Methods of treating neurodegenerative disorders with tramiprosate

Abstract

Provided herein are methods for treating Alzheimer's disease using a combination of tramiprosate, a tramiprosate prodrug, or an active tramiprosate metabolite and at least one amyloid plaque removing agent.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 429,637, filed December 2, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting more than 6 million people in the United States. Currently ranked as the sixth leading cause of death, AD is characterized by extracellular amyloid-β (Aβ) plaques, which are generated by the deposition of beta-amyloid protein and the intracellular accumulation of tau protein, resulting in cytoplasmic neurofibrillary tangles (NFTs). Aβ causes synaptic dysfunction and neurodegeneration, contributing to the cognitive dysfunction and progressive cognitive and functional deficits observed in AD. In recent years, immunotherapy has emerged as a promising strategy to actively remove aggregated Aβ (amyloid plaques), reduce Aβ accumulation in the brain, and potentially treat the underlying cause of AD. Such treatments include both active and passive immunization.

[0003] Although certain immunotherapies have been shown to reduce Aβ plaques in the brain, they carry significant risks. Immunotherapies, such as the administration of certain monoclonal antibodies, break down Aβ aggregated plaques from the brain parenchyma and vascular walls by forming immune complexes, recruiting microglia, and inducing inflammation. These immune complexes and the inflammatory responses they induce damage to the walls of cerebral blood vessels, causing amyloid-associated imaging abnormalities, including vasogenic edema (ARIA-E) and cerebral hemorrhage (ARIA-H). These ARIA events can manifest as headache, worsening confusion, dizziness, visual disturbances, nausea, and seizures. ARIA-E and ARIA-H can lead to serious events, such as stroke, seizures, and status epilepticus, and can even be fatal. Furthermore, the risk of ARIA events is particularly high in subjects receiving anticoagulant therapy, and even higher if the subject also has evidence of cerebral amyloid angiopathy ("CAA"). Recently, AD subjects treated with both anticoagulants and amyloid plaque-clearing antibodies have been shown to be at higher risk for vascular damage or amyloid-related imaging abnormalities than AD subjects treated with antibodies alone, and the risk is even higher if anticoagulant-treated subjects have evidence of CAA.

[0004] Therefore, there is a need for safe and effective alternative strategies for using immunotherapy in the context of treating AD. Summary of the Invention

[0005] ALZ-801, a potential novel treatment for AD, is currently being studied in clinical trials for subjects with early-stage AD (MMSE > 22). ALZ-801 removes plasma Aβ42 from the brain, thereby reducing the brain burden of soluble aggregated forms of Aβ42 (called oligomers), the building blocks and primary toxic components of plaques. (See, e.g., Figure 2.) Therefore, unlike recent antibody-based immunotherapies that directly target and bind to plaques, ALZ-801 blocks oligomer formation, preventing new plaque formation. Furthermore, ALZ-801 reduces plasma Aβ40 burden by removing it from the brain, the main component of vascular amyloid, and also induces an early reduction in plasma p-tau, a marker of Aβ-induced neuronal stress and damage. (See, e.g., Figures 1 and 3.)

[0006] The significant reduction in Aβ40 suggests that ALZ-801 reduces the intravascular Aβ40 burden, resulting in healthier small- to medium-sized cerebral vessels. This is further supported by the early and significant reduction in plasma p-tau, a marker of neuronal injury, indicating a reduction in amyloid-induced neuronal stress. See Figure 3 for an example. Unlike amyloid immunotherapy, AD patients treated with ALZ-801 for one year did not experience amyloid-associated imaging abnormalities with edema (ARIA-E) events and did not experience major hemorrhage (bleeding greater than 1 cm in diameter).

[0007] Provided herein are administration protocols for treating subjects suffering from AD using a combination of ALZ-801 and at least one amyloid plaque-removing agent (e.g., an antibody). The disclosed protocols first involve administering ALZ-801 for a first period to neutralize and reduce the toxicity of Aβ42 and reduce vascular amyloid burden. Next, because amyloid plaques can act as reservoirs for toxic oligomers and ALZ-801 does not directly target existing plaques, an amyloid plaque-removing agent is then introduced as part of a co-treatment with ALZ-801 for a second period. In one embodiment, it is hypothesized that the ability to clear Aβ40 resulting from pre-treating a subject with ALZ-801 for the first period leads to improved overall health and function of small and medium-sized vessels in the cortex, where amyloid typically accumulates. Aβ40 is the main component of vascular amyloid that deposits in and around the smooth muscle layer, reducing vascular elasticity and integrity. Therefore, pretreatment with ALZ-801 for a period of time is believed to reduce the risk of a subject experiencing vascular damage or amyloid-related imaging abnormalities, such as ARIA-E or ARIA-H, when taking an amyloid plaque removal agent. This risk reduction is particularly advantageous for subjects taking anticoagulants, especially those with evidence of CAA. Finally, after the second period, the amyloid plaque removal agent is no longer administered, and treatment with ALZ-801 is then continued as maintenance therapy to prevent the re-accumulation of Aβ plaques in the AD brain.

[0008] Other compounds that act in a manner similar to ALZ-801 to reduce aggregated forms of Aβ42 are also contemplated to be useful in the present administration protocols, including, but not limited to, tramiprosate, tramiprosate prodrugs other than ALZ-801, and active metabolites of tramiprosate. [Brief explanation of the drawings]

[0009] [Figure 1]1 shows the effect (change from baseline) in plasma Abeta40 after 52 weeks of treatment with 265 mg of ALZ-801 administered orally twice daily in subjects who are APOE4+ and have early AD. [Figure 2] 1 shows the effect (change from baseline) in plasma Abeta42 after 52 weeks of treatment with 265 mg of ALZ-801 administered orally twice daily in subjects who are APOE4+ and have early AD. [Figure 3] 1 shows the effect (change from baseline) in plasma p-tau181 after 52 weeks of treatment with 265 mg of ALZ-801 administered orally twice daily in subjects who are APOE4+ and have early AD. DETAILED DESCRIPTION OF THE INVENTION

[0010] As part of a first embodiment, provided herein is a method of treating a subject suffering from Alzheimer's disease, the method comprising the steps of: a. administering to a subject for a first period of time an effective dose of tramiprosate, a tramiprosate prodrug, a tramiprosate metabolite, or a deuterated form of any of the foregoing; b. During the second period, co-administer the following: i. an effective dose of tramiprosate, a tramiprosate prodrug, a tramiprosate metabolite, or a deuterated form of any of the foregoing; and ii. an effective dose of an amyloid plaque removing agent; and c. Thereafter, administering to the subject an effective dose of tramiprosate, a tramiprosate prodrug, a tramiprosate metabolite, or a deuterated form of any of the foregoing.

[0011] As part of a second embodiment, provided herein is a method of treating a subject suffering from Alzheimer's disease, the method comprising the steps of: a. administering to a subject an effective dose of ALZ-801 or a deuterated form thereof for a first period of time; b. During the second period, co-administer the following: i. an effective amount of ALZ-801 or a deuterated form thereof, and ii. an effective dose of an amyloid plaque removing agent; and c. Thereafter, administering to the subject an effective dose of ALZ-801 or a deuterated form thereof.

[0012] As part of a third embodiment, provided herein is a method of treating a subject suffering from Alzheimer's disease, the method comprising the steps of: a. administering to a subject an effective dose of tramiprosate or a deuterated form thereof for a first period of time; b. During the second period, co-administer the following: i. an effective amount of tramiprosate or a deuterated form thereof, and ii. an effective dose of an amyloid plaque removing agent; and c. Thereafter, administering an effective dose of tramiprosate to the subject.

[0013] As part of a fourth embodiment, provided herein is a method of treating a subject suffering from Alzheimer's disease, the method comprising the steps of: a. administering to the subject an effective dose of 3-SPA for a first period of time; b. During the second period, co-administer the following: i. an effective amount of 3-SPA, and ii. an effective dose of an amyloid plaque removing agent; and c. Thereafter, administering to the subject an effective dose of 3-SPA.

[0014] "Tramiprosate" (homotaurine, 3-amino-1-propanesulfonic acid (3-APS) or Alzhemed™) is an oral amyloid anti-aggregating agent that inhibits the formation of amyloid beta oligomers and reduces oligomer-associated neurotoxicity in the brain. See, e.g., J Nutr Health Aging 13, 550-557 (2009). Tramiprosate has the following chemical structure: [ka]

[0015] "Tramiprosate prodrug" or "prodrug of tramiprosate" refers to a compound that is metabolized to tramiprosate after administration to a subject. Such prodrugs include those having the formula: [ka] and pharmaceutically acceptable salts thereof, wherein R is selected from the group consisting of (AA 1 ) q (AA 2 ) t -H;AA 1 and A.A. 2 are each independently selected from alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), β-alanine (β-ALA), and γ-aminobutyric acid (GABA); q is 1; and t is 0 or 1. In certain embodiments, the tramiprosate prodrug is ALZ-801. Additional tramiprosate prodrugs useful in the present invention are disclosed in WO2015 / 143447, WO2009 / 019534, WO2017 / 027582, WO2004 / 113275, WO2006 / 085149, WO1994 / 022437, WO2000 / 064420, WO1999 / 040909, WO1999 / 059571, WO2004 / 112762, and WO2018 / 156845, the contents of each of which are incorporated herein by reference.

[0016] ALZ-801 refers to valyl-3-amino-1-propanesulfonic acid, a prodrug of tramiprosate, represented by the following structure: [ka]

[0017] "Active tramiprosate metabolite" refers to the metabolized form of tramiprosate that continues to produce effects in the body. Active tramiprosate metabolites include the compound 3-SPA, which has the formula: [ka] and pharmaceutically acceptable salts thereof. See, e.g., WO2020 / 028348, the entire contents of which are incorporated herein by reference.

[0018] Deuterated forms of tramiprosate or tramiprosate prodrugs, such as ALZ-801, are described in U.S. Patent Publication Nos. US2009 / 0076167 and US2018 / 0273471.

[0019] An "effective amount" or "effective dose" refers to the amount of a compound or biologic agent described herein that is sufficient, under the conditions of administration, to achieve the desired therapeutic effect (e.g., reduction of plaque, reduction of one or more fluid or imaging biomarkers associated with AD, or treatment of AD). An effective amount can vary, as recognized by those skilled in the art, depending on, for example, the severity of AD, the route of administration, the patient's sex, age, and general health, the use of excipients, the possibility of coadministration with other therapies, such as the use of other medications, and the judgment of the treating physician or other healthcare professional. In some embodiments, an effective amount of an amyloid plaque removal agent is an amount sufficient to reduce plaque (e.g., as measured by PET scan, CSF or plasma amyloid biomarkers, or other means known to those skilled in the art). In some embodiments, an effective amount of tramiprosate, a tramiprosate prodrug (e.g., ALZ-801), or an active tramiprosate metabolite (e.g., 3-SPA) is an amount sufficient to reduce plaque (e.g., as measured by PET scan, CSF or plasma amyloid biomarkers, or other means known to those skilled in the art) and / or to reduce one or more biomarkers associated with AD (e.g., plasma levels of Aβ40, Aβ42, and / or p-tau). 181The effective amount of the compound or biologic agent described herein is an amount sufficient to reduce a neurodegenerative disorder (e.g., a neurodegenerative disorder, or an MRI measure such as hippocampal volume) below a certain threshold. In some embodiments, an effective amount of the compound or biologic agent described herein refers to a dose of 0.01 to 100 mg / kg body weight / day.

[0020] As used herein, the terms "treat," "treating," or "treatment" mean reversing, alleviating, inhibiting, or slowing the progression of Alzheimer's disease (AD), including cognitive decline or one or more symptoms associated therewith.

[0021] As used herein, the term "co-administration" with respect to administration of tramiprosate, a tramiprosate prodrug, or an active tramiprosate metabolite with at least one amyloid plaque removal agent means that the at least one amyloid plaque removal agent can be administered before, simultaneously with, or after administration of tramiprosate, a tramiprosate prodrug, or an active tramiprosate metabolite. Thus, tramiprosate, a tramiprosate prodrug, or an active tramiprosate metabolite need not be administered simultaneously with the at least one amyloid plaque removal agent. However, in one embodiment, effective amounts of tramiprosate, a tramiprosate prodrug, or an active tramiprosate metabolite and the at least one amyloid plaque removal agent will be present in the subject at the same time. Similarly, in certain embodiments, co-administration refers to the administration of tramiprosate, a tramiprosate prodrug, or an active tramiprosate metabolite at a time significantly separated from that of at least one amyloid plaque removing agent, but the effects of the at least one amyloid plaque removing agent and tramiprosate, a tramiprosate prodrug, or an active tramiprosate metabolite are simultaneous. As used herein, a subtherapeutic dose refers to an amount of an amyloid plaque removing agent that is less than the amount required to reverse, alleviate, inhibit, or slow the progression of Alzheimer's disease (AD), including cognitive decline, when used as a monotherapy, i.e., without the co-administration of tramiprosate, a tramiprosate prodrug, or an active tramiprosate metabolite. In certain embodiments, a subtherapeutic dose of an amyloid plaque removing agent is an amount sufficient to reduce amyloid plaque burden.

[0022] The terms "subject" and "patient" are used interchangeably. In one embodiment, the subject is a human. In some embodiments, the subject is a human under 100 years of age, under 95 years of age, under 90 years of age, or under 85 years of age. In other embodiments, the subject is a human between 65 and 100 years of age, between 65 and 95 years of age, between 65 and 90 years of age, or between 65 and 85 years of age. In yet other embodiments, the subject is a human over 58 years of age. In still other embodiments, the human is in need of treatment.

[0023] Suitable routes for administering tramiprosate, tramiprosate prodrugs (e.g., ALZ-801), tramiprosate active metabolites (e.g., 3-SPA), and amyloid plaque removal agents include, but are not limited to, oral, parenteral, topical, nasal, buccal, or via an implanted reservoir, by inhalation spray. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the pharmaceutical compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. In some embodiments, tramiprosate, a prodrug of tramiprosate (e.g., ALZ-801), an active metabolite of tramiprosate (e.g., 3-SPA), or an amyloid plaque removal agent is administered orally. In some embodiments, tramiprosate, a prodrug of tramiprosate (e.g., ALZ-801), or an active metabolite of tramiprosate (e.g., 3-SPA) is administered orally.

[0024] As used herein, amyloid plaque removal agents refer to compounds or biological agents that remove insoluble amyloid plaques from the brain. Amyloid plaque removal agents include immunotherapeutic agents (such as monoclonal antibodies, fusion proteins, soluble cytokine receptors, recombinant cytokines, small molecule mimetics, and cellular therapeutic agents) and polypeptides, including bacteriophages. In some aspects, as part of the fifth embodiment, the amyloid plaque removal agent is an antibody (e.g., lecanemab, aducanumab, donanemab, bapineuzumab, solanezumab, crenezumab, and gantenerumab); a bacteriophage g3p-derived polypeptide (see, e.g., WO2013 / 082114, WO2014 / 055515, WO2014 / 193935, WO2016 / 090022, and WO2019 / 241628); or a vaccine targeting Abeta42 or Abeta40 (e.g., AN-1792, CAD106, ACI-24, UB311, DNA-encoding Abeta42 vaccine, and Lu AF20513). In some aspects, the amyloid plaque removal agent is administered parenterally. In some embodiments, the amyloid plaque removing agent is administered intravenously.

[0025] In a sixth embodiment, the first period in the described administration protocol (e.g., in any one of the first through fifth embodiments) refers to a period sufficient to reduce Aβ42 toxicity and / or reduce vascular amyloid burden. In another aspect, as part of the sixth embodiment, the first period in the described administration protocol (e.g., in any one of the first through fifth embodiments) refers to a period sufficient to reduce Aβ40, Aβ42, and / or p-tau in the brain. 181In another aspect, as part of the sixth embodiment, the first period of time in the described administration protocols (e.g., in any one of the first through fifth embodiments) refers to a period of time sufficient to reduce serum levels of Aβ40 in the brain to below a particular threshold level. In another aspect, as part of the sixth embodiment, the first period of time in the described administration protocols (e.g., in any one of the first through fifth embodiments) refers to a period of time sufficient to reduce serum levels of Aβ42 in the brain to below a particular threshold level. In another aspect, as part of the sixth embodiment, the first period of time in the described administration protocols (e.g., in any one of the first through fifth embodiments) refers to a period of time sufficient to reduce serum levels of p-tau biomarkers (e.g., p-tau 181 ) to or below a particular threshold level. In some aspects, as part of the sixth embodiment, the first period of time in the described administration protocols (e.g., in any one of the first through fifth embodiments) is at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, or at least about 24 months. In some aspects, as part of the sixth embodiment, the first period of time in the described administration protocols (e.g., in any one of the first through fifth embodiments) is from about 6 months to about 24 months, from about 6 months to about 18 months, from about 6 months to about 12 months, from about 10 months to about 14 months, or from about 11 months to about 13 months. In some aspects, as part of the sixth embodiment, the first period in the described administration protocol (e.g., in any one of the first through fifth embodiments) is at least about 12 months. In some aspects, as part of the sixth embodiment, the first period in the described administration protocol (e.g., in any one of the first through fifth embodiments) is at least about 12 months.

[0026] In a seventh embodiment, the threshold level referred to for Aβ40 and / or Aβ42 in the sixth embodiment is characterized as a brain serum level of Aβ40 and / or Aβ42 that is at least 5% lower, at least 10% lower, at least 15% lower, at least 20% lower, at least 25% lower, at least 30% lower, at least 35% lower, at least 40% lower, at least 45% lower, at least 50% lower, at least 55% lower, at least 60% lower, at least 65% lower, at least 70% lower, or at least 75% lower than the brain serum level of Aβ40 and / or Aβ42 determined less than 30 days, less than 60 days, less than 90 days, less than 4 months, less than 5 months, less than 6 months, less than 7 months, less than 8 months, less than 9 months, less than 10 months, less than 11 months, or less than 12 months prior to the start of treatment. In one aspect, as part of the seventh embodiment, the threshold level referred to in the sixth embodiment for Aβ40 and / or Aβ42 is characterized as a brain serum level of Aβ40 and / or Aβ42 that is at least 5% lower than the brain serum level of Aβ40 and / or Aβ42 determined less than 60 days prior to the start of treatment.

[0027] In an eighth embodiment, the threshold level referred to for the p-tau biomarker in the sixth embodiment is a p-tau biomarker determined less than 30 days, less than 60 days, less than 90 days, less than 4 months, less than 5 months, less than 6 months, less than 7 months, less than 8 months, less than 9 months, less than 10 months, less than 11 months, or less than 12 months prior to initiation of treatment. 181 at least 30% lower, at least 35% lower, at least 40% lower, at least 45% lower, at least 50% lower, at least 55% lower, at least 60% lower, at least 65% lower, at least 70% lower, or at least 75% lower than brain serum levels of p-tau 181In one aspect, as part of an eighth embodiment, the threshold level referred to for a p-tau biomarker in the sixth embodiment is characterized as a brain serum level of such p-tau biomarker that is at least 40% lower than the brain serum level of the same p-tau biomarker determined less than 60 days prior to the start of treatment. In some embodiments, the p-tau biomarker is 181 In some embodiments, the p-tau biomarker is p-tau 217 In some embodiments, the p-tau biomarker is p-tau 231 In some embodiments, the p-tau biomarker is p-tau 243 is.

[0028] In a ninth embodiment, the second period of time in the described administration protocols (e.g., in any one of the first through eighth embodiments) refers to a period of time sufficient to remove amyloid plaques. In one aspect, as part of the ninth embodiment, the second period of time in the described administration protocols (e.g., in any one of the first through eighth embodiments) refers to a period of time sufficient to remove existing amyloid plaques, i.e., plaques that existed before the start of treatment. In one aspect, as part of the ninth embodiment, the second period of time in the described administration protocols (e.g., in any one of the first through eighth embodiments) refers to a period of time sufficient to remove remaining amyloid plaques, i.e., plaques that existed before administration of the amyloid plaque-removing agent. In one aspect, as part of the ninth embodiment, the second period of time in the described administration protocols (e.g., in any one of the first through eighth embodiments) is from about 3 months to about 12 months, from about 3 months to about 6 months, from about 6 months to about 18 months, or from about 6 months to about 12 months. In one aspect, as part of the ninth embodiment, the second period in the described administration protocol (e.g., in any one of the first through eighth embodiments) is from about 6 months to about 12 months. In one aspect, as part of the ninth embodiment, the second period in the described administration protocol (e.g., in any one of the first through eighth embodiments) ends when the subject obtains a negative amyloid PET scan.

[0029] In a tenth embodiment, the amyloid plaque removal agent used in the described administration protocols (e.g., in any one of the first through ninth embodiments) is lecanemab, donanemab, or aducanumab. Alternatively, as part of the tenth embodiment, the amyloid plaque removal agent used in the described administration protocols (e.g., in any one of the first through ninth embodiments) is lecanemab or aducanumab, and the effective amount of donanemab and aducanumab is about 10 mg / kg monthly, and the effective amount of lecanemab is 10 mg / kg twice monthly.

[0030] In an eleventh embodiment, the amyloid plaque removal agents used in the described administration protocols (e.g., in any one of the first through tenth embodiments) are administered at sub-therapeutic doses, e.g., less than 10 mg / kg / month for the amyloid plaque removal agents donanemab and aducanumab, and less than 20 mg / kg / month for lecanemab.

[0031] In a twelfth embodiment, a subject is treated only by the method (including any one of the first through eleventh embodiments) if they have mild to moderate AD, including subjects with an MMSE of 16 to 26. Alternatively, as part of the twelfth embodiment, a subject is treated only by the method (including any one of the first through eleventh embodiments) if they have moderate to severe AD, including subjects with an MMSE of less than 20 or less than 22. In another alternative, as part of the twelfth embodiment, a subject is treated only by the method (including any one of the first through eleventh embodiments) if they have an MMSE score of 22 or greater. In another alternative, as part of the twelfth embodiment, a subject is treated only by the method (including any one of the first through eleventh embodiments) if they have an MMSE score of 22 to 28. In another alternative, as part of the twelfth embodiment, a subject is treated only by the method (including any one of the first through eleventh embodiments) if they have an MMSE score of 22 to 26. In another alternative, as part of the twelfth embodiment, a subject is only treated with the method (including any one of the first through eleventh embodiments) if their MMSE score is 21 or less.

[0032] In a thirteenth embodiment, a subject is only treated by the method (including any one of the first through twelfth embodiments) if certain parameters are met. In some aspects of this thirteenth embodiment, the subject is treated with: (a) a subject having at least one APOE4 allele, i.e., APOE4 positive or APOE4 +Only subjects who are APOE4-positive are treated, or (b) subjects who are APOE4-negative, i.e., APOE4- (non-carriers of the APOE4 allele) and have evidence of cerebral amyloid angiopathy on imaging, or (c) subjects who are APOE4- and receiving anticoagulant therapy. In some aspects, as part of the thirteenth embodiment, subjects are only treated by the method (including any one of the first through twelfth embodiments) if they are (a) APOE4 homozygous, i.e., APOE4 / 4, or (b) APOE4- or APOE4 heterozygous (having only one APOE4 allele) and have evidence of cerebral amyloid angiopathy on imaging, or (c) APOE4- or APOE4 heterozygous and receiving anticoagulant therapy. In alternative aspects of the thirteenth embodiment, only subjects who are APOE4-positive are treated. In other aspects, only subjects who are APOE4 homozygous are treated. In yet other embodiments, only subjects who are APOE4 positive and either (i) have evidence of cerebral amyloid angiopathy or (ii) are receiving anticoagulant therapy are treated. In yet other embodiments, only subjects who are APOE4 homozygous and either (i) have evidence of cerebral amyloid angiopathy or (ii) are receiving anticoagulant therapy are treated.

[0033] In a fourteenth embodiment, the effective dose of ALZ-801 used in the methods (including any one of the first, second, and sixth through thirteenth embodiments) is about 530 mg / day. Alternatively, as part of the fourteenth embodiment, the effective dose of ALZ-801 used in the methods (including any one of the first, second, and sixth through thirteenth embodiments) is about 265 mg BID.

[0034] In a fifteenth embodiment, ALZ-801 as defined herein (including any one of the first, second, and sixth to fourteenth embodiments) is orally administered to a subject.

[0035] In a sixteenth embodiment, ALZ-801 as defined herein (including any one of the first, second, and sixth through fourteenth embodiments) is formulated in a tablet, capsule, liquid, orally dissolving tablet, sachet, or sprinkle. In some aspects of the sixteenth embodiment, ALZ-801 as defined herein (including any one of the first, second, and sixth through fifteenth embodiments) is formulated in a capsule. In some aspects of the sixteenth embodiment, ALZ-801 as defined herein (including any one of the first, second, and sixth through fifteenth embodiments) is formulated in an immediate-release capsule. In other aspects of the sixteenth embodiment, ALZ-801 as defined herein (including any one of the first, second, and sixth through fifteenth embodiments) is formulated in an extended-release capsule. In still other aspects of the sixteenth embodiment, each capsule contains about 265 mg of ALZ-801. [Example]

[0036] An evaluation of the disease-modifying effects of ALZ-801 (valiltramiprosate) from a phase 2 study in subjects with early Alzheimer's disease was conducted. The study enrolled 84 patients with early AD who possessed the APOE4 / 4 or APOE3 / 4 genotype and had MMSE scores ranging from 22 to 30 (CDR-G 0.5 or 1). Each patient received 265 mg of ALZ-801 twice daily. The mean MMSE score of subjects was 26 (mean age 69 years, 52% women). Subjects were either amyloid PET-positive or A+ / T+ by CSF assay. CSF criteria were as follows: Aβ42 / 40×10 ratio <0.61, and p-tau 181 >61 pg / ml. CSF was assessed at week 52, and plasma biomarkers were assessed at each visit.

[0037] Subjects treated with ALZ-801 demonstrated significant benefits in core plasma biomarkers of AD. Both Aβ40 and Aβ42 plasma levels demonstrated a biphasic response compared to baseline levels (see Figures 1 and 2). Aβ40 demonstrated a significant early increase at week 13, followed by a significant decrease of approximately 5% at week 52 (see Figure 1). Aβ42 demonstrated a significant increase at week 26, followed by a significant decrease of approximately 5% at week 52 (see Figure 2). Plasma p-tau began to significantly decrease at week 13, progressing to a 41% decrease at week 52 (see Figure 3). These benefits were associated with benefits in a composite cognitive outcome testing memory and learning. ALZ-801 demonstrated a significant reduction in HV atrophy of approximately 19-23% when compared to a matched external control group in the ADNI-1 observational study. The HV sparing effect correlated with the effect on cognitive function (Spearman's coefficient r=0.27, p=0.02).

[0038] Over the course of one year of ALZ-801 treatment, no subjects experienced vasogenic edema (ARIA-E or ARIA-H) or major bleeding events. Given the safety of the drug and its ability to reduce Aβ40, leading to a hypothesized improvement in the overall health and function of small and medium-sized vessels in the cortex, the following dosage protocol is contemplated as a safe and effective means of clearing amyloid plaques in subjects with AD. Phase 1: 265 mg BID ALZ-801 for at least 1 year; Phase 2: An effective amount of an amyloid plaque remover administered with 265 mg BID of ALZ-801 for a period of approximately 6 to 12 months or until the patient achieves a negative amyloid PET scan; and Phase 3: Discontinue administration of amyloid plaque removal agents and continue administration of ALZ-801 at 265 mg BID.

[0039] Having described several embodiments of the present invention, it will be apparent that our basic examples may be modified to provide other embodiments that utilize the compounds and methods of the present invention. It will therefore be understood that the scope of the present invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

[0040] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) that may be cited throughout this application are expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to those skilled in the art.

Claims

1. 1. A method of treating a subject suffering from Alzheimer's disease, comprising the steps of: a. administering to the subject for a first period of time an effective dose of tramiprosate, a tramiprosate prodrug, an active tramiprosate metabolite, or a deuterated form of any of the foregoing; b. during a second period, co-administering to said subject: i. an effective dose of tramiprosate, a tramiprosate prodrug, an active tramiprosate metabolite, or a deuterated form of any of the foregoing, and ii. an effective dose of an amyloid plaque removing agent, and c. then administering to the subject an effective dose of tramiprosate, a tramiprosate prodrug, an active tramiprosate metabolite, or a deuterated form of any of the foregoing; The method comprising:

2. 10. The method of claim 1, wherein in each of steps a., b., and c., the subject is administered a tramiprosate prodrug that is a tramiprosate amino acid prodrug.

3. The tramiprosate amino acid prodrug has the chemical formula: 【Chemistry 1】 3. The method of claim 2, comprising:

4. 10. The method of claim 1, wherein in each of steps a., b., and c., the subject is administered tramiprosate.

5. In each of steps a., b., and c., the object is a compound having the chemical formula: 【Chemistry 2】 10. The method of claim 1, wherein the patient is administered a tramiprosate metabolite having the formula:

6. The method of any one of claims 1 to 5, wherein the amyloid plaque removing agent is an antibody or a bacteriophage g3p-derived polypeptide.

7. 7. The method of claim 6, wherein the amyloid plaque removing agent is selected from lecanemab, aducanumab, bapineuzumab, solanezumab, crenezumab, and gantenerumab.

8. 7. The method of claim 6, wherein the amyloid plaque removing agent is lecanemab or aducanumab.

9. The method of any one of claims 1 to 8, wherein the first period of time is at least about 12 months.

10. 10. The method of any one of claims 1 to 9, wherein the first period of time ends when a serum biomarker selected from Aβ40, Aβ42, and p-tau falls below a threshold level.

11. The p-tau serum biomarker is １８１ The method of claim 9, wherein

12. 11. The method of claim 10, wherein the threshold level of Aβ40 or the threshold level of Aβ42 is at least 5% lower than the level determined less than 60 days before initiation of treatment.

13. The p-tau or p-tau １８１ 12. The method of claim 10 or 11, wherein the threshold level of is at least 40% lower than the level determined less than 60 days before the start of treatment.

14. 14. The method of any one of claims 1 to 13, wherein the second period of time is from about 6 months to about 12 months.

15. 14. The method of any one of claims 1 to 13, wherein the second time period ends when the subject obtains a negative amyloid PET scan.

16. 16. The method of claim 14 or 15, wherein the amyloid plaque removing agent is administered at a sub-therapeutic dose.

17. The method of any one of claims 1 to 16, wherein the subject is undergoing treatment with an anticoagulant.

18. 18. The method of any one of claims 1 to 17, wherein the subject has evidence of cerebral amyloid angiopathy ("CAA").

19. The subject is ＋ The method of any one of claims 1 to 18, wherein treatment is administered only if

20. 20. The method of claim 19, wherein the subject is treated only if the subject is ApoE4 homozygous.

21. 21. The method of any one of claims 1 to 20, wherein the subject receives treatment only if the subject has an MMSE score of 22 or greater.

22. The chemical formula is: 【Transformation 3】 22. The method of any one of claims 1 to 21, wherein the effective dose of the tramiprosate amino acid prodrug is about 265 mg BID.

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