Methods of treating a neurodegenerative disease

Abstract

The present disclosure provides a method of treating a neurodegenerative disease such as Alzheimer's disease in a subject. The method includes administering to the subject about 30 mg of AR1001 orally once daily, or a pharmaceutically acceptable salt thereof, and monitoring plasma phosphorylated tau 181 (pTau181) or phosphorylated tau 217 (pTau217) levels in the subject during treatment. The method may further include continuing AR1001 treatment if the subject's plasma pTau181 or pTau217 levels decrease during treatment. The subject may have mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia. The method may also include assessing the subject's cognitive function using one or more standardized tests during treatment. AR1001 may be administered in a pharmaceutical composition in the form of a tablet or capsule.

Description

METHODS OF TREATING A NEURODEGENERATIVE DISEASECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority of U. S. Provisional Application No. 63 / 710,879, filed October 23, 2024, and U. S. Provisional Application No. 63 / 851,156, filed July 25, 2025. The entirety of each of these prior applications is incorporated by reference herein.FIELD

[0002] The present disclosure relates to methods of treating a neurodegenerative disease. The neurodegenerative disease may be an amyloidosis-associated condition, and more particularly, Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, preclinical Alzheimer’s disease, using ARI 001, a phosphodiesterase-5 inhibitor.BACKGROUND

[0003] Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, memory- loss, and behavioral changes. It is the most common cause of dementia, affecting millions of people worldwide. The pathological hallmarks of AD include the accumulation of amyloid-beta (Ap) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein in the brain.

[0004] Despite decades of research, the exact mechanisms underlying AD pathogenesis remain incompletely- understood. Current therapeutic approaches for AD are limited and primarily focus on managing symptoms rather than modifying disease progression. Approved medications include cholinesterase inhibitors and N-methyl-D-aspartate (NMD A) receptor antagonists, which provide modest sy mptomatic relief but do not alter the underlying disease course.

[0005] The complex nature of AD pathology presents significant challenges tor developing effective treatments. Multiple pathways and processes are implicated in AD, including neuroinflammation, oxidative stress, synaptic dysfunction, and neuronal loss. Thismultifaceted pathology suggests that targeting a single mechanism may be insufficient to meaningfully impact disease progression.

[0006] There is a growing recognition of the potential benefits of multi-target therapeutic approaches for AD. Compounds that can modulate multiple pathways involved in AD pathogenesis may offer advantages over single-target therapies. Additionally, repurposing existing drugs with established safety profiles for AD treatment has gained interest as a strategy to accelerate drug development.

[0007] Biomarkers play an increasingly important role in AD research and clinical management. Blood-based biomarkers, such as plasma levels of phosphorylated tau (pTau), have shown promise for early detection and monitoring of AD pathology. However, further research is needed to fully validate and implement these biomarkers in clinical practice.

[0008] As the global population ages, the prevalence of AD is expected to rise dramatically in the coming decades. This impending health crisis underscores the urgent need for novel therapeutic approaches that can effectively modify disease progression and improve outcomes for individuals affected by AD,SUMMARY

[0009] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.

[0010] Embodiments of the present disclosure provide a method of treating a neurodegenerative disease in a subject, the method comprising: obtaining a plasma sample from the subject; determining a level of phosphorylated tau 217 (pTau217) in the plasma sample; and administering to the subject a therapeutically effective amount of mirodenafil or a pharmaceutically acceptable salt thereof

[0011] Embodiments of the present disclosure provide mirodenafil or a pharmaceutically acceptable salt thereof for use in a method of treating a neurodegenerative disease in a subject, the method comprising: obtaining a plasma sample from the subject; determining a level of phosphorylated tau 217 (pTau217) in the plasma sample; and administering to the subject a therapeutically effective amount of mirodenafil or the pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the administering is performed when the levelexceeds a predetermined value of at least about 0.185 pg / ml.

[0013] In some embodiments, the administering is performed when the level exceeds a predetermined value ranging from about 0.01 pg / ml to about 10 pg / ml, preferably from about 0.041 pg / ml to about 5.028 pg / ml.

[0014] In some embodiments, the therapeutically effective amount is from about 10 mg to about 50 mg per day.

[0015] In some embodiments, the therapeutically effective amount is about 30 mg per day.

[0016] In some embodiments, the administering is performed orally.

[0017] In some embodiments, the administering is performed once daily.

[0018] In some embodiments, the method further comprises monitoring the level during or after the administering.

[0019] In some embodiments, the administering is repeated if the level is less than the predetermined value during or after the administering.

[0020] In some embodiments, the neurodegen erative disease is an amyloidosis-associated condition, dementia, Parkinson's disease (PD), Parkinson’s disease dementia, Dementia with Lewy body (DLB), Alzheimer's disease (AD), Huntington's disease (HD), Multiple sclerosis (MS), Vascular Dementia (VaD), Amyotrophic Lateral Sclerosis (ALS), Down’s syndrome dementia, or frontotemporal dementia.

[0021] In some embodiments, the amyloidosis-associated condition is Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, early-on set Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, or preclinical Alzheimer’s disease.

[0022] In some embodiments, the amyloidosis-associated condition is mild cognitive impairment, due to Alzheimer's disease or mild Alzheimer's disease dementia.

[0023] In some embodiments, the method further comprises assessing cognitive function of the subject using one or more standardized tests.

[0024] In some embodiments, the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini-Mental State Examination (MMSE).

[0025] Embodiments of the present disclosure provide a method of treating a neurode generative disease in a subject, the method comprising: obtaining a plasma samplefrom the subject; determining a ratio between a level of phosphorylated tau 217 (pTau217) and a level of amyloid beta 42 (A^42) in the plasma sample; and administering to the subject a therapeutically effective amount of mirodenafil or a pharmaceutically acceptable salt thereof.

[0026] Embodiments of the present disclosure provide mirodenafil or a pharmaceutically acceptable salt thereof for use in a method of treating a neurodegenerative disease in a subject, the method comprising: obtaining a plasma sample from the subject; determining a ratio between a level of phosphorylated tau 217 (pTau217) and a level of amyloid beta 42 (Ap42) in the plasma sample; and administering to the subject a therapeutically effective amount of mirodenafil or the pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the administering is performed when the ratio exceeds a predetermined value of at least about 0.00370.

[0028] In some embodiments, the administering is performed when the ratio exceeds a predetermined value ranging from about 0.001 to about 10, preferably from about 0.0019 to about 0.4788.

[0029] In some embodiments, the therapeutically effective amount is from about 10 mg to about 50 mg per day.

[0030] In some embodiments, the therapeutically effective amount is about 30 mg per day.

[0031] In some embodiments, the administering is performed orally.

[0032] In some embodiments, the administering is performed once daily.

[0033] In some embodiments, the method further comprises monitoring the ratio during or after the administering.

[0034] In some embodiments, the administering is repeated if the ratio is less than the predetermined value during or after the administering.

[0035] In some embodiments, the neurodegenerative disease is an amyloidosis-associated condition, dementia, Parkinson's disease (PD), Parkinson’s disease dementia, Dementia with Lewy body (DLB), Alzheimer's disease (AD), Huntington's disease (HD), Multiple sclerosis (MS), Vascular Dementia (VaD), Amyotrophic Lateral Sclerosis (ALS), Down’s syndrome dementia, or frontotemporal dementia.

[0036] In some embodiments, the amyloidosis-associated condition is Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's diseasedementia, prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, or preclinical Alzheimer's disease.

[0037] In some embodiments, the amyloidosis-associated condition is mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia.

[0038] In some embodiments, the method further comprises assessing cognitive function of the subject using one or more standardized tests.

[0039] In some embodiments, the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini-Mental State Examination (MMSE).

[0040] Embodiments of the present disclosure provide a method of treating a neurodegenerative disease in a subject, the method comprising: obtaining a plasma sample from the subject; determining a level of phosphorylated tau 181 (pTaul 81) in the plasma sample; and administering to the subject a therapeutically effective amount of mirodenafil or a pharmaceutically acceptable salt thereof.

[0041] Embodiments of the present disclosure provide mirodenafil or a pharmaceutically acceptable salt thereof for use in a method of treating a neurodegenerative disease in a subject, the method comprising: obtaining a plasma sample from the subject; determining a level of phosphorylated tau 181 (pTaulSl) in the plasma sample; and administering to the subject a therapeutically effective amount of mirodenafil or the pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the administering is performed when the level exceeds a predetermined value of at least about 2.2 pg / ml, preferably at least about 5.0 pg / ml.

[0043] In some embodiments, the administering is performed when the level exceeds a predetermined value ranging from about 0.1 pg / ml to about 100 pg / ml, preferably from about 1.05 pg / ml to about 12.33 pg / ml.

[0044] In some embodiments, the therapeutically effective amount is from about 10 mg to about 50 mg per day.

[0045] In some embodiments, the therapeutically effective amount is about 30 mg per day.

[0048] In some embodiments, the administering is performed orally.

[0047] In some embodiments, the administering is performed once daily.

[0048] In some embodiments, the method further comprises monitoring the levelduring or after the administering.

[0049] In some embodiments, the administering is repeated if the level is less than the predetermined value during or after the administering.

[0050] In some embodiments, the neurodegenerative disease is an amyloidosis-associated condition, dementia, Parkinson's disease (PD), Parkinson’s disease dementia, Dementia with Lewy body (DLB), Alzheimer's disease (AD), Huntington's disease (HD), Multiple sclerosis (MS), Vascular Dementia (VaD), Amyotrophic Lateral Sclerosis (ALS), Down’s syndrome dementia, or frontotemporal dementia.

[0051] In some embodiments, the amyloidosis-associated condition is Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, or preclinical Alzheimer’s disease.

[0052] In some embodiments, the amyloidosis-associated condition is mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia,

[0053] In some embodiments, the method further comprises assessing cognitive function of the subject using one or more standardized tests.

[0054] In some embodiments, the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini-Mental State Examination (MMSE).

[0055] Embodiments of the present disclosure provide a method of a neurodegenerative disease in a subject, the method comprising: administering to the subject, about 30 mg of mirodenafil or a pharmaceutically acceptable salt thereof orally once daily; and monitoring a level of phosphorylated tau 217 (pTau217) in a plasma of the subject during or after the administering.

[0056] Embodiments of the present disclosure provide mirodenafil or a pharmaceutically acceptable salt thereof for use in a method of treating a neurodegenerative disease in a subject, the method comprising: administering to the subject about 30 rng of mirodenafil or a pharmaceutically acceptable salt thereof orally once daily; and monitoring a level of phosphorylated tau 217 (pTau217) in a plasma of the subject during or after the administering.

[0057] In some embodiments, the administering is repeated if the level is less than that prior to the administering.

[0058] In some embodiments, the neurodegenerative disease is an amyloidosis-associated condition, dementia, Parkinson's disease (PD), Parkinson’s disease dementia. Dementia with Lewy body (DLB), Alzheimer's disease (AD), Huntington's disease (HD), Multiple sclerosis (MS), Vascular Dementia (VaD), Amyotrophic Lateral Sclerosis (ALS), Down’s syndrome dementia, or frontotemporal dementia.

[0059] In some embodiments, the amyloidosis-associated condition is Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, or preclinical Alzheimer's disease.

[0060] In some embodiments, the amyloidosis-associated condition is mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia.

[0061] In some embodiments, the method further comprises assessing the subject's cognitive function using one or more standardized tests.

[0062] In some embodiments, the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini-Mental State Examination (MMSE).

[0063] In some embodiments, the level after 26 weeks is at least about 10% less than that prior to the administering.

[0064] In some embodiments, mirodenafil or the pharmaceutically acceptable salt thereof is in a tablet or a capsule.

[0065] In some embodiments, the method further comprises: obtaining a plasma sample from the subject before prior to the administering; and determining a baseline level of pTau217 in the plasma sample.

[0066] Embodiments of the present disclosure provide a method of treating a neurodegenerative disease in a subject, the method comprising: administering to the subject about 30 mg of mirodenafil or a pharmaceutically acceptable salt thereof orally once daily; and monitoring a ratio between a level of phosphorylated tau 217 (pTau217) and a level of amyloid beta 42 (Ap42) in a plasma of the subject during or after the administering.

[0067] Embodiments of the present disclosure provide mirodenafil or a pharmaceutically acceptable salt thereof for use in a method of treating a neurodegenerative disease in a subject, the method comprising: administering to the subject about 30 mg of mirodenafil or a pharmaceutically acceptable salt thereof orally once daily; and monitoring aratio between a level of phosphorylated tau 217 (pTau217) and a level of amyloid beta 42 (A 42) in a plasma of the subject during or after the administering.

[0068] In some embodiments, the administering is repeated if the ratio is less than that prior to the administering.

[0069] In some embodiments, the neurodegenerative disease is an amyloidosis-associated condition, dementia, Parkinson’s disease (PD), Parkinson’s disease dementia, Dementia with Lewy body (DLB), Alzheimer's disease (AD), Huntington's disease (HD), Multiple sclerosis (MS), Vascular Dementia (VaD), Amyotrophic Lateral Sclerosis (ALS), Down’s syndrome dementia, or frontotemporal dementia.

[0070] In some embodiments, the amyloidosis-associated condition is Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, or preclinical Alzheimer’s disease.

[0071] In some embodiments, the amyloidosis-associated condition is mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia.

[0072] In some embodiments, the method further comprises assessing the subject's cognitive function using one or more standardized tests.

[0073] In some embodiments, the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini-Mental State Examination (MMSE).

[0074] In some embodiments, the ratio after 26 weeks is at least about 10% less than that prior to the administering.

[0075] In some embodiments, mirodenafil or the pharmaceutically acceptable salt thereof is in a tablet or a capsule.

[0076] In some embodiments, the method further comprises: obtaining a plasma sample from the subject before prior to the administering; and determining a baseline ratio between a baseline level of pTau217 and a baseline level of Ap42 in the plasma sample.

[0077] Embodiments of the present disclosure provide a method of treating a neurodegenerative disease in a subject, the method comprising: administering to the subject about 30 mg of mirodenafil or a pharmaceutically acceptable salt thereof orally once daily; and monitoring a level of phosphorylated tau 181 (pTau181) in a plasma of the subject during or after the administering.

[0078] Embodiments of the present disclosure provide mirodenafil or a pharmaceutically acceptable salt thereof for use in a method of treating a neurodegenerative disease in a subject, the method comprising: administering to the subject about 30 mg of mirodenafil or a pharmaceutically acceptable salt thereof orally once daily; and monitoring a level of phosphorylated tau 181 (pTau 181) in a plasma of the subject during or after the administering.

[0079] In some embodiments, the administering is repeated if the level is less than that prior to the administering.

[0080] In some embodiments, the neurodegenerative disease is an amyloidosis-associated condition, dementia, Parkinson's disease (PD), Parkinson’s disease dementia. Dementia with Lewy body (DLB), Alzheimer's disease (AD), Huntington's disease (HD), Multiple sclerosis (MS), Vascular Dementia (VaD), Amyotrophic Lateral Sclerosis (ALS), Down’s syndrome dementia, or frontotemporal dementia.

[0081] In some embodiments, the amyloidosis-associated condition is Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, or preclinical Alzheimer's disease.

[0082] In some embodiments, the amyloidosis-associated condition is mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia.

[0083] In some embodiments, the method further comprises assessing the subject's cognitive function using one or more standardized tests,

[0084] In some embodiments, the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini-Mental State Examination (MMSE).

[0085] In some embodiments, the level after 26 weeks is at least about 10% less than that prior to the administering.

[0088] In some embodiments, mirodenafil or the pharmaceutically acceptable salt thereof is in a tablet or a capsule.

[0087] In some embodiments, the method further comprises: obtaining a plasma sample from the subject before prior to the administering; and determining a baseline level of pTau181 in the plasma sample.

[0088] Embodiments of the present disclosure provide a method for identifying asubject responsive to early Alzheimer's disease treatment using mirodenafil or a pharmaceutically acceptable salt thereof, the method comprising: obtaining a plasma sample from a candidate; determining a level of phosphorylated tau 217 (pTau217) in the plasma sample; and selecting the subject based on the level exceeding a predetermined value

[0089] In some embodiments, the predetermined value is at least about 0.185 pg / ml.

[0090] In some embodiments, the predetermined value is about 0.01 pg / ml to about 10 pg / ml, preferably from about 0.041 pg / ml to about 5.028 pg / ml.

[0091] In some embodiments, the method further comprises administering from about 10 mg to about 50 mg of mirodenafil or the pharmaceutically acceptable salt thereof orally once daily to the subject.

[0092] In some embodiments, the method further comprises administering about 30 mg of mirodenafil or the pharmaceutical] y acceptable salt thereof orally once daily to the subject.

[0093] In some embodiments, the method further comprises monitoring the level during or after the administering.

[0094] In some embodiments, the administering is repeated if the level is less than the predetermined value during or after the administering.

[0095] In some embodiments, the subject has mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer's disease dementia.

[0098] In some embodiments, the method further comprises assessing cognitive function of the subject using one or more standardized tests.

[0097] In some embodiments, the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Di sease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini-Mental State Examination (MMSE).

[0098] Embodiments of the present disclosure provide a method for identifying a subject responsive to early Alzheimer's disease treatment using mirodenafil or a pharmaceutically acceptable salt thereof, the method comprising: obtaining a plasma sample from a candidate; determining a ratio between a level of phosphorylated tau 217 (pTau217) and a level of amyloid beta 42 (Ap42) in the plasma sample; and selecting the subject based on the ratio exceeding a predetennined value.

[0099] In some embodiments, the predetermined value is at least about 0.00370.

[0100] In some embodiments, the predetermined value is from about 0.001 to about 10, preferably from about 0.0019 to about 0.4788.

[0101] In some embodiments, the method further comprises administering from about 10 mg to about 50 mg of mirodenafil or the pharmaceutically acceptable salt thereof orally once daily to the subject.

[0102] In some embodiments, the method further comprises administering about 30 mg of mirodenafil or the pharmaceutically acceptable salt thereof orally once daily to the subject.

[0103] In some embodiments, the method further comprises monitoring the ratio during or after the administering.

[0104] In some embodiments, the administering is repeated if the ratio is less than the predetermined value during or after the administering.

[0105] In some embodiments, the subject has mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia.

[0108] In some embodiments, the method further comprises assessing cognitive function of the subject using one or more standardized tests.

[0107] In some embodiments, the one or more standardi zed tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini-Mental State Examination (MMSE).

[0108] Embodiments of the present disclosure provide a method for identifying a subject responsive to early Alzheimer's disease treatment using mirodenafil or a pharmaceutically acceptable salt thereof, the method comprising: obtaining a plasma sample from a candidate; determining a level of phosphorylated tau 181 (pTau181) in the plasma sample; and selecting the subject based on the level exceeding a predetermined value

[0109] In some embodiments, the predetermined value is at least about 2.2. pg / ml, preferably at least about 5.0 pg / ml.

[0110] In some embodiments, the predetermined value is from about 0.1 pg / ml to about 100 pg / ml, preferably from about 1.05 pg / ml to about 12.33 pg / ml.

[0111] In some embodiments, the method further comprises administering from about 10 mg to about 50 mg of mirodenafil or the pharmaceutically acceptable salt thereof orally once daily to the subject.

[0112] In some embodiments, the method further comprises administering about 30 mg of mirodenafil or the pharmaceutically acceptable salt thereof orally once daily to the subject.

[0113] In some embodiments, the method further comprises monitoring the levelduring or after the administering.

[0114] In some embodiments, the administering is repeated if the level is less than the predetermined value during or after the administering.

[0115] In some embodiments, the subject has mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia.

[0116] In some embodiments, the method further comprises assessing cognitive function of the subject using one or more standardized tests.

[0117] In some embodiments, the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini-Mental State Examination (MMSE).

[0118] Embodiments of the present disclosure provides a pharmaceutical composition comprising: mirodenafil or a pharmaceutically acceptable salt thereof in an amount of about 10 mg to about 50 mg; a filler or a binder in an amount of about 40% to about 80% w / w of the pharmaceutical composition; a disintegrant in an amount of about 10% to about 30% w / w of the pharmaceutical composition; a lubricant, in an amount of about 1% to about 5% w / w of the pharmaceutical composition; and a glidant in an amount of about 1 % to about 5% w / w of the pharmaceutical composition.

[0119] In some embodiments, the amount of mirodenafil or the pharmaceutically acceptable salt thereof is about 30 mg.

[0120] In some embodiments, the filler comprises microcrystalline cellulose, anhydrous lactose, spray-dried lactose, dibasic calcium phosphate, glucose, dextrose, fructose. lactose, mannitol, or sorbitol.

[0121] In some embodiments, the filler is microcrystalline cellulose.

[0122] In some embodiments, the binder comprises microcrystalline cellulose, polyvinylpyrrolidone, sucrose, liquid glucose, acacia, tragacanth, gelatin, alginic acid, cellulose, methyl cellulose, ethyl cellulose, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose, sodium carboxy methyl cellulose, polyethylene glycol (PEG), polyvinyl alcohols, or poly methacrylates.

[0123] In some embodiments, the binder is microcrystalline cellulose.

[0124] In some embodiments, the amount of the filler or the binder is about 60% to about 65% w / w of the pharmaceutical composition.

[0125] In some embodiments, the amount of the filler or the binder is about 61.75% w / w of the pharmaceutical composition.

[0126] In some embodiments, the amount of the filler is about 61.75% w / w of the pharmaceutical composition.

[0127] In some embodiments, the disintegrant comprises croscarmeliose sodium, crospovidone, sodium starch glycolate, Starch NF, Starch 1500, or alginic acid.

[0128] In some embodiments, the disintegrant is croscarmellose sodium.

[0129] In some embodiments, the amount of the disintegrant is about 15% to about 25% w / w of the pharmaceutical composition.

[0130] In some embodiments, the amount of the disintegrant is about 20% w / w of the pharmaceutical composition.

[0131] In some embodiments, the lubricant comprises magnesium stearate, sodium stearyl fumarate, glyceryl dibehenate, stearic acid, talc, colloidal silicon dioxide, or sodium stearyl fumarate.

[0132] In some embodiments, the lubricant is magnesium stearate.

[0133] In some embodiments, the amount of the lubricant is about 1.5% to about 2% w / w of the pharmaceutical composition,

[0134] In some embodiments, the amount of the lubricant is about 1.75% w / w of the pharmaceutical composition.

[0135] In some embodiments, the glidant comprises colloidal silicon dioxide, hydrous magnesium silicate, or calcium silicate.

[0138] In some embodiments, the glidant is colloidal silicon dioxide.

[0137] In some embodiments, the amount of the glidant is about 1.25% to about 1.75% w / w of the pharmaceutical composition.

[0138] In some embodiments, the amount of the glidant is about 1.5% w / w of the pharmaceutical composition.

[0139] Embodiments of the present disclosure provide a dosage form comprising: an intragranular component comprising: mirodenafil or a pharmaceutically acceptable salt thereof in an amount of about 10 mg to about 50 mg; an intragranular filler or an intragranular binder in an amount of about 40% to about 80% w / w of the dosage form; an intragranular disintegrant in an amount of about 0.1% to about 5% w / w of the dosage form; an intragranular lubricant in an amount of about 0.1% to about 5% w / w of the dosage form; and an intragranular glidant in an amount of about 0.1% to about 5% w / w of the dosage form; and an extragranular component comprising: an extragranular disintegrant in an amount of about 10% to about 25% w / w of the dosage form; an extragranular lubricant in an amount ofabout 0.1% to about 5% w / w of the dosage form; and an extragranular glidant in an amount of about 0.1% to about 5% w / w of the dosage form, wherein the intragranular component constitutes from about 60% to about 90% w / w of the dosage form.

[0140] In some embodiments, the amount of mirodenafil or the pharmaceutically acceptable salt thereof is about 30 mg.

[0141] In some embodiments, the intragranular component constitutes from about 75% to about 85% w / w of the dosage form.

[0142] In some embodiments, the intragranular component constitutes from about 80.75% w / w of the dosage form.

[0143] In some embodiments, the intragranular filler comprises microcrystalline cellulose, dibasic calcium phosphate, glucose, dextrose, fructose, lactose, mannitol, or sorbitol.

[0144] In some embodiments, the intragranular filler is microcrystalline cellulose.

[0145] In some embodiments, the intragranular binder comprises microcrystalline cellulose, polyvinylpyrrolidone, sucrose, liquid glucose, acacia, tragacanth, gelatin, alginic acid, cellulose, methyl cellulose, ethyl cellulose, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose, sodium carboxy methyl cellulose, polyethylene glycol (PEG), polyvinyl alcohols, or polymethacrylates.

[0146] In some embodiments, the intragranular binder is microcrystalline cellulose.

[0147] In some embodiments, the amount of the intragranular filler or the intragranular binder is about 60% to about 65% w / w of the dosage form.

[0148] In some embodiments, the amount of the intragranular filler or the intragranular binder is about 61.75% w / w of the dosage form.

[0149] In some embodimetns, the intragranular disintegrant comprises croscarmellose sodium, crospovidone, sodium starch glycolate, Starch NF, Starch 1500, or alginic acid.

[0150] In some embodiments, the intragranular disintegrant is croscarmellose sodium.

[0151] In some embodiments, the amount of the intragranular disintegrant is about 2% to about 3% wAv of the dosage form.

[0152] In some embodiments, the amount of the intragranular disintegrant is about 2.5% w / w of the dosage form.

[0153] In some embodiments, the intragranular lubricant comprises magnesium stearate, sodium stearyl fumarate, glyceryl dibehenate, stearic acid, talc, colloidal silicon dioxide, or sodium stearyl fumarate.

[0154] In some embodiments, the intragranular lubricant is magnesium stearate.

[0155] In some embodiments, the amount of the intragranular lubricant is about 0.5% to about 1.5% w / w of the dosage form.

[0156] In some embodiments, the amount of tire intragranular lubricant is about 1 % w / w of the dosage form.

[0157] In some embodiments, the intragranular glidant comprises colloidal silicon dioxide, hydrous magnesium silicate, or calcium silicate.

[0158] In some embodiments, the intragranular glidant is colloidal silicon dioxide.

[0159] In some embodiments, the amount of the intragranular glidant is about 0.25% to about 0.75% w / w of the dosage form.

[0160] In some embodiments, the amount of the intragranular binder is about 0.5% w / w of the dosage form.

[0181] In some embodiments, the extragranular disintegrant comprises croscarmellose sodium, crospovidone, sodium starch glycolate, Starch NF, Starch 1500, or alginic acid.

[0162] In some embodiments, the extragranular disintegrant is croscarmellose sodium.

[0163] In some embodiments, the amount of the extragranular disintegrant is about 1 % to about 20% w / w of the dosage form.

[0164] In some embodiments, the amount of the extragranular disintegrant is about 17.5% w / w of the dosage form.

[0165] In some embodiments, the extragranular lubricant comprises magnesium stearate, sodium stearyl fumarate, glyceryl dibehenate, stearic acid, talc, colloidal silicon dioxide, or sodium stearyl fumarate.

[0166] In some embodiments, the extragranular lubricant is magnesium stearate.

[0167] In some embodiments, the amount of the extragranular lubricant is about 0.5% to about 1% w / w of the dosage form.

[0168] In some embodiments, the amount of the extragranular lubricant is about 0.75% w / w of the dosage form.

[0169] In some embodiments, the extragranular glidant comprises colloidal silicondioxide, hydrous magnesium silicate, or calcium silicate.

[0170] In some embodiments, the extragranular glidant is colloidal silicon dioxide.

[0171] In some embodiments, the amount of the extragranular glidant is about 0.5% to about 1.5% w / w of the dosage form.

[0172] In some embodiments, the amount of the extragranular glidant is about 1 % w / w of the dosage form.

[0173] In some embodiments, the dosage form is a tablet or a capsule.

[0174] In some embodiments, the dosage form further comprises a film coating.

[0175] In some embodiments, the film coating comprises Opadry White, Sepifilm White, or Aquarius Prime White.

[0176] In some embodiments, the film coating is Opadry White.

[0177] Embodiments of the present disclosure provide a method of manufacturing the dosage form, comprising: preparing the intragranular component via dry granulation; applying the extragranular component to the intragranular component to form a blend; and compressing the blend,

[0178] In some embodiments, the method further comprises applying the film coating.

[0179] The foregoing general description of the illustrative embodiments and the following detailed description thereof are merely exemplary aspects of the teachings of this disclosure and are not restrictive.BRIEF DESCRIPTION OF THE DRAWINGS

[0180] Those of skill in the art will understand that the drawings, described below, are for illustrative purposes only. The drawings are not intended to limit the scope of the present teachings in any way.

[0181] Figs, 1A-1B show's trial summary' and patient disposition. Fig. 1A illustrates an exemplary study design. Fig. IB illustrates a patient disposition flowchart for a clinical trial of ARI 001, according to aspects of the present disclosure.

[0182] Figs. 2. A-2H show changes in biomarker levels over time for different treatment groups in a clinical study, according to aspects of the present disclosure.

[0183] Figs. 3A-3B depict a primary endpoint analysis with baseline pTau 181 as a covariate, according to aspects of the present disclosure.

[0184] Figs. 4A-4C illustrate primary endpoint and pTau181 changes in a highpTau subgroup (> 5.0 pg / ml), according to an embodiment. Figs. 4D-4E illustrate primary endpoint and pTaulS 1 changes in a low pTau subgroup (< 5.0 pg / ml), according to an embodiment. Fig. 4F illustrates primary endpoint and pTau217 change from baseline (pg / ml) at Week 26 in sub-group (pTau217 > 0.185 pg / ml). Fig. 4G illustrates primary endpoint and pTau217 / Ap42 ratio change from baseline (pg / ml) at Week 26 sub-group (pTau217 / Ap42 ratio > 0.00371).

[0185] Figs. 5A-5B illustrate changes in cGMP and BDNF in mice model. PDE5 inhibition with AR 1001 resulted in increase of cGMP / PKG / pCREB / BDNF signaling. cGMP levels in the hippocampus; ARlOOl was orally administered via gavage at the doses of 3, 6, and 9 mg / kg once daily early morning after overnight fasting for 7 days; cGMP levels were measured from the hippocampi dissected 15 min after the final dose (Fig. 5A). BDNF levels in the hippocampus; AR1001 was orally administered via gavage at the doses of 3, 6, and 9 mg / kg once daily early morning after overnight fasting for 7 days; cGMP levels were measured from the hippocampi dissected 15 min after the final dose (Fig. 5B). *p < 0.05, **p < 0.01 between indicated groups.

[0186] Fig. 6 illustrates subgroup analysis - placebo AD drug split, and 30mg, pTau-181.

[0187] Fig. 7 illustrates subgroup analysis - placebo AD dnig split, and 30mg, pTau-217.

[0188] Fig. 8 illustrates subgroup analysis - placebo AD drug split, and 30mg, Adas-cog 13.DETAILED DESCRIPTION

[0189] Abbreviations and Definitions

[0190] To facilitate understanding of the invention, a number of terms and abbreviations as used herein are defined below as follows:

[0191] All patents, applications, published applications and other publications cited herein are incorporated by reference in their entirety. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. The chemical structures and formulae set forth herein are constructed according to the standard rales of chemical valency known in the chemical arts. Should a discrepancy exist between a depicted structure and a name given forthat structure, the depicted structure is to be accorded more weight.Where the stereochemistry of a structure or a portion of a structure is not indicated in a depicted structure or a portion of the depicted structure, the depicted structure is to be interpreted as encompassing all of its possible stereoisomers.

[0192] Any methods, devices and materials similar or equivalent to those described herein can be used hi the practice of this invention. Hie following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. Headings used herein are for organizational purposes only and in no way limit the invention described herein.

[0193] The terms “therapies” and “therapy” refer to any protocol(s), method(s), and / or agent(s) that can be used in the prevention, treatment, management, and / or amelioration of a disease, disorder, or condition or one or more symptoms thereof. In certain instances the term refers to active agents such as an anti-neurodegenerative agent described herein. The terms “therapy” and “therapy” can also refer to anti-viral therapy, anti-bacterial therapy, anti-fungal therapy, anti-neurodegenerative therapy, biological therapy, supportive therapy, and / or other therapies useful in treatment, management, prevention, or amelioration of a disease, disorder, or condition or one or more symptoms thereof known to one skilled in the art, for example, a medical professional such as a physician.

[0194] The term “patient” or “subject” refers to a mammal, such as a human, bovine, rat, mouse, dog, monkey, ape, goat, sheep, cow, or deer. Generally a patient as described herein is human. The subject according to the present disclosure may be a human subject suffering from a neurodegenerative disease such as Alzheimer's disease (e.g., AD, Alzheimer's type dementia) or a human subject possibly suffering from a neurodegenerative disease such as Alzheimer's disease. In these cases, whether a human subject is suffering from or likely to suffer from a neurodegenerative disease such as Alzheimer's disease may be determined by the methods disclosed in the Examples provided herein, and by methods commonly practiced by those skilled in the art. Human subjects suffering from or potentially suffering from a neurodegenerative disease such as Alzheimer's disease include, for example, those for whom a cognitive function test such as the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or the Mini-Mental State Examination (MMSE) suggests a decline in cognitive function or the possibility thereof. The subject may be a human subject with brain deposits or cerebrospinal fluid concentrations of proteins known to accumulate in neurodegenerativedisease patients such as Alzheimer's disease patients, such as amyloid-P and tau proteins, a human subject with decreased metabolic function of the brain or atrophy of brain tissue.

[0195] The terms “treating” or “treatment” refer to any indicia of success or amelioration of the progression, severity, and / or duration of a disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a patient’s physical or mental well-being.

[0196] The term “administering” refers to the act of delivering a combination or composition described herein into a subject by such routes as oral, mucosal, topical, suppository, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration. Parenteral administration includes intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Administration generally occurs after the onset of the disease, disorder, or condition, or its symptoms but, in certain instances, can occur before the onset of the disease, disorder, or condition, or its symptoms (e.g., administration for patients prone to such a disease, disorder, or condition).

[0197] The terms “ARI 001” and “mirodenafil” refer to the chemical compound, 5-ethyl-2-[5-[4-(2-hydroxyethyl)piperazin-1-yl]sulfonyl-2-propoxyphenyl]-7-propyl-3H-pyrrolo[3,2-d]pyrimidin-4-one, which has the following chemical formula:The terms “ARI 001” and “mirodenafil” also refer to the free base form and any pharmaceutically acceptable salts, such as an HC1 salt or a 2. HCI salt. Mirodenafii is a member of the class of pyrrol opyrimidines that is 3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one having a 5-{[4-(2-hydroxyethyl)piperazin-l-yl]sulfonyl}-2-propoxyphenyl group at position 2, ethyl group at position 5, and a propyl group at position 7. It is a phosphodiesterase type 5 inhibitor which is used for the treatment of erectile dysfunction. It has a role as an EC 3.1.4.35 (3',5'-cyclic-GMP phosphodiesterase) inhibitor and a vasodilatoragent. It is a sulfonamide, a pyrrolopyrimidine, a N-alkylpiperazine, a primary alcohol and an aromatic ether. Mirodenafil has been used in trials studying the treatment and supportive care of Kidney Diseases, Urologic Diseases, Renal Insufficiency, Erectile Dysfunction, and Male Erectile Dysfunction. More information about mirodenafil can be found in U. S. Pat. No. 9,750,743, and at Kang, B. W., Kim, J., Cho, JY. etal. Phosphodiesterase 5 inhibitor mirodenafil ameliorates Alzheimer-like pathology and symptoms by multimodal actions. Alz Res Therapy 14, 92 (2.022). https: / / doi.org / 10.1186 / s13195-022-01034-3. Mirodenafil is commercially available from vendors including Cooke Chemical Co., Ltd. (#M4050735), AstaTech, Inc. (#C16519), and RR Scientific (#R772058), among others.

[0198] All doses or dosages recited herein for “AR1001” and “mirodenafil,” or the pharmaceutically acceptable salt thereof are based on the molecular weight of the 2HC1 salt thereof, unless otherwise stated. For example, administration of “ARI 001” or “mirodenafil,” or the pharmaceutically acceptable salt thereof at a dosage of 30 mg per day means administration of 30 mg of the 2HC1 salt of “ARI 001” or “mirodenafil” per day.

[0199] In some embodiments, the term “neurodegenerative disease” refers to a group of diseases including, but not limited to, Parkinson's disease (PD); sporadic or heritable dementia with Lewy bodies (DLB); pure autonomic failure (PAF) with a S deposition; multiple system atrophy (MSA); hereditary neurodegeneration with brain iron accumulation; and incidental Lewy body disease of advanced age; Alzheimer's disease of the Lewy body variant; Down's syndrome; progressive supranuclear palsy; essential tremor with Lewy bodies; familial parkinsonism with or without dementia resulting from a mutant gene and loci where no gene mutation has yet been identified; Creutzfeldt Jakob disease; bovine spongiform encephalopathy; secondary Parkinson disease / parkinsonism resulting from neurotoxin exposure / drug-induced parkinsonism with a -synuclein deposition; sporadic or heritable spinocerebellar ataxia; amyotrophic lateral sclerosis (ALS); idiopathic rapid eye movement sleep behavior disorder; and other conditions associated with central and / or peripheral a -synuclein accumulation in mammals accompanying a primary disease process. In some embodiments, the term “neurodegenerative disease” also refers to a group of diseases including, but not limited to, Alzheimer’ s disease. Vascular dementia, Frontotemporal dementia (FID), Lewy body dementia (LBD), Mixed dementia, Posterior cortical atrophy (PCA), Primary progressive aphasia (PPA), Corticobasal degeneration (CBD), and Progressive supranuclear palsy (PSP), idiopathic myeloma, amyloid polyneuropathy, amyloidcardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Down's syndrome. Scrapie, medullary carcinoma of the thyroid, isolated atrial amyloidosis, 2-microglobulm amyloidosis, inclusion body myositis, muscle wasting disease. Islets of Langerhans diabetes. Type 1 diabetes, insulinoma. Type 2 diabetes mellitus, hereditary cerebral hemorrhage amyloidosis (Dutch), amyloid A (reactive) amyloidosis, secondary’ amyloidosis, familial Mediterranean fever, familial amyloid nephropathy with urticaria and deafness (Muckle-wells Syndrome), amyloid lambda L-chain amyloidosis, amyloid kappa L-chain amyloidosis, idiopathic associated amyloidosis, myeloma-associated amyloidosis, macroglobulinemia-associated amyloidosis, A beta 2M amyloidosis (chronic hemodialysis), ATTR amyloidosis (familial amyloid polyneuropathy (Portuguese, Japanese, Swedish)), familial amyloid cardiomyopathy (Danish), isolated cardiac amyloidosis, systemic senile amyloidosis, AIAPP or amylin insulinoma, atrial natriuretic factor amyloidosis (isolated atrial amyloidosis), procalcitonin amyloidosis (medullary’ carcinoma of the thyroid),gelsolin amyloidosis (familial amyloidosis (Finnish)), cystatin C (hereditary cerebral hemorrhage with amyloidosis (Icelandic)), AApo-A-I amyloidosis (familial amyloidotic polyneuropathy-Iowa), AApo-A-II amyloidosis, traumatic brain injury, fibrinogen-associated amyloidosis, Creutzfeldt-J kob disease, Gertsmann-Straussler-Sche inker syndrome, bovine spongiform encephalitis, condition associated with homozygosity for the apolipoprotein E4 allele, and Huntington’s disease. In some embodiments, the tenn “neurodegenerative disease” also refers to a group of diseases including, but not limited to, dementia, Parkinson's disease (PD), Parkinson’ s disease dementia. Dementia with Lewy body (DLB), Alzheimer's disease (AD), Huntington's disease (HD), Multiple sclerosis (MS), Vascular Dementia (VaD), Amyotrophic Lateral Sclerosis (ALS), Down’ s syndrome dementia, frontotemporal dementia. In some embodiments, the term “neurodegenerative disease” also refers to a group of diseases including, but not limited to, an amyloidosis-associated condition.

[0200] The term “amyloidosis” refers to a group of diseases that involve the accumulation of amyloid proteins in the body. Amyloid proteins can be deposited in one part of the body, called localized amyloidosis, or in multiple parts, called systemic amyloidosis. Many forms of amyloidosis exist, and the disease can be classified into four groups: primary amyloidosis, secondary amyloidosis, hereditary amyloidosis, and amyloidosis associated with normal aging. Primary7amyloidosis (light chain amyloidosis) occurs with abnormalities ofplasma cells, and some people with primary' amyloidosis also have multiple myeloma (cancer of the plasma cells). Typical sites of amyloid buildup in primary amyloidosis are the heart, lungs, skin, tongue, thyroid gland, intestines, liver, kidneys, and blood vessels. Secondary amyloidosis may develop in response to various diseases that cause persistent infection or inflammation, such as tuberculosis, rheumatoid arthritis, and familial Mediterranean fever. Typical sites of amyloid buildup in secondary amyloidosis are the spleen, liver, kidneys, adrenal glands, and lymph nodes. Hereditary amyloidosis has been noted in some families, particularly those from Portugal, Sweden, and Japan. Tire amyloid-producing defect occurs because of mutations in specific proteins in the blood. Typical sites for amyloid buildup in hereditary amyloidosis are the nerves, heart, blood vessels, and kidney s. Alzheimer's disease is a type of localized amyloidosis where amyloid-beta proteins build up in the brain. This is the most common type of amyloidosis in humans and the most common form of demen tia. The ‘"amyloid hypothesis” is the prevailing theory- that Alzheimer's disease is caused by the accumulation of beta-amyloid proteins m the brain. Some studies have shown that amyloid triggers a binding of two proteins in the brain's neurons, which can lead to the rapid accumulation of tau proteins. Tau proteins are a primary driver of neurodegeneration in Alzheimer's disease. Amyloidosis can be caused by chronic inflammation or genetic mutation. There are many different types of amy loid proteins involved in amyloidosis, and each type of amyloid deposit can characterize a different disease.

[0201] The term “amyloidosis-associated condition” refers to a disease that is associated with amyloid deposition and can include but not be limited to Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, preclinical Alzheimer’s disease, idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Down's syndrome, Scrapie, medullary' carcinoma of the thyroid, isolated atrial amyloid, p2 -microglobulin amyloid in dialysis patients, inclusion body myositis, p2 -amyloid deposits in muscle wasting disease, and Islets of Langerhans diabetes Type II insulinoma. Type 2 diabetes mellitus, hereditary' cerebral hemorrhage amyloidosis (Dutch), amyloid A (reactive), secondary' amyloidosis, familial Mediterranean fever, familial amyloid nephropathy with urticaria and deafness (Muckle-wells Syndrome), amyloid lambda L-chain or amy loid kappa L-chain (idiopathic, myeloma or macroglobulinemia-associated) A beta 2M(chronic hemodialysis), ATTR (familial amyloid polyneuropathy (Portuguese, Japanese, Swedish)), familial amyloid cardiomyopathy (Danish), isolated cardiac amyloid, systemic senile amyloidoses, A1APP or amylin insulinoma, atrial nahiretic factor (isolated atrial amyloid), procalcitonin (medullary carcinoma of the thyroid), gelsolin (familial amyloidosis (Finnish)), cystatin C (hereditary cerebral hemorrhage with amyloidosis (Icelandic)), AApo-A-l (familial amyloidotic polyneuropathy ~Iowa), AApo-A-II (accelerated senescence in mice), head injuries (traumatic brain injury), dementia, fibrinogen-associated amyloid: and Asor or Pr P-27 (scrapie, Creutzfeld Jacob disease, Gertsmann-Straussler-Scheinker syndrome, bovine spongiform encephalitis) or in cases of persons who are homozygous for the apolipoprotein E4 allele, and the condition associated with homozygosity for the apolipoprotein E4 allele or Huntington's disease.

[0202] The term “early-onset Alzheimer’s disease” or “EO AD” refers to AD cases where symptoms appeal' before age 65. EOAD includes, but is not limited to: Genetic (Familial) Alzheimer's Disease and its phenotypic variants including Logopenic Variant Primary Progressive Aphasia, Posterior Cortical Atrophy, Behavioral / Dysexecutive Alzheimer's Disease, and Acalculia Variant.

[0203] As used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0204] As used herein, the term “pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient, or vehicle with which a compound is administered. Such earners can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, polyethylene glycols, glycerine, propylene glycol, or other synthetic solvents. Water is a preferred carrier when a compound is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. A compound, if desired, can also combine minor amount of wetting or emulsifying agents, or pH buffering agents such as acetates, citrates, or phosphates. Antibacterial agents such as a benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; and agents for the adjustment of tonicity such as sodium chloride or dextrose may also be a carrier. Methods for producing compounds in combination with carriers are known to those of skill in the art.

[0205] As used herein, the term “pharmaceutically acceptable salt” includes those salts of a pharmaceu tically acceptable compound formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, and tartaric acids, and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropyl amine, triethylamine, 2-ethylamino ethanol, histidine, and procaine. If the compound is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include acetic, benzene -sulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and the like. Particularly preferred are besylate, hydrobromic, hydrochloric, phosphoric, and sulfuric acids. If the compound is acidic, salts may be prepared from pharmaceutically acceptable organic and inorganic bases. Suitable organic bases include, but are not limited to, lysine, N, N’-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylene diamine, meglumine (N-methyl-glucamine) and procaine. Suitable inorganic bases include, but are not limited to, alkaline and earth -alkaline metals such as aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Methods for synthesizing such salts are known to those of skill in the art.

[0206] The term “therapeutically effective amount” refers to the amount of a therapy which is sufficient to accomplish a stated purpose or otherwise achieve the effect for which it is administered. An effective amount can be sufficient to reduce and / or ameliorate the progression, development, recurrence, severity and / or duration of a given disease, disorder or condition and / or a symptom related thereto. An effective amount can be a “therapeutically effective amount” which refers to an amount sufficient to provide a therapeutic benefit such as, for example, the reduction or amelioration of the advancement or progression of a given disease, disorder or condition, reduction or amelioration of the recurrence, development or onset of a given disease, disorder or condition, and / or to improve or enhance the prophylactic or therapeutic effect(s) of another therapy. A therapeutically effective amount of a composition described herein can enhance the therapeutic efficacy of another therapeutic agent.

[0207] The terms “therapies” and “therapy” and “therapeutic” refer to any protocol(s), method(s), and / or agent(s) that can be used in the prevention, treatment, management, and / or amelioration of a disease, disorder, or condition or one or more symptoms thereof.

[0208] Methods of Treating Amyloidosis-Associated Conditions

[0209] The following description sets forth exemplary aspects of the present disclosure. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure. Rather, the description also encompasses combinations and modifications to those exemplary aspects described herein.

[0210] The present disclosure relates to methods for treating a neurodegenerative disease such as Alzheimer's disease, a progressive neurodegenerative disease that is the most common cause of dementia worldwide. Alzheimer's disease is characterized by cognitive decline, memory loss, and behavioral changes, and its pathological hallmarks include the accumulation of amyloid-beta plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein in the brain. Despite extensive research, the exact mechanisms underlying the pathogenesis of Alzheimer's disease remain incompletely understood, and current therapeutic approaches are primarily focused on managing symptoms rather than modifying disease progression. This highlights the urgent need for novel therapeutic approaches that can effectively modify disease progression and improve outcomes for individuals affected by Alzheimer's disease.

[0211] In this context, the present, disclosure provides methods for treating a neurodegenerative disease such as Alzheimer's disease using ARI 001, a phosphodiesterase-5 inhibitor. ARI 001 has been shown to have potential therapeutic benefits in Alzheimer's disease, and its use is being investigated m clinical trials. The methods disclosed herein may offer a new approach to treating a neurodegenerative disease such as Alzheimer's disease, poten tially providing benefi ts in terms of disease modification and improved patient outcomes.

[0212] According to an aspect of the present disclosure, a method of treating a neurodegenerative disease, including an amyloidosis-associated condition, in a subject is provided. The method includes administering to the subject about 10 mg to about 50 mg of ARI 001 orally once daily. The method includes administering to the subject about 30 mg of ARI 001 orally once daily.

[0213] According to other aspects of the present disclosure, the method may include one or more of the following features. The subject may have Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, or preclinical Alzheimer’s disease. In various aspects, the subject has mild cognitive impairment due to Alzheimer s disease or mild Alzheimer's disease dementia. The method may further include measuring one or more biomarkers in a biological sample from the subject, wherein the one or more biomarkers include pTau. In some embodiments, the biomarker includes magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET), amyloid positron emission tomography (PET), cerebrospinal fluid (CSF) tests (including AJ342 / AP40, pTau, and total Tan), and plasma tests (including AP42 / AP40, pTau181, pTau217, pTau231, pTau217 / A 42, and neurofilament light chain (NfL)). The pTau may be pTaulSl, pTau217, or pTau217 / AP42 and the biological sample may be plasma. ’Die method may further include selecting the subject for treatment based on the subject having ap’TaulS l, pTau217, or pTau217 / Ap42 level greater than about 5.0 pg / ml in the plasma sample. Tire method may reduce the level ofpTau181, pTau217, or pTau217 / Ap42 in the subject compared to baseline. Ihe method may reduce plasma pTaul81, pTau217, or pTau217 / Ap42 levels by at least about 10% compared to baseline after 26 weeks of treatment. The ethod may reduce plasma pTau181 levels by at least about 20% compared to baseline after 52 weeks of treatment. The method may improve or maintain cognitive function in the subject as measured by one or more cognitive tests. The one or more cognitive tests may include at least one of the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and the Mini-Mental State Examination (MMSE). The method may further include continuing administration of ARI 001 for at least 52 weeks. Ihe method may further include monitoring plasma pTau181, pTau217, or pTau217 / A 2 levels in the subject during treatment. The method may further include continuing ARI 001 treatment if the subject's plasma pTaul 81, pTau217, or pTau217 / Ap42 levels decrease during treatment. ARI 001 may be administered in a pharmaceutical composition in the form of a tablet or capsule. The pharmaceutical composition may further include one or more pharmaca.lly acceptable carriers.

[0214] According to another aspect of the present disclosure, a method for treating a neurodegenerative disease such as Alzheimer's Disease, mild cognitive impairment due toAlzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, or preclinical Alzheimer’s disease is provided. In various aspects, a method for treating early Alzheimer's disease in a subject is provided. The method includes obtaining a plasma sample from the subject, measuring the level of pTaul 81, pTau217, or pTau217 / Ap42 in the plasma sample, administering about 30 mg of ARI 001 orally once daily to the subj ect if the measured pTau 181, pTau217, or pTau217 / Aj342 level exceeds a predetermined value, monitoring the plasma pTaul 81, pTau217, or pTau217 / Ap42 level of the subject during ARI 001 treatment, and continuing AR1001 treatment if the subject's plasma pTaul81, pTau217, or pTau217 / Ap42 level decreases.

[0215] According to other aspects of the present disclosure, the method may include one or more of the following features. The predetermined value for pTau217 may be at least about 0.2 pg / ml, or at least about 0.185 pg / ml, or at least 0.325 pg / ml, or any subrange thereof. Those of skill in the ait will recognize that the predetermined value for pTau2.17 may also include values from about 0.0001 pg / ml to about 200 pg / ml, about 0,001 pg / ml to about 200 pg / ml, about 0.01 pg / ml to about 200 pg / ml, about 0.01 pg / ml to about 150 pg / ml, about 0.01 pg / ml to about 100 pg / ml, about 0.01 pg / ml to about 50 pg / ml, about 0.01 pg / ml to about 25 pg / ml, about 0.01 pg / ml to about 10 pg / ml, or about 0.01 pg / ml to about 5 pg / ml, about 0.05 pg / ml to about 200 pg / ml, about 0,05 pg / ml to about 150 pg / ml, about 0.05 pg / ml to about 100 pg / ml, about 0.05 pg / ml to about 50 pg / ml, about 0.05 pg / ml to about 25 pg / ml, about 0.05 pg / ml to about 10 pg / ml, or about 0.05 pg / ml to about 5 pg / ml, about 0.5 pg / ml to about 200 pg / ml, about 0.5 pg / ml to about 150 pg / ml, about 0.5 pg / ml to about 100 pg / ml, about 0.5 pg / ml to about 50 pg / ml, about 0.5 pg / ml to about 25 pg / ml, about 0.5 pg / ml to about 10 pg / ml, or about 0.5 pg / ml to about 5 pg / ml, or any number therebetween, hr other instances, the predetermined value for pTau217 includes ranges from about 1 pg / ml to about 200 pg / ml, about 1 pg / ml to about 150 pg / ml, about 1 pg / ml to about 100 pg / ml, about 1 pg / ml to about 50 pg / ml, about 1 pg / ml to about 25 pg / ml, about 1 pg / ml to about 10 pg / ml, or about 1 pg / ml to about 5 pg / ml, or any number therebetween. In oilier instances, the predetermined value for pTau217 includes ranges from about 0.1 pg / ml to about 1000000 pg / ml, about 0.1 pg / ml to about 100000 pg / ml, about 0.1 pg / ml to about 10000 pg / ml, about 0.1 pg / ml to about 1000 pg / ml, about 0.1 pg / ml to about 100 pg / ml, about 0.1 pg / ml to about 10 pg / ml, or about 0.1 pg / ml to about 5 pg / ml, or any number therebetween, hr other instances, the predetermined value for pTau217 includes a range fromabout 0.041 pg / ml to about 5.028 pg / ml.

[0216] According to other aspects of the present disclosure, the method may include one or more ofthe following features. The predetermined value for pTaul81 may be at least about 2.2 pg / ml, or at least about 5.0 pg / ml, or subrange thereof. Those of skill in the art will recognize that the predetermined value tor pTau181 may also include values from about 0.0001 pg / ml to about 200 pg / ml, about 0.001 pg / ml to about 200 pg / ml, about 0.01 pg / ml to about 200 pg / ml, about 0.01 pg / ml to about 150 pg / ml, about 0.01 pg / ml to about 100 pg / ml, about 0.01 pg / ml to about 50 pg / ml, about 0.01 pg / ml to about 25 pg / ml, about 0.01 pg / ml to about 10 pg / ml, or about 0.01 pg / ml to about 5 pg / ml, about 0.05 pg / ml to about 200 pg / ml, about 0.05 pg / ml to about 150 pg / ml, about 0.05 pg / ml to about 100 pg / ml, about 0,05 pg / ml to about 50 pg / ml, about 0.05 pg / ml to about 25 pg / ml, about 0.05 pg / ml to about 10 pg / ml, or about 0.05 pg / ml to about 5 pg / ml, about 0.5 pg / ml to about 200 pg / ml, about 0.5 pg / ml to about 150 pg / ml, about 0.5 pg / ml to about 100 pg / ml, about 0.5 pg / ml to about 50 pg / ml, about 0.5 pg / ml to about 25 pg / ml, about 0.5 pg / ml to about 10 pg / ml, or about 0.5 pg / ml to about 5 pg / ml, or any number therebetween. In other instances, the predetermined value for pTaul 81 includes ranges from about 1 pg / ml to about 200 pg / ml, about 1 pg / ml to about 150 pg / ml, about 1 pg / ml to about 100 pg / ml, about 1 pg / ml to about 50 pg / ml, about 1 pg / ml to about 25 pg / ml, about 1 pg / ml to about 10 pg / ml, or about 1 pg / ml to about 5 pg / ml, or any number therebetween. In other instances, the predetermined value for pTau181 includes ranges from about 0.1 pg / ml to about 1000000 pg / ml, about 0.1 pg / ml to about 100000 pg / ml, about 0.1 pg / ml to about 10000 pg / ml, about 0.1 pg / ml to about 1000 pg / ml, about 0.1 pg / ml to about 100 pg / ml, about 0.1 pg / ml to about 10 pg / ml, or about 0.1 pg / ml to about 5 pg / ml, or any number therebetween. In other instances, the predetermined value forpTauI81 includes a range from about 1.05 pg / ml to about 12.33 pg / ml.

[0217] According to other aspects of the present disclosure, the method may include one or more ofthe following features. The predetermined value for thepTau217 / AP40 ratio may be at least about 0.00370, or at least about 0.00738, or any subrange thereof. Those of skill in the art will recognize that the predetermined value for the pTau217 / Ap40 ratio may also include values from about 0.0001 to about 200, about 0.001 to about 200, about 0.01 to about 200, about 0,01 to about 150, about 0.01 to about 100, about 0.01 to about 50, about 0.01 to about 25, about 0.01 to about 10, or about 0.01 to about 5, about 0.05 to about 200, about 0.05 to about 150, about 0.05 to about 100, about 0.05 to about 50, about 0.05 to about 25, about 0.05 to about 10, or about 0.05 to about 5, about 0.1to about 200, about 0.1 to about 150, about 0.1 to about 100, about 0.1 to about 50, about 0.1 to about 25, about 0.1 to about 10, or about 0.1 to about 5, or any number therebetween. In other instances, the predetermined value fortlie pTau217 / Ap40 ratio includes ranges from about 0.00001 to about 200, about 0.0005 to about 150, about 0.001 to about 100, about 0.005 to about 50, about 0.01 to about 25, about 0.05 to about 5.0, or about 0.1 to about 1.0, or any number therebetween. In other instances, the predetermined value for pTau217 / Ap40 ratio includes ranges from about 0.001 to about 1000000, about 0.001 to about 100000, about 0.001 to about 10000, about 0.001 to about 1000, about 0.001 to about 100, about 0.001 to about 10, about 0.001 to about 1, about 0.001 to about 0.1, about 0.001 to about 0.01, or any number therebetween, hi other instances, the predetermined value for pTau217 / Ap40 ratio includes a range from about 0.0019 to about 0.4788.

[0218] Tire method may further include assessing the subject's cognitive function using one or more standardized tests. The method may further include adjusting the dosage of ARI 001 based on changes in the subject's plasma pTaul 81, pTau217, or pTau217 / Ap42 level.

[0219] According to another aspect of the present disclosure, a method for identifying subjects likely to respond to ARI 001 treatment for Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, preclinical Alzheimer’s disease is provided. In various aspects, a method for identifying subjects likely to respond to ARI 001 treatment for early Alzheimer's disease is provided. The method includes obtaining plasma samples from a plurality of subjects, measuring the level of pTaul 81, pTau217, or pTau217 / Ap42 in each plasma sample, and selecting subjects for ARlOOl treatment whose measured pTau181, pTau217, or pTau217 / Ap42 level exceeds a predetermined value.

[0220] According to other aspects of the present disclosure, the method may include one or more of the following features. The method may birther include administering about 30 mg of ARlOOl orally once daily to the selected subjects. The method may further include monitoring the plasma pTaul 81, pTau2I7, or pTau217 / Ap42 levels of the selected subjects during ARlOOl treatment. The method may birther include continuing ARlOOl treatment in subjects whose plasma pTaul 81, pTau217, or pTau217 / Ap42 levels decrease during treatment.

[0221] According to another aspect of tire present disclosure, a method formonitoring response to ARI 001 treatment in a subject with a neurodegenerative disease such as Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer's disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, preclinical Alzheimer’s disease is provided. In various aspects, a method for monitoring response to ARI 001 treatment in a subject with early Alzheimer's disease is provided, lire method includes obtaining a baseline plasma sample from tire subject before initiating AR1001 treatment, measuring the baseline level of pTaul 81, pTau217, or pTau217 / Ap42 in the baseline plasma sample, administering about 30 mg of ARI 001 orally once daily to the subject, obtaining one or more follow-up plasma samples from the subject during ARI 001 treatment, measuring the level of pTaul 81, p'Tau217, or pTau217 / Ap42 in each follow-up plasma sample, and comparing the pTau181, pTau217, or pTau217 / Ap42 levels in the follow-up plasma samples to the baseline pTaul81, pTau217, or pTau217 / Ap42 levels.

[0222] According to other aspects of the present disclosure, the method may include continuing ARI 001 treatment if the pTaul 81, pTau217, or pTau217 / AP42 levels in the follow-up plasma samples are lower than the baseline pTaul 81, pTau217, or pTau217 / Ap42 level.

[0223] According to another aspect of the present disclosure, a method of treating a neurodegenerative disease such as Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, or preclinical Alzheimer’s disease in a subject is provided. The method includes obtaining a plasma sample from the subject, measuring the level of pTaul 81, pTau217, or pTau217 / A 42 in the plasma sample, selecting the subject for treatment if the measured pTau217 level exceeds a predetermined value, and administering to the selected subject a therapeutically effective amount of AR1001.

[0224] The method may further include monitoring the plasma pTaul 81, pTau217, or pTau217 / Ap42 levels of the subject during AR1001 treatment. The method may further include continuing AR1001 treatment if the subject's plasma pTau 181, pTau217, or pTau217 / A 42 levels decrease during treatment. Tire subject may have a neurodegenerative disease such as Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, early-onsetAlzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, preclinical Alzheimer’s disease. In various aspects, the subject may have mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia. The method may further include assessing the subject's cognitive function using one or more standardized tests. The one or more standardized tests may include at least one of the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and the Mini-Mental State Examination (MMSE).

[0225] According to other aspects of the present disclosure, the method may include one or more of the following features. The levels of Tau!81 or Tau217 m the plasma sample may range from about 0.0001 pg / ml to about 200 pg / ml, about 0.001 pg / ml to about 200 pg / ml, about 0.01 pg / ml to about 200 pg / ml, about 0.01 pg / ml to about 150 pg / ml, about 0.01 pg / ml to about 100 pg / ml, about 0.01 pg / ml to about 50 pg / ml, about 0.01 pg / ml to about 25 pg / ml, about 0.01 pg / ml to about 10 pg / ml, or about 0.01 pg / ml to about 5 pg / ml, about 0.05 pg / ml to about 200 pg / ml, about 0,05 pg / ml to about 150 pg / ml, about 0.05 pg / ml to about 100 pg / ml, about 0.05 pg / ml to about 50 pg / ml, about 0.05 pg / ml to about 25 pg / ml, about 0.05 pg / ml to about 10 pg / ml, or about 0.05 pg / ml to about 5 pg / ml, about 0.1 pg / ml to about 200 pg / ml, about 0.1 pg / ml to about 150 pg / ml, about 0.1 pg / ml to about 100 pg / ml, about 0, 1 pg / ml to about. 50 pg / ml, about 0.1 pg / ml to about 25 pg / ml, about 0.1 pg / ml to about 10 pg / ml, or about 0.1 pg / ml to about 5 pg / ml, or any number therebetween. In other instances, the levels of pTau181 or pTau217 in the plasma sample may range from about 0.00001 pg / ml to about 2.00 pg / ml, about. 0.0005 pg / ml to about 150 pg / ml, about 0.001 pg / ml to about 100 pg / ml, about 0.005 pg / ml to about 50 pg / ml, about 0.01 pg / ml to about 2.5 pg / ml, about 0.05 pg / ml to about 5.0 pg / ml, or about 0.1 pg / ml to about 1.0 pg / ml, or any number therebetween. The pTau217 / Ap42 ratio in tire plasma sample may range from about 0.0001 to about 200, about 0.001 to about 200, about 0.01 to about 2.00, about 0.01 to about 150, about 0.01 to about 100, about 0.01 to about 50, about 0.01 to about 25, about 0.01 to about 10, or about 0.01 to about 5, about 0.05 to about 200, about 0.05 to about 150, about 0.05 to about 100, about 0.05 to about 50, about 0.05 to about 25, about 0.05 to about 10, or about 0.05 to about 5, about 0.1 to about 2.00, about 0.1 to about 150, about 0.1 to about. 100, about 0.1 to about 50, about 0.1 to about 25, about 0.1 to about 10, or about 0.1 to about 5, or any number therebetween. In other instances, the pTau217 / A 42 ratio in the plasma sample may range from about 0.00001 to about 200, about 0.0005 to about 150, about 0.001 to about 100,about 0.005 to about 50, about 0.01 to about 25, about 0.05 to about 5.0, or about 0.1 to about 1.0, or any number therebetween. In some embodiments, the pTau217 / A342 ratio in the plasma sample may be at least about 0.00370. The AP42 / A 40 ratio in the cerebral spinal fluid (CSF) may range from about 0.0001 to about 200, about 0.001 to about 200, about 0.01 to about 200, about 0.01 to about 150, about 0.01 to about 100, about 0.01 to about 50, about 0.01 to about 25, about 0.01 to about 10, or about 0.01 to about 5, about 0.05 to about 200, about 0.05 to about 150, about 0.05 to about 100, about 0.05 to about 50, about 0.05 to about 25, about 0.05 to about 10, or about 0.05 to about 5, about 0.1 to about 200, about 0.1 to about 150, about 0.1 to about 100, about 0.1 to about 50, about 0.1 to about 25, about 0.1 to about 10, or about 0.1 to about 5, or any number therebetween. In other instances, the Ap42 / A 40 ratio in the cerebral spinal fluid may range from about 0.00001 to about 200, about 0.0005 to about 150, about 0.001 to about 100, about 0.005 to about 50, about 0.01 to about 25, about 0.05 to about 5.0, or about 0.1 to about 1.0, or any number therebetween. In some embodiments, tire AP42 / A 40 ratio in the cerebral spinal fluid may range from about 0.058 to about 0.1782.

[0226] The therapeutically effective amount of ARI 001 may be about 10 mg to about 50 mg. The therapeutically effective amount of AR1001 may be about 30 mg.

[0227] The therapeutically effective amount of AR1001 may be about 10 mg to about 50 mg administered orally. The therapeutically effective amount of AR 1001 may be about 30 mg administered orally.

[0228] Hie therapeutically effective amount of ARI001 may be about 10 mg to about 50 mg administered once daily. The therapeutically effective amount of AR 1001 may be about 30 mg administered once daily,

[0229] The therapeutically effective amount of AR100I may be about 10 mg to about 50 mg administered orally once daily. Ihe therapeutically effective amount of AR1001 may be about 30 mg administered orally once daily.

[0230] According to another aspect of the present disclosure, a method of treating Alzheimer's disease in a subject is provided. The method includes administering to the subject about 10 mg to about 50 mg of AR1001 orally once daily for at least 26 weeks. The method includes administering to the subject about 30 mg of ARI 001 orally once daily for at least 26 weeks.

[0231] According to other aspects of the present disclosure, the method may include one or more of the following features. The method may reduce plasma pTau181,pTau217, orpTau217 / Ap42 levels in the subject by at least about 10% compared to baseline after 26 weeks of treatment. The method may improve or maintain cognitive function in the subject as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) after 26 weeks of treatment. The subject may have mild cognitive impairment due to Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer's disease, early Alzheimer’s disease, preclinical Alzheimer’s disease. In various aspects, the subject may have a neurodegenerative disease such as Alzheimer's disease or mild Alzheimer's disease dementia, lire method may further include continuing administration of about 30 mg of ARI 001 orally once daily for at least 52 weeks. The method may reduce plasma pTaul 81, pTau217, or pTau217 / Ap42 levels m the subject by at least about 20% compared to baseline after 52 weeks of treatment.

[0232] According to another aspect of the present disclosure, a method of reducing pTau levels in a subject with a neurodegenerative disease such as Alzheimer's disease is provided. The method includes administering to the subject about 10 mg to about 50 mg of AR1001 orally once daily for at least 26 weeks, wherein the pTau is pTaulSl, pTau217, or pTau217 / Ap42. Ihe method includes administering to the subject about 30 mg of AR1001 orally once daily for at. least 26 weeks, wherein the pTau is pTau 181, pTau217, or pTau217 / AP42.

[0233] According to other aspects of the present disclosure, the method may include one or more of the following features. The method may reduce plasma pTaul81, p"fau217, or p’Tau217 / Ap42 levels in the subject by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at. least, about 60%, at. least about 65%), at least about 70 ), at least about 75%, at least about 80%, at least about 85%, at least about 90%>, at least about 95%, at least about 96%, at least about 97%, at least about 98%o, at least about 99%>, or about 100% compared to baseline after 26 weeks of treatment. The method may further include continuing administration of about. 10 mg to about 50 mg of ARI 001 orally once daily tor at least 52 weeks. The method may further include continuing administration of about 30 mg of AR1001 orally once daily for at least 52 weeks. The method may reduce plasma pTau181, pTau217, or pTau217 / Ap42 levels in the subject by at leastabout 10% compared to baseline after 52 weeks of treatment.

[0234] According to another aspect of the present disclosure, a method of treating Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, eariy-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, or preclinical Alzheimer's disease is provided. In various aspects, a method of treating early Alzheimer's disease in a subject is provided. The method includes administering to the subject about 10 mg to about 50 mg of AR1001 orally once daily and monitoring plasma pTaulSl, pTau217, or pTau217 / Ap42 levels in the subject during treatment. The method includes administering to the subject about 30 mg of AR1001 orally once daily and monitoring plasma pTaul 81, p'Tau217, or pTau217 / Ap42 levels in the subject during treatment.

[0235] According to other aspects of the present disclosure, the method may further include continuing ARI 001 treatment if the subject's plasma pTaul81, pTau217, or pTau217 / Ap42 levels decrease during treatment.

[0236] Referring to Figs. 1 A-1B, a patient disposition flowchart for a clinical trial of AR1001 is illustrated. The flowchart pro ides a visual representation of the progression of patients through the clinical trial, including tlie number of patients assessed for eligibility, the number of patients randomized into different treatment groups, and the number of patients completing each phase of the study.

[0237] In the depicted clinical trial, a total of 324 patients were initially assessed for eligibility. Of these, 1 14 patients were excluded, primarily due to not meeting the inclusion / exclusion criteria. The remaining 2.10 patients were randomized into three treatment groups, each consisting of 70 patients. These groups included a placebo group, a group receiving a 10 mg dose of ARI 001, and a group receiving a 30 mg dose of ARI 001.

[0238] The flowchart further illustrates the progression of patients through two main phases of the clinical trial: a Treatment Phase and an Extension Phase. During the Treatment Phase, each treatment group experienced some discontinuations. Specifically, the 10 mg AR1001 group had 9 discontinuations, the 30 mg AR1001 group had 13 discontinuations, and the placebo group had 15 discontinuations. The reasons for discontinuation varied and included adverse events, withdrawal of consent, loss of follow-up, and other reasons. At the end of the Treatment Phase, which lasted 26 weeks, a total of 61 patients in the 10 mg AR 1001 group, 57 patients in the 30 mg ARI 001 group, and 55 patientsin the placebo group completed the phase.

[0239] Following the Treatment Phase, patients had the option to continue into the Extension Phase. In tins phase, patients who were initially assigned to the placebo group were re-randomized to receive either a 10 mg or 30 mg dose of ARI 001. Hie Extension Phase lasted an additional 26 weeks, and the number of patients completing this phase was also tracked.

[0240] hr some cases, the patient disposition flowchart may also include information on the number of patients experiencing adverse events, the number of patients discontinuing treatment due to adverse events, and other relevant data. This detailed tracking of patient progression through the clinical trial can provide valuable insights into the safety and efficacy of the treatment under investigation.

[0241] Referring to Figs. 2A and 2F-2H, the figures illustrate changes in plasma biomarker levels over 26 weeks of treatment with ARI 001 compared to placebo. Referring to Figs. 2B-2E, the figures illustrate changes in plasma biomarker levels over 26 and 52 weeks of treatment with ARI 001 compared to placebo.

[0242] Figs. 2A and 2F show the adjusted mean percent change from baseline for four biomarkers, namely pTau181, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), amyloid p (Ap) 42 / 40 ratio, and pTau217 at Week 26 for placebo, 10 mg ARI 001, and 30 mg AR1001 groups. The baseline is normalized to 0 at Week 0 and the percentage change from baseline at Week 26 is shown.

[0243] Figs. 2B-2E show the mean change from baseline over 52 weeks for pTaulSl, GFAP, NfL, and AP42 / 40 ratio, respectively. Each panel includes data points at 0, 26, and 52 weeks with error bars. The number of subjects at each time point is indicated below' each graph. Asterisks denote statistical significance levels. Arrows on the y-axes indicate the direction of improvement for each bioniarker.

[0244] Figs, 2G-2H show the mean change from baseline over 26 weeks for pTau217 and pTau217 / Ap42, respectively. Each panel includes data points at 0 and 26 weeks with error bars. The number of subjects at each time point is indicated below each graph. Asterisks denote statistical significance levels. Arrows on the y-axes indicate tire direction of improvement for each biomarker.

[0245] In some cases, the plasma levels of these biomarkers may be measured to monitor disease progression and response to treatment in patients with Alzheimer's disease. For example, pTau! 1 is a biomarker associated with tau pathology, a hallmark ofAlzheimer's disease. GFAP is a marker of astrocyte activation and is associated with neuroinflammation. NfL is a marker of neuroaxonal damage, and the Ap42 / 40 ratio is associated with amyloid pathology, another hallmark of Alzheimer's disease.

[0246] Prior references discuss the measurement of pTau181 levels in a subject plasma. For example, WO Pub. No. 2023 / 081422 focuses on using pTau181 levels to identify a subset of patients with Dementia with Lewy Bodies (DLB) who do not have substantial tau pathology, and treating those patients with neflamapimod. Specifically, the publication describes using pTaul 81 levels to select DLB patients without substantial tau pathology for treatment with neflamapimod, a selective p3 a MAPK inhibitor. A plasma ptau!81 level below 2.2 pg / ml is used to indicate no substantial tau pathology in DLB patients. Patients with DLB and ptaul81 levels below this threshold are considered more likely to respond to neflamapimod treatment. The method specifically excludes patients with Alzheimer's disease or Alzheimer's disease-like pathology. The patent publication therefore does not discuss using ptau!81 as a biomarker for treating Alzheimer s disease patients.

[0247] In some aspects, the methods disclosed herein may include administering ARI 001 to a subject for a period of 52 weeks. Tire administration of ARI 001 may be performed orally once daily. The dosage of ARI 001 may be about 10 mg or about 30 mg, depending on the specific needs of the subject. The administration of ARI 001 may be continued for the entire 52-week period, or it may be discontinued earlier based on the subject's response to treatment.

[0248] In some cases, the methods may further include monitoring the plasma levels of one or more biomarkers, such as pTau 181, GFAP, NfL, and A [$42 / 40 ratio, during the 52-week treatment period. The plasma levels of these biomarkers may be measured at various time points, such as at baseline (Week 0), at Week 26, and at Week 52. The changes in plasma biomarker levels over the 52-week treatment period may provide valuable insights into the disease-modifying potential of ARI 001 in treating Alzheimer's disease.

[0249] Referring to Figs. 3A-3B, the figures illustrate the relationship between baseline pTau181 levels and changes in cognitive endpoints, specifically ADAS-Cogl3 and ADCS-CG1C, for placebo and AR1001 treatment groups. Each of the figures show a scatter plot with trend lines for different treatment groups.

[0250] Fig. 3A displays the ADAS-Cogl3 Change from Baseline on the y-axis and Baseline pTaulSl on the x-axis. Three trend lines are shown, corresponding to placebo, lOmg, and 30mg treatment groups, with p-values of 0.04, 0.46, and 0.91 respectively. Thissuggests that in the placebo group, there is a significant correlation between baseline pTaulSl and worsening ADAS-Cog 13, whereas in the lOmg and 30mg AR1001 groups, this correlation is not statistically significant. This may indicate that ARI 001 treatment could potentially mitigate the cognitive decline associated with higher baseline pTaul 81 levels.

[0251] Fig. 3B show's the ADCS-CGIC Change from Baseline on the y-axis and Baseline pTaul 81 on the x-axis, with similar trend lines for the three treatment groups. The scatter plots in both panels contain numerous data points representing individual subjects, with different symbols used to distinguish between treatment groups.

[0252] In some aspects, the methods disclosed herein may include administering ARI 001 to a subject and monitoring the subject's cognitive function using cognitive assessments such as ADAS-Cogl3 and ADCS-CGIC. The subject's baseline pTaul 81 level may be measured and used as a covariate in the analysis of cognitive endpoints. This may provide valuable insights into the potential benefits of ARI 001 treatment in subjects with different baseline pTaul 81 levels.

[0253] In some cases, the methods may further include comparing the relationship between baseline pTaul 81 levels and changes in cognitive endpoints between different treatment groups. This may help to evaluate the efficacy of ARI 001 treatment in mitigating the cognitive decline associated with higher baseline pTaul 81 levels.

[0254] In other cases, the methods ay include analyzing the correlation between baseline pTaul 81 levels and changes in cognitive endpoints within each treatment group. Ulis may provide further insights into the potential disease -modifying effects of ARI 001 in treating Alzheimer's disease.

[0255] Referring to Figs. 4A-4C, the figures illustrate the effects of ARI 001 treatment on cognitive endpoints and pTaul 81 levels in the subgroup of participants with high baseline pTau181 (>5.0 pg / ml). Referring to Figs. 4D-4E, the figures illustrate the effects of AR I 001 treatment on cognitive endpoints and pTau l 81 levels in the subgroup of participants with low baseline pTaul 81 (<5.0 pg / ml).

[0258] Figs. 4A and 4D display the Alzheimer’s Disease Assessment Scale -Cognitive Subscale 13 (ADAS-Cog 13) scores overtime for the placebo, 10 mg AR1001, and 30 mg AR1001 treatment groups. The ADA S-Cog 13 is a cognitive assessment tool used to evaluate the severity and progression of cognitive impairment in patients with Alzheimer's disease. The scores range from 0 to 70, with higher scores indicating greater cognitive impairment. In some cases, the ADAS-Cog 13 may be used to assess the efficacy of atreatment, such as ARlOOl, in improving cognitive function in patients with Alzheimer's disease.

[0257] Figs. 4B and 4E displays the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scores overtime for the same three treatment groups. The ADCS-CGIC is a measure used to assess global changes in a patient's clinical condition overtime. It is based on a clinician's judgment of the patient’s change in cognitive function, behavior, and activities of daily living. The ADCS-CGIC scores range from 1 (marked improvement) to 7 (marked worsening), with a score of 4 indicating no change.

[0258] Fig. 4C illustrates pTaul 81 levels over 52 weeks for placebo, 10 mg ARI 001, and 30 mg AR 1001 groups. Each graph includes error bars and sample si zes for each time point and treatment group. The y-axes are oriented to show improvement upwards for graphs A and B, and downwards for graph C. The x-axes indicate weeks of treatment, with measurements taken at 0, 26, and 52 weeks as applicable.

[0259] Fig. 4F illustrates pTau217 change from baseline (pg / ml) at Week 26 in sub-group (pTau217 > 0.185 pg / ml). Fig. 4G illustrates pTau2I7 / Ap42 ratio change from baseline (pg / ml) at Week 26 sub-group (pTau217 / A|}42 ratio > 0.00371). The following denote standard error in the Figs. 4F and 4G: * lOmg vs Placebo, 30mg vs Placebo, *p<0.05, **p<0.01, ***p<0.001; * Baseline vs week 52, #p<0.05, ##p<0.01, ###p<0,001,

[0280] In some aspects, the methods disclosed herein may include administering ARlOOl to a subject with a high baseline pTauISl level (>5.0 pg / ml). The administration of ARlOOl may be performed orally once daily. The dosage of ARlOOl may be about 10 mg or about 30 mg, depending on the specific needs of the subject. The administration of ARlOOl may be continued for the entire 52-week period, or it may be discontinued earlier based on the subject's response to treatment.

[0261] In some cases, the methods may further include monitoring the plasma levels of pTaul 81 during the 52-week treatment period. Tire plasma levels of pTaul 81 may be measured at various time points, such as at baseline (Week 0), at Week 26, and at W eek 52. The changes in plasma pTau181 levels over the 52-week treatment period may provide valuable insights into the disease-modifying potential of ARlOOl in treating Alzheimer's disease in subjects -with high baseline pTaul81 levels.

[0262] Pharmaceutical Compositions

[0263] Combinations described herein can be provided as a pharmaceutical composition suitable for administration via any route to a patient described herein including but not limited to: oral, mucosal (e.g., nasal, inhalation, pulmonary, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intra-arterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal or transcutaneous administration to a patient. The preparation of these formulations are within the skill of the art; methods for preparing fonnulations are provided, for example in Remington's Pharmaceutical Sciences (A. R. Gennaro, Ed.), 20th edition, Williams & Wilkins PA, USA (2000).

[0264] Exemplary of dosage forms include: tablets; caplets; capsules (e.g., gelatin capsules); cachets; lozenges; suppositories; powders; gels; liquid dosage forms suitable for parenteral administration or other liquid dosage forms to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

[0265] Pharmaceutical compositions and dosage forms described herein typically include one or more carriers. Suitable carriers are well known to those skilled in the art of pharmacy. Whether a particular carrier is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors such as, for example, the intended route of administration to the patient. Pharmaceutical compositions described herein can include other agents such as stabilizers, lubricants, buffers, and disintegrants that can reduce the rate by which an active ingredient can decompose in a particular formulation.

[0266] In one embodiment, AR 1001 is provided in an oral dosage form such as a tablet or capsule. In another embodiment, the compound of Formula I is supplied as a powder (e.g., lyophilized powder) that can be resuspended in a liquid suitable for parenteral administration or as another liquid dosage form.

[0267] AR1001 can be provided in forms convenient to or facilitate their administration to a patient. For example, AR1001 can be formulated as a tablet, capsule, or as a powder (e.g., lyophilized powder) that can be resuspended in a liquid suitable for parenteral administration or other liquid dosage form.

[0263] ARI 001 can be provided as controlled release pharmaceutical products, which have a goal of improving drug therapy over that achieved by their non-controlled counterparts. Controlled release formulations can extend activity of the drug, reduce dosage frequency, and increase subject compliance. In addition, controlled release fonnulations canbe used to affect the time of onset of action or other characteris tics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.

[0269] Typical compositions of the invention include ARI 001 with pharmaceutically acceptable earners, which may be a pharmaceutically acceptable excipient or a diluent, by way of example. As provided above, and in the Examples below, such compositions can be in the form of a capsule, sachet, paper or other container. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, ARI 001 can be mixed with a pharmaceutically acceptable carrier, or diluted by a pharmaceutically acceptable carrier, or enclosed within a pharmaceutically acceptable carrier that may be in tire form of an ampoule, capsule, sachet, paper, or other container. When the pharmaceutically acceptable carrier serves as a diluent, it may be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. ARI 001 can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable pharmaceutically acceptable carriers are water, pharmaceutically acceptable salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fattyracids, fatty' acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty' acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone.Similarly, the pharmaceutically acceptable carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of ARI 001 after administration to the patient by employing procedures well known in the art.

[0270] AR1001 can be sterilized and mixed, if desired, with auxiliary' agents, emulsifiers, pharmaceutically acceptable salt for influencing osmotic pressure, buffers and / or coloring substances and the like, which do not deletenously react with the active compounds.

[0027] For nasal or intranasal administration, the preparation may contain ARI 001 dissolved or suspended in a liquid pharmaceutically acceptable carrier, in particular an aqueous pharmaceutically acceptable carrier, for aerosol application. The pharmaceutically acceptable carrier may contain additives such as solubilizing agents, e.g., propylene glycol.surfactants, absorption enhancers such as lecithin (phosphatidylcholine), or cyclodextrin, or preservatives such as parabens.

[0272] For oral administration, either solid or fluid unit dosage forms can be prepared. For preparing solid compositions such as tablets, the compound of interest is mixed into formulations with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical diluents or pharmaceutically acceptable carriers.

[0273] Capsules are prepared by mixing ARI 001 with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size. Soft gelatin capsules are prepared by machine encapsulation of slurry of the compound of interest with an acceptable vegetable oil, light liquid petrolatum or other inert oil. Fluid unit dosage forms for oral administration such as syrups, elixirs and suspensions can be prepared. The water-soluble forms can be dissolved in an aqueous vehicle together with sugar, aromatic flavoring agents and preservatives to form syrup. An elixir is prepared by using a hydroalcoholic (e. g., ethanol) vehicle with suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent. Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.

[0274] Furthermore, additives can be included in the formulation. Examples include cosolvents, surfactants, oils, humectants, emollients, preservatives, stabilizers and antioxidants. Any pharmacologically acceptable buffer may be used, e.g., tris or phosphate buffers. Effective amounts of diluents, additives, and excipients are those amounts that are effective to obtain a pharmaceutically acceptable formulation in terms of solubility, biological activity, etc.

[0275] The compound of interest may be incorporated into a microsphere. The compound of interest can be loaded into albumin microspheres, from which it is possible to recover such microspheres in a dry powder for nasal administration. Other materials suitable for the preparation of microspheres include agar, alginate, chitosan, starch, hydroxyethyl starch, albumin, agarose, dextran, hyaluronic acid, gelatin, collagen, and casein. The microspheres can be produced by various processes known to the person skilled in the art such as a spray drying process or an emulsification process.

[0276] For example, albumin microspheres can be prepared by adding rabbit serum albumin in phosphate buffer to olive oil with stirring to produce water in oil emulsion.Glutaraldehyde solution is then added to the emulsion and the emulsion stirred to cross-link the albumin. The microspheres can then be isolated by centrifugation, the oil removed and the spheres washed, e. g., with petroleum ether followed by ethanol. Finally, the microspheres can be sieved and collected and dried by filtration.

[0277] Starch microspheres can be prepared by adding a warm aqueous starch solution, e. g. of potato starch, to a heated solution of polyethylene glycol in water with stirring to form an emulsion. When the two-phase system has formed (with the starch solution as the inner phase) the mixture is then cooled to room temperature under continued stirring whereupon the inner phase is converted into gel particles. These particles are then filtered off at room temperature and slurred in a solvent such as ethanol, after which the particles are again filtered off and laid to dry in air. The microspheres can be hardened by well-known cross-linking procedures such as heat treatment or by using chemical crosslinking agents.

[0278] Another embodiment of the invention is the dosage scheme. The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for subjects, each unit containing a predetermined quantity of active material calculated to produce the desired pharmaceutical effect in association with the required pharmaceutically acceptable diluent, carrier or vehicle, The specifications for the unit dosage forms of this invention are dictated by and dependent on (a) the unique characteristics of the active material and the particular effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for use in humans and animals. Examples of unit dosage forms are tablets, capsules, pills, powder packets, wafers, suppositories, granules, cachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampoules, vials, aerosols with metered discharges, segregated multiples of any of the foregoing, and other forms as herein described. The compositions can be included in kits, which can contain one or more unit dosage forms of the composition and instructions for use to treat one or more of the disorders described herein,

[0279] According to another aspect of the present disclosure, a pharmaceutical composition is provided. The pharmaceutical composition includes ARI 001 and one or more pharmaceutically acceptable carriers, wherein the composition is formulated to provide about 10 mg to about 50 mg of AR1001 when administered to a subject. In some embodiments, the composition is formulated to provide about 30 mg of AR1001 when administered to a subject

[0280] The pharmaceutical composition includes about 10 mg to about 50 mg of AR1001 and one or more pharmaceutically acceptable carriers. In some embodiments, thepharmaceutical composition includes about 30 mg of AR1001 and one or more pharmaceutically acceptable carriers.

[0281] According to other aspects of the present disclosure, the pharmaceutical composition may include one or more of the following features. The composition may be in the form of a tablet, or capsule. The pharmaceutical composition may include one or more pharmaceutically acceptable carriers including at least one of a binder, a filler, a disintegrant, a lubricant, or a coating agent. The pharmaceutical composition may be formulated for oral administration. The composition may be formulated for once daily administration.

[0282] According to another aspect of the present disclosure, a unit dosage form is provided. The unit dosage form includes the pharmaceutical composition described above.

[0283] According to other aspects of the present disclosure, the unit dosage form may be a tablet or capsule.

[0284] Slow or extended-release delivery systems, including any of a number of biopolymers (biological-based systems), systems employing liposomes, colloids, resins, and other polymeric delivery systems or compartmentalized reservoirs, can be utilized with the compositions described herein to provide a continuous or long-term source of therapeutic compound.

[0285] In an embodiment, the pharmaceutical composition and / or dosage form contains mirodenafil or a pharmaceutically acceptable salt thereof in an amount equivalent to about 0.5 mg to about 50 mg, or about 1 mg to about 50 mg, or about 1 mg to about 30 mg, or about 1 mg to about 25 mg, or about 1 mg to about 20 mg, or about 1 mg to about 15 mg, or about 1 mg to about 10 mg, or about 1 mg to about 5 mg, or about 1 mg to about 4.5 mg, or about 2 mg to about 25 mg, or about 2 mg to about 20 mg, or about 2 mg to about 15 mg, or about 2 mg to about 10 mg, or about 2 mg to about 5 mg, or about 2 mg to about 4.5 mg, or about 5 mg to about 25 mg, or about 5 mg to about 20 mg, or about 5 mg to about 15 mg, and any amount in between. In an embodiment, the dosage form contains about 1 mg, or about 1.5 mg or about 2 mg, about 2.5 mg, or about 3 mg, or about 3.5 mg, or about 4 mg, or about 4.5 mg, or about 5 mg, or about 7.5 mg, or about 10 mg, or about 12.5 mg, or about 15 mg, or about 20 mg, or about 25 mg, or about 30 mg, or about 35 mg, or about 40 mg, or about 45 mg, or about 50 mg, or about 60 mg, or about 70 mg, or any amount therebetween of mirodenafil or a pharmaceutically acceptable salt thereof. In one embodiment, the amount of mirodenafil or the pharmaceutically acceptable salt thereof is about 30 mg.

[0286] In an embodiment, the pharmaceutical composition and / or dosage formcontains a filler. Examples of fillers that may be used in the pharmaceutical composition and / or dosage form as disclosed herein include microcrystalline cellulose, anhydrous lactose, spray-dried lactose, dibasic calcium phosphate, glucose, dextrose, fructose, lactose, mannitol and / or sorbitol. In an embodiment, the filler is microcrystalline cellulose. In an embodiment, the filler content in the pharmaceutical composition and / or dosage form is about 50% to about 65% w / w, or about 55% to about 70% w / w, or about 60% to about 75% w / w, or about 60% to about 65% w / w, or about 65% to about 80% w / w, or about 70% to about 85% w / w, or about 80% w / w to about 95% w / w, or about 82% w / w to about 93% w / w, or about 84% w / w to about 89% w / w, or any number therebetween, of the pharmaceutical composition and / or dosage form. In an embodiment, the filler content in the pharmaceutical composition and / or dosage form is about 60% to about 65% w / w of the pharmaceutical composition and / or dosage form. In an embodiment, the filler content in the pharmaceutical composition and / or dosage form is about 61.75% w / w of the pharmaceutical composition and / or dosage form.

[0287] hr an embodiment, the pharmaceutical composition and / or dosage form comprises at least about 30% w / w, or at least about 35% w / w, or at least about 40% w / w, or at least about 45% w / w, or at least about 50% w / w, or at least about 55% w / w, or at least about 60% w / w, or at least about 65% w / w or more, but not more than 95% w / w, or any amount therebetween, of microcrystalline cellulose.

[0288] According to other aspects of the present disclosure, the filler is microcrystalline cellulose. According to other aspects of the present disclosure, the amount of the filler is about 60% to about 65% w / w of the pharmaceutical composition and / or dosage form. According to other aspects of the present disclosure, the amount of the filler is about 61.75% w / w of the pharmaceutical composition and / or dosage form.

[0289] In an embodiment, the pharmaceutical composition and / or dosage form contains a binder. Such binders include natural binders, synthetic / semisynthetic polymers, and sugars. For example, at least one binder may be a dry binder and / or a wet binder.Examples of binders that may be used in the pharmaceutical composition and / or dosage form as disclosed herein include microcrystalline cellulose, polyvinylpyrrolidone, sucrose, liquid glucose, acacia, tragacanth, gelatin, alginic acid, cellulose, methyl cellulose, ethyl cellulose, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose, sodium carboxy methyl cellulose, polyethylene glycol (PEG), polyvinyl alcohols, or polymethacrylates. In an embodiment, the binder is microcrystalline cellulose. In an embodiment, the binder content in the pharmaceutical composition and / or dosage form is about 50% to about 65% w / w, orabout 55% to about 70% w / w, or about 60% to about 75% w / w, or about 60% to about 65% w / w, or about 65% to about 80% w / w, or about 70% to about 85% w / w, or about 80% w / w to about 95% w / w, or about 82% w / w to about 93% w / w, or about 84% w / w to about 89% w / w, or any number therebetween, of the pharmaceutical composition and / or dosage form. In an embodiment, the binder content in the pharmaceutical composition and / or dosage form is about 60% to about 65% w / w of the pharmaceutical composition and / or dosage form, in an embodiment, the binder content in the pharmaceutical composition and / or dosage form is about 61.75% w / w of the pharmaceutical composition and / or dosage form.

[0290] In an embodiment, the pharmaceutical composition and / or dosage form comprises at least about 30% w / w, or at least about 35% w / w, or at least about 40% w / w, or at least about 45% w / w, or at least about 50% w / w, or at least about 55% w / w, or at least about 60% w / w, or at least about 65% w / w or more, but not more than 95% w / w, or any amount therebetween, of microcrystalline cellulose.

[0291] According to other aspects of the present disclosure, the binder is microcrystalline cellulose. According to other aspects of the present disclosure, the amount of the binder is about 60% to about 65% w / w of the pharmaceutical composition and / or dosage form. According to other aspects of the present disclosure, the amount of the binder is about 61.75% w / w of the pharmaceutical composition and / or dosage form.

[0292] In an embodiment, the pharmaceutical composition and / or dosage form contains a disintegrant. Various types of disintegrants may be used in the pharmaceutical composition and / or dosage form as disclosed herein. For example, at least one disintegrant that may be used is a superdisintegrant, such as croscarmellose sodium, crospovidone and / or sodium starch glycolate (“SSG”). In an embodiment, the disintegrant may be Starch NF, Starch 1500, alginic acid and / or any other components known in the art which aid disintegration, hi an embodiment, the dosage form comprises about 1% w / w to about 45% w / w, or about 2% to about 43%, or about 3% to 40%, or about 4% to about 40%, or about 5% to about 40%, or about 10% to about 40%, or about 20% to about 40%, or about 30% to about 40% or about 35% to about 40%, or any number therebetween, of a disintegrant. In an embodiment, the pharmaceutical composition and / or dosage form comprises at least about 2% w / w, or at least about 2.5 % w / w, or at least about 3% w / w, or at least about 3.5% w / w, or at least about 4% w / w, or at least about 4.5% w / w, or at least about 5% w / w, or at least about 5.5% w / w, or at least about 6% w / w, or at least about 6.5% w / w, at least about 9% w / w, at least about 10% w / w, or at least about 15% w / w, or at least about 20% w / w, or atleast about 25% w / w, or at least about 30% w / w, or at least about 35% w / w, or at least about 36% w / w, or at least about 37% w / w, or at least about 38% w / w, or at least about 39% w / w or at least about 40% w / w, or at least about 41% w / w or at least about 42% w / w, or at least about 43% w / w, or at least about 44% w / w, but not more than 45% w / w, or any number therebetween, of the at least one disintegrant. In an embodiment, the pharmaceutical composition and / or dosage form comprises about 1% w / w to about 10% w / w, or about 2% w / w to about 9% w / w, or 2% w / w to about 8%, or about 2% w / w to about 7%, or about 3% w / w to about 8% w / w, or about 3% w / w to about 7% or about or about 4% w / w to about 7% w / w, or about 4% w / w to about 6% w / w, or any number therebetween, of the disintegrant, for instance a superdisintegrant. In an embodiment, the pharmaceutical composition and / or dosage form comprises at least about 2% w / w, or at least about 2.5 % w / w, or at least about 3% w / w, or at least about 3.5% w / w, or at least about 4% w / w, or at least about 4.5% w / w, or at least about 5% w / w, or at least about 5.5% w / w, or at least about 6% w / w, or at least about 6.5% w / w, but not more than 9% w / w, or any number therebetween, of the at least one disintegrant, for instance a superdisintegrant. In an embodiment, the disintegrant is croscarmellose sodium. In an embodiment, the amount of the disintegrant is about 15% to about 25% w / w of the pharmaceutical composition and / or dosage form. In an embodiment, the amount of the disintegrant is about 20% w / w of the pharmaceutical composition and / or dosage form.

[0293] According to other aspects of the present disclosure, the disintegrant is croscarmellose sodium. According to other aspects of the present disclosure, the amount of the disintegrant is about 15% to about 25% w / w of the dosage form. According to other aspects of the present disclosure, the amount of the disintegrant is about 20% w / w of the pharmaceutical composition and / or dosage form.

[0294] In some embodiments, the pharmaceutical composition and / or dosage fonn comprises, but not limited to, a lubricant, an antioxidant, a flavoring agent, a sweetener, or a coloring agent. In an embodiment, the lubricant includes magnesium stearate, sodium stearyl fumarate, glyceryl dibehenate, stearic acid, talc, colloidal silicon dioxide, or sodium stearyl fumarate. In an embodiment, the lubricant is magnesium stearate.

[0295] In an embodiment, the pharmaceutical composition and / or dosage form comprises at least about 0.5% w / w, or at least about 1.0% w / w, or at least about 1.5% w / w, or at least about 2.0% w / w, or at least about 2.5% w / w, or at least about 3.0% w / w, or at least about 3.5% w / w, or at least about 4.0% w / w or more, but not more than 10% w / w, or notmore than 5.0% w / w, or any amount therebetween of lubricant.

[0296] According to other aspects of the present disclosure, the lubricant is magnesium stearate. According to other aspects of the present disclosure, the amount of the lubricant is about 1.5% to about 2% w / w of the pharmaceutical composition and / or dosage form. According to other aspects of the present disclosure, the amount of the lubricant is about 1.75% w / w of the pharmaceutical composition and / or dosage form.

[0297] In some embodiments, the pharmaceutical composition and / or dosage form comprises a glidant. Various types of glidants may be used in the pharmaceutical composition and / or dosage form as disclosed herein. In an embodiment, the glidant may be colloidal silicon dioxide, hydrous magnesium silicate, or calcium silicate. In an embodiment, the glidant is colloidal silicon dioxide. In an embodiment, the pharmaceutical composition and / or dosage form comprises about 0.5% w / w to about 10% w / w, or about 2% w / w to about 9% w / w, or 2% w / w to about 8%, or about 2% w / w to about 7%, or about 3% w / w to about 8% w / w, or about 3% w / w to about 7% or about or about 4% w / w to about 7% w / w, or about 4% w / w to about 6% w / w, or about 1 % to about 5%, or any number therebetween of the glidant. In an embodiment, the pharmaceutical composition and / or dosage form comprises at least about 2% w / w, or at least about 2.5 % w / w, or at least about 3% w / w, or at least about 3.5% w / w, or at least about 4% w / w, or at least about 4.5% w / w, or at least about 5% w / w, or at least about 5.5% w / w, or at least about 6% w / w, or at least about 6.5% w / w, but not more than 9% w / w, or any amount therebetween of the glidant. In an embodiment, the amount of the glidant is about 1.25% to about 1.75% w / w of the pharmaceutical composition and / or dosage form, In an embodiment, the amount of the glidant is about 1.5% w / w of the pharmaceutical composition and / or dosage form.

[0298] According to other aspects of the present disclosure, the glidant is colloidal silicon dioxide. According to other aspects of the present disclosure, the amount of the glidant is about 1.25% to about 1.75% w / w of the pharmaceutical composition and / or dosage form. According to other aspects of the present disclosure, the amount of the glidant is about 1.5% w / w of the pharmaceutical composition and / or dosage form.

[0299] In some embodiments, the pharmaceutical composition comprises: mirodenafil or a pharmaceutically acceptable salt thereof in an amount of about 10 mg to about 50 mg; a filler or a binder in an amount of about 40% to about 80% w / w of the pharmaceutical composition; a disintegrant in an amount of about 10% to about 30% w / w of the pharmaceutical composition; a lubricant in an amount of about 1% to about 5% w / w ofthe pharmaceutical composition; and a glidant in an amount of about 1% to about 5% w / w of the pharmaceutical composition.

[0300] In some embodiments, the dosage form includes an intragranular component and an extragranular component.

[0301] In some embodiments, the intragranular component constitutes about 20% to about 99% w / w, or about 30% to about 98% w / w, or about 40% to about 97% w / w, or about 40% to about 96% w / w, or about 50% to about 95% w / w, or about 60% to about 90% w / w, or about 70% to about 90% w / w, or about 75% to about 85% w / w, or any number therebetween, of the dosage form. In an embodiment, the intragranular component constitutes about 75% to about 85% w / w of the dosage form. In an embodiment, the intragranular component constitutes about 80.75% w / w of the dosage form.

[0302] The intragranular component comprises one or more pharmaceutically acceptable carriers including at least one of an intragranular binder, an intragranular filler, an intragranular disintegrant, an intragranular lubricant, or an intragranular glidant.

[0303] In an embodiment, the intragranular filler content in the dosage form is about 50% to about 65% w / w, or about 55% to about 70% w / w, or about 60% to about 75% w / w, or about 60% to about 65% w / w, or about 65% to about 80% w / w, or about 70% to about 85% w / w, or about 80% w / w to about 95% w / w, or about 82% w / w to about 93% w / w, or about 84% w / w to about 89% w / w, or any number therebetween, of the dosage form, In an embodiment, the intragranular filler content in the dosage form is about 60% to about 65% w / w of the dosage form. In an embodiment, the intragranular filler content in the dosage form is about 61.75% w / w of the dosage form.

[0304] In an embodiment, the intragranular binder content in the dosage form is about 50% to about 65% w / w, or about 55% to about 70% w / w, or about 60% to about 75% w / w, or about 60% to about 65% w / w, or about 65% to about 80% w / w, or about 70% to about 85% w / w, or about 80% w / w to about 95% w / w, or about 82% w / w to about 93% w / w, or about 84% w / w to about 89% w / w, or any number therebetween, of the dosage form. In an embodiment, the intragranular binder content in the dosage form is about 60% to about 65% w / w of the dosage form. In an embodiment, the intragranular binder content in the dosage form is about 61.75% w / w of the dosage form.

[0305] In an embodiment, the intragranular disintegrant content in the dosage form is about 0.01% to about 40% w / w, or about 0.05% to about 30% w / w, or about 0.1% to about 20% w / w, or about 0.1% to about 15% w / w, or about 0.1% to about 10% w / w, or about 0.1%to about 5% w / w, or about 1 % to about 5% w / w, or about 2% to about 4% w / w, or about 2% to about 3% w / w, or any number therebetween of the dosage form. In an embodiment, the intragranular filler content in the dosage form is about 2% to about 3% w / w of the dosage form. In an embodiment, the intragranular filler content in the dosage form is about 2.5% w / w of the dosage form.

[0306] In an embodiment, the intragranular lubricant content in the dosage form is about 0.01% to about 40% w / w, or about 0.05% to about 30% w / w, or about 0.1% to about 20% w / w, or about 0.1% to about 15% wAv, or about 0.1% to about 10% w / w, or about 0.1% to about 5% w / w, or about 0.1% to about 4% w / w, or about 0.1% to about 3% w / w, or about 0.5% to about 5% w / w, or about 0.5% to about 4% w / w, or about 0.5% to about 3% w / w, or about 0.5% to about 2% w / w, or about 0.5% to about 1.5% w / w, or any number therebetween of the dosage form. In an embodiment, the intragranular filler content in the dosage form is about 0.5% to about 1.5% w / w of the dosage form. In an embodiment, the intragranular filler content in the dosage form is about 1% w / w of the dosage form.

[0307] In an embodiment, the intragranular glidant content in the dosage form is about 0.01% to about 40% w7w, or about 0.05% to about 30% w7w, or about 0.1% to about 20% w / w, or about 0.1% to about 15% w / w, or about 0.1% to about 10% w / w, or about 0.1% to about 5% w / w, or about 0.1% to about 4% w / w, or about 0.25% to about 5% w / w, or about 0.25% to about 4% w / w, or about 0.25% to about 2% w / w, or about 0.25% to about 1.5% w / w, or about 0.25% to about 1% w / w, or about 0.25% to about 0.75% w / w, or any number therebetween of the dosage form. In an embodiment, the intragranular glidant content in the dosage form is about 0.25% to about 0.75% w / w of the dosage form. In an embodiment, the intragranular glidant content in the dosage form is about 0.5% w / w of the dosage form.

[0308] The extragranular component comprises one or more pharmaceutically acceptable carriers including at least one of a binder, a filler, a disintegrant, a lubricant, or a glidant,

[0309] In an embodiment, the extragranular disintegrant content in the dosage form is about 1% to about 50% w / w, or about 5% to about 40% w / w, or about 5% to about 30% w / w, or about 5% to about 25% w / w, or about 10% to about 30% w / w, or about 10% to about 25% w / w, or about 15% to about 20% w / w, or any number therebetween of the dosage form. In an embodiment, the extragranular filler content in the dosage form is about 15% to about 20% w / w of the dosage form. In an embodiment, the extragranular filler content in the dosage form is about 17.5% w / w of tire dosage form.

[0310] In an embodiment, the extragranular lubricant content in the dosage form is about 0.01% to about 10% w / w, or about 0.05% to about 10% w / w, or about 0.1% to about 10% w / w, or about 0.1% to about 5% w / w, or about 0.1% to about 4% w / w, or about 0.1% to about 3% w / w, or about 0.5% to about 5% w / w, or about 0.5% to about 4% w / w, or about 0.5% to about 3% w / w, or about 0.5% to about 2% w / w, or about 0.5% to about 1% w / w, or any number therebetween of the dosage form. In an embodiment, the extragranular filler content in the dosage form is about 0.5% to about 1% w / w of the dosage form. In an embodiment, the extragranular filler content in the dosage form is about 0.75% w / w of the dosage form.

[0311] In an embodiment, the extragranular glidant content in the dosage form is about 0.01% to about 10% w / w, or about 0.05% to about 10% w / w, or about 0.1% to about 10% w / w, or about 0.1% to about 5% w / w, or about 0.1% to about 4% w / w, or about 0.1% to about 3% w / w, or about 0.5% to about 5% w / w, or about 0.5% to about 4% w / w, or about 0.5% to about 3% w / w, or about 0.5% to about 2% w / w, or about 0.5% to about 1.5% w / w, or any number therebetween of the dosage form, In an embodiment, the extragranu lar glidant content in the dosage form is about 0.5% to about 1.5% w / w of the dosage form. In an embodiment, the extragranular glidant content in the dosage form is about 1 % w / w of the dosage form.

[0312] The dosage form may further comprise a coating agent which can be applied as a film coating. Examples of the coating agent that may be used in the pharmaceutical composition and / or dosage form as disclosed herein include Opadry White, Sepifilm White, or Aquarius Prime White, In an embodiment, the coating agent is Opadry White.

[0313] A number of implementations have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other implementations are within the scope of the following claims.

[0314] EXAMPLES

[0315] Aspects of the present teachings may be further understood in light of the following examples, which should not be construed as limiting the scope of the present teachings in any way.

[0316] Example 1 - A Phase 2 Study on the Efficacy and Safety of ARI 001, aPhosphodiesterase-5 Inhibitor, in Patients with Miki-to-Moderate Alzheimer’s Disease

[0317] ABSTRACT

[0318] Background: Studies have found a potential relationship between use of PDE5 inhibitors and neuroprotection from Alzheimer’s disease (AD). This Phase 2 study evaluated the efficacy and safety of ARlOOl, a PDE5 inhibitor, in patients with mild-to-moderate AD.

[0319] Objectives: To evaluate the efficacy and safety of ARlOOl when administered to adults with mild-to-moderate Alzheimer’s disease.

[0320] Design: This was a Phase 2, double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of 10 mg ARlOOl and 30 mg ARlOOl compared to placebo for the treatment of patients with ild-to-moderate AD. The treatment phase was 26 weeks, followed by an optional 26-week extension phase.

[0321] Setting: The trial was conducted at 21 sites in the United States.

[0322] Participants: The trial enrolled 210 adults, aged 55-80 years with mild-to-moderate cognitive dementia. The study population was 66% female, 13% African-American, and 20% Hispanic / Latino participants.

[0323] Intervention: Participants were randomized 1: 1: 1 at 70 participants per group to receive placebo, 10 mg ARlOOl, or 30 mg ARlOOl, once daily by oral administration, for 26 weeks. Participants who completed the 26-week treatment phase had the option to continue in a 26-week extension phase, during which participants receiving ARlOOl remained at their dose and placebo patients were re-randomized to receive 10 or 30 mg ARlOOl.

[0324] Measurements: Co-primary’ efficacy endpoints were change from baseline at Week 26 in 1) Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13) and 2) Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). Secondary' endpoints included measures of cognition, daily’ living, and depression. Plasma levels of AD biomarkers pTau 181, glial fibrillary' acidic protein (GFAP), neurofilament light (NfL), and amyloid p (A ) 42 / 40 ratio were examined. Safety was assessed by adverse events, clinical laboratory’ values, vital signs, and electrocardiograms.

[0325] Results: Of 210 randomized participants, 173 (82%) completed the 26-week double-blind treatment phase, with 141 participants entering the extension phase and 115 (82%) of those participants completing it. ARlOOl was safe and well-tolerated, with no differences in the number or seventy of adverse events in ARlOOl treatment groupscompared to placebo, and 1 serious adverse event, syncope, considered related to treatment. There were no statistical differences between placebo and ARI 001 treatment groups in primary and secondary efficacy endpoints at 26 weeks. Treatment with 30 mg AR1001 resulted in a reduction in pTaul81 and GFAP biomarker levels compared to placebo at 26 weeks (p <.05), and pTau181 levels were significantly reduced at 52 weeks in both 10 mg ARI 001 and 30 nig AR1001 groups compared to baseline values (p <.001). Post-hoc analyses showed that higher baseline pTaul81 levels correlated with greater cognitive decline over 26 weeks in the placebo group, but that this correlation was abrogated by ARI 001.

[0326] Conclusions: In this Phase 2 study in patients with mild to moderate AD, ARI 001 was well tolerated and safe. The biomarker analyses suggest a possible diseasemodifying effect of 30 mg AR1001 as indicated by reduction of pTaul81, GFAP, pTau217, and pTau217 / AP42.

[0327] INTRODUCTION

[0328] Alzheimer’s disease (AD) is the most common cause of dementia, accounting for 60-70% of cases worldwide. According to the World Health Organization, more than 55 million people worldwide had dementia in 2021, with 10 million new' cases per year, at a global cost expected to reach $2.8 trillion USD per year by 2030. There are no medications or therapies that can arrest AD-related neurodegeneration and cognitive decline, creating a need for treatment options that, at a minimum, maintain quality of life for AD patients.

[0329] It is widely believed that the pathogenesis of AD is multifactorial, involving genetic factors, cholinergic dysfunction, amyloid plaque formation, tau aggregation, inflammation, and oxidative stress. Monoclonal antibodies that target cerebral amyloid have recently received FDA approval for the treatment of early AD, but these drugs have safety concerns in the form of amyloid-related imaging abnormalities (ARIA) and are currently administered intravenously, limiting access for some patients. Targeting amyloid alone appears to be insufficient to alter the clinical course of the disease. Polypharmacologic and combined therapeutic approaches that target multiple pathogenic pathways may hold promise, lire development of safe and easily administered medicines would provide additional treatment options to patients, particularly those who are not suitable for monoclonal antibody therapy, particularly those who are at risk for ARIA from monoclonal antibody therapy, such as ApoE4 homozygotes, patients with cerebral amyloid angiopathy, and patients taking concomitant antithrombotic or thrombolytic medication.

[0330] Phosphodiesterase-5 (PDE5) inhibitors, which include sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis), have been widely used for the treatment of erectile dysfunction (ED) and pulmonary arterial hypertension, and have extensive clinical and safety data. Retrospective clinical studies examining the effect of PDE5 inhibitors on the development of AD have demonstrated reduced risk of development of AD in patients taking PDE5 inhibitors. An analysis of > 7 million US health insurance claims found that use of sildenafil was associated with a 30-60% reduced risk of AD compared to non-sildenafil users. Tn a. study of UK health records, men > 40 years taking an ED medication had a reduced hazard ratio of receiving an AD diagnosis compared to men not taking ED medication, and the hazard ratios were lowest among men frequently issued ED prescriptions.

[0331] PDE5 inhibitors increase cellular levels of cycli c GMP (cGMP), activating protein kinase G (PKG) and its downstream effectors including cyclic adenosine monophosphate responsive element binding protein (CREB) and phosphatidylinositol 3-kinase (PI3k) / Akt. CREB has been linked to preservation of neuronal signaling and synaptic plasticity, and Akt activation protects neurons through inhibition of glycogen synthase kinase 3P and reduced phosphorylation of Tau.

[0332] Preclinical studies of PDE5 inhibitors in cell and animal models of neurode generative diseases support a role in neuroprotective and anti-inflammatory processes. In pluripotent stem cells derived from AD patients, sildenafil treatment reduced hyperphosphorylated Tau levels and enhanced neurite outgrowth. Treatment with sildenafil and tadalafil reduced expression of pro-inflammatory cytokines, reduced apoptosis and autophagy, increased neurogenesis, and ameliorated cognitive and behavioral deficits in rodent models of neurodegenerative diseases including AD.

[0333] ARI 001 (mirodenafil) is a PDE5 inhibitor with high inhibition toward PDE5 (ICso:=:0.34 nM). ARI 001 appears to penetrate the blood-brain barrier, as levels of14C[mirodenafil] were present in the brains of rats. Mirodenafil inhibits the transcriptional activity of the glucocorticoid receptor and activates the Wnt / p-catenin signaling pathway, which enhances synaptic plasticity recover. In neuroblastoma SH-SY 5Y cells treated with the toxic amyloid fonn Ap42, administration of mirodenafil reduced levels of Ap and markers of apoptosis (cleaved caspase-3 and poly ADP-ribose pol merase), and increased levels of the autophagy marker p62. In the APP-C105 and ApoE4 knock-in transgenic mouse models of AD, mirodenafil-treated mice showed significant improvements in cognitive performance in the Morris Water Maze and passive avoidance tests compared to controlanimals, had lower levels of Aj342 and phosphorylated Tau, and had improved cerebrovascular perfusion and tight junction gene expression. Mirodenafil inhibits the transcriptional activity of the glucocorticoid receptor and activates the Wnt / p-catenin signaling pathway, providing additional synaptic plasticity recovery. A recent study also showed that mirodenafil significantly improved sensorimotor and cognitive recovery and reduced the amount of degenerative and apoptotic cell ne urons in experimental models of stroke.

[0334] Due to the potent inhibition of PDE5 by ARlOOl, its blood-brain barrier penetration, and its amelioration of AD pathology and symptoms in preciinical models, ARI 001 as evaluated in a Phase 2 study in patients with mild-to-moderate AD to determine its safety and preliminary efficacy. The design of the study and the results are described below.

[0335] METHODS

[0336] Trial Conduct and Oversight

[0337] ARI 001-ADP2-US01 (NCT03625622) was a 26-week, Phase 2, randomized, placebo-controlled, double-blinded study conducted across 21 sites in the United States from January 2019 to June 2021. The study was conducted in accordance with the protocol, provisions in the Declaration of Helsinki, regulations of tire United States Food and Drug Administration, and guidelines of Good Clinical Practice as outlined by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Institutional Review Boards at each site reviewed and approved the study protocol and amendments. All participants and / or appropriate caregivers provided informed consent. The trial was sponsored by AriBio. Authors from the company contributed to the study design, data analysis, and results interpretation, inclusive of writing this report and submitting it for publication.

[0338] Study Participants

[0339] Key eligibility criteria were 55-80 years of age, dementia clinical staging 4 or 5 by 2011 National Institute on Aging and Alzheimer’s Association (NIA-AA) criteria, and a mini-mental state exam (MMSE) score between 16 and 26 (moderate to mild cognitive impairment) (Fig. 1 A). Study participants were required to have an MRI or CT scan after the onset of dementia symptoms that showed findings consistent with a diagnosis of AD at the time of the study, without clinically significant comorbid pathologies. Amyloid pathologyconfirmation was not required.

[0340] FDA-approved Alzheimer’s disease medications (donepezil, rivastigmine, galantamine, memantine, or combinations of these) were allowed if doses were stable for > 3 months at tire time of study enrollment.

[0341] ApoE4 prototypic status was determined using Lumipulse G ApoE4 and Lumipulse G Pan-ApoE protein assays.

[0342] Randomization and intervention

[0343] Eligible patients were randomized 1:1: 1 with a randomization block size of 6 to receive a daily oral dose of placebo, 10 mg AR1001, or 30 mg AR1001 for 26 weeks. The study was double blinded to participant and investigator. Upon completion of the 26-week treatment phase, participants were given the option to continue for an additional 26-week extension phase. Participants assigned to ARI 001 for the treatment phase continued at the same dose in the extension phase, and participants assigned to placebo were rerandomized 1:1 with a block size of 2 to receive 10 mg or 30 mg ARI 001 (Fig. 1A).

[0344] Endpoints and Assessments

[0345] The co-primary efficacy endpoints were: 1) change from baseline to Week 26 in the 13-item Alzheimer’s Disease Assessment Scale -Cognitive Subscale 13 (ADAS-Cog 13), with scores ranging from 0 (no impairment) to 85; and 2) change from baseline to Week 26 in the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), a 7-point scale that evaluates improvement or worsening of AD symptoms.

[0348] Secondary efficacy endpoints included changes from baseline to Week 26 in MMSE-2, Neuropsychiatric Inventory (NPI), Geriatric Depression Scale (GDS), and Quality of Life in Alzheimer’s Disease (QOL-AD) (Fig. 1A).

[0347] Plasma samples for analysis of putative AD biomarkers pTau-181, Ap42 / 40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and pTau-217 were collected from consented participants in 10 ml EDTA tubes, centrifuged, and stored frozen in 1 ml aliquots. Plasma samples were diluted 4x and ran in duplicate. The mean of duplicates for each sample -was determined and included in the analysis if the coefficient of variation was < 25%. Plasma levels of pTau-181 were quantified using the Simoa Human pTau-181 Advantage V2 Kit (Quanterix). Plasma pTau-217 was quantified using Lumipulse® G pTau 217 kit (Fujirebio, Malvern, PA), Plasma levels of GFAP, A 42 / 4O ratio, and NfL were quantified using the Simoa Neurology 4-Plex E Advantage Kit (Quanterix). pTau-217 was quantified using Lumipulse® G pTau 217 kit (Fujirebio, Malvern, PA).

[0348] Investigators reported adverse events using MedDRA Versiion 24.0 based on assessments of patient symptoms, vital signs, physical examinations, electrocardiography (ECG) readings, clinical laboratory tests (hematology, blood chemistry, and urinalysis), and the Columbia Suicide Severity Rating Scale (C-SSRS).

[0349] Cognitive and safety assessments were conducted at baseline (Week 0) and during tire treatment phase at Weeks 4, 13, and 26, along with a safety phone call at Week 20. During the extension phase, cognitive and safety assessments were conducted at Weeks 30, 39, and 52, with a safety phone call at Week 46. A safety follow-up visit was conducted 2 weeks after the last dose of study drug (Fig. 1A). Plasma was collected for biomarker assessment at baseline (Week 0), Week 13, Week 26, Week 39, and Week 52.

[0350] Statistical Methodology

[0351] Efficacy outcomes were analyzed in the Intent-to-Treat (ITT) population, which included patients who took at least one dose of study drug and had at least one postdose efficacy measurement. Descriptive statistics were used to summarize continuous variables by treatment group. For the primary analysis, the change from baseline in ADAS-Cog 13 at Week 26 was analyzed with an ANC-OVA model including the factor of treatment and the Baseline ADAS-Cog 13 result as a covariate. No repeated measures were included in the model. For the co-pnmary endpoints, the overall Type I error of 0.05 was controlled using the Holm step-down procedure. To reject the null hypothesis that ARlOOl was not different from placebo with respect to changes from baseline in ADAS-Cog 13 and ADCS-CGIC at Week 26, both co-prirnary endpoints needed to show statistical significance. Similar ANCOVA models were used to analyze secondary outcomes at Week 26. Paired sample t tests were used to compare Week 52 to baseline for exploratory’ efficacy endpoints.

[0352] Biomarker analyses evaluated changes from baseline to Week 26 in pTau-181, in Ap 42 / 40 ratio, GFAP, NfL, pTau-217, and pTau-217 / Ap42 ratio with independent samples tests for comparisons between treatment groups and placebo. Safety’ outcomes were summarized overall and by the treatment group to which patients were randomized.Outcomes were further classified by severity, seriousness, and relation to the study drug. Descriptive statistics were used to describe the data.

[0353] Post-hoc analyses were performed in participants in the top tertile of baseline pTau-181 levels (corresponding to > 5.0 pg / mL) and corresponding lower two tertiles using Mann-Whitney U tests to compare between groups. The analysis was conducted for each treatment group using a linear mixed effect model with baseline pTau181 as apredictor. Efficacy endpoints and pTau181 levels were also examined in the top third of participants with the highest baseline pTaulSl (> 5.0 pg / ml) using Mann-Whitney U tests to compare between groups and Wilcoxon Signed Ranks Test to compare between baseline and Week 52. Similarly, analyses were conducted for pTau-217 (> 0.185 pg / mL) and the pTau-217 / Ap42 ratio (> 0.00371) at Week 26 using Mann-Whitney U tests.

[0354] Sample Size Calculation

[0355] "Die population of 210 participants was selected based an assumed 20% drop-out rate that would yield an evaluable sample size of 168 patients, providing the trial with 90% power to show that the ARI 001 treatment groups altered disease progression compared to placebo, as measured by a 2-point difference at Week 26 in the group means of ADAS-Cog 13 scores, with an overall standard deviation of 6.7 points. For ADCS-CGIC, a 0.35 difference in group means can be detected as statistically significant with a sample size of 58 subjects per group assuming the change from baseline in ADCS-CGIC has an overall standard deviation of 1.2 points.

[0356] RESULTS

[0357] Trial Population

[0358] The completion rate for the 26-week treatment phase was 78.6% in the placebo group, 87.1% in the 10 mg AR1001 group, and 81.4% in the 30 mg AR1001 group. Of 324 patients screened, 2.10 (64.8%) were randomized at 70 participants per group into placebo, 10 mg ARI001, and 30 mg AR1001 (Fig. IB). Of the 173 participants who completed the treatment phase, 141 continued to the optional extension phase. The completion rate for participants entering the extension phase was 81.5% (115 / 141) (Fig, IB).

[0359] Mean age of participants was 70.6 years and the population was 65.7% female (Table 1). Tire racial and ethnic makeup of participants who were enrolled reflected a diverse AD population, with 13.3% African-American and 20.0% Latino or Hispanic participants. Most baseline measurements were similar across groups, although there were more participants with mild dementia (MMSE-2 > 21) in the placebo group (74.3%) than hi 10 mg ARI 001 (62.9%) or 30 mg AR1001 (52.9%) groups. The remaining participants had moderate dementia (MMSE-2 16-20).

[0366] Of 181 participants screened for ApoE4 status, 27 (14.9%) were homozygous and 77 (42.5%) were heterozygous, an overall ApoE4 carrier rate of 57.4% (Table 1).

[0361] Safety Assessments

[0362] During the 26-week placebo-controlled treatment phase, ARI 001 at 10 and 30 mg had similar adverse event profiles compared to placebo (Table 2). There was 1 serious adverse event of syncope in the 30 mg ARI 001 group that was considered related to study treatment. One participant in the 10 mg ARI 001 group died during the treatment phase due to a serious adverse event of COVID- 19 that was not considered related to study treatment. Fourteen participants had adverse events that led to treatment discontinuation, with no notable differences in discontinuations between treatment groups. All adverse events considered related to treatment intervention were graded as mild or moderate (Grade 1 or 2) in severity.

[0363] The most common adverse events during the treatment phase, occurring in >5% of participants in any treatment group, were fall, nausea, headache, urinary tract infection, dizziness, and arthralgia (Table 2).

[0384] During the extension phase, in which placebo subjects were randomized to receive 10 or 30 mg ARIOCH, there were no Grade 3 or higher adverse events, SAEs, or study discontinuations related to study treatment. The only AE occurring in 5% or more of participants in either the 10 mg or 30 mg ARI 001 groups during the extension phase was urinary tract infection (Table 2).

[0365] Biomarker Analysis

[0366] We examined levels of pTau 181, GFAP, NfL, the AP42 / 40 ratio, pTau217, and the pTau217 / Ap42 ratio in placebo and AR1001 treatment groups. Change from baseline in plasma levels of biomarkers. Comparisons of treatment groups at Week 26. Baseline was normalized to 0 at Week 0 and the percentage change from baseline at Week 26 is shown (Figs. 2A and 2F-H). pTaul81 change from baseline (pg / ml) at Weeks 26 and 52 (Fig. 2B), GFAP change from baseline (pg / ml) at Weeks 26 and 52 (Fig. 2C). NfL change from baseline (pg / ml) at Weeks 2.6 and 52 (Fig. 2D). Ap42 / Ap40 ratio change from baseline at Weeks 26 and 52. Lines have been shifted slightly off center at Weeks 2.6 and 52 to allow distinguishing between them. (Fig. 2E). pTau217 change from baseline (pg / ml) at Week 26 (Fig. 2G). pTau217 / Ap42 ratio change from baseline (pg / ml) at Weeks 26 and 52 (Fig. 2H). The following denote standard error m the figure: * p <.05 30 mg ARI 001 vs. placebo by Mann-Whitney. **p<.001 Week 52 vs baseline by Wilcoxon Signed Ranks Test, Ap: amyloid beta; GFAP: glial fibrillary' acidic protein; NfL; neurofilament light; pTaul 81: phosphorylated Tau-181; pTau217: phosphorylated Tau-217; SE: standard error. (Figs. 2A-2H).

[0367] Comparison between placebo and ARI 001 treatment groups at Week 26 found that participants on placebo had increased (worsening) mean change from baseline for pTaul81, GFAP, and NfL, whereas participants on 30 mg ARI 001 had decreased (improved) mean change from baseline for these biomarkers. In participants treated with 10 mg ARI 001. biomarker levels of pTaul 81 improved, and GFAP and NfL worsened. There was no appreciable change from baseline in AP42 / 40 ratio across groups (Fig. 2A).

[0368] "Die difference in the change from baseline in pTaul81 levels was statistically significant between placebo (0.31 pg / ml; [95% CI: -0.09, 0.70]) and 30 mg AR1001 (-0.46 pg / ml; [95% CI: -1.04, 0.12]; p.034). The 10 mg AR100I group also had decreased change from baseline compared to placebo (-0.29 pg / ml; [95% CI: -0.85, 0.26], although the difference was not statistically significant (Figs. 2A-B). There was also a significant difference in change from baseline in GFAP levels between placebo (23.9 pg / ml;[95% CI: -3.8, 51.6]) and 30 mg AR1001 (-7.0 pg / ml; [95% CI: 26.2, 12.2]; p= ==0.042) (Fig.2A, 2C). lire difference in the change from baseline in pTau217 levels was statistically significant between placebo (0.037 pg / ml; [95% CI: -0.104, 0.162]) and 30 mg AR1001 (-0.118 pg / ml; [95% CI: -0.223, -0.037]; p=.009), and between placebo (0.037 pg / ml; [95% CI: -0.104, 0.162]) and 10 mg AR1001 (0.020 pg / ml; [95% CI: -0.112, 0.123]; p.53’!).

[0369] To analyze the effects of ARI 001 on biomarkers through 52 weeks, we calculated change from baseline from Week 0 to Week 52 m participants treated for the entire duration with ARI 001 (Fig. 2B-2E). For pTau181, statistically significant improvements from baseline were observed for both lO mg ARlOOl (-1.21 pg / ml; [95% CI: -1.78, -0.65]; p< 0001) and 30 mg AR1001 (-1.36 pg / ml; [95% CI: -2.21, -0.50]; p<.0001) (Fig. 2B).GFAP levels remained near baseline through 52 weeks for 10 and 30 mg ARI 001 groups (Fig. 2C). NfL levels in the 30 mg AR1001 group remained lower (improved) or at baseline through Week 52, although the assay had high variability (Fig. 2D). Change from baseline in the AP42 / 40 ratio increased (improved) in the 30 mg AR1001 group at Week 52, although the result -was not statistically significant (Fig. 2E).

[0370] Post-hoc Analyses

[0371] Plasma samples were collected for analysis of biomarkers pTau- 1 1, AP42 / 40 ratio, GFAP, NfL, pTau-217, and pTau-2.17 / Ap42 ratio. Participants on placebo had worsening mean change from baseline at Week 26 for pTau-181, GFAP, NfL, pTau-217, and pTau-217 / Ap42 ratio. In contrast, participants on 30 mg AR1001 had improved mean change from baseline at Week 26 for the same biomarkers (Table 3). There were no appreciablechanges in AP42 / 40 ratio in any group. A Forest plot of the mean percentage difference from placebo in biomarker levels in 10 mg and 30 mg ARI 001 groups is shown in Fig. 2F.Variability was high in the biomarker assays, nevertheless the difference m mean change from baseline between the 30 mg ARI 001 group and placebo was p <.05 for pTau-181, pTau-217, GFAP, and pTau-217 / Ap42 ratio.

[0372] Baseline pTaulSl as Covariate

[0373] At time of the trial, NIA-AA criteria did not require biomarker confirmation of cerebral amyloid in clinical trials. In basing eligibility on cognitive measures (e.g., MMSE), there was a possibility that the population had mixed AD and non-AD forms of dementia. To select for participants with a likelihood of having AD, we performed post-hoc analyses on participants in the top tertile of baseline pTau-181 (corresponding to > 5.0 pg / mL), along with the corresponding lower two tertiles (pTau-181 < 5.0 pg / mL). pTau-181 has been shown to correlate with cerebral amyloid PET. A similar post-hoc tertile analysis was used to analyze donanemab and baseline tau PET. Consistent with findings that the rate of cognitive decline in AD patients correlates with plasma pTaulSl levels, it was found in the placebo group that baseline p'Taul 81 was a significant predictor of worsening ADAS-Cogl 3 (p=. O4) (Fig. 3A). This association between baseline pTaul81 and ADAS-Cogl 3 decline was blunted in the ARI 001 treatment groups, which found no association between baseline pTaulSl and ADAS-Cogl3 at 10 mg AR1001 (p-,46) or 30 mg AR100I ( p== =.91 ).

[0374] Participants taking placebo in the high pTau-181 cohort showed worsening performance in ADAS-Cog-13 (Fig. 4A, 4D) and ADCS-CGIC (Fig. 4B, 4E) at Week 26, whereas participants in the lower pTau-181 cohort had improved cognitive performance. These data support a scenario in which higher pTau-181 correlates with more rapid AD progression.

[0375] Participants in the high pTau-181 cohort treated with AR1001 had slower cognitive decline in ADAS-Cogl3 and ADCS-CGIC relative to participants treated with placebo (Figs. 4A-4C), though sample sizes were small and the study was not powered to detect a statistical difference.

[0376] A similar trend was evident with ADAS-CGIC, as baseline pTaulSl was more predictive of cognitive decline in the placebo group than in either AR1001 treatment group, although the relationship was not statistically significant.

[0377] DISCUSSION

[0378] This Phase 2 study aimed to evaluate the efficacy and safety of AR I 001 inpatients with mild-to-moderate AD, Oral ARI 001 at 10 or 30 mg once daily was well-tolerated, with a safety profile similar to that of placebo and few serious or severe adverse events related to treatment over 52 weeks. The only serious adverse event was syncope, which resolved during the trial. The completion rate in both the 26-week treatment phase and 26-week extension phase was 82%. The favorable safety profile of AR 1001 and its oral administration are strengths of this treatment compared to infusion-based therapies.

[0379] In post-hoc analyses, differences were observed between 30 mg ARI 001 and placebo in change from baseline in levels of plasma AD biomarkers pTau-181, GFAP,pTau-217, and pTau-217 / Ap42 ratio. The biomarker findings are consistent with effects observed in preclinical models of AD in which treatment with AR1001 and other PDE5 inhibitors resulted in lower levels of toxic Aβ and phosphorylated Tau.

[0380] A limitation of the study was the possible heterogeneity of the population, which may have included participants with both Alzheimer’s and non-Alzheimer’s dementias. The use of biomarkers to determine cerebral amyloid was not required by NIA-AA criteria at the time of the trial. The possible inclusion of participants who may have had other types of dementia is supported by the lower level of participants who were ApoE4 positive (57%) compared to other AD trials that required amyloid positivity, which had ApoE4 carriers in the range of 65-70%. To analyze participants who were most likely to have AD, we performed analyses on those with the highest baseline levels of pTau 181 and found a slower rate of cognitive decline in participants treated with AR1001 as measured by ADAS-Cogl3. Supporting the relationship between pTau 181 and AD pathology, we found a significant correlation between baseline level of p'Tau181 and the rate of cognitive decline, and this relationship was blunted by treatment with AR 1001.

[0381] CONCLUSIONS

[0382] This Phase 2 study was designed to evaluate the safety and efficacy of ARI 001 for the treatment of mild to moderate Alzheimer’s disease. AR 1001 treatment was well-tolerated and safe. When patients with a likelihood of having AD were examined, declines in cognitive performance were reduced relative to placebo in AR 1001 -treated subjects. There were improvements in levels of pTau-181, GFAP, pTau-217, and pTau-217 / AP42 ratio biomarkers in the 30 mg group compared to placebo.

[0383] GraphicsTable 1. Baseline characteristics of the study populationPlacebo AR1001 10 mg AR1001 30 mg CharacteristicAge (years), mean (SD) 70.4 (5.5) 70.9 (6.5) 70.4 (6.8) Gender, n (%)Female 48 (68.6) 43 (61.4) 47 (67.1) Male 22 (31.4) 27 (38.6) 23 (32.9) Race, n (%)Black or African American 12 (17.1) 8 (11.4) 8 (11.4) White 58 (82.9) 60 (85.7) 62 (88.6) Other 0 2 (2.8) 0 Hispanic or Latino ethnicity, n (%) 13 (18.6) 13 (18.6) 16 (22.9) BMI (kg / m2), mean (SD) 28.1 (5.5) 29.6 (7.0) 28.7 (6.5) Ongoing AD treatment*, n (%) 36 (51.4) 40 (57.1) 46 (65.7) Baseline severity of cognitiveimpairment, n (%)Mild (MMSE-2 > 21) 52 (74.3) 44 (62.9) 37 (52.9) Moderate (MMSE-2 of 16-20) 18 (25.7) 26 (37.1) 33 (47.1) Outcome scores at baseline,mean (SD)ADAS-Cog 13 24.6 (10.0) 25.2 (9.6) 26.3 (11.0) MMSE-2: BV 11.8 (2.6) 11.3 (2.6) 10.4 (2.7) MMSE-2: SV 22.4 (3.8) 21.8 (3.8) 20.7 (3.9) NPI 8.0 (11.4) 7.7 (8.8) 7.9 (9.9) GDS 2.6 (2.2) 2.2 (2.3) 2.9 (2.4) QOL-AD: FV 34.5 (5.6) 34.8 (6.5) 34.7 (6.4) QOL-AD: PV 38.1 (6.1) 38.7 (6.5) 38.0 (6.5) Biomarkers at baseline, mean(SD)A342 / AB40 ratio 0.089 (0.014) 0.084 (0.016) 0.086 (0.041) pTau181 (pg / ml) 4.24 (2.16) 4.65 (2.43) 4.65 (2.66) NfL (pg / ml) 29.4 (16.5) 28.0 (14.6) 33.2 (38.8)GFAP (pg / ml) 256 (108) 259 (119) 257 (114) Apo E4 Status 62 subjects 59 subjects tested 60 subjects tested tested Homozygous 6 (9.7) 11 (18.6) 10 (16.7) Heterozygous 30 (48.4) 18 (30.5) 29 (48.3) ADAS-Cogl3 = Alzheimer’s Disease Assessment Scale - Cognitive Subscale 13; BMI = body mass index; GDS = Geriatric Depression Scale; GFAP = glial fibrillary acidic protein; MMSE-2: BV = Mini-mental Status Examination, 2nd Edition: Brief Version; MMSE-2: SV = Mini-mental Status Examination, 2nd Edition: Standard Version; NfL = neurofilament light; NPI = neuropsychiatric inventory; QOL-AD: FV = Quality' of Life in Alzheimer’s Disease: Family Version; QOL-AD: PV = Quality of Life in Alzheimer’s Disease: Participant Version; SD = standard deviation.*Ongoing AD treatment indicates concomitant administration of an approved medication for Alzheimer's disease (donepezil, rivastigmine, galantamine, or memantine) at a stable dose.Table 2 Summary of adverse eventsA. Treatment Phase (Weeks 0-26)Event, n (%) Placebo AR1001 10 mg AR1001 30( 8 - 70} n (%} n (%) n (%) Any adverse event 42 (60.0) 39 (55.7) 47 (67.1) Adverse event related to study drug 13 (18.6) 4 (5.7) 7 (10.0) Grade 1 (mild) 8 (11.4) 2 (2.9) 2 (2.9) Grade 2 (moderate) 5 (7.1) 2 (2.9) 5 (7.1) > Grade 3 0 0 0 Any serious adverse event 6 (8.6) 6 (8.6) 8 (11.4) Serious adverse event related to study 0 0 1 (1.4) treatmentDeath 0 1 (1.4) 0Death related to study treatment 0 0 0 Adverse event leading to treatment 7 (10.0) 3 (4.3) 4 (5.7) discontinuationAdverse event leading to study 6 (8.6) 3 (4.3) 4 (5.7) discontinuationAdverse events in clinical laboratory 9 (12.9) 12 (17.1) 15 (21.4) parametersAdverse events for >5% of patients in anygroupFall 2 (2.9) 2 (2.9) 5 (7.1) Nausea 2 (2.9) 1 (1.4) 5 (7.1) Headache 3 (4.3) 2 (2.9) 4 (5.7) Urinary tract infection 2 (2.9) 2 (2.9) 4 (5.7) Dizziness 5 (7.1) 0 1 (1.4) Arthralgia 5 (7.1) 0 0B. Extension Phase (Weeks 26-52)Event, n (%) 10 mg AR1001 30 mg AR1001 (M = 73)* (N = 68)* n (%) n (%) Any adverse event 38 (52.1) 33 (48.5) Adverse event related to study drug 4 (5.5) 6 (8.8) Grade 1 (mild) 2 (2.7) 6 (8.8) Grade 2 (moderate) 2 (2.7) 0 > Grade 3 0 0 Any serious adverse event 2 (2.7) 2 (2.9) Serious adverse event related to study treatment 0 0 Deaths 0 0 Adverse event leading to treatment discontinuation 3 (4.3) 4(5.7) Adverse event leading to study discontinuation 0 0 Adverse events in clinical laboratory parameters 10 (13.7) 9 (13.2)Adverse events for >5% of patients in any groupUrinary tract infection 6 (8.2) 3 (4.4) * Subjects who received placebo during the treatment phase and opted to continue to the extension phase were randomized to receive 10 mg ARI 001 (n=19) or 30 mg ARI 001 (n=20). These subjects were included in the extension phase safety analysis along with subjects who continued their ARI 001 treatment from the treatment phase.Table 3. Summary of Biomarker ResultsPlacebo 10 mg AR1001pTau-181 (pg / mL)Baseline value (SD) 4.24(2.16) 4.65 (2.43) 4.65 (2.66)No. participants evaluated* 41 51 45Mean change from baseline (95% CI) 0.31 (-0.09, 0.70) -0.29 (-0.85, 0.26) -0.46 (-1.04, 0.12) Mean difference vs. placebo -0.60 -0.77P value vs. placebo 0.093 0.034A 842 / 40 ratioBaseline value (SD) 0.089 (0.014) 0.084 (0.016) 0.086 (0.041)No. participants evaluated 40 49 41Mean change from baseline (95% Cl) 0 (-0.004, 0.003) 0.001 (-0.001, 0.005) 0.001 (-0.003, 0.004) Mean difference vs. placebo 0.001 0.001P value vs. placebo 0.483 0.932GFAPBaseline value (SD) 255.7 (107.8) 259.2 (118.6) 256.6 (113.8)No. participants evaluated 41 50 45Mean change from baseline (95% Cl) 23.9 (-3.8, 51.6) 11.9 (-14.0, 37.8) -7.0 (-26.2, 12.2) Mean difference vs. placebo -12.0 -30.9P value vs. placebo 0.393 0.042£Baseline value (SD) 29.4 (16.5) 28.0 (14.6) 33.2 (38.8)No. participants evaluated 41 50 45Mean change from baseline (95% Cl) 1.06 (-2.69, 4.82) 0.95 (-2.69, 4.59) -6.65 (-19.09, 5.79) Mean difference vs. placebo -0.25 -1.6P value vs. placebo .473 .052pTau-217Baseline value (SD) 0.622 (0.609) 0.632 (0.531) 0.734 (0.744)No. participants evaluated 40 51 42Mean change from baseline (95% Cl) 0.037 (-0.104, 0.162) 0.020 (-0.112, 0.123) -0.118 (-0.223, -0.037) Mean difference vs. placebo -0.017 -0.155P value vs. placebo .530 .009pTau-217 / A342 ratioBaseline value (SD) 0.027 (0.027) 0.030 (0.028) 0.041 (0.068)No. participants evaluated 40 51 41Mean change from baseline (95% Cl) 0.001 (-0.008, 0.006) -0.002 (-0.009, 0.003) -0.008 (-0.012, 0.001) Mean difference vs. placebo -0.003 -0.009P value vs. placebo .302 .020

[0384] Example 2: Plasma pTau217 and plasma pTau217 / Aβ42 ratioperformance in predicting amyloid positivity compared to CSF Ap42 / 40 ratio or PET in a screening cohort from a phase 3 registrational study

[0385] Background

[0386] Currently acceptable diagnostics to verify amyloid plaque in a dementia population are positron emission tomography (PET) or cerebral spinal fluid (CSF) ratios with FDA / EMA -approved amyloid tracers and assays. Blood-based biomarker (BBM) assays have shown promising concordance with PET amyloid and CSF ratios. BBMs can be considered as atool to triage screening patients into three groups: 1) amyloid positive; 2) amyloid negative; and 3) to be confirmed. Triaging using BBMs would limit time-consuming and difficult to schedule procedures and help democratize the diagnostic pathway, leading to more inclusivity in AD clinical trials. By referring fewer patients for lumbar puncture, which is needed to obtain CSF, and with limited access to PET scans and / or amyloid tracers, significant cost and time saving can be realized using BBMs. To achieve results that are adequately robust for triaging, BBM assays should have high sensitivity to detect true positive results and high specificity to limit false positives, and should limit the percentage of results that require confirmatory testing with PET or CSF. Phosphorylated tan variants, specifically pTau217 and / or pTau217 / amyloid P (A£) 1- 42 ratio, have demonstrated the best accuracy to detect amyloid pathology with specificity and sensitivity similar to PET or CSF. Here we show screening data from potential participants in a Phase 3 AD trial who had amyloid determined by pTau217 BBM assays along with PET or CSF.

[0387] Methods

[0388] Polaris-AD is a Phase 3, randomized, double-blind, placebo-controlled study of ARI 001, an oral phosphodiesterase-5 inhibitor, in participants with mild cognitive impairment or mild dementia due to AD. Participants are required to have a PET or CSF result positive for amyloid for inclusion. To test BBM triage models and determine assay performance, blood samples collected during screening were analyzed to determine plasma pTau217 and pTau217 / Ap42 ratio and compared to PET or CSF results obtained during the screening period. The Lumipulse G pTau217 and p-Amyloid 1-42 Investigational Use Only (IUO) plasma kits from Fujirebio were used to test 272 unique screening plasma samples. Samples were tested in singlicate on a Lumipulse G 1200 analyzer. Results for pTau217 and pTau217 / Ap42 ratio were compared to FDA-cleared Lumipulse®’ G P-Amyloid Ratio (1-42 / 1-40) for CSF with > 0.073 considered a negative result and < 0.072 a positive result. Triage models were analyzed in aggregate, by age and sex, and by baseline AD cognitiveresults.

[0389] Results

[0390] Of 272 samples collected, 256 (94.1%) were evaluable for pTau217 / Ap42 ratio (excluded if no CSF ratio or pTau217 result was below range of assay) and 265 (97.4%) were evaluable for pTau 217 (excluded if no CSF ratio). The plasma pTau217 / Ap42 ratio resolved 78.9% of patients: 45.3% were positive and 33.6% were negative, with 21.1% requiring confirmation by PET or CSF for amyloid positivity (Table 4).

[0391] For the plasma pTau217 / A 42 ratio assay, there was strong concordance with PET or CSF A 42 / 40 ratio, as the positive predictive value (PPV) was 91.4% (106 / 116) for positive results, and 2.3% (2 / 86) for negative results. Of the 54 assays that required confirmation, 30 were positive and 24 were negative upon confirmation by PET / CSF. The positive likelihood ratio (PLR) of 9.06 suggests that PPV is an informative statistic in predicting positivity, whereas the PLR for negative plasma assay results was 0.02, indicating that negative predictive value (NP V) is an informative statistic in predicting negativity (Table 4).

[0392] The plasma pTau217 assay also performed with high sensitivity, with a 92.9% PPV for positive samples (92 / 99) and a 3% PPV for negative samples (2 / 67).However, the ability to resolve positive and negative results was lower for pTau217 alone than pTau217 / A 42, as 37.4% of samples required confirmation by PET or CSF compared to 21.1% (Table 5).Table 4. Plasma pTau217 / Ap Ratio Assay ResultsPlasma Positive Positive pTau217 / Ap Predictive Likelihood Ratio Result N (%) PET or CSF Validation Value (PPV) Ratio (PL R)Positive Negative116Positive (45.3%) 106 10 91.40% 9.06 To be confirmed 54 (21.1%) 30 24 55.60% 1.07 Negative 86 (33.6%) 2 84 2.30% 0.02 Total 256 138 118Table 5. Plasma pTau217 Assay ResultsPositive Positive Plasma pTau217 Predictive Likelihood Result N (%) PET or CSF V alidation Value (PPV) Ratio (PLR)Positive Negative99Positive (37.4%) 7 92.90% 11.7499To be confirmed (37.4%) 46 53 46.50% 0.7867Negative (25.3%)65 3.00% 0.03 Total 265125

[0393] Variables of age, sex, and baseline cognitive performance (Mini-mental State Exam and Clinical Dementia Rating) were examined to determine if the results obtained for all subjects with pTau217 BBM assays were reproducible across different groups (Table 6). For all demographic groups, it was found that the pTau217 / Ap42 assay performed with high sensitivity, with PPVs >87% for positive results and <5% for negative results. The pTau217 / Ap42 assay was able to resolve 75-80% of samples into positive or negative amyloid, with 20-25% requiring confirmatory testing.Table 6. Plasma pTau217 / AP Ratio Assay Results, Demographic GroupsPlasma Positive Positive pTau217 / Ap Predictive Likelihood Ratio Result N (%) PET or CSF Validation Value (PP V) Ratio (PLR)NegativeDemographic Group: Age >71 Years55Positive (45.5%) 48 7 87.30% 6.3127To be confirmed (22.3%) 15 12 55.60% 1.1539Negative (32.2%) 0 39 0% 0 Demographic Group: Age <71 Years55Positive (43.0%) 52 3 94.60% 14.827To be confirmed (21.1 %) 15 12 55.60% 1.0746Negative (35.9%) 2. 44 4.40% 0.04 Demographic Group: Females55Positive (46.2%) 49 6 89.10% 7.2628To be confirmed (23.5%) 13 15 46.40% 0.7736Negative (30.3%) 1 35 2.80% 0.03 Demographic Group: Males59Positive (42.3%) 55 4 92.70% 11.2826To be confirmed (20.0%) 17 9 65.40% 1.6749Negative (37.7%) 1 48 2.00% 0.02 Demographic Group: MMSE 20-256Positive (39.4%) 52 4 92.90% 12.6430To be confirmed (21.1 %) 19 11 63.3% 1.756Negative (39.4’%) 1 55 1.80% 0.02 Demographic Group: MMSE >2554Positive (50.9%) 48 6 88.90% 6.1324To be confirmed (22.6%) 11 13 45.80% 0.6528Negative (26.4%) 1 2.7 3.60% 0.03 Demographic Group: Clinical Dementia Rating 0 or 0.581Positive (39.9%) 73 8 90.10% 9.0448To be confirmed (23.6%) 27 211.2774Negative (36.5%) 90.03 Demographic Group: Clinical Dementia Rating > 132Positive (65.3%) 3093.80% 7.276To be confirmed (12.2%) 3 3 50.00% 0.49 Negative (22.4%) 0 11 0% 0

[0394] Conclusions

[0395] An assessment of plasma from potential participants in AriBio’s Phase 3 trial of AR1001 for early AD found that both pTau2.17 and pTau217 / Ap42 ratio assays had high sensitivity for determining presence of cerebral amyloid. The pTau217 / Ap42 assay wassuperior to the pTau217 assay alone in resolving positive and negative amyloid status. These results demonstrate the robustness of using a plasma biomarker, pTau217 / Ap42, as a triage tool for screening clinical trial participants with amyloid positivity in AD trials. Using plasma pTau217 / Ap42 ratio as BBM for screening can reduce the need for PET and CSF testing and save time and money when screening into clinical trials for AD.

[0396] Example 3: AR1001 Tablet

[0397] A 30 mg tablet dosage form of ARI 001 can be prepared.

[0398] Method of Preparation:

[0399] Step 1: Weighing and Mixing of Ingredients

[0400] Weigh the following ingredients:® 30 mg of ARI 001® 150 mg of Microcry stall ine Cellulose (e.g., Avicel PHI 02)® 10 mg of Hydroxypropyl Methylcellulose (e.g., Methocel K4M)» 5 mg of Croscarmellose Sodium (e.g., Ac-Di-Sol)» 2 mg of Magnesium Stearate

[0401] Mix the AR1001, Microcrystalline Cellulose, Hydroxypropyl Methylcellulose, and Croscarmellose Sodium in a suitable mixing vessel until a uniform blend is achieved.

[0402] Step 2: Granulation

[0403] Granulate the blend using a wet granulation method with a suitable solvent such as purified water. The granules are then dried in a fluid bed dryer or tray dryer until the moisture content is below 2%.

[0404] Step 3: Compression

[0405] Compress the dried granules into tablets using a tablet press. Tlie tablets should have a weight of approximately 197 mg each.

[0406] Step 4: Optional Coating

[0407] Coat the tablets with Opadry Write YS-1-18114- A using a pan coater or fluid bed coater.

[0408] This method ensures the production of a stable and effective 30 mg tablet dosage form of AR 1001,

[0409] Example 4: AR1001 Caplet

[0040] A 30 mg caplet dosage form of AR1001 can be prepared.

[0411] Method of Preparation:

[0412] Step 1: Weighing and Mixing of Ingredie ts

[0413] Weigh the following ingredients:* 30 nig of AR1001® 120 mg of Microcrystalline Cellulose (Avicel PH102)* 40 mg of Lactose Monohydrate (Pharmatose 200M)® 10 mg of Hydroxypropyl Methylcellulose (Methocel K4M) * 5 mg of Croscarmellose Sodium (Ac-Di-Sol)® 2 mg of Magnesium Stearate® Optional: Titanium Dioxide and Natural flavor

[0414] Inactive ingredients may be obtained from the following:* Filler: A mixture of Microcrystalline Cellulose (Avicel PHI 02 by FMC Biopolymer) and Lactose Monohydrate (Pharmatose 200M by DFE Pharma)* Binder: Hydroxypropyl Methylcellulose (Methocel K4M by Dow Chemical)® Disintegrant: Croscarmellose Sodium (Ac-Di-Sol by FMC Biopolymer) * Lubricant: Magnesium Stearate (Mallinckrodt's Magnesium Stearate) * Coating: Opadry White YS-1-18114-A (Colorcon)® Optional Colorant and Flavor: Titanium Dioxide (Ti-Pure R-706 by Chemours) as a colorant; Natural flavor (e.g., grapefruit flavor by Givaudan) in an amount of 0.5% by weight.

[0415] Mix these ingredients in a suitable mixing vessel until a uniform blend is achieved.[0041 S] Step 2: Granulation

[0417] Granulate the blend using a wet granulation method with a suitable solvent such as purified water. The granules are then dried in a fluid bed dryer or tray dryer until the moisture content is below' 2%.

[0418] Step 3: Compression

[0419] Compress the dried granules into caplets using a rotary tablet press. The caplets should have a weight of approximately 207 mg each and be shaped to facilitate easy swallowing.

[0420] Step 4: Coating

[0041] Coat the caplets with Opadry White YS- 1-18114- A using a pan coater orfluid bed coater. If desired, add a colorant such as Titanium Dioxide to the coating formulation.

[0422] Step 5: Testing

[0423] Test the caplets tor critical quality attributes such as:* Hardness and friability: Ensure the caplets have sufficient hardness to withstand handling but are friable enough to disintegrate quickly.® Disintegration and dissolution: Ensure at least 90% of ARI 001 is released within the specified time frame.* Content uniformity: Ensure ARI 001 is uniformly distributed throughout the caplets.* Stability: Test the caplets for stability under various conditions to ensure ARI 001 remains potent and the excipients do not degrade.

[0424] This method ensures the production of a stable and effective 30 mg caplet dosage form of ARI 001.

[0425] Example 5: AR1001 Capsule

[0428] A 30 mg capsule dosage form of ARI 001 can be prepared.

[0427] Method of Preparation:

[0428] Step 1: Weighing and Mixing of Ingredients

[0429] Weigh the following ingredients:* 30 mg of AR1001* 120 mg of Microcrystalline Cellulose (Avicel PH102)® 40 mg of Lactose Monohydrate (Pharmatose 200M)® 10 mg of Hydroxypropyl Methylcellulose (Methocel K4M) ® 5 mg of Croscarmellose Sodium (Ac-Di-Sol)* 2 mg of Magnesium Stearate® Optional: Colloidal Anhydrous Silica and Silica Gel

[0430] Inactive ingredients can be obtained from the following:® Filler: A mixture of Microcrystalline Cellulose (Avicel PH102 by FMC Biopolymer) and Lactose Monohydrate (Pharmatose 200M by DFE Ph anna)® Binder: Hydroxypropyl Methylcellulose (Methocel K4M by Dow Chemical)® Disintegrant: Croscarmellose Sodium (Ac-Di-Sol by FMC Biopolymer)• Lubricant: Magnesium Stearate (Mallinckrodt's Magnesium Stearate) ® Capsule Shell: Gelatin capsules (Quali-V or Quali-G by Rousselot); The capsule shell composition may include additional ingredients such as Titanium Dioxide (Ti-Pure R-706 by Chemours) for coloring and Purified Water.® Optional Excipients: Anti-caking agent: Colloidal Anhydrous Silica (Syloid 244 FP by Grace Materials Technologies); Moisture absorber: Silica Gel (Syloid 244 FP by Grace Materials Technologies)

[0431] Mix these ingredients in a suitable mixing vessel until a uniform blend is achieved.

[0432] Step 2: Granulation

[0433] Granulate the blend using a wet granulation method with a suitable solvent such as purified water. The granules are then dried in a fluid bed dryer or tray dryer until the moisture content is below' 2%.

[0434] Step 3: Filling into Capsules

[0435] Fill the dried granules into gelatin capsules using a capsule filling machine. Ensure the fill weight is consistent to achieve the desired 30 mg dose of ARI 001.

[0438] Step 4: Sealing and Coating (Optional)

[0437] Seal the capsules and apply a coating if desired. Hie coating can include ingredients like Opadry White YS-1-18114-A (Colorcon) for aesthetic purposes and to enhance swallowability.

[0438] Step 5: Testing

[0439] Test the capsules for critical quality attributes such as:® Hardness and friability: Ensure the capsules have sufficient hardness to ■withstand handling but are friable enough to disintegrate quickly.® Disintegration and dissolution: Ensure at least 90% of AR1001 is released within the specified time frame.• Content, uniformity: Ensure ARI 001 is uniformly distributed throughout the capsules.® Stability: Test the capsules for stability under various conditions to ensure ARI 001 remains potent and the excipients do not degrade.

[0440] This method ensures the production of a stable and effective 30 mg capsule dosage form of AR 1001.

[0441] Example 6: AR1001 Sachet

[0442] A 30 mg sachet dosage form of AR1001 can be prepared.

[0443] Method of Preparation:

[0444] Step 1: Weighing and Mixing of Ingredients[0044S] Weigh the following ingredients:® 30 nig of ARlOOl® 12.0 mg of Microcrystalline Cellulose (Avicel PH 102)® 40 mg of Lactose Monohydrate (Pharmatose 200M)* 10 mg of Hydroxypropyl Methylcellulose (Methocel K4M) » 5 mg of Croscarmellose Sodium (Ac-Di-Sol)• 2 mg of Magnesium Stearate

[0446] Inactive Ingredients may be obtained from:® Filler: A mixture of Microcrystalline Cellulose (Avicel PHI 02 by FMC Biopolymer) and Lactose Monohydrate (Pharmatose 200M by DFE Pharma)® Binder: Hydroxypropyl Methylcellulose (Methocel K4M by Dow Chemical)® Disintegrant: Croscarmellose Sodium (Ac-Di-Sol by FMC Biopolymer) ® Lubricant: Magnesium Stearate (Mallinckrodfs Magnesium Stearate) ® Cachet Shell Composition: Gelatin (Quali-V or Quali-Gby Rousselot);Water; Optional: Titanium Dioxide (Ti-Pure R-706 by Chemours) for coloring, and other excipients like Propylene Glycol, Colloidal Anhydrous Silica (Syloid 244 FP by Grace Materials Technologies), and Glycerol.

[0447] Mix these ingredients in a suitable mixing vessel until a uniform blend is achieved.

[0448] Step 2: Granulation

[0449] Granulate the blend using a wet granulation method with a suitable solvent such as purified water. The granules are then dried in a fluid bed dryer or tray dryer until the moisture content is below 2%.

[0450] Step 3: Preparing the Cachet Shell

[0451] Prepare the cachet shell composition by dissolving gelatin in purified water. Add optional excipients such as Titanium Dioxide for coloring, Propylene Glycol, Colloidal Anhydrous Silica, and Glycerol to the gelatin solution.

[0452] Step 4: Encapsulating the Fill Composition

[0453] Encapsulate the dried granules into the cachet shell using a starch molding process or a similar method suitable for cachet formation. Ensure the fill weight is consistent to achieve the desired 30 mg dose of ARI 001.

[0454] Step 5: Drying and Finishing

[0455] Dry tire cachets to remove any excess moisture. Apply any additional coatings or finishes as necessary to enhance appearance and stability.

[0458] Step 6: Testing

[0457] Test the cachets for critical quality attributes such as:* Hardness and friability: Ensure die cachets have sufficient hardness to withstand handling but are friable enough to disintegrate quickly.® Disintegration and dissolution: Ensure at least 90% of ARI 001 is released within die specified time frame.® Content uniformity: Ensure ARI 001 is uniformly distributed throughout the cachets.* Stability: Test the cachets for stability under various conditions to ensure ARI 001 remains potent and the excipients do not degrade.

[0458] This method ensures the production of a stable and effective 30 mg sachet dosage form of A RI 001.

[0459] Example 7: AR1001 Lozenge

[0480] A 30 mg lozenge dosage form of AR1001 can be prepared.

[0461] Method of Preparation:

[0462] Step 1: Weighing and Mixing of Ingredients

[0463] Weigh the following ingredients:* 30 mg of AR1001® 1.5 grams of Sucrose® 0.5 grams of Com Syrup® 0.1 grams of Gelatin® 0.2 grams of Glycerin® 0.05 grams of Natural Mint Flavor® 0.01 grams of Aspartame or Sodium Saccharinate* Optional: 0.005 grams of Titanium Dioxide

[0464] Inactive Ingredients above can be obtained from tire following sources:® Base: A mixture of Sucrose (C& H Sugar) and Com Syrup (Karo Light Corn Syrup)* Binder: Gelatin (Quali-V or Quali-G by Rousselot)® Humectant: Glycerin (Glycerin USP by Dow Chemical)* Flavoring Agent: Natural Mint Flavor (available from Givaudan)* Sweetener: Aspartame (Searle) or Sodium Saccharinate (Jungbunzlauer) * Colorant (Optional): Titanium Dioxide (Ti-Pure R-706 by Chemours)

[0465] Mix these ingredients in a suitable mixing vessel until a uniform blend is achieved.

[0466] Step 2: Heating and Dissolving

[0467] Heat the ixture of Sucrose, Com Syrup, and Glycerin in a suitable heating vessel to a temperature of approximately 150°C to 160°C until the sugars are fully dissolved. Add the Gelatin and stir until it is completely dissolved.

[0468] Step 3: Cooling and Adding ARI 001 and Flavor

[0469] Cool the sugar syrup to a temperature of approximately 100°C to 110°C. Add the ARI 001, Natural Mint Flavor, Aspartame or Sodium Saccharinate, and optional Titanium Dioxide to the syrup. Mix thoroughly to ensure uniform distribution.

[0470] Step 4: Forming the Lozenges

[0471] Pour the mixture into a lozenge mold and allow it to cool and set. Once set, remove the lozenges from the mold.

[0472] Step 5: Testing

[0473] Test the lozenges for critical quality' atributes such as:* Hardness and friability: Ensure the lozenges have sufficient hardness to withstand handling but are friable enough to dissolve quickly in the mouth. * Dissolution: Ensure the lozenges dissolve within a specified time frame (e.g., 2-5 minutes).® Content uniformity: Ensure ARI 001 is uniformly distributed throughout the lozenges.® Stability: Test the lozenges for stability under various conditions to ensure ARI 001 remains potent and the excipients do not degrade,

[0474] This method ensures the production of a stable and effective 30 mg lozenge dosage form of AR 1001.

[0475] Example 8: Suppository AR1001

[0476] A 30 mg suppository' dosage form of ARI 001 can be prepared.

[0477] Method of Preparation:

[0478] Step 1: Weighing and Mixing of Ingredients

[0479] Weigh the following ingredients:* 30 mg ofAR1001® 1.5 grams ofWitepsol H15* 0.5 grams of Suppocire AM® 0.05 grams of Polysorbate 80® 0.01 grams of Butylated Hydroxytoluene* Optional: 0.005 grams of Titanium Dioxide

[0480] Inactive Ingredients above can be obtained from the following sources:® Base: A mixture of itepsol H15 (a hardened vegetable fat, available from Sasol) and Suppocire AM (a mixture of faty acid esters, available from Gattefosse)® Emulsifier: Polysorbate 80 (Tween 80 by Croda)® Antioxidant: Butylated Hydroxytoluene (BHT, available from Eastman Chemical Company)* Optional Colorant: Titanium Dioxide (Ti-Pure R-706 by Chemours)

[0481] Mix these ingredients in a suitable mixing vessel until a uniform blend is achieved.

[0482] Step 2: Melting the Base

[0483] Melt the Witepsol H15 and Suppocire AM in a double boiler or a suitable heating vessel at a temperature of approximately 40°C to 50°C until the base is fully melted.

[0484] Step 3: Adding AR 1001 and Oilier Ingredients

[0485] Add ARI 001, Polysorbate 80, Butylated Hydroxytoluene, and optional Titanium Dioxide to the melted base. Mix thoroughly to ensure uniform distribution.

[0488] Step 4: Pouring into Molds

[0487] Pour the mixture into suppository molds. Ensure the molds are filled to a weight that corresponds to the desired 30 mg dose of ARI 001.

[0488] Step 5: Cooling and Hardening

[0489] Allow the mixture to cool and harden in the molds. Once hardened, remove the suppositories from the molds.

[0490] Step 6: Testing

[0491] Test the suppositories for critical quality atributes such as:* Hardness and friability: Ensure the suppositories have sufficient hardness to withstand handling but are friable enough to melt and release ARI 001 upon rectal administration.* Dissolution: Ensure the suppositories dissolve within a specified time frame (e.g., 30 minutes) in a simulated rectal environment.* Content uniformity: Ensure ARI 001 is uniformly distributed throughout the suppositories.* Stability: Test the suppositories for stability' under various conditions to ensure ARI 001 remains potent and the excipients do not degrade.

[0492] This method ensures the production of a stable and effective 30 mg suppository dosage form of ARI 001.

[0493] Example 9: AR1001 Powder

[0494] A 30 mg powder dosage form of ARI 001 can be prepared.

[0495] Method of Preparation:

[0498] Step 1: Weighing and Mixing of Ingredients

[0497] Weigh the following ingredients:* 30 nig of AR1001* 100 mg of Microcrystalline Cellulose (Avicel PH 102)® 10 mg of Hydrox propyl Methylcellulose (Methocel K4M) * 5 mg of Croscarmellose Sodium (Ac-Di-Sol)® 2 mg of Magnesium Stearate® 0.5 mg of Butylated Hydroxytoluene (BHT)* Optional: 0.5 mg of Natural Mint Flavor» 1 mg of Silica Gel (Syloid 244 FP)

[0498] Inactive Ingredients above can be obtained from the following sources:® Filler: Microciystalline Cellulose (Avicel PHI 02 by FMC Biopolymer) ® Binder: Hydroxypropyl Methylcellulose (Methocel K4M by Dow Chemical)® Disintegrant: Croscarmellose Sodium (Ac-Di-Sol by FMC Biopolymer) ® Lubricant: Magnesium Stearate (Mallinckrodt's Magnesium Stearate) * Antioxidant: Butylated Hydroxytoluene (BHT, available from Eastman Chemical Company)® Flavoring Agent (Optional): Natural Mint Flavor (available from Givaudan)* Moisture Absorber: Silica Gel (Syloid 244 FP by Grace Materials Technologies)

[0499] Mix these ingredients in a suitable mixing vessel until a uniform blend is achieved.

[0500] Step 2: Milling

[0501] Mill the blend using a jet mill or an air classifier mill to achieve a uniform particle size distribution. Ensure the particle size is suitable for the intended use, typically less than 100 pin.

[0502] Step 3: Sieving

[0503] Sieve the milled powder to ensure uniform particle size distribution and to remove any lumps or large particles.

[0504] Step 4: Packaging

[0505] Fill the powder into suitable containers such as sachets, bottles, or inhalation devices. Ensure the fill weight is consistent to achieve the desired 30 mg dose of AR 1001.

[0506] Step 5: Testing

[0507] Test the powder for critical quality attributes such as:® Particle size distribution: Ensure the powder has a uniform particle size. * Flowability: Ensure the powder flows freely and does not clump.® Content uniformity: Ensure ARI 001 is uniformly distributed throughout the powder,* Stability: Test the powder for stability under various conditions to ensure ARI 001 remains potent and the excipients do not degrade.

[0598] This method ensures the production of a stable and effective 30 mg powder dosage form of ARI 001.

[0509] Example 10: AR1001 Gel

[0510] A 30 mg gel dosage form of ARI 001 can be prepared.

[0511] Method of Preparation:

[0512] Step 1: Weighing and Mixing of Ingredients

[0513] Weigh the following ingredients:® 30 mg of AR1001® 1.5% w / w Carbomer 974P* Sodium Hydroxide for pH adjustment* 20% w / w Glycerin® Purified Water q.s. to 100%* 0.01% w / w Benzalkonium Chloride* Optional: 0.5% w / w Hydroxyethyl Cellulose and 0.1% w / w Natural Mint Flavor

[0514] Inactive Ingredients above can be obtained from the following sources:® Gelling Agent: Carbomer 974P (Carbopol 974P by Lubrizol) * pH Adjuster: Sodium Hydroxide (available from Fisher Scientific) * Humectant: Glycerin (Glycerin USP by Dow Chemical)® Solvent: Purified Water (USP)® Preservative: Benzalkonium Chloride (available from Sigma- Aldrich) ® Optional Thickening Agent: Hydroxyethyl Cellulose (Natrosol 2.50HHX by Ashland)® Optional Flavoring Agent: Natural Mint Flavor (available from Givaudan)

[0515] Step 2: Preparation of the Gel Base

[0516] In a mixing vessel, slowly add the Carbomer 974P to the purified water while stirring to avoid lumps. Continue stirring until the Carbomer is fully dispersed.

[0517] Step 3: Addition of Glycerin and Preservative

[0518] Add the Glycerin and Benzalkonium Chloride to the mixing vessel. Stir until well combined.

[0059] Step 4: pH Adjustment

[0520] Add Sodium Hydroxide to adjust the pH of the gel base to a range of 5.5- 6.5. Stir until the pH is stable.

[0521] Step 5: Addition of ARlOOl and Optional Ingredients

[0522] Add ARlOOl to the gel base and stir until AR1001 is fully dissolved. If using, add the Hydroxyethyl Cellulose and Natural Mint Flavor and stir until well combined.

[0523] Step 6: Filling and Packaging

[0524] Fill the gel into suitable containers such as tubes or sachets. Ensure the fill weight is consistent to achieve the desired 30 mg dose of ARlOOl.

[0525] Step 7: Testing

[0526] Test the gel for critical quality attributes such as:® Viscosity: Ensure the gel has the desired viscosity' for easy application. * pH: Ensure the pH is within the specified range.® Content uniformity: Ensure ARI 001 is uniformly distributed throughout the gel.* Stability: Test the gel for stability under various conditions to ensure ARI 001 remains potent and the excipients do not degrade.

[0527] This method ensures the production of a stable and effective 30 mg gel dosage form of AR 1001.

[0528] Example 11: AR1001 Liquid

[0529] A 30 mg liquid dosage form of AR1001 can be prepared.

[0530] Method of Preparation:

[0531] Step 1: Preparation of the Solution

[0532] Dissolve AR1001 in Water for Injection (WFI) or deionized water in a suitable mixing vessel. Ensure AR1001 is fully dissolved before proceeding.

[0533] Step 2: Addition of Buffering Agents

[0534] Add Sodium Citrate Dihydrate and Citric Acid to the solution. Stir until both are fully dissolved.

[0535] Step 3: pH Adjustment

[0536] Adjust the pH of the solution to a range of 5.5-6.5 using Sodium Hydroxide and / or Hydrochloric Acid. Stir until the pH is stable.

[0537] Step 4: Addition of Preservative and Antioxidant

[0538] Add Benzalkonium Chloride and Butylated Hydroxytoluene to the solution. Stir until well combined,

[0539] Step 5: Addition of Isotonic Agent

[0549] Add Sodium Chloride to the solution to ensure isotonicity. Stir until fully dissolved.

[0541] Inactive Ingredients above can be obtained from the following sources:« Solvent: Water for Injection (WFI, available from various pharmaceutical grade suppliers) or deionized water® pH Adjuster: Sodium Hydroxide (available from Fisher Scientific) and / or Hydrochloric Acid (available from Fisher Scientific)* Buffering Agent: Sodium Citrate Dihydrate (available from J. T. Baker) and Citric Acid (available from Merck)• Preservative: Benzalkonium Chloride (available from Sigm -Aldrich) • Antioxidant: Butylated Hydroxytoluene (BHT, available from Eastman Chemical Company)«> Isotonic Agent: Sodium Chloride (available from Hospira)

[0542] Step 6: Filtration and Sterilization

[0543] Filter the solution through a 0.22 m filter to ensure sterility and freedom from particulate mater. Sterilize the solution using a validated sterilization process such as autoclaving or sterile filtration.

[0544] Step 7: Filling and Packaging

[0545] Fill the sterile solution into sterile vials, ampules, prefilled syringes, or other vessel. Ensure the fill volume is consistent to achieve the desired 30 mg dose of ARI 001.

[0548] Step 8: Testing

[0547] Test the liquid dosage form for critical quality attributes such as:® Sterility: Ensure the solution is free from microbial contamination.• Pyrogenicity: Ensure the solution is free from pyrogens.• Particulate Matter: Ensure the solution is free from visible and subvisible particles.® pH: Ensure the pH is within the specified range.® Content Uniformity: Ensure ARI 001 is uniformly distributed throughout the solution.• Stability: Test the solution for stability under various conditions to ensure ARI 001 remains potent and the excipients do not degrade,[0G54S] This method ensures the production of a stable and effective 30 mg liquid dosage form of ARI 001.

[0549] Example 12: Amorphous AR1001 Sterile Solid

[0550] A 30 mg amorphous sterile solid dosage form of AR1001 can be prepared.

[0551] Method of Preparation:

[0552] Step 1: Preparation of Amorphous ARI 001

[0553] Prepare the amorphous form of ARI 001 using a method such as spray drying, freeze-drying, or solvent evaporation. Ensure the amorphous form is free from any crystalline content.

[0554] Step 2: Weighing and Mixing of Ingredients

[0555] Weigh the following ingredients:* 30 mg of amorphous ARI 001* 10 nig of Polysorbate 80 (Tween 80)® 20 mg of Hydroxypropyl Methylcellulose (Methocel K4M) * 1 mg of Butylated Hydroxy toluene (BHT)® 10 mg of Sodium Chloride® 40 mg of Mannitol (Pearlitol 200SD)® 2 mg of Magnesium Stearate

[0556] Inactive Ingredients above can be obtained from the following sources:® Pharmaceutically Acceptable Excipient: Polysorbate 80 (Tween 80 by Croda)® Stabilizer: Hydroxypropyl Methylcellulose (Methocel K4M by Dow Chemical)® Antioxidant: Butylated Hydroxytoluene (BHT, available from Eastman Chemical Company)® Isotonic Agent: Sodium Chloride (available from Hospira) * Filler: Mannitol (Pearlitol 200SD by Roquette)® Lubricant: Magnesium Stearate (Mallinckrodfs Magnesium Stearate)

[0557] Mix these ingredients in a suitable mixing vessel until a uniform blend is achieved.

[0558] Step 3: Granulation

[0559] Granulate the blend using a wet granulation method with a suitable solvent such as purified water or a non-aqueous solvent like ethanol. The granules are then dried in a fluid bed dryer or tray dryer until the moisture content is below 2%.

[0560] Step 4: Milling and Sieving

[0561] Mill the dried granules using a jet mill or an air classifier mill to achieve a uniform particle size distribution. Sieve the milled powder to ensure uniform particle size and to remove any lumps or large particles.

[0562] Step 5: Sterilization

[0563] Sterilize the powder using a validated sterilization process such as gamma radiation, ethylene oxide sterilization, or sterile filtration if applicable.

[0564] Step 6: Filling and Packaging

[0565] Fill die sterile powder into sterile vials, ampules, or other suitablecontainers. Ensure the fill weight is consistent to achieve the desired 30 mg dose of ARI 001.

[0566] Step 7: Testing

[0567] Test the amorphous sterile solid dosage form for critical quality attributes such as:* Sterility: Ensure the solution is free from microbial contamination.* Pyrogenicity: Ensure tire solution is free from pyrogens.* Particulate Matter: Ensure the solution is free from visible and subvisible particles.* Content Uniformity: Ensure ARI 001 is uniformly distributed throughout the powder.* Stability: Test the powder for stability7under various conditions to ensure ARI 001 remains potent and the excipients do not degrade.

[0568] Tliis method ensures the production of a stable and effective 30 rng amorphous sterile solid dosage form of ARI 001.

[0569] Example 13: Extended Release ARW01

[0570] A 30 mg extended release dosage form of ARI 001 can be prepared.

[0571] Method of Preparation:

[0572] Step 1: Preparation of Immediate Release Particles

[0573] Inactive Ingredients above can be obtained from the following sources:® Polymeric Matrix:» Film Forming Agent: Ethylcellulose (Ethocel by Dow' Chemical) » Plasticizer: Triethyl Citrate (Citroflex 2 by Vertellus)» Pore Former: Sodium Chloride (available from Hospira)» Immediate Release Component:* Core: AR1001® Inert Spherical Substrate Particles: Microcrystalline Cellulose (Avicel PH 102 by FMC Biopolymer)® Binder: Hydroxypropyl Methylcellulose (Methocel K4M by Dow Chemical)» Lubricant: Magnesium Stearate (Mallinckrodt’s Magnesium Stearate)« Coating: Talc (available from Imerys)* Optional Enteric Coating:« Enteric Coating Material: Eudragit L100 (by Evonik)

[0574] Mix AR 1001, Microcrystalline Cellulose, Hydroxypropyl Methylcellulose, and Magnesium Stearate in a suitable mixing vessel until a uniform blend is achieved. Add Talc to the mixture and blend until the particles are evenly coated.

[0575] Step 2: Granulation

[0576] Granulate the biend using a wet granulation method with a suitable solvent such as purified water. The granules are then dried in a fluid bed dryer or tray dryer until the moisture content is below 2%.

[0577] Step 3: Milling and Sieving

[0578] Mill the dried granules using a jet mill or an air classifier mill to achieve a uniform particle size distribution. Sieve the milled powder to ensure uniform particle size and to remove any lumps or large particles. Recover particles falling between -10 and +60 mesh.

[0579] Step 4: Preparation of Polymeric Matrix

[0580] Mix Ethylcellulose, Triethyl Citrate, and Sodium Chloride in a suitable mixing vessel until a uniform blend is achieved. This mixture forms the polymeric matrix that will control the release of AR 1001.

[0581] Step 5: Blending Immediate Release and Polymeric Matrix

[0582] Blend the immediate release particles with the polymeric matrix to achieve the desired activity and release pattern. The ratio of immediate release particles to polymeric matrix can be adjusted to achieve a zero-order release profile over 12 to at least 24 hours.

[0583] Step 6: Compression into Tablets

[0584] Compress the blended mixture into tablets using standard tablet compression equipment. Ensure the tablet weight is consistent to achieve the desired 30 mg dose of AR 1001.

[0585] Step 7: Optional Enteric Coating

[0586] Apply an enteric coating using Eudragit L.100 to the tablets if desired. This coating serves to resist disintegration in the stomach and permits the tablet to pass intact into the duodenum or to be delayed in release.

[0587] Step 8: Testing

[0588] Test the extended release dosage form for critical quality attributes such as:® Dissolution Profile: Ensure the formulation exhibits a controlled release profile over the specified time period.* Content Uniformity: Ensure ARI 001 is uniformly distributed throughoutthe tablets.* Stability: Test the tablets for stability under various conditions to ensure ARI 001 remains potent and the excipients do not degrade.

[0589] This method ensures the production of a stable and effective 30 mg extended release oral dosage form of AR 1001.

[0590] Example 14: Intranasal AR1001

[0591] A 30 mg intranasal dosage form of AR1001 can be prepared.

[0592] Method of Preparation:

[0593] Step 1: Preparation of AR1001 Solution

[0594] Dissolve 30 mg of AR1001 m a suitable solvent such as purified water to create a concentrated solution.

[0595] Step 2: Preparation of the Nasal Spray Formulation

[0598] Combine the following ingredients in a mixing vessel:® 30 mg of ARI 001 solution« 0,01% w / w Benzalkonium Chloride* 0,01 % w / w Butylated Hydroxytoluene (BHT)* 0.5% w / w Sodium Citrate Dihydrate® 0.5% w / w Citric Acid* 0.5% w / w Polysorbate 20«> 5% w / w Sorbitol

[0597] The inactive ingredients above can be obtained from the following sources:* Preservative: Benzalkonium Chloride (available from Sig a-Aldrich) * Antioxidant: Butylated Hydroxytoluene (BHT, available from Eastman Chemical Company)® Buffering Agent: Sodium Citrate Dihydrate (available from J. T. Baker) and Citric Acid (available from Merck)«> Solubilizer: Polysorbate 20 (available from Croda)« Humectant: Sorbitol (available from Roquette)«> pH Adjuster: Sodium Hydroxide and / or Hydrochloric Acid (available from Fisher Scientific)

[0598] Adjust the pH of the formulation to a target of 5.2 using Sodium Hydroxide and / or Hydrochloric Acid.

[0599] Step 3: Filling and Sealing the Nasal Spray Bottles

[0600] Fill the nasal spray formulation into 25 mL HDPE spray bottles fitted with a meter pump, nasal adapter, and a protective cap. Each bottle should be designed to deliver 200 metered sprays.

[0601] Step 4: Priming the Nasal Spray Unit

[0602] Prime the nasal spray unit by actuating the pump 5 to 6 times until a consistent spray is achieved.

[0603] The intranasal dosage form is designed to optimize therapeutic efficacy and patient compliance. The specific combination and proportions of the inactive ingredients enhance the stability, solubility, and bioavailability of ARI 001.

[0604] Example 15: Pulmonary AR1001

[0605] A 30 mg pulmonary' dosage form of AR1001 can be prepared.

[0606] Method of Preparation:

[0607] Step 1: Weighing and Mixing of Ingredients

[0608] Weigh the following ingredients:® 30 mg of ARI 001® 50 mg of Lactose Monohydrate (Pharmatose 200M)® 20 mg of Mannitol (Pearlitol 200SD)* 1 mg of Polysorbate 80 (Tween 80)® 0.5 mg of Butylated Hydroxytoluene (BHT)® Optional: 1 mg of Natural Mint Flavor

[0609] The inactive ingredients above are available from:® Carrier: Lactose Monohydrate (Pharmatose 200M by DFE Pharma) ® Fine Particle Carrier: Mannitol (Pearlitol 200SD by Roquette) ® Surfactant: Polysorbate 80 (Tween 80 by Croda)® Antioxidant: Butylated Hydroxytoluene (BHT, available from Eastman Chemical Company)® Flavoring Agent (optional): Natural Mint Flavor (available from Givaudan)« Moisture Absorber: Silica Gel (Syloid 244 FP by Grace Materials Technologies)

[0610] Mix these ingredients in a suitable mixing vessel until a uniform blend is achieved.

[0611] Step 2: Milling and Sieving

[0062] Mill the blend using a jet mill or an air classifier mill to achieve a particle size suitable for pulmonary delivery (typically less than 5 m). Sieve the milled powder to ensure uniform particle size distribution.

[0613] Step 3: Filling into Inhalation Devices

[0614] Fill the milled and sieved powder into inhalation devices such as dry' powder inhalers (DPIs) or metered-dose inhalers (MDls). For DPIs, fill the powder into capsules or blisters. For MDIs, fill the powder into canisters along with a propellant such as Hydrofluoroalkane (HFA) 134a or 227.

[0065] Step 4: Assembly and Testing

[0616] Assemble the inhalation devices according to the manufacturer's instructions. Test the devices for dose uniformity, particle size distribution, and other relevant parameters to ensure compliance with regulatory' standards.

[0617] Tliis method ensures the production of a stable and effective 30 rng pulmonary dosage form of ARI 001.

[0618] Example 16: Sublingual AR1001

[0619] A 30 mg sublingual dosage form of ARI 001 can be prepared.

[0620] Method of Preparation:

[0621] Step 1: Weighing and Mixing of Ingredients

[0622] Weigh the following ingredients:* 30 mg of AR1001* 25 mg of Mannitol (Pearlitol 200SD)® 41.140 mg of Lactose Monohydrate (Pharmatose 200M)® 1.310 mg of Gelatin* 1.750 mg of Sodium Starch Glycolate (Explotab)» 0.800 mg of Magnesium Stearate® Optional: 0.01% by weight of Aspartame or Sodium Saccharinate and 0.5% by weight of Natural flavor

[0623] Mix these ingredients in a suitable mixing vessel until a uniform blend is achieved.

[0624] Step 2: Granulation

[0625] Granulate the blend using a wet granulation method with a suitable solvent such as purified water. The granules are then dried in a fluid bed dryer or tray dryer until the moisture content is below 2%.

[0626] Step 3: Compression

[0627] Compress the dried granules into tablets using a rotary tablet press. The tablets should have a diameter and weight that ensure the total weight of the dosage form is approximately 100 mg.

[0628] Step 4: Testing

[0629] Test the tablets for critical quality attributes such as:® Disintegration and dissolution: Ensure at least 90% of ARI 001 is released within 2 minutes.* Hardness and friability: Ensure the tablets have sufficient hardness to withstand handling but are friable enough to disintegrate quickly under the tongue.® Content uniformity: Ensure that AR1001 is uniformly distributed throughout the tablets.® Stability: Test the tablets for stability under various conditions to ensure ARI 001 remains potent and the excipients do not degrade,

[0630] This method ensures the production of a stable and effective 30 mg sublingual dosage form of ARI 001.

[80631] Example 17: Buccal AR1001

[0632] A 30 mg buccal dosage form of AR 1001 can be prepared.

[0633] Method of Preparation:

[0634] Step 1: Weighing and Mixing of Ingredients

[0635] Weigh the following ingredients:® 30 mg of ARI 001® 10 mg of Sodium Carboxymethyl Cellulose (SCMC low viscosity) * 15 mg of Hydroxypropyl Methylcellulose (HPMC 15cps) ® 20 mg of Mannitol (Pearlitol 200SD)® 20 mg of Lactose Monohydrate (Pharmatose 200M)® 2 mg of Gelatin® 3 mg of Sodium Starch Glycolate (Explotab)® 1 mg of Magnesium Stearate® Optional: 0.01 % by weight of Aspartame or Sodium Saccharinate and 0.5% by weight of Natural flavor

[88636] Mix these ingredients in a suitable mixing vessel until a uniform blend isachieved.

[0637] Step 2: Granulation

[0638] Granulate the blend using a wet granulation method with a suitable solvent such as purified water. The granules are then dried in a fluid bed dryer or tray dryer until the moisture content is below' 2%.

[0639] Step 3: Compression

[0640] Compress the dried granules into tablets using a rotary tablet press. The tablets should be small, flat, and oval, with a diameter of approximately 5-8 mm to ensure ease of administration and minimal discomfort.

[0641] Step 4: Testing

[0642] Test the tablets for critical quality attributes such as:® Mucoadhesion: Ensure the tablets adhere to the buccal mucosa.• Disintegration and dissolution: Ensure at least 90% of ARI 001 is released within 2 minutes.® Hardness and friability: Ensure the tablets have sufficient, hardness to withstand handling but are friable enough to disintegrate quickly.® Content uniformity: Ensure ARI 001 is uniformly distributed throughout the tablets.® Stability: Test the tablets for stability under various conditions to ensure ARI 001 remains potent and the excipients do not degrade.

[0643] Tliis method ensures the production of a stable and effective 30 mg buccal dosage form of AR 1001,

[0644] Example 18: Changes in cGMP and BDNF in mice model

[0645] Material and Methods

[0646] AR1001 administration: AR1001 (mirodenafil 2HC1) was dissolved in distilled water (DW) for administration. For hippocampal cGMP measurement, AR1001 was orally given via gavage at doses of 3, 6, and 9 mg / kg once daily, early in the morning after overnight fasting for 7 days. The 6 mg / kg / day dose in mice is equivalent to 30 mg / day in humans (Nair & Jacob, 2016). For hippocampal BDNF measurement, AR1001 was orally given via gavage at doses of 3, 6, and 9 mg / kg once daily, early in the morning after overnight fasting for 7 days. cGMP levels and BDNF levels were measured from the hippocampi 15 min and 1 h after the final dose, respectively.

[0647] Measurement of cGMP and BDNF: cGMP and BDNF levels weremeasured using a cGMP Complete ELISA Kit and a mouse BDNF ELISA kit, respectively, following the manufacturer’s instructions.

[0648] Statistical analysis: All data in the tables were presented as mean ± standard deviation of the mean (SD). All data in the figures were presented as mean ± standard error of the mean (SEM). Statistical analyses were conducted using Prism software (GraphPad, Ver. 10.2.2). Mann-Whitney U test was used. P-value of less than 0.05 was considered statistically significant.

[0649] RESULTS

[0650] Administration of AR1001 increased hippocampal cGMP and BDNF levels in mice: Administration of ARI 001 at the doses of 6 and 9 mg / kg for 7 days led to a significant increase (22%) in hippocampal cGMP levels (Table 7, Fig. 5A). Administration of ARI 001 at the doses of 6 and 9 mg / kg for 7 days led to a significant increase (35%) in hippocampal BDNF levels (Table 8, Fig. 5B)

[0651] Oral administration of AR1001 at the doses of 6 and 9 mg / kg for 7 days effectively increased hippocampal cGMP levels and its subsequent signaling sequela BDNF levels, demonstrating the valid target engagement of this dose. The hippocampal cGMP and BDNF levels were not further increased at the dose of 9 mg / kg, suggesting that the ARI 001 dose of 6 mg / kg (equivalent to 30 mg / day in humans) is optimal one for increasing cGMP and BDNF levels. List of Relevant Documentation to Support Designation Request

[0652] AR1001 at the oral dose of 30 mg / day in human is equivalent to 6 mg / kg / day in mice. Oral administration of AR1001 at 6 and 9 mg / kg / day for 7 days induced an increase in both hippocampal cGMP and BDNF levels m mice. These data indicate that AR 1001 has clear target engagement m mice.Table 7. Effects of ARI 001 administration on hippocampal cGMP levels in mice.Table 8. Effects of AR1001 administration on hippocampal BDNF levels in mice.

[0653] Example 19: ARI 001 as Monotherapy

[0654] Evaluating ARI 001 as Monotherapy from a Phase 2 Study in Mild to Moderate Alzheimer’s Disease Patients.

[0655] In this double-blind, randomized, placebo-controlled, parallel -group trial, 210 patients diagnosed with mild to moderate AD were randomized to receive either placebo, ARI 001 10 mg, or AR1001 30 mg. Participants were administered treatment once-daily for 26 weeks. Participants were diagnosed clinically based on 2011 National Institute of Aging and Alzheimer’s Associations criteria and were allowed to be on concomitant AD medication such as acetylcholinesterase inhibitors and NMD A receptor antagonists with at least 3 months of stable dose prior to screening. Pre-specified subgroup analyses based on concomitant AD medication were conducted for key plasma biomarkers, including pTau-181 and pTau-217.

[0656] Sixty-seven and 69 participants were assigned to the placebo and AR1001 30 mg groups, respectively. At baseline, 36 of 67 (51.4%) participants on placebo and 46 of 69 (65.7%) participants on 30 mg ARI 001 were on concomitant AD medication. Participants without concomitant AD medication treated with ARI 001 30 mg (monotherapy) demonstrated reductions of 1.361 pg / ml in plasma pTau-181 (p=0.023) (Fig. 6) and 0.426 pg / mL in plasma pTau-217 compared to placebo at Week 26 (Fig. 7). Participants without concomitant AD medication treated with AR 1001 30 mg (monotherapy) demonstrated a statistically significant improvement of 4.019 points over baseline at Week 26 (p=0.012) on AD S -Cog 13 (Fig. 8).

[0657] The subgroup analysis of participants on AR I 001 30 mg without concomitant AD medication suggests potential for ARI 001 as a monotherapy for the treatment of Alzheimer’s disease

[0658] Example 20: Manufacturing Process for 30 mg AR1001 Oral Solid Dosage Form

[0659] Overview

[0660] The 30 mg oral solid dosage form of ARI 001 was manufactured via a dry'granulation process utilizing roller compaction, selected to ensure process robustness, scalability, and batch-to-batch reproducibility. This method facilitated the production of pharmaceutically acceptable tablets exhibiting uniformity in content and mechanical integrity, while maintaining chemical and physical stability throughout shelflife.

[0661] Tire manufacturing process consisted of the following unit operations, executed in a defined sequence: intragranular blending, roller compaction followed by milling of the compacted ribbons, extragranular blending and lubrication, tablet compression, and application of a film coating. A simplified high-level summary of each manufacturing stage is outlined below:

[0662] Intragranular Blend Preparation

[0663] The process began with the dispensing of AR1001 under a nitrogen atmosphere to mitigate moisture uptake, as ARI 001 is hygroscopic and susceptible to degradation in the presence of water. The dispensed API was combined with excipients selected from tire group consisting of Microcrystalline Cellulose PH-102, Croscarmellose Sodium, and Colloidal Silicon Dioxide. These components were individually screened and collected into a polyethylene (PE)-lined container.

[0664] The screened intragranular components were then transferred to a V -shell blender and blended for a predetermined time and speed to ensure homogeneity.Subsequently, Magnesium Stearate was screened and introduced into the blend, followed by a lubrication step. The resulting intragranular blend was discharged into a double PE -lined container containing a desiccant.

[0665] Roller Compaction and Milling

[0666] The lubricated intragranular blend was subjected to roller compaction using a compactor. The resultant ribbons were immediately milled through an in-line oscillating granulator equipped with a defined granulator screen size, The milled granules were collected into a double PE-lined container with desiccant to prevent moisture ingress.

[0667] Extragranular Blending and Lubrication

[0668] The quantity of extragranular materials was adjusted based on the yield obtained from the granulation process. Extragranular materials comprised Croscarmellose Sodium and Colloidal Silicon Dioxide, which were screened and combined with the milled granules in a V-shell blender. The mixture was blended for a specified duration and intensity to ensure uniform distribution. Subsequently, Magnesium Stearate, also adjusted based on granule yield, was screened and added. The final blend was subjected to a second lubricationstep under controlled conditions.

[0669] Tablet Compression

[0670] The lubricated blend was compressed using a rotary tablet press. The compression parameters were adjusted to achieve a target tablet core weight of approximately 200 mg. Compression force, dwell time, and turret speed were controlled to ensure uniformity in tablet weight, hardness, and disintegration properties.

[0671] Film Coating

[0672] Compressed tablet cores were film-coated using Opadry® White 06K580000 in a perforated coating pan. Coating process parameters, including spray rate, inlet temperature, and pan speed, were controlled to achieve a uniform and functional coating layer. Upon completion, coated tablets were collected and stored in double PE-lined drums, with desiccant placed between liners to protect against residual moisture.

[0673] Tlie resulting tablet had a composition as shown in Table 9.Table 9. Formulation,

[0674] Other Embodiments

[0675] The detailed description set-forth above is provided to aid those skilled in the art in practicing the present invention. However, the invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed because these embodiments are intended as illustration of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description which do not depart from the spirit or scope of the present inventive discovery. Such modifications are also intended to fall within the scope of the appended claims.

[0676] References Cited

[0677] Ail publications, patents, patent applications and other references cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be construed as an admission that such is prior art to the present invention.

[0678] Specifically intended to be within the scope of the present invention, and incorporated herein by reference in its entirety, is the following publication:

[0679] 6th Clinical Trials on Alzheimer's Disease (CTAD) Boston, MA (USA) October 24-27, 2023: Posters, J. Prev. Alz. Dis. 2023;10(4):56-240 (supplement).

[0680] Other publications incorporated herein by reference in their entirety include:1. WHO. Fact sheets of dementia. 2017 (https: / / www.who.int / news-room / fact-sheets / detail / dementia).2. Tanzi RE, Bertram L. New frontiers in Alzheimer's disease genetics. Neuron 2001;32(2): 181 -4. DOI: 10.1016 / s0896-6273(01)00476-7.3. Francis PT, Palmer AM, Snape M, Wilcock GK. 'The cholinergic hypothesisof Alzheimer's disease: a review of progress. J Neurol Neurosurg Psychiatry 1999;66(2): 137-47. DOI: 10.1136 / jnnp.66.2.137.4. Hampel H, Mesulam MM, Cuello AC, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer's disease. Brain 2018; 141 (7): 1917-1933. DOI: 10.1093 / brain / awy 132.5. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 2016;8(6):595-608. DOI: 10.15252 / emmm.201606210. 6. Small SA, Duff K. Linking Abeta and tan in late-onset Alzheimer's disease: a dual pathway hypothesis. Neuron 2008;60(4):534-42. DOI:10.1016 / j.neuron.2008.11.007.7. Amsten AFT, Datta D, Del Tredici K, Braak H, Hypothesis: Tan pathology is an initiating factor in sporadic Alzheimer's disease. Alzheimers Dement 2021;17(l):l 15-124. DOI: 10.1002 / alz.l2192.8. Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement ( Y) 2018;4:575-590. DOI: 10.1016 / j.trci.2018.06.014.9. Zotova E, Nicoll JA, Kalaria R, Holmes C, Boche D. Inflammation in Alzheimer's disease: relevance to pathogenesis and therapy. Alzheimers Res Ther 2010;2(l):l. DOI: 10.1186 / alzrt24.10. Markesbery WR. Oxidative stress hypothesis in Alzheimer's disease. Free Radic Biol Med 1997;23(1): 134-47. DOI: 10.10I6 / s0891-5849(96)00629-6.11. Budd Haeberlein S, Aisen PS, Barkbof F, et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease. J Prev Alzheimers Dis 2022;9(2): 197-210. DOI: 10.14283 / jpad.2022.30.12. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med 2023;388(l):9-21. DOI: 10.1056 / NEJMoa2212948.13. Sims JR, Zimmer J, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA 2023;330(6): 512-527. DOI: 10.1001 / j ama.2023.13239.14. Cavalli A, Bolognesi ML, Minarini A, et al. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem 2008;51(3):347-72. DOI:10.1021 / jm7009364.15. Albertini C, Salerno A, de Sena Murteira Pinheiro P, Bolognesi ML. Fromcombinations to multi target-directed ligands: A continuum in Alzheimer's disease polypharmacology. Med Res Rev 2021;41(5): 2606-2633. DOI: 10.1002 / med.21699.16. Boche D, Nicoll JAR. Invited Review - Understanding cause and effect in Alzheimer's pathophysiology: Implications tor clinical trials. Neuropathol Appl Neurobiol 2020;46(7):623-640. DOI: 10.1111 / nan.12642.17. Proschak E, Stark H, Merk D. Polypharmacology by Design: A Medicinal Chemist's Perspective on Multitargeting Compounds. J Med Chem 2019;62(2):420-444. DOI: 10.1021 / acs.jmedchem.8b00760.18. Fang J, Zhang P, Zhou Y, et al. Endophenotype -based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer's disease, Nat Aging 2021; 1(12): 1175-1188. DOI: 10.1038 / s43587-021 -00138-z.19. Adesuyan M, Jani YH, Alsugeir D, et al. Phosphodiesterase Type 5 Inhibitors in Men With Erectile Dysfunction and tire Risk of Alzheimer Disease: A Cohort Study. Neurology 2024;102(4):e209131. DOI: 10.1212 / WNL.0000000000209131.20. Zuccarello E, Acquarone E, Calcagno E, et al. Development of novel phosphodiesterase 5 inhibitors for the therapy of Alzheimer's disease. Biochem Pharmacol 2020;176: 113818. DOI: 10.1016 / j.bcp.2020.113818.21. Park HJ, Moon KH, Lee SW, et al. Mirodenafil for the treatment of erectile dysfunction: a systematic review of the literature. World J Mens Health 2014;32(l):18-27. DOI: 10.5534 / wjmh.2014.32.1.18.22. Kang BW, Kim F, Cho JY, Kim S, Rhee J, Choung JJ. Phosphodiesterase 5 inhibitor mirodenafil ameliorates Alzheimer-like pathology and symptoms by multimodal actions. Alzheimers Res Ther 2022;14(l):92. DOI: 10.1186 / s 13195-022-01034-3.23. Lleo A, Greenberg SM, Growdon JH. Current pharmacotherapy for Alzheimer's disease. Annu Rev Med 2006;57:513-33. DOI:10.1146 / annurev.med.57.121304.131442.24. Posner K. Brown GK. Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity7and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry 2011; 168( 12): 1266-77. DOI:10.1176 / appi.ajp.2011.10111704.25. Holm S. A simple sequentially rejective multiple test procedure. ScandinavianJournal of Statistics 1979;6:2:65-70.26. FDA. Approved Package for Exelon Transdermal Patch. 2012.27. Jack CR, Wiste HJ, Algeciras-Schimnich A, et al. Predicting amyloid PET and tau PET stages with plasma biomarkers. Brain 2023;146(5):2029-2044. DOI:10.1093 / brain / awad042.28. Thijssen EH, La Joie R, Wolf A, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration. Nat Med 2020;26(3):387-397. DOI: 10.1038 / s41591-020-0762-2.29. Bateman RJ, Smith J, Donohue MC, et al. Two Phase 3 Trials of Ganteneramab in Early Alzheimer's Disease. N Engl J Med 2023;389(20): 1862-1876. DOI: 10.1056 / NEJMoa2304430.30. Lansdall CJ, McDougall F, Butler LM, et al. Establishing Clinically Meaningful Change on Outcome Assessments Frequently Used in Trials of Mild Cognitive Impairment Due to Alzheimer's Disease. J Prev Alzheimers Dis202.3; 10( 1 ):9- 18. DOI: 10.14283 / j pad.2022.102.

Claims

CLAIMSWhat is claimed is:

1. A method of treating a neurodegenerative disease in a subject, the method comprising:obtaining a plasma sample from the subject;determining a level of phosphorylated tau 217 (pTau217) in the plasma sample; and administering to the subject a therapeutically effective amount of mirodenafil or a pharmaceutically acceptable salt thereof.

2. Mirodenafil or a pharmaceutically acceptable salt thereof for use in a method of treating a neurodegenerative disease in a subject, the method comprising:obtaining a plasma sample from the subject;determining a level of phosphorylated tau 217 (pTau217) in the plasma sample; and administering to the subject a therapeutically effective amount of mirodenafil or the pharmaceutically acceptable salt thereof.

3. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 1 or 2, wherein the administering is performed when the level exceeds a predetermined value of at least about 0.185 pg / ml.

4. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein the administering is performed when the level exceeds a predetermined value ranging from about 0.01 pg / ml to about 10 pg / ml, preferably from about 0.041 pg / ml to about 5.028 pg / ml.

5. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 1-4, wherein the therapeutically effective amount is from about 10 mg to about 50 mg per day.

6. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein the therapeutically effective amount is about 30 mg per day.

7. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 1-6, wherein the administering is performed orally.

8. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein the administering is performed once daily,9. Tire method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 1-8, wherein the method further comprises monitoring the level during or after tire administering.

10. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 9, wherein the administering is repeated if the level is less than the predetermined value during or after the administering.

11. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 1-10, wherein the neurodegenerative disease is an amyloidosis-associated condition, dementia, Parkinson’s disease (PD), Parkinson’s disease dementia, Dementia with Lewy body (DLB), Alzheimer's disease (AD), Huntington’s disease (HD), Multiple sclerosis (MS), Vascular Dementia (VaD), Amyotrophic Lateral Sclerosis (ALS), Down’s syndrome dementia, or frontotemporal dementia.

12. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 11, wherein the amyloidosis-associated condition is Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, or preclinical Alzheimer's disease,13. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 11, wherein the amyloidosis-associated condition is mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia.

14. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 1-13, wherein the method further comprises assessing cognitive function of the subject using one or more standardized tests.

15. The method or mirodenafil or the phar aceutically acceptable salt thereof of claim 14, wherein the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini -Mental State Examination (MMSE).

16. A method of treating a neurodegenerative disease in a subject, the method comprising:obtaining a plasma sample from the subject;determining a ratio between a level of phosphorylated tau 217 (pTau217) and a level of amyloid beta 42 (AP42) in the plasma sample; andadministering to the subject a therapeutically effective amount of mirodenafil or a pharmaceutically acceptable salt thereof.

17. Mirodenafil or a pharmaceutically acceptable salt thereof for use in a methodof treating a neurodegenerative disease in a subject, the method comprising:obtaining a plasma sample from the subject;determining a ratio between a level of phosphorylated taxi 217 (pTau217) and a level of amyloid be ta.42 (Ap42) in the plasma sample; andadministering to the subject a therapeutically effective amount of mirodenafil or the pharmaceutically acceptable salt thereof.

18. lire method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 16 or 17, wherein the administering is performed when the ratio exceeds a predetermined value of at least about 0.00370.

19. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 16-18, w herein the ad inistering is performed when the ratio exceeds a predetermined value ranging from about 0.001 to about 10, preferably from about 0.0019 to about 0.4788.

20. lire method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 16-19, wherein the therapeutically effective amount is from about 10 mg to about 50 mg per day.

21. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 16-20, wherein tire therapeutically effective amount is about 30 m per day.

22. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 16-21, wherein the administering is performed orally.

2. The method or mirodenafil or the phar aceutically acceptable salt thereof of any one of claims 16-22, wherein the administering is performed once daily.

24. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 16-23, wherein tire method further comprises monitoring the ratio during or after the administering.

25. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 24, wherein the administering is repeated if the ratio is less than the predetermined value during or after tire administering.

26. The method or mirodenafil or the phar aceutically acceptable salt thereof of any one of claims 16-25, wherein the neurodegenerative disease is an amyloidosis-associated condition, dementia, Parkinson's disease (PD), Parkinson’s disease dementia. Dementia with Lewy body (DLB), Alzheimer’s disease (AD), Huntington's disease (HD), Multiple sclerosis(MS), Vascular Dementia (VaD), Amyotrophic Lateral Sclerosis (ALS), Down’s syndrome dementia, or frontotemporal dementia.

27. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 26, wherein the amyloidosis-associated condition is Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer's disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, or preclinical Alzheimer's disease.

28. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 26, wherein the amyloidosis-associated condition is mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia.

29. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 16-28, wherein the method further comprises assessing cognitive function of the subject using one or more standardized tests.

30. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 29, wherein the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini -Mental State Examination (MMSE).

31. A method of treating a neurodegenerative disease in a subject, the method comprising:obtaining a plasma sample from the subject;determining a level of phosphorylated tau 181 (pTau181) in the plasma sample; and administering to the subject a therapeutically effective amount of mirodenafil or a pharmaceutically acceptable salt thereof.

32. Mirodenafil or a pharmaceutically acceptable salt thereof for use in a method of treating a neurodegenerative disease in a subject, the method comprising:obtaining a plasma sample from the subject;determining a level of phosphorylated tau 181 (pTau 181 ) in the plasma sample; and administering to the subject a therapeutically effective amount of mirodenafil or the pharmaceutically acceptable salt thereof.

33. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 31 or 32, wherein the administering is performed when the level exceeds a predetermined value of at least about 2.2 pg / ml, preferably at least about 5.0 pg / ml.

34. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 31-33, wherein the administering is performed when the level exceeds a predetermined value ranging from about 0.1 pg / ml to about 100 pg / ml, preferably from about 1.05 pg / ml to about 12.33 pg / ml.

35. The method or mirodenafil or the pharmaceutically accep table salt thereof of any one of claims 31-34, wherein the therapeutically effective amount is from about 10 mg to about 50 mg per day.

36. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 31-35, wherein the therapeutically effective amount is about 30 mg per day.

37. The m ethod or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 31-36, wherein the administering is performed orally.

38. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 31-37, wherein the administering is performed once daily.

39. The method or mirodenafil or the phar aceutically acceptable salt thereof of any one of claims 31-38, wherein the method further comprises monitoring the level during or after the administering.

40. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 39, wherein the administering is repeated if the level is less than the predetermined value during or after the administering.

41. The me thod or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 31-40, wherein the neurodegenerative disease is an amyloidosis-associated condition, dementia, Parkinson's disease (PD), Parkinson’s disease dementia, Dementia with Lewy body (DLB), Alzheimer's disease (AD), Huntington's disease (HD), Multiple sclerosis (MS), Vascular Dementia (VaD), Amyotrophic Lateral Sclerosis (ALS), Down’s syndrome dementia, or frontotemporal dementia.

42. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 41, wherein the amyloidosis-associated condition is Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, or preclinical Alzheimer’s disease.

43. The method or mirodenafil or the pharmaceutically acceptable salt thereof ofclaim 41, wherein the amyloidosis-associated condition is mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia.

44. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 31-43, wherein the method further comprises assessing cognitive function of the subject using one or more standardized tests.

45. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 44, wherein the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini-Mental State Examination (MMSE).

46. A method of treating a neurodegenerative disease in a subject, tire method comprising:administering to the subject about 30 mg of mirodenafil or a pharmaceutically acceptable salt thereof orally once daily; andmonitoring a level of phosphorylated tan 217 (pTau217) in a plasma of the subject during or after the administering.

47. Mirodenafil or a pharmaceu tically acceptable salt thereof for use in a me thod of treating a neurodegenerative disease in a subject, the method comprising:administering to the subject about 30 mg of mirodenafil or a pharmaceutically acceptable salt thereof orally once daily; andmonitoring a level of phosphorylated tan 217 (pTau217) in a plasma of the subject during or after the administering.

48. The method or mirodenafil or the phar aceutically acceptable salt thereof of claim 46 or 47, wherein the administering is repeated if the level is less than that prior to the administering.

49. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 46-48, wherein the neurodegenerative di sease is an amyloidosis-associated condition, dementia, Parkinson's disease (PD), Parkinson’s disease dementia. Dementia with Lewy body (DLB), Alzheimer's disease (AD), Huntington's disease (HD), Multiple sclerosis (MS), Vascular Dementia (VaD), Amyotrophic Lateral Sclerosis (ALS), Down's syndrome dementia, or frontotemporal dementia.

50. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 49, wherein the amyloidosis-associated condition is Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia.prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, or preclinical Alzheimer’s disease.

51. The method or mirodenafil or the pharmaceutically accep table salt thereof of claim 49, wherein the amyloidosis-associated condition is mild cognitive impairment due to Alzheimer's disease or mild Alzheimer’s disease dementia.

52. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 46-51, wherein the method further comprises assessing the subject's cognitive function using one or more standardized tests.

53. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 52, wherein the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini-Mental State Examination (MMSE).

54. ’Die method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 46-53, wherein the level after 26 weeks is at least about 10% less than that prior to the administering.

55. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 46-54, wherein mirodenafil or the pharmaceutically acceptable salt thereof is in a tablet or a capsule.

56. The method of claim 55, wherein the tablet or the capsule comprises one or more pharmaceutically acceptable carriers.

57. The method or mirodenafil or the phar aceutically acceptable salt thereof of any one of claims 46-56, wherein the method further comprises:obtaining a plasma sample from the subject before prior to the administering; and determining a baseline level of pTau217 in the plasma sample.

58. A method of treating a neurodegenerative disease in a subject, the method comprising:administering to the subject about 30 mg of mirodenafil or a pharmaceutically acceptable salt thereof orally once daily; andmonitoring a ratio between a level of phosphorylated tau 2.17 (pTau217) and a level of amyloid beta 42 (Ap42) in a plasma of the subject during or after the administering.

59. Mirodenafil or a pharmaceutically acceptable salt thereof for use in a method of treating a neurodegenerative disease in a subject, the method comprising:administering to the subject about 30 mg of mirodenafil or a pharmaceutically acceptable salt thereof orally once daily; andmonitoring a ratio between a level of phosphorylated tau 217 (pTau217) and a level of amyloid beta 42 (Ap42) in a plasma of the subject during or after the administering.

60. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 58 or 59, wherein the administering is repeated if the ratio is less than that prior to the administering.

61. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 58-60, wherein the neurodegenerative disease is an amyloidosis-associated condition, dementia, Parkinson's disease (PD), Parkinson’s disease dementia. Dementia with Lewy body (DLB), Alzheimer's disease (AD), Huntington's disease (HD), Multiple sclerosis (MS), Vascular Dementia (VaD), Amyotrophic Lateral Sclerosis (ALS), Down’s syndrome dementia, or frontotemporal dementia.

62. ’Die method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 61, wherein the amyloidosis-associated condition is Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia, prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer's disease, early Alzheimer’s disease, or preclinicai Alzheimer’s disease.

63. Die method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 61, wherein the amyloidosis-associated condition is mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia.

64. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 58-63, wherein the method further comprises assessing the subject's cognitive function using one or more standardized tests.

65. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 64, wherein the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini -Mental State Examination (MMSE).

66. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 58-65, wherein the ratio after 26 weeks is at least about 10% less than that prior to the administering.

67. The method or mirodenafil or the pharmaceutically acceptable salt thereof ofany one of claims 58-66, wherein mirodenafil or the pharmaceutically acceptable salt thereof is in a tablet or a capsule.

68. The method of claim 67, wherein the tablet or the capsule comprises one or more pharmaceutically acceptable earners.

69. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 58-68, wherein the method further comprises:obtaining a plasma sample from the subject before prior to the administering; and determining a baseline ratio between a baseline level of pTau217 and a baseline level of Ap42 in the plasma sample.

70. A method of treating a neurodegenerative disease in a subject, tire method comprising:administering to the subject about 30 mg of mirodenafil or a pharmaceutically acceptable salt thereof orally once daily; andmonitoring a level of phosphorylated tau 181 (pTaul81) in a plasma of the subject during or after the administering.

71. Mirodenafil or a pharmaceutically acceptable salt thereof for use in a method of treating a neurodegenerative disease in a subject, the method comprising:administering to tire subject about 30 mg of mirodenafil or a pharmaceutically acceptable salt thereof orally once daily; andmonitoring a level of phosphorylated tau 181 (pTaul 81) in a plasma of the subject during or after the administering.

72. The method or mirodenafil or the phar aceutically acceptable salt thereof of claim 70 or 71, wherein the administering is repeated if the level is less than that prior to the administering.

73. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 70-72, wherein the neurodegenerative di sease is an amyloidosis-associated condition, dementia, Parkinson's disease (PD), Parkinson’s disease dementia. Dementia wi th Lewy body (DLB), Alzheimer's disease (AD), Huntington's disease (HD), Multiple sclerosis (MS), Vascular Dementia (VaD), Amyotrophic Lateral Sclerosis (ALS), Down's syndrome dementia, or frontotemporal dementia.

74. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 73, wherein the amyloidosis-associated condition is Alzheimer's Disease, mild cognitive impairment due to Alzheimer's disease, mild Alzheimer's disease dementia.prodromal stage of Alzheimer’s disease, early-onset Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, early Alzheimer’s disease, or preclinical Alzheimer’s disease.

75. The method or mirodenafil or the pharmaceutically accep table salt thereof of claim 73, wherein the amyloidosis-associated condition is mild cognitive impairment due to Alzheimer's disease or mild Alzheimer’s disease dementia.

76. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 70-75, wherein the method further comprises assessing the subject's cognitive function using one or more standardized tests.

77. The method or mirodenafil or the pharmaceutically acceptable salt thereof of claim 76, wherein the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini-Mental State Examination (MMSE).

78. ’Die method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 70-77, wherein the level after 26 weeks is at least about 10% less than that prior to the administering.

79. The method or mirodenafil or the pharmaceutically acceptable salt thereof of any one of claims 70-78, wherein mirodenafil or the pharmaceutically acceptable salt thereof is in a tablet or a capsule.

80. The method of claim 79, wherein the tablet or the capsule comprises one or more pharmaceutically acceptable carriers.

81. The method or mirodenafil or the phar aceutically acceptable salt thereof of any one of claims 70-80, wherein the method further comprises:obtaining a plasma sample from the subject before prior to the administering; and determining a baseline level of pTau181 in the plasma sample.

82. A method for identifying a subject responsive to early Alzheimer's disease treatment using mirodenafil or a pharmaceutically acceptable salt thereof, the method comprising:obtaining a plasma sample from a candidate;determining a level of phosphorylated tau 217 (pTau.217) in the plasma sample; and selecting the subject based on the level exceeding a predetermined value.

83. The method of claim 82, wherein the predetermined value is at least about 0.185 pg / ml.

84. The method of claim 82 or 83, wherein the predetermined value is about 0.01 pg / ml to about 10 pg / ml, preferably from about 0.041 pg / ml to about 5.028 pg / ml.

85. The method of any one of claims 82-84, further comprising administering from about 10 mg to about 50 mg of mirodenafil or the pharmaceutically acceptable salt thereof orally once daily to the subject.

86. The method of any one of claims 82-85, further comprising administering about 30 mg of mirodenafil or tire pharmaceutically acceptable salt thereof orally once daily to the subject.

87. The method of any one of claims 82-86, further comprising monitoring the level during or after the administering.

88. The method of claim 87, wherein the administering is repeated if the level is less than the predetennined value during or after the administering.

89. The method of any one of claims 82-88, wherein the subject has mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s disease dementia.

90. The method of any one of claim s 82-89, further compri sing assessing cognitive function of the subject using one or more standardized tests.

91. The method of claim 90, wherein the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini-Mental State Examination (MMSE).

92. A method for identifying a subject responsive to early Alzheimer's disease treatment using mirodenafil or a pharmaceutically acceptable salt thereof, the method comprising:obtaining a plasma sample from a candidate;determining a ratio between a level of phosphorylated tau 217 (pTau217) and a level of amyloid beta 42 (Ap42.) in the plasma sample; andselecting the subject based on the ratio exceeding a predetermined value,93. The method of claim 92, wherein the predetermined value is at least about 0.00370.

94. Die method of claim 92 or 93, wherein the predetermined value is from about 0.001 to about 10, preferably from about 0.0019 to about 0.4788.

95. The method of any one of claims 92-94, further comprising administering from about 10 mg to about 50 mg of mirodenafil or the pharmaceutically acceptable salt thereof orally once daily to the subject.

96. The method of any one of claims 92-95, further comprising administering about 30 mg of mirodenafil or the pharmaceutically acceptable salt thereof orally once daily to the subject.

97. The method of any one of claims 92-96, further comprising monitoring the ratio during or after the administering.

98. lire method of claim 97, wherein the administering is repeated if the ratio is less than the predetermined value during or after the administering.

99. The method of any one of claims 92-98, wherein the subject has mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia.

100. The method of any one of claims 92-99, further comprising assessing cognitive function of the subject using one or more standardized tests.

101. The method of claim 100, wherein the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini-Mental State Examination (MMSE).

102. A method for identifying a subject responsive to early Alzheimer's disease treatment using mirodenafil or a pharmaceutically acceptable salt thereof, the method comprising:obtaining a plasma sample from a candidate;determining a level of phosphorylated tau 181 (pTaulSl) in the plasma sample; and selecting the subject based on the level exceeding a predetermined value.

103. The method of claim 102, wherein the predetermined value is at least about 2.2 pg / ml, preferably at least about 5.0 pg / ml.

104. The method of claim 102 or 103, wherein the predetermined value is about 0.1 pg / ml to about 100 pg / ml, preferably from about 1.05 pg / ml to about 12.33 pg / ml.

105. The method of any one of claims 102-104, further comprising administering from about 10 mg to about 50 mg of mirodenafl or the pharmaceutically acceptable salt thereof orally once daily to the subject.

106. lire method of any one of claims 102-105, further comprising administering about 30 mg of mirodenafil or the pharmaceutically acceptable salt thereof orally once daily to the subject.

107. The method of any one of claims 102-106, further comprising monitoring the level during or after the administering.

108. The method of claim 107, wherein the administering is repeated if the level is less than the predetermined value during or after the administering.

109. The method of any one of claims 102-108, wherein the subject has mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia.

110. The method of any one of claims 102-109, further comprising assessing cognitive function of the subject using one or more standardized tests.

111. lire method of claim 110, wherein the one or more standardized tests comprise Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), or Mini-Mental State Examination (MMSE).

112. A pharmaceutical composition, comprising:mirodenafil or a pharmaceutically acceptable salt thereof in an amoun t of about 10 mg to about 50 mg;a filler or a binder m an amount of about 40% to about 80% w / w of the pharmaceutical composition;a disintegrant in an amount of about 10% to about 30% w / w of the pharmaceutical composition;a lubricant in an amount of about 1% to about 5% w / w of tire pharmaceutical composition; anda glidant in an amount of about 1% to about 5% w / w of the pharmaceutical composition.

113. The pharmaceutical composition of claim 112, wherein the amount of mirodenafil or the pharmaceutically acceptable salt thereof is about 30 mg.

114. The pharmaceutical composition of claim 112 or 113, wherein the filler comprises microcrystalline cellulose, anhydrous lactose, spray-dried lactose, dibasic calcium phosphate, glucose, dextrose, fructose, lactose, mannitol, or sorbitol.

115. The pharmaceutical composition of any one of claims 112-114, wherein the filler is microcrystalline cellulose.

116. lire pharmaceutical composition of any one of claim 112-115, wherein the binder comprises microcrystalline cellulose, polyvinylpyrrolidone, sucrose, liquid glucose, acacia, tragacanth, gelatin, alginic acid, cellulose, methyl cellulose, ethyl cellulose, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose, sodium carboxy methyl cellulose, polyethylene glycol (PEG), polyvinyl alcohols, or polymethacrylates.

117. The pharmaceutical composition of any one of claim 112-116. wherein the binder is microcrystalline cellulose.

118. The pharmaceutical composition of any one of claims 112-117, wherein the amount of the filler or the binder is about 60% to about 65% w / w of the pharmaceutical composition.

119. The pharmaceutical composition of any one of claims 112-118, wherein the amount of the filler or the binder is about 61.75% w / w of the pharmaceutical composition.

120. The pharmaceutical composition of any one of claims 112-119, wherein the disintegrant comprises croscarmellose sodium, crospovidone, sodium starch glycolate, Starch NF, Starch 1500, or algimc acid.

121. The pharmaceutical composition of any one of claims 112-120, wherein the disintegrant is croscarmellose sodium.

122. The pharmaceutical composition of any one of claims 112-121, wherein the amount of the disintegrant is about 15% to about 25% w / w of the pharmaceutical composition.

123. The pharmaceutical composition of any one of claims 112-122, wherein the amount of the disintegrant is about 20% w / w of the pharmaceutical composition.

124. The pharmaceutical composition of any one of claims 112-123, wherein the lubricant comprises magnesium stearate, sodium stearyl fumarate, glyceryl dibehenate, stearic acid, talc, colloidal silicon dioxide, or sodium stearyl fumarate.

125. The pharmaceutical composition of any one of claims 112-124, w'herein the lubricant is magnesium stearate.12.

6. The pharmaceutical composition of any one of claims 112-125, wherein the amount of the lubricant is about 1.5% to about 2% w / w of the pharmaceutical composition.

127. The pharmaceutical composition of any one of claims 112-126, wherein the amount of the lubricant is about 1.75% wAv of the pharmaceutical composition.

128. The pharmaceutical composition of any one of claims 112-127, wherein the glidant comprises colloidal silicon dioxide, hydrous magnesium silicate, or calcium silicate.

129. lire pharmaceutical composition of any one of claims 112-128, wherein the glidant is colloidal silicon dioxide.

130. Tire pharmaceutical composition of any one of claims 112-129, wherein the amount of the glidant is about 1.25% to about 1.75% w / w of the dosage form.

131. The pharmaceutical composition of any one of claims 112-130, wherein theamount of the glidant is about 1.5% w / w of the dosage form.

132. A dosage form comprising:an intragranular component comprising:mirodenafil or a pharmaceutically acceptable salt thereof in an amount of about 10 mg to about 50 mg;an intragranular filler or an intragranular binder in an amount of about 40% to about 80% w / w of the dosage form;an intragranular disintegrant in an amount of about 0.1% to about 5% w / w of the dosage form;an intragranular lubricant in an amount of about 0.1% to about 5% w / w of the dosage form; andan intragranular glidant in an amount of about 0.1% to about 5% w / w of the dosage form; andan extragranular component comprising:an extragranular disintegrant in an amount of about 10% to about 25% w / w of the dosage form;an extragranular lubricant in an amount of about 0.1% to about 5% w / w of the dosage form; andan extragranular glidant in an amount of about 0.1% to about 5% w / w of the dosage form,wherein the intragranular component constitutes from about 60% to about 90% w / w of the dosage form.

133. The dosage form of claim 132, wherein the amount, of mirodenafil or the pharmaceutically acceptable salt thereof is about 30 mg.

134. The dosage form of claim 132 or 133, wherein the intragranular component constitutes from about 75% to about. 85% w / w of the dosage form.

135. The dosage form of any one of claims 132-134, wherein the intragranular component constitutes from about 80.75% ' / w of the dosage form.

136. lire dosage form of any one of claims 132-135, wherein the intragranular filler comprises microcrystalline cellulose, dibasic calcium phosphate, glucose, dextrose, fructose, lactose, mannitol, or sorbitol.

137. The dosage form of any one of claims 132-136, wherein the intragranular filler is microcrystalline cellulose.

138. The dosage form of any one of claim 132-137, wherein the intragranular binder comprises microcrystalline cellulose, polyvinylpyrrolidone, sucrose, liquid glucose, acacia, tragacanth, gelatin, alginic acid, cellulose, methyl cellulose, ethyl cellulose, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose, sodium carboxy methyl cellulose, polyethylene glycol (PEG), polyvinyl alcohols, or polymethacrylates.

139. Idle pharmaceutical composition of any one of claim 132-138, wherein the intragranular binder is microcrystalline cellulose.

140. The dosage form of any one of claims 132-139, wherein the amount of the intragranular filler or the intragranular binder is about 60% to about 65% w / w of the dosage form.

141. The dosage form of any one of claims 132-140, wherein the amount of the intragranular filler or the intragranular binder is about 61.75% w / w of the dosage form.

142. The dosage form of any one of claims 132-141, wherein the intragranular disintegrant comprises croscarmellose sodium, crospovidone, sodium starch gly colate. Starch NF, Starch 1500, or alginic acid.

143. The dosage form of any one of claims 132-142, wherein the intragranular disintegrant is croscarmellose sodium.

144. The dosage form of any one of claims 132-143, wherein the amount of the intragranular disintegrant is about 2% to about 3% w / w of the dosage for,145. Tire dosage form of any one of claims 132-144, wherein the amount of the intragranular disintegrant is about 2.5% w / w of the dosage form.

146. The dosage form of any one of claims 132-145, wherein the intragranular lubricant comprises magnesium stearate, sodium stearyl fumarate, glyceryl dibehenate, stearic acid, talc, colloidal silicon dioxide, or sodium stearyl fumarate.

147. The dosage form of any one of claims 132-146, wherein the intragranular lubricant is magnesium stearate.

148. The dosage form of any one of claims 132-147, wherein the amount of the intragranular lubricant is about 0.5% to about 1.5% w / w of the dosage form.

149. lire dosage form of any one of claims 132-148, wherein the amount of the intragranular lubricant is about 1 % w / w of the dosage form.

150. Tire dosage form of any one of claims 132-149, wherein the intragranular glidant comprises colloidal silicon dioxide, hydrous magnesium silicate, or calcium silicate.

151. The dosage form of any one of claims 132-150, wherein the intragranularglidant is colloidal silicon dioxide.

152. The dosage form of any one of claims 132-151, wherein the amount of the intragranular glidant is about 0.25% to about 0.75% w / w of the dosage form.

153. The dosage form of any one of claims 132-152, wherein the amount of the intragranular glidant is about 0.5% w / w of the dosage form.

154. The dosage form of any one of claims 132-153, wherein the extragranular disintegrant comprises croscaimellose sodium, crospovidone, sodium starch glycolate. Starch NF, Starch 1500, or alginic acid.

155. The dosage form of any one of claims 132-154, wherein the extragranular disintegrant is croscaimellose sodium.

156. The dosage form of any one of claims 132-155, wherein the amount of the extragranular disintegrant is about 15% to about 20% w / w of the dosage form.

157. The dosage form of any one of claims 132-156, wherein the amount of the extragranular disintegrant is about 17.5% w / w of the dosage form.

158. The dosage form of any one of claims 132-157, wherein the extragranular lubricant comprises magnesium stearate, sodium stearyl fumarate, glyceryl dibehenate, stearic acid, talc, colloidal silicon dioxide, or sodium stearyl fumarate.

159. The dosage form of any one of claims 132-158, wherein the extragranular lubricant is magnesium stearate.

160. The dosage form of any one of claims 132-159, wherein the amount of the extragranular lubricant is about 0.5% to about 1% w / w of the dosage form.

161. The dosage form of any one of claims 132-160, wherein the amount of the extragranular lubricant is about. 0.75% w / w of the dosage form.

162. The dosage form of any one of claims 132-161, wherein the extragranular glidant comprises colloidal silicon dioxide, hydrous magnesium silicate, or calcium silicate.

163. The dosage form of any one of claims 132-162, wherein the extragranular glidant is colloidal silicon dioxide.

164. The dosage form of any one of claims 132-163, wherein the amount of the extragranular glidant is about 0.5% to about 1.5% w / w of the dosage form.

165. The dosage form of any one of claims 132-164, wherein the amount of the extragranular glidant is about 1% w / w of the dosage form.

166. The dosage form of any one of claims 132-165, wherein the dosage form is a tablet or a capsule.

167. The dosage form of any one of claims 132-166. further comprising a film coating.

168. The dosage form of claim 167, wherein the film coating comprises Opadry White, Sepifilm White, or Aquarius Prime Write.

169. The dosage form of claim 16s7 or 168, wherein the film coating is Opadry White.

170. A method for manufacturing the dosage form of any one of claims 130-164, comprising:preparing the intragranular component via dry granulation;applying the extragranular component to the intragranular component to form a blend; andcompressing the blend.

171. The method of claim 170, further comprising applying the film coating.

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