Combination therapy with an LP-PLA2 inhibitor and a second drug.

Abstract

The present invention provides a combination therapy comprising inhibition of lipoprotein-related phospholipase A2 (Lp-PLA2) and a second therapy. To facilitate the implementation of the method of the present invention, the present invention also provides a composition comprising a first agent comprising an Lp-PLA2 inhibitor molecule, a second agent, and a pharmaceutically acceptable carrier. In certain embodiments, the second agent comprises an amyloid target molecule, an agent that reduces amyloid levels in the brain or body, a tau target molecule, a vascular target molecule, an inflammation target molecule, and / or a molecule that modulates a mechanism of action orthogonal to Lp-PLA2 inhibition. Combinations of such second agents are also envisioned. While the present invention can be used for the prevention and treatment of a variety of disorders, in certain embodiments, the present invention is employed for vascular injury or inflammation associated with disease, condition or treatment-related side effects, particularly in the context of nervous system or neuromuscular conditions.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority and the benefit thereof with respect to U.S. Patent Application No. 63 / 496,892, filed on April 18, 2023, the entire content of which is hereby incorporated by reference in its entirety.

Background Art

[0002] Background of the Invention Medical complications, conditions, and age - related diseases such as diabetes, neurodegenerative diseases (NDDs), nervous system injuries or diseases, mental disorders, proteinopathies, and vascular diseases are diverse in type and scope. Many treatments, often monotherapies, are approved and in research for use in the treatment or prevention of numerous such conditions, diseases, and disorders. However, because such conditions, diseases, and disorders are often multifactorial, such treatments are not as safe and effective as desired, nor are they available to as broad a patient population as desired.

[0003] Neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington's disease (HD), are defined both symptomatically and pathophysiologically. For example, the diagnosis of AD is usually defined by clinical symptoms as well as the presence of amyloid plaques and tau fibers in postmortem brain specimens. Recently, AD has been biologically defined as a disease characterized by the presence of amyloid-beta (Aβ) plaques and tau fibers, regardless of the presence of clinical symptoms. The presence of Aβ plaques and tau fibers can be measured in vivo by various imaging and fluid biomarkers. While positron emission tomography (PET) imaging using specific tracers can directly detect Aβ amyloid and tau fibers in the brain, levels of fluid biomarkers such as Aβ42, Aβ40, total tau protein, or phosphorylated tau (pTau) species including but not limited to pTau181 and pTau217, as well as the Aβ42 / 40 ratio, can serve as surrogates for brain Aβ amyloid and tau fibers. Neurodegeneration is often measured by flu-deoxyglucose (FDG) PET and magnetic resonance imaging (MRI) and is associated with the development of Alzheimer's disease (AD), but it is not a prerequisite for AD. Therefore, AD patients can be asymptomatic (preclinical stage) or symptomatic (clinical stage).

[0004] Disease-modifying therapies for treating AD were not available until recently. These are exemplified by anti-amyloid drugs such as aducanumab and lecanemab, which are typically employed as monotherapy. However, the safety of these drugs is a significant concern, limiting their therapeutic doses and potential for higher efficacy. These, and other current therapies targeting amyloid protein, including anti-Aβ monoclonal antibodies, show promise in disease-modifying treatment of AD by dose-dependently reducing Aβ levels; however, their overall efficacy in slowing cognitive decline is moderate, suggesting that further pathogenic pathways independent of amyloid, such as vascular damage and inflammation, also contribute to cognitive decline. Furthermore, anti-amyloid therapies often induce dose-dependent cerebral microhemorrhages and vascular damage as drug-treatment-induced side effects. Such vascular damage and inflammation are heterogeneous and manifest in various forms, including, but not limited to, amyloid-related imaging abnormalities (ARIA), particularly ARIA-E, associated with angioedema due to blood-brain barrier (BBB) ​​leakage and fluid retention, and ARIA-H, associated with micro or massive cerebral hemorrhage caused by vascular rupture. These treatment-induced side effects limit the safety margin of these drugs, and therefore the effective dose has not been optimized. Currently, if a patient experiences treatment-related vascular side effects, the clinical response is usually discontinuation of treatment, and unfortunately, the benefit of anti-amyloid therapy for such patients is negated.

[0005] In addition to directly targeting amyloid, certain therapies aim to restore homeostasis or improve the phagocytic efficiency of glial cells in the brain, including astrocytes and microglia. For example, therapies targeting trigger receptor 2 (TREM2), which is expressed on myeloid cells, have been shown to reduce amyloid levels in the brain in preclinical animal models. In clinical trials, treatment with monoclonal antibodies targeting TREM2 also induced vascular damage consistent with the aforementioned ARIA.

[0006] Similarly, heterogeneous vascular damage and inflammation are independent pathological conditions of NDD, as well as defined as vascular dementia or vascular cognitive impairment and dementia (VCID). Cerebral small vessel disease (CSVD) is common and is a pathological, clinical, and radiological heterogeneous deterioration of cerebral blood vessels associated with VCID. VCID leads to cognitive decline as a result of vascular damage and is subdivided into four main categories: post-stroke dementia, subcortical ischemic vascular dementia, polyinfarct dementia, and mixed dementia. Because the biological mechanisms of VCID and CSVD are largely unrelated to the pathophysiology of AD, they cannot be addressed by molecules targeting amyloid and / or tau load in the brain and body, further suggesting the need for improved treatments for these conditions.

[0007] Potential disease-modifying and life-saving amyloid-targeted therapies are contraindicated not only in patients with advanced Alzheimer's disease (AD) but also in many elderly patients or those with a history of or co-existing cerebral hemorrhage and microbleeds, thus limiting or preventing their access. For example, patients with cerebral amyloid angiopathy (CAA), a common disease affecting cerebral blood vessels characterized by the deposition of Aβ protein in small and medium-sized leptomeningeal and cortical vessels, are at risk of ARIA, and in CAA patients, the rapid removal of cerebral parenchymal Aβ mediated by anti-amyloid antibody treatment can induce significant inflammatory and autoimmune reactions that further increase vascular and neuronal damage. In cases of cerebral amyloid angiopathy-associated inflammation (CAAri), the APOE4 genotype, an allele carried by certain individuals, is overemphasized, and this genotype increases the risk of patients developing these types of pathologies and conditions.

[0008] Furthermore, the pathological mechanisms that promote the onset, progression, and severity of neurodegenerative diseases (NDDs) are often complex. Therefore, treating such polygenetic and multifactorial diseases may require the normalization of multiple biological pathways. This is consistent with the low success rates of monotherapy in treating neurological diseases and demonstrates an urgent need for more robust approaches that target different aspects of disease-promoting pathways.

[0009] To address this urgent need, the present invention relates to combination therapy comprising a lipoprotein-related phospholipase A2 (Lp-PLA2) inhibitor and other agents for treating human diseases, as will be described in more detail later.

[0010] Lp-PLA2 is a secretory enzyme that plays a crucial role in lipoprotein metabolism. It is primarily expressed in the liver, from where it is secreted into the bloodstream and often binds to low-density lipoprotein (LDL) particles. Catalytic processing of LDL particles by Lp-PLA2 in the bloodstream generates a potent pro-inflammatory mediator that promotes vascular damage, such as the acceleration of atherosclerosis development. In preclinical animal models of atherosclerosis, genetic deficiency of Lp-PLA2 or inhibition of its enzymatic activity reduced the development and progression of atherosclerotic lesions. In humans, elevated levels of Lp-PLA2 are associated with an increased risk of cardiovascular events and pathological conditions.

[0011] In the central nervous system (CNS), upmodulation of Lp-PLA2, for example, caused by stroke, exacerbates post-stroke ischemic lesions and tissue damage. In AD patients, inhibition of Lp-PLA2 has been shown to repair vascular damage and slow cognitive decline.

[0012] Lp-PLA2 inhibitors are being developed for the treatment of cardiovascular disease. Clinical trial results suggest that daraprazib, an Lp-PLA2 inhibitor, may only be effective in patients with high levels of Lp-PLA2.

[0013] In animal models of blood-brain barrier (BBB) ​​leakage, treatment with Lp-PLA2 inhibitors such as daraprazib reduced BBB leakage and improved the pathophysiology of vascular dementia. In a placebo-controlled, randomized phase 2 clinical trial, the Lp-PLA2 inhibitor lilapradib was well-tolerated, improved disease biomarkers, and, importantly, delayed cognitive decline in AD patients.

[0014] Mechanistically, some preclinical data suggested that Lp-PLA2 inhibition may reduce amyloid levels, but this has not been independently replicated. Similarly, analyses of CSF and plasma amyloid metabolism, turnover, and kinetics in the aforementioned lilapradib phase 2 trial did not support the involvement of Lp-PLA2 in amyloid kinetics. Instead, the beneficial effects observed in lilapradib-treated AD patients suggested that they were mediated by the improvement or prevention of BBB leakage, disruption, and / or vascular inflammation and injury. Therefore, Lp-PLA2 inhibition is a promising mechanism for treating and / or preventing diseases and disorders with vascular injury elements such as BBB leakage, and inflammatory elements, including neurological disorders such as (but not limited to) NDD, either alone or in combination with other therapies. [Overview of the project]

[0015] Summary of the present invention The present invention provides such alternative therapies for effectively treating diseases and disorders of the nervous system, neuromuscular system, and other conditions, including polygenic and multifactorial neurological diseases. The present invention provides a combination therapy comprising inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) and a second therapy. While the present invention can be used for the prevention and treatment of various disorders, in certain embodiments, the method and use are employed therapeutically or prophylactically to prevent, improve and / or treat vascular damage or inflammation, particularly in the context of nervous system or neuromuscular conditions, caused, for example, by aging, human disease and / or drug treatment, or a combination thereof.

[0016] In one embodiment, the present invention provides a method of treatment comprising administering a first agent comprising a Lp-PLA2 inhibitor molecule to a subject, and the use of such a first agent in connection with such administration, and administering a second agent to the subject, and the use of such a second agent in connection with such administration, thereby achieving a preventive or therapeutic treatment of a disease state in the subject. Furthermore, the second agent for implementation in the context of the present invention may include many types of agents, but in certain embodiments, the second agent includes an amyloid target molecule, an agent that reduces amyloid levels in the brain or body, a tau target molecule, a vascular target molecule, an inflammation target molecule, or a molecule that modulates a mechanism of action orthogonal to Lp-PLA2 inhibition. The combination of the second agent is also envisioned.

[0017] In this regard, the present invention provides an improved method of treatment or prevention comprising such a second agent. The improvement lies in combining monotherapy with the first agent comprising a Lp-PLA2 inhibitor molecule, as described herein. As a result of this improvement, the side effects of such monotherapy agents (some of which are discussed above) may be reduced. Furthermore, as a result of the improvements provided by the present invention, the combination treatment may expand the clinically safe / approved dose range of the monotherapy agent or disease-modifying treatment. Co-treatment comprising an Lp-PLA2 inhibitor according to the present invention allows, for example, an increase in the safety margin of the second agent. The results include, in non-limiting examples, an expansion of the clinically safe / approved dose range of the second agent, such as aducanumab and lecanemab, a safe and effective extension of the treatment regimen compared to monotherapy alone, and an expansion of indications to include patient groups that would normally be unsuitable for or excluded from such monotherapy.

[0018] Furthermore, to facilitate the inventive use and implementation of the method of the present invention, the present invention also provides a composition comprising a first agent containing an Lp-PLA2 inhibitory molecule, a second agent, and a pharmaceutically acceptable carrier.

[0019] Detailed description of the present invention In one aspect, the present invention provides a method for the therapeutic or prophylactic treatment of a disease having an element of vascular injury and / or inflammation in a subject, comprising administering a first agent comprising a helipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor molecule to a subject, and administering a second agent to the subject, thereby achieving therapeutic prevention or treatment of vascular injury and / or inflammation in the subject through the combined administration of the first and second agents. In a related aspect, the present invention provides the use of a first agent comprising an Lp-PLA2 inhibitor molecule and a second agent in the treatment or prevention of vascular injury and / or inflammation in a subject.

[0020] In the context of the present invention, the method (or “use”) may be used prophylactically to reduce possible vascular injury and / or inflammation that may be associated with the administration of the second agent or that result from an underlying disease or risk factors present in the subject. The prophylactic effect does not need to be absolute, and in the context of the present invention, a sufficient prophylactic effect is achieved if the risk to the subject of vascular injury and / or inflammation is reduced as a result of the method or use of the present invention. Also in the context of the present invention, the method (or “use”) may be employed to therapeutically treat patients who already have vascular injury and / or inflammation (e.g., symptomatic) or patients who are diagnosed with vascular injury and / or inflammation (symptomatic or asymptomatic). The therapeutic effect does not need to be absolute, and in the context of the present invention, a sufficient therapeutic effect is achieved if the vascular injury and / or inflammation is reduced or mitigated as a result of the method or use of the present invention. In one embodiment, an Lp-PLA2 inhibitor is used to mediate a reduction in vascular injury and / or inflammation, extending the clinically safe / approved dose range of the second agent or disease-modifying treatment.

[0021] Any suitable agent capable of inhibiting Lp-PLA2 may be employed as the “first agent” in the context of the present invention, but preferred agents include daraprazib, lilaprazib, GSK3206906A(SNP318), and combinations thereof, which are presented as non-limiting examples. Furthermore, the “first agent” may be or include fragments, derivatives, modifiers, or mimics of daraprazib, lilaprazib, GSK3206906A(SNP318), and combinations thereof, which retain the ability to inhibit Lp-PLA2. Further non-limiting examples of Lp-PLA2 inhibitors that can be used as the “first agent” in the context of the present invention include, for example, International Patent Publications WO96 / 13484, WO96 / 19451, WO97 / 02242, WO97 / 217675, WO97 / 217676, WO97 / 41098, WO97 / 41099, WO99 / 2 4420, WO00 / 10980, WO00 / 66566, WO00 / 66567, WO00 / 68208, WO01 / 60805, WO01 / 60805, WO 02 / 030904A1, WO02 / 030911A1, WO02 / 30904, WO02 / 30911, WO03 / 016287, WO03 / 041712, WO 03 / 042179, WO03 / 042206, WO03 / 042218, WO03 / 086400, WO03 / 087088, WO05 / 021002, WO06 / 063791A1, WO06 / 063811A1, WO06 / 063812A1, WO06 / 063813A1, WO21 / 089032A1; U.S. Patent Publications These inventions are described in US2006 / 106017A1 and US2015 / 0183748; U.S. Patents 6,649,619, 7,153,861 and 7,169,924, and U.S. Provisional Patent Applications 60 / 829,327 and 60 / 829,328, each incorporated herein by reference in its entirety. Irreversible acylation inhibitors that may be used in embodiments of the present invention are described, for example, in Tew et al, Biochemistry, 37, 10087 (1998), each incorporated herein by reference in its entirety.Furthermore, or alternatively, reversible inhibitors that may be used in embodiments of the present invention are described, for example, in U.S. Patent Publication US2005 / 0033052A1 and International Patent Publications WO02 / 30904, WO03 / 042218, WO03 / 042206, WO03 / 042179, WO03 / 041712, WO03 / 086400 and WO03 / 87088, each incorporated herein in whole by reference. Further or alternative Lp-PLA2 inhibitors that may be used in embodiments of the present invention include known agents such as statins with niacin and fenofibrate.

[0022] The present invention is not limited to the agents presented above as non-limiting examples, but may include the use of any agent that can inhibit Lp-PLA2 and is suitable for therapeutic use in the context of the present invention. These may be agents that are known as known agents or agents that are discovered as Lp-PLA2 inhibitors. Typically, in vitro enzymatic analysis with colorimetric detection or radiodetection of the signal is used as a means of inhibiting Lp-PLA2 and thus identifying a suitable first agent. However, any method suitable for identifying Lp-PLA2 inhibitors may be employed.

[0023] In the context of the present invention, Lp-PLA2 inhibition can be evaluated by any suitable method known to those skilled in the art. For example, the inhibition can be evaluated by analyzing the inhibition of Lp-PLA2 expression and / or protein activity. Furthermore, complete inhibition is not essential, and the agent may achieve Lp-PLA2 inhibition at a level of at least about 20%, for example, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98% at the time of evaluation. In this regard, for example, lilapradib has been reported to achieve approximately 80% inhibition of Lp-PLA2 at a dose of 250 mg in human subjects. However, other doses are also conceivable in the context of the present invention.

[0024] For use in the context of the present invention, the second agent may be or include any agent that acts in a manner other than as an inhibitor of Lp-PLA2. For example, and not to be construed as limiting the scope of the present invention, the second agent may be or include amyloid target molecules (e.g., molecules that target Aβ amyloid protein), tau target molecules, vascular target molecules, inflammatory target molecules, or molecules that modulate a mechanism of action orthogonal to Lp-PLA2 inhibition (e.g., agents with mechanisms of action other than those listed above, e.g., epigenetic target therapy, metabolic target therapy, bioenergetic target therapy, neurodevelopmental target therapy, neurotransmitter target therapy, neurotransmitter receptor target therapy, oxidative stress target therapy, proteostasis target therapy, synaptic plasticity target therapy, neuroprotective target therapy, etc.). Several compounds suitable for use as “second agent” are also in the clinical trial stage. For example, see Cummings et al., Alzheimer's & Dementia: Translational Research & Clinical Interventions 2022; doi.org / 10.1002 / trc2.12295, which is incorporated herein in its entirety by reference. Naturally, the present invention is not limited to these agents. Furthermore, combinations of these agents, as well as agents acting through other mechanisms, are explicitly envisioned for use in the context of the present invention.

[0025] As a non-limiting example, for instance, when the second agent contains an amyloid target molecule, the second agent can be one or more of agents such as ABvac40, ACU193, aducanumab (ADUHELM), APH-1105, Brain Shuttle gantenerumab (RO7126209), crenezumab, donanemab (LY3002813), gantenerumab, lecanemab (BAN2401, LEQEMBI), LY3372993, MIB-626, SHR-1707, solanezumab, thieethylperazine (TEP), valiltraprostat (ALZ-801), baloglutamstat (PQ912). Also, multiple such (and / or other) amyloid target molecules can also be employed as the "second agent". In the context of the present invention (i.e., in combination with the first agent targeting Lp-PLA2), some non-limiting examples of amyloid inhibitors suitable for use as the "second agent" are either approved or in various stages of investigational clinical trial phases. The following table (Table 1) lists some of these examples, and these approaches can be combined with the first agent targeting Lp-PLA2 in the context of the present invention.

Table 1

[0026] Furthermore, as a non-limiting example, for instance, when the second agent comprises a tau target molecule, the second agent can be one or more of agents such as ACI-35, ASN51, bepranemab, BIIB080 / IONIS-MAPTRx, E2814, IONIS MAPTRx (BIIB080), JNJ-63733657, Lu AF87908, LY3372689, nicotinamide, PU-AD, semorinemab (RO7105705), TB006, etc. A plurality of such (and / or other) tau target molecules can also be employed as the "second agent". In the context of the present invention (i.e., in combination with the first agent targeting Lp-PLA2), some non-limiting examples of tau target molecules suitable for use as the "second agent" are either approved or in various stages of investigational clinical trial stages. The following table (Table 2) lists some of these examples, and those approaches can be combined with the first agent targeting Lp-PLA2 in the context of the present invention.

Table 2

[0027] Furthermore, as a non-limiting example, if the second agent includes a vascular target molecule, the second agent could be one or more of the following: amlodipine, AR1001, atorvastatin, davisatran, losartan, omega-3 PUFA, perindolpil, Renew NCP5, telmisartan, and nourishing serum brain pills. Multiple such (and / or other) vascular target molecules may also be employed as the “second agent.” In fact, in some embodiments, it is envisioned that the present invention includes two or more vascular target molecules. This may increase efficacy by simultaneously targeting distinct vascular pathways (for example, BBB leakage / integrity in addition to vascular inflammation, as a non-limiting example). In the context of the present invention (i.e., in combination with the first agent targeting Lp-PLA2), some non-limiting examples of vascular target molecules suitable for use as the “second agent” are approved or in various stages of experimental clinical trials. The following table (Table 3) lists some of these examples, and these approaches can be used in combination with a first agent targeting Lp-PLA2 in the context of the present invention. [Table 3]

[0028] Furthermore, as a non-limiting example, if the second agent contains an inflammatory target molecule, the second agent could be one or more of the following agents: AL002, baricitinib, BCG vaccine, canakinumab, curcumin, daratumumab, dasatinib, edicotinib (JNJ-40346527), emtricitabine, GB301, L-serine, lenalidomide, montelukast, NE3107, pepinemab (VX15), quercetin, salsalat, salglamostim, senikapok, TB006, Tdap vaccine, valacyclovir, VT301, XPro1595, etc. Multiple such (and / or other) inflammatory target molecules may also be adopted as the “second agent”. In the context of the present invention (i.e., in combination with the first agent targeting Lp-PLA2), some non-limiting examples of inflammatory target molecules suitable for use as the “second agent” are approved or in various stages of experimental clinical trials. The following table (Table 4) lists some of these examples, and their approaches may be used in combination with the first agent targeting Lp-PLA2 in the context of the present invention. [Table 4]

[0029] Furthermore, as a non-limiting example, if the second agent includes an agent having a mechanism of action orthogonal to Lp-PLA2 inhibition, the second agent may be AAV-Htert, AD-35, AGB101 (low-dose levetiracetam), allopregnanolone, atuzaginstat (COR388), AVP-786, AXS-05, BDPP (bioactive food polyphenol preparation), BEY2153, brarcamecin (ANAVEX2-73), BMS-984923, BPDO-1603, BP N14770, Brexpiprazole, Bromocriptine, Briostatin 1, BXCL-501, Caffeine, Contraloid Acetate, COR588, CORT108297, CST-2032, CY6463, DAOIB, Dapagliflozin, Deferipron, DHA, Donepezil, Dronabinol, Ednerpic (T-817MA), Efavirenz, Elaita (CT1812), Escitalopram, ExPlas (Exercise Plasma), Fosgonimetone (ATH-1017), GC AD1, grape seed extract, guanfacine, GV-971, GV1001, hydralazine, eicosapent ethyl (IPE), imufilam (PTI-125), nasal insulin, nasal insulin + empagliflozin, lamivudine (3TC), levetiracetam, Lupron (leuprorelin acetate depot), LX1001, memantine, metabolic cofactor replacement, metformin, MK-1942 + donepezil, MW150, nabilon, neframapimod (VX-745), nicotine transdermal patch, niro The drugs may be one or more of the following: tinib BE, NNI-362, ovicetrapib, octohydroaminoacridine succinate, omega-3 (DHA+EPA), posifen, prazosin, rapamycin (sirolimus), REM0046127, semaglutide, symphyllam (PTI-125), sobatertide (PMZ-1620), suvorexant, T3D-959, THC-free CBD oil, trehalose, tricaprylin, tricaprylin (AC-1202), troriruzole (BHV4157), zanamem, etc. The following table (Table 5) lists some examples of these, and their approaches may be used in combination with a first drug targeting Lp-PLA2 in the context of the present invention. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0030] It has been observed that the first agent (Lp-PLA2 inhibitor) and the second agent can be formulated together in a common configuration as desired, or administered separately. When administered separately, the first agent and the second agent can be administered simultaneously or sequentially. "Simultaneously" means that the first and second agents are administered together at the same time, whether in the same formulation or in separate formulations. "Sequentially" means that the administration of either the first or second agent precedes the administration of the other. Furthermore, the administration of the first and second agents may be such that one administration begins before the other, and / or one administration finishes before the other, but there is an overlapping period during which the administrations occur simultaneously. In some embodiments, the first agent may be administered before the second agent (e.g., repeatedly before the second agent) to establish conditions favorable to the administration of the second agent. For example, the first agent may exert a protective effect against vascular damage and / or inflammation that may be otherwise caused by the administration of the second agent when the second agent is administered either as monotherapy or concurrently with the first agent. Furthermore, either or both agents may be administered simultaneously or sequentially (repeatedly), once or multiple times (e.g., at least two times, or at least three times, or at least four times or more), simultaneously or prior to other administrations.

[0031] Furthermore, the combination therapy of the present invention may be repeated over a period of time (e.g., one day or several days, or several weeks or several months (e.g., about 24 weeks or more), once, twice, three, or four times a day). The dosage and administration regimen will inevitably vary depending not only on the properties of the first and second drugs but also on the mode and route of administration. However, selecting appropriate dosages and routes of administration for delivering the first and second drugs to the target according to the method of the present invention is within the scope of the skill of those skilled in the art.

[0032] Since many of the aforementioned agents suitable for use in the context of the present invention are approved drugs or in the human clinical trial stage (see the table above for non-limiting examples), in many embodiments, existing formulations, doses, and regimens approved or in trial for such agents may also be adopted in the context of the present invention. For example, if lilaprazib is adopted as the first agent as stated above, it may be administered according to the regimen adopted in the clinical trial (at a dose of 2.5 to 400 mg / day for up to 24 weeks, for example, 250 mg of lilaprazib once daily (see clinical trial identifiers NCT01750827, NCT00387257, NCT01745458, and NCT01428453)), or as otherwise deemed appropriate by the treating physician. In this regard, as stated above, lilaprazib has been reported to achieve approximately 80% inhibition of Lp-PLA2 in human subjects at a dose of 250 mg. However, the present invention also provides a pharmaceutical composition comprising a first agent and a second agent as described herein, as well as pharmaceutically acceptable excipients.

[0033] For use in the context of the present invention, the compositions of the present invention can be formulated for any desired mode and route of administration, such as orally, transdermally, intraperitoneally, intravenously, intracerebrally, or other as deemed appropriate by the treating physician for a particular subject or patient. Accordingly, the compositions of the present invention may include a variety of adjuvants and excipients as components of pharmaceutically acceptable carriers, as commonly employed by methodologies for drug formulation. Thus, for example for injection (including, but not limited to, intravenous or intraperitoneal injection), the formulation may be or may contain aqueous solutions or suspensions comprising saline and other desired components. The compositions may also contain preservatives, other active or inactive agents, stability enhancers, etc. Furthermore, the compositions of the present invention may be placed in vials, compressed into tablets, placed in capsules, or otherwise packaged for unit-dose formulations or repeated administration, as desired.

[0034] The methods and related compositions of the present invention, including combination therapy, have been observed to be usable for the treatment and / or prevention of a variety of conditions, diseases, and disorders. These include those involving vascular damage and / or inflammation, and in particular (but not limited to) those relating to nervous system or neuromuscular conditions. Such diseases can be defined clinically in the sense that they do not need (but may) manifest as symptoms in the patient or subject. For example, Alzheimer's disease (AD) can be identified in vivo (diagnostically) by analyzing the Aβ42 / 40 ratio of CSF or plasma, or the pTau181 or pTau217 levels of CSF or plasma, and does not need to rely on the presentation of identifiable symptoms. In this regard, the following are specific publicly available diagnostic criteria for Alzheimer's disease (see the media and investor releases “Roche Alzheimer's disease Cerebrospinal Fluid (CSF) assays receive FDA clearance, supporting more accurate and timely diagnosis” (December 8, 2022) and “The Power of Elecsys® in Alzheimer's disease” (Roche), which are fully incorporated herein): • If Aβ42 ≤ 1,000 pg / mL, the test result is positive. • If Aβ42 > 1,000 pg / mL, the test result is negative. • A pTau / Aβ42 ratio > 0.024 indicates a positive test result. • If the pTau / Aβ42 ratio is ≤ 0.024, the test result is negative. ·tTau / Aβ42 ratio * If the value is >0.28, the test result is positive. ·tTau / Aβ42 ratio * If the value is ≤0.28, the test result is negative. Similarly, these published diagnostic criteria also include thresholds for identifying patients at risk of cognitive decline: • A pTau / Aβ42 ratio > 0.024 indicates a positive test result. • If the pTau / Aβ42 ratio is ≤ 0.024, the test result is negative. ·tTau / Aβ42 ratio * If the value is >0.28, the test result is positive. ·tTau / Aβ42 ratio * If the value is ≤0.28, the test result is negative.

[0035] The use of the combination therapy of the present invention, including the aforementioned methods and related compositions, may be employed as a preventive or treatment for a variety of conditions, diseases, and disorders. However, the present invention is assumed to be particularly useful in the context of conditions, diseases, and disorders related to age-related diseases, diabetes, mental disorders, NDD, VCID, CSVD, nerve damage or disease, proteinopathy, tauopathy, vascular disease, and combinations of one or more of these. For example, non-limiting examples of age-related disease-related conditions, diseases, and disorders that may be addressed by the use, methods, and compositions of the present invention in certain embodiments include hypertension, heart disease, congestive heart failure, and high blood pressure. This includes, but is not limited to, coronary artery disease, coronary heart disease, dementia, Alzheimer's disease, Lewy body dementia, vascular dementia, frontotemporal dementia, delirium, depression, anxiety, epilepsy, high cholesterol, hypertension, motor neuron disease, multiple sclerosis, osteoporosis, Paget's disease of bone, herpes zoster, stroke, incontinence (urinary and intestinal), urinary tract infection (UTI), chronic kidney disease, deep vein thrombosis, arthritis, osteoporosis, diabetes mellitus, lung disease, asthma, chronic obstructive pulmonary disease, bronchitis, pneumonia, influenza, frequent falls that may cause fractures, Parkinson's disease, sleep disorders, insomnia, sleep apnea, restless legs syndrome, cancer, eye diseases, blindness, cataracts, glaucoma, macular degeneration, dry eye, decreased vision, weight loss, and one or more combinations of these.

[0036] Furthermore, in certain embodiments, non-limiting examples of mental disorders, conditions, and disorders that can be addressed by the use, methods, and compositions of the present invention include, but are not limited to, autism, ADHD, dyslexia, Tourette syndrome, schizophrenia, bipolar disorder, clinical depression, panic disorder, phobias, generalized anxiety disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), depersonalization disorder, dissociative identity disorder, illness anxiety disorder, conversion disorder, anorexia nervosa, bulimia nervosa, narcolepsy, oppositional defiant disorder, conduct disorder, and one or more combinations thereof. Similarly, in certain embodiments, non-limiting examples of NDD-related conditions, conditions, conditions, and disorders that can be addressed by the use, methods, and compositions of the present invention include, but are not limited to, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Lewy body dementia, multiple sclerosis, multiple system atrophy, Parkinson's disease, prion disease, HIV, and dementia, and one or more combinations thereof.

[0037] Furthermore, in certain embodiments, non-limiting examples of mental disorders, conditions, and disabilities that can be addressed by the use, methods, and compositions of the present invention include central nervous system disorders, peripheral nervous system disorders, and neuromuscular disorders. These examples are presented to illustrate and not limit the scope of the present invention, and include, for example, brachial neuritis, carpal tunnel syndrome, diabetic neuropathy, paresthesia of femoral neuralgia, neurofibroma, peripheral neuropathy, sciatica, tardive dyskinesia, thoracic outlet syndrome, ulnar nerve compression, painful disorders, burning pain, complex regional pain syndrome, glossopharyngeal neuralgia, phantom limb pain, postherpetic neuralgia, trigeminal neuralgia, ALS, amyotrophic lateral sclerosis (Lou Gehrig's disease), ataxia, brachial neuritis, carnitine palmitoyltransferase deficiency, and carpal tunnel syndrome. , Charcot-Marie-Tooth disease, chronic inflammatory demyelinating polyneuropathy, polyradiculopathy, diabetic neuropathy, Friedreich's ataxia, Guillain-Barré syndrome, hemivalism, Lambert-Eaton syndrome, McArdle disease, multiple system atrophy (MSA), muscular dystrophy, distal muscular dystrophy, Duchenne muscular dystrophy, oculopharyngeal muscular dystrophy (OPMD), myasthenia gravis, myopathy, myositis, neuromuscular disorders, polymyositis, polymyositis and dermatomyositis, postherpetic neuralgia, postpolio syndrome, spinal muscular atrophy, multiple sclerosis, cerebellar tremor tremor), clinically isolated syndrome (cis), collagen disease, multiple sclerosis (multipleSclerosis (MS), fulminant MS, MS and pregnancy, neuromyelitis optica (NMO) (Devic's disease), neurosarcoidosis, primary progressive MS (PPMS), progressive relapsing MS (PRMS), radiological isolation syndrome (RIS), relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), transverse myelitis, mass-like MS, sitting incapacitation, ataxia, athetosis, atypical parkinsonism, ballism, blepharospasm, cerebellar tremor, chorea, corticobasal degeneration (CBD), dyskinesia, dystonia, dystonic tremor, Friedreich's ataxia, childhood Emery-Dreyfus muscular dystrophy, essential tremor tremor), focal myatopathy, motor and vocal tics, Parkinson's disease and dementia, paroxysmal dyskinesia, progressive supranuclear palsy (PSP), restless legs syndrome (RLS), Sydenham chorea, spasmodic torticollis, spastic, tardive dyskinesia, tic disorders, tremor, torticollis, Tourette's syndrome, Wilson's disease, writer's cramp, epilepsy and seizures, absence seizures, akinesia, cataplexy, atypical absence seizures, aura, benign childhood Rolandic epilepsy, menstrual epilepsy, cerebellar tremor, complex partial seizures, collapsing seizures, dystonic tremor, persistent partial epilepsy, epilepsy, epilepsy and seizures seizures), epilepsy caused by vascular tumors or malformations, Janz's epilepsy, essential tremorExamples include tremors, focal seizures, fugue states, laughing seizures, generalized seizures, grand mal seizures, infantile seizures, Jacksonian seizures, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, perimenstrual epilepsy, medial frontal lobe epilepsy, medial temporal lobe epilepsy, motor seizures, myoclonic epilepsy, myoclonus, nocturnal seizures, other extratemporal lobe epilepsy, parasomnia epilepsy, partial seizures, petit mal seizures, photosensitive epilepsy, physiological tremors, post-traumatic seizures, violent seizures, Rasmussen encephalitis, reading epilepsy, refractory seizures, sensory seizures, simple partial seizures, silent seizures, status epilepticus, headache, cluster headache, headache, migraine, tension headache, trigeminal neuralgia, chemo brain, and one or more combinations of these.

[0038] Furthermore, in certain embodiments, non-limiting examples of tauopathy-related conditions, diseases, and disorders that can be addressed by the use, methods, and compositions of the present invention include, but are not limited to, primary age-related tauopathy, chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal degeneration, chromosome 17-related frontotemporal dementia and Parkinson's disease, vacuolar tauopathy, Ritico-Bodig disease, ganglioglioma, gangliocytoma, meningeal hemangioma, post-encephalitis-related Parkinson's disease, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, pantothenate kinase-related neurodegeneration, lipofuscinosis, behavioral frontotemporal dementia (Pick's disease), argyrophilic granulopathy, and one or more combinations thereof.

[0039] Furthermore, in certain embodiments, non-limiting examples of vascular disease-related conditions, diseases, and disorders that can be addressed by the use, methods, and compositions of the present invention include cerebrovascular disease, cerebral small vessel disease, blood-brain barrier leakage, atherosclerosis, cerebral amyloid angiopathy, peripheral vascular disease, peripheral artery disease, carotid artery disease, pulmonary embolism, abdominal aortic aneurysm, collagen vascular disease, chronic venous insufficiency, deep vein thrombosis, acute subdural hematoma, craniocervical artery injury, arteriovenous fistula: of the brain or spine, arteriovenous malformation (AVM), cerebral aneurysm (cerebral Aneurysms), carotid artery dissection, carotid artery stenosis, cavernous hemangioma, cavernous malformation, cerebral arteriovenous malformation, cerebral contusion and intracerebral hematoma, extracranial-intracranial bypass, fibromuscular malformation, intracranial artery stenosis, moyamoya disease, unruptured cerebral aneurysm, spasticity, spina bifida in children, spinal arteriovenous malformation (AVM), subarachnoid hemorrhage, subdural hematoma, venous sinus thrombosis, vertebral artery dissection, vertebral artery stenosis, pyogenic spondylitis, vascular diseases with CSF leakage including cerebrospinal fluid conversion shunts, cerebrospinal fluid leakage, intracranial hypotension, normal pressure hydrocephalus, pseudotumor, traumatic brain injury, and one or more combinations thereof.

[0040] Furthermore, in certain embodiments, non-limiting examples of proteinopathy-related conditions, diseases, and disorders that can be addressed by the use, methods, and compositions of the present invention include, but are not limited to, Creutzfeldt-Jakob disease, prion diseases, Alzheimer's disease, Parkinson's disease, tauopathy, alpha-synucleinopathy, Lewy body dementia, amyloidosis, multiple system atrophy, frontotemporal dementia with tau inclusions, frontotemporal dementia with TDP-43 inclusions, frontotemporal dementia with FUS inclusions, amyotrophic lateral sclerosis with SOD1 inclusions, amyotrophic lateral sclerosis with FUS inclusions, amyotrophic lateral sclerosis with TDP-43 inclusions, Huntington's disease, progressive supranuclear palsy, posterior cortical atrophy, and one or more combinations thereof.

[0041] The use of the combination therapy and prevention and related methods and compositions of the present invention can be advantageous in several respects. For example, in certain embodiments, the present invention may beneficially reduce vascular damage and vascular inflammation and improve the safety, therapeutic index, and efficacy of existing monotherapy. The present invention also has the advantage of expanding the potential patient population eligible for specific treatments.

[0042] For example, treatment of Alzheimer's disease (AD) is currently expected to be possible through therapies targeting amyloid proteins (such as Aβ-targeted therapies and monoclonal antibodies). However, in certain patients, such amyloid-targeted drugs cause clinical side effects. For instance, while Aβ-targeted therapies such as monoclonal antibodies have been shown to reduce Aβ levels in the brain, they are also associated with treatment-related cerebral microhemorrhages and vascular damage (such as ARIA-E and ARIA-H). Currently, when a patient experiences such side effects, the clinical response is to discontinue treatment. Therefore, considering the vascular protection provided by targeting Lp-PLA2, the present invention, which involves using Lp-PLA2 inhibitors in conjunction with such amyloid-targeted therapies, may mitigate adverse vascular events and thereby improve the safety and tolerability of amyloid-targeted therapy in such patients. The repair of vascular damage contributed by Lp-PLA2 inhibition may help mitigate, for example, the ARIA-E and / or ARIA-H side effects of anti-amyloid antibody therapy, and may offer superior efficacy by optimizing the administration regimen, particularly for patients carrying one (heterozygous) or two (homozygous) apolipoprotein E epsilon 4 (APOE-ε4 or APOE4) alleles of the APOE gene. Furthermore, since discontinuation of such therapy may not be necessary when administered in combination with Lp-PLA2 inhibitors according to the present invention, the patient population suitable for anti-amyloid therapy may thereby increase.

[0043] Similarly, many elderly patients, as well as patients with advanced-stage Alzheimer's disease (AD), or those with a history of or co-existing cerebral hemorrhage and microbleeds, currently have limited or no access to potentially life-saving amyloid-targeted therapies. However, given the vascular protection provided by targeting Lp-PLA2, the present invention, which involves using Lp-PLA2 inhibitors in conjunction with such amyloid-targeted therapies, may mitigate disease-related vascular events and thereby improve the safety and tolerability of amyloid-targeted therapies for this AD patient population for whom current treatments are contraindicated. Furthermore, the population of AD patients suitable for anti-amyloid therapy may increase as a result.

[0044] As another non-limiting example, the present invention may beneficially improve the potential of current or experimental CNS disease-modifying monotherapy. The pathological mechanisms that promote the onset, progression, and severity of NDD are diverse and often not well understood. Therefore, the treatment of such polygenic and multifactorial diseases may require the normalization of multiple biological pathways. This coincides with the low success rate of monotherapy in the treatment of diseases of the nervous system and demonstrates an urgent need to provide more potent therapeutic approaches. As a non-limiting example, for NDD, proteinopathy, Lp-PLA2 inhibitors used in combination with other agents targeting orthogonal mechanisms are envisioned. For example, Lp-PLA2 inhibition that benefits the vascular-involved portion of the pathogenesis of CNS diseases is envisioned in combination with another agent that targets the accumulation of pathogenic proteins such as tau, α-synuclein, and TDP43.

[0045] In the context of this invention, the subject being treated is usually a human (i.e., a patient), but it is understood that the subject may instead be a non-human animal, usually a mammal (pet animals, livestock, or animals commonly employed in laboratory research, such as cats, dogs, horses, cattle, mice, rats, and rabbits). If the patient is human, for example, patients who carry the APOE4 allele or who exhibit cerebral amyloid angiopathy (CAA) may be contraindicated for monotherapy.

[0046] All documents cited herein, including publications, patent applications, and patents, are incorporated herein by reference to the same extent as if they were included herein in their entirety, as is individually and specifically indicated, that each document is incorporated by reference.

[0047] In the context describing this invention (in particular in the context of the following claims), the terms “a,” “an,” “the,” and “at least one,” and similar demonstrative pronouns, are to be interpreted as encompassing both singular and plural forms, unless otherwise stated herein or unless the context clearly contradicts this interpretation. The use of the term “at least one” following an enumeration of one or more items (e.g., “at least one A and B”) is to be interpreted as meaning one item (A or B) selected from the enumerated items, or any combination of two or more enumerated items (A and B), unless otherwise stated herein or unless the context clearly contradicts this interpretation. The terms “comprising,” “having,” “including,” and “containing” are to be interpreted as open terms (i.e., “including but not limited to”), unless otherwise specified herein. The descriptions of value ranges herein are intended solely as a convenient way to individually refer to each individual value that falls within that range, unless otherwise stated herein, and each individual value is incorporated herein as if it were individually enumerated herein. All methods described herein may be performed in any suitable order unless otherwise stated herein or unless it is clearly inconsistent with the context. Any and all examples or illustrative language provided herein (e.g., “etc.”) are intended solely to better illustrate the invention and do not limit the scope of the invention unless otherwise stated in the claims. Nothing in this specification should be construed as indicating that any element not described in the claims is essential for the practice of the invention.

[0048] Preferred embodiments of the present invention are described herein, and the best modes known to the inventors for carrying out the invention are listed. Variations of these preferred embodiments may become apparent to those skilled in the art by reading the preceding description. The inventors expect that skilled technicians will appropriately adopt such variations, and the inventors intend that the invention may be carried out in ways different from those specifically described herein. Accordingly, the invention includes all modifications and equivalents of the subject matter described herein in the claims appended herein, as permitted by applicable law. Furthermore, any combination of all possible variations of the elements described herein is incorporated by the invention unless otherwise stated herein or unless it is clearly inconsistent with the context.

Claims

1. A method for the therapeutic or prophylactic treatment of vascular injury and / or inflammation related to a disease, condition, or treatment within the scope of the subject, The procedure includes the step of administering a first agent to a subject, wherein the first agent comprises a lipoprotein-related phospholipase A2 (Lp-PLA2) inhibitor molecule, and The procedure includes the step of administering a second agent to a subject, wherein the second agent includes an amyloid target molecule, an agent that reduces amyloid levels in the brain or body, a tau target molecule, a vascular target molecule, an inflammation target molecule, a molecule that modulates a mechanism of action orthogonal to Lp-PLA2 inhibition, or a combination thereof. A method by which the combined administration of the first and second drugs results in the therapeutic prevention or treatment of vascular damage and / or inflammation within the subject.

2. In methods of therapeutic or prophylactic treatment for vascular injury and / or inflammation related to a disease, condition, or treatment within the scope of the subject, The procedure includes the step of administering a second agent to a subject, wherein the second agent includes an amyloid target molecule, an agent that reduces amyloid levels in the brain or body, a tau target molecule, a vascular target molecule, an inflammation target molecule, a molecule that modulates a mechanism of action orthogonal to Lp-PLA2 inhibition, or a combination thereof. A method comprising the step of administering a first agent to the subject, wherein the first agent comprises a lipoprotein-related phospholipase A2 (Lp-PLA2) inhibitor molecule.

3. The method of claim 2, wherein, when the second agent is used as monotherapy, the improvement, including the administration of the first agent, includes reducing side effects caused by the second agent, or treatment-related vascular damage or inflammation.

4. The use of a first agent comprising a lipoprotein-related phospholipase A2 (Lp-PLA2) inhibitor molecule, and a second agent comprising an amyloid target molecule, an agent that reduces amyloid levels in the brain or body, a tau target molecule, a vascular target molecule, an inflammation target molecule, a molecule that modulates a mechanism of action orthogonal to Lp-PLA2 inhibition, or a combination thereof, in the treatment or prevention of vascular injury and / or inflammation within a subject.

5. The method of any one of claims 1 to 3, or the use of claim 4, wherein the first agent comprises daraprazib, lilaprazib, GSK3206906A (SNP318), fragments and derivatives, modified or mimetic forms of daraprazib, lilaprazib or GSK3206906A (SNP318) that inhibit Lp-PLA2, or a combination thereof.

6. The method or use according to any one of claims 1 to 5, wherein the first agent comprises lilapradib or GSK3206906A (SNP318).

7. The method or use according to any one of claims 1 to 6, wherein the second agent comprises an amyloid target molecule.

8. The method or use of claim 7, wherein the amyloid target molecule includes ABvac40, ACU193, aducanumab (ADUHELM), APH-1105, Brain Shuttle, gantenerumab (RO7126209), crenezumab, donanemab (LY3002813), gantenerumab, lecanemab (BAN2401, Leqembi), LY3372993, MIB-626, SHR-1707, solanezumab, thiethylperazine (TEP), valyltramiprosate (ALZ-801), baloglutamstat (PQ912), and combinations thereof.

9. The method or use of any one of claims 1 to 6, wherein the second agent comprises an agent that reduces the level of amyloid in the brain or body.

10. The method or use of claim 9, wherein the agent that reduces amyloid levels in the brain or body comprises an APOE target molecule, a TREM2 target molecule, or a combination thereof, wherein the molecule optionally comprises a monoclonal antibody.

11. The method or use according to any one of claims 1 to 6, wherein the second agent comprises a tau target molecule.

12. The method or use of claim 11, wherein the tau target molecule includes ACI-35, ASN51, bepranemab, BIIB080 / IONIS-MAPTRx, E2814, IONIS-MAPTRx (BIIB080), JNJ-63733657, Lu AF87908, LY3372689, nicotinamide, PU-AD, semolinemab (RO7105705), TB006, and combinations thereof.

13. The method or use according to any one of claims 1 to 6, wherein the second drug comprises a vascular target molecule.

14. The method or use of claim 13, wherein the vascular target molecule includes amlodipine, AR1001, atorvastatin, davisatran, losartan, omega-3 PUFA, perindolpil, Renew NCP5, telmisartan, nourishing serum brain pills, and combinations thereof.

15. The method or use according to any one of claims 1 to 6, wherein the second agent comprises an inflammation target molecule.

16. The method or use of claim 15, wherein the inflammatory target molecule includes AL002, baricitinib, BCG vaccine, canakinumab, curcumin, daratumumab, dasatinib, edicotinib (JNJ-40346527), emtricitabine, GB301, L-serine, lenalidomide, montelukast, NE3107, pepinemab (VX15), quercetin, sarsalat, salglamostim, senicapok, TB006, Tdap vaccine, valacyclovir, VT301, XPro1595, and combinations thereof.

17. The method or use according to any one of claims 1 to 6, wherein the second agent comprises a molecule that modulates a mechanism of action orthogonal to Lp-PLA2 inhibition.

18. The molecules that modulate the mechanism of action orthogonal to Lp-PLA2 inhibition are AAV-Htert, AD-35, AGB101 (low-dose levetiracetam), allopregnanolone, atuzaginstat (COR388), AVP-786, AXS-05, BDPP (bioactive food polyphenol preparation), BEY2153, brarcamecin (ANAVEX2-73), BMS-984923, BPDO-1603, BPN14770, brexpiprazole, and Romocriptine, bryostatin 1, BXCL-501, caffeine, contraloid acetate, COR588, CORT108297, CST-2032, CY6463, DAOIB, dapagliflozin, deferipron, DHA, donepezil, dronabinol, ednerpic (T-817MA), efavirenz, elaita (CT1812), escitalopram, ExPlas (exercise plasma), fosgonimeton (ATH-1017), GC AD1, grape seed extract, guanfacine, GV-971, GV1001, hydralazine, eicosapent ethyl (IPE), imufilam (PTI-125), nasal insulin, nasal insulin + empagliflozin, lamivudine (3TC), levetiracetam, Lupron (leuprorelin acetate depot), LX1001, memantine, metabolic cofactor replacement, metformin, MK-1942 + donepezil, MW150, nabilon, neframapimod (VX-745), nicotine transdermal patch, nilotinib BE, N The method or use of claim 17, comprising NI-362, ovicetrapib, octohydroaminoacridine succinate, omega-3 (DHA + EPA), posifen, prazosin, rapamycin (sirolimus), REM0046127, semaglutide, symphyllam (PTI-125), sobaterutide (PMZ-1620), suvorexant, T3D-959, THC-free CBD oil, trehalose, tricaprylin, tricaprylin (AC-1202), trorilluzole (BHV4157), zanamem, and combinations thereof.

19. The method or use of any one of claims 1 to 18, wherein the vascular injury or inflammation is related to a disease or disorder including age-related disease, diabetes, mental disorder, neurodegenerative disease (NDD), vascular cognitive impairment and dementia (VCID), cerebral small vessel disease (CSVD), injury or disease of the nervous system, proteinopathy, tauopathy, vascular disease, treatment-related vascular injury or inflammation, or a combination thereof.

20. The method or use of claim 19, wherein the vascular injury or inflammation is related to an age-related disease.

21. The aforementioned age-related diseases include hypertension, heart disease, congestive heart failure, high blood pressure, coronary artery disease, coronary heart disease, dementia, Alzheimer's disease, Lewy body dementia, vascular dementia, frontotemporal dementia, delirium, depression, anxiety, epilepsy, high cholesterol, hypertension, motor neuron disease, multiple sclerosis, osteoporosis, Paget's disease of bone, herpes zoster, stroke, incontinence (urinary and intestinal), urinary tract infection (UTI), chronic kidney disease, and deep vein thromboembolism. The method or use of claim 20, including venous thrombosis, arthritis, osteoporosis, diabetes, lung disease, asthma, chronic obstructive pulmonary disease, bronchitis, pneumonia, influenza, frequent falls that may cause fractures, Parkinson's disease, sleep disorders, insomnia, sleep apnea, restless legs syndrome, cancer, eye disease, blindness, cataracts, glaucoma, macular degeneration, dry eye, decreased visual acuity, weight loss, and combinations thereof.

22. The method or use of claim 19, wherein the vascular damage or inflammation is associated with a mental disorder.

23. The method or use of claim 22, wherein the mental disorder includes autism, ADHD, dyslexia, Tourette syndrome, schizophrenia, bipolar disorder, clinical depression, panic disorder, phobias, generalized anxiety disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), depersonalization disorder, dissociative identity disorder, illness anxiety disorder, conversion disorder, anorexia nervosa, bulimia nervosa, narcolepsy, oppositional defiant disorder, conduct disorder, and combinations thereof.

24. The method or use of claim 19, wherein the vascular injury or inflammation is related to a neurodegenerative disease (NDD).

25. The method or use of claim 24, wherein the NDD includes Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Lewy body dementia, multiple sclerosis, multiple system atrophy, Parkinson's disease, frontotemporal dementia, prion disease, HIV, and dementia, and combinations thereof.

26. The method or use of claim 19, wherein the vascular injury or inflammation is related to a disorder of the nervous system.

27. The method or use of claim 26, wherein the disorder of the nervous system includes central nervous system disorders, peripheral nervous system disorders, neuromuscular disorders, and combinations thereof.

28. The aforementioned neurological disorders include brachial neuritis, carpal tunnel syndrome, diabetic neuropathy, paresthesia of femoral neuralgia, neurofibroma, peripheral neuropathy, sciatica, tardive dyskinesia, thoracic outlet syndrome, ulnar nerve compression, painful disorders, burning pain, complex regional pain syndrome, glossopharyngeal neuralgia, phantom limb pain, postherpetic neuralgia, trigeminal neuralgia, ALS, amyotrophic lateral sclerosis (Lou Gehrig's disease), ataxia, and brachial neuritis. neuritis, carnitine palmitoyltransferase deficiency, carpal tunnel syndrome, Charcot-Marie-Tooth disease, chronic inflammatory demyelinating polyneuropathy, polyradiculopathy, diabetic neuropathy, Friedreich's ataxia, Guillain-Barré syndrome, hemivalism, Lambert-Eaton syndrome, McArdle disease, multiple system atrophy (MSA), muscular dystrophy, distal muscular dystrophy, Duchenne muscular dystrophy, oculopharyngeal muscular dystrophy (OPMD), myasthenia gravis, myopathy, myositis, neuromuscular disorders, polymyositis, polymyositis and dermatomyositis, postherpetic neuralgia Neurolgia, post-polio syndrome, spinal muscular atrophy, multiple sclerosis, cerebellar tremor, clinically isolated syndrome (CIS), collagen disease, multiple sclerosis Sclerosis (MS), fulminant MS, MS and pregnancy, neuromyelitis optica (NMO) (Devic's disease), neurosarcoidosis, primary progressive MS (PPMS), progressive relapsing MS (PRMS), radiological isolation syndrome (RIS), relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), transverse myelitis, tumor-like MS, sitting incapacitation, ataxia, athetosis, atypical parkinsonism, ballism, blepharospasm, cerebellar tremorPhysiological disorders (including dyskinesia, chorea, corticobasal degeneration (CBD), dyskinesia, dystonia, dystonic tremor, Friedreich's ataxia, childhood Emery-Dreyfus muscular dystrophy, essential tremor, focal myatonia, motor and vocal tics, Parkinson's disease and dementia, paroxysmal dyskinesia, progressive supranuclear palsy (PSP), restless legs syndrome (RLS), Sydenham chorea, spasmodic torticollis, spasmodic and tardive dyskinesia, tic disorders, tremor, torticollis, Tourette's syndrome, Wilson's disease, writer's cramp, epilepsy and seizures) seizures), absence seizures, akinesia, cataplexy, atypical absence seizures, aura, benign childhood Rolandic epilepsy, menstrual epilepsy, cerebellar tremor, complex partial seizures, collapsing seizures, dystonic tremor, persistent partial epilepsy, epilepsy, epilepsy and seizures, epilepsy caused by vascular tumors or malformations, Jantz's epilepsy, essential tremor Tremor, focal seizures, fugue, laughing seizures, generalized seizures, grand mal seizures, infantile seizures, Jacksonian seizures, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, epmenorrhea, medial frontal lobe epilepsy, medial temporal lobe epilepsy, motor seizures, myoclonic epilepsy, myoclonus, nocturnal seizures, other extratemporal lobe epilepsy, parasomnia epilepsy, partial seizures, petit mal seizures, photosensitive epilepsy, physiological tremor, post-traumatic seizures, violent seizures, Rasmussen's encephalitis, reading epilepsy, intractable seizures, sensory seizures, simple partial seizures, silent seizures, status epilepticus, headache, cluster headache, headache, migraine, tension headache, trigeminal neuralgia The method or use of claim 19, 26, or 27, comprising neuralgia, chemobrain, and combinations thereof.

29. The method or use of claim 19, wherein the vascular damage or inflammation is associated with tauopathy.

30. The method or use of claim 29, wherein the tauopathy includes primary age-related tauopathy, chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia and Parkinson's disease associated with chromosome 17, vacuolar tauopathy, Ritico Bodig disease, ganglioglioma, gangliocytoma, meningeal hemangioma, post-encephalitis Parkinson's disease, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, lipofuscinosis, behavioral frontotemporal dementia (Pick's disease), argyrophilic granulopathy, and combinations thereof.

31. The method or use of claim 19, wherein the vascular damage or inflammation is related to a vascular disease.

32. The aforementioned vascular diseases include cerebrovascular disease, cerebral small vessel disease, blood-brain barrier leakage, atherosclerosis, cerebral amyloid angiopathy, peripheral vascular disease, peripheral artery disease, carotid artery disease, pulmonary embolism, abdominal aortic aneurysm, collagen vascular disease, chronic venous insufficiency, deep vein thrombosis, acute subdural hematoma, craniocervical artery injury, arteriovenous fistula: of the brain or spine, arteriovenous malformation (AVM), cerebral aneurysm (cerebral aneurysm) The method or use of claim 31, including aneurysms), carotid artery dissection, carotid artery stenosis, cavernous hemangioma, cavernous malformation, cerebral arteriovenous malformation, cerebral contusion and intracerebral hematoma, extracranial-intracranial bypass, fibromuscular malformation, intracranial artery stenosis, moyamoya disease, unruptured cerebral aneurysm, spasticity, spina bifida in children, spinal arteriovenous malformation (AVM), subarachnoid hemorrhage, subdural hematoma, venous sinus thrombosis, vertebral artery dissection, vertebral artery stenosis, pyogenic spondylitis, vascular disease with CSF leakage including cerebrospinal fluid conversion shunt, cerebrospinal fluid leakage, intracranial hypotension, normal pressure hydrocephalus, pseudotumor, traumatic brain injury, and combinations thereof.

33. The method or use of claim 19, wherein the vascular damage or inflammation is associated with proteinopathy.

34. The method or use of claim 33, wherein the vascular disease includes Creutzfeldt-Jakob disease, prion disease, Alzheimer's disease, Parkinson's disease, tauopathy, alpha-synucleinopathy, Lewy body dementia, amyloidosis, multiple system atrophy, frontotemporal dementia with tau inclusions, frontotemporal dementia with TDP-43 inclusions, frontotemporal dementia with FUS inclusions, amyotrophic lateral sclerosis with SOD1 inclusions, amyotrophic lateral sclerosis with FUS inclusions, amyotrophic lateral sclerosis with TDP-43 inclusions, Huntington's disease, progressive supranuclear palsy, posterior cortical atrophy, and combinations thereof.

35. The method or use of claim 19, wherein the vascular injury or inflammation is related to the procedure-related vascular injury or inflammation.

36. The method of claim 35, wherein, when the second drug is used as monotherapy, the treatment-related vascular damage or inflammation is caused by the second drug.

37. The method or use of claim 19, wherein the vascular injury or inflammation is associated with vascular cognitive impairment and dementia (VCID).

38. The method or use of claim 19, wherein the vascular damage or inflammation is related to cerebral small vessel disease (CSVD).

39. A method of use according to any one of claims 19 to 38, wherein the disease or disorder is biologically diagnosed, and optionally, the subject is asymptomatic.

40. A method of use according to any one of claims 19 to 38, wherein the disease or disorder is clinically diagnosed.

41. The method or use according to any one of claims 1 to 40, wherein the first drug and the second drug are administered simultaneously.

42. The method or use according to any one of claims 1 to 40, wherein the first drug and the second drug are administered sequentially.

43. The method or use of claim 42, wherein the first drug is administered prior to the second drug.

44. The method or use of claim 42, wherein the first drug is administered repeatedly prior to the second drug.

45. The method or use according to any one of claims 1 to 44, wherein the first drug and / or the second drug are administered repeatedly.

46. The method or use according to any one of claims 1 to 45, wherein the subject is a human patient.

47. The method or use of claim 46, wherein the human patient possesses the APOE4 allele.

48. The method or use of claim 46, wherein the human patient has cerebral amyloid angiopathy (CAA).

49. The first drug contains a lipoprotein-related phospholipase A2 (Lp-PLA2) inhibitor molecule. A second agent comprising amyloid target molecules, agents that reduce amyloid levels in the brain or body, tau target molecules, vascular target molecules, inflammation target molecules, molecules that modulate mechanisms of action orthogonal to Lp-PLA2 inhibition, or combinations thereof, and Including pharmaceutical carriers, composition.

50. The composition of claim 49, wherein the first agent comprises daraprazib, lilaprazib, GSK3206906A (SNP318), fragments and derivatives, modified or mimicked forms of daraprazib, lilaprazib, or GSK3206906A (SNP318) that inhibit Lp-PLA2, or a combination thereof.

51. The composition of claim 49 or 50, wherein the first drug comprises lilapradib.

52. The composition of claim 49 or 50, wherein the first agent comprises GSK3206906A (SNP318).

53. The composition according to any one of claims 49 to 52, wherein the second agent comprises an amyloid target molecule.

54. The method or use of claim 53, wherein the amyloid target molecule includes ABvac40, ACU193, aducanumab (ADUHELM), APH-1105, Brain Shuttle, gantenerumab (RO7126209), crenezumab, donanemab (LY3002813), gantenerumab, lecanemab (BAN2401, Leqembi), LY3372993, MIB-626, SHR-1707, solanezumab, thiethylperazine (TEP), valyltramiprosate (ALZ-801), baloglutamstat (PQ912), and combinations thereof.

55. The composition according to any one of claims 49 to 52, wherein the second agent comprises an agent that reduces the level of amyloid in the brain or body.

56. The method or use of claim 55, wherein the agent that reduces amyloid levels in the brain or body comprises an APOE target molecule, a TREM2 target molecule, or a combination thereof, wherein the molecule optionally comprises a monoclonal antibody.

57. The composition according to any one of claims 49 to 52, wherein the second agent comprises a tau target molecule.

58. The method of claim 57, wherein the tau target molecule includes ACI-35, ASN51, bepranemab, BIIB080 / IONIS-MAPTRx, E2814, IONIS-MAPTRx (BIIB080), JNJ-63733657, Lu AF87908, LY3372689, nicotinamide, PU-AD, semolinemab (RO7105705), TB006, and combinations thereof.

59. The composition according to any one of claims 49 to 52, wherein the second drug comprises a vascular target molecule.

60. The method or use of claim 59, wherein the vascular target molecule includes amlodipine, AR1001, atorvastatin, davisatran, losartan, omega-3 PUFA, perindolpil, Renew NCP5, telmisartan, nourishing serum brain pills, and combinations thereof.

61. The composition according to any one of claims 49 to 52, wherein the second agent comprises an inflammation target molecule.

62. The method or use of claim 61, wherein the inflammatory target molecule includes AL002, baricitinib, BCG vaccine, canakinumab, curcumin, daratumumab, dasatinib, edicotinib (JNJ-40346527), emtricitabine, GB301, L-serine, lenalidomide, montelukast, NE3107, pepinemab (VX15), quercetin, sarsalat, salglamostim, senicapok, TB006, Tdap vaccine, valacyclovir, VT301, XPro1595, and combinations thereof.

63. The composition according to any one of claims 49 to 52, wherein the second agent comprises a molecule that modulates a mechanism of action orthogonal to Lp-PLA2 inhibition.

64. The molecules that modulate the mechanism of action orthogonal to Lp-PLA2 inhibition are AAV-Htert, AD-35, AGB101 (low-dose levetiracetam), allopregnanolone, atuzaginstat (COR388), AVP-786, AXS-05, BDPP (bioactive food polyphenol preparation), BEY2153, brarcamecin (ANAVEX2-73), BMS-984923, BPDO-1603, BPN14770, brexpiprazole, and Romocriptine, bryostatin 1, BXCL-501, caffeine, contraloid acetate, COR588, CORT108297, CST-2032, CY6463, DAOIB, dapagliflozin, deferipron, DHA, donepezil, dronabinol, ednerpic (T-817MA), efavirenz, elaita (CT1812), escitalopram, ExPlas (exercise plasma), fosgonimeton (ATH-1017), GC AD1, grape seed extract, guanfacine, GV-971, GV1001, hydralazine, eicosapent ethyl (IPE), imufilam (PTI-125), nasal insulin, nasal insulin + empagliflozin, lamivudine (3TC), levetiracetam, Lupron (leuprorelin acetate depot), LX1001, memantine, metabolic cofactor replacement, metformin, MK-1942 + donepezil, MW150, nabilon, neframapimod (VX-745), nicotine transdermal patch, nilotinib BE, N The method or use of claim 63, comprising NI-362, ovicetrapib, octohydroaminoacridine succinate, omega-3 (DHA + EPA), posifen, prazosin, rapamycin (sirolimus), REM0046127, semaglutide, symphyllam (PTI-125), sobaterutide (PMZ-1620), suvorexant, T3D-959, THC-free CBD oil, trehalose, tricaprylin, tricaprylin (AC-1202), trorilluzole (BHV4157), zanamem, and combinations thereof.

65. A composition according to any one of claims 49 to 64, formulated for intravenous or intraperitoneal injection.

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