ANAVEX2-73 for the treatment of Alzheimer's disease

Abstract

Pharmaceutical compositions and methods for the treatment of Alzheimer's disease are provided. Compositions and methods comprising ANAVEX 2-73 for the treatment of Alzheimer's disease. A method for treating Alzheimer's disease using a pharmaceutical composition comprising ANAVEX 2-73 according to an intermittent dosing regimen.

Description

Technical Field

[0001] The present disclosure relates to pharmaceutical compounds and pharmaceutical compositions for the treatment of Alzheimer's disease. Specifically, the present disclosure relates to the use of pharmaceutical compositions comprising ANAVEX2-73 (also known as A2-73) for the treatment of Alzheimer's disease.

Background Art

[0002] Despite significant efforts to discover treatments for Alzheimer's disease, the development of compounds that can reduce the cognitive deficits associated with the disease has progressed slowly. ANAVEX2-73 or A-273 (tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride) is a compound that is thought to bind to sigma-1 receptors and muscarinic acetylcholine receptors with low micromolar affinity. ANAVEX2-73 has the following chemical structure.

[0003]

Chemical Formula

[0004] The sigma-1 receptor is a chaperone protein within the endoplasmic reticulum (ER) that associates with the IP3 receptor at the contact site between the ER and mitochondria to ensure proper Ca 2+ signaling from the ER to the mitochondria. In pathological situations where cells encounter stress and as a result the ER loses its overall Ca 2+ homeostasis, the sigma-1 receptor translocates and suppresses apoptosis induction. As a result, the sigma-1 receptor is an essential receptor chaperone for metabolic regulatory receptor signaling and survival against cellular stress. See Centr. Nerv. Syst. Agents Med. Chem. 9(3), 184-189 (2009).

[0005] ANAVEX2-73 has been reported to exhibit potential neuroprotective ability against amyloid toxicity in mice. Specifically, ANAVEX2-73 attenuated oxidative stress, caspase induction, cell loss, and deficits in learning and memory observed in mice one week after intracerebroventricular injection of an oligomeric preparation of amyloid β 25-35 peptide (Aβ 25-35 ). See J. Psychopharmacol. 25(8), 1101-1117 (2011). More recently, ANAVEX2-73 has been reported to block Aβ 25-35 -induced decreases in P-Akt and increases in P-GSK-3β, indicating activation in the PI3K neuroprotective pathway. See Neuropsychopharmacology 38, 1706-1723 (2013). Within the dose range tested, ANAVEX2-73 attenuated hyperphosphorylation of tau at physiological epitopes (AT-8 antibody clone) and pathological epitopes (AT-100 clone). Also, ANAVEX2-73 has been reported to decrease Aβ 25-35 -induced endogenous Aβ 1-42 seeding.

[0006] See the following applications: "ANAVEX2-73 AND CERTAIN ANTICHOLINESTERASE INHIBITORS COMPOSITION AN U.S. Patent Publication No. 2014 / 0296211 to Vamvakides et al. entitled "D METHOD FOR NEUROPROTECTION" (filed Jul. 12, 2013); U.S. Patent Application No. 62 / 065,833 entitled "A19-144, A2-73 AND CERTAIN ANTICHOLINESTERASE INHIBITOR COMPOSITIONS AND METHOD FOR ANTI-SEIZURE THERAPY" (filed Oct. 20, 2014); U.S. Patent Application (filed on the same date as this application) entitled "CRYSTAL FORMS OF TETRAHYDRO-N,N-DIMETHYL-2,2-DIPHENYL-3-FURANMETHANAMINE HYDROCHLORIDE, PROCESSES OF MAKING SUCH FORMS, AND THEIR PHARMACEUTICAL COMPOSITIONS"; U.S. Patent Application (filed on the same date as this application) entitled "ENANTIOMERS OF A2-73, ANALOGUES, AND SIGMA AGONIST ACTIVITY". The teachings of these applications and publications and all references cited herein are incorporated by reference in their entirety.

SUMMARY OF THE INVENTION

[0007] The present disclosure includes a pharmaceutical composition comprising a therapeutically effective amount of ANAVEX2-73 for the treatment of Alzheimer's disease. Specific reference is made to the treatment (where Alzheimer's disease is mild to moderate) using the composition, and more particularly, ANAVEX2-73 is characterized not only by the PXRD pattern shown in FIG. 1, but also by thermogravimetric analysis of FIG. 2a or FIG. 2b and by differential scanning calorimetry analysis of FIG. 3a, 3b, or 3c.

[0008] Furthermore, a pharmaceutical composition is included in which ANAVEX2-73 is characterized by the shape or size of the particles shown in FIG. 4a, FIG. 4b, or FIG. 4c. Specific reference is made to particle sizes between 1 and 50 μm.

[0009] Known therapeutic effective amounts of ANAVEX2-73 include from about 1 mg to about 60 mg, particularly from about 30 mg to about 50 mg. Further, therapeutic effective amounts of from about 3 mg to about 5 mg are known, particularly for intravenous administration. Oral dosage forms are known.

[0010] Still further, combination dosages are included with at least one acetylcholinesterase inhibitor, particularly with respect to donepezil, galantamine, rivastigmine, or memantine.

[0011] The present disclosure contemplates a method of treating Alzheimer's disease in a subject, the method comprising administering to the subject the pharmaceutical composition and combination described above.

[0012] The contemplated dosage regimen includes administering to the subject a pharmaceutical composition comprising ANAVEX2-73 according to an intermittent dosing regimen of at least two cycles, each cycle including (a) a dosing period during which a therapeutic effective amount of the pharmaceutical composition is administered to the subject, and thereafter (b) a drug-free period. In some embodiments, the dosing period and the drug-free period are of the same length or of different lengths.

[0013] Note that for the dosing period and the drug-free period, the range is from a lower limit of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, and 14 days to an upper limit of about 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, and 14 days. Also known are dosing periods between about 1 day and 12 days and drug-free periods between about 1 day and 12 days, particularly with respect to a dosing period of 12 days and a drug-free period of 12 days. Such regimens are usefully employed when the therapeutic effective amount of the pharmaceutical composition of ANAVEX2-73 is from about 1 mg to about 60 mg, particularly from about 30 mg to about 50 mg, and particularly for oral dosage forms. Further contemplated are dosages of ANAVEX2-73 of from about 3 mg to about 5 mg, particularly using intravenous administration.

[0014] To describe the manner in which the advantages and features of the present disclosure can be obtained, reference is made to the embodiments of the present disclosure illustrated in the accompanying drawings. Understanding that these drawings show only exemplary embodiments of the present disclosure and should not be considered as limiting the scope of the present disclosure, the principles of this specification will be further described and explained in more specific and detailed manner through the use of the following accompanying drawings.

Brief Description of the Drawings

[0015]

Figure 1

Figure 2a

Figure 2b

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Figure 3b

Figure 3c

Figure 4a

Figure 4b

Figure 4c

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Figure 9

[0016] Various embodiments of the present disclosure are discussed in detail below. It should be understood that specific implementations are discussed for illustrative purposes only. Those skilled in the relevant art will recognize that other components and configurations may be used without departing from the spirit and scope of the present disclosure.

[0017] Exemplary implementations of one or more embodiments are illustrated below, but it should first be understood that the methods of the present disclosure can be implemented using various techniques. The present disclosure should in no way be limited to the exemplary implementations, drawings, and techniques illustrated herein, but may be modified along with the full scope of its equivalents within the scope of the appended claims.

[0018] In the following description and claims, the terms "including" and "comprising" are used in an open-ended fashion and should be interpreted to mean "including, but not limited to." The various features described in more detail below will be readily apparent to those skilled in the art by utilizing the present disclosure, reading the following detailed description of the invention, and referring to the accompanying drawings.

[0019] The present disclosure generally relates to pharmaceutical compounds and compositions for the treatment of Alzheimer's disease. More particularly, the present disclosure relates to the use of pharmaceutical compositions containing ANAVEX2-73 for the treatment of Alzheimer's disease.

[0020] According to an embodiment of the present disclosure, ANAVEX2-73 can be produced by filling isopropanol into a solution of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine free base in ethyl acetate. The ethyl acetate is removed by distillation, and the remaining isopropanol solution containing tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine free base is clarified by filtration. The isopropanol solution is filled with an aqueous hydrochloric acid solution (1.1 equivalents), and the formed crystalline HCl salt of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine, tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), is isolated by filtration and dried under vacuum at 55 °C for 3 days. The ANAVEX2-73 thus obtained is characterized by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM) as shown in FIGS. 1-4.

[0021] Figure 1 shows the powder X-ray diffraction (PXRD) pattern of ANAVEX2-73 according to an embodiment of the present disclosure. The PXRD pattern shown in Figure 1 was collected using a Siemens D5000 powder diffractometer with CuKα radiation (1.54056 Å). The voltage and current of the electron tube were set to 40 kV and 40 mA, respectively. The settings of the divergence slit and anti-scattering slit were variable for illumination of the 20 mm sample area. Each sample was scanned at 2θ from 5° to 40° with a step size of 0.02°. The measurement time per step was 2 seconds. The instrument was calibrated in advance using a silicon standard substance. As shown in Figure 1, the PXRD shows that the ANAVEX2-73 material is highly crystalline and has several characteristic peaks within the 2θ range of 10-20°.

[0022] Figures 2a and 2b show the thermogravimetric analysis (TGA) data of ANAVEX2-73 according to an embodiment of the present disclosure. Using a Thermal Advantage TGA Q5000IR (TA instrument) module, the weight loss of the sample was measured as a function of temperature. The sample (about 7.8 mg) was placed on a platinum pan (100 μL) and heated from 25° to 350° at a heating rate of 10 °C / min under a nitrogen purge. As shown in Figures 2a-2b, the curves of the TGA (and the differential coefficient of the weight change) show a slight weight change around 80 °C, and then, two main steps (the first step is about 29% at 228 °C), indicating that continuous weight loss occurs from 150 °C to 275 °C. The first weight loss may be due to the evaporation of adsorbed water or solvent in crystallization, and the later weight change may be due to the decomposition of the impure solid phase (or impurities) and then the melting decomposition of ANAVEX2-73.

[0023] Figures 3a, 3b, and 3c show the differential scanning calorimetry (DSC) data for ANAVEX2-73 according to an embodiment of the present disclosure. Thermal with a refrigerated cooling system The thermal behavior of ANAVEX2-73 was investigated using an Advantage DSC Q1000 (TA Instruments). The instrument was calibrated for temperature and enthalpy using indium. Samples of 1-2 mg were accurately weighed and placed into unsealed aluminum pans, which were then crimped. The samples were scanned from 25 °C to 275 °C at a heating rate of 10 °C / min under a continuous nitrogen purge (50 mL / min). As shown in FIGS. 3a-3c, the DSC thermogram shows endothermic events starting at approximately 80 °C (minor) and 115 °C (extensive), followed by an exothermic peak and a sharp endothermic event starting at 227 °C. The DSC analysis appears to be consistent with the TGA analysis, suggesting that the compound underwent melting decomposition. However, it is also possible that decomposition of the major phase in the vicinity started prior to melting.

[0024] Figs. 4a, 4b, and 4c show scanning electron microscope (SEM) micrographs demonstrating the size and morphology of the particles of ANAVEX2-73 according to embodiments of the present disclosure. The size and morphology of the particles were investigated using a Philips XL30 (Netherlands) scanning electron microscope (SEM). The samples were sprinkled onto double-sided adhesive tape fixed on an aluminum stub and then gold sputter-coated at mA for 40 seconds under an argon atmosphere. The particles were analyzed at a suitable accelerating voltage and magnification. Representative micrographs were taken and the particle size was estimated. The SEM micrographs demonstrated that ANAVEX2-73 was mainly composed of aggregated crystals (from prisms to blocks), and the main particle size distribution was from 1 to 50 μm.

[0025] The safety of ANAVEX2-73 has been demonstrated in a randomized, placebo-controlled, single-ascending-dose Phase 1 study of ANAVEX2-73 in 22 healthy male volunteers. See poster presentation: A Phase 1 Dose Escalation Study to Investigate Safety, Tolerability, and Pharmacokinetics of ANAVEX2-73 in Healthy Male Subjects, CNS Summit 2014, Boca Raton, FL, by Ole Voges, Ingo Weigmann, Norman Bitterlich, Christoph Schindler and Christopher Missling. In healthy subjects, single oral dose escalations of 1 mg, 10 mg, 30 mg, 40 mg, 50 mg, and 55 mg of ANAVEX2-73 were safe and well tolerated. No serious adverse events occurred. Based on the frequency and intensity of treatment-emergent adverse events (TEAEs), the maximum tolerated dose (MTD) and minimum intolerable dose (MID) were defined as 55 mg and 60 mg, respectively. Adverse events observed at the highest dose included moderate, reversible dizziness and headache, which are common to drugs targeting the central nervous system. No clinically relevant or dose-dependent changes were shown from blood pressure and resting heart rate and other clinical parameters (e.g., vital signs and 12-lead electrocardiogram (ECG)). No clinically problematic changes were shown from QT interval and QTcB. The pharmacokinetics of ANAVEX2-73 were found to be suitable for once-daily oral dosing.

[0026] The efficacy of ANAVEX2-73 in the treatment of Alzheimer's disease in multiple forms has been demonstrated by the first clinical data from the ongoing Phase 2a clinical trial. The 36-day multi-site randomized clinical trial included both male and female patients with mild to moderate Alzheimer's disease. ANAVEX2-73 was administered to 12 subjects as an add-on therapy to the current standard treatment of donepezil. ANAVEX2-73 was administered according to a two-period on-off-on crossover dosing regimen, in which subjects were given ANAVEX2-73 for 12 days (Period 1), followed by a 12-day drug washout period, and then a second 12-day period (Period 2) of ANAVEX2-73 administration. Subjects who received ANAVEX2-73 orally during Period 1 received ANAVEX2-73 intravenously during Period 2, and vice versa. Approximately half of the subjects were given a 30 mg oral dosage form, while the other half were given a 50 mg oral dosage form. The intravenous dose was either 3 mg or 5 mg, and approximately half of the subjects were given 3 mg and the other half 5 mg.

[0027] The cognitive effects of ANAVEX2-73 administration were evaluated using resting electroencephalogram (EEG) activity and event-related potentials (EEG / ERP). As recorded by EEG, event-related potentials (ERP) are voltage changes time-locked to some physical or mental occurrence of ongoing electrical brain activity. Event-related potentials (ERP) provide a sensitive and reliable measure of cognitive effects associated with early Alzheimer's disease. ERP has been found to reflect and vary in the well-characterized brain responses to sensory, motor, and cognitive events in Alzheimer's disease patients at the very early stages of Alzheimer's disease. See, e.g., New Encycl. Neurosci., Oxford Academic Press, pp. 13-18 (2009). For example, ERP tests in young individuals who carry mutations in the presenilin-1 and amyloid precursor protein genes and who are not yet symptomatic show significant changes in ERP patterns years before the onset of behavioral symptoms and Alzheimer's disease. See, e.g., Neurology 73, 1649-1655 (2009); Neurology 77, 469-475 (2011). Also, ERP has been shown to reliably track cognitive decline associated with the progression of Alzheimer's disease. For example, in longitudinal studies of individuals with mild cognitive impairment (MCI) and Alzheimer's disease patients, the ERP markers of cognitive function are gradually changing. See, e.g., Clin. Neurophysiol. 122, 1322-1326 (2011); Clin. Neurophysiol. 121, 194-199 (2010). In addition, ERP has been shown to be sensitive to the effects of cognitive enhancing drugs currently used in the treatment of Alzheimer's disease. For example, the ERP measure has been demonstrated to be a reliable means for evaluating cognitive responses to cholinesterase inhibitors (e.g., donepezil), and as measured by ERP, the effects of memantine, a selective NMDA antagonist, have been shown to correlate with changes in mini-mental state examination (MMSE) scores.See, for example, Neurol. Neurochir. Pol. 35 Suppl 3, 37-43 (2001); Clin. Neuropharmacol. 25, 207-215 (2002); Neurosci. Biomed. Eng. 1, 34-39 (2013).

[0028] In particular, since the auditory P300 component of ERP is thought to reflect attentional and memory processes, it has been widely applied in research on age-related cognitive decline. Auditory P300 is a positive deflection that occurs approximately 300 ms after stimulus onset. Auditory P300 is generated by the activation of multiple neocortical and limbic regions. Auditory P300 has two functionally distinct components, an early P3a component that is maximal over the fronto-central region and a late P3b component (hereinafter "P300") that is maximal over the posterior scalp position. See, for example, Int. J. of Alzheimer’s Dis. 2011, Article ID 653173, 1-7 (2011). P300 amplitude data collected as part of a double-blind 6-month study of donepezil compared to vitamin E baseline in 15 patients with mild Alzheimer's disease showed that the P300 amplitude data correlated with the ADAS-Cog and MMSE data of the same patients. See Clin. Neuropharmacol. 25(4), 207-215 (2002).

[0029] The subjects were tested using a 3-stimulus oddball paradigm. The stimuli consisted of a standard tone (1000 Hz), a target tone (2000 Hz), and an unexpected interfering tone (white noise), which were played with probabilities of 0.75, 0.15, and 0.10. T The tones were presented in a pseudo-random order so that the target tone and the interfering tone were not presented continuously. The subjects were instructed to respond to the target stimulus by pressing a button with their dominant hand. In each test, stimuli from 300 to 400 were presented to both ears through insert earphones at a volume of 70 dB. The duration of each stimulus tone was set to a rise time of 100 ms and a fall time of 10 ms. The interval between stimuli was randomized between 1.5 s and 2 s. Electroencephalogram (EEG) activity from seven electrode sites (Fz, Cz, Pz, F3, P3, F4, and P4) of the international 10-20 method was recorded using a COGNISION (trademark) headset (Neuronetrix). The electrodes were referenced to the averaged mastoids (M1, M2) and Fpz that served as common electrodes. The headset used for data collection was confirmed to perform reliable ERP recordings when the skin contact impedance was less than 70 kΩ. The impedance was automatically checked for all electrodes after each target or interfering tone and was kept below this limit throughout each test. Data from 240 to 1,000 ms before and after the stimulus were collected, digitized at 125 Hz, and band-pass filtered at 0.3 to 35 Hz. For the test, an automatic artifact threshold detection limit of ±100 μV was set. Sets of trials (epoch sets) of deviating tones with artifacts exceeding the threshold and the immediately preceding standard tones were excluded in real time and immediately repeated.

[0030] Figure 5 illustrates P300 ERP wave data (at baseline and on the 36th day after an on-off-on dosing regimen of ANAVEX2-73) for 12 patients without any dose optimization. Figure 5 also illustrates data from a healthy control group obtained from a manuscript recently submitted by Cecchi et al. to the journal Alzheimer’s & Dementia. The P300 ERP wave data indicate that the administration of ANAVEX2-73 improved the measured cognitive performance compared to the baseline data. In addition, the P300 ERP wave plots of subjects receiving the ANAVEX2-73 dosing regimen were more similar to the P300 ERP wave plots obtained for healthy subjects.

[0031] Figure 6 illustrates the P300 amplitude data of 12 patients (at baseline and on the 36th day after the on-off-on dosing regimen of ANAVEX2-73) compared to a healthy control group. The same data is shown in Table 1. As shown in Table 1, the P300 amplitude of subjects receiving the ANAVEX2-73 dosing regimen increased by 38% compared to the baseline P300 amplitude. In addition, the P300 amplitude in subjects receiving the ANAVEX2-73 dosing regimen was more similar to the P300 amplitude data obtained in the healthy control group than to the baseline P300 amplitude data.

[0032]

Table 1

[0033] Table 2 demonstrates the effect of the ANAVEX2-73 dosing regimen on the cognitive performance of 12 subjects at baseline and on the 36th day after the on-off-on dosing regimen of ANAVEX2-73, as measured by the target detection task of the ERP test. Table 2 also shows the data of the target detection task for the healthy control group. As shown in Table 2, the button pressing accuracy of subjects receiving the ANAVEX2-73 dosing regimen was improved compared to the baseline. In addition, in subjects administered ANAVEX2-73, the median reaction time and false alarm percentage decreased compared to the baseline line. The healthy control group had better results in button pressing accuracy and median reaction time than the ANAVEX2-73 subjects on the 36th day. However, the ANAVEX2-73 subjects on the 36th day had better results in false alarm percentage than the healthy control group. The data shown in Table 2 indicates that administration of ANAVEX2-73 improves both the accuracy and reaction time of subjects performing the target detection task of the ERP test.

[0034]

Table 2

[0035] Figure 7 illustrates the P300 amplitude data of 12 patients (at 36 days (1 month) after the on-off-on dosing regimen of ANAVEX2-73) compared to the historical data of donepezil and controls obtained from Clin. Neuropharmacol. 25(4), 207-215 (2002). As shown in Figure 7, the change in the P300 amplitude measured for subjects receiving the ANAVEX2-73 dosing regimen was approximately 4-fold higher than the change in the P300 amplitude at 1 month in patients administered donepezil, as observed in the historical data, compared to the baseline P300 amplitude. Further, the percent change in the P300 amplitude after 1 month was greater than the percent change in the P300 amplitude observed in the historical data of patients administered donepezil after 6 months. The data shown in Figure 7 suggest that administration of ANAVEX2-73 increases the P300 amplitude measured for subjects at an earlier time point in the dosing regimen and to a greater extent than administration of donepezil.

[0036] Figure 8 is a plot illustrating the electroencephalogram (EEG) alpha wave peak frequency (PAF) data of 12 patients (at baseline and at 36 days after the on-off-on dosing regimen of ANAVEX2-73) compared to a healthy control group. The electroencephalogram (EEG) alpha wave peak frequency (PAF) (measured in Hz) is a unique individual "fingerprint", associated with cognitive performance, and reflects the characteristics or state of cognitive preparation. It has been found that Alzheimer's disease patients have a reduced PAF compared to age-matched controls. PAF measures the discrete frequency with the highest amplitude within the alpha range. For example, Figure 9 illustrates an EEG power spectrum showing the alpha wave peak frequency (PAF). As shown in Figure 8, the PAF measured for subjects receiving the ANAVEX2-73 dosing regimen was higher than the baseline PAF measurement. Figure 8 shows that ANAVEX2-73 can shift the PAF of subjects compared to the measured PAF baseline. In addition, ANAVEX2-73 was found to improve the P300 signal in 10 out of 12 patients (83%) studied.

[0037] The results of the on - off - on dosing regimen of ANAVEX2 - 73 in 12 subjects shown in FIGS. 5 - 9 were achieved without any dose optimization. Changes in the pre - measured Mini - Mental State Examination (MMSE) and Cogstate scales are consistent with the observed trends in cognitive EEG / ERP effects. The safety profile of ANAVEX2 - 73 during the Phase 2a trial appears to be consistent with the Phase 1 data. An additional 20 subjects will be studied during the remaining period of the Phase 2a clinical trial. The Phase 2b clinical trial is ongoing with an additional 26 - week extension of once - daily oral dosing of ANAVEX2 - 73.

[0038] According to the present disclosure, ANAVEX2 - 73 can be administered according to an intermittent dosing schedule, where a subject is administered ANAVEX2 - 73 for a number of days, followed by a period of days without ANAVEX2 - 73 administration, and then the administration of ANAVEX2 - 73 is resumed once again. In some cases, the dosing period is the same as the non - dosing period. In other cases, the dosing period can be longer or shorter than the non - dosing period. In some cases, ANAVEX2 - 73 is administered according to an intermittent dosing regimen of at least two cycles, each cycle including (a) a dosing period during which a therapeutically effective amount of ANAVEX2 - 73 is administered to the patient and (b) a washout period thereafter. In one embodiment, the dosing period is from 1 to 12 days and the washout period is from 1 to 12 days. In other embodiments, the dosing period can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In some embodiments, the washout period can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.

[0039] In some cases, the dosing period described herein can range from a lower limit of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 days to an upper limit of about 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, and 14 days. In some cases, the drug withdrawal period described herein can range from a lower limit of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 days to an upper limit of about 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, and 14 days.

[0040] In one embodiment, the intermittent dosing schedule described herein includes an oral dosage form containing about 30 mg of ANAVEX2-73. In another embodiment, the intermittent dosing schedule described herein includes an oral dosage form containing about 50 mg of ANAVEX2-73. In another embodiment, the intermittent dosing schedule described herein includes an oral dosage form containing ANAVEX2-73 between about 30 mg and 50 mg. In another embodiment, the intermittent dosing schedule described herein includes an oral dosage form containing ANAVEX2-73 between about 1 mg and 55 mg.

[0041] In some cases, the oral dosage form described herein can be within the range of a lower limit of about 1, 5, 10, 15, 20, 25, and 30 mg of ANAVEX2-73 to an upper limit of about 60, 55, 50, 45, 40, 35, and 30 mg of ANAVEX2-73.

[0042] In one embodiment, the intermittent dose schedule described herein comprises an intravenous administration of about 3 mg of ANAVEX2-73. In another embodiment, the intermittent dose schedule described herein comprises an intravenous administration of about 5 mg of ANAVEX2-73. In another embodiment, the intermittent dose schedule described herein comprises an intravenous administration of between about 3 mg and 5 mg of ANAVEX2-73. In another embodiment, the intermittent dose schedule described herein comprises an intravenous administration of between about 1 mg and 10 mg of ANAVEX2-73. In some cases, the intravenous administration described herein can be within a range of about 1 mg, 2 mg, 3 mg, 4 mg, and 5 mg of ANAVEX2-73 at lower limits to about 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, and 5 mg of ANAVEX2-73 at upper limits.

[0043] All numbers and ranges disclosed above are subject to some variation. Whenever a numerical range with a lower and upper limit is disclosed, the range Any number that falls within a range and any encompassed range is intended to be specifically disclosed. In particular, any range of values disclosed herein (in the form "from about a to about b," or, similarly, "from approximately a to b," or, similarly, "from approximately a to b") is to be understood to refer to any number or range encompassed within the broader range of values.

[0044] The compositions disclosed herein, either individually or in combination, are used in admixture with conventional excipients that do not react detrimentally with the active composition and are suitable for parenteral, enteral (e.g., oral or inhalation), or topical application, i.e., mixed with pharmaceutically acceptable organic or inorganic carrier substances. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohol, gum arabic, vegetable oils, benzyl alcohol, polyethylene glycol, gelatin, carbohydrates (e.g., lactose, amylose, or starch), magnesium stearate, talc, titanium dioxide, silicic acid, viscous paraffin, sesame oil, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, etc. The pharmaceutical preparations are sterilized and, if desired, can be mixed with auxiliaries that do not react detrimentally with the active composition, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, flavoring agents, and / or flavoring substances, etc. They can also be combined with other active agents, such as vitamins, if desired.

[0045] In some embodiments, the dosage form includes instructions for use of such compositions. For parenteral application, in particular, there are injection solutions, sterile solutions, preferably oily or aqueous solutions, further suspensions, emulsions, or intracerebral implants, including suppositories. Ampoules, vials, and injection cartridges are convenient unit dosages. A "unit dosage form" shall mean an entity for single administration. Examples include a single tablet, capsule, dragee, or troche, suppository, or syringe.

[0046] Also, for parenteral application, tablets, dragees, liquids, drops, suppositories, or capsules are particularly suitable. In some cases, syrups, elixirs, etc. can be used, and a sweetened vehicle is employed. Sublingual and buccal forms are also noted.

[0047] Sustained or immediate release compositions can be formulated, for example, in liposomes or in compositions protected by coatings that are differentially degradable by the active ingredient (e.g., by microencapsulation, multilayers coating, etc.). Also, novel compositions can be lyophilized and the resulting lyophilizates can be used, for example, for the preparation of injectable products.

Examples

[0048] The following examples illustrate the use of ANAVEX2-73 in the treatment of patients with Alzheimer's disease or patients showing early signs of Alzheimer's disease. Clinical determination of whether a patient may have Alzheimer's disease or shows early signs of Alzheimer's disease is well known in the art. By way of example, the following references (and all publications cited herein) are hereby incorporated by reference in their entirety: Dementia: From Diagnosis to Management - A Functional Approach 1 st Edition, Psychology Press (February 17, 2009); Clinician’s Guide to Psychological Assessment and Testing: With Forms and Templates for Effective Practice 1 st Edition, Springer Publishing Company (September 18, 2012); Neurodegener. Dis. Manag. 5(3), 191 - 201(2015); Artif. Intell. Med. 64(1), 59 - 74(2015); Clin. Chem. 60(12), 1585 - 1586(2014); and Metabolism 64(3 Suppl 1), S47 - 5 0(2014).

[0049] Example 1 A 63-year-old male shows early signs of Alzheimer's disease. This male is orally administered a pharmaceutical composition containing 30 mg of ANAVEX2-73 according to an intermittent dosing regimen that includes daily administration for 10 days (dosing period) for each cycle and then 10 days without administration (drug holiday period). The patient is administered 30 mg of ANAVEX2-73 for 6 months according to the intermittent dosing regimen. The patient's loss of cognitive function stabilizes during this period.

[0050] Example 2 A 58-year-old male shows signs of early-onset Alzheimer's disease. This male is orally administered a pharmaceutical composition containing 50 mg of ANAVEX2-73 according to an intermittent dosing regimen that includes daily administration for 10 days (dosing period) for each cycle and then 20 days without administration (drug holiday period). The patient's loss of cognitive function stabilizes during this period.

[0051] Example 3 A 60-year-old female shows signs of early-onset Alzheimer's disease. This female is intravenously administered 3 mg of ANAVEX2-73 for 1 year according to an intermittent dosing regimen that includes daily administration for 5 days (dosing period) for each cycle and then 20 days without administration (drug holiday period). The patient's loss of cognitive function stabilizes during this period.

[0052] Example 4 A 55-year-old male shows signs of early-onset Alzheimer's disease. This male is intravenously administered 5 mg of ANAVEX2-73 for 1 year according to an intermittent dosing regimen that includes daily administration for 14 days (dosing period) for each cycle and then 7 days without administration (drug holiday period). The patient's loss of cognitive function stabilizes during this period.

[0053] Example 5 A 64-year-old woman shows early signs of Alzheimer's disease. This woman is orally administered a pharmaceutical composition containing 50 mg of ANAVEX2-73 according to an intermittent dosing regimen that includes daily dosing for 14 days (the dosing period) for each cycle and then 7 days without dosing (the withdrawal period). The patient is administered 50 mg of ANAVEX2-73 for 6 months according to the intermittent dosing regimen. The patient's loss of cognitive function is stabilized during this period.

[0054] (Appendix) The present disclosure includes the following aspects. <1> A pharmaceutical composition for the treatment of Alzheimer's disease, comprising a therapeutically effective amount of ANAVEX2-73. <2> The pharmaceutical composition according to <1>, wherein the Alzheimer's disease is mild to moderate Alzheimer's disease. <3> The pharmaceutical composition according to any one of <1> to <2>, wherein the ANAVEX2-73 is characterized by the PXRD pattern shown in FIG. 1. <4> The pharmaceutical composition according to any one of <1> to <3>, wherein the ANAVEX2-73 is characterized by the thermogravimetric analysis of FIG. 2a or FIG. 2b. <5> The pharmaceutical composition according to any one of <1> to <4>, wherein the ANAVEX2-73 is characterized by the differential scanning calorimetry analysis of FIG. 3a, 3b, or 3c. <6> The pharmaceutical composition according to any one of <1> to <5>, wherein the ANAVEX2-73 is characterized by the particle shape shown in FIG. 4a, FIG. 4b, or FIG. 4c. <7> The pharmaceutical composition according to any one of <1> to <6>, wherein the ANAVEX2-73 is characterized by the particle size shown in FIG. 4a, FIG. 4b, or FIG. 4c. <8> The pharmaceutical composition according to any one of <1> to <7>, wherein the ANAVEX2-73 is characterized by a particle size between 1 and 50 μm. <9> The pharmaceutical composition according to any one of <1> to <8>, wherein the therapeutically effective amount is about 1 mg to about 60 mg. <10> The pharmaceutical composition according to any one of <1> to <9>, wherein the therapeutically effective amount is about 30 mg to about 50 mg. <11> The pharmaceutical composition according to any one of <1> to <9>, wherein the therapeutically effective amount is from about 3 mg to about 5 mg. <12> The pharmaceutical composition according to any one of <1> to <11>, wherein the pharmaceutical composition is in an oral dosage form. <13> The pharmaceutical composition according to any one of <1> to <12>, wherein the pharmaceutical composition is in an intravenous dosage form. <14> The pharmaceutical composition according to any one of <1> to <13>, further comprising at least one acetylcholinesterase inhibitor. <15> The pharmaceutical composition according to any one of <1> to <14>, wherein the at least one acetylcholinesterase inhibitor is selected from the group consisting of donepezil, galantamine, rivastigmine, or memantine. <16> A method for treating Alzheimer's disease in a subject, comprising administering to the subject the pharmaceutical composition according to any one of <1> to <15>. <17> A method for treating Alzheimer's disease in a subject, comprising administering to the subject a pharmaceutical composition comprising ANAVEX2-73, wherein each cycle comprises (a) a dosing period during which a therapeutically effective amount of the pharmaceutical composition is administered to the patient, and then (b) a drug withdrawal period, and the pharmaceutical composition is administered according to an intermittent dosing regimen of at least two cycles. <18> The method according to <17>, wherein the dosing period and the drug withdrawal period are the same period. <19> The method according to <17>, wherein the dosing period and the drug withdrawal period are different periods. <20> The method according to <17>, wherein the dosing period and the drug withdrawal period are within a range from a lower limit of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, and 14 days to an upper limit of about 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, and 14 days. <21> The method according to <17>, wherein the dosing period is between about 1 day and 12 days, and the drug withdrawal period is between about 1 day and 12 days. <20> The method according to <17>, wherein the dosing period is 12 days and the drug-free period is 12 days. <21> The method according to any one of <17> to <20>, wherein the therapeutically effective amount of the pharmaceutical composition is from about 1 mg to about 60 mg. <22> The method according to any one of <17> to <20>, wherein the therapeutically effective amount of the pharmaceutical composition is from about 30 mg to about 50 mg. <23> The method according to any one of <17> to <20>, wherein the therapeutically effective amount of the pharmaceutical composition is from about 3 mg to about 5 mg. <24> The method according to any one of <17> to <20>, wherein the pharmaceutical composition is administered orally. <25> The method according to any one of <17> to <20>, wherein the pharmaceutical composition is administered intravenously. <26> The method according to <17>, wherein the pharmaceutical composition is the pharmaceutical composition according to any one of <1> to <16>. <27> The method according to any one of <17> to <25>, wherein the pharmaceutical composition is the pharmaceutical composition according to any one of <1> to <16>.

Claims

1. A pharmaceutical composition for the treatment of early-onset Alzheimer's disease in a subject in need thereof, comprising a therapeutically effective amount of Anavex 2-73, which is characterized by crystalline forms with PXRD peaks where the 2θ values are substantially 11.86, 12.85, 13.66, 14.14, 16.12, 16.64, 19.24, 20.54, 21.59, 22.16, 23.36, 27.09, 27.50, 28.20, 28.79, 29.83, 31.57, 32.09, 33.01, and 33.68, wherein the therapeutically effective amount of Anavex 2-73 is from 30 mg to 50 mg, and the pharmaceutical composition is administered to the subject according to an intermittent dosing regimen of at least two cycles, including (a) a dosing period during which the pharmaceutical composition is administered to the subject and (b) a subsequent drug withdrawal period.

2. The pharmaceutical composition according to claim 1, wherein the dosing period and the drug withdrawal period are different periods.

3. The pharmaceutical composition according to claim 1 or claim 2, wherein the dosing period is between 1 day and 12 days and the drug withdrawal period is between 1 day and 12 days.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the subject is an elderly human.

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