Therapeutic composition for treating mild cognitive impairment and method of use of combination therapy

Abstract

The present invention recognizes that there is an unsatisfied need for the treatment of mild cognitive disorders. A first aspect of the present invention relates generally to a method of treating, alleviating or ameliorating mild cognitive impairment in a subject. A second aspect of the invention generally relates to a method of treating, alleviating or ameliorating Alzheimer's disease in a subject. A third aspect of the present invention generally relates to a method of treating, alleviating or ameliorating Alzheimer's disease psychosis in a subject. A fourth aspect of the invention generally relates to a method of treating, alleviating or ameliorating Alzheimer's disease behavior, aggressiveness, agitation, anger, astrophe, or a combination thereof in a subject. A fifth aspect of the invention generally relates to a method of treating, alleviating or ameliorating early onset Alzheimer's disease in a subject.

Description

Cross Reference to Related Applications

[0001] This application: claims priority to U.S. Provisional Patent Application Serial No. 63 / 526,195, filed July 12, 2023, which is currently pending; the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0002] The present invention relates generally to novel cyclic dipeptide compounds structurally related to diketopiperazines and methods of therapeutic applications thereof. In particular, the present invention relates generally to cyclic prolyl glycine (“cyclic GP” or “cPG”) and cPG analogs and cPG compounds, pharmacologically effective analogs thereof, and pharmaceutical compositions thereof in combination with specific binding members (e.g., antibodies or active fragments thereof, such as but not limited to the monoclonal antibody Lecanemab) for the treatment and prevention of progression of cognitive impairment and related neurodegenerative diseases and psychological disorders (e.g., but not limited to mild cognitive impairment, such as but not limited to diseases related to Alzheimer’s disease). BACKGROUND

[0003] Mild cognitive impairment (MCI) is a syndrome defined as a decline in cognitive abilities beyond what is expected for an individual’s age and education level. Mild cognitive impairment refers to a memory and other cognitive dysfunction that involves more than what is normal for age but does not reach the characteristics of dementia.

[0004] The prevalence of MCI varies with age. The prevalence of MCI in different age groups is as follows: 6.7% for ages 60-64; 8.4% for ages 65-69; 10.1% for ages 70-74; 14.8% for ages 75-79; and 25.2% for ages 80-84. More than half of people with MCI will develop dementia within 5 years. (Petersen RC, Lopez O, Armstrong MJ, Getchius T, Ganguli M, Gloss D, Gronseth GS, Marson D, Pringsheim T, Day GS, Sager M, Stevens J, Rae-Grant A (January 2018). "Practice guideline update summary: Mild cognitive impairment - Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology". Neurology. Special article. 90 (3): 1-10. :10.1212 / WNL.0000000000004826. https: / / en.wikipedia.org / wiki / PubMed_Identifier" \o "PubMed Identifier 29282327.).

[0005] Dementia is an umbrella term describing a group of symptoms associated with an ongoing decline of memory or other mental abilities severe enough to reduce a person's ability to perform everyday activities. Alzheimer's disease accounts for 60% to 80% of these cases. Vascular dementia (usually occurring after a stroke) is the second most common type of dementia. But there are many other diseases that also cause symptoms of dementia, including some reversible conditions such as abnormal thyroid function and vitamin deficiency.

[0006] While symptoms of dementia can vary greatly, at least two of the core psychological functions must be significantly impaired for a person to be diagnosed with dementia: memory, communication and language abilities, ability to pay attention and sustain focus, reasoning and judgment abilities, and visual perception abilities.

[0007] Alzheimer’s disease (AD) is a progressive brain disease characterized by memory loss that eventually leads to impairment in reasoning, planning, language, and perception. In 2018, there were more than 6 million people in the United States and 50 million people worldwide with Alzheimer’s disease (see: Alzheimer’s Disease International’s World Alzheimer Report 2018). The projected growth in the prevalence of Alzheimer’s disease over the coming decades will place significant strain on social and healthcare systems in both developed and developing countries. There remains a long-standing unmet clinical need for therapies that can arrest, significantly slow, slow, or otherwise improve the progression or symptoms of this and related diseases, or provide palliative or palliative care.

[0008] Currently approved AD therapeutics include the cholinesterase inhibitors donepezil, rivastigmine, and galantamine, which are said to address cholinergic deficits in AD by increasing acetylcholine levels in the central nervous system (CNS); and the N-methyl-D-aspartate receptor antagonist memantine. Memantine, approved in 2003, is the newest approved AD drug of a new class; its mechanism of action is postulated to be preferential binding to the N-methyl-D-aspartate (NMDA) receptor-gated cation channel, thereby blocking the persistent activation of the excitatory amino acid glutamate. These drugs can provide some benefit to AD patients, but it is not known whether they slow or arrest neurodegeneration in AD patients. In 2021, the anti-amyloid beta-directed antibody Aducanumab was approved for the treatment of Alzheimer’s disease through the accelerated approval pathway, particularly recommended for patients in the mild cognitive impairment or mild dementia stage of the disease. This approval was based on PET imaging showing reduction in brain amyloid beta (Ab) plaques, an alternative endpoint believed to be reasonably predictive of clinical benefit.

[0009] A number of anti-Ab monoclonal antibodies have been studied in AD, all with negative results in Phase III clinical development; however, it is difficult to compare them to the aducanumab program due to differences in enrollment criteria, study design, and trial endpoints. In addition, there are significant differences between anti-Ab monoclonal antibodies in their binding to different epitopes and selectivity for different Ab variants (e.g., monomers, soluble oligomers, aggregated forms) (Linse et al., 2020). The degree of amyloid reduction also varies among these studies.

[0010] Monoclonal antibodies to aggregated forms of beta amyloid protein, such as lecanemab, can cause amyloid-related imaging abnormalities (ARIA), which are characterized as ARIA with edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions; and ARIA with hemosiderin deposits (ARIA-H), which include microhemorrhages and superficial siderosis.

[0011] In participants receiving lecanemab 10 mg / kg every two weeks, 12% of participants observed ARIA (20 of 161), compared to 5% of participants in the placebo group (13 of 245). In the group receiving lecanemab 10 mg / kg every two weeks, 10% of treated participants observed ARIA-E, compared to 1% of participants in the placebo group. In Eisai-sponsored Study 201, 3% of participants receiving lecanemab 10 mg / kg every two weeks (5 of 161) had symptomatic ARIA, compared to no participants in the placebo group. In participants receiving lecanemab 10 mg / kg every two weeks, the most common symptoms that occurred in participants with ARIA were headache, confusion / altered mental status, agitation, and visual disturbances, in 2 or more cases. Four of the 5 participants had resolution of clinical symptoms during the observation period. (van Dyck CH, et al. Lecanemab in Early Alzheimer’s Disease - DOI: 10.1056 / NEJMoa2212948 N Engl J Med 2023; 388:9-21. DOI: 10.1056 / NEJMoa2212948).

[0012] The incidence of ARIA-E was higher in apolipoprotein E epsilon 4 (ApoE epsilon 4) homozygotes (5 of 10) than in heterozygotes (2 of 39) or non-carriers (9 of 112). Four of the ApoE epsilon 4 homozygote subjects had symptomatic ARIA, two of which were severe. Because of the protocol modification to reduce risk in the lower dose group during the conduct of Study 201, only 30% of participants receiving 10 mg / kg of lucatumumab biweekly were ApoE epsilon 4 carriers, whereas 60-70% of the general population have individuals with AD. Therefore, the interpretation of analyses related to ARIA should take into account the limitation of the small number of ApoE epsilon 4 carriers in the lower dose group. However, the Study 301 topline results also indicated that the overall incidence of ARIA and symptomatic ARIA were higher in ApoE epsilon 4 homozygotes compared to heterozygotes and non-carriers.

[0013] Most ARIA-E imaging events occurred within the first three months of treatment, although ARIA can occur at any time. Of the 16 participants who experienced ARIA-E receiving 10 mg / kg of lucatumumab biweekly, the highest imaging severity was mild in 7, moderate in 7, and severe in 2. In the 10 mg / kg biweekly group, 62% of ARIA-E participants resolved within 12 weeks of detection, 81% within 21 weeks, and 94% overall. There was no imbalance between the lucatumumab and placebo groups in the occurrence of isolated ARIA-H. In Study 201, 1 participant receiving 10 mg / kg of lucatumumab biweekly reported a cerebral hemorrhage greater than 1 cm, while no such events occurred in the placebo group. In Study 301 and its extension, intracerebral hemorrhagic events greater than 1 cm in diameter were also reported in patients receiving 10 mg / kg of lucatumumab biweekly.

[0014] In the placebo-controlled period of Study 201, if an ARIA occurred, lumatepemab was discontinued. There were limited data available from the open-label extension phase of Study 201 regarding the safety of continuing lumatepemab dosing after an ARIA-E occurred. In patients who received lumatepemab 10 mg / kg every two weeks, 20% experienced infusion-related reactions, compared to 3% in the placebo group. Infusion reactions were mild (56%) or moderate (44%) in severity, with 88% occurring at the first infusion. Symptoms included fever and flu-like symptoms (chills, generalized aches, chills, and joint pain). The most common drug adverse reactions for lumatepemab were ARIA-E, infusion-related reactions, and headache. In participants who received the proposed dose of lumatepemab 10 mg / kg every two weeks, the incidence of all of these adverse reactions was at least 10% and at least 2% higher than the placebo group during the control period of Study 201. SUMMARY

[0015] The present invention recognizes a long-felt need for treating mild cognitive impairment.

[0016] As a non-limiting introduction to the scope of the present invention, the present invention includes several general and useful aspects, including but not limited to: A first aspect of the present invention generally relates to a method of treating, ameliorating, or lessening mild cognitive impairment in a subject.

[0017] A second aspect of the present invention generally relates to a method of treating, ameliorating, or lessening Alzheimer’s disease in a subject.

[0018] A third aspect of the present invention generally relates to a method of treating, ameliorating, or lessening psychosis in a subject with Alzheimer’s disease. A fourth aspect of the present invention generally relates to a method of treating, ameliorating, or lessening behavior, aggression, agitation, irritability, apathy, or a combination thereof in a subject with Alzheimer’s disease.

[0019] A fifth aspect of the present invention generally relates to a method of treating, ameliorating, or lessening early onset Alzheimer’s disease in a subject.

[0020] These aspects of the present invention, as well as other aspects described herein, can be achieved using the methods, articles of manufacture, and compositions of matter described herein. To fully appreciate the scope of the present invention, it should also be recognized that the various aspects of the present invention can be combined to form the desired embodiments of the present invention.

[0021] Applicants do not wish to be bound by any of the mechanisms of action set forth herein. The present invention is not limited to any particular mechanism of action.

[0022] The neurotoxicity of amyloidogenic proteins has been shown to affect long-term potentiation, plasticity, synaptic signaling, dendritic morphology, and cognitive function in a preclinical study. Tran’s patent has reported that NA-831 induces hippocampal neurogenesis (see: Lloyd Tran, U.S. Patent No. 11,090,303, issued August 17, 2021).

[0023] In the present invention, the combination therapy is considered to also induce neurogenesis, and the effect of the combination therapy is compared with the use of NA-831 or LEQ alone. The administration of the combination therapy of NA-831 and LEQ results in an increased survival rate of newly generated and differentiated neuronal cells compared to the use of NA-831 or LEQ alone.

[0024] Hippocampal neurogenesis plays a key role in long-term memory and cognitive function. In addition, brain-derived neurotrophic factor (BDNF) has been reported to be one of the most important factors for inducing neurogenesis, and it has been reported that NA-831 can increase the expression level of BDNF.

[0025] Studies have shown that BDNF contributes to the neurogenesis of dentate gyrus granule cells. This is a very important issue because the neurogenesis of granule cells is considered to be related to learning, depression, and possibly other neurological and mental functions (Eisch, 2002; Jacobs et al., 2000). In addition, the results suggest that it may be possible in the future to utilize BDNF to increase the number of granule cells after neuronal loss. It is particularly promising that the administration of BDNF alone to one region of the hippocampus appears to have a widespread effect on both sides of the hippocampus. This can have an advantage in terms of treatment.

[0026] Taken together, these results suggest that the combination therapy can improve the survival rate of new cells, which suggests that LEQ can have a potential impact on the toxic microenvironment in part.

[0027] Approximately 55 million people worldwide suffer from Alzheimer’s disease. Neuropsychiatric symptoms (NPS) are almost universally present in dementia patients, with an estimated prevalence of up to 97% (Steinberg, M. et al., Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study, Int. J. Geriatr. Psychiatry 23, 170-177 (2008)).

[0028] These noncognitive symptoms not only cause suffering for people with Alzheimer's disease (AD) or other types of dementia, but also for their caregivers, and are associated with poor outcomes in terms of function, quality of life, disease progression, mortality, and economic costs.

[0029] These NPS include impairments in motivation, interest, social behavior, and insight; mood disorders; anxiety; agitation; impulsive behavior; hallucinations; and delusions—all of which typically require clinical intervention. Without treatment, psychotic symptoms often have an intermittent and fluctuating course, exhibiting a pattern of remission and relapse, with varying degrees of severity.

[0030] Psychosis symptoms (consisting of hallucinations and delusions) are among the most clinically relevant NPS, associated with hospitalization or institutional treatment, cognitive and functional impairment, accelerated cognitive decline and death, and caregiver stress.

[0031] Although antipsychotic drugs are often used to treat psychosis in Alzheimer's patients, no drugs have been approved for the treatment of psychosis in Alzheimer's disease.

[0032] The use of antipsychotic drugs in Alzheimer's disease patients is associated with a variety of side effects, including accelerated cognitive decline; an increased incidence of serious adverse medical events such as stroke, bronchopneumonia, and pulmonary embolism; and a higher short-term mortality rate. Therefore, despite the significant impact of psychosis on Alzheimer's disease patients, no safe and effective drug treatment has been approved, creating a significant unmet therapeutic need. (Ismail, Z., Creese, B., Aarsland, D. et al., Psychosis in Alzheimer disease — mechanisms, genetics and therapeutic opportunities. NatRev Neurol 18, 131-144 (2022). https: / / doi.org / 10.1038 / s41582-021-00597-3).

[0033] In a preferred but non-limiting embodiment of the present invention, the present invention provides the following preferred embodiment: NA-831 combined with a specific binding member or its active fragment (e.g., but not limited to the monoclonal antibody lencanetumab) to reduce the side effects of lencanetumab while enhancing the efficacy of both drugs in treating Alzheimer's disease psychosis.

[0034] One aspect of the present application provides cyclic prolyl glycine compounds suitable for use in combination therapy with a specific binding member (e.g., an antibody or active fragment thereof, such as a monoclonal antibody, such as rancatamab) for the treatment and prevention of diseases and injuries in animals and humans. The cyclic PG is preferably selected from the group consisting of cPG, cPG analogs, cPG peptidomimetics, and compounds that promote or cause the formation of cPG or cPG analogs in vivo.

[0035] Another aspect of the present application relates to a method for restoring axonal myelination in a mammal in need of restoring myelination due to a neural injury or disease, the method comprising administering a therapeutic amount of a cPG compound, wherein the cPG compound comprises cPG, a biologically active cPG analog (e.g., c(PG)3 and cGAL), a biologically active cPG peptidomimetic, a compound that increases the concentration of cPG, or a compound that increases the concentration of a cPG analog, effective to restore myelination of axons in the mammal. In one aspect of the present application, the method for restoring myelination of axons (comprising administering a therapeutic amount of a cPG compound) comprises stimulating astrocytes to promote remyelination. In another aspect of the present application, the method for restoring myelination of axons (comprising administering a therapeutic amount of a cPG compound) comprises stimulating oligodendrocytes to produce myelin.

[0036] In yet another aspect of the present application, the method for restoring myelination of axons in a mammal in need of restoring myelination further comprises administering a therapeutic amount of a cPG compound in combination with a compound selected from the group consisting of IGF-I and an interferon. In one aspect of the present application, the method for restoring myelination of axons comprises administering a therapeutic amount of a cPG compound in combination with IGF-I or an interferon to stimulate astrocytes to promote remyelination. In another aspect of the present application, the method for restoring myelination of axons comprises administering a therapeutic amount of a cPG in combination with IGF-I or an interferon to stimulate oligodendrocytes to produce myelin. In a preferred embodiment, the interferon comprises interferon beta-1 b (Betaseron). In a further most preferred embodiment, the interferon comprises consensus interferon (Infergen®, i.e., interferon alfacon-1).

[0037] In yet another aspect of the application, a method for treating or preventing cell injury and death due to injury and disease comprises administering a therapeutic amount of a cPG compound, preferably but not limited to about 10 μg to about 150 mg of cPG per kilogram of body weight of a mammal. Suitable dosages of cPG for administration can be, for example, preferably but not limited to about 0.1 mg to about 100 mg per kilogram of body weight, about 1 mg to about 100 mg per kilogram of body weight, about 5 mg to about 70 mg per kilogram of body weight, about 10 mg to about 50 mg per kilogram of body weight, or about 20 mg to about 40 mg per kilogram of body weight. The dosage, route of administration, and regimen of cPG can vary for different diseases, disorders, and conditions. For example, the dosage for mild cognitive impairment can be lower than for Alzheimer's disease, using the same or different routes of administration. For example: a typical dosage for a patient with mild cognitive impairment can be about 10 mg to 50 mg per day for oral administration (1 capsule of 20 mg or 2 capsules per day as prescribed). Whereas for a more severe case of Alzheimer's disease or severe traumatic brain injury, intravenous administration can be used, ranging from about 50 mg to 300 mg per day. Specific details of the dosage, route of administration, and regimen for a particular disease, disorder, or condition can be assessed generally, or for a particular subject or patient.

[0038] In yet another aspect of the application, a method for restoring myelination of axons in a mammal in need of such restoration further comprises administering a therapeutic amount of a cPG compound in combination with about 1 mg to about 10 mg of IGF-I per kilogram of body weight of the mammal or about 1.0 μg to about 10 μg of interferon per kilogram of body weight of the mammal. In a preferred embodiment, the interferon is interferon beta. Suitable dosages of cPG for administration can be, for example, preferably but not limited to about 0.1 mg to about 100 mg per kilogram of body weight, about 1 mg to about 100 mg per kilogram of body weight, about 5 mg to about 70 mg per kilogram of body weight, about 10 mg to about 50 mg per kilogram of body weight, or about 20 mg to about 40 mg per kilogram of body weight. The dosage, route of administration, and regimen of cPG can vary for different diseases, disorders, and conditions. For example, the dosage for mild cognitive impairment can be lower than for Alzheimer's disease, using the same or different routes of administration. For example: a typical dosage for a patient with mild cognitive impairment can be about 10 mg to 40 mg per day for oral administration (1 capsule of 20 mg or 2 capsules per day as prescribed). Whereas for a more severe case of Alzheimer's disease or severe traumatic brain injury, intravenous administration can be used, ranging from about 50 mg to 300 mg per day. Specific details of the dosage, route of administration, and regimen for a particular disease, disorder, or condition can be assessed generally, or for a particular subject or patient.

[0039] In another preferred embodiment of the method of treating or preventing cell injury and death due to injury and disease, the method comprises administering a cPG compound, which is administered to the ventricle of the brain of the mammal via a shunt.

[0040] In another preferred embodiment of the method of treating or preventing cell injury and death due to injury and disease, the method comprises administering a cPG compound, which is administered to the mammal via peripheral administration.

[0041] The present application provides a therapeutic method for stimulating mature astrocytes to promote myelination following hypoxic-ischemic injury, comprising the step of increasing the active concentration of cPG and / or the concentration of a cPG analog in the CNS of the mammal.

[0042] Most preferably, the effective amount of IGF-I itself is increased within the CNS of the mammal. This can be accomplished by direct administration of a cPG compound (e.g., cPG, c(PG)3, cGAL or cGMeP), and this is indeed the preferred method. However, administration of a compound that indirectly increases the effective amount of IGF-I (e.g., a prodrug that is cleaved in the patient to release cPG) is by no means excluded.

[0043] The active compound (IGF-I or an analog or mimetic thereof) can be administered alone, or preferably as part of a pharmaceutical composition.

[0044] The formulation can be administered directly to the central nervous system. The latter route of administration can include, for example, lateral ventricle injection, focal injection or implantation of a shunt into the lateral ventricle of the brain of the patient by surgery.

[0045] Conveniently, in the prevention or treatment of demyelinating diseases such as multiple sclerosis, the production of myelin in oligodendrocytes is stimulated and promoted by administration of a cPG compound, and myelin regeneration mediated by mature astrocytes is supported, stimulated and promoted.

[0046] In yet other aspects, the present application provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient or carrier and a therapeutically effective amount of a cyclic GP or analog thereof of the structure described above, for the treatment of a disease, disorder or condition, including but not limited to Alzheimer's disease and related conditions thereof, such as cognitive dysfunction.

[0047] In other aspects, the present application provides a method of treating an animal having a cognitive disorder, comprising administering to the animal an effective amount of a composition comprising a cyclic GP or analog thereof. In yet other aspects, the animal to be treated is a human.

[0048] One aspect of the present invention relates generally to the treatment of nervous system diseases and injuries. The present invention is not limited to any particular mechanism of action, and can be based in part on inducing neurogenesis, particularly the proliferation of neural stem or progenitor cells, proliferation of neural stem cells. According to one aspect of the present invention, cyclic prolyl glycine and its analogs ("cPG compounds") act as key regulators of neurogenesis, promoting and inducing proliferation and / or differentiation of neural cells.

[0049] "Neurogenesis" is defined herein as the proliferation, differentiation, migration or survival of neural cells in vivo or in vitro. In a preferred aspect of the present invention, the neural cells can be adult, fetal or embryonic neural stem or progenitor cells. Neurogenesis also refers to a net increase in cell number or a net increase in cell survival. As used herein, "neural stem cells (NSCs)" include at least all brain stem cells, all brain progenitor cells and all brain precursor cells.

[0050] It has been previously shown that elevated levels of cAMP and / or Ca 2+ can trigger adult neural stem cell proliferation. In some cases, this induction occurs following activation of G protein-coupled receptors (GPCRs). Increasing intracellular cAMP and / or Ca 2+ levels via GPCR ligands can induce increased proliferation of adult neural stem cells.

[0051] G protein-coupled receptors (GPCRs), also known as G protein-linked receptors (GPLRs), constitute a large family of receptor proteins that are capable of detecting molecules outside the cell and activating internal signal transduction pathways that ultimately elicit a cellular response.

[0052] Ligands that bind to and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, which range in size from small molecules to peptides to large proteins. GPCRs in the mammalian brain bind to a variety of different neurotransmitters, including serotonin, dopamine, GABA, and glutamate. G protein-coupled receptors are associated with a variety of diseases and are the target of about 34% of all modern pharmaceutical drugs.

[0053] One aspect of the present invention includes, without being limited to any proposed mechanism, that cPG and its analogs can act as regulators of neurogenesis to modulate intracellular cAMP and / or Ca 2+ levels. It has been chemically and biologically demonstrated that cPG is capable of increasing cAMP (e.g., by increasing synthesis or decreasing breakdown) and / or Ca 2+ (e.g., by increasing influx or decreasing efflux).

[0054] One aspect of the present invention describes a novel method of promoting regeneration of damaged neural tissue comprising administering an effective amount of cycloprolyl glycine (cPG) and analogs thereof that reduce the rate of growth of glial cells, thereby promoting growth of neural tissue.

[0055] Neurons are surrounded closely by glial cells or astrocytes. One of the difficulties in achieving regeneration of neurons after injury or breakage is that glial cells proliferate and form a barrier that hinders the regeneration of neurons. As a result, further extension of neurons to intended connection sites is blocked and regeneration of structure and function is terminated. It has been observed that the formation of astroglial scars and connective tissue scars and progressive necrosis have a detrimental effect on the regeneration of neuronal function.

[0056] Accordingly, one aspect of the present invention is a method of promoting regeneration of damaged neural tissue in a mammal, such as a human, comprising administering to the site of injury an effective amount of a cPG compound (cPG and analogs thereof).

[0057] Some of the experiments provided herein are directed at providing support for the practicability of the claimed method of regeneration of neurons and glial cells or the claimed method of repair of damaged neurons and glial cells.

[0058] One aspect of the present invention includes cycloprolyl glycine (cPG) and pharmaceutically active analogs thereof as modulators of neurons for the treatment of depression and other mental disorders. The N-methyl-d-aspartate receptor ("NMDA receptor") is a glutamate receptor and ion channel protein found in nerve cells. The NMDA receptor is one of three ionotropic glutamate receptors, the other two being the AMPA receptor and the kainate receptor. The NMDA receptor is activated when glutamate and glycine bind to it, and upon activation, it allows positively charged ions to pass through the cell membrane. (Furukawa, Hiroyasu; Singh, Satinder K; Mancussol, Romina; Gouaux, Eric (November 2005). "Subunit arrangement and function in NMDA receptors". Nature . 438 (7065): 185-192. doi:10.1038 / nature04089. PMID 16281028).

[0059] The NMDA receptor channel plays an important role in synaptic plasticity and synaptogenesis, which are dependent on memory, learning, and neural network formation during development of the central nervous system (CNS). Over-activation of this receptor can lead to Ca 2+Excessive influxes of ions can trigger excitotoxicity, which is believed to be involved in certain neurodegenerative diseases. Thus, theoretically, blocking NMDA receptors can be useful in treating such diseases.

[0060] NMDA receptors are ion channel protein receptors that are activated upon binding of glycine and glutamate thereto. The receptor is a heteromeric complex that interacts with multiple intracellular proteins through three different subunits (NR1, NR2, and NR3). NR1 exists in eight different subunits, produced by alternative splicing from a single gene. There are four different NR2 subunits (A-D), and NR3A and NR3B subunits have been reported. NR2 and NR3 are encoded by six different genes. [Loftis J. M., Janowsky A. (2003). "The N-methyl-D-aspartate receptor subunit NR2B: localization, functional properties, regulation, and clinical implications" (Pharmacol Ther. 97 (1): 55-85. doi: 10.1016 / s0163-7258(02)00302-9).

[0061] Agonists or allosteric modulators of NMDA receptors, particularly the channel containing the NR2B subunit, have been investigated as drugs for the treatment of major depressive disorder (G. Sanacora, 2008, Nature Rev. Drug Disc. 7: 426-437). The NR2B subunit is involved in the regulation of activities such as learning, memory, information processing, and feeding behavior, and is associated with a variety of human functional disorders. The basic structure and function of NMDA receptors can be attributed to the NR2B subunit.

[0062] An allosteric, non-competitive binding site was also found in the N-terminal domain of NR2B. NR2 subunits act as binding sites for glutamate, one of the major excitatory neurotransmitters receptors in the mammalian brain.[Yoshimura Y, Ohmura T, Komatsu Y (July 2003). "Two forms of synaptic plasticity with distinct dependence on age, experience, and NMDA receptor subtype in rat visual cortex" (The Journal of Neuroscience. 23 (16): 6557-66. PMID 12878697).

[0063] NR2B is associated with age- and experience-dependent plasticity in the rat neocortex, where an increase in the NR2B / NR2A ratio is directly correlated with stronger excitatory LTP in young animals. This is thought to contribute to the experience-dependent refinement of developing cortical circuits.

[0064] The role of the NR2B subunit of the NMDA receptor in the action of different antidepressants has been demonstrated.[Poleszak E, Wla P, Szewczyk B, Wla A, Kasperek R, Wróbel A, Nowak G (2011) A complex interaction between glycine / NMDA receptors and serotonergic / noradrenergic antidepressants in the forced swim test in mice. J Neural Transm 118: 1535-1546].

[0065] G protein-coupled receptors (GPCRs), also known as G protein-linked receptors (GPLR), constitute a large family of receptor proteins that are able to detect molecules outside the cell, activate internal signal transduction pathways, and ultimately elicit a cellular response.

[0066] GPCRs in the mammalian brain bind to a variety of different neurotransmitters, including serotonin, dopamine, GABA, and glutamate. G protein-coupled receptors are associated with a variety of diseases and are the target of about 34% of all modern pharmaceuticals.

[0067] One aspect of the present application includes cyclic prolyl glycine (cPG) and pharmaceutically active analogs thereof as neuronal modulators for the treatment of depression and other psychiatric disorders. One possible mechanism (but explicitly not limited to any mechanism) is the modulation of intracellular levels of cAMP and / or Ca 2+ 2+ It has been chemically and biologically demonstrated herein that cPG is capable of increasing cAMP (e.g., by increasing synthesis or decreasing breakdown) and / or Ca

[0068] Furthermore, cyclic prolyl glycine and pharmaceutically active analogs thereof have been shown to selectively bind to the N-terminal domain of NR2B, which can be responsible for maintaining antidepressant responses in humans.

[0069] The present application provides the technical advantage of cyclic prolyl glycine ("cPG") and pharmaceutically active analogs thereof (collectively, cPG compounds) that are ligands for the NR2B receptor and are useful in the treatment of a variety of central nervous system disorders. Furthermore, cPG compounds also provide advantages in pharmaceutical applications, for example, in one or more of their mechanism of action, binding properties, inhibitory potency, target selectivity, solubility, safety, or bioavailability.

[0070] In practicing the methods of the present application, the combination of substances is administered to a patient in a pharmaceutically effective dosage level using an appropriate route and regimen of administration. The substances can be administered in the form of a single dosage unit in which the active ingredients are combined with a suitable carrier; or they can be administered in separate dosage units in which the active substances are each combined with a suitable carrier. When administered separately, they can be administered simultaneously or at selected intervals of time.

[0071] The choice of one or more carriers is also made with this in mind, preferably by oral administration. Other modes of administration of the two substances and mixtures of the substances are, however, also considered to be part of the present application.

[0072] The dosage levels of the substances will vary with the particular substance used and the severity of the condition in the patient being treated. Cyclic prolyl glycine (cPG) is used in amounts of about 0.1 mg to 10 mg per kilogram of body weight. Oral administration in a dosage of about 20 mg to 80 mg per day is recommended, and for some severe cases, up to about 100 mg per day, as prescribed by a physician.

[0073] ​The pharmaceutical compositions of the present application are prepared by bringing into association active ingredients with the pharmaceutical carrier(s) typically employed in such compositions. The compositions of the present application are typically intended for oral administration to achieve an anti-depressive effect. The dosage forms can be tablets, capsules, powders, suspensions, solutions, syrups and the like, including sustained release formulations. The term "dosage form" as used in the specification and claims refers to a physically discrete unit suitable for single or multiple dosing, each unit containing a predetermined quantity of active material in association with the required diluent, carrier or vehicle. The quantity of active material is that which is calculated to achieve the desired therapeutic effect in a single or multiple dosing.

[0074] The present application primarily contemplates oral administration, but other modes of administration are of course also not excluded. Ampoules for parenteral administration can be prepared, preferably containing an aqueous solution of a water-soluble salt of the active substance and possibly a buffer substance. In liquid compositions of the active substances combined, whether designed for oral or parenteral administration, care must be taken to ensure the stability of the active substances.

[0075] In case the active substances are to be administered separately, then each individual composition is prepared according to the above described methods. These individual compositions can then be administered directly, or combined into a single dosage unit while remaining separate, such as a multi-layer tablet or multiple discrete particles comprising the two components in a single capsule.

[0076] The application will be described with reference to specific embodiments. Other aspects of the application can be appreciated in view of the drawings.

[0077] The above and the following drawings provide illustrations, further drawings are provided below and their description is provided at the respective location. BRIEF DESCRIPTION OF DRAWINGS

[0078] Figure 1 Overall time taken by rats to reach the platform in the Morris Water Maze (MWM) learning and memory model, which was used to assess the effect of cyclic prolyl glycine (cPG), lunakine and donanemab, and the combination of cPG + lunakine and cPG + donanemab.

[0079] Figure 2 Overall mean change from baseline to week 12 in NPI-NH Psychosis score (cPG vs. placebo).

[0080] Figure 3 Overall mean change from baseline to week 12 in NPI-NH Psychosis score (cPG, lunakine vs. placebo, and cPG + lunakine vs. placebo). DETAILED DESCRIPTION

[0081] The present invention recognizes that there has long been a need for treating mild cognitive impairment.

[0082] As a non-limiting introduction to the scope of the present invention, the present invention includes several general and useful aspects, including but not limited to: A first aspect of the present invention generally relates to a method of treating, ameliorating, or lessening mild cognitive impairment in a subject.

[0083] A second aspect of the present invention generally relates to a method of treating, ameliorating, or lessening Alzheimer's disease in a subject.

[0084] A third aspect of the present invention generally relates to a method of treating, ameliorating, or lessening psychosis in a subject with Alzheimer's disease.

[0085] A fourth aspect of the present invention generally relates to a method of treating, ameliorating, or lessening behavior, aggression, agitation, anger, apathy, or a combination thereof in a subject with Alzheimer's disease.

[0086] A fifth aspect of the present invention generally relates to a method of treating, ameliorating, or lessening early onset Alzheimer's disease in a subject.

[0087] These aspects of the present invention, as well as other aspects described herein, can be achieved by using the methods, articles of manufacture, and compositions of matter described herein. To fully appreciate the scope of the present invention, it should also be recognized that the various aspects of the present invention can be combined to form the desired embodiments of the present invention.

[0088] I. Methods of treating, ameliorating or lessening mild cognitive impairment A first aspect of the present invention includes a method of treating, ameliorating, or lessening mild cognitive impairment in a subject, comprising: a) providing a subject in need of treatment, amelioration, or lessening of mild cognitive impairment; b) administering to the subject a pharmaceutically effective amount of at least one cyclic prolyl glycine (cPG) or analog thereof (cyclic tri(prolyl glycine) or cyclic glycy-2-allyl proline or cyclic glycy-alkyl proline or cyclic glycy-2-methyl proline (cPMeG) or a combination thereof, collectively referred to as cPG compounds; c) administering to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and / or operably binds to an Aβ soluble protofibril; wherein the cPG compound and the specific binding member are each administered to the subject in an effective amount to collectively treat the mild cognitive impairment in the subject; further wherein the mild cognitive impairment in the subject is treated.

[0089] A. Mild Cognitive Impairment One aspect of the present invention includes: wherein the mild cognitive impairment is associated with Alzheimer's disease.

[0090] B. cPG Compounds Another aspect of the application includes: wherein the pharmaceutically effective amount of the cPG compound is about 1 μg to about 100 mg per kg of body mass.

[0091] Another aspect of the application includes: wherein the pharmaceutically effective amount of the cPG compound is administered in an amount of about 0.1 mg / kg to about 10 mg / kg per day, about 0.5 mg / kg to about 20 mg / kg per day, about 0.2 mg / kg to about 40 mg / kg per day, about 5 mg / kg to about 50 mg / kg per day, or about 10 μg / kg to about 100 mg / kg per day.

[0092] Another aspect of the application includes: wherein the pharmaceutically effective amount of the cPG compound has a lower limit of about 0.1 milligrams per kilogram of mass of the mammal (mg / kg) and an upper limit of about 10 mg / kg of the subject.

[0093] An aspect of the application includes: wherein the pharmaceutically effective amount of the cPG compound is about 20 mg to about 80 mg per day, or about 20 mg to about 100 mg per day.

[0094] Another aspect of the application includes: wherein administration of the pharmaceutically effective amount of the cPG compound is in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0095] Another aspect of the application includes: wherein administration of the pharmaceutically effective amount of the cPG compound is in combination with artificial cerebrospinal fluid.

[0096] Another aspect of the application includes: wherein administration of the pharmaceutically effective amount of the cPG compound is by intravenous route.

[0097] An aspect of the application includes: wherein administration of the pharmaceutically effective amount of the cPG compound is in combination with administration of a neuroprotective agent, insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), or a combination thereof.

[0098] Another aspect of the application includes: wherein administration of the pharmaceutically effective amount of the cPG compound is in combination with administration of an anti-inflammatory agent, an anti-integrin alpha 4 subunit agent, or a combination thereof.

[0099] Another aspect of the application includes: wherein administration of the pharmaceutically effective amount of the cPG compound is in combination with administration of an anti-inflammatory agent.

[0100] Another aspect of the application includes: wherein the cPG compound is provided in an aqueous solution and contains one or more pharmaceutically acceptable excipients, additives, carriers, adjuvants, or a combination thereof.

[0101] One aspect of the application includes: wherein the cPG compound comprises one or more pharmaceutically acceptable excipients, carriers, additives, adjuvants, binders, or combinations thereof.

[0102] Another aspect of the application includes: wherein the pharmaceutically effective amount of the cPG compound is administered orally, intraperitoneally, intravascularly, peripherally, subcutaneously, intraorbitally, ocularly, intraspinally, intracisternally, topically, by infusion, by implantation, by aerosol, by inhalation, by scarification, intracapsularly, intramuscularly, intranasally, buccally, transdermally, pulmonarily, rectally, vaginally, or combinations thereof.

[0103] Another aspect of the application includes, wherein the cPG compound is in the form of a tablet, a capsule, or combinations thereof.

[0104] C. Specific binding member that specifically and operably binds to AB soluble protofibrils Another aspect of the application includes: wherein the specific binding member comprises a receptor, a receptor agonist, a polypeptide, a ligand, an antibody, a polyclonal antibody, a monoclonal antibody, a humanized antibody, an active fragment thereof, or combinations thereof.

[0105] The terms used herein all have the usual meanings and usage known in the art.

[0106] One aspect of the application includes: wherein the specific binding member comprises Lanadelumab, Aducanumab, Donanemab, Crenezumab, Semorinemab, Gantenerumab, and active fragments thereof, or combinations thereof.

[0107] The compounds and their related compositions are known in the art and commercially available. Specific features thereof can not yet be publicly disclosed.

[0108] Another aspect of the application includes: wherein the specific binding is to amyloid beta soluble protofibrils.

[0109] Another aspect of the application includes: wherein the specific binding is to amyloid beta (Aβ42) soluble protofibrils.

[0110] Another aspect of the application includes: wherein the operable binding is to amyloid beta soluble protofibrils to modulate at least one activity thereof.

[0111] Modulation of an activity is related to the ability to provide a desired effect, such as but not limited to a pharmaceutical effect, such as but not limited to a pharmaceutical effect described or demonstrated herein.

[0112] One aspect of the application includes: wherein the operable binding is to soluble protofibrils of amyloid-beta (Αβ42) to modulate at least one activity thereof.

[0113] Another aspect of the application includes: wherein the pharmaceutically effective amount of the specific binding member is about 1 μg to about 100 mg per kg of body mass.

[0114] Another aspect of the application includes: wherein the pharmaceutically effective amount of the specific binding member is administered in an amount of about 0.1 mg / kg to about 10 mg / kg per day, about 0.5 mg / kg to about 20 mg / kg per day, about 0.2 mg / kg to about 40 mg / kg per day, about 5 mg / kg to about 50 mg / kg per day, or about 10 μg / kg to about 100 mg / kg per day.

[0115] Another aspect of the application includes: wherein the lower limit of the pharmaceutically effective amount of the specific binding member is about 0.1 milligrams per kilogram of mass of the mammal (mg / kg) and the upper limit is about 100 mg / kg of the subject.

[0116] One aspect of the application includes: wherein the pharmaceutically effective amount of the specific binding member is about 20 mg to about 80 mg per day, or about 20 mg to about 100 mg per day.

[0117] Another aspect of the application includes: wherein the administration of the pharmaceutically effective amount of the specific binding member is in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0118] Another aspect of the application includes: wherein the administration of the pharmaceutically effective amount of the specific binding member is in combination with artificial cerebrospinal fluid.

[0119] Another aspect of the application includes: wherein the administration of the pharmaceutically effective amount of the specific binding member is by intravenous route.

[0120] One aspect of the application includes: wherein the administration of the pharmaceutically effective amount of the specific binding member is in combination with the administration of a neuroprotective agent, insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), or a combination thereof.

[0121] Another aspect of the application includes: wherein the administration of the pharmaceutically effective amount of the specific binding member is in combination with the administration of an anti-inflammatory agent, an anti-integrin alpha 4 subunit agent, or a combination thereof.

[0122] Another aspect of the application includes: wherein the administration of the pharmaceutically effective amount of the specific binding member is in combination with the administration of an anti-inflammatory agent.

[0123] Another aspect of the application includes: wherein the pharmaceutically effective amount of the specific binding member Leqembi® is administered at a dose of 10 mg / kg once every two weeks in a pharmaceutical composition comprising a pharmaceutically acceptable carrier such as 0.9% sodium chloride injection.

[0124] An aspect of the application includes: wherein the specific binding member is provided in an aqueous solution and contains one or more pharmaceutically acceptable excipients, additives, carriers, adjuvants, or combinations thereof.

[0125] Another aspect of the application includes: wherein the specific binding member comprises one or more pharmaceutically acceptable excipients, carriers, additives, adjuvants, binders, or combinations thereof.

[0126] Another aspect of the application includes: wherein the pharmaceutically effective amount of the specific binding member is administered orally, intraperitoneally, intravascularly, peripherally, subcutaneously, intraorbitally, ocularly, intraspinally, intracisternally, topically, by infusion, by implantation, by aerosol, by inhalation, by scarification, intracapsularly, intramuscularly, intranasally, buccally, transdermally, pulmonarily, rectally, vaginally, or combinations thereof.

[0127] Another aspect of the application includes: wherein the specific binding member is in the form of a tablet, capsule, nasal spray, injection, intravenous infusion, or combinations thereof.

[0128] D. Subject An aspect of the application includes: wherein the subject is a mammal.

[0129] Another aspect of the application includes: wherein the subject is a human.

[0130] E. Effective amount to co-treat the subject for mild cognitive impairment Another aspect of the application includes: wherein the effective amount to co-treat the subject for mild cognitive impairment is about 0.1 mg / kg body weight to about 20 mg / kg body weight of cPG administered in combination with about 1 μg / kg body weight to about 100 mg / kg body weight of the specific binding member.

[0131] F. Treat, ameliorate, or alleviate Another aspect of the application includes: wherein the treat, ameliorate, or alleviate is a treatment.

[0132] Treating a condition means curing the disease, disorder, or condition, such that the patient is completely recovered and no longer exhibits symptoms of the disease, disorder, or condition. Treatment can include alleviating, delaying onset of, relieving symptoms of, mitigating, or a combination thereof. These are different from the concept of curing, which means that the disease is ended in the subject, or as the meaning of the term is generally known in the art, especially in the medical arts.

[0133] One aspect of the application includes wherein the treating, alleviating, or mitigating is alleviating.

[0134] Alleviating means reducing the severity of, and making more tolerable, the problems and symptoms described above.

[0135] Another aspect of the application includes wherein the treating, alleviating, or mitigating is mitigating.

[0136] Mitigating means reducing the severity of, and making more tolerable, the problems and symptoms described above.

[0137] II. Methods of treating, ameliorating or lessening Alzheimer's disease A second aspect of the application includes a method of treating, alleviating, or mitigating Alzheimer's disease in a subject, comprising: a) providing a subject in need of treatment, alleviation, or mitigation of Alzheimer's disease; b) administering to the subject a pharmaceutically effective amount of at least one cyclic prolyl glycine (cPG) or analog thereof (cyclic tri(prolyl glycine) or cyclic glycy-2-allyl proline or cyclic glycy-alkyl proline or cyclic glycy-2-methyl proline (cPMeG) or a combination thereof, collectively referred to as cPG compounds; c) administering to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and / or operably binds to an Aβ soluble protofibril; wherein the cPG compound and the specific binding member are each administered to the subject in an effective amount to collectively treat the Alzheimer's disease in the subject; further wherein the Alzheimer's disease in the subject is treated.

[0138] III. Methods of treating, ameliorating or lessening psychosis in Alzheimer's disease A third aspect of the present application includes a method of treating, ameliorating, or lessening psychosis in a subject with Alzheimer's disease, comprising: a) providing a subject in need of treatment, amelioration, or lessening of psychosis in Alzheimer's disease; b) administering to the subject a pharmaceutically effective amount of at least one cyclic prolyl glycine (cPG) or analog thereof (cyclic tri(prolyl glycine) or cyclic glycyi-2-allyl proline or cyclic glycyi-alkyl proline or cyclic glycyi-2-methyl proline (cPMeG) or a combination thereof, collectively referred to as cPG compounds; c) administering to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and / or operably binds to an Ab soluble protofibril; wherein the cPG compound and the specific binding member are each administered to the subject in an effective amount to collectively treat the subject's psychosis in Alzheimer's disease; further wherein the subject's psychosis in Alzheimer's disease is treated.

[0139] IV. Methods of treating, ameliorating or lessening behavior, aggression, agitation, anger, apathy in Alzheimer's disease A fourth aspect of the present application includes a method of treating, ameliorating, or lessening behavior, aggression, agitation, anger, apathy, or a combination thereof in a subject with Alzheimer's disease, comprising: a) providing a subject in need of treatment, amelioration, or lessening of behavior, aggression, agitation, anger, apathy, or a combination thereof in Alzheimer's disease; b) administering to the subject a pharmaceutically effective amount of at least one cyclic prolyl glycine (cPG) or analog thereof (cyclic tri(prolyl glycine) or cyclic glycyi-2-allyl proline or cyclic glycyi-alkyl proline or cyclic glycyi-2-methyl proline (cPMeG) or a combination thereof, collectively referred to as cPG compounds; c) administering to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and / or operably binds to an Ab soluble protofibril; wherein the cPG compound and the specific binding member are each administered to the subject in an effective amount to collectively treat the subject's behavior, aggression, agitation, anger, apathy, or a combination thereof in Alzheimer's disease; further wherein the subject's behavior, aggression, agitation, anger, apathy, or a combination thereof in Alzheimer's disease is treated.

[0140] V. Methods of treating, ameliorating or lessening early onset Alzheimer's disease A fifth aspect of the present invention comprises a method of treating, ameliorating or lessening early onset Alzheimer's disease in a subject, comprising: a) providing a subject in need of treatment, amelioration or lessening of early onset Alzheimer's disease; b) administering to the subject a pharmaceutically effective amount of at least one cyclic prolyl glycine (cPG) or analog thereof (cyclic tri(prolyl glycine) or cyclic glycy-2-allyl proline or cyclic glycy-alkyl proline or cyclic glycy-2-methyl proline (cPMeG) or a combination thereof, collectively referred to as cPG compounds; c) administering to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and / or operably binds to an Ab soluble protofibril; wherein the cPG compound and the specific binding member are each administered to the subject in an effective amount to collectively treat the early onset Alzheimer's disease in the subject; further wherein the early onset Alzheimer's disease in the subject is treated.

[0141] cPG compounds As generally described in U.S. Published Patent Application US20100247483A1, which is expressly incorporated herein in its entirety by this reference, cyclic prolyl glycine ("cyclic PG" or "cPG") has the following structure;

[0142] Structure 1 : cyclic prolyl glycine (the structure and compound are also referred to as NA-831, and the terms are used interchangeably herein).

[0143] The present invention includes novel diketopiperazines related to the structure of cPG.

[0144] One aspect of the present invention provides novel cyclic compounds having the following structural formula and substituents.

[0145]

[0146] Structure 2 : cyclic glycy-2-allyl proline, or cyclic glycy-alkyl proline, referred to herein as "cGAL" where R can be "alkyl", which refers to a saturated branched, straight-chain or cyclic hydrocarbon group. Exemplary alkyl groups include methyl, ethyl, isopropyl, cyclopropyl, t-butyl, cyclopropylmethyl, hexyl, and the like.

[0147] where R can be allyl, which refers to a substituent having the structural formula H2C=CH-CH2R, where R is the remainder of the molecule.

[0148] When R is methyl, one aspect of the application encompasses a cyclic glycyi-2-alkyl proline which is (8aS)-methyl-hexahydro-pyrrolo[l,2-a]pyrazine-l,4-dione, referred to as cyclic glycyi-2-methyl-proline or cyclic GMeP or cGMeP.

[0149]

[0150] Structure 3 : cyclic G-2MeP (available from polypeptide suppliers such as Bachem Americas, Inc. (Torrance, California, USA).

[0151] Generally, c(PG)3and cGAL can be prepared by methods well known to those of ordinary skill in the art of peptide and modified peptide synthesis. See, for example, Bodanzsky: Principles of Peptide Synthesis, Berlin, New York: Springer-Verlag 1993. Synthesis of the diketopiperazine compounds of the application can be carried out by solution phase synthesis as discussed in the examples, or by solid phase synthesis as exemplified by Merrifield et al. 1963 J. Amer. Chem. Soc. : 85, 2149-2156. Specific examples of diketopiperazine synthesis can be found in Fischer, 2003, J. Peptide Science : 9: 9-35 and references therein. Those of ordinary skill in the art, with the benefit of this disclosure, will not have difficulty developing one or more synthetic methods suitable for the compounds of the application.

[0152] In this application, including but not limited to this section which provides compound names, structures and abbreviations, various compounds can be used in all aspects of the application. For example, if the specification refers to cPG, then all other compounds which are cPG compounds and related derivatives thereof (such as but not limited to cGAL) are encompassed by that description and other descriptions, including but not limited to the treatment methods of various conditions described herein.

[0153]

[0154] Structure 4 : Cyclic (glycyl-L-prolyl glycyl-L-prolyl glycyl-L-prolyl) One possible structure of cGAL.

[0155] The chemical synthesis of cyclic (glycyl-L-prolyl glycyl-L-prolyl glycyl-L-prolyl) is described in Israel Journal of Chemistry, Vol. 12, Nos. 1-2, 1974, pp.15-29 "CYCLIC Peptides VII: The Synthesis and Characterization of Cyclic Peptides with Repeating Pro-Gly Sequences" by Charles M. Deber and Elkan R. Blout.

[0156] Synthesis of cyclic (glycyl-L-prolyl-glycyl-L-prolyl-glycyl-L-prolyl) A solution of p-nitrophenyl ester hydrochloride (500 mg) in dimethylformamide (DMF) (20 mL, dried over sodium sulfate) was added dropwise to 500 mL of reagent grade pyridine over 6 hours with stirring at room temperature. The bright yellow mixture was stirred at room temperature for 48 hours. The solvent was removed by a rotary evaporator-high vacuum pump system at 45°. The residue was washed with 20 mL of acetone, which dissolves the p-nitrophenol and the pyridine hydrochloride, but the peptide fraction remains insoluble. The insoluble material and acetone were transferred to a flask and the acetone was evaporated at 45°. The material was then dissolved in a minimum amount of DMF. A white microcrystalline precipitate was identified as cyclic (glycyl-L-prolyl-glycyl-L-prolyl-glycyl-L-prolyl) (155 mg, 28% yield) complexed with DMF. 100 mg of this material was recrystallized from methanol-ethyl ether to give crystalline (Pro-Gly)3 free of DMF (55 mg).

[0157] Chemical analysis: C 21 H 30 N6O6H2O Calc: C, 52.49; H, 6.71; N, 17.49. Found: C, 52.60; H, 6.81; N, 17.38.

[0158] One example of a cPG analog is cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl), or simply cyclic (tri(Pro-Gly)), or referred to herein as c(PG)3.

[0159] Another example of a cPG analog is cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline, referred to herein simply as "cGAL".

[0160] cPG, c(PG)3, cGAL, and cyclic glycyl-2-methylproline, and pharmaceutically acceptable salts thereof, are collectively referred to herein as "cPG compounds".

[0161] Further, cyclo-glycyl-2-methylproline is a compound that belongs to the class of cyclo(glycyl-2-alkylproline) compounds.

[0162] Further, any of the cPG compounds disclosed herein or known in the art, derivatives thereof, analogs thereof, and the like, can be provided in the form of a pharmaceutically acceptable salt.

[0163] Preferably, the cPG compounds are administered in a pharmaceutically acceptable composition, e.g., containing a pharmaceutically acceptable carrier.

[0164] More preferably, the composition further comprises a therapeutic amount of a cPG compound in combination with a compound selected from the group consisting of growth factors and related derivatives (insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), GPE, transforming growth factor-βl, activin, growth hormone, nerve growth factor, growth hormone binding protein, JQF binding protein (especially JGFBP-3), basic fibroblast growth factor, acidic fibroblast growth factor, hst / Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-induced growth factor). Other members of the FGF family include, for example, int-2, fibroblast growth factor homologous factor-1 (FHF-1), FHF-2, FHF-3 and FHF-4, karatinocyte growth factor 2, glial activating factor, FGF-10 and FGF-16, ciliary neurotrophic factor, brain-derived growth factor, neurotrophin 3, neurotrophin 4, bone morphogenetic protein 2 (BMP-2), glial cell line-derived neurotrophic factor, activity-dependent neurotrophic factor, cytokine leukemia inhibitory factor, oncostatin M, interleukins), beta / alpha / chi type or consensus interferons, TNF-alpha; clomethiazole; kynurenic acid, Semax, FK506 (tacrolimus), L-threo-1-phenyl-2-decanoylamido-3-morpholinyl-1-propanol, andrenocorticotropin-(4-9_analogue) [ORG2766] and dizolcipine [MK-801], selegiline; glutamate ants, such as NPS1506, GV1505260, MK-801, GV150526; AMPA ants, such as 2,3-dihydroxy-6-nitro-7-sulfonamidobenzo[f]quinoxaline (NBQX), LY303070 and LY300164; anti-inflammatory agents against the addressin MAdCAM-1 and / or its integrin alpha4 receptor (alpha4beta1 and alpha4beta7), such as the anti-MAdCAM-1 lmAb MECA-367 (ATCC Accession No. HB-9478), interferons including interferon beta-1b and interferon alfacon-1.

[0165] Specific binding members and active fragments thereof, such as the monoclonal antibody lucanumab Lencanetumab, or BAN2401, is a humanized immunoglobulin G (IgG1) version of the mouse monoclonal antibody mAb158 that selectively binds to large, soluble Aβ primary fibrils. This therapeutic antibody stems from the discovery of an "Arctic" mutation in amyloid precursor protein (APP), which leads to a clinically typical form of Alzheimer's disease characterized by exceptionally high levels of Aβ primary fibrils and a relative lack of amyloid plaques (see Nilsberth et al., 2001). mAb158 was originally developed by Uppsala University in Sweden. Lencanetumab targets soluble AP aggregates (oligomers and primary fibrils) with high selectivity.

[0166] SPR analysis showed that lencanetumab is highly selective for primary fibrils compared to monomers, with its binding affinity to primary fibrils (small and large primary fibrils, respectively) being approximately 2,300 and 14,300 times that of monomers.

[0167] Oligomerization of amyloid-β (Aβ) is considered a key event in the development of Alzheimer's disease (AD). Aβ mainly exists as a peptide of 40 or 42 amino acids, the only difference being that the former has two additional hydrophobic residues (I41 and A42) at its C-terminus. This small difference in primary structure leads to significant differences in the oligomerization patterns of Aβ40 and Aβ42.

[0168] The significant importance of the C-terminus in Aβ42 assembly and the particularly strong association between Aβ42 and AD suggest that the C-terminus of Aβ42 is a promising target for developing inhibitors that disrupt Aβ42 oligomerization as a means of preventing and treating AD. Recent experiments have shown that the C-terminal fragment (CTF) of Aβ42 can disrupt the oligomerization of full-length Aβ42 and inhibit its neurotoxicity. Among the tested CTFs (Aβ(x-42), x=28-39), three fragments showed particularly strong inhibitory effects: Aβ(31-42), Aβ(30-42), and Aβ(39-42) (the shortest CTF tested). In particular, Aβ(31-42), Aβ(30-42), and Aβ(39-42) inhibited 100%, 80%, and 80% of Aβ-induced toxicity, respectively. Although both Aβ(31-42) and Aβ(39-42) form non-toxic heterooligomers with Aβ42 monomers, their mechanisms of action differ: Aβ(31-42) has a stronger inhibitory effect on the intermolecular interactions between Aβ42 monomers, while Aβ(39-42) has a stronger inhibitory effect on the intramolecular interactions within Aβ42 monomers. (Wu C,Murray MM, Bernstein SL, Condron MM, Bitan G, Shea JE, Bowers MT. The structure of Abeta42 C-terminal fragments probed by a combined experimental and theoretical study. J Mol Biol. 2009 Mar 27;387(2):492-501. doi: 10.1016 / j.jmb.2009.01.029. Epub 2009 Jan 23. PMID: 19356595; PMCID: PMC2712569).

[0169] Aβ is a product of the hydrolysis of amyloid precursor protein by β-secretase and γ-secretase. Inaccurate cleavage of the C-terminus of the Aβ sequence by γ-secretase produces two main Aβ isoforms: Aβ42 (42 residues long) and Aβ40 (40 residues long). The only difference between Aβ42 and Aβ40 is that Aβ42 has two additional residues at the C-terminus. The concentration of Aβ40 in cerebrospinal fluid has been found to be several times higher than that of Aβ42. However, Aβ42 is a major component of amyloid plaques in the brains of AD patients. (Gu L, Guo Z. Alzheimer's Aβ42 and Aβ40 peptides form interlaced amyloid fibrils. JNeurochem. 2013 Aug;126(3):305-11. doi: 10.1111 / jnc.12202. Epub 2013 Mar 12. PMID:23406382: PMCID: PMC3716832).

[0170] Lencanemab targets the N-terminus (residues 1-16) of Aβ, which overlaps with the binding site of fibrinogen on Aβ. Lencanemab blocks the binding of Aβ42 to fibrinogen in a dose-dependent manner, while human IgG does not have this effect. The Aβ42 formulation used consists of curved linear aggregates (small protofibrils) with a length of 30-90 nm. ([Singh PK, PiresENS, Chen ZL, Torrente D, Calvano M, Sharma A, Strickland S, Norris EH. Lecanemab Blocks the Effects of the Aβ / Fibrinogen Complex on Blood Clots andSynapse Toxicity in Organotypic Culture. bioRxiv [Preprint]. 2024 Jan 21:2024.01.20.576458. doi: 10.1101 / 2024.01.20.576458. Updated: Proc Natl Acad Sci US A. 2024 Apr 23;121(17):e2314450121. doi: 10.1073 / pnas.2314450121. PMID: 38293058; PMCID: PMC10827200).

[0171] Extracellular accumulation of Aβ in neuroinflammatory plaques and binding of Aβ to multiple receptors appear to be characteristic hallmarks of Alzheimer's disease. Aβ binding to multiple receptors has been identified as a cause of neurotoxicity: Aβ oligomers are thought to induce mitochondrial dysfunction and oxidative stress in AD neurons, leading to a large influx of calcium ions and inducing neurotoxicity. Furthermore, soluble oligomeric Aβ is believed to exert toxicity through binding to multiple receptors, including lipids, proteoglycans, and proteins, such as the Aβ-binding p75 neurotrophic factor receptor (P75NTR), low-density lipoprotein receptor-associated protein (LRP), cytokinin (PrPc), metabolite glutamate receptor (mGluR5), α-subunit-containing nicotinic acetylcholine receptor (α7nAChR), N-methyl-D-aspartate receptor (NMDAR), β-adrenergic receptor (β-AR), erythropoietin-producing liver cancer cell line receptor (EphR), and paired immunoglobulin-like receptor B (PirB)97. The interaction of Aβ / Aβ receptors is thought to generate neurotoxic signals and transduce them into neurons, leading to cellular defects such as mitochondrial dysfunction and ER stress response. Furthermore, some Aβ receptors are highly likely to internalize Aβ into neurons, thereby exhibiting unique cellular damage. (Chen GF, Xu TH, Yan Y, Zhou YR, Jiang Y, Melcher K, Xu HE. Amyloid beta:structure, biology and structure-based therapeutic development. ActaPharmacol Sin. 2017 Sep;38(9):1205-1235. doi: 10.1038 / aps.2017.28. Epub 2017Jul 17. PMID: 28713158; PMCID: PMC5589967).

[0172] In summary, based on the unique structure of cPG, it is speculated that cPG binds to the C-terminus during the assembly of Aβ42, thereby inhibiting the neurotoxicity of full-length Aβ42.

[0173] The potential combination of IGF-1 and its analogue NA-831 with lencanetumab may have advantages over monotherapy with either lencanetumab or NA-831 alone.

[0174] For example, see: Sehlin D, Englund H, Simu B, Karlsson M, Ingelsson M, Nikolajeff F, et al. Large aggregates are the major soluble Abeta species in AD brain fractionated with density gradient ultracentrifugation, PLoS ONE. 2012;7(2):e32014. doi: 10.1371 / journal.pone.0032014; Magnusson K, Sehlin D, Syvanen S, Svedberg MM, Philipson O, Soderberg L, et al. Specifc uptake of an amyloid-beta protofibril-binding antiboxdy-tracer in AbetaPP transgenic mouse brain. JAlzheimcrs Dis. 2013;37(1):29-40. doi: 10.3233 / JAD-130029; Söderberg L, Johannesson M, Nygren P, Laudon H, Eriksson F, Osswald G, Möller C, Lannfelt L. Lecanemab, Aducanumab, and Gantenerumab - Binding Profiles to Different Forms of Amyloid-Beta Might Explain Efficacy and Side Effects in Clinical Trials for Alzheimer's Disease. Neurotherapeutics. 2023 Jan;20(1):195-206. doi: 10.1007 / s13311-022-01308-6. Epub 2022 Oct 17. PMID: 36253511; PMCID: PMC10119362。

[0175] Late-stage clinical trial data showed that Aβ immunotherapy can have positive efficacy. However, amyloid-related imaging abnormalities (ARIA), primarily edema (ARIA-E), have been observed. The main identified risk factors for ARIA-E are antibody dosage and the presence of the apolipoprotein E4 (ApoE4) allele. The exact mechanism of ARIA-E remains unclear, but possible explanations include direct binding of Aβ antibodies to cerebral amyloid angiopathy (CAA). CAA is a pathological condition characterized by fibrillary Aβ (mainly Aβ1-40) deposition in the walls of cerebral blood vessels and is relatively common in patients with Alzheimer's disease (AD).

[0176] Lencanemab-irmb is a recombinant human immunoglobulin γ1 (IgG1) monoclonal antibody that targets aggregated soluble and insoluble forms of β-amyloid protein. It is expressed in the Chinese hamster ovary (CHO) cell line. Lencanemab-irmb injection is a preservative-free, sterile, clear to opalescent, colorless to yellow solution, diluted for intravenous infusion. It is provided in single-dose vials at concentrations of 500 mg / 5.0 mL (100 mg / mL) and 200 mg / 2 mL (100 mg / mL).

[0177] Lencanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble primary fibrils and has been tested in patients with early-stage Alzheimer's disease. A multicenter, double-blind, phase 3 clinical trial was conducted over 18 months and enrolled 1795 participants aged 50 to 90 years with early-stage Alzheimer's disease. The primary endpoint was the change from baseline in the Clinical Dementia Rating Scale Total Score (CDR-SB, score 0 to 18, with higher scores indicating more severe impairment) at 18 months. The mean CDR-SB score at baseline was approximately 3.2 in both groups. At 18 months, the adjusted least-squares mean change from baseline was 1.21 in the lencanemab group and 1.66 in the placebo group (difference: -0.45; 95% confidence interval [CI]: -0.67 to -0.23; P < 0.001). In the lecanemab group, 26.4% of participants experienced infusion-related reactions, and 12.6% developed amyloid-related imaging abnormalities with edema or effusion. (See: Lecanemab in Early Alzheimer's Disease. Christopher H. van Dyck et al. January 5, 2023- N Engl J Med2023; 388:9-21- DOI:10.1056 / NEJMoa2212948).

[0178] It is noteworthy that in the lencanemab group, the CDR-SB score increased from 3.2 at baseline to 4.41, a change of 1.21; in the placebo group, it increased to 4.86, a change of 1.65. The difference between the two groups, -0.45 (4.41-4.86), is often presented as a 27% reduction in cognitive decline (0.45 / 1.65), indicating a clinical benefit of lencanemab treatment. This percentage is misleading, based on an incorrect conclusion derived from using an incorrect denominator. The actual CDR-SB score shows a clinical benefit of 9.3% (0.45 / 4.86), not 27%. This lower figure is unlikely to have any impact on patients with early-stage Alzheimer's disease.

[0179] The study concluded that lencanemab reduces amyloid markers in early Alzheimer's disease and, at 18 months, showed a less severe decline in cognitive and functional indicators compared to placebo, but also included adverse events. Despite recommendations for longer-term trials to determine the efficacy and safety of lencanemab in early Alzheimer's disease, the FDA approved lencanemab on July 6, 2023.

[0180] Based on its evaluation of efficacy in clinical trials, the FDA approved lencanezumab (trade name Leq®, abbreviated as "LEQ") for the treatment of early-onset Alzheimer's disease (AD). However, high-dose LEQ (approximately 10 mg / kg) resulted in infusion-related reactions in 26.4% of participants, and amyloid-related imaging abnormalities with edema or effusion in 12.6% of participants. In a phase 3 clinical trial, patients treated with 10 mg / kg LEQ experienced ARIA-E, accompanied by headache, confusion, dizziness, and nausea; microbleeds; and surface hemosiderin deposition. Therefore, reducing the dosage of LEQ may be key to safety, but this would reduce the drug's efficacy in treating early-onset AD.

[0181] In this invention, the combination therapy comprises intravenous administration of a reduced dose of LEQ at 5 mg / kg and oral administration of a reduced dose of cPG at approximately 0.5 mg / kg. In a typical combination therapy, the patient is given intravenous administration of approximately 5 mg / kg of lencanezumab every two weeks, in addition to oral administration of approximately 30 mg to approximately 60 mg of cPG daily.

[0182] This is a proposed clinical regimen for combination therapy in which the dose of lencanezumab will be halved from 10 mg / kg to 5 mg / kg to reduce adverse reactions to ARIA, while the patient will take cPG at half dose of 0.5 mg / kg.

[0183] It is noteworthy that the combined treatment significantly improved cognitive impairment after 12 months of treatment.

[0184] Although cPG is believed to act based on promoting neurogenesis and may have different mechanisms and biological significance than in AD treatment, the effects of NA-831 have been found to synergize with the perceived LEQ mechanism, a human monoclonal antibody targeting Aβ pathology in AD. Multiple clinical trials aiming to target key pathogenic proteins involved in AD pathogenesis (such as Aβ and Tau) through disease-modifying therapies (DMTs) have failed to halt AD progression. This can be attributed to limited understanding of how to effectively overcome the blood-brain barrier (BBB) ​​in the development of novel therapies for central nervous system (CNS) disorders. Therefore, multi-target drugs capable of addressing multiple pathologies simultaneously may be preferred. Developing multi-target drugs for dementia treatment aligns with the idea of ​​repositioning antidiabetic drugs for dementia, as the insulin / IGF-1 signaling pathway is associated with multiple dementia subtypes. From a molecular perspective, repositioning antidiabetic drugs such as IGF-1 for disease-modifying therapies (DMTs) targeting multiple dementia subtypes appears to be a reasonable strategy.

[0185] As a metabolite of IGF-1, cPG can cross the blood-brain barrier and has been shown to have neuroprotective and neurogenic properties.

[0186] Combinations of cPG and specific binding members Preferably, the combination therapy of cPG compounds with lencanezumab can be used to treat or prevent cell damage or cell death caused by the following diseases and injuries: septic shock, ischemia, cytokine administration, cytokine overexpression, ulcers, gastritis, ulcerative colitis, Crohn's disease, diabetes, rheumatoid arthritis, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, cirrhosis, allogeneic transplant rejection, transplant rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphadenitis. Cellular choroid plexus meningitis, glomerulonephritis, uveitis, glaucoma, blepharitis, meibomian gland cysts, allergic eye disease, corneal ulcer, keratitis, cataracts, retinopathy, age-related macular degeneration, optic neuritis, ileitis, inflammation induced by excessive production of inflammatory cytokines, hemorrhagic shock, anaphylactic shock, burns, infections caused by bacteria, viruses, fungi, and parasites that lead to excessive production of inflammatory cytokines, hemodialysis, chronic fatigue syndrome, stroke, cancer, and related conditions involving excessive inflammatory cytokines. This condition can lead to various cardiovascular diseases, heart disease, cardiopulmonary bypass, ischemia / reperfusion injury, ischemia / reperfusion with excessive production of inflammatory cytokines, toxic shock syndrome, adult respiratory distress syndrome, cachexia, myocarditis, autoimmune diseases, eczema, psoriasis, heart failure, dermatitis, urticaria, cerebral ischemia, systemic lupus erythematosus, AIDS, AIDS-related dementia, chronic neurodegenerative diseases, chronic pain, priapism, cystic fibrosis, amyotrophic lateral sclerosis (ALS), and psychosis. Schizophrenia, depression, premenstrual syndrome, anxiety, addiction, migraine, Huntington's disease, epilepsy, gastrointestinal motility disorders, obesity, hyperappetite, neuroblastoma, malaria, hematologic malignancies, myelofibrosis, lung injury, graft-versus-host disease, head injury, central nervous system trauma, hepatitis, kidney failure, chronic hepatitis C, paraquat poisoning, transplant rejection and preservation, fertility enhancement, bacterial translocation, circulatory shock, traumatic shock, hemodialysis, hangover, and combinations of two or more of these conditions.

[0187] Preferably, the combination therapy of cPG compounds and lencanezumab can be used to restore myelin formation in axons in mammals that have suffered myelin depletion due to nerve injury or disease.

[0188] Preferably, cPG compounds can be used to restore myelin formation depleted due to: trauma, toxin exposure, asphyxia or hypoxia-ischemia, perinatal hypoxic-ischemic injury, CNS white matter injury or disease, acute brain injury, chronic neurodegenerative diseases (including multiple sclerosis), and demyelinating diseases and disorders (including acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, Devic disease, leukodystrophy); non-inflammatory involvement: progressive multifocal leukoencephalopathy and central pontine myelinolysis.

[0189] Preferably, the cPG compound can be administered at a dose of about 1 μg to about 150 mg per kilogram of body weight. Suitable doses of cPG may be, for example, preferably but not limited to, about 0.1 mg to about 100 mg per kilogram of body weight, about 1 mg to about 100 mg per kilogram of body weight, about 5 mg to about 70 mg per kilogram of body weight, about 10 mg to about 50 mg per kilogram of body weight, or about 20 mg to about 40 mg per kilogram of body weight. The dose, route of administration, and regimen of cPG may vary depending on the disease, disorder, and condition. For example, the dose for mild cognitive impairment may be lower than that for Alzheimer's disease, using the same or different routes of administration.

[0190] For example, the typical dose for patients with mild cognitive impairment may be approximately 0.2 mg to approximately 1 mg daily (e.g., one 20 mg capsule or two capsules daily as prescribed). For patients with more severe Alzheimer's disease or severe traumatic brain injury, intravenous administration may be used, ranging from approximately 50 mg to 300 mg daily. Specific details regarding the dosage, route of administration, and regimen for a particular disease, disorder, or condition can be assessed generally or on a specific subject or patient basis.

[0191] Pharmacology and utility cPGs can exert anti-necrosis and anti-apoptotic effects during cell death. Their in vivo anti-apoptotic and anti-necrosis activities can be measured by cell counting. cPGs can also be measured in vitro. (Gudasheva TA et al., FEBS Letters, Vol. 391, Issues 1-2, 5 August 1996, pp. 149-152). CNS damage can be clinically assessed, for example, by the degree of permanent neurological deficit, cognitive function, and / or seizure tendency. (Rakic ​​LJ et al., Peptide and Amino Acid Transport Mechanisms in The Central Nervous System, 1988, The MacMillan Press Ltd. (London) pp. 167-181).

[0192] Pharmaceutical compositions and administration As part of this invention, cPGs themselves can be used to prevent or treat cell damage and programmed cell death, and to induce myelination. Typically, this is achieved by administering cPGs directly to the patient. If desired, combinations of cPG compounds and their analogues can be administered in pharmaceutically acceptable compositional forms.

[0193] Those skilled in the art will understand that the applicant does not intend to exclude the administration of other forms of cPG and its analogues. For example, the effective amount of cPG in the CNS can be increased by administering a cPG prodrug form comprising cPG and a carrier, the cPG and the carrier being linked by a linking group that is readily cleaved or digested in the patient's body. Any suitable linking group that can be cleaved or digested after administration to release cPG may be used.

[0194] Furthermore, it is envisioned that cPG levels could be increased through an implant containing a cell line capable of actively expressing cPG within the patient's CNS.

[0195] Prodrugs of cPG and its analogues may also be administered. In this case, the prodrug is metabolized or otherwise altered in the subject's body to form cPG. cPG and its analogues, such as, but not limited to, c(PG)3 and cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline, or cyclic glycyl-2-methylproline, may be administered as part of a drug or a drug formulation. This may include combining cPG with any pharmaceutically suitable carrier, adjuvant, or excipient. The choice of carrier, adjuvant, or excipient, of course, generally depends on the route of administration used.

[0196] The route of administration can be varied and can be any suitable route. One advantage of cPG is that it can be administered via a peripheral route. This means that it can exert its effects in the CNS without being administered directly to the patient's CNS.

[0197] Any peripheral route known in the art may be used. These routes may include, but are not limited to, parenteral routes, such as injection into the peripheral circulation, subcutaneous, intraorbital, ocular, spinal cord, intracisternal, local, infusion (using, for example, controlled-release devices or micropumps, such as osmotic pumps or skin patches), implantation, aerosol, inhalation, scratching, intraperitoneal, intracystic, intramuscular, intranasal, oral, buccal, pulmonary, rectal, or vaginal administration. The composition may be formulated to be administered parenterally to humans or other mammals in a therapeutically effective amount (e.g., an amount that eliminates or reduces the pathological condition in a patient) to provide treatment for the aforementioned neurological diseases.

[0198] Two preferred routes of administration are subcutaneous injection (e.g., but not limited to, dissolved in 0.9% sodium chloride) or oral administration (in capsules).

[0199] It should also be understood that sometimes it may be necessary to administer cPG compounds directly to the patient's CNS. Again, this can be achieved via any suitable route of direct administration. Examples include intraventricular injection or administration to the lateral ventricles of the patient's brain via a surgically inserted shunt.

[0200] Calculating the effective amount of the cPG compound to be administered is within the capabilities of those skilled in the art and is routine practice for them. Needless to say, the final dosage depends on the route of administration and the nature of the neurological disorder or condition to be treated. Preferably, when administered centrally, the cPG compound is administered at a dose of about 1 μg to 100 mg per kilogram of body weight. Suitable dosages of cPG may be, for example, about 0.1 mg to about 10 mg per kilogram of body weight, or about 1 mg to about 5 mg per kilogram of body weight.

[0201] When used in pharmaceutical formulations, cPG compounds can be obtained from suitable commercial sources, such as Bachem AG of Bubendorf, Switzerland. Alternatively, cPGs can be synthesized directly using conventional methods, such as the stepwise solid-phase synthesis described by Merrifield et al. (1963, J. Amer. Chem. Soc.: 85, 2149-2156). Alternatively, synthesis can be performed using commercially available peptide synthesizers, such as the Applied Biosystems 430A.

[0202] cGAL can be prepared by methods known to those skilled in the art, such as those in the field of peptide and analogue synthesis. For example, “Principles of Peptide Synthesis”, by Bodanzsky, Springer-Verlag 1993.

[0203] c(PG)3 can be prepared by the following disclosed method: Israel Journal of Chemistry, Vol. 12, Nos. 1-2, 1974, pp. 15-29 “CYCLIC Peptides VII: The Synthesis and Characterization of Cyclic Peptides with Repeating Pro-Gly Sequences” by Charles M. Deber and Elkan R. Blout.

[0204] Generally, the total pharmaceutically effective amount of cPG compound administered each time via parenteral administration will fall within a range that can be determined using a dose-response curve. Patients can be administered gradually increasing amounts of cPG compound, and serum cPG levels can be measured. The amount of cPG compound used can then be calculated in moles based on these serum cPG levels.

[0205] Specifically, one method for determining an appropriate dosage of a compound involves measuring cPG levels in biological fluids (e.g., bodily fluids or blood). This measurement can be performed in any manner, including RIA and ELISA. After measuring the cPG level, the fluid is contacted with the compound via a single or multiple administration. Following this contact step, the cPG level in the fluid is measured again. If the cPG level in the fluid decreases to a level sufficient to produce the intended therapeutic effect of the molecule to be administered, the dosage of the molecule can be adjusted to produce maximum efficacy. This method can be performed in vitro or in vivo. Preferably, the method is performed in vivo, i.e., after extracting bodily fluids from a mammal and measuring cPG levels, the compound described herein is administered to the mammal via a single or multiple administration (i.e., the contact step is achieved by administration to the mammal), and then the cPG level in the bodily fluids extracted from the mammal is measured again.

[0206] This compound can also be appropriately administered via a sustained-release system. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of molded articles, such as films or microcapsules. Sustained-release matrices include polylactic acid (US Patent No. 3,773,919; EP 58,481), copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid (Sidman et al., 1983), poly(2-hydroxyethyl methacrylate) (Langer et al., 1981), ethylene vinyl acetate (Langer et al., ibid.), or poly-D-(-)-3-hydroxybutyric acid (EP 133,988).

[0207] The sustained-release composition also comprises a compound encapsulated in liposomes. Liposomes containing this compound are prepared by methods known per se: German Patent 3,218,121; Epstein et al., 1985; Hwang et al., 1980; European Patent 52,322; European Patent 36,676; European Patent 88,046; European Patent 143,949; European Patent 142,641; Japanese Patent Application 83-118008; US Patents 4,485,045 and 4,544,545; and EP 102,324. Typically, these liposomes are small (from about 200 to 800 angstroms) monolayer liposomes with a lipid content greater than about 30 molar percentage of cholesterol, the selected ratio adjusted according to the most effective therapy.

[0208] Alternatively, longer-lived polyethylene glycol-modified peptides can be used, for example, based on the coupling technique described in WO 95 / 32003 published on November 30, 1995.

[0209] If parenteral administration is preferred, the compound is typically formulated in the desired concentration and unit dose injectable form (solution, suspension, or emulsion) with a pharmaceutically or parenterally acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dose and concentration used and compatible with other components in the formulation).

[0210] Typically, formulations are prepared by contacting a compound with a liquid carrier or a finely pulverized solid carrier, or both. The product is then shaped into the desired formulation, if desired. Preferably, the carrier is a parenteral carrier, more preferably a solution isotonic with the recipient's blood. Examples of such carrier solvents include water, saline, Ringer's solution, buffer solutions, and glucose solutions. Non-aqueous solvents, such as fixed oils and ethyl oleate, can also be used.

[0211] The carrier may also contain additives, such as substances that enhance isotonicity and chemical stability. These substances are non-toxic to the recipient at the doses and concentrations used, including buffers such as phosphates, citrates, succinates, acetic acid, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) peptides such as polyarginine or tripeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; glycine; amino acids such as glutamic acid, aspartic acid, histidine, or arginine; monosaccharides, disaccharides, and other carbohydrates, including cellulose or its derivatives, glucose, mannose, trehalose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; nonionic surfactants such as polysorbate, poloxamer, or polyethylene glycol (PEG); and / or neutral salts such as NaCl, KCl, MgCl2, CaCl2, etc.

[0212] cPG compounds are typically formulated in this solvent at a pH of about 5.5 to about 8.0. Typical adjuvants that can be added to dosage forms such as tablets and capsules are binders (such as gum arabic, corn starch, or gelatin); excipients (such as microcrystalline cellulose); disintegrants (such as corn starch or alginate); lubricants (such as magnesium stearate); sweeteners (such as sucrose or lactose); and flavoring agents (such as peppermint, wintergreen, or cherry). When the dosage form is a capsule, in addition to the above substances, a liquid carrier (such as fatty oil) may also be included. Various other types of materials can be used as coatings or modifiers of the physical form of dosage units. Syrups or elixirs may contain active compounds, sweeteners (such as sucrose), preservatives (such as propylparaben), colorants, and flavoring agents (such as cherry). Sterile compositions for injection can be formulated according to routine pharmaceutical practice. For example, it may be desirable to dissolve or suspend the active compound in a solvent, such as water or natural vegetable oils (e.g., sesame oil, peanut oil, or cottonseed oil) or synthetic fatty solvents (e.g., ethyl oleate). Buffers, preservatives, antioxidants, etc., may be added according to accepted pharmaceutical practices.

[0213] Compounds used for therapeutic administration must be sterile. Aseptic processing can be easily achieved through sterile filtration membranes (e.g., 0.2-micron membranes). Therapeutic compositions are typically placed in containers with sterile access ports, such as intravenous vials or bags with stoppers that can be punctured by a hypodermic needle.

[0214] This compound is typically stored in single- or multi-dose containers, such as sealed glass ampoules or vials, in the form of an aqueous solution or a lyophilized formulation (for reconstitution). As an example of a lyophilized formulation, 5 mL of a sterile, filtered 1% (w / v) aqueous solution of the compound is added to a 10 mL vial, and the resulting mixture is lyophilized. An infusion solution is prepared by reconstitution of the lyophilized compound with antibacterial water for injection.

[0215] Combination therapy with the cPG compounds described herein and one or more other suitable agents that can increase the total cPG level in the blood or enhance the effect of cPG is also being considered. These agents typically enable the cPG compounds described herein to release the generated cPG.

[0216] Furthermore, one aspect of the invention includes treating mammals with gene therapy using nucleic acids encoding cPG compounds (if they are peptides). Typically, gene therapy is used to increase (or overexpress) cPG levels in mammals. Nucleic acids encoding cPG peptides can be used for this purpose. Once the amino acid sequence is known, multiple nucleic acid molecules can be generated using the degeneracy of the genetic code, and nucleic acid molecules for gene therapy can be selected.

[0217] There are two main methods for gene therapy: in vivo and in vitro, to introduce nucleic acids (optionally contained in a vector) into patient cells. For in vivo delivery, the nucleic acid is injected directly into the patient, typically at the site where the cPG compound is needed. For in vitro therapy, the patient's cells are removed, the nucleic acid is introduced into these isolated cells, and the modified cells are applied directly to the patient, or, for example, encapsulated in a porous membrane and then implanted into the patient. See, for example, U.S. Patent Nos. 4,892,538 and 5,283,187.

[0218] Various techniques exist for introducing nucleic acids into living cells. These techniques differ depending on whether the nucleic acid is transferred to in vitro cultured cells or to target host cells in vivo. Techniques suitable for transferring nucleic acids into mammalian cells in vitro include liposomes, electroporation, microinjection, cell fusion, DEAE-glucan, and calcium phosphate precipitation. Retroviruses are commonly used vectors for in vitro gene delivery.

[0219] Currently preferred in vivo nucleic acid transfer techniques include transfection with viral vectors (e.g., adenovirus, herpes simplex virus type I, or adeno-associated virus) and lipid-based systems (e.g., lipids that can be used for lipid-mediated gene transfer include DOTMA, DOPE, and DC-Chol). In some cases, it is necessary to provide the nucleic acid source with reagents that target target cells, such as antibodies specific to cell surface membrane proteins or target cells, ligands for target cell receptors, etc. When using liposomes, proteins that bind to cell surface membrane proteins associated with endocytosis can be used for targeting and / or promoting uptake, such as capsid proteins or fragments thereof that are tropic to specific cell types, antibodies against proteins that are internalized in circulation, and proteins that target intracellular localization and prolong intracellular half-life. Receptor-mediated endocytosis techniques are described, for example, in Wu et al., 1987; Wagner et al., 1990. For a review of currently known gene markers and gene therapy protocols, see Anderson 1992. See also WO 93 / 25673 and its cited references.

[0220] The present invention also envisions kits. A typical kit may include a container (preferably a vial) for a cPG compound formulation containing a cPG compound in a pharmaceutically acceptable buffer, and instructions for the user to use the pharmaceutical formulation, such as a product information leaflet or label.

[0221] Some aspects of the present invention include the use of cPG to treat age-related cognitive impairment, which is associated with neurodegenerative diseases or occurs in the absence of obvious neurodegenerative lesions.

[0222] Other drugs of this class may be selected from, for example, non-restricted classes of growth factors and their related derivatives, such as insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), growth hormone, nerve growth factor, growth hormone-binding protein and / or IGF-binding protein.

[0223] Lucanumab Lencanemab (formerly known as BAN2401) is a humanized immunoglobulin G1 (IgG1) anti-amyloid β (Aβ) monoclonal antibody that targets the aggregated form of Aβ. Extracellular deposits of Aβ are known as amyloid plaques. The accumulation of Aβ in the brain is considered a major driver of disease progression and precedes tau pathological accumulation and neurodegeneration.

[0224] Lencanemab has received FDA approval based on a reduction in amyloid plaque burden as measured by positron emission tomography (PET) imaging, which was deemed reasonably likely to predict clinical benefit. The FDA application included biomarker, efficacy, and safety data from Study 201, a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in patients with MCI due to Alzheimer's disease or mild Alzheimer's dementia.

[0225] Therapeutic applications The compositions and methods of the present invention can be used to treat animals with cognitive impairment, such as human patients. More generally, the compositions and methods of the present invention can be used to treat mammals (e.g., but not limited to human patients and subjects) with memory impairment, mild cognitive impairment, or dementia, including brain atrophy-related dementia caused by Alzheimer's disease, Lewy body disease, frontotemporal degeneration, vascular dementia, head trauma, Huntington's disease, Parkinson's disease, or Down syndrome.

[0226] Pharmaceutical compositions and administration Cyclic PG compounds can be administered as part of a drug or a pharmaceutical formulation. This includes using the compounds of the present invention in combination with any pharmaceutically suitable carrier, adjuvant, or excipient. The choice of carrier, adjuvant, or excipient depends, of course, on the route of administration employed.

[0227] Generally, the compounds of the present invention will be administered at a therapeutically effective dose, alone or in combination with other conventional therapeutic agents for treating the disease, by any commonly known method in the art. The therapeutically effective dose may vary depending on the type and severity of the disease or lesion, the age and relative health of the animal being treated, the potency of the compound, and other factors. The therapeutically effective dose of cyclic prolyl glycine ranges from 0.01 to 10 mg per kilogram of animal mass, wherein lower doses (e.g., 0.01 mg / kg to 0.1 mg / kg) are suitable for administration via cerebrospinal fluid, such as intraventricular administration; and higher doses (e.g., 0.1 mg / kg to 10 mg / kg) are suitable for administration via methods such as oral, systemic (e.g., transdermal), or parenteral (e.g., intravenous) administration. Those skilled in the art can determine the therapeutically effective dose of the compounds of the present invention for a specific disease or lesion based on their expertise and the disclosure of this invention without extensive experimentation.

[0228] Cyclic prolyl glycine and cPG compounds can be administered orally or peripherally via any peripheral route known in the art. These include, but are not limited to, parenteral routes such as injection into the peripheral circulation, subcutaneous, intraorbital, ocular, spinal cord, intracisternal, local, intravenous infusion, aerosol, inhalation, scratching, intraperitoneal, intracystic, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, or vaginal administration.

[0229] For patient convenience, the cyclic prolyl glycine and cPG compounds can be administered orally. The amount of the compounds in the composition can vary considerably depending on the composition type, unit dose, type of excipients, and other factors well known to those skilled in the art. Typically, for a typical adult weighing 50 kg to 120 kg, the final composition may contain 5 mg to 50 mg of cPG, or 1 × 10⁻⁶ mg by weight. -5 Up to 3 × 10 -4 Percentage (% w), the remainder being one or more excipients.

[0230] Other convenient routes of administration include subcutaneous injection or intravenous infusion (e.g., dissolving the active cPG in a biocompatible carrier, such as a 0.9% sodium chloride solution or glucose solution) or direct administration to the CNS. Using stereotaxic devices and precise mapping of the animal's CNS, compounds can be injected directly into the site of nerve injury.

[0231] By administering a compound in a prodrug form, the effective amount of the compound in the CNS can be increased. This prodrug form comprises the compound of the present invention and a carrier, wherein the carrier is linked to the compound of the present invention via a linking group that is readily cleaved or digested in the patient's body. Any suitable linking group that can be cleaved or digested after administration can be used.

[0232] However, the applicant does not intend to exclude other forms of administration. In other embodiments of the invention, restoring neurological function in animals may include administering a therapeutic amount of a cyclic prolyl glycine or cPG compound in combination with another neuroprotective agent selected, for example, from growth factors and related derivatives (insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), transforming growth factor-β1, activin, growth hormone, nerve growth factor, growth hormone-binding protein, IGF-binding protein, keratinocyte growth factor, and androgen-induced growth factor). Other members of the FGF family include, for example, fibroblast growth factor homolog-1 (FHF-1), FHF-2, FHF-3 and FHF-4, keratinocyte growth factor 2, brain-derived growth factor, neurotrophic factor 3 and neurotrophic factor 4. Other forms of neuroprotective agents include clomethasone, kynurenic acid, Semax, tacrolimus; glutamate agonists, such as NPS1506, GV1505260, MK-801, GV150526; AMPA antagonists, such as 2,3-dihydroxy-6-nitro-7-sulfonamidobenzo(f)quinoxaline (NBQX); and anti-inflammatory agents targeting addressin MAdCAM-1 and / or its integrin α4 receptors (α4β1 and α4β7), such as anti-MAdCAM-1 mAb MECA-367 (ATCC accession number HB-9478).

[0233] Cyclic prolyl glycine compounds can be suitably administered via sustained-release systems. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of molded articles, such as films or microcapsules.

[0234] For parenteral administration, in one embodiment, the cyclic prolyl glycine or cPG compound is typically formulated by mixing, in a unit-dose injectable form (solution, suspension, or emulsion) at the desired purity with a pharmaceutically or parenterally acceptable carrier (e.g., a carrier that is non-toxic to the recipient at the dose and concentration used and is compatible with other components in the formulation).

[0235] Typically, formulations are prepared by uniformly and closely contacting a cyclic prolylglycine or cPG compound with a liquid carrier or a finely pulverized solid carrier, or both. The product is then shaped into the desired formulation, if necessary. Preferably, the carrier is a parenteral carrier, or more preferably, a solution isotonic with the recipient's blood. Examples of such carrier solvents include water, saline, Ringer's solution, buffer solutions, and glucose solutions. Non-aqueous solvents, such as fixed oils and ethyl oleate, may also be used herein.

[0236] Cyclic prolyl glycine or cPG compounds are typically formulated in this solvent at a pH of approximately 4.5 to 8. It should be understood that the use of certain excipients, carriers, or stabilizers described above may result in the formation of a salt from this compound. The final product may be a stable liquid or a lyophilized solid.

[0237] Formulations of cyclic prolyl glycine or cPG compounds in pharmaceutical compositions may also include adjuvants. Typical adjuvants that can be added to tablets, capsules, etc., include binders (such as gum arabic, corn starch, or gelatin), excipients (such as microcrystalline cellulose), disintegrants (such as corn starch or alginate), lubricants (such as magnesium stearate), sweeteners (such as sucrose or lactose), and flavoring agents (such as peppermint, wintergreen, or cherry). When the dosage form is tablet, the cyclic prolyl glycine or cPG compound and the composition may include a binder and optionally a smooth coating. When the dosage form is capsule, in addition to the above substances, a liquid carrier (such as fatty oil) may be included. Various other types of materials may also be used as coatings or modifiers of the physical form of dosage units. Syrups or elixirs may include active compounds, sweeteners (such as sucrose), preservatives (such as propylparaben), colorants, and flavoring agents (such as cherry). Sterile compositions for injection may be formulated according to routine pharmaceutical practice. For example, it may be desirable to dissolve or suspend the active compound in a solvent, such as water or natural vegetable oil (e.g., sesame oil, peanut oil, or cottonseed oil) or a synthetic fatty solvent (e.g., ethyl oleate).

[0238] For injection, intraventricular administration, and other invasive routes of administration, cyclic prolyl glycine or cPG compounds are preferably sterile. Aseptic processing can be achieved by any method known in the art, such as filtration through a sterile filter membrane (e.g., a 0.2-micron membrane). Therapeutic compositions are typically placed in containers with sterile dispensing ports, such as intravenous vials or bags with stoppers that can be punctured by a subcutaneous injection needle.

[0239] Preferred aspects of the invention This invention provides a method for treating mild cognitive impairment and related neurodegenerative and mental disorders by using NA-831 and cPG analogs and cPG compounds in combination with antibodies or their active fragments (e.g., lencanezumab, a monoclonal antibody that specifically binds to them).

[0240] A first aspect of the invention includes a method for alleviating or reducing Alzheimer's disease psychosis in a mammal due to disease, injury, or condition, the method comprising: a) providing a mammal requiring relief or reduction of Alzheimer's disease psychosis caused by disease, injury, or condition; and b) administering to said mammal a pharmaceutically effective amount of cyclic prolyl glycine (cPG) or an analogue thereof (cyclic tri(prolyl glycine) or cyclic glycyl-2-allyl proline, cyclic glycyl-alkyl proline, or cyclic glycyl-2-methylproline (cPMeG, collectively referred to as cPG compounds), or a combination thereof with lencanezumab; wherein said disease is selected from Alzheimer's disease psychosis.

[0241] Another aspect of the invention includes: wherein the administration of cPG and lencanezumab is in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0242] Another aspect of the invention includes: wherein the effective amount of the cPG compound is about 1 μg to about 100 mg per kg body weight.

[0243] Another aspect of the invention includes the fact that the application is performed in conjunction with artificial cerebrospinal fluid.

[0244] Another aspect of the invention includes the fact that the administration is performed via intravenous injection.

[0245] Another aspect of the invention includes the following: wherein the administration is carried out in combination with a neuroprotective agent, insulin-like growth factor-I (IGF-I) or insulin-like growth factor-II (IGF-II).

[0246] Another aspect of the invention includes the following: wherein the administration is carried out in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier thereof.

[0247] Another aspect of the invention includes the fact that the application is performed in conjunction with artificial cerebrospinal fluid.

[0248] Another aspect of the invention includes the following: wherein the administration is carried out in combination with a neuroprotective agent, insulin-like growth factor-I (IGF-I) or insulin-like growth factor-II (IGF-II).

[0249] Another aspect of the invention includes the fact that the application is carried out in conjunction with an anti-inflammatory agent.

[0250] A second aspect of the invention includes a method for alleviating or reducing cognitive impairment in a mammal due to disease, injury, or condition, the method comprising: a) providing a mammal requiring relief or reduction of cognitive impairment due to disease, injury, or condition; and b) administering to said mammal a pharmaceutically effective amount of cyclic prolyl glycine (cPG) or an analogue thereof (cyclic tri(prolyl glycine)). Cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline, or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds, or combinations thereof with lencanezumab; wherein the diseases are selected from the group consisting of: Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, multiple infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegenerative changes associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, early-onset dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy, or cortical-basal degeneration; furthermore, the injuries are selected from the group consisting of: neurotoxic injury, cerebral hypoxia / ischemia, traumatic brain injury, and coronary artery bypass grafting. (bypass surgery), wherein the condition is normal aging, age-related memory loss, memory impairment, cholinergic hypofunction, cerebral vascular stenosis or occlusion, neuroinflammation, mild cognitive impairment, brain atrophy, frontotemporal degeneration, Pick's disease, HIV infection, Down syndrome, and loss of synaptic plasticity; furthermore, the mammals mentioned are used to alleviate or reduce cognitive impairment caused by disease, injury, or condition, including Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegenerative changes associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, early-onset dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy, or cortical-basal degeneration.

[0251] Relieving cognitive impairment generally refers to methods that can alleviate symptoms associated with memory, thinking, language, and other cognitive processes. In addition, these methods may also help improve mood, agitation, and other behavioral problems.

[0252] Another aspect of the invention includes: wherein the cyclic prolyl glycine (cPG) or its analogues (cyclic tri(prolyl glycine) or cyclic glycyl-2-allyl proline, or cyclic glycyl-alkyl proline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds, or combinations thereof with lencanetumab, comprises an aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers or adjuvants.

[0253] Another aspect of the invention includes: wherein the cyclic prolyl glycine (cPG) or its analogues (cyclic tri(prolyl glycine) or cyclic glycyl-2-allyl proline, or cyclic glycyl-alkyl proline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds, or combinations thereof with lencanetumab, further includes one or more excipients, carriers, additives, adjuvants or binders in tablets or capsules.

[0254] Another aspect of the invention includes: wherein the disease is mild cognitive impairment, Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegenerative changes associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, early-onset dementia, senile dementia, Parkinson's disease-related dementia, progressive supranuclear palsy, or cortical-basal degeneration.

[0255] Another aspect of the invention includes: wherein cyclic prolyl glycine (cPG) or its analogues (cyclic tri(prolyl glycine) or cyclic glycyl-2-allyl proline, or cyclic glycyl-alkyl proline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds, or combinations thereof with lencanezumab, are administered via oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ocular, intraspinal, intracisional, local, infusion, implantation, aerosol, inhalation, scratch, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, vaginal, or combinations thereof.

[0256] Another aspect of the invention includes: wherein the lower limit of the pharmaceutically effective amount is about 0.001 mg / kg of the mammalian mass (mg / kg), and the upper limit is about 100 mg / kg of the mammalian mass.

[0257] Another aspect of the invention includes: wherein the cognitive impairment is caused by cholinergic dysfunction.

[0258] Another aspect of the invention includes the fact that the cognitive impairment is caused by a reduction in glutamate receptors in the granule cell layer (CA1) of the mammalian hippocampus.

[0259] Another aspect of the invention includes: wherein cyclic prolyl glycine (cPG) or its analogues (cyclic tri(prolyl glycine) or cyclic glycyl-2-allyl proline, cyclic glycyl-alkyl proline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds, or combinations thereof, can lead to an increase in AMPA receptors in the granule cell layer (CA1) of the mammalian hippocampus.

[0260] Another aspect of the invention includes: wherein cyclic prolyl glycine (cPG) or its analogues (cyclic tri(prolyl glycine) or cyclic glycyl-2-allyl proline, cyclic glycyl-alkyl proline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds, or a combination thereof with lencanezumab, can lead to an increase in neuronal plasticity induced by said cPG compounds in the granule cell layer (CA1) and pyramidal cell layer (CA3) regions of the mammalian hippocampus.

[0261] Another aspect of the invention includes: wherein cerebral hypoxia / ischemia is caused by traumatic brain injury.

[0262] Another aspect of the invention includes: wherein the cognitive impairment is caused by multiple infarct dementia.

[0263] Another aspect of the invention includes a situation where the cognitive impairment is caused by coronary artery bypass grafting (CABG).

[0264] Another aspect of the invention includes: wherein the cognitive impairment is caused by Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegenerative changes associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, early-onset dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy, or cortical-basal degeneration.

[0265] A third aspect of the invention includes a method for preventing mild cognitive impairment symptoms caused by or related to disease, injury, or condition in mammals in need, comprising: a) providing the mammal in need of prevention of cognitive impairment caused by disease, injury, or condition; b) administering to the mammal a pharmaceutically effective amount of cyclic prolyl glycine (cPG) or an analogue thereof (cyclic tri(prolyl glycine)). Or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline, or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds, or combinations thereof with lencanezumab; wherein the diseases are selected from the group consisting of: Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, multiple infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegenerative changes associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, early-onset dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy, or cortical-basal degeneration.

[0266] Preventing mild cognitive impairment symptoms typically refers to taking measures to prevent the onset of symptoms, with the primary goal of reducing the risk of developing the disease. Generally, dementia prevention can be divided into three levels: primary prevention, secondary prevention, and tertiary prevention.

[0267] In degenerative dementia, the secondary prevention phase can be applied to the mild cognitive impairment stage. At this stage, symptoms have appeared, but are not severe enough to diagnose dementia. Therefore, treatment with cPG compounds in combination with lencanezumab in subjects with mild cognitive impairment (MCI) can be considered a secondary prevention study.

[0268] Tertiary prevention refers to treatments implemented after a disease is diagnosed, aimed at halting its progression. The goal is to reduce the degree of disability in individuals with mild cognitive impairment and improve their long-term prognosis.

[0269] A fourth aspect of the invention includes a method for treating mild cognitive impairment symptoms in mammals caused or associated with a disease, injury, or condition, comprising: a) providing the mammal with the cognitive impairment caused by the disease, injury, or condition requiring treatment; and b) administering to the mammal a pharmaceutically effective amount of cyclic prolyl glycine (cPG) or an analogue thereof (cyclic tri(prolyl glycine)). Or cyclic glycyl-2-allylproline or cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds, or combinations thereof with lencanezumab; wherein the diseases are selected from the group consisting of: Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, multiple infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegenerative changes associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, early-onset dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical-basal degeneration.

[0270] Treatment for mild cognitive impairment typically refers to treating cognitive functions, or thought processes, including but not limited to the ability to learn, read, speak, and write. Patients with mild cognitive impairment (MCI) retain these essential cognitive skills sufficient to cope with daily activities, but they have difficulty remembering recent events or recently acquired information.

[0271] A fifth aspect of the invention includes a method for alleviating or reducing cognitive impairment in mammals due to disease, injury, or symptom, comprising: a) providing a mammal requiring relief or reduction of cognitive impairment due to disease, injury, or symptom; b) administering to the mammal a pharmaceutically effective amount of cyclic prolyl glycine (cPG) or an analogue thereof (cyclic tri(prolyl glycine)). Cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline, or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds, or combinations thereof with lencanezumab; wherein the disease is selected from the group consisting of: Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, multiple infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegenerative changes associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, early-onset dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy, or cortical-basal degeneration; furthermore, wherein the injury is selected from the group consisting of: neurotoxic injury, cerebral hypoxia / ischemia. Traumatic brain injury, coronary artery bypass grafting; wherein the conditions include normal aging, age-related memory loss, memory impairment, cholinergic hypofunction, cerebral vascular stenosis or occlusion, neuroinflammation, mild cognitive impairment, brain atrophy, frontotemporal degeneration, Pick's disease, HIV infection, Down syndrome, and loss of synaptic plasticity; furthermore, the mammals mentioned are used to alleviate or reduce cognitive impairment caused by disease, injury, or condition, including Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegenerative changes associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, early-onset dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy, or cortical-basal degeneration.

[0272] Another aspect of the invention includes: wherein cyclic prolyl glycine (cPG) or its analogues (cyclic tri(prolyl glycine) or cyclic glycyl-2-allyl proline or cyclic glycyl-alkyl proline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds, or combinations thereof with lencanetumab, comprises an aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers or adjuvants.

[0273] Another aspect of the invention includes: wherein cyclic prolyl glycine (cPG) or its analogues (cyclic tri(prolyl glycine) or cyclic glycyl-2-allyl proline or cyclic glycyl-alkyl proline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds, or combinations thereof with lencanetumab, further comprises one or more excipients, carriers, additives, adjuvants or binders in tablets or capsules.

[0274] Another aspect of the invention includes: wherein the disease is mild cognitive impairment, Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegenerative changes associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, early-onset dementia, senile dementia, Parkinson's disease-related dementia, progressive supranuclear palsy, or cortical-basal degeneration.

[0275] Another aspect of the invention includes: wherein cyclic prolyl glycine (cPG) or its analogues (cyclic tri(prolyl glycine) or cyclic glycyl-2-allyl proline or cyclic glycyl-alkyl proline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds, or combinations thereof with lencanezumab) are administered via oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ocular, intraspinal, intracisional, local, infusion, implantation, aerosol, inhalation, scratch, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, vaginal, or combinations thereof.

[0276] Another aspect of the invention includes: wherein the pharmaceutically effective amount of cPG is limited to a lower limit of about 0.001 mg / kg of the mammalian mass (mg / kg) and an upper limit of about 100 mg / kg of the mammalian mass.

[0277] Another aspect of the invention includes: wherein the pharmaceutically effective amount of lencanezumab is limited to a lower limit of about 1.00 mg / kg of the mammalian mass (mg / kg) and an upper limit of about 10.00 mg / kg of the mammalian mass.

[0278] Another aspect of the invention includes: wherein the cognitive impairment is caused by cholinergic dysfunction.

[0279] Another aspect of the invention includes: wherein the cholinergic dysfunction is caused by scopolamine.

[0280] Another aspect of the invention includes: wherein the cognitive impairment is age-related memory loss, cognitive impairment, MCI (“mild cognitive impairment”), Alzheimer’s disease, memory loss, attention deficit symptoms associated with Alzheimer’s disease, neurodegenerative changes associated with Alzheimer’s disease, mixed vascular dementia, degenerative dementia, early-onset dementia, senile dementia, Parkinson’s disease-related dementia, progressive supranuclear palsy, or cortical-basal degeneration.

[0281] Another aspect of the invention includes the fact that the cognitive impairment is caused by a reduction in glutamate receptors in the granule cell layer (CA1) of the mammalian hippocampus.

[0282] Another aspect of the invention includes a cPG compound that causes an increase in AMPA receptors in the granule cell layer (CA1) of the mammalian hippocampus.

[0283] Another aspect of the invention includes: wherein cyclic prolyl glycine (cPG) or its analogues (cyclic tri(prolyl glycine) or cyclic glycyl-2-allyl proline or cyclic glycyl-alkyl proline or cyclic glycyl-2-methyl-proline (cPMeG), collectively referred to as cPG compounds, or a combination thereof with lencanezumab, can lead to an increase in neuronal plasticity induced by said cPG compounds in the granule cell layer (CA1) and pyramidal cell layer (CA3) regions of the mammalian hippocampus.

[0284] Another aspect of the invention includes: wherein cerebral hypoxia / ischemia is caused by traumatic brain injury.

[0285] Another aspect of the invention includes: wherein the cognitive impairment is caused by multiple infarct dementia.

[0286] Another aspect of the invention includes: wherein the cognitive impairment is caused by coronary artery bypass grafting (CABG).

[0287] Another aspect of the invention includes: wherein the cognitive impairment is caused by Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegenerative changes associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, early-onset dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy, or cortical-basal degeneration.

[0288] A sixth aspect of the invention includes a method for preventing mild cognitive impairment symptoms caused by or related to disease, injury, or condition in mammals in need, comprising: a) providing the mammal in need of prevention of cognitive impairment caused by disease, injury, or condition; b) administering to the mammal a pharmaceutically effective amount of cyclic prolyl glycine (cPG) or an analogue thereof (cyclic tri(prolyl glycine)). Or cyclic glycyl-2-allylproline or cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG, or a combination thereof with lencanezumab; wherein the disease is selected from the group consisting of: Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, multiple infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegenerative changes associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, early-onset dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical-basal degeneration.

[0289] A seventh aspect of the invention includes a method for treating mild cognitive impairment symptoms in mammals caused or associated with a disease, injury, or condition, comprising: a) providing the mammal requiring treatment for cognitive impairment caused by a disease, injury, or condition; and b) administering to the mammal a pharmaceutically effective amount of cyclic prolyl glycine (cPG) or an analogue thereof (cyclic tri(prolyl glycine)). Or cyclic glycyl-2-allylproline or cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds, or combinations thereof with lencanezumab; wherein the diseases are selected from the group consisting of: Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, multiple infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegenerative changes associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, early-onset dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical-basal degeneration.

[0290] Examples The following in vitro and in vivo studies demonstrate the effectiveness of the combination of cyclic prolyl glycine and lencanezumab in alleviating cognitive impairment. These studies are not intended to limit the invention, and other compositions and methods of the invention may be developed without excessive experimentation. All the following experiments were conducted in accordance with protocols established in accordance with guidelines approved by the Animal Ethics Committee and Institutional Review Board.

[0291] Cyclic prolyl glycine is available from commercial suppliers such as Bachem (Torrance, Calif.) and Sigma (St. Louis, Mo.). Lencanemab and doneemab (humanized forms of IgG1-type anti-soluble aggregated amyloid β (Aβ) monoclonal antibodies) are supplied by Med Chem Express (Monmouth Junction, NJ 08852).

[0292] Example 1 Morris Water Maze (MWM) for assessing the effects of cyclic prolyl glycine and lucanumab on cognitive function Learning and memory model.

[0293] Administration of cPG to animals treated with scopolamine-induced cognitive impairment produced clinical improvements similar to those observed in humans with cholinergic hypofunction. Scopolamine is commonly used in animal models of cholinergic hypofunction associated with Alzheimer's disease. The functional deficits observed after scopolamine treatment include those found in human patients with Alzheimer's disease. Therefore, scopolamine treatment can reasonably predict cognitive impairment in human patients with the disease. Furthermore, scopolamine treatment can also mimic cognitive impairment in humans without neurodegenerative disease.

[0294] The aim of this study was to investigate cyclic prolyl glycine to assess its effects on cognitive deficits and affective states (anxiety).

[0295] Methods The first part of this study involved an acute test of cyclic prolyl glycine in the Morris water maze memory model. The MWM test is one of the most commonly used tests for assessing spatial memory in rats and is recognized as an accurate predictor of the overall effects of disease and treatment on spatial memory. Therefore, the MWM test can reflect the effects of disease and treatment in human subjects.

[0296] The standard procedure for the MWM (Multiple Motion Mechanism) was followed. A circular swimming pool (80 cm deep × 150 cm in diameter) was filled with opaque water, maintained at 20°C. A platform was hidden 1 cm below the water surface, marked with a white flag (10 cm × 10 cm). For visual cues, the flag was placed 20 cm above the platform; for spatial cues, it was positioned at the 3 o'clock position relative to the starting position. From day 1 to day 4, rats underwent memory acquisition tests, six times daily (60 seconds each time) (habituation phase). The latency to reach the platform was recorded, and the ability to learn the location of the hidden platform was measured by the reduction in the average daily latency.

[0297] On day 5 of the experiment, normal, non-aged Wistar rats were divided into several groups and given either saline (N=12) or scopolamine (0.5 mg / kg, intraperitoneal injection, N=12) to induce memory deficits. Scopolamine was administered half an hour before the start of the probe test.

[0298] Ten minutes after scopolamine treatment, cyclic prolyl glycine (cPG) was administered either alone via intraperitoneal injection (ip), or in combination with lencanemab (ip), or in combination with donepemab (ip), at doses given in Table 1. Solvent-treated animals received the same treatment regimen, with the diluent administered orally via gavage (n=15).

[0299] Table 1: Animals used to test the effects of cPG and its combination with lenkanemab and donepemab on memory.

[0300] The acute effects of cPG, cPG + lencanemab, and cPG + donepemab were then tested in animals with scopolamine-induced memory impairment and age-matched control animals without memory impairment to determine their direct pharmacological effects on memory processing. Experimental groups are detailed in Table 1 below.

[0301] On day 5, a probe-based MWM test was performed, with the platform removed. Six trials were conducted, each lasting a maximum of 60 seconds, with at least a 5-minute rest between trials. The time spent swimming near the platform was used to measure the extent to which the rats relied on visual and spatial cues to locate the platform, rather than employing non-spatial strategies. Data collection and analysis were performed using Any-maze (v4.2) software.

[0302] One-way ANOVA was used to determine differences between age groups in the data generated from behavioral tests. Two-way ANOVA was used to examine changes in behavioral outcomes over time, with time points as the dependent variable. Data analysis was performed using GraphPad Prism version 3.02 software.

[0303] Results The result is Figure 1 As shown in the text, treatment with scopolamine significantly impaired the acquisition of spatial memory in the treated animals.

[0304] Cyclic prolyl glycine (10 mg / kg, daily), cyclic prolyl glycine combined with lencanemab (5 mg / kg cPG + 5 mg lencanemab), and cyclic prolyl glycine combined with donepemab (5 mg / kg cPG + 5 mg donepemab) all significantly reversed scopolamine-induced cognitive impairment. However, lencanemab alone or donepemab alone did not significantly reverse scopolamine-induced cognitive impairment.

[0305] These results confirm that cPG (also known as NA-831) and cPG in combination with lencanemab or donepemab have a cholinergic-positive effect on the recovery of learned underwater platform locating skills (spatial memory). Combination therapy of cPG with lencanemab and cPG with donepemab may be effective in patients with mild cognitive impairment.

[0306] Example 2: A phase II randomized, placebo-controlled, double-blind study to evaluate the safety, tolerability, and efficacy of NA-831 and lencanezumab compared to placebo in Alzheimer's disease patients with psychosis. Methods The study was conducted at research centers and nursing homes in Australia and New Zealand.

[0307] The nursing home had obtained a site exemption from the research ethics committee; therefore, all research procedures were completed on-site by the clinical research team at the nursing home, and nursing home staff were not involved in the research team. This study was conducted in accordance with the Declaration of Helsinki, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice guidelines, and the US Code of Federal Regulations.

[0308] Patients will be assessed during the screening period to ensure they meet all study participation criteria. These assessments will include specific indicators of psychotic severity, delirium, dementia, cardiovascular status, and pregnancy status. Based on these assessment results, patients may be excluded from the study (especially if it is determined that the patient's baseline health and mental status do not meet all the inclusion criteria specified in the protocol).

[0309] Table 2 presents the participants' baseline demographic and clinical characteristics.

[0310] Table 2: Baseline Demographic and Clinical Characteristics

[0311] Inclusion criteria: Participants aged 50 years or older, regardless of gender, with probable or likely Alzheimer's disease as defined by the National Institute of Neurological and Communicative Disorders and Stoke-Alzheimer's Disease and Related Disorders Association, and meeting the diagnostic criteria for Alzheimer's disease psychiatric disorders established by Dilip Jeste and Sandy Finkel (Jeste DV, Finkel SI, Psychosis of Alzheimer's disease and related dementias: Diagnostic criteria for a distinct syndrome. Am J Geriatr Psychiatry. 2000 Winter;8(1):29-34).

[0312] Participants were eligible if they developed psychotic symptoms after diagnosis, including visual or auditory hallucinations, delusions, or both. Participants must also have been residing in a nursing home for at least four weeks prior to randomization, not bedridden, and expected to remain in the facility throughout the study period. Furthermore, they must have actively experienced and verbally reported psychotic symptoms within one month prior to screening, occurring at least once a week within two weeks prior to baseline, and requiring treatment for Alzheimer's disease psychotic symptoms. The severity of symptoms at screening and baseline must be sufficient to require antipsychotic medication, and participants must have scored 4 or higher on the hallucination item.

[0313] Exclusion criteria: Participants were excluded if they had previously received antipsychotic medications, QT-prolonging drugs, centrally acting anticholinergic drugs, mianserin, nefazodone, cyproheptadine, or fluvoxamine. Additionally, participants who used antidepressants or anxiolytics during the study and whose dosage changed were also excluded. Participants currently receiving acetylcholinesterase inhibitors or memantine, or both, must maintain a stable dosage for three months prior to baseline and throughout the study. Furthermore, participants who were unable to communicate verbally, or who had a significant history of psychotic disorders (including but not limited to schizophrenia or bipolar disorder) prior to or concurrently with an Alzheimer's disease diagnosis, or who had any medical conditions or surgical history that could interfere with the study, were also excluded. Written informed consent was obtained from the participant or their legally authorized representative before the study commenced.

[0314] Randomization and blinding Participants (1:1) were randomly assigned to receive either NA-831 (60 mg orally daily) or a placebo (60 mg orally daily) and were assigned to four groups based on their baseline Mini-Mental State Examination (MMSE) 24 total score and NPI-NH psychosis score: MMSE <10 and NPI-NH psychosis score <12, MMSE ≥10 and NPI-NH psychosis score <12, MMSE <10 and NPI-NH psychosis score ≥12, and MMSE ≥10 and NPI-NH psychosis score ≥12. Randomization sequences were generated by an independent statistician with no other association to this study using a permutation block size of 4, implemented using Trident software (version 1.2).

[0315] At the clinical trial site, participants, caregivers, study sponsors, and researchers were unaware of the treatment allocation. Blinding of the active treatment and placebo was achieved by using tablets that appeared identical. The study was unblinded after all participants completed the study and the database was locked. See Table 3.

[0316] Table 3: Treatment Interventions

[0317] Outcomes Primary outcomesThe efficacy of NA-831 compared to placebo was defined as the change in NPI-NH psychotic scores (hallucinations + delusions) from baseline to week 6. Pre-specified sensitivity analyses for the primary outcome included responder analyses and various imputation models (mixed model and last-observation carryover). Correlation analyses were also performed at weeks 6 and 12 (NPI-NH psychotic score, NPI-NH total score, NPI-NH agitation / aggression score, Alzheimer's Disease Collaborative Study-Clinical Global Impression Change Scale (ADCS-CGIC), Alzheimer's Disease Collaborative Study-Activities of Daily Living Scale (ADCS-ADL) total score, and Cohen-Mansfield Agitation Scale-Short Version (CMAI-SF) total score).

[0318] Secondary outcomes To assess behavioral symptoms (to evaluate the impact on all clinical domains, including cognition and function, and to evaluate any overall decline in treatment-related outcomes) using ADCS-CGIC at weeks 6 and 12, NPI-NH agitation / aggression and sleep and nocturnal behavior disorder domains, and CMAI-SF total score and subdomain scores as indicators of agitation, we used ADCS-CGIC at weeks 6 and 12.

[0319] Pre-defined exploratory outcomes included the NPI-NH total score and its other independent domains as an overall assessment indicator of neuropsychiatric symptoms, NPI-NH psychosis scores by subgroup, persistence of response from week 6 to week 12, NPI-NH occupational distress total score, ADCS-ADL (total score, basic and instrumental subdomain scores), and emergency medication use for behavioral disorders and sleep.

[0320] Pre-specified subgroup analyses focused on baseline NP1-NH psychotic score (<12 or ≥12), baseline MMSE (<10 or ≥10), sex (male or female), age (≤85 years or >85 years), combination therapy with selective serotonin reuptake inhibitors, combination therapy with antidementia medications, and prior antipsychotic medication use. Furthermore, cognitive impairment was assessed using the MMSE, and extrapyramidal symptoms were assessed from baseline to week 12 using Part III of the Unified Parkinson's Disease Rating Scale (UPDRS). Part III of the 1987 version of the UPDRS was used because it has been validated in dementia patients.

[0321] All participants who were randomly assigned and received the study intervention were included in the safety analysis. Safety outcomes assessed during the 12-week period included reported adverse events, adverse events leading to study withdrawal, serious adverse events, and death, as well as assessments by physical examination, vital signs (electrocardiograms (ECG) taken at baseline, day 15, day 85, or early termination, with corrected QT interval [QTcF] calculated using the Fridricia method), and clinical laboratory tests (hematology, clinical biochemistry, urinalysis).

[0322] Statistical analysis To calculate sample size, an effect size of 0.4 to 0.5 standard deviations between the active treatment and placebo was assumed to be clinically significant. The true difference in the mean change in NPI-NH psychotic score between NA-831 and placebo from baseline to week 6 was assumed to be 3 points, with a co-SD of 6 points. All statistical analyses were performed using SAS (version 9.3).

[0323] Results A total of 287 participants were screened, and 101 were excluded. 186 participants were enrolled and assigned. Of these 186 participants, 93 (93) were randomized to receive NA-831 orally 60 mg daily. 93 (93) were randomized to receive placebo and were included in the modified intention-to-treat population. A separate group of 34 participants was selected from the 186 participants to evaluate the potential efficacy of NA-831 in combination with lencanezumab for Alzheimer's disease psychosis. Of the 93 participants in the drug treatment group, 17 were randomized to receive NA-831 orally 30 mg daily, with lencanezumab administered intravenously every two weeks during the 12-week study period. Of the 93 participants in the placebo group, 17 were randomized to receive NA-831 orally daily, with placebo administered intravenously every two weeks during the 12-week study period.

[0324] Table 1 presents the baseline demographic and clinical characteristics of the participants.

[0325] Six of the 93 participants in the NA-831 group (6.5%) and eight of the 93 participants in the placebo group (8.6%) used emergency medication for behavioral or sleep disorders.

[0326] The baseline demographics and clinical characteristics of participants were generally balanced across the treatment groups. 23 (24.7%) of the 93 participants in the NA-831 group and 24 (25.8%) of the 93 participants in the placebo group had more severe psychotic symptoms, based on an NPI-NH psychotic score of 12 or higher; 16 (17.2%) of the 93 participants in the NA-831 group and 17 (18.3%) of the 93 participants in the placebo group had MMSE scores below 10.

[0327] For the primary outcome, the adjusted mean change in NPI-NH psychosis score at week 6 was -3.7 points (SE 0.58) in the NA-831 group and -2.2 points (0.66) in the placebo group. At week 12, the adjusted mean change in NPI-NH psychosis score was -4.2 points (SE 0.63) in the NA-831 group and -2.8 points (0.67) in the placebo group.

[0328] On average, at week 12, participants in the NA-831 group had a 42.7% reduction in their NPI-NFI psychosis scores, compared to an 18.7% reduction in the placebo group.

[0329] No significant difference was observed between the group receiving lencanemab and the group receiving placebo.

[0330] However, the group receiving the combination therapy of NA-831 and lencanezumab showed a significant improvement at week 12 compared to the group receiving NA-831 at week 12.

[0331] Figure 2 : Shows the adjusted mean change of the NPI-NH psychotic score of NA-831 from baseline to week 12.

[0332] Figure 3 The image shows the adjusted mean change in NPI-NH psychotic score from baseline to week 12 in patients treated with combination therapy of NA-831 and lencanezumab.

[0333] A response (defined as an improvement of ≥30%) was observed in 52 cases (55.9%) in the NA-831 group and 32 cases (34.4%) in the placebo group (p=0.012).

[0334] Three (3.2%) of the 93 participants in the NA-831 group reported adverse events, compared to two (2.1%) of the 93 participants in the placebo group.

[0335] No significant differences were observed in physical examination, vital signs, or clinical laboratory findings among the treatment groups. At week 12, the mean weight change was -4 kg (SE 0.66) in the NA-831 group and -0.3 kg (SE 0.28) in the placebo group. Categorical analysis showed that, compared to the placebo group (3 / 93 or 2.9%), 18% (17 / 93 or 18.3%) of participants with diabetes in the NA-831 group experienced a 10% weight loss over 12 weeks.

[0336] In the NA-831 group, 6 out of 93 participants (6.4%) experienced adverse cardiac events related to the study treatment, compared to 17 out of 93 participants (18.3%) in the placebo group.

[0337] Conclusions: Results from a clinical trial of NA-831 showed that, at the primary time point of week 6 and the secondary time point of week 12, NA-831 demonstrated significant therapeutic benefits compared to placebo, was well-tolerated, and had no negative impact on cognition.

[0338] The results showed that lencanemab did not demonstrate a significant therapeutic benefit compared to placebo at the primary time point of week 6 and the secondary time point of week 12.

[0339] Notably, participants treated with the combination of NA-931 and lencanezumab showed significant improvement at week 12 compared to those treated with NA-831 alone.

[0340] All publications mentioned in this application, including patent documents and scientific articles, as well as any references, are incorporated herein by reference in their entirety, as if each published document were individually incorporated into this document. All headings are for convenience only and, unless otherwise expressly stated, shall not be used to limit the meaning of the text below the heading.

[0341] As used in this article, “about” or other similar terms refer to plus or minus 10% of the value shown.

[0342] When a range is included and referenced as “between” or “from”, it is intended to include the end values ​​within the range, not the range without end values.

Claims

1. A method for treating, alleviating, or reducing mild cognitive impairment in a subject, comprising: a) Provide treatment, relief, or reduction for subjects with mild cognitive impairment; b) Administer to the subject a pharmaceutically effective amount of at least one cyclic prolyl glycine (cPG) or its analogue (cyclic tri(prolyl glycine) or cyclic glycyl-2-allyl proline or cyclic glycyl-alkyl proline or cyclic glycyl-2-methylproline (cPMeG) or a combination thereof, collectively referred to as cPG compounds); c) Administer to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and / or operablely binds to Aβ soluble primary fibrils; The cPG compound and the specific binding member are each administered to the subject in an effective amount to jointly treat the subject's mild cognitive impairment. Furthermore, the mild cognitive impairment of the subject was treated.

2. The method according to claim 1, The mild cognitive impairment mentioned above is associated with Alzheimer's disease.

3. The method according to claim 1, in, The pharmaceutically effective amount of the cPG compound is about 1 μg to about 100 mg per kg body weight.

4. The method according to claim 1, in, The pharmaceutically effective amount of the cPG compound is administered at a dose of about 0.1 mg / kg to about 10 mg / kg daily, 0.5 mg / kg to about 20 mg / kg daily, about 0.2 mg / kg to about 40 mg / kg daily, about 5 mg / kg to about 50 mg / kg daily, or about 10 μg / kg to about 100 mg / kg daily.

5. The method according to claim 1, in, The lower limit of the pharmaceutically effective amount of the cPG compound is about 0.1 mg / kg of the mammalian mass (mg / kg), and the upper limit is about 10 mg / kg of the subject.

6. The method according to claim 1, in, The pharmaceutically effective amount of the cPG compound is about 20 mg to about 80 mg per day, or about 20 mg to about 100 mg per day.

7. The method according to claim 1, in, The administration of the pharmaceutically effective amount of the cPG compound is carried out in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

8. The method according to claim 1, in, The administration of the pharmaceutically effective amount of the cPG compound is carried out in combination with artificial cerebrospinal fluid.

9. The method according to claim 1, in, The administration of the pharmaceutically effective amount of the cPG compound is via an intravenous route.

10. The method according to claim 1, in, The administration of the pharmaceutically effective amount of the cPG compound is carried out in combination with the administration of a neuroprotective agent, insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), or a combination thereof.

11. The method according to claim 1, in, The administration of the pharmaceutically effective amount of the cPG compound is carried out in combination with the administration of an anti-inflammatory agent, an anti-integrin α4 subunit agent, or a combination thereof.

12. The method according to claim 1, in, The administration of the pharmaceutically effective amount of the cPG compound is carried out in conjunction with the administration of an anti-inflammatory agent.

13. The method according to claim 1, in, The cPG compound is provided in aqueous solution and contains one or more pharmaceutically acceptable excipients, additives, carriers, adjuvants, or combinations thereof.

14. The method according to claim 1, in, The cPG compound comprises one or more pharmaceutically acceptable excipients, carriers, additives, adjuvants, binders, or combinations thereof.

15. The method according to claim 1, in, The pharmaceutically effective amount of the cPG compound is administered via oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ocular, intraspinal, intracisional, local, infusion, implantation, aerosol, inhalation, scratch, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, vaginal, or a combination thereof.

16. The method according to claim 1, in, The cPG compound is in the form of tablets, capsules, or a combination thereof.

17. The method according to claim 1, in, The specific binding members include receptors, receptor agonists, peptides, ligands, antibodies, polyclonal antibodies, monoclonal antibodies, humanized antibodies, their active fragments, or combinations thereof.

18. The method according to claim 1, in, The specific binding members include lencanemab, aducanumab, donepemab, crenezumab, semorinemab, gantenerumab, their active fragments, or combinations thereof.

19. The method according to claim 1, in, The specific binding is with amyloid β-soluble primary fibrils.

20. The method according to claim 1, in, The specific binding is to the soluble primary fibrils of amyloid-β (Aβ42).

21. The method according to claim 1, in, The operable binding is to bind to amyloid β-soluble primary fibrils to modulate at least one of their activities.

22. The method according to claim 1, in, The operable binding is to bind to soluble primary fibrils of amyloid-β (Aβ42) to modulate at least one of its activities.

23. The method according to claim 1, in, The pharmaceutically effective amount of the specific binding member is about 1 μg to about 100 mg per kg body weight.

24. The method according to claim 1, in, The pharmaceutically effective amount of the specific binding member is administered at a dose of about 0.1 mg / kg to about 10 mg / kg daily, about 0.5 mg / kg to about 20 mg / kg daily, about 0.2 mg / kg to about 40 mg / kg daily, about 5 mg / kg to about 50 mg / kg daily, or about 10 μg / kg to about 100 mg / kg daily.

25. The method according to claim 1, in, The lower limit of the pharmaceutically effective amount of the specific binding member is about 0.1 mg / kg of the mammalian mass (mg / kg), and the upper limit is about 100 mg / kg of the subject.

26. The method according to claim 1, in, The pharmaceutically effective amount of the specific binding member is about 20 mg to about 80 mg daily, or about 20 mg to about 100 mg daily.

27. The method according to claim 1, in, The administration of the pharmaceutically effective amount of the specific binding member is carried out in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

28. The method according to claim 1, in, The administration of the pharmaceutically effective amount of the specific binding member is carried out in conjunction with artificial cerebrospinal fluid.

29. The method according to claim 1, in, The administration of the pharmaceutically effective amount of the specific binding member is via an intravenous route.

30. The method according to claim 1, in, The administration of the pharmaceutically effective amount of the specific binding member is carried out in combination with the administration of a neuroprotective agent, insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), or a combination thereof.

31. The method according to claim 1, in, The administration of the pharmaceutically effective amount of the specific binding member is carried out in conjunction with the administration of an anti-inflammatory agent, an anti-integrin α4 subunit agent, or a combination thereof.

32. The method according to claim 1, in, The administration of the pharmaceutically effective amount of the specific binding member is carried out in conjunction with the administration of an anti-inflammatory agent.

33. The method according to claim 1, in, The pharmaceutically effective amount of the specific binding member lencanezumab (Lysap®) is administered at a dose of 10 mg / kg every two weeks in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier such as 0.9% sodium chloride injection.

34. The method according to claim 1, in, The specific binding member is provided in aqueous solution and contains one or more pharmaceutically acceptable excipients, additives, carriers, adjuvants or combinations thereof.

35. The method according to claim 1, in, The specific binding member comprises one or more pharmaceutically acceptable excipients, carriers, additives, adjuvants, binders, or combinations thereof.

36. The method according to claim 1, in, The pharmaceutically effective amount of the specific binding member is administered via oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ocular, intraspinal, intracisional, local, infusion, implantation, aerosol, inhalation, scratch, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, vaginal, or a combination thereof.

37. The method according to claim 1, in, The specific binding member is in the form of tablets, capsules, nasal sprays, injections, intravenous infusions, or combinations thereof.

38. The method according to claim 1, The subjects mentioned are mammals.

39. The method according to claim 1, The subjects mentioned were humans.

40. The method according to claim 1, in, The effective dose for co-treatment of the subject’s mild cognitive impairment is approximately 0.1 mg / kg body weight to approximately 20 mg / kg body weight of cPG, administered in combination with approximately 1 μg / kg body weight to approximately 100 mg / kg body weight of a specific binding member.

41. The method according to claim 1, The treatment, relief, or reduction mentioned therein refers to treatment.

42. The method according to claim 1, The treatment, relief, or reduction mentioned therein refers to relief.

43. The method according to claim 1, The treatment, relief, or reduction mentioned therein refers to relief.

44. A method for treating, alleviating, or reducing Alzheimer's disease in a subject, comprising: a) To provide subjects who require treatment, relief, or reduction of Alzheimer's disease; b) Administer to the subject a pharmaceutically effective amount of at least one cyclic prolyl glycine (cPG) or its analogue (cyclic tri(prolyl glycine) or cyclic glycyl-2-allyl proline or cyclic glycyl-alkyl proline or cyclic glycyl-2-methylproline (cPMeG) or a combination thereof, collectively referred to as cPG compounds); c) Administer to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and / or operablely binds to Aβ soluble primary fibrils; The cPG compound and the specific binding member are each administered to the subject in an effective amount to jointly treat the subject's Alzheimer's disease; Furthermore, the subject's Alzheimer's disease was treated.

45. A method for treating, alleviating, or reducing psychosis in a subject with Alzheimer's disease, comprising: a) Provide subjects who require treatment, relief, or reduction of psychosis due to Alzheimer's disease; b) Administer to the subject a pharmaceutically effective amount of at least one cyclic prolyl glycine (cPG) or its analogue (cyclic tri(prolyl glycine) or cyclic glycyl-2-allyl proline or cyclic glycyl-alkyl proline or cyclic glycyl-2-methylproline (cPMeG) or a combination thereof, collectively referred to as cPG compounds); c) Administer to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and / or operablely binds to Aβ soluble primary fibrils; The cPG compound and the specific binding member are each administered to the subject in an effective amount to jointly treat the subject's Alzheimer's disease psychosis; Furthermore, the Alzheimer's disease psychosis of the subject was treated.

46. ​​A method for treating, alleviating, or reducing Alzheimer's disease behaviors, aggression, agitation, anger, apathy, or combinations thereof in a subject, comprising: a) Provide subjects who require treatment, relief or reduction of Alzheimer's disease behaviors, aggression, agitation, anger, apathy or combinations thereof; b) Administer to the subject a pharmaceutically effective amount of at least one cyclic prolyl glycine (cPG) or its analogue (cyclic tri(prolyl glycine) or cyclic glycyl-2-allyl proline or cyclic glycyl-alkyl proline or cyclic glycyl-2-methylproline (cPMeG) or a combination thereof, collectively referred to as cPG compounds); c) Administer to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and / or operablely binds to Aβ soluble primary fibrils; The cPG compound and the specific binding member are each applied to the subject in an effective amount to jointly treat the subject’s Alzheimer’s disease behaviors, aggression, agitation, anger, apathy or combinations thereof; Furthermore, the Alzheimer's disease behaviors, aggression, agitation, anger, apathy, or combinations thereof of the subject are treated.

47. A method for treating, alleviating, or reducing early-onset Alzheimer's disease in a subject, comprising: a) To provide subjects who require treatment, relief, or reduction of early-onset Alzheimer's disease; b) Administer to the subject a pharmaceutically effective amount of at least one cyclic prolyl glycine (cPG) or its analogue (cyclic tri(prolyl glycine) or cyclic glycyl-2-allyl proline or cyclic glycyl-alkyl proline or cyclic glycyl-2-methylproline (cPMeG) or a combination thereof, collectively referred to as cPG compounds); c) Administer to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and / or operablely binds to Aβ soluble primary fibrils; The cPG compound and the specific binding member are each administered to the subject in an effective amount to jointly treat the subject's early-onset Alzheimer's disease. Furthermore, the early-onset Alzheimer's disease of the subject was treated.

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