Patent Description:
Sleep fragmentation, decreased REM and slow-wave sleep (SWS) and circadian rhythm dysfunction are hallmarks of Alzheimer's disease (AD), causing substantial distress for both patients and their caregivers, and contributing to early institutionalization. Sleep disturbances are among the earliest signs of cognitive decline and may accelerate disease progression but there is a distinct lack of evidence to help guide drug treatment. Recent work supports a role for sleep in the development of AD by influencing amyloid beta (Aβ) physiology. Aβ reportedly fluctuates with the sleep-wake cycle with Aβ levels being higher during wakefulness and lower during sleep. Relatedly, sleep deprivation in transgenic mice accelerates Aβ deposition, whereas improvement of sleep decreases it. Amyloid deposition further disrupts sleep, potentially through increased astrocytosis.

Insomnia can be grouped into primary and secondary insomnia. Primary insomnia is a sleep disorder not due to a medical, psychiatric, or environmental cause. It is described as a complaint of prolonged sleep onset latency, disturbance of sleep maintenance, or the experience of non-refreshing sleep. Conditions that reportedly result in insomnia include depression, pain, benign prostatic hypertrophy, obstructive sleep apnea, restless leg syndrome, and substance misuse. A diagnosis will differentiate between primary insomnia, insomnia as secondary to another condition, and primary insomnia co-morbid with one or more conditions.

Agitation often accompanies dementia and often precedes the diagnosis of common age-related disorders of cognition such as Alzheimer's disease. More than <NUM>% of people who develop AD eventually become agitated or aggressive.

Occasional anxiety is a normal part of life. Anxiety disorders are characterized by frequent intense, excessive and persistent worry and fear about everyday situations. The disorders often involve repeated episodes of sudden feelings of intense anxiety and fear or terror that reach a peak within minutes (panic attacks).

Reference is made to <NUM>-(<NUM>,<NUM>-diphenyltetrahydrofuran-<NUM>-yl)-N-methylmethanamine hydrochloride (ANAVEX™ <NUM>-<NUM>, or A19-<NUM>). A19-<NUM> is a compound which is believed to bind to muscarinic acetylcholine and sigma-<NUM> receptors with affinities in the low micromolar range. A19-<NUM> functions similarly to A2-<NUM>. Reference is similarly made to tetrahydro-N,N-dimethyl-<NUM>,<NUM>-diphenyl-<NUM>-furanmethanamine hydrochloride (Anavex1-<NUM>). Further, note is made of tetrahydro-N,N-dimethyl-<NUM>,<NUM>-diphenyl-<NUM>-furanmethanamine hydrochloride (ANAVEX™<NUM>-<NUM>, AV2-<NUM>, or A2-<NUM>) in methods of treatment for neurodevelopmental disorders (<CIT>).

Sigma-<NUM> (σ1) receptors are small proteins located in the endoplasmic reticulum (ER), in the subregion contacting the mitochondria. They regulate NMDA receptors and have been reported as reducing mitochondrial dysfunction and oxidative stress. Reportedly, in the absence of Aβ aggregation, there is: i) neuronal coupling of lactate with diurnal Aβ oscillations; and, ii) glutamate supply back to neurons by the astrocytes, as a mechanism involved in the fine tuning of sleep oscillations. According to the "astrocyte-neuron-lactate shuttle hypothesis" (<NPL>)), lactate coupling with diurnal oscillation of Aβ could be lost after Aβ aggregation, as astrocytes responsible for clearing Aβ become mobilized moving toward plaques. This is believed to initiate a positive feedback loop in which astrocytes no longer metabolize Aβ or remove glutamate from nearby neurons, leading to further aggregation of Aβ and to neuronal injury due to glutamate excitoxicity. In parallel, this is believed to increase sleep fragmentation due to increased hyperexcitability of glutamate neurons and to loss of synchronized activation of neuronal columns during sleep.

Literature reports evidence linking high blood pressure to increased risk of cognitive decline and dementia. Anti-hypertensive medications reportedly protect the brain from AD.

"Anavex Announces Two-Year Clinical Extension Study of ANAVEX <NUM>-<NUM> and Presents Phase 2a Dose-Response Analysis at AAT Conference", Press Release (non-patent literature reference number XP055459569) relates to a clinical study of A2-<NUM>. <CIT> relates to a method for treating depression. <CIT> relates to methods and pharmaceutical compositions for the treatment of symptoms of anxiety and panic. <CIT> relates to a method of treating neurodevelopmental autism spectrum disorder in a subject by administering to said subject a therapeutically effective amount of a therapeutic agent selected from the group consisting of A2-<NUM>, ANAVEX1-<NUM>, Anavex19-<NUM> or combinations thereof. N Rebowe: "ANAVEX <NUM>-<NUM> as a Potential Treatment for Rett Syndrome and Other Pediatric or Infantile Disorders with Seizure Pathology (non-patent literature reference number XP055358591) relates to A2-<NUM><NUM> as a potential treatment for Rett Syndrome. Anavex Life Sciences: "Assessment of ANAVEX <NUM>-<NUM> in a MECP2 Rett Syndrome Mouse Model, <NUM> Epilepsy Pipeline Conference February 26th <NUM>" (non-patent literature reference number XP055358593) relates to the assessment of A2-<NUM> in a mouse model for Rett Syndrome.

Note is made of the following publications:.

Disclosed is a method for treating insomnia, anxiety, or agitation in a subject in need of such therapy. Particular note is made of subjects suffering from Alzheimer's disease. The method comprises the step of administering to the subject pharmaceutically effective amount of a pharmaceutical selected from the group consisting of Anavex™<NUM>-<NUM> (also termed A2-<NUM>), A1-<NUM> or A19-<NUM>, and optionally as a dosage form comprising a pharmaceutically acceptable carrier. The method of administering is selected from the group consisting of oral administration, subcutaneous injection, intravenous injection, intraocular injection, intradermal injection, intramuscular injection, intraperitoneal injection, intratracheal administration, inhalation, intranasal administration, sublingual administration, buccal administration, rectal administration, vaginal administration, or topical administration.

The method contemplates a pharmaceutically effective amount is from about <NUM> to about <NUM> per day or more. Particular reference is made to a daily pharmaceutically effective amount of from about <NUM> to about <NUM>, and particularly from about <NUM> to about <NUM>.

The practice of the method draws particular attention to the use of A2-<NUM>, administering by oral dosing and administering is daily, every other day, or for about <NUM> or more days out of <NUM> days. Chronic dosing is contemplated.

Further contemplated is a method for treating insomnia, anxiety, or agitation in a subject in need of such therapy and further exhibiting systolic hypertension, comprising the step of administering to the subject pharmaceutically effective amount of a pharmaceutical selected from the group consisting of A2-<NUM>, A1-<NUM> or A19-<NUM>.

Without being bound by any particular theory, it is believed that that ANAVEX <NUM>-<NUM> as well as A1-<NUM> and A19-<NUM> reduce glutamate toxicity, oxidative stress and consequently improve sleep efficiency through σ1 agonism, and improved REM sleep duration and sleep efficiency though M<NUM>-<NUM> muscarinic agonism. In a phase-2A trial performed on a group of <NUM> community-dwelling mild AD patients with a DSM-<NUM> diagnosis of insomnia dosing with ANAVEX <NUM>-<NUM> (a sigma-<NUM> and muscarinic receptor agonist), the patients showed marked insomnia improvements at <NUM> weeks.

A2-<NUM> is a useful therapeutic in the treatment of humans suffering from insomnia, anxiety or agitation. Particular attention is drawn to oral daily doses of from about <NUM> to about <NUM> and up to <NUM>, with particular reference to about <NUM> to <NUM>. Attention is also directed to A1-<NUM> and A19-<NUM> as similarly useful therapeutics in insomnia, anxiety or agitation.

This invention will be better understood with reference to the following definitions:
The term "pharmaceutically effective amount" as used herein as to insomnia refers to a dose or quantity that causes improvement in at least one objective or subjective sleep parameter deficiency associated with insomnia including, but not limited to: difficulty falling asleep; difficulty maintaining sleep; decrease in total sleep time; persistent waking after sleep onset (WASO); and poor sleep quality.

Although the present invention calls for methods of treating insomnia, some primary sleep disorders, such as circadian rhythm disorders, advanced sleep phase disorder also termed sleep onset insomnia, mid-nocturnal insomnia, early morning insomnia, hyper insomnia, trouble staying asleep, jet lag, narcolepsy, non-<NUM>-hour sleep-wake syndrome, include insomnia as a component of the disorder. Thus, the term "insomnia" should be understood to also include the insomnia component of these disorders.

Aβ -- Amyloid beta is abbreviated as Aβ.

AD -- Alzheimer's disease is abbreviated as AD.

ADCS-ADL -- Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory is abbreviated as ADCS-ADL.

Cogstate tasks -- Cogstate tasks refers to Cogstate cognitive tests (Cogstate Alzheimer's Battery) using visual and verbal stimuli to ensure assessment. These tests assess cognitive function in adults with mild cognitive impairment and clinically-diagnosed Alzheimer's disease. The test is culture-neutral and not limited by a subject or participant's level of education. A Cogstate battery comprises a number of individual tests - each designed to test a specific area of cognition. When a number of these individual tests are put together to form a test battery, a more complete picture of a person's cognitive state can be defined.

EEG/ERP -- EEG/ERP is a reference to ERP measured via EEG.

ERP -- Event-related potential is abbreviated as ERP.

HAM-D -- Hamilton Depression Rating Scale is abbreviated as HAM-D.

MCI -- Mild cognitive impairment is abbreviated as MCI.

MMSE -- MMSE refers to the Mini-Mental State Examination (MMSE) or Folstein test. This test is a <NUM>-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment.

SWS -- Slow-wave sleep is abbreviated as SWS.

-- Waking after sleep onset is abbreviated WASO.

An event-related potential (ERP) is the measured brain response that is the direct result of a specific sensory, cognitive, or motor event. More formally, it is any stereotyped electrophysiological response to a stimulus. The study of the brain in this way provides a noninvasive means of evaluating brain functioning. ERPs are measured by means of electroencephalography (EEG).

The safety and efficacy of A2-<NUM> has been studied Phase 2a Study in mild-moderate Alzheimer's disease patients. A study of <NUM> patients with mild-to-moderate Alzheimer's disease (AD) demonstrated a favorable safety and tolerability/risk profile for A2-<NUM>. Without being bound by any particular theory, it is believed that A2-<NUM> activates the stress-reducing and survival protein, the Sigma-<NUM> receptor.

Efficacy data is presented through <NUM> week from the randomized (into different treatment regimens) open-label study with ANAVEX <NUM>-<NUM> oral daily dosing ranging from <NUM> to <NUM>. The data establish a method for treating insomnia, anxiety, or agitation in a subject. Efficacy extends to daily doses of up to about <NUM> of A2-<NUM>, A1-<NUM> or A19-<NUM>. Note is made of doses of A2-<NUM>, A1-<NUM> or A19-<NUM> of about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>. Oral dosing daily or every other day is contemplated.

Particular efficacy data measurements addressed cognition and function. Cognitive measures include MMSE and Cogstate battery. Functional measures were ADCS-ADL. Supportive Biomarker Measurements include ERP (P300): fundamental measures of synaptic network performance and target engagement. ERP target detection task measures is a direct measure of attention, speed of brain processing, and simple functional performance.

<FIG> presents MMSE mean scores over <NUM> weeks. Statistical analysis of MMSE revealed no other grouping factors (sex, ApoE4, age, donepezil, baseline value) influencing the analysis. Statistical analyses also revealed overall Δ-MMSE-scores maintained at the same level and effects were confirmed with Bayesian inference calculations. In a disease state where progression is invariable over time, a stable MMSE score represents a positive outcome treating insomnia, anxiety, or agitation.

<FIG> is a graphic presentation of ADCS-ADL data. Data speaks to a quality of life score ADCS-ADL (Activities of Daily Living), here, as maintained through week <NUM> of A2-<NUM> dosing. ADCS-ADL-Δ-scores were also maintained at a constant level through week <NUM> and effects were confirmed with Bayesian inference calculations. Again, in a disease state where progression is invariable over time as is the case here, a stable ADCS-ADL score is considered a positive outcome.

<FIG> presents data on both MMSE MCI and Mild-to-Moderate Patients. Given unequal sample size, data after stratification are considered preliminary. Similar effect are noted on MMSE in both MCI and Mild-to-Moderate AD patients.

<FIG> presents data on both ADCS-ADL MCI and Mild-to-Moderate Patients. Similar ADCS-ADL score effect between MCI and Mild-to-Moderate AD patients are noted.

<FIG> presents data on MMSE ANAVEX <NUM>-<NUM> Alone vs A2-<NUM> in combination with donepezil. Similar MMSE score effect and no notable difference between exploratory analysis of ANAVEX <NUM>-<NUM> alone and ANAVEX <NUM>-<NUM> with DPZ are noted.

<FIG> presents data on ADCS-ADL ANAVEX <NUM>-<NUM> Alone vs A2-<NUM> in combination with donepezil. Similar ADCS-ADL score and no notable difference between exploratory analysis of ANAVEX <NUM>-<NUM> alone and ANAVEX <NUM>-<NUM> with DPZ are noted.

<FIG> of ANAVEX <NUM>-<NUM> treatment demonstrates reduction in overall Hamilton Depression Rating Scale (HAM-D) after <NUM> weeks of dosing with A2-<NUM>. This is consistent with Table <NUM> showing a reduction in insomnia, anxiety, and other symptoms.

The data of Table <NUM> is from an open-label, clinical trial, performed on a group of <NUM> mild-to-moderate AD patients (MMSE range <NUM>-<NUM>, <NUM>% female) on donepezil treatment, with ANAVEX <NUM>-<NUM>. Patients showed marked improvements on subjective reports of insomnia (the sleep items of the Hamilton Depression Rating scale, HAM-D) (see also, Table <NUM>) from baseline to week <NUM> (t=<NUM>; p<. Changes in other behavioral items were not statistically significant. Anavex <NUM>-<NUM> at <NUM> was well tolerated with the most common adverse events (AEs) being mild dizziness (<NUM>%) and headache (<NUM>%), and no significant changes in clinical labs and EKGs.

<FIG> is a chart of Anavex <NUM>-<NUM> improving components of cogstate tasks. ANAVEX <NUM>-<NUM> treatment demonstrates reduction in overall Hamilton Depression Rating Scale (HAM-D) after <NUM> weeks. Over <NUM> weeks of treatment, ANAVEX <NUM>-<NUM> was associated with a sustained benefit in psychomotor function, attention and working memory. The specificity and consistency of these benefits establish that ANAVEX <NUM>-<NUM> sustains activation of attentional and working memory functions with repeated dosing in Alzheimer's disease.

ANAVEX <NUM>-<NUM> effect on synaptic networks and effect on cognition and behavior at daily doses of <NUM>-<NUM> is shown. ERP peak measures (P300) are shown. The P300 (P3) wave is an event related potential (ERP) component elicited in the process of decision making. It is considered to be an endogenous potential, as its occurrence links not to the physical attributes of a stimulus, but to a person's reaction to it. More specifically, the P300 is thought to reflect processes involved in stimulus evaluation or categorization. ERP target detection task is a direct measure of attention, speed of brain. processing, and simple behavioral performance. Psychometric measures (Cogstate) cognitive measures: Detection: processing speed (psychomotor function), Identification: reaction time (attention), One Back: working memory (cognition), One Card Learning: visual learning (visual memory), ISLT: verbal learning, ISLT-delay: verbal memory. Psychometric measures (MMSE): cognitive measures.

Behavioral measures (ADCS-ADL): behavioral measures. Notably, <FIG> shows that all tested areas exhibited improvement at <NUM> weeks as compared with the starting baseline (hence, absent expected decline).

Oral daily doses of ANAVEX <NUM>-<NUM> ranging from <NUM> to <NUM> exhibit a converging and consistent response for all measurements (MMSE, ADCS-ADL, Cogstate, EEG/ERP) throughout <NUM> weeks (<NUM> months) of ANAVEX <NUM>-<NUM> treatment. Patient retention rate at week <NUM> was <NUM>%. Treatment of ANAVEX <NUM>-<NUM> and related drugs demonstrates reduction in overall HAM-D score after <NUM> weeks, notably through reductions in insomnia, anxiety and agitation. Seventeen week data as well as <NUM> week data of all available patients demonstrate that ANAVEX <NUM>-<NUM> preserves average MMSE and ADCS-ADL scores across the entire patient group. In a disease state where progression is invariable over time, a stable MMSE and ADCS-ADL score is considered a positive outcome. When the group is tentatively stratified into mild to moderate and MCI (mild cognitive impaired) AD patients, no significant difference was observed within the MMSE or the ADCS-ADL score, respectively. Likewise, when tentatively stratified between ANAVEX <NUM>-<NUM> alone and ANAVEX <NUM>-<NUM> PLUS donepezil administration, no significant difference was observed within the MMSE or the ADCS-ADL score, respectively. For cognitive assessment using the Cogstate test batteries, ANAVEX <NUM>-<NUM> continues to show benefits over baseline at <NUM> weeks and <NUM> weeks. ANAVEX <NUM>-<NUM> related improvement in psychomotor function, attention and working memory are preserved through <NUM> weeks and <NUM> weeks of treatment. Repeated-measures ANOVA reveals that Cogstate values maintained the baseline values through week <NUM>.

An additional benefit of the therapeutic regimen disclosed herein is the beneficial control of systolic blood pressure in AD subjects taking daily oral dosages of A2-<NUM> of from about <NUM> to about <NUM>. Systolic blood pressure was monitored over the first <NUM> days of dosing. A1-<NUM> and A19-<NUM> are similarly useful therapeutics.

A <NUM> year old female presents as suffering from maintenance insomnia for one year. She is started on oral A2-<NUM> at <NUM>/day. Follow up at <NUM> days of daily dosing reveals she is sleeping well. She is currently maintained on <NUM> of A2-<NUM> and is sleeping well.

A <NUM> year old female presents with anxiety of three years' duration. She is administered A2-<NUM> at <NUM> oral per day every other day. Resolution of the anxiety is noted after two days of dosing. She is maintained on this dosing schedule for <NUM> days.

The patient is a <NUM>-year-old male exhibiting agitation. He is treated with <NUM> A2-<NUM> oral daily for <NUM> days. Clinical evaluation reveals normal affect without agitation, depression, anxiety, or substance use. He is currently maintained at that dosage and is not anxious.

A <NUM> year old female presents with MCI and reports maintenance insomnia for one year. She is started on oral A1-<NUM> at <NUM>/day. Follow up at <NUM> days of daily dosing reveals she is sleeping well. She is currently maintained on <NUM> of A1-<NUM> and is sleeping well.

The patient is a <NUM> year old female with diagnosed AD and reported anxiety of three years' duration. She is administered A19-<NUM> at <NUM> oral per day every day for <NUM> days. Resolution of the anxiety is noted after two days of dosing. She is chronically maintained on this dosing schedule.

A <NUM> year old male diagnosed with mild cognitive impairment presents as suffering from maintenance insomnia for one year. He is started on oral A2-<NUM> at <NUM>/day. Follow up at <NUM> days of daily dosing reveals he is sleeping well. He is currently maintained on <NUM> of A2-<NUM> daily and is sleeping well.

A <NUM> year old male diagnosed with Alzheimer's disease presents with insomnia/WASO and agitation and a systolic blood pressure of <NUM> Hg. He is started on oral A2-<NUM> at <NUM>/day. Follow up at <NUM> days of daily dosing reveals he is sleeping well through the night and not waking up repeatedly and his systolic BP is <NUM>. He is also less agitated. His results on all cognitive tests and HAM-D improve. He is currently maintained on <NUM> of A2-<NUM> daily.

A <NUM> year old male diagnosed with Alzheimer's disease presents with insomnia/WASO and agitation. He is started on oral A2-<NUM> at <NUM>/day. Follow up at <NUM> days of daily dosing reveals he is sleeping well through the night and not waking up repeatedly. He is also less agitated. His results on all cognitive tests and HAM-D improve. He is currently maintained on <NUM> of A2-<NUM> every other day.

A <NUM> year old male diagnosed with Alzheimer's disease presents with insomnia/WASO and agitation. He is started on oral A19-<NUM> at <NUM>/day. Follow up at <NUM> days of daily dosing reveals he is sleeping well through the night and not waking up repeatedly. He is also less agitated. His results on all cognitive tests and HAM-D improve. He is currently maintained on <NUM> of A19-<NUM> daily.

A <NUM> year old male diagnosed with Alzheimer's disease presents with insomnia/WASO and agitation. He is started on oral A1-<NUM> at <NUM>/day. Follow up at <NUM> days of daily dosing reveals he is sleeping well through the night and not waking up repeatedly. He is also less agitated. His results on all cognitive tests and HAM-D improve. He is currently maintained on <NUM> of A1-41daily.

The pharmacologically active compositions of this invention can be processed in accordance with conventional methods of Gaenlic pharmacy to produce medicinal agents for administration to subjects, e.g., mammals including humans.

The compositions of this invention individually or in combination are employed in admixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral (e.g., oral or inhalation) or topical application which do not deleteriously react with the active compositions. Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, titanium dioxide, silicic acid, viscous paraffin, perfume oil, fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc. The pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compositions. They can also be combined where desired with other active agents, e.g., vitamins.

In some embodiments of the present invention, dosage forms include instructions for the use of such compositions.

Claim 1:
Pharmaceutical selected from the group consisting of A2-<NUM> or A1-<NUM> for use in the treatment of maintenance insomnia in a subject in need of such therapy,
wherein the pharmaceutical is A2-<NUM>, and the treatment comprises oral administration of <NUM>/day of A2-<NUM>; or
wherein the pharmaceutical is A2-<NUM>, the subject has mild cognitive impairment (MCI), and the treatment comprises oral administration of <NUM>/day of A2-<NUM>; or
wherein the pharmaceutical is A1-<NUM>, the subject has MCI, and the treatment comprises oral administration of <NUM>/day of A1-<NUM>.