How to Treat Alzheimer's Disease

Abstract

The present disclosure is directed to treating Alzheimer's disease by oral administration of 1',3'-dihydro-2H-spiro[imidazo[1,2α]pyridine-3,2'-inden]-2-one at a daily dose of 180 mg either as the sole active agent or in combination with donepezil hydrochloride and / or memantine hydrochloride.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 190,299, filed May 19, 2021, U.S. Provisional Patent Application No. 63 / 192,398, filed May 24, 2021, and U.S. Provisional Patent Application No. 63 / 331,011, filed April 14, 2022, the contents of all of which are incorporated herein by reference.

[0002] The present disclosure describes the administration of 1',3'-dihydro-2H-spiro[imidazo-[1,2α]pyridin-3,2'-inden]-2-one ("AD101") to treat patients with Alzheimer's disease. In one embodiment, AD101 is administered in an improved dosing regimen. In one embodiment, AD101 is administered to patients undergoing memantine hydrochloride therapy. [Background technology]

[0003] Alzheimer's disease ("AD") is a neurodegenerative disorder for which only symptomatic treatments exist with limited therapeutic efficacy. The global prevalence of AD is predicted to quadruple to over 100 million by 2050, when 1 in 85 people worldwide will be living with AD disease. Over 40% of those cases are in late stage AD, requiring high levels of attention equivalent to nursing home care. AD begins with mild cognitive impairment, such as forgetfulness, and eventually progresses to a stage where the individual is unable to live independently. The main risk factor for developing AD is age, with the chance of developing the disease doubling approximately every 5 years after age 65, and reaching nearly 50% risk after age 85. Family history also increases the risk of developing the disease, which may be due to genetics or environmental factors.

[0004] AD is the most common cause of dementia. The term dementia describes a syndrome characterized by memory impairment, intellectual disability, personality changes, and behavioral abnormalities. These symptoms lead to a decline in social and occupational abilities. Dementia has multiple etiologies and pathophysiologies, and a variety of drugs have been developed to treat the condition. Dementia of the Alzheimer's type ("DAT") is defined as a progressive, fatal neurodegenerative condition characterized by deterioration of cognition and memory, progressive impairment of the ability to perform activities of daily living, and a host of neuropsychiatric and behavioral symptoms. DAT is the most common form of dementia in older adults and is expected to increase with age.

[0005] Currently, the four drugs approved for the treatment of cognitive symptoms of AD are divided into two groups. 1. Cholinesterase inhibitors (ChEIs): donepezil, rivastigmine and galantamine. These drugs increase cholinergic transmission by inhibiting cholinesterase, which hydrolyzes the drug. Galantamine is used to treat mild to moderate AD, while ARICEPT® (donepezil hydrochloride tablets) and rivastigmine are also indicated for AD and can be used in patients with mild, moderate or severe disease. 2. NMDA (N-methyl-D-aspartate) receptor antagonist: Memantine hydrochloride. This drug modulates the effects of pathologically enhanced elevated concentrations of glutamate that can cause neurological dysfunction. NAMENDA® (Memantine hydrochloride tablets) is indicated only for the treatment of patients with moderate to severe DAT.

[0006] None of these approved drugs are therapeutic for the disease. Moreover, nonselective ChEIs are notable for undesirable side effects such as vomiting and diarrhea. Therefore, other treatment options are needed to alleviate cognitive impairment and decline in global function (i.e., the patient's overall ability to function in daily activities) in AD patients. Furthermore, memantine hydrochloride, although generally well tolerated when administered to AD patients, exhibits certain side effects that may exacerbate and / or cause therapeutic complications when combined with other AD drugs.

[0007] AD101 (previously reported as AD101, ST101 or ZTET1446) is a small molecule with the chemical name 1',3'-dihydro-2H-spiro[imidazo[1,2α]pyridin-3,2'-inden]-2-one. AD101 and its preparation were first described in WO 2001 / 09131A1, the contents of which are incorporated herein by reference. The present disclosure provides a daily dose of AD101 that may be particularly effective in treating subjects with Alzheimer's disease (AD), including subjects currently receiving a stable regimen of donepezil hydrochloride. Thus, oral administration of AD101 at 180 mg once daily (QD) results in relief of symptoms in AD subjects, including reduction in cognitive impairment and global function in patients exhibiting onset or progression of AD, and / or improvement in cognitive impairment and global function in treated subjects.

[0008] The present disclosure also provides a novel combination therapy that may be particularly effective in treating AD subjects. Thus, the present disclosure describes that memantine hydrochloride and AD101 can be safely co-administered. Surprisingly, AD101 can be administered to AD subjects taking a stable dose of memantine hydrochloride at a daily dose of at least 180 mg without causing significant side effects. It is also surprising that this favorable side effect profile is maintained 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 at least 180 mg.

[0009] Coadministration of AD101 and memantine hydrochloride may provide particularly symptomatic relief to AD subjects (including those currently receiving a stable regimen of donepezil hydrochloride), including reducing cognitive impairment and global function in patients exhibiting the onset or progression of Alzheimer's disease, and / or improving cognitive and global function in treated subjects. Combination therapy may be effective without significant safety issues. Thus, administration of AD101 (e.g., 180 mg AD101 QD) to AD subjects currently being treated with memantine hydrochloride and / or donepezil hydrochloride may provide particularly effective symptomatic relief without raising significant drug-related safety concerns. Summary of the Invention

[0010] The present disclosure describes, in one embodiment, that AD101 can be safely administered to subjects with Alzheimer's disease at a daily dose (QD) of 180 mg.

[0011] The present disclosure describes, in one aspect, that AD101 can be safely administered to subjects with Alzheimer's dementia at a daily dose (QD) of 180 mg.

[0012] The present disclosure describes that, in one aspect, AD101 can be safely administered together with memantine hydrochloride to a subject with Alzheimer's disease.In one embodiment of this aspect, AD101 can be administered at a daily dose (QD) of at least 180mg.In a further embodiment of this aspect, the subject is also administered donepezil hydrochloride (including, for example, when AD101 is administered at a daily dose (QD) of at least 180mg).

[0013] The present disclosure describes that, in one aspect, AD101 can be safely co-administered with memantine hydrochloride to the subject of Alzheimer's dementia.In one embodiment of this aspect, AD101 can be administered at a daily dose (QD) of at least 180mg.In a further embodiment of this aspect, donepezil hydrochloride is also administered to the subject (including, for example, when AD101 is administered at a daily dose (QD) of at least 180mg).

[0014] The present disclosure also describes that AD101 can be orally administered up to at least 180 mg QD to a subject with Alzheimer's disease for periods of more than 12 weeks, such as 24 or 36 weeks or longer, without raising significant safety concerns in the subject, including when AD101 is administered in combination with memantine hydrochloride and / or donepezil hydrochloride.

[0015] The present disclosure further describes that administration of up to at least 180 mg QD of AD101 to subjects with Alzheimer's disease receiving treatment with memantine hydrochloride and / or donepezil hydrochloride (e.g., Aricept®) can be particularly effective in improving cognition and global function, and / or slowing the decline of both these outcomes in treated subjects.

[0016] Thus, in one aspect, the disclosure provides a method of treating Alzheimer's disease in a human subject suffering from Alzheimer's disease, comprising orally administering to the subject a daily dose of 180 mg of AD101.

[0017] In one aspect, the disclosure provides a method of treating Alzheimer's dementia in a human subject suffering from Alzheimer's dementia, comprising orally administering to the subject a daily dose of 180 mg of AD101.

[0018] In one aspect, the disclosure provides a method of treating Alzheimer's disease in a human subject suffering from Alzheimer's disease, comprising orally administering to the subject a daily dose of 180 mg of AD101 and a dose of donepezil hydrochloride.

[0019] In one aspect, the disclosure provides a method of treating Alzheimer's dementia in a human subject suffering from Alzheimer's dementia, the method comprising orally administering to the subject a daily dose of 180 mg of AD101 and a dose of donepezil hydrochloride.

[0020] In one embodiment of any of the foregoing aspects, the subject has already been treated with donepezil hydrochloride prior to the first administration of AD101.

[0021] In one embodiment of any of the foregoing aspects, the subject is already being treated with a stable dose of donepezil hydrochloride prior to the first administration of AD101.

[0022] In one aspect, the disclosure provides a method of treating Alzheimer's disease in a human subject suffering from 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.

[0023] In one aspect, the disclosure provides a method of treating Alzheimer's disease in a human subject suffering from Alzheimer's disease, the method comprising orally administering to the subject a daily dose of 180 mg of AD101 and a therapeutically effective amount of memantine hydrochloride.

[0024] In one aspect, the disclosure provides a method of treating Alzheimer's dementia in a human subject suffering from Alzheimer's dementia, the method comprising orally administering to the subject a therapeutically effective amount of AD101 and a therapeutically effective amount of memantine hydrochloride.

[0025] In one aspect, the disclosure provides a method of treating Alzheimer's dementia in a human subject suffering from Alzheimer's dementia, the method comprising orally administering to the subject a daily dose of 180 mg of AD101 and a therapeutically effective amount of memantine hydrochloride.

[0026] In one embodiment of any of the foregoing aspects, the subject has already been treated with memantine hydrochloride prior to the first administration of AD101.

[0027] In one embodiment of any of the foregoing aspects, the subject is already being treated with a stable dose of memantine hydrochloride prior to the first administration of AD101.

[0028] In one embodiment of any of the foregoing aspects, the subject has already been treated with memantine hydrochloride and donepezil hydrochloride prior to the first administration of AD101.

[0029] In one embodiment of any of the foregoing aspects, the subject is already being treated with stable doses of memantine hydrochloride and donepezil hydrochloride prior to the first administration of AD101.

[0030] Donepezil hydrochloride (e.g., Aricept®) may be conveniently administered orally to a subject in a daily dose of about 5 mg to about 50 mg, including 5 mg, 10 mg, or 23 mg, or via a transdermal patch once weekly in a daily dose of 5 mg or 10 mg. The administration period of donepezil hydrochloride may be one month or longer, such as at least 30 days. A subject may be initiated on a lower dose of donepezil hydrochloride (e.g., 5 mg or 10 mg QD) and then increased to a maintenance dose (e.g., 23 mg QD).

[0031] Memantine hydrochloride may be conveniently orally administered to a subject in a daily dose of about 5 mg to about 30 mg. In one embodiment, memantine hydrochloride is administered in a daily dose of 5 mg. In one embodiment, memantine hydrochloride is administered in a daily dose of 20 mg. In one embodiment, memantine hydrochloride is administered at an initial dose of 5 mg per day, which is then increased to a maintenance dose of 20 mg per day. In one embodiment, memantine hydrochloride is orally administered to a subject in a sustained release capsule in a daily dose of 7 mg, 14 mg, or 28 mg. In one embodiment, memantine hydrochloride is initially administered in a sustained release capsule in a daily dose of 7 mg, which is then increased to a maintenance dose of 14 mg or 28 mg. [Brief description of the drawings]

[0032] [Figure 1]Flowchart of a randomized, double-blind, placebo-controlled, Phase 3 clinical trial of the efficacy, safety, and tolerability of AD101 for the treatment of AD in subjects stably treated with donepezil hydrochloride. Primary, secondary, and exploratory efficacy outcomes will be monitored along with safety and tolerability variables, including treatment-emergent signs and symptoms (TESS), treatment-emergent laboratory abnormalities (TEAV), serious adverse events (SAEs), and therapeutic drug monitoring (TDM). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] AD101 has shown pharmacological activity in rodent models of learning and memory associated with AD after both acute and chronic administration. AD101 has also been shown to increase acetylcholine (ACh) levels in rodent brains and improve learning and memory in a number of 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 functional improvement was associated with enhancements in long-term potentiation (LTP), electrophysiological correlates of memory formation, as well as biochemical changes associated with enhanced LTP, such as protein kinase C and Ca. 2+ / This correlated with increased activity of calmodulin-dependent protein kinase II (CaMK II) (Han, F., et al., J. Pharmacol. Exp. Ther. 326:127-134(2008)).

[0034] Further experiments showed that AD101 enhanced nicotine-stimulated ACh release, increased extracellular ACh concentrations in the cerebral cortex, and increased extracellular concentrations of both ACh and dopamine in the hippocampus. The breadth of models in which AD101 exerts its effects suggests possible involvement of upstream targets of the signaling pathway(s) involved in those processes.

[0035] AD101 also reduces the accumulation of Aβ-like deposits and leads to improved learning and memory function, suggesting that the behavioral effects of AD101 may be related to reduced Aβ production and / or accumulation (see U.S. Patent Application Publication No. 2008 / 103158). AD101 has also been shown to induce cleavage of amyloid precursor protein, reduce levels of pro-ADAM10 and / or BACE proteins, and enhance activity of the ubiquitin-proteasome pathway (see U.S. Patent Application Publication Nos. 2010 / 0168135, 2010 / 0267763, and 2010 / 0298348). The contents of U.S. Patent Application Publication Nos. 2008 / 103158, 2010 / 0168135, 2010 / 0267763, and 2010 / 0298348 are incorporated herein by reference.

[0036] AD101 therefore differs from commercially available treatments in that it exhibits a dual effect in animal research studies: it improves cognition and also reduces the accumulation of abnormal protein deposits in the brain. These two properties suggest that AD101 may be a promising agent for the treatment of AD.

[0037] Proof-of-concept human studies have examined the safety and tolerability of various doses of AD101 and its ability to improve cognitive and global function over a 12-week treatment period. In one such study, subjects aged 50 years or older with a high probability of AD [defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and National Institute of Neurological and Communicative Disorders and Stroke / Alzheimer's Disease and Related Disorders Association criteria], MMSE scores between 10 and 20, and a CT or MRI scan consistent with AD within 18 months of enrollment were administered AD101 at doses of 10 mg, 60 mg, or 120 mg daily for 12 weeks. Patients were required to have been on a stable regimen of donepezil hydrochloride 10 mg QD for at least 90 days prior to treatment with AD101 and to have continued treatment with donepezil hydrochloride 10 mg QD during the AD101 treatment period.

[0038] The primary results of this study are reported by S. Gauthier et al. in J Alzheimer's Dis. 2015;48(2):473-481. No significant AD101-related safety concerns were identified during the study up to doses of 120 mg QD, and efficacy results support the possibility that AD101 may provide further symptomatic benefit in moderate AD in patients receiving stable doses of donepezil hydrochloride. Importantly, there was no discernible dose response between treatment groups in the primary outcome measure when the three doses were analyzed separately, and there was no indication that further increasing the dose of AD101 would lead to further improvements in treatment outcomes in the control group or would not pose safety concerns. However, it has now surprisingly been found that AD101 can be safely administered to AD subjects in daily doses of at least up to 180 mg, and that administration of 180 mg of AD101 per day to subjects with DAT who are also being treated with Aricept® (donepezil hydrochloride) can be particularly effective in alleviating the symptoms of AD, without raising significant safety concerns associated with AD101.

[0039] Thus, the inventors of the present disclosure have identified a daily dose of AD101 that may be particularly effective in treating subjects with Alzheimer's Disease (AD), including subjects currently receiving a stable regimen of donepezil hydrochloride. Oral administration of 180 mg QD AD101 may provide particular symptomatic relief to such subjects, including reducing cognitive impairment and global function in patients exhibiting the onset or progression of Alzheimer's Disease, and / or improving cognitive and global function in treated subjects.

[0040] The inventors of the present disclosure have also identified a novel combination therapy that may be particularly effective in treating AD subjects.Accordingly, co-administration of AD101 and memantine hydrochloride may provide particular symptomatic relief to such subjects (including those currently receiving a stable regimen of donepezil hydrochloride), including reducing cognitive impairment and global function in patients exhibiting the onset or progression of Alzheimer's disease, and / or improving cognitive and global function in treated subjects.The combination therapy may be effective without significant safety issues. In one embodiment of this aspect, AD101 can be conveniently orally administered to a subject in a daily amount of about 50 mg to about 250 mg, for example, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg. In one particular embodiment, AD101 is orally administered in a daily amount of about 120 mg. In one particular embodiment, AD101 is orally administered in a daily amount of about 180 mg.

[0041] A stable regimen of donepezil hydrochloride and / or memantine hydrochloride, as used herein, refers to a daily dose of donepezil hydrochloride and / or memantine hydrochloride administered to treat a subject with Alzheimer's disease for an extended period of time, usually at least about 1, 2, 3, 4, 5, or 6 months or more (e.g., at least about 30 days), before the subject receives a first dose of AD101. Typically, the subject continues to receive donepezil hydrochloride and / or memantine hydrochloride during AD101 therapy.

[0042] In general practice, a subject may receive 5mg of donepezil hydrochloride as one tablet daily, or 10mg of donepezil hydrochloride as one or two tablets daily (e.g., 5mg or 10mg of donepezil hydrochloride QD) during the treatment period, or 10mg of donepezil hydrochloride as one or two tablets daily (e.g., 10mg of donepezil hydrochloride QD) for at least 30 days, and then switch to a higher daily dose of 23mg of donepezil hydrochloride as one tablet. Thus, a subject who receives an initial dose of 180mg of AD101 may also receive either 5mg of donepezil hydrochloride QD, 10mg of donepezil hydrochloride QD, or 23mg of donepezil hydrochloride QD. Subjects with more severe AD may have been receiving donepezil hydrochloride for a longer period of time and therefore would likely receive donepezil hydrochloride 23 mg QD at the time of their first dose of AD101 180 mg.

[0043] Alternatively, donepezil hydrochloride can be administered via a transdermal patch, which can be replaced, for example, weekly. Such patch(es) can conveniently administer donepezil hydrochloride at a daily dose of 5 mg or 10 mg. An example of a transdermal patch used herein includes ADLARITY®, which is a rectangular 6-layer laminate that includes a brown overlay / adhesive layer without donepezil, a separation layer, a drug matrix, a film, a contact adhesive, and a release liner, and uses CORPLEX technology.

[0044] When a subject is treated with AD101 and memantine hydrochloride, the subject may be conveniently administered 5 mg of memantine hydrochloride during the combination therapy period. Alternatively, the subject is usually initially treated with 5 mg of memantine hydrochloride before the first administration of AD101, and then (e.g., after 3 months or more) increased to a daily maintenance dose of 20 mg. In one embodiment, memantine hydrochloride is orally administered to the subject as a sustained release capsule at a daily dose of 7 mg during the combination therapy period. In a further embodiment, memantine hydrochloride is orally administered to the subject as a sustained release capsule at a daily dose of 14 mg during the combination therapy period. In another embodiment, memantine hydrochloride is usually initially administered as a sustained release capsule at a daily dose of 7 mg before the first administration of AD101, and then increased to a daily maintenance dose of 14 mg or 28 mg. In one embodiment, subjects are also typically treated with a daily dose of 10 mg donepezil hydrochloride administered as one or two tablets for the duration of combination therapy prior to the initial administration of AD101, or donepezil hydrochloride 10 mg QD administered for three or more months, and then switched to a higher daily dose of donepezil hydrochloride 23 mg as one tablet.

[0045] A subject receiving AD101 for the first time may already be taking memantine hydrochloride at a lower or higher maintenance dose. Similarly, a subject receiving AD101 for the first time may already be taking donepezil hydrochloride at a lower or higher maintenance dose. Subjects with more severe AD may have been receiving memantine hydrochloride and / or donepezil hydrochloride for a longer period of time, and therefore are more likely to be receiving a maintenance dose of memantine hydrochloride and / or a maintenance dose of donepezil hydrochloride at the time of first administration of AD101.

[0046] When both memantine hydrochloride and donepezil hydrochloride are administered to a subject with AD, they may be administered as separate oral compositions or as a single oral composition. In one embodiment, memantine hydrochloride and donepezil hydrochloride are administered together as a capsule containing memantine hydrochloride extended release (14 mg or 28 mg) and donepezil hydrochloride 10 mg.

[0047] Namenda® (memantine hydrochloride) is available as a film-coated capsule containing 5 mg or 10 mg of memantine hydrochloride, or as a 2 mg / mL oral solution. Namenda® XR (memantine hydrochloride) is available as an extended release capsule containing 7 mg, 14 mg, 21 mg, or 28 mg of memantine hydrochloride.

[0048] Aricept® (donepezil hydrochloride) is commercially available in film-coated pills containing 5 mg, 10 mg, or 23 mg of donepezil hydrochloride.

[0049] AD101 may be administered orally as a tablet or capsule which may contain from about 0.01% to about 99%, or from about 0.25% to about 75%, of the active ingredient together with one or more excipients or carriers.

[0050] AD101 may be used in combination with memantine hydrochloride and / or donepezil hydrochloride in a single oral dosage form, however, conveniently, AD101, memantine hydrochloride and donepezil hydrochloride are administered in separate oral dosage forms.

[0051] A common test for assessing the severity of AD or related dementia in a subject is the Mini-Mental State Examination (MMSE). The MMSE is used to measure thinking ability (or "cognitive impairment"). It evaluates six items: orientation, learning, attention, word recall, language use and comprehension, and constructional ability. Higher scores indicate better cognitive function. The maximum score for the MMSE is 30 points. Scores are generally grouped as follows: 25-30 points: normal cognition 21-24 points: Mild dementia 10-20 points: Moderate dementia 9 points or less: severe dementia

[0052] In the present disclosure, a subject with Alzheimer's disease is a subject with an MMSE score of 24 or less, for example, a subject with an MMSE score of 10-24 at the start of AD101 treatment.

[0053] A pharmaceutical composition containing AD101 can be conveniently obtained by combining AD101 with a solid excipient / carrier, optionally grinding the mixture, and further processing it using standard procedures well known to those skilled in the art to produce tablets or capsules. Suitable excipients include, for example, fillers such as sugars such as lactose, sucrose, mannitol, sorbitol, cellulose preparations (e.g., microcrystalline cellulose) and / or calcium phosphates such as tricalcium phosphate and calcium hydrogen phosphate, and binders such as starch pastes using corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If desired, disintegrants can be added, for example, the above-mentioned starches and celluloses (including low-substituted HPC such as LH-31), as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts such as sodium alginate. Flow regulators and lubricants such as, for example, silica, talc, stearic acid or salts thereof (e.g., magnesium stearate or calcium stearate), and / or polyethylene glycol can also be utilized. Tablets can be coated using suitable cellulose preparations such as, for example, acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments can be added to the tablets.

[0054] Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient in the form of granules that 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 can be dissolved or suspended in a suitable liquid, such as fatty oils or liquid paraffin. In addition, stabilizers may be added.

[0055] Also included herein are dosage forms of AD101 in which the oral pharmaceutical formulation comprises an enteric coating. The term "enteric coating" herein refers to any coating on an oral pharmaceutical dosage form or more that inhibits the dissolution of the compound in acidic media, but dissolves quickly in neutral to alkaline media and has good stability for long-term storage. Alternatively, the dosage form with an enteric coating may comprise a water-soluble separating layer between the enteric coating and the core. The core of the enteric coated dosage form comprises AD101. Optionally, the core also comprises pharmaceutical additives and / or excipients. The separating layer may be a water-soluble inactive ingredient or a polymer for film coating applications. The separating layer is applied onto the core by any conventional coating technique known to those skilled in the art. Examples of separating layers include, but are not limited to, sugars, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, polyvinyl acetal diethyl amino acetate, and hydroxypropyl methyl cellulose. The enteric coating is applied onto the separating layer by any conventional coating technique. Examples of enteric coating agents include, but are not limited to, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, copolymers of methacrylic acid and methacrylic acid methyl ester, such as Eudragit® L 12,5 or Eudragit® L 100 (Rohm Pharma), aqueous dispersions, such as Aquateric® (FMC Corporation), Eudragit® L 100-55 (Rohm Pharma), Coating CE 5142 (BASF), and those containing water-soluble plasticizers, such as Citroflex® (Pfizer). The final dosage form is an enteric coated tablet, capsule or pellet. AD101 is conveniently used as an oval film-coated tablet containing 180 mg of AD101.

[0056] AD101 may be administered in suitable dosage units (e.g., individual tablets), such as 10 mg, 30 mg, 60 mg, 90 mg or 180 mg units / tablet. Alternatively, larger dosage units may be provided, including, for example, units of about 200 mg to about 360 mg and all mg dosage units therebetween, and may optionally be scored to allow easy division into smaller units for administration. One or more such units may be administered to a subject to achieve a desired daily dose of 180 mg, e.g., 6×30 mg, 3×60 mg, 2×90 mg or 1×180 mg. When administered as a tablet, the tablet shape may conveniently be round, oval or elliptical.

[0057] As will be appreciated, individual small units of a drug, such as mini-tablets, may be combined to provide a unit suitable for administration as a daily dose of 180 mg. Such small units (such as mini-tablets) may be combined to produce, for example, 10 mg, 30 mg, 60 mg, 90 mg or 180 mg units (such as capsules).

[0058] Examples of 10 mg, 30 mg, 60 mg, 90 mg and 180 mg tablets are shown in Table 1 below. [Table 1]

[0059] In one embodiment, 180mg of AD101 is administered QD every morning. In one embodiment, 5mg, 10mg or 23mg of donepezil hydrochloride is also administered daily (e.g. 5mg QD, 10mg QD or 23mg QD). The co-administration of 180mg QD of AD101 and 5mg, 10mg or 23mg of donepezil hydrochloride (e.g. 5mg QD, 10mg QD or 23mg QD) can be continued until unacceptable safety issues appear or the subject no longer benefits from the drug combination. In practice, AD101 and donepezil hydrochloride should be administered daily without interruption as long as the subject benefits. Certain subjects receiving the above AD101 and donepezil hydrochloride may also receive an appropriate dose of memantine hydrochloride.

[0060] In one embodiment, subjects who may particularly benefit from treatment with 180 mg QD AD101 include individuals diagnosed with possible AD (e.g., as defined by the National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders Association).

[0061] In one embodiment, subjects who may benefit from treatment with 180 mg QD AD101 include individuals diagnosed with dementia due to Alzheimer's disease (e.g., meeting NIA / AA criteria) and who do not have vascular cognitive impairment (e.g., as defined by the 2014 VASCOG criteria or a modified Hachinski score >4).

[0062] One or more additional therapeutic agents may be administered together with AD101, memantine hydrochloride and / or donepezil hydrochloride in accordance with the present disclosure. Such agents may also include therapeutic agents useful for subjects with Alzheimer's disease. When present, each active ingredient is conveniently administered as a separate composition.

[0063] During treatment, the efficacy of treatment with 180 mg QD AD101 can be measured at different time points, for example, using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the Alzheimer's Disease Cooperative Study-Clinical Global Impression Plus Edition (ADCS-CGI) for global functioning, or other measures of the subject's functioning as judged by the subject's healthcare provider, including, but not limited to, the MMSE for cognitive functioning, the Clinical Dementia Rating Sum of Boxes (CDR-SB) for global functioning, and the Neuropsychiatric Inventory (NPI) for behavioral symptoms. Changes in the appearance and presence of certain biomarkers can also be measured, such as changes over time in plasma concentrations of phospho-tau 217, beta amyloid 42, and 4.

[0064] Example 1 below is a safety extension study in which a 3-month dose escalation study was conducted in subjects who had completed a previous AD101 monotherapy AD study or a previous AD101+Aricept® AD study, increasing the AD101 dose from 60 mg QD to 180 mg QD. Five subjects from the AD101+Aricept® AD study who were also receiving memantine hydrochloride were enrolled in the extension study.

[0065] Example 1 Extended safety study A 12-week open-label, multicenter, safety extension study was conducted in AD subjects who completed a lead pilot study of AD101 efficacy and safety in AD (Clinicaltrials.gov ID: NCT00842673, ST101-A001-201) and in AD subjects who completed a lead pilot study of AD101 and Aricept® efficacy and safety in AD (Clinicaltrials.gov ID: NCT00842816, ST101-A001-202). Subjects were titrated as follows: all subjects received 60 mg once daily for the first month, 120 mg once daily for the second month, and 180 mg once daily for the third month. Dose escalation was dependent on the subject's tolerance of the previous dose. The purpose of this study is to evaluate the safety and tolerability in this population with additional exposure to AD101.

[0066] result Table 2 summarizes subject disposition. A total of 293 AD subjects were enrolled (126 (89%) eligible) from ST101-A001-201 and 167 (90%) from ST101-A001-202). 257 (87.7%) subjects completed the extension study. More than 95% of subjects eligible for escalation to 180 mg did so at the week 8 visit. Discontinuations were similar at each dose level, with 5.5% (16 subjects), 4.8% (14 subjects), and 2.0% (6 subjects) discontinuing the study at the 60 mg, 120 mg, and 180 mg dose levels, respectively. [Table 2]

[0067] Overall safety and tolerability The safety population of this study consisted of 293 subjects.

[0068] Seventeen serious adverse events (SAEs) occurred in 17 subjects (one was a death due to multiple cerebrovascular events that occurred 10 days into the study after the subject had received AD101 60 mg, 120 mg, and 180 mg for 4 weeks, respectively, and was deemed unrelated; seven with AD101 60 mg, five with AD101 120 mg, and four with AD101 180 mg), and the results are summarized in Table 3. Eleven of the 17 subjects discontinued and six completed the study. All SAEs were deemed unrelated to study drug by the investigator, except for SAE#00036 (syncope in an 86-year-old female receiving ST101 180 mg). [Table 3-1] [Table 3-2]

[0069] Table 4 summarizes the number and percentage of subjects who experienced adverse events (AEs) by preferred term with an incidence of 2% or more. Of the 293 subjects enrolled in the study, 51.2% experienced an adverse event. AEs were assigned to treatment arms according to the dose the subject was taking at the time the event occurred. Because all subjects received AD101, it is reasonable to compare the AEs reported in this study with those considered to be commonly reported in Studies 201 and 202, which contributed subjects to this study. Of the 10 AEs that met the 2% criterion above in this study, 3 / 10 did not meet the 5% criterion in Studies 201 or 202 (agitation, fatigue, contusion). There do not appear to be any patterns related to AD101 dose regarding the nature or frequency of specific AEs. [Table 4]

[0070] Subjects in the safety extension study who started administering memantine hydrochloride Five subjects initiated memantine hydrochloride upon enrollment in the open-label extension study (Study 401) from Study ST101-A001-202. In all cases, subjects completed Study 401 and received up to 180 mg of AD101 per protocol. Information on these five subjects, including adverse events, is summarized in Table 5. No clinically significant laboratory or vital sign abnormalities were observed. [Table 5]

[0071] conclusion Study 401 was an open-label extension study that enrolled subjects who completed Studies 201 or 202. No new safety or tolerability issues were identified in this 3-month open-label safety extension study. AD101 180 mg QD was at least as safe as the lower doses of 60 mg QD and 120 mg QD. Additionally, no clinically significant laboratory or vital sign abnormalities were observed in the five subjects receiving memantine hydrochloride.

[0072] 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 of any references, articles, publications, patents, patent publications, and patent applications cited herein is not, and should not be considered as, an admission or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

Claims

A pharmaceutical composition for use in a method of treating Alzheimer's disease, comprising 1',3'-dihydro-2H-spiro[imidazo[1,2α]pyridine-3,2'-indene]-2-one (AD101) and orally administering to a human subject a daily dose of 180 mg of AD101. A pharmaceutical composition for use in a method of treating Alzheimer's disease, comprising 1',3'-dihydro-2H-spiro[imidazo[1,2α]pyridine-3,2'-indene]-2-one (AD101) and orally administering to a human subject a daily dose of 180 mg of AD101 and a dose of donepezil hydrochloride.

3. The pharmaceutical composition according to claim 1 or 2, wherein the subject has been previously treated with a stable dose of donepezil hydrochloride prior to the first administration of AD101.

4. The pharmaceutical composition according to claim 2, wherein donepezil hydrochloride is administered to the subject at a daily dose of 5 mg, 10 mg or 23 mg.

5. The pharmaceutical composition according to claim 2, wherein donepezil hydrochloride is administered as film-coated tablets or orally disintegrating tablets.

6. The pharmaceutical composition according to claim 2, wherein donepezil hydrochloride is administered by a transdermal patch once a week.

7. The pharmaceutical composition according to claim 2, wherein donepezil hydrochloride is initially administered at a daily dose of 10 mg of donepezil hydrochloride and increased to a maintenance daily dose of 23 mg of donepezil hydrochloride.

8. The pharmaceutical composition according to claim 1 or 2, wherein AD101 is administered as three tablets each containing 60 mg of AD101, two tablets each containing 90 mg of AD101 or a single tablet containing 180 mg of AD101.

9. The pharmaceutical composition according to claim 2, wherein donepezil hydrochloride is administered once daily (QD).

10. The pharmaceutical composition according to claim 1 or 2, wherein the subject is treated with one or more additional therapeutic agents.

11. The pharmaceutical composition according to claim 2, wherein the combined administration of AD101 and donepezil hydrochloride has a further beneficial effect on the condition of the treated subject compared to the administration of AD101 or donepezil hydrochloride alone.

12. The pharmaceutical composition according to claim 1 or 2, wherein the subject is administered memantine hydrochloride in combination.

13. The pharmaceutical composition according to claim 27 or claim 12, wherein the subject has been previously treated with a stable dose of memantine hydrochloride prior to the first administration of AD101.

14. The pharmaceutical composition according to claim 12, wherein memantine hydrochloride is orally administered to the subject in a daily dose of about 5 mg to about 30 mg.

15. The pharmaceutical composition according to claim 14, wherein memantine hydrochloride is orally administered to the subject in a daily dose of 5 mg or 20 mg.

16. The pharmaceutical composition according to claim 12, wherein memantine hydrochloride is orally administered to the subject in a daily dose of 7 mg, 14 mg or 28 mg.

17. The pharmaceutical composition according to claim 12, wherein the combined administration of AD101, memantine hydrochloride and donepezil hydrochloride has a further beneficial effect on the condition of the treatment subject as compared with the single administration of AD101, memantine hydrochloride or donepezil hydrochloride.

18. The pharmaceutical composition according to claim 1 or 2, wherein the subject shows improvement in cognitive function or overall ability to function in daily activities (global function) after treatment.

19. The pharmaceutical composition according to claim 1 or 2, wherein the human subject has a Mini-Mental State Examination (MMSE) score of 10 to 24 at the start of treatment with AD101.

20. The pharmaceutical composition according to claim 1 or 2, wherein the subject shows Alzheimer's type dementia.

21. The pharmaceutical composition according to claim 1 or 2, wherein 180 mg of AD101 is included in one or more excipients and / or carriers and one or more oral pharmaceutical preparations.

22. The pharmaceutical composition according to claim 21, wherein the oral pharmaceutical preparation is a tablet.

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