Methods for treating neurodegenerative disorders with tromitaux

Abstract

Provided herein are methods for the treatment of Alzheimer's disease using a combination of tramixate, a tramixate prodrug, or an active tramixate metabolite with at least one amyloid plaque scavenger.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 429,637, filed on December 2, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0003] Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects more than 6 million people in the United States. Currently, AD is the sixth leading cause of death and is characterized by extracellular amyloid beta (Aβ) plaques produced by β-amyloid deposition and intracellular tau protein accumulation, leading to intracytoplasmic neurofibrillary tangles (NFTs). Aβ causes synaptic damage and neurodegeneration, leading to cognitive dysfunction and progressive cognitive and functional deficits observed in AD. Recently, immunotherapy has emerged as a potential strategy to actively clear aggregated Aβ (amyloid plaques) and reduce the accumulation of Aβ in the brain, and may treat the root cause of AD. Such therapies include active immunization and passive immunization.

[0004] Although certain immunotherapies have been shown to reduce Aβ plaques in the brain, they also come with significant risks. Immunotherapies, such as the administration of certain monoclonal antibodies, break down Aβ aggregated plaques in the brain parenchyma and blood vessel walls by forming immune complexes, recruiting microglia, and inducing inflammation. These immune complexes and the inflammatory response they induce can damage the walls of brain blood vessels, leading to amyloid-related imaging abnormalities, including vasogenic edema (ARIA-E) and intracerebral hemorrhage (ARIA-H). These ARIA events may manifest as headaches, increased confusion, dizziness, visual impairment, nausea, and seizures. ARIA-E and ARIA-H may lead to serious events such as stroke, epilepsy, and status epilepticus, and may even be fatal. In addition, subjects receiving anticoagulant therapy are at particularly high risk for ARIA events, and the risk is even higher if the subject also has evidence of cerebral amyloid angiopathy (CAA). Recent studies have shown that AD subjects treated with both anticoagulants and amyloid plaque-clearing antibodies are at higher risk for vascular damage or amyloid-related imaging abnormalities than AD subjects treated with antibodies alone. The risk is greater if subjects treated with anticoagulants have evidence of CAA.

[0005] Therefore, safe and effective alternative strategies for using immunotherapy in the setting of treating AD are needed. Summary of the Invention

[0006] ALZ-801 is a promising new treatment for AD and is currently being studied in clinical trials for subjects with early-stage AD (MMSE>22). ALZ-801 can reduce the burden of soluble aggregated forms of Aβ42 (called oligomers) in the brain by clearing Aβ42 from the brain to the plasma. Oligomers are the building blocks and main toxic components of plaques. See, for example, Figure 2 Thus, unlike recent antibody-based immunotherapies that directly target and bind to plaques, ALZ-801 blocks the formation of oligomers to prevent new plaques from forming. Furthermore, ALZ-801 reduces the burden of Aβ40, the major component of vascular amyloid, by clearing it from the brain into the plasma and also induces an early reduction in plasma p-tau, a marker of Aβ-induced neuronal stress and damage. See, e.g., Figure 1 and Figure 3 .

[0007] The significant reduction in Aβ40 suggests that ALZ-801 reduces the Aβ40 burden in blood vessels, leading to healthier small and medium-sized brain vessels. This is further supported by the early significant decrease in plasma p-tau, a marker of neuronal damage, which suggests a reduction in amyloid-induced neuronal stress. See, for example, Figure 3 Unlike amyloid immunotherapy, AD patients treated with ALZ-801 for 1 year did not develop amyloid-related abnormal imaging of edema (ARIA-E) or major hemorrhages (bleeds greater than 1 cm in diameter).

[0008] Provided herein is an administration regimen for treating subjects with AD using a combination of ALZ-801 and at least one amyloid plaque remover (e.g., an antibody). The disclosed regimen first includes administering ALZ-801 over a first time period to offset and reduce Aβ42 toxicity and reduce vascular amyloid burden. Next, since amyloid plaques may act as a reservoir for toxic oligomers, and since ALZ-801 does not directly target pre-existing plaques, an amyloid plaque remover is then introduced over a second time period as part of a simultaneous treatment with ALZ-801. In one aspect, it is assumed that the clearance of Aβ40 after pre-treatment of the subject with ALZ-801 for a first time period results in improved overall health and function of cortical small and medium vessels that typically accumulate amyloid. Aβ40 is the main component of vascular amyloid, deposited in and around the smooth muscle layer, and reduces vascular elasticity and integrity. Therefore, it is believed that if a subject is treated with ALZ-801 for a period of time beforehand, the risk of developing vascular damage or amyloid-related imaging abnormalities (such as ARIA-E or ARIA-H) while taking an amyloid plaque clearing agent is reduced. This risk reduction is particularly beneficial for subjects taking anticoagulants, especially those with evidence of CAA. Finally, after the second period of time, the amyloid plaque clearing agent is no longer administered, and treatment with ALZ-801 is continued thereafter as maintenance therapy to prevent the re-accumulation of Aβ plaques in AD brains.

[0009] Other compounds that similarly reduce the aggregated form of Aβ42 (such as ALZ-801) are also considered useful in the administration regimens of the present invention. These include, but are not limited to, tramiprosate, prodrugs of tramiprosate other than ALZ-801, and active metabolites of tramiprosate. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 The effect of 265 mg ALZ-801 orally administered twice daily on plasma Abeta40 (change from baseline) after 52 weeks of treatment in subjects with APOE4+ and early AD is described.

[0011] Figure 2 The effect of 265 mg ALZ-801 orally administered twice daily on plasma Abeta42 (change from baseline) after 52 weeks of treatment in subjects with APOE4+ and early AD is described.

[0012] Figure 3 The effect of 265 mg ALZ-801 orally administered twice daily on plasma p-tau in subjects with APOE4+ and early AD for 52 weeks was described. 181 Effect of (change from baseline). DETAILED DESCRIPTION

[0013] 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:

[0014] a. administering to the subject an effective dose of tromisat, tromisat prodrug, tromisat metabolite, or a deuterated form of any of the foregoing within a first period of time;

[0015] b. Co-administered to the subject during the second time period:

[0016] i. an effective amount of tromisat, a prodrug of tromisat, a metabolite of tromisat, or a deuterated form of any of the foregoing; and

[0017] ii. an effective amount of an amyloid plaque clearing agent; and

[0018] c. Thereafter administering to the subject an effective dose of tramiphasat, a tramiphasat prodrug, a tramiphasat metabolite, or a deuterated form of any of the foregoing.

[0019] 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:

[0020] a. administering to the subject an effective dose of ALZ-801 or a deuterated form thereof during a first period of time;

[0021] b. Co-administered to the subject during the second time period:

[0022] i. an effective amount of ALZ-801 or a deuterated form thereof; and

[0023] ii. an effective amount of an amyloid plaque clearing agent; and

[0024] c. Thereafter administering to the subject an effective dose of ALZ-801 or a deuterated form thereof.

[0025] 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:

[0026] a. administering to the subject an effective dose of tramisate or a deuterated form thereof within a first period of time;

[0027] b. Co-administered to the subject during the second time period:

[0028] i. an effective dose of trimesate or a deuterated form thereof; and

[0029] ii. an effective amount of an amyloid plaque clearing agent; and

[0030] c. Thereafter administering to the subject an effective dose of trimisater.

[0031] 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:

[0032] a. administering an effective dose of 3-SPA to the subject within a first period of time;

[0033] b. Co-administered to the subject during the second time period:

[0034] i. an effective dose of 3-SPA; and

[0035] ii. an effective amount of an amyloid plaque clearing agent; and

[0036] c. Thereafter administering an effective dose of 3-SPA to the subject.

[0037] "Tremisat" (homotaurine, 3-amino-1-propanesulfonic acid (3-APS) or Alzhemed TM ) is an oral amyloid beta anti-aggregant that inhibits the formation of amyloid beta oligomers and reduces oligomer-related neurotoxicity in the brain. See, for example, J Nutr Health Aging 13, 550–557 (2009). Tramisart has the following chemical structure:

[0038]

[0039] "Prodrug of tramiphasart" or "prodrug of tramiphasart" refers to a chemical compound that is metabolized to tramiphasart after administration to a subject. Such prodrugs include, but are not limited to, those having the formula:

[0040]

[0041] and pharmaceutically acceptable salts, wherein R is (AA 1 ) q (AA 2 ) t -H;AA 1 and AA 2Each is 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 aspects, the tramisate prodrug is ALZ-801. Additional prodrugs of tramisater that may be used in the present invention are disclosed in WO 2015 / 143447, WO 2009 / 019534, WO 2017 / 027582, WO 2004 / 113275, WO 2006 / 085149, WO 1994 / 022437, WO 2000 / 064420, WO 1999 / 040909, WO 1999 / 059571, WO 2004 / 112762, and WO 2018 / 156845, the contents of each of which are incorporated herein by reference.

[0042] ALZ-801 refers to valyl-3-amino-1-propanesulfonic acid (a prodrug of tramisartane) and is represented by the following structure:

[0043]

[0044] "Active tramiphetide metabolites" refer to metabolic forms of tramiphetide that continue to exert their effects in the body. Active tramiphetide metabolites include the compound 3-SPA having the formula

[0045]

[0046] and pharmaceutically acceptable salts thereof. See, for example, WO 2020 / 028348, the entire contents of which are incorporated herein by reference.

[0047] U.S. Patent Publication Nos. US2009 / 0076167 and US2018 / 0273471 describe deuterated forms of tramiphetamine or tramiphetamine prodrugs, such as ALZ-801.

[0048] "Effective amount" or "effective dose" refers to the amount of a compound or biologic described herein that is sufficient to achieve the desired therapeutic effect (such as reducing plaques, reducing one or more fluid or imaging biomarkers associated with AD, or treating AD) under the conditions of administration. As will be appreciated by one of ordinary skill in the art, the effective amount may vary, depending on, for example, the severity of AD, the route of administration, the sex, age and general health of the patient, the use of excipients, the possibility of co-use with other therapeutic treatments (such as the use of other agents), and the judgment of the treating physician or other medical provider. In some aspects, an effective amount of an amyloid plaque clearing agent is an amount sufficient to reduce plaques (e.g., as measured by PET scans, CSF or plasma amyloid biomarkers, or other methods known to those skilled in the art). In some aspects, an effective amount of tramisart, a tramisart prodrug (e.g., ALZ-801), or an active tramisart metabolite (e.g., 3-SPA) is an amount sufficient to reduce one or more biomarkers associated with AD (e.g., Aβ40, Aβ42, and / or p-tau). 181 In some aspects, an effective amount of a compound or biologic described herein refers to a dosage between 0.01-100 mg / kg body weight / day.

[0049] 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.

[0050] As used herein, the term "co-administered" with respect to the administration of tramisart, a tramisart prodrug, or an active tramisart metabolite and at least one amyloid plaque clearing agent means that the at least one amyloid plaque clearing agent can be administered before, simultaneously with, or after the administration of tramisart, a tramisart prodrug, or an active tramisart metabolite. Thus, tramisart, a tramisart prodrug, or an active tramisart metabolite need not be administered simultaneously with the at least one amyloid plaque clearing agent. However, in one aspect, an effective amount of tramisart, a tramisart prodrug, or an active tramisart metabolite and the at least one amyloid plaque clearing agent will be present in the subject at the same time. Similarly, in certain aspects, co-administered means that the administration time of tramisart, a tramisart prodrug, or an active tramisart metabolite is significantly different from that of the at least one amyloid plaque clearing agent, but the at least one amyloid plaque clearing agent and the effects of tramisart, a tramisart prodrug, or an active tramisart metabolite are present simultaneously. As used herein, a subtherapeutic dose refers to an amount of an amyloid plaque clearing 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 co-administration of tramiphet, a tramiphet prodrug, or an active tramiphet metabolite. In certain aspects, a subtherapeutic dose of an amyloid plaque clearing agent is an amount sufficient to reduce the burden of amyloid plaques.

[0051] The terms "subject" and "patient" are used interchangeably. In one aspect, the subject is a human. In some aspects, the subject is a human who is 100 years of age or younger, 95 years of age or younger, 90 years of age or younger, or 85 years of age or younger. In other aspects, the subject is a human who is 65-100 years of age, 65-95 years of age, 65-90 years of age, or 65-85 years of age. In other aspects, the subject is a human who is 58 years of age or older. In yet other aspects, the human is in need of treatment.

[0052] Suitable routes of administration of tramisart, a prodrug of tramisart (e.g., ALZ-801), an active metabolite of tramisart (e.g., 3-SPA), and an amyloid plaque clearing agent include, but are not limited to, oral, parenteral, inhalation spray, topical, nasal, buccal, or via an implantable reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the composition is administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the pharmaceutical compositions described herein can be aqueous or oily suspensions. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. In some aspects, tramisart, a prodrug of tramisart (e.g., ALZ-801), an active metabolite of tramisart (e.g., 3-SPA), or an amyloid plaque clearing agent is administered orally. In some aspects, tramiphetide, a prodrug of tramiphetide (eg, ALZ-801), or an active metabolite of tramiphetide (eg, 3-SPA) is administered orally.

[0053] As used herein, amyloid plaque clearing agents refer to compounds or biological agents that clear insoluble amyloid plaques in the brain.Amyloid plaque clearing agents include immunotherapeutics (such as monoclonal antibodies, fusion proteins, soluble cytokine receptors, recombinant cytokines, small molecule mimetics and cell therapies) and polypeptides comprising phages. In some aspects, as part of the fifth embodiment, the amyloid plaque clearing agent is an antibody (e.g., Lecanemab, Aducanumab, Donanemab, Bapineuzumab, Solanezumab, Crenezumab, and Gantenerumab); a bacteriophage g3p-derived polypeptide (see, e.g., WO 2013 / 082114, WO 2014 / 055515, WO 2014 / 193935, WO 2016 / 090022, and WO 2019 / 241628); or a vaccine against Abeta42 or Abeta 40 (e.g., AN-1792, CAD106, ACI-24, UB311, a DNA vaccine encoding Abeta 42, and Lu AF20513). In some aspects, the amyloid plaque clearing agent is administered parenterally. In some aspects, the amyloid plaque clearing agent is administered intravenously.

[0054] In a sixth embodiment, the first period of time in the administration regimen (e.g., in any one of the first through fifth embodiments) is an amount of time sufficient to reduce Aβ42 toxicity and / or reduce vascular amyloid burden. In other aspects, as part of the sixth embodiment, the first period of time in the administration regimen (e.g., in any one of the first through fifth embodiments) is an amount of time sufficient to reduce Aβ40, Aβ42, and / or p-tau in the brain. 181 In other aspects, as part of a sixth embodiment, the first time period in the administration regimen (e.g., in any one of the first to fifth embodiments) refers to the amount of time sufficient to reduce serum levels of Aβ40 in the brain to below a threshold level. In other aspects, as part of a sixth embodiment, the first time period in the administration regimen (e.g., in any one of the first to fifth embodiments) refers to the amount of time sufficient to reduce serum levels of Aβ42 in the brain to below a threshold level. In other aspects, as part of a sixth embodiment, the first time period in the administration regimen (e.g., in any one of the first to fifth embodiments) refers to the amount of time sufficient to reduce serum levels of Aβ42 in the brain to below a threshold level. 181 ) to the amount of time below a certain threshold level. In some aspects, as part of the sixth embodiment, the first time period in the administration regimen (e.g., in any one of the first to the fifth embodiment) 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 time period in the administration regimen (e.g., in any one of the first to the fifth embodiment) is about 6 months to about 24 months, about 6 months to about 18 months, about 6 months to about 12 months, about 10 months to about 14 months, or about 11 months to about 13 months. In some aspects, as part of the sixth embodiment, the first time period in the administration regimen (e.g., in any one of the first to the fifth embodiment) is at least about 12 months. In some aspects, as part of the sixth embodiment, the first time period in the administration regimen (e.g., in any one of the first to the fifth embodiment) is about 12 months.

[0055] In a seventh embodiment, the threshold levels of Aβ40 and / or Aβ42 referred to in the sixth embodiment are characterized by brain serum levels of Aβ40 and / or Aβ42 that are 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 compared to brain serum levels of Aβ40 and / or Aβ42 determined within 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 before start of treatment. In one aspect, as part of a seventh embodiment, the threshold level of Aβ40 and / or Aβ42 referred to in the sixth embodiment is characterized in that the brain serum level of Aβ40 and / or Aβ42 is at least 5% lower than the brain serum level of Aβ40 and / or Aβ42 determined less than 60 days before the start of treatment.

[0056] In an eighth embodiment, the threshold level of the p-tau biomarker referred to in the sixth embodiment is characterized by a p-tau level determined within 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 before the start of treatment. 181 Compared with the serum levels of p-tau in the brain 181 In one aspect, as part of the eighth embodiment, the threshold level of a p-tau biomarker recited in the sixth embodiment is characterized in that the brain serum level of the p-tau biomarker is 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 the same p-tau biomarker determined less than 60 days before the start of treatment. In some embodiments, the p-tau biomarker is p-tau 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 .

[0057] In the ninth embodiment, the second time period in the administration regimen (e.g., in any one of the first to eighth embodiments) refers to the amount of time sufficient to clear amyloid plaques. In one aspect, as part of the ninth embodiment, the second time period in the administration regimen (e.g., in any one of the first to eighth embodiments) refers to the amount of time sufficient to clear pre-existing amyloid plaques (i.e., plaques that existed before treatment began). In one aspect, as part of the ninth embodiment, the second time period in the administration regimen (e.g., in any one of the first to eighth embodiments) refers to the amount of time sufficient to clear residual amyloid plaques (i.e., plaques that existed before the administration of the amyloid plaque clearing agent). In one aspect, as part of the ninth embodiment, the second time period in the administration regimen (e.g., in any one of the first to 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 time period in the administration regimen (e.g., in any one of the first to eighth embodiments) is from about 6 months to about 12 months. In one aspect, as part of the ninth embodiment, the second time period in the administration regimen (eg, in any one of the first through eighth embodiments) ends when the subject's amyloid PET scan is negative.

[0058] In a tenth embodiment, the amyloid plaque clearing agent used in the administration regimen (e.g., in any one of the first to ninth embodiments) is lencanezumab, donetumab, or aducanumab. Alternatively, as part of the tenth embodiment, the amyloid plaque clearing agent used in the administration regimen (e.g., in any one of the first to ninth embodiments) is lencanezumab or aducanumab, wherein the effective amount of donetumab and aducanumab is about 10 mg / kg per month, and the effective amount of lencanezumab is 10 mg / kg twice per month.

[0059] In an eleventh embodiment, the amyloid plaque clearing agent used in the administration regimen (e.g., in any one of the first to tenth embodiments) is administered at a subtherapeutic dose, e.g., less than 10 mg / kg / month for the amyloid plaque clearing agents donetumab and aducanumab, and less than 20 mg / kg / month for lencanirumab.

[0060] In the twelfth embodiment, only when the subject suffers from mild to moderate AD, the present method (including any one of the first to eleventh embodiments) is used for treatment, including subjects with an MMSE between 16 and 26. Alternatively, as part of the twelfth embodiment, only when the subject suffers from moderate to severe AD, the present method (including any one of the first to eleventh embodiments) is used for treatment, including subjects with an MMSE <20 or <22. In another alternative, as part of the twelfth embodiment, only when the subject's MMSE score is ≥22, the present method (including any one of the first to eleventh embodiments) is used for treatment. In another alternative, as part of the twelfth embodiment, only when the subject's MMSE score is 22 to 28, the present method (including any one of the first to eleventh embodiments) is used for treatment. In another alternative, as part of the twelfth embodiment, only when the subject's MMSE score is 22 to 26, the present method (including any one of the first to eleventh embodiments) is used for treatment. In another alternative, as part of the twelfth embodiment, treatment by the present method (including any one of the first to eleventh embodiments) is performed only if the subject has an MMSE score ≤ 21.

[0061] In a thirteenth embodiment, treatment is performed by the present method (including any of the first through twelfth embodiments) only if the subject meets certain parameters. In some aspects of the thirteenth embodiment, treatment is performed only on subjects who: (a) have at least one APOE4 allele, i.e., are APOE4 positive or APOE4 +Subject; or (b) is APOE4 negative, i.e., APOE4- (non-APOE4 allele carrier), and imaging examination shows evidence of cerebral amyloid angiopathy; or (c) is APOE4- and is administering anticoagulant therapy. In some aspects, as part of the thirteenth embodiment, the subject is treated by this method (including any one of the first to twelfth embodiments) only if the subject meets the following conditions: (a) APOE4 homozygote, i.e., APOE4 / 4; or (b) APOE4- or APOE4 heterozygote (having only one APOE4 allele) and imaging examination shows evidence of cerebral amyloid angiopathy; or (c) APOE4- or APOE4 heterozygote and is administering anticoagulant therapy. In alternative aspects of the thirteenth embodiment, only APOE4-positive subjects are treated. In other aspects, only subjects who are APOE4 homozygotes are treated. In other aspects, only subjects who are APOE4 positive and (i) have evidence of cerebral amyloid angiopathy or (ii) are currently taking anticoagulant therapy are treated. In still other aspects, only subjects who are APOE4 homozygous and (i) have evidence of cerebral amyloid angiopathy or (ii) are currently taking anticoagulant therapy are treated.

[0062] In a fourteenth embodiment, the effective dose of ALZ-801 used in the methods of the present invention (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 of the present invention (including any one of the first, second, and sixth through thirteenth embodiments) is about 265 mg BID.

[0063] In a fifteenth embodiment, ALZ-801 as defined herein (including any one of the first, second, and sixth through fourteenth embodiments) is orally administered to a subject.

[0064] In a sixteenth embodiment, ALZ-801 as defined herein (including any one of the first, second, and sixth through fourteenth embodiments) is formulated as a tablet, capsule, liquid, orally disintegrating 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 fourteenth embodiments) is formulated as a capsule. In some aspects of the sixteenth embodiment, ALZ-801 as defined herein (including any one of the first, second, and sixth through fourteenth embodiments) is formulated as 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 fourteenth embodiments) is formulated as a sustained-release capsule. In still other aspects of the sixteenth embodiment, each capsule contains approximately 265 mg of ALZ-801.

[0065] example

[0066] The disease-modifying effect of ALZ-801 (valiltramiprosate) was evaluated in a Phase 2 trial in patients with early Alzheimer's disease. The study enrolled 84 patients with early AD who carried the APOE4 / 4 or APOE3 / 4 genotype and had an MMSE score 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 the subjects was 26 (mean age 69 years, 52% were female). For CSF determination, the subjects were amyloid PET positive or A+ / T+. The CSF criteria were: Aβ42 / 40x10 ratio <0.61 and p-tau 181 >61 pg / ml. CSF was assessed at week 52, and plasma biomarkers were assessed at each visit.

[0067] Subjects treated with ALZ-801 showed significant effects on core plasma biomarkers of AD. Plasma levels of both Aβ40 and Aβ42 showed a biphasic response compared to baseline levels. See, Figure 1 and Figure 2 Aβ40 showed a significant early increase at 13 weeks, followed by a significant decrease of approximately 5% at 52 weeks. Figure 1 Aβ42 showed a significant increase at 26 weeks, followed by a significant decrease of approximately 5% at 52 weeks. Figure 2 Plasma p-tau decreased significantly starting at 13 weeks and was reduced by 41% by 52 weeks. Figure 3 These effects were associated with benefits on a composite cognitive outcome testing memory and learning ability. When compared to a matched external control group in the ADNI-1 observational study, ALZ-801 demonstrated a significant reduction in HV atrophy of approximately 19-23%. The HV preservation effect was associated with cognitive benefits (Spearman's coefficient r = 0.27, p = 0.02).

[0068] After more than one year of treatment with ALZ-801, no subjects experienced vasogenic edema (ARIA-E or ARIA-H) or major bleeding events. Given the safety profile of the drug and its ability to reduce Aβ40, which in turn presumably improves the overall health and function of small and medium-sized cortical vessels, the following dosing regimen is considered a safe and effective approach to removing amyloid plaques in subjects with AD:

[0069] Phase 1: 265 mg ALZ-801 administered BID for at least 1 year;

[0070] Phase 2: An effective amount of the amyloid plaque clearing agent ALZ-801, 265 mg, administered BID over a period of approximately 6 to 12 months, or until the patient obtains a negative amyloid PET scan result; and

[0071] Phase 3: The amyloid plaque clearing agent was discontinued and 265 mg ALZ-801 was continued BID thereafter.

[0072] Although we have described many embodiments of the present invention, it is apparent that our basic examples can be modified to provide other embodiments utilizing the compounds and methods of the present invention. It will be understood, therefore, that the scope of the invention will be limited by the appended claims rather than by the specific embodiments presented by way of example.

[0073] All references cited throughout this application (including literature references, issued patents,

[0074] The contents of the patent applications and co-pending patent applications are hereby incorporated by reference

[0075] Unless otherwise defined, all technical and scientific terms used herein are

[0076] The meanings generally known to those skilled in the art.

Claims

1. 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 tramiphasat, tramiphasat prodrug, active tramiphasat metabolite, or a deuterated form of any one of the foregoing within a first period of time; b. co-administering to the subject during a second period of time: i. an effective amount of tramisater, a tramisater prodrug, an active tramisater metabolite, or a deuterated form of any of the foregoing; and ii. an effective amount of an amyloid plaque clearing agent; and c. thereafter administering to the subject an effective dose of tramiphaser, a tramiphaser prodrug, an active tramiphaser metabolite, or a deuterated form of any of the foregoing.

2. The method of claim 1, wherein in each of steps a., b., and c., a tramiphet prodrug is administered to the subject, the tramiphet prodrug being a tramiphet amino acid prodrug.

3. The method of claim 2, wherein the tramisate amino acid prodrug has the following chemical formula:

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

5. The method of claim 1, wherein in each of steps a., b., and c., the subject is administered a tramiphetide metabolite having the following chemical formula:

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

7. The method of claim 6, wherein the amyloid plaque clearing agent is selected from lencanezumab, aducanumab, bapinezumab, solanezumab, cremizumab, and gantuzumab.

8. The method of claim 6, wherein the amyloid plaque clearing agent is lencanezumab or aducanumab.

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

10. The method of any one of claims 1-9, 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 method of claim 9, wherein the p-tau serum biomarker is p-tau 181 .

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

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

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

15. The method of any one of claims 1-13, wherein the second time period ends when the subject's amyloid PET scan result is negative.

16. The method of claim 14 or 15, wherein the amyloid plaque clearing agent is administered at a subtherapeutic dose.

17. The method of any one of claims 1-16, wherein the subject is being treated with an anticoagulant.

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

19. The method of any one of claims 1 to 18, wherein the subject is ApoE4 + Treating the subject.

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

21. The method of any one of claims 1-20, wherein the subject is treated only if the subject's MMSE score is ≥22.

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

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