degrades Aβ fibrils; (ii) prevents Aβ binding to fibrils; (iii) increases soluble Aβ levels in brain interstitial fluid; and (iv) increases Aβ uptake by microglia; and (v) reduces Aβ burden and increases Aβ clearance in a subject in need of treatment at an effective concentration of about 5-10 μM.

30. 1. A method of treating a patient with Alzheimer's disease in whom the presence of amyloid-β pathology has been confirmed, comprising: (i) pretreating the subject with a pharmaceutically effective amount of scyllo-inositol; (ii) obtaining a brain MRI of the subject to assess for pre-existing amyloid-related imaging abnormalities (ARIA) within one year of initiating treatment with a monoclonal antibody selected from lecanemab; and (ii) administering lecanemab in a diluted formulation at a dose of about 10 mg / kg, and administering the diluted lecanemab formulation together with a pharmaceutically effective amount of scyllo-inositol (at a dose of 125-250 mg BID or 500 mg QD) as an intravenous infusion over about one hour once every two weeks.

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