CN117529318A

CN117529318A - Methods of treating Alzheimer's disease

Info

Publication number: CN117529318A
Application number: CN202280036530.4A
Authority: CN
Inventors: S·L·罗杰斯
Original assignee: Amiliad Pharmaceutical Co
Current assignee: Amiliad Pharmaceutical Co
Priority date: 2021-05-19
Filing date: 2022-05-19
Publication date: 2024-02-06

Abstract

The present disclosure relates to the treatment of alzheimer's disease by orally administering a 180mg daily dose of 1',3 '-dihydro-2H-spiro [ imidazo [1,2 a ] pyridin-3, 2' -inden-2-one as a single active agent or co-administered with donepezil hydrochloride and/or memantine hydrochloride.

Description

Methods of treating Alzheimer's disease

Cross Reference to Related Applications

The present application claims priority from U.S. provisional patent application Ser. No. 63/190,299, issued on Ser. No. 63/192,398, issued on Ser. No. 63/299, issued on Ser. No. 2021, 5/24, and issued on Ser. No. 63/331,011, issued on Ser. No. 4/2022, the contents of which are hereby incorporated by reference in their entirety.

Technical Field

The present disclosure describes the administration of 1',3' -dihydro-2H-spiro [ imidazo- [1,2 a ] pyridin-3, 2 '-inden-2-one ("AD 101") for the treatment of patients suffering from alzheimer's disease. In one aspect, AD101 is administered in a modified dosage regimen. In one aspect, AD101 is administered to a patient undergoing memantine hydrochloride therapy.

Background

Alzheimer's disease ("AD") is a neurodegenerative disorder for which symptomatic treatment is only possible, but has limited efficacy. It is predicted that by 2050 the prevalence of AD worldwide will double to over 1 million, at which time 1 out of every 85 people worldwide suffers from this disease. Where more than 40% of these cases will be in advanced AD, a high degree of care equivalent to nursing home care is required. AD begins with mild cognitive problems, such as memory loss, and eventually progresses to a stage where independent life is disabled. The main risk factor for developing AD is age; the likelihood of developing alzheimer's disease doubles about every five years after age 65 and reaches approximately 50% after age 85. Family history may also increase the risk of developing the disease, possibly due to genetic or environmental factors.

AD is the most common cause of dementia. The term dementia describes a syndrome characterized by memory impairment, mental deterioration, personality changes and behavioral abnormalities. These symptoms lead to social and occupational decline. Dementia may have a variety of etiologies and pathophysiology, and a range of drugs are being developed to treat this condition. Dementia of the Alzheimer's type ("DAT") is defined as a progressive, fatal neurodegenerative disorder characterized by deterioration of cognition and memory, progressive impairment of the ability to conduct activities of daily living, and many neuropsychiatric and behavioral symptoms. DAT is the most common form of dementia in elderly people and is expected to increase as the population ages.

There are currently four drugs approved for the treatment of cognitive symptoms of AD, which fall into two groups:

1. cholinesterase inhibitors (ChEI): donepezil (cababa)Latine (rivastigmine) and galantamine (galantamine). These drugs increase cholinergic transmission by inhibiting cholinesterase that hydrolyzes them. Galantamine is used for the treatment of mild to moderate AD,(donepezil hydrochloride tablets) and rivastigmine are also suitable for AD and can be used in patients suffering from mild, moderate or severe disease.

Nmda (N-methyl-D-aspartate) receptor antagonist: memantine hydrochloride. This drug modulates the effects of pathologically elevated glutamate replenishment levels that may lead to neuronal dysfunction.(Memantine hydrochloride tablets) are only suitable for treating patients with moderate to severe DAT.

None of these approved drugs cure the disease. In addition, non-selective ChEI has significant adverse side effects such as vomiting and diarrhea. Thus, other treatment options are needed to alleviate cognitive impairment and deterioration of overall function (i.e., the patient's overall ability to perform his daily activities) in AD patients. Furthermore, while memantine hydrochloride is generally well-tolerated when administered to subjects with AD, it exhibits certain side effects that may exacerbate and/or lead to treatment complications when administered in combination with other AD drugs.

AD101 (previously reported as AD101, ST101, or ZTET 1446) is a small molecule with the chemical name 1',3' -dihydro-2H-spiro [ imidazo [1,2 a ] pyridin-3, 2' -inden-2-one. AD101 and its preparation are described for the first time in WO 2001/09131A1, the content of which is hereby incorporated by reference. The present disclosure provides daily doses of AD101 that are particularly effective in treating subjects with Alzheimer's Disease (AD), including subjects currently receiving a donepezil hydrochloride stabilization regimen. Thus, once daily (QD) oral administration of AD101 at 180mg provides symptomatic relief to AD subjects, including alleviating cognitive impairment and overall function in patients exhibiting AD onset or progression and/or improving cognitive and overall function in treated subjects.

The present disclosure also provides a novel combination therapy that may be particularly effective in treating subjects suffering from AD. Thus, the present disclosure describes that memantine hydrochloride and AD101 can be co-administered safely. Surprisingly, AD101 can be administered to subjects suffering from AD who are taking stable doses of memantine hydrochloride at daily doses up to at least 180mg without any resulting significant side effects. It is also surprising that this beneficial side effect profile is retained when AD101 is administered to AD subjects taking a stable dose of memantine hydrochloride and a stable dose of donepezil hydrochloride at a daily dose of up to at least 180 mg.

Co-administration of AD101 and memantine hydrochloride can provide AD subjects (including subjects currently receiving a stable donepezil hydrochloride regimen) with particular symptomatic relief, including alleviation of cognitive impairment and overall function in patients exhibiting the onset or progression of Alzheimer's disease and/or improvement of cognitive and overall function in the treated subjects. Combination therapy may be effective without major safety issues. Thus, administration of AD101 (e.g., 180mg of AD101, QD) to AD subjects currently treated with memantine hydrochloride and/or donepezil hydrochloride can provide particularly effective symptomatic relief without introducing significant drug-related safety issues.

Disclosure of Invention

In one aspect, the present disclosure describes that AD101 can be safely administered to a subject with alzheimer's disease at a daily dose (QD) of 180 mg.

In one aspect, the present disclosure describes that AD101 can be safely administered to a subject suffering from dementia of the alzheimer's type at a daily dose (QD) of 180 mg.

In one aspect, the present disclosure describes that AD101 may be safely co-administered with memantine hydrochloride to a subject suffering from alzheimer's disease. In one embodiment of this aspect, AD101 may be administered in a daily dose (QD) up to at least 180 mg. In another embodiment of this aspect, donepezil hydrochloride is also administered to the subject (e.g. including when AD101 is administered in a daily dose (QD) up to at least 180 mg).

In one aspect, the present disclosure describes that AD101 may be safely co-administered with memantine hydrochloride to a subject suffering from dementia of the alzheimer's type. In one embodiment of this aspect, AD101 may be administered in a daily dose (QD) up to at least 180 mg. In another embodiment of this aspect, donepezil hydrochloride is also administered to the subject (e.g. including when AD101 is administered in a daily dose (QD) up to at least 180 mg).

The present disclosure also describes that AD101 may be orally administered to a subject suffering from alzheimer's disease in a dose of up to at least 180mg QD over a period of time longer than 12 weeks (e.g., 24 weeks or 36 weeks or more) without causing significant safety problems in the subject, including when AD101 is co-administered with memantine hydrochloride and/or donepezil hydrochloride.

The present disclosure further describes the administration of a dose of up to at least 180mg QD to a pharmaceutical composition also in use with memantine hydrochloride and/or donepezil hydrochloride (e.g.) The treated AD101 of subjects with alzheimer's disease may be particularly effective in improving cognitive and overall function and/or delaying the decline in both outcomes in the treated subjects.

Accordingly, in one aspect, the present disclosure provides a method of treating alzheimer's disease in a human subject having alzheimer's disease, the method comprising orally administering to the subject a 180mg daily dose of AD101.

In one aspect, the present disclosure provides a method of treating dementia of the alzheimer's type in a human subject suffering from dementia of the alzheimer's type, the method comprising orally administering to the subject a 180mg daily dose of AD101.

In one aspect, the present disclosure provides a method of treating alzheimer's disease in a human subject having alzheimer's disease, the method comprising orally administering to the subject a 180mg daily dose of AD101 and a dose of donepezil hydrochloride.

In one aspect, the present disclosure provides a method of treating dementia of the alzheimer's type in a human subject suffering from dementia of the alzheimer's type, the method comprising orally administering to the subject a 180mg daily dose of AD101 and a dose of donepezil hydrochloride.

In one embodiment of any of the above aspects, the subject has been treated with donepezil hydrochloride prior to the first administered dose of AD 101.

In one embodiment of any of the above aspects, the subject has been treated with a stable dose of donepezil hydrochloride prior to the first administered dose of AD 101.

In one aspect, the present disclosure provides a method of treating alzheimer's disease in a human subject having alzheimer's disease, the method comprising orally administering to the subject a therapeutically effective amount of AD101 and a therapeutically effective amount of memantine hydrochloride.

In one aspect, the present disclosure provides a method of treating alzheimer's disease in a human subject having alzheimer's disease, the method comprising orally administering to the subject a 180mg daily dose of AD101 and a therapeutically effective amount of memantine hydrochloride.

In one aspect, the present disclosure provides a method of treating dementia of the alzheimer's type in a human subject suffering from dementia of the alzheimer's type, the method comprising orally administering to the subject a therapeutically effective amount of AD101 and a therapeutically effective amount of memantine hydrochloride.

In one aspect, the present disclosure provides a method of treating dementia of the alzheimer's type in a human subject suffering from dementia of the alzheimer's type, the method comprising orally administering to the subject a 180mg daily dose of AD101 and a therapeutically effective amount of memantine hydrochloride.

In one embodiment of any of the above aspects, the subject has been treated with memantine hydrochloride prior to the first administered dose of AD 101.

In one embodiment of any of the above aspects, the subject has been treated with a stable dose of memantine hydrochloride prior to the first administered dose of AD 101.

In one embodiment of any of the above aspects, the subject has been treated with memantine hydrochloride and donepezil hydrochloride prior to the first administered dose of AD 101.

In one embodiment of any of the above aspects, the subject has been treated with a stable dose of memantine hydrochloride and donepezil hydrochloride prior to the first administered dose of AD 101.

Donepezil hydrochloride (e.g) The subject may conveniently be administered orally at a daily dose of about 5mg to about 50mg (including 5mg, 10mg or 23 mg), or a daily dose of 5mg or 10mg via transdermal patches once a week. The administration of donepezil hydrochloride may be one or more months, for example at least 30 days. The subject may begin administering donepezil hydrochloride at a lower dose (e.g., 5mg or 10mg QD) and later increase to a maintenance dose (e.g., 23mg QD).

Memantine hydrochloride may conveniently be administered orally to a subject in a daily dose of from about 5mg to about 30 mg. In one embodiment, memantine hydrochloride is administered at a daily dose of 5 mg. In one embodiment, memantine hydrochloride is administered at a daily dose of 20 mg. In one embodiment, memantine hydrochloride is administered at an initial daily dose of 5mg, which is then increased to a maintenance daily dose of 20 mg. In one embodiment, memantine hydrochloride is orally administered to a subject as a sustained release capsule at a daily dose of 7mg, 14mg, or 28 mg. In one embodiment, memantine hydrochloride is initially administered as a slow release capsule at a daily dose of 7mg, which is then increased to a maintenance daily dose of 14mg or 28 mg.

Drawings

Figure 1 is a flow chart of a randomized, double-blind, placebo-controlled phase 3 clinical study of the efficacy, safety and tolerability of AD101 in the treatment of AD in subjects stably treated with donepezil hydrochloride. Primary, secondary and exploratory efficacy outcomes were monitored, as well as safety and tolerability variables including signs and symptoms at Treatment (TESS), abnormal laboratory values at Treatment (TEAV), serious Adverse Events (SAE), and Therapeutic Drug Monitoring (TDM).

Detailed Description

AD101 showed pharmacological activity in learning and memory rodent models associated with AD, both after acute and chronic administration. AD101 has also been shown to increase acetylcholine (ACh) levels in rodent brains and improve learning and memory in many animal behavioral tests. (Yamaguchi Y. Et al, J.Pharmacol. Exp. Ther.577:1079-1087 (2006); ito Y. Et al, J.Pharmacol. Exp. Ther.520:819-827 (2007)). This improvement in function is associated with an enhancement of long-term potentiation (LTP) (electrophysiological correlation of memory formation) and with biochemical changes associated with an enhancement of LTP (e.g., protein kinases C and Ca) ²⁺ Increased activity of calmodulin-dependent protein kinase II (CaMK II) is relevant (Han, F. Et al, J. Pharmacol. Exp. Ther.326:127-134 (2008)).

Additional experiments have shown that AD101 enhances nicotine stimulated ACh release, increases extracellular ACh concentration in the cerebral cortex, and increases extracellular concentrations of both ACh and dopamine in the hippocampus. The breadth of the model in which AD101 exerts its effects suggests the possibility of participating in upstream targets in signaling pathways associated with these processes.

AD101 also reduced the accumulation of aβ -like deposits and produced improvements in learning and memory functions, suggesting that behavioral effects of AD101 may be associated with reduced aβ production and/or accumulation (see U.S. patent application publication No. 2008/103158). AD101 has also been demonstrated to induce cleavage of amyloid precursor proteins, reduce the levels of pre-ADAM 10 and/or BACE proteins, and enhance the activity of ubiquitin-proteasome system pathways (see U.S. patent application publication nos. 2010/0168135, 2010/0267763, and 2010/0298348). The contents of each of U.S. patent application publications 2008/103158, 2010/0168135, 2010/0267763, and 2010/0298348 are incorporated herein by reference.

Thus, AD101 differs from commercially available therapies in that it exhibits two roles in animal research testing. It improves cognition and it also reduces the accumulation of abnormal protein deposits in the brain. Both of these properties indicate that AD101 is a promising agent for the treatment of AD.

Human proof of concept tests have investigated the safety and tolerability of AD101 at various doses and its ability to improve cognitive and overall function during 12 weeks of administration. In one such trial, AD101 was administered to subjects who were 50 years of age or higher who were likely to have AD [ defined by national neuropathy, language communication disorder, and institute of research for stroke/alzheimer's disease standards, fourth edition (DSM-IV) and national neurological disorder, with MMSE scores of 10 to 20, and recruited CT or MRI scans for 18 months, at doses of 10mg, 60mg, and 120mg per day over 12 weeks. Patients were required to receive a stabilization regimen of 10mg donepezil hydrochloride QD for at least 90 days prior to treatment with AD101 and continued treatment with 10mg donepezil hydrochloride QD during the trial with AD 101.

Gauthier et al J Alzheimer's Dis.2015;48 The top line results of this test (topline results) are reported in 473-481 (2). No significant safety issues associated with AD101 were identified during the test with doses up to 120mg QD and efficacy results support the following possibilities: AD101 may provide additional symptomatic benefits in moderate AD in patients who are receiving stable doses of donepezil hydrochloride. Importantly, when three doses were analyzed separately, there was no discernable dose response across the entire treatment group in terms of the primary outcome measure, and there was no indication that further increasing the dose of AD101 would result in additional improvement in the outcome of treatment in the subject group or would not introduce safety concerns. Surprisingly, however, it has now been found that AD101 can be safely administered to AD subjects in daily doses up to at least 180mg, and that AD101 in daily doses of 180mg is administered to also be used A DAT subject treated with (donepezil hydrochloride) may provide particularly effective relief of AD symptoms without introducing significant safety issues associated with AD 101.

Thus, the inventors of the present disclosure have identified a daily dose of AD101 that is particularly effective in treating subjects with Alzheimer's Disease (AD), including subjects currently receiving a donepezil hydrochloride stabilization regimen. AD101 administered orally at 180mg QD may provide special symptomatic relief to such subjects, including alleviating cognitive impairment and overall function in patients exhibiting alzheimer's disease onset or progression and/or improving cognitive and overall function in the treated subjects.

The inventors of the present disclosure have also identified a new combination therapy that may be particularly effective in treating subjects suffering from AD. Thus, co-administration of AD101 and memantine hydrochloride may provide special symptomatic relief for such subjects (including subjects currently receiving a stable donepezil hydrochloride regimen), including reducing cognitive impairment and overall function in patients exhibiting the onset or progression of alzheimer's disease and/or improving cognitive and overall function in the treated subjects. Combination therapy may be effective without major safety issues. In one embodiment of this aspect, AD101 may conveniently be administered orally to a subject in a daily dose of about 50mg to about 250mg, for example 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg or 250 mg. In a specific embodiment, AD101 is administered orally at a daily dose of about 120 mg. In a specific embodiment, AD101 is administered orally at a daily dose of about 180 mg.

By a stable regimen of donepezil hydrochloride and/or memantine hydrochloride is meant herein that a daily dose of donepezil hydrochloride and/or memantine hydrochloride has been administered for an extended period of time, typically at least about 1, 2, 3, 4, 5 or 6 months or more (e.g. at least about 30 days), before the subject receives the first dose of AD101 to treat a subject suffering from alzheimer's disease. Conventionally, the administration of donepezil hydrochloride and/or memantine hydrochloride to the subject is continued during AD101 therapy.

In conventional practice, the subject may be treated with a daily dose of 5mg of donepezil hydrochloride administered as a single tablet, or a daily dose of 10mg of donepezil hydrochloride administered as one or two tablets for the duration of the treatment (e.g. 5mg or 10mg of donepezil hydrochloride administered as QD), or with 10mg of donepezil hydrochloride administered daily as one or two tablets (e.g. 10mg of donepezil hydrochloride administered as QD) for at least 30 days, and then switched to a daily dose of 23mg or higher of donepezil hydrochloride administered as a single tablet. Thus, subjects administered a first dose of 180mg AD101 may also receive 5mg QD donepezil hydrochloride, 10mg QD donepezil hydrochloride, or 23mg QD donepezil hydrochloride. A subject with a more severe AD may have been administered donepezil hydrochloride Ji Da for a longer period of time and thus may be more likely to be receiving 23mg QD of donepezil hydrochloride when AD101 is administered at the 180mg first dose.

Alternatively, donepezil hydrochloride may be administered via a transdermal patch, which may be replaced, for example, once a week. Such patches may conveniently deliver a daily dose of 5mg or 10mg of donepezil hydrochloride. Examples of transdermal patches for use herein includeWhich is a rectangular 6-layer laminate containing a donepezil-free, brown, overlying backing/adhesive layer, a release layer, a drug matrix, a film, a contact adhesive and a release liner, and using the CORPLEX technology.

When treating a subject with AD101 and memantine hydrochloride, the subject may conveniently be administered 5mg of memantine hydrochloride for a combination therapy duration. Alternatively, the subject is initially treated with 5mg memantine hydrochloride, which is then (e.g. after 3 months or more) typically increased to a maintenance daily dose of 20mg before the first dosing of AD 101. In one embodiment, memantine hydrochloride is orally administered to a subject as a sustained release capsule at a daily dose of 7mg for the duration of the combination therapy. In further embodiments, memantine hydrochloride is orally administered to a subject as a slow release capsule at a daily dose of 14mg for the duration of the combination therapy. In another embodiment, memantine hydrochloride is initially administered as a slow release capsule at a daily dose of 7mg, which daily dose is then typically increased to a maintenance daily dose of 14mg or 28mg prior to the first dosing of AD 101. In one embodiment, the subject may also conveniently be treated with a daily dose of 10mg of donepezil hydrochloride administered as one or two tablets for the duration of the combination therapy, or with 10mg QD of donepezil hydrochloride for 3 months or more, and then typically switched to a daily dose of 23mg higher of donepezil hydrochloride administered as a single tablet before dosing AD101 for the first time.

The subject to whom AD101 is first administered may already be taking a lower dose or a higher maintenance dose of memantine hydrochloride. Similarly, the subject who is first administered AD101 may already be taking a lower dose or a higher maintenance dose of donepezil hydrochloride. Subjects with more severe AD may have been administered memantine hydrochloride and/or donepezil hydrochloride Ji Da for a longer period of time, and thus may be more likely to be receiving a maintenance dose of memantine hydrochloride and/or a maintenance dose of donepezil hydrochloride when AD101 is first administered.

When memantine hydrochloride and donepezil hydrochloride are both administered to a subject suffering from AD, they may be administered as separate oral compositions or in a single oral composition. In one aspect, memantine hydrochloride and donepezil hydrochloride are administered together as a capsule comprising a sustained release agent of memantine hydrochloride (14 mg or 28 mg) and 10mg of donepezil hydrochloride.

(Memantine hydrochloride) is commercially available and supplied as a capsule film coated tablet containing 5mg or 10mg Memantine hydrochloride or as a 2mg/mL oral solution. />XR (memantine hydrochloride) is commercially available and supplied as a slow release capsule containing 7mg, 14mg, 21mg or 28mg of memantine hydrochloride.

(donepezil hydrochloride) is commercially available and is applied as a film coating circle containing 5mg, 10mg or 23mg of donepezil hydrochlorideA shaped tablet supply.

AD101 may be administered orally as a tablet or capsule that may contain from about 0.01% to about 99%, or from about 0.25% to about 75%, of the active ingredient, along with one or more excipients or carriers.

Although AD101 may be combined with memantine hydrochloride and/or donepezil hydrochloride and used in a single oral dosage form, AD101, memantine hydrochloride and donepezil hydrochloride are conveniently administered in separate oral dosage forms.

A common test used to assess the severity of AD or associated dementia in a subject is the brief mental state examination (MMSE). MMSE is used to measure the ability to think (or "cognitive impairment"). It rated six items: orientation, learning, attention, word recall, language use and understanding, and construction practices. Higher scores indicate better cognitive function. The highest score of MMSE is 30 points. The scores are typically grouped as follows:

● 25-30 minutes: cognitive normal

● 21-24 minutes: mild dementia

● 10-20 minutes: moderate dementia

● 9 minutes or less: severe dementia

In the present disclosure, subjects with alzheimer's disease are subjects with an MMSE score of up to 24, and for example subjects with an MMSE score at the onset of AD101 treatment that may be between 10 and 24.

Pharmaceutical compositions comprising AD101 may be conveniently obtained by combining AD101 with a solid excipient/carrier, optionally milling the mixture and further processing to produce tablets or capsules using standard procedures well known to those skilled in the art. Suitable excipients include, for example: fillers such as sugars (e.g., lactose or sucrose, mannitol, or sorbitol), cellulose preparations (e.g., microcrystalline cellulose), and/or calcium phosphates (e.g., tricalcium phosphate or calcium hydrogen phosphate); and binders such as starch paste (using, for example, corn starch, wheat starch, rice starch, potato starch), gelatin, tragacanth, methyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose, and/or polyvinylpyrrolidone. If desired, disintegrating agents can be added, such as the starches and celluloses described above (including low substituted HPCs such as LH-31) as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate. Flow regulators and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, may also be used. The tablets may be coated, for example, with a suitable cellulose preparation such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. Dyes or pigments may be added to the tablet.

Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredient in particulate form, which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid, such as a fatty oil or liquid paraffin. In addition, stabilizers may be added.

Also included herein are AD101 for each dosage form, wherein the oral pharmaceutical preparation comprises an enteric coating. The term "enteric coating" is used herein to refer to any coating on an oral pharmaceutical dosage form that inhibits dissolution of the compound in an acidic medium, but dissolves rapidly in neutral to alkaline medium and has good long-term storage stability. Alternatively, the dosage form with an enteric coating may also comprise a water-soluble separation layer between the enteric coating and the core. The core of the enteric coated dosage form comprises AD101. Optionally, the core further comprises pharmaceutical additives and/or excipients. The separating layer may be a water-soluble inert active ingredient or polymer for film coating applications. The release layer is applied over the core by any conventional coating technique known to those of ordinary skill in the art. Examples of separating layers include, but are not limited to, sugars, polyethylene glycols, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose. By any means Conventional coating techniques apply an enteric coating over the separating layer. Examples of enteric coatings include, but are not limited to, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethyl ethylcellulose, copolymers of methacrylic acid and methyl methacrylate (such asL12, 5 or->L100 (Rohm Pharma)), water-based dispersions (such as +.>(FMC Corporation)、/>L100-55 (Rohm Pharma) and Coating CE 5142 (BASF)), and those containing water-soluble plasticizers, such as +.>(Pfizer). The final dosage form is an enteric coated tablet, capsule or pill. AD101 is conveniently supplied for use as an oval film coated tablet containing 180mg AD 101.

AD101 may be administered in suitable dosage units (e.g. as individual tablets), such as 10mg, 30mg, 60mg, 90mg or 180mg units/tablet. Alternatively, larger dosage units may be provided, including, for example, units of about 200mg to about 360mg and all mg dosage units therebetween, which may be scored if appropriate so that the units may be readily divided into smaller units for administration. One or more such units may be administered to a subject to achieve a desired daily dose of 180mg, e.g., 6 x 30mg, 3 x 60mg, 2 x 90mg, or 1 x 180 mg. When administered as a tablet, the tablet shape may conveniently be circular, oblong or oval.

It will be appreciated that individual small units of drug, such as mini-tablets, may be combined to provide a unit suitable for administration as a 180mg daily dose. Such small units (e.g., mini-tablets) may be combined to produce, for example, 10mg, 30mg, 60mg, 90mg, or 180mg units (e.g., capsules).

Examples of 10mg, 30mg, 60mg, 90mg and 180mg tablets are presented in table 1 below:

table 1:

* D-Pearlitol 160C; * Avicel PH101; * LH-31; * HPC-SL; * Removal by drying during processing

In one aspect, 180mg of AD101 is administered daily QD in the morning. In one aspect, 5mg, 10mg or 23mg of donepezil hydrochloride (e.g. 5mg QD, 10mg QD or 23mg QD) is also administered daily. Simultaneous administration of AD101 of 180mg QD and 5mg, 10mg or 23mg donepezil hydrochloride (e.g. 5mg QD, 10mg QD or 23mg QD) may continue until an unacceptable safety issue arises or the subject no longer receives benefit from the pharmaceutical combination. In practice, AD101 and donepezil hydrochloride should be administered daily uninterrupted as long as the subject benefits. Some subjects receiving AD101 and donepezil hydrochloride as described above may also be receiving a suitable dose of memantine hydrochloride.

In one aspect, subjects who may benefit particularly from treatment with AD101 of 180mg QD include individuals diagnosed with likely AD (e.g., as defined by national neuropathy, language communication disorder, and the association of stroke-alzheimer's disease and related diseases).

In one aspect, subjects who may benefit particularly from treatment with AD101 with 180mg QD include individuals diagnosed with dementia due to alzheimer's disease (e.g., meeting the NIA/AA standard) and in the absence of vascular cognitive impairment (e.g., hachinski score >4 as defined or modified by the 2014 vacog standard).

In accordance with the present disclosure, one or more additional therapeutic agents may be administered with AD101, memantine hydrochloride, and/or donepezil hydrochloride. Such agents may include therapeutic agents useful for treating subjects with alzheimer's disease. When present, each active ingredient may conveniently be administered as a separate composition.

The effectiveness of AD101 treatment with 180mg QD can be measured at different time points during therapy using, for example, the alzheimer's disease rating scale, the cognitive score scale (ADAS-Cog), and the alzheimer's disease collaborative study-clinical global impression enhancement version (ADCS-CGI) for global function, or any other subject function metric at the discretion of the subject's healthcare provider, including, but not limited to, MMSE for cognition, clinical dementia assessment box sum (CDR-SB) for global function, and neuropsychiatric scale (NPI) for behavioral symptoms. Changes in the appearance and presence of certain biomarkers, such as longitudinal changes in plasma concentrations of phospho-tau 217, beta amyloid 42, and 4, can also be measured.

Example 1 below is a safety extension study in which an early AD101 monotherapy AD assay or early stage was completedSubjects in the AD trial received an up-dosing trial of 3 months in which AD101 dose was increased from 60mg QD to 180mg QD. From->5 subjects in AD trials who were also receiving memantine hydrochloride were recruited into the extension study.

Example 1

Safety extension research

For AD subjects who completed early preliminary efficacy and safety studies of AD101 in AD (clinical trial government identifier: NCT00842673; ST 101-A001-201) and who completed AD101 plusAD subjects (clinical trial government identifier: NCT00842816; ST 1)01-a 001-202) one extended study of safety was performed for 12 weeks, open label, multicenter. The subjects had progressively higher doses as follows: all subjects received 60mg once a day for the first month, 120mg once a day for the second month, and 180mg once a day for the third month. The increase in dose depends on the subject's tolerance to the previous dose. The purpose of this study was to assess the safety and tolerability of this population that was additionally exposed to AD 101.

Results

Table 2 summarizes the subjects' trends. A total of 293 AD subjects were recruited (126 subjects from the ST101-a001-201 study [89% of eligible subjects ] and 167 subjects from the ST101-a001-202 study [90% of eligible subjects ]). 257 (87.7%) subjects completed the extension study. More than 95% of subjects eligible to increase the dose to 180mg have such an increase in dose at the 8 th week visit. The discontinuation rates for each dose level were similar, with discontinuation rates for the study at 60mg, 120mg, and 180mg dose levels being 5.5% (16 subjects), 4.8% (14 subjects), and 2.0% (6 subjects), respectively.

Table 2:

note that: the subject may be in more than one AD101 treatment group. 60mg (4 weeks) →120mg (4 weeks) →180mg (4 weeks); QD administration for a total of 3 months; dose escalation is performed if subject and investigator agree; the total column counts unique subjects; the denominator for all percentages is 293 (total recruitment).

Overall safety and tolerability

The safety population for this study consisted of 293 subjects.

There were 17 Severe Adverse Events (SAE) that occurred in 17 subjects (1 was considered unrelated due to multiple cerebrovascular accident death, which occurred at 10 days after study after subjects received 60mg, 120mg and 180mg of AD101 for 4 weeks each, 7 subjects took 60mg of AD101,5 subjects took 120mg of AD101, and 4 subjects took 180mg of AD 101), summarized in table 3. Eleven out of seventeen subjects discontinued and six subjects completed the study. The investigators considered that all SAEs were independent of study drug except SAE number 00036 (syncope in an 86 year old female taking 180mg of ST 101).

Table 3:

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* When an event occurs

Table 4 summarizes the number and percentage of subjects with Adverse Events (AE) in the preferred terminology that occurs in > 2% of subjects. Of the 293 subjects recruited into the study, 51.2% experienced adverse events. AE are assigned to dose groups based on the dose taken by the subject at the time of the event. Since all subjects received AD101, it is reasonable to compare the AEs reported in this study with those considered commonly reported in studies 201 and 202, which provided subjects for this study. Of the 10 AEs that caused 2% cessation of the study, 3/10 did not reach 5% cessation in 201 or 202 (anxiety, fatigue, and bruise). There appears to be no pattern associated with the AD101 dose in terms of the nature or frequency of a particular AE.

Table 4:

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note that: the subject may be in more than one AD101 treatment group. The total column counts unique subjects. All AEs were occurring at the time of treatment and were coded using med dra 12.1.

Subjects were in a safety extension study starting with memantine hydrochloride

There were 5 subjects from the ST101-a001-202 study who began using memantine hydrochloride upon recruitment into the open label extension study (study 401). In all cases, subjects completed the 401 study and were dosed with up to 180mg of AD101 according to the protocol. Information for these 5 subjects, including adverse events, is summarized in table 5. No clinically significant laboratory or vital sign abnormalities were observed.

Table 5:

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conclusion(s)

Study 401 is an open-label extended study that recruited subjects who completed study 201 or 202. In this open label security extension study, which was 3 months old, no new security or tolerability issues were confirmed. AD101 was found to be at least as safe as administration of the drug at a dose of 180mg QD as at lower doses of 60mg QD and 120mg QD. Furthermore, no clinically significant laboratory or vital sign abnormalities were observed for 5 subjects taking memantine hydrochloride.

All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entirety for all purposes. However, the mention herein of any reference, article, publication, patent publication, and patent application is not, and should not be taken as an admission or any form of suggestion that they form part of the common general knowledge in the art, effectively in any country in the world.

Claims

1. A method of treating dementia of the alzheimer's type, the method comprising orally administering to a human subject a 180mg daily dose of AD101.

2. A method of treating dementia of the alzheimer's type, the method comprising orally administering to a human subject a 180mg daily dose of AD101 and a dose of donepezil hydrochloride.

3. A method of treating alzheimer's disease comprising orally administering to a human subject a 180mg daily dose of AD101.

4. A method of treating alzheimer's disease comprising orally administering to a human subject a 180mg daily dose of AD101 and a dose of donepezil hydrochloride.

5. A method of treating dementia of the alzheimer's type in a human subject having an MMSE score of 10 to 24 at the onset of AD101 treatment, the method comprising orally administering to the subject a daily dose of AD101 of 180 mg.

6. A method of treating dementia of the alzheimer's type in a human subject having an MMSE score of 10 to 24 at the onset of AD101 treatment, the method comprising orally administering to the subject a 180mg daily dose of AD101 and a dose of donepezil hydrochloride.

7. A method of treating alzheimer's disease in a human subject having an MMSE score of 10 to 24 at the onset of AD101 treatment, the method comprising orally administering to the subject a daily dose of 180mg of AD101.

8. A method of treating alzheimer's disease in a human subject having an MMSE score of 10 to 24 at the onset of AD101 treatment, the method comprising orally administering to the subject a 180mg daily dose of AD101 and a dose of donepezil hydrochloride.

9. The method of treatment according to any one of claims 1-8, wherein the subject has been treated with donepezil hydrochloride prior to the first administered dose of AD101.

10. The method of treatment according to any one of claims 1-8, wherein the subject has been treated with a stable dose of donepezil hydrochloride prior to the first administered dose of AD101.

11. The method of treatment according to any one of claims 2, 4, 6, 8, 9 and 10, wherein donepezil hydrochloride is administered to the subject in a daily dose of 5mg, 10mg or 23 mg.

12. The method of treatment according to any one of claims 2, 4, 6, 8, 9 and 10, wherein donepezil hydrochloride is orally administered to the subject in a daily dose of 5mg (e.g. as a film coated tablet or an orally disintegrating tablet).

13. The method of treatment according to any one of claims 2, 4, 6, 8, 9 and 10, wherein donepezil hydrochloride is administered via a transdermal patch once a week, whereby the subject receives a daily dose of 5mg donepezil hydrochloride.

14. The method of treatment according to any one of claims 2, 4, 6, 8, 9 and 10, wherein donepezil hydrochloride is orally administered to the subject in a daily dose of 10mg (e.g. as a film coated tablet or an orally disintegrating tablet).

15. The method of treatment according to any one of claims 2, 4, 6, 8, 9 and 10, wherein donepezil hydrochloride is administered via a transdermal patch once a week, whereby the subject receives a daily dose of 10mg of donepezil hydrochloride.

16. The method of treatment according to any one of claims 2, 4, 6, 8, 9 and 10, wherein donepezil hydrochloride is orally administered to the subject in a daily dose of 23mg (e.g. as a film coated tablet).

17. The method of treatment according to any one of claims 2, 4, 6, 8, 9 and 10, wherein donepezil hydrochloride is orally administered to the subject in a daily dose of 10mg (e.g. as a film coated tablet or an orally disintegrating tablet) for at least 30 days.

18. The method of treatment according to claim 17, wherein the initial daily dose of 10mg of donepezil hydrochloride is increased to a maintenance daily dose of 23mg of donepezil hydrochloride.

19. The method of treatment of any one of claims 1-18, wherein AD101 is administered once daily (QD) as one or more tablets.

20. The method of treatment of claim 19, wherein AD101 is administered as a 3 x 60mg, 2 x 90mg, or 1 x 180mg tablet.

21. The method of treatment according to any one of claims 2, 4, 6 and 8-20, wherein donepezil hydrochloride is administered once daily (QD).

22. The method of treatment of any one of claims 1-21, wherein the subject is treated with one or more additional therapeutic agents.

23. The method of treatment of claim 22, wherein the one or more additional therapeutic agents are used to treat a subject suffering from alzheimer's disease.

24. The method of treatment according to any one of claims 2, 4, 6 and 8-23, wherein AD101, donepezil hydrochloride and one or more additional therapeutic agents if present are each administered as separate compositions.

25. The method of treatment according to any one of claims 2, 4, 6 and 8-24, wherein co-administration of AD101 and donepezil hydrochloride has an additional beneficial effect on the condition of the subject being treated relative to administration of AD101 or donepezil hydrochloride alone.

26. The method of treatment of any one of claims 1-25, wherein the subject exhibits an improvement in cognitive or overall function following treatment.

27. A method of treating alzheimer's disease comprising orally administering to a human subject a therapeutically effective amount of AD101 and a therapeutically effective amount of memantine hydrochloride.

28. A method of treating dementia of the alzheimer's type, the method comprising orally administering to a human subject a therapeutically effective amount of AD101 and a therapeutically effective amount of memantine hydrochloride.

29. The method of treatment of claim 27 or claim 28, wherein the subject has been treated with memantine hydrochloride prior to the first administered dose of AD 101.

30. The method of treatment of claim 27 or claim 28, wherein the subject has been treated with a stable dose of memantine hydrochloride prior to the first administered dose of AD 101.

31. The method of treatment according to any one of claims 27-30, wherein AD101 is administered once daily.

32. The method of treatment according to any one of claims 27-31, wherein AD101 is administered at a daily dose of 180 mg.

33. The method of treatment of claim 32, wherein AD101 is administered once daily (QD) as one or more tablets.

34. The method of treatment of claim 33, wherein AD101 is administered as a 3 x 60mg, 2 x 90mg, or 1 x 180mg tablet.

35. The method of treatment of any one of claims 27-34, wherein memantine hydrochloride is administered orally to the subject at a daily dose of about 5mg to about 30 mg.

36. The method of treatment according to any one of claims 27-34, wherein memantine hydrochloride is administered orally to the subject at a daily dose of 5 mg.

37. The method of treatment according to any one of claims 27-34, wherein memantine hydrochloride is administered orally to the subject at a daily dose of 20 mg.

38. The method of treatment according to claim 36, wherein the initial daily dose of 5mg memantine hydrochloride is increased to a maintenance daily dose of 20mg memantine hydrochloride.

39. The method of treatment according to any one of claims 27-34, wherein memantine hydrochloride is orally administered to the subject as a slow release capsule at a daily dose of 7mg, 14mg, or 28 mg.

40. The method of treatment according to claim 39, wherein the initial daily dose of 7mg memantine hydrochloride is increased to a maintenance daily dose of 14mg or 28mg memantine hydrochloride.

41. The method of treatment of any one of claims 27-40, wherein the subject is treated with one or more additional therapeutic agents.

42. The method of treatment of claim 41, wherein the one or more additional therapeutic agents are used to treat a subject suffering from alzheimer's disease.

43. The method of treatment of any one of claims 27-42, wherein AD101, memantine hydrochloride, and one or more additional therapeutic agents if present, are each administered as separate compositions.

44. The method of treatment according to any one of claims 41-43, wherein the additional therapeutic agent is donepezil hydrochloride.

45. The method of treatment according to claim 44, wherein donepezil hydrochloride is administered orally to the subject in a daily dose of 10 mg.

46. The method of treatment according to claim 44, wherein donepezil hydrochloride is administered orally to the subject at a daily dose of 23 mg.

47. The method of treatment according to claim 44, wherein donepezil hydrochloride is administered orally to the subject in a daily dose of 10mg for at least three months.

48. The method of treatment according to claim 45, wherein the initial daily dose of 10mg of donepezil hydrochloride is increased to a maintenance daily dose of 23mg of donepezil hydrochloride.

49. The method of treatment according to claim 41, wherein the additional therapeutic agent is donepezil hydrochloride, and wherein memantine hydrochloride and donepezil hydrochloride are administered together in a single composition.

50. The method of treatment according to claim 49, wherein memantine hydrochloride and donepezil hydrochloride are administered together as a capsule comprising a sustained release agent of memantine hydrochloride (14 mg or 28 mg) and 10mg of donepezil hydrochloride.

51. The method of treatment according to any one of claims 27-50, wherein co-administration of AD101 and memantine hydrochloride has a synergistic effect on the condition of the subject being treated.

52. The method of treatment according to any one of claims 27-50, wherein co-administration of AD101, memantine hydrochloride, and donepezil hydrochloride has a synergistic effect on the condition of the subject being treated.

53. The method of treatment of any one of claims 27-52, wherein the subject exhibits an improvement in cognitive or overall function following treatment.

54. A method of treating alzheimer's disease in a human subject having an MMSE score of 10 to 24 at the onset of AD101 treatment, the method comprising orally administering to the human subject a therapeutically effective amount of AD101 and a therapeutically effective amount of memantine hydrochloride.

55. The method of treatment according to claim 54, wherein AD101 is administered once daily.

56. The method of treatment according to claim 54 or claim 55, wherein AD101 is administered at a daily dose of 180 mg.

57. The method of treatment of claim 56, wherein AD101 is administered once daily (QD) as one or more tablets.

58. The method of treatment of claim 57, wherein AD101 is administered as a 3 x 60mg, 2 x 90mg, or 1 x 180mg tablet.

59. A method of treating alzheimer's disease in a human subject having an MMSE score of 10 to 24 at the onset of AD101 treatment, the method comprising orally administering to the human subject a therapeutically effective amount of AD101, a therapeutically effective amount of memantine hydrochloride, and a therapeutically effective amount of donepezil hydrochloride.

60. The method of treatment of claim 59, wherein AD101 is administered once daily.

61. The method of treatment according to claim 59 or claim 60, wherein AD101 is administered at a daily dose of 180 mg.

62. The method of treatment of claim 61, wherein AD101 is administered once daily (QD) as one or more tablets.

63. The method of treatment of claim 62, wherein AD101 is administered as a 3 x 60mg, 2 x 90mg, or 1 x 180mg tablet.

64. The method of treatment of any one of claims 1-63, wherein the subject exhibits mild dementia of the alzheimer's type.

65. The method of treatment of any one of claims 1-63, wherein the subject exhibits moderate dementia of the alzheimer's type.

66. The method of treatment of any one of claims 1-63, wherein the subject exhibits severe dementia of the alzheimer's type.