ANAVEX2-73 for the treatment of Alzheimer's disease

Abstract

This invention provides pharmaceutical compositions and therapeutic methods for the treatment of Alzheimer's disease. [Solution] A composition and method comprising ANAVEX2-73 for the treatment of Alzheimer's disease. A method for treating Alzheimer's disease using a pharmaceutical composition comprising ANAVEX2-73 according to an intermittent drug administration regimen.

Description

[Technical Field]

[0001] This disclosure relates to pharmaceutical compounds and pharmaceutical compositions for the treatment of Alzheimer's disease. More specifically, this disclosure relates to the use of pharmaceutical compositions comprising ANAVEX2-73 (also known as A2-73) for the treatment of Alzheimer's disease. [Background technology]

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

[0003] [ka]

[0004] The sigma-1 receptor is a chaperone protein in the endoplasmic reticulum (ER) that accompanies the IP3 receptor at the ER-mitochondrial contact site, ensuring appropriate Ca2+ transmission from the ER to the mitochondria. 2+ It ensures signaling. When a cell encounters stress, the ER (Energy Receptor) signals its own overall Ca (Ca) 2+ Under pathological conditions that disrupt homeostasis, the sigma-1 receptor migrates and suppresses apoptosis. As a result, the sigma-1 receptor is a receptor chaperone essential for metabolic regulatory receptor signaling and survival against cellular stress. See Centr.Nerv.Syst.Agents Med.Chem.9(3),184-189(2009).

[0005] It has been reported that ANAVEX2-73 has shown potential neuroprotective properties against amyloid toxicity in mice. Specifically, ANAVEX2-73 is effective against amyloid-beta 25-35 Peptide (Aβ 25-35 It has been reported that intracerebrovascular injection of an oligomeric preparation of ) reduces oxidative stress, caspase induction, cell loss, and learning and memory deficits observed in mice one week later. See J.Psychopharmacol.25(8),1101-1117(2011). More recently, ANAVEX2-73 has been reported to reduce Aβ 25-35 It has been reported that it blocked inducible P-Akt decrease and P-GSK-3β increase, indicating activation in the PI3K neuroprotective pathway. See Neuropsvchopharmacoloav 38,1706-1723(2013). Within the tested dose range, ANAVEX2-73 attenuated tau hyperphosphorylation in physiological epitopes (AT-8 antibody clone) and pathological epitopes (AT-100 clone). In addition, ANAVEX2-73 attenuated Aβ 25-35 Inducible endogenous Aβ 1-42 It has also been reported that it can reduce sowing.

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

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

[0008] Furthermore, ANAVEX2-73 includes pharmaceutical compositions characterized by the particle shape or size shown in Figure 4a, Figure 4b, or Figure 4c. Specific references are given for particle sizes between 1 and 50 μm.

[0009] The known effective therapeutic dose of ANAVEX2-73 is approximately 1 mg to 60 mg, particularly 30 mg to 50 mg. Furthermore, an effective therapeutic dose of approximately 3 mg to 5 mg is known, especially for intravenous administration. An oral dosage form is also known.

[0010] Furthermore, the regimen may include at least one acetylcholinesterase inhibitor and combination doses, particularly donepezil, galantamine, rivastigmine, or memantine.

[0011] This disclosure envisions a method for treating Alzheimer's disease in a subject, comprising administering the aforementioned pharmaceutical compositions and combinations to the subject.

[0012] The intended dose regimen comprises administering a pharmaceutical composition containing ANAVEX2-73 to a subject according to an intermittent dosing regimen of at least two cycles, each cycle comprising (a) a dosing period in which a therapeutically effective dose of the pharmaceutical composition is administered to the subject, and (b) a rest period thereafter. In some embodiments, the dosing period and the rest period may be of the same length or of different lengths.

[0013] It should be noted that the duration of medication and the rest period are within the range from a lower limit of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 days to an upper limit of approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, and 14 days. Furthermore, durations of medication and rest periods between approximately 1 and 12 days are also known, particularly those with a 12-day duration of medication and a 12-day rest period. Such regimens are useful when the therapeutic effective dose of the ANAVEX2-73 pharmaceutical composition is approximately 1 mg to 60 mg, especially 30 mg to 50 mg, and are particularly suitable for oral dosage forms. Furthermore, dosages of approximately 3 mg to 5 mg of ANAVEX2-73, particularly for intravenous administration, are also being considered.

[0014] To illustrate the forms in which the advantages and features of this disclosure can be obtained, refer to the embodiments of this disclosure illustrated in the accompanying drawings. Understanding that these drawings only illustrate exemplary embodiments of this disclosure and should not be considered to limit the scope of this disclosure, the principles of this specification are described and explained more specifically and in detail through the use of the following accompanying drawings. [Brief explanation of the drawing]

[0015] [Figure 1] Figure 1 shows the powder X-ray diffraction (PXRD) pattern of ANAVEX2-73 according to an embodiment of the present disclosure. [Figure 2a] Figure 2a shows the thermogravimetric analysis (TGA) of ANAVEX2-73 according to an embodiment of the present disclosure. [Figure 2b] Figure 2b shows the thermogravimetric analysis (TGA) of ANAVEX2-73 according to an embodiment of the present disclosure. [Figure 3a] Figure 3a shows differential scanning calorimetry (DSC) analysis data of the ANAVEX2-73 according to an embodiment of the present disclosure. [Figure 3b] Figure 3b shows differential scanning calorimetry (DSC) analysis data of the ANAVEX2-73 according to an embodiment of the present disclosure. [Figure 3c] Figure 3c shows differential scanning calorimetry (DSC) analysis data of ANAVEX2-73 according to an embodiment of the present disclosure. [Figure 4a] Figure 4a shows SEM micrographs demonstrating the size and morphology of ANAVEX2-73 particles according to an embodiment of the present disclosure. [Figure 4b] Figure 4b shows SEM micrographs demonstrating the size and morphology of ANAVEX2-73 particles according to an embodiment of the present disclosure. [Figure 4c] Figure 4c shows SEM micrographs demonstrating the size and morphology of ANAVEX2-73 particles according to an embodiment of the present disclosure. [Figure 5] Figure 5 is a plot exemplifying P300 ERP wave data (at baseline and on day 36 after an on-off-on ANAVEX2-73 dosing regimen) from 12 patients, in comparison with a healthy control group. [Figure 6] Figure 6 exemplifies P300 amplitude data (at baseline and on day 36 after an on-off-on ANAVEX2-73 dosing regimen) from 12 patients, in comparison with a healthy control group. [Figure 7] Figure 7 exemplifies P300 amplitude data (on day 36 (1 month) after an on-off-on ANAVEX2-73 dosing regimen) from 12 patients, in comparison with donepezil and historical control data. [Figure 8] Figure 8 is a plot exemplifying P300 electroencephalogram (EEG) alpha wave peak frequency (PAF) data (at baseline and on day 36 after an on-off-on ANAVEX2-73 dosing regimen) from 12 patients, in comparison with a healthy control group. [Figure 9] Figure 9 exemplifies an electroencephalogram (EEG) power spectrum showing an alpha wave peak frequency (PAF). DETAILED DESCRIPTION OF THE INVENTION

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

[0017] While one or more exemplary implementations of the embodiments are illustrated below, it should be understood from the outset that the methods of this disclosure can be implemented using a variety of techniques. This disclosure is not to be limited in any way to the exemplary implementations, drawings, and techniques illustrated herein, and may be modified along with the full scope of their equivalents within the scope of the accompanying claims.

[0018] In the following description and claims, the terms “including” and “comprising” are used in open-ended form and should be interpreted as “including, but not limited to.” Various features described in more detail below will be readily apparent to those skilled in the art by reading the embodiments for carrying out the subsequent invention using this disclosure and referring to the accompanying drawings.

[0019] This disclosure relates, in general, to pharmaceutical compounds and pharmaceutical compositions for the treatment of Alzheimer's disease. More specifically, this disclosure relates to the use of pharmaceutical compositions containing ANAVEX2-73 for the treatment of Alzheimer's disease.

[0020] According to embodiments of this disclosure, ANAVEX2-73 can be produced by filling an ethyl acetate solution of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine free base with isopropanol. The ethyl acetate is removed by distillation, and the remaining isopropanol solution containing tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine free base is filtered for clarification. 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-furamethaneamine, tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride (ANAVEX2-73), is isolated by filtration and dried under vacuum at 55°C for 3 days. The resulting ANAVEX2-73 was characterized by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM), as shown in Figures 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 electron tube voltage and amperage were set to 40 kV and 40 mA, respectively. The settings for the divergence slit and anti-scattering slit were variable for illumination of a 20 mm sample area. Each sample was scanned with a step size of 0.02° between 5° and 40° at 2θ. The measurement time per step was 2 seconds. The instrument was pre-calibrated using a silicon standard. As shown in Figure 1, the PXRD indicates 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 thermogravimetric analysis (TGA) data of ANAVEX2-73 according to embodiments of this disclosure. The weight loss of the sample was measured as a function of temperature using the Thermal Advantage TGA Q5000IR (TA instrument) module. The sample (approximately 7.8 mg) was placed on a platinum pan (100 μL) and heated from 25° to 350° under nitrogen purging at a heating rate of 10°C / min. As shown in Figures 2a and 2b, the TGA (and derivative of weight change) curves show a slight weight change around 80°C, followed by a sustained weight loss from 150°C to 275°C in two main steps (the first step being approximately 29% at 228°C). The initial weight loss may be due to the evaporation of adsorbed water or solvent during crystallization, while the later weight change may be due to the decomposition of an impure solid phase (or impurities) followed by the melting and decomposition of ANAVEX2-73.

[0023] Figures 3a, 3b, and 3c show differential scanning calorimetry (DSC) data for the ANAVEX2-73 according to an embodiment of the present disclosure. 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. 1-2 mg of sample was accurately weighed and placed in an unsealed aluminum pan, then compressed. The sample was scanned from 25°C to 275°C under continuous nitrogen purging (50 mL / min) at a heating rate of 10°C / min. As shown in Figures 3a-3c, the DSC thermograms show that endothermic events began at approximately 80°C (mild) and 115°C (extensive), followed by an exothermic peak and a severe endothermic event at 227°C. The DSC analysis appears to be consistent with the TGA analysis, suggesting that the compound underwent molten decomposition. However, it is possible that decomposition of the surrounding major phases began before moltenness.

[0024] Figures 4a, 4b, and 4c show scanning electron microscope (SEM) images demonstrating the particle size and morphology of ANAVEX2-73 according to embodiments of this disclosure. The particle size and morphology were investigated using a Philips XL30 (Netherlands) scanning electron microscope (SEM). The sample was sprinkled onto double-sided adhesive tape fixed to an aluminum stub, and then gold sputter coating was performed in an argon atmosphere at mA for 40 seconds. The particles were analyzed at suitable acceleration voltages and magnifications. Representative micrographs were taken, and particle sizes were estimated. SEM images demonstrated that ANAVEX2-73 is mainly composed of aggregated crystals (from prismatics to blocks), with a main particle size distribution of 1 to 50 μm.

[0025] The safety of ANAVEX2-73 has been demonstrated in a randomized, placebo-controlled, single-dose escalation phase 1 trial 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-dose oral dose escalation of ANAVEX2-73 at 1 mg, 10 mg, 30 mg, 40 mg, 50 mg, and 55 mg was safe and well-tolerated. No serious adverse events occurred. Based on the frequency and severity of adverse events (TEAEs) occurring in the untreated environment, the maximum tolerable dose (MTD) and minimum tolerable 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 observed in blood pressure, resting heart rate, or other clinical parameters (e.g., vital signs and 12-lead electrocardiogram (ECG)). No clinically significant changes were observed in the QT interval or QTcB. The pharmacokinetics of ANAVEX2-73 were found to be suitable for daily oral administration.

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

[0027] The cognitive effects of ANAVEX2-73 administration were evaluated using resting electroencephalogram (EEG) activity and event-related potentials (EEG / ERPs). As recorded by EEG, event-related potentials (ERPs) are voltage changes that are time-locked to some physical or mental occurrence of ongoing electrical brain activity. Event-related potentials (ERPs) provide a sensitive and reliable measure of cognitive effects associated with early Alzheimer's disease. ERPs have been found to reflect and alter well-characterized brain responses to perceptual, motor, and cognitive events in Alzheimer's disease patients where the very early stages of the disease have begun. See, for example, New Encycl. Neurosci., Oxford Academic Press, pp. 13-18 (2009). For example, ERP tests performed on young, asymptomatic individuals carrying mutations in the presenilin-1 and amyloid precursor protein genes show significant changes in ERP patterns years before the onset of behavioral symptoms and Alzheimer's disease. See, for example, Neurology 73, 1649-1655 (2009); Neurology 77, 469-475 (2011). Furthermore, 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 patients with Alzheimer's disease, ERP markers of cognitive function gradually change. See, for example, 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 enhancers currently used to treat Alzheimer's disease. For example, the ERP scale has demonstrated to be a reliable tool for assessing cognitive responses to cholinesterase inhibitors (e.g., donepezil), and the effect of memantine, a selective NMDA antagonist, as measured by ERP, has been shown to correlate with changes in Mini-Mental State Examination (MMSE) scores.For example, see 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, the auditory P300 component of the ERP is widely applied in the study of age-related cognitive decline because it is thought to reflect attentional and memory processes. Auditory P300 is a positive amplitude that occurs approximately 300 ms after stimulus generation. 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 in the central frontal region and a later P3b component (hereinafter "P300") that is maximal in the posterior scalp region. 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 P300 amplitude data correlated with ADAS-Cog and MMSE data from the same patients. See Clin. Neuropharmacol. 25(4), 207-215 (2002).

[0029] The subjects were tested using a three-stimulus oddball paradigm. The stimuli consisted of a standard tone (1000 Hz), a target tone (2000 Hz), and an unexpected distracting tone (white noise), which were played with probabilities of 0.75, 0.15, and 0.10. The tones were presented in a pseudo-random order so that the target tone and distracting tone were not presented consecutively. Subjects were instructed to respond to the target stimulus by pressing a button with their dominant hand. In each test, 300 to 400 stimuli were presented to both ears through in-ear headphones 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 was recorded from seven electrode sites (Fz, Cz, Pz, F3, P3, F4, and P4) using the COGNISION® headset (Neuronetrix) according to the international 10-20 protocol. The electrodes referenced were the averaged mastoid (M1, M2) and Fpz, which served as common electrodes. The headset used for data acquisition was verified to provide reliable ERP recordings when the skin contact impedance was less than 70 kΩ. Impedance was automatically checked for all electrodes after each target or interfering tone and maintained below this limit throughout each test. Data were collected 240–1,000 ms before and after stimulation, digitized at 125 Hz, and band-pass filtered from 0.3–35 Hz. An automated artifact threshold detection limit of ±100 μV was set for the tests. Trial sets (epoch sets) of deviant tones with artifacts exceeding the threshold and the preceding standard tone were excluded in real time and immediately repeated.

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

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

[0032] [Table 1]

[0033] Table 2 demonstrates the effect of the ANAVEX2-73 dose regimen on cognitive performance in 12 subjects at baseline and at day 36 after the ANAVEX2-73 on-off-on dose regimen, measured using the target detection task in the ERP study. Table 2 also shows data for the target detection task in a healthy control group. As shown in Table 2, button-pressing accuracy improved in subjects receiving the ANAVEX2-73 dose regimen compared to baseline. In addition, median reaction time and false alarm percentage decreased in subjects treated with ANAVEX2-73 compared to baseline. The healthy control group performed better than the ANAVEX2-73 subjects at day 36 in both button-pressing accuracy and median reaction time. However, the ANAVEX2-73 subjects performed better than the healthy control group in false alarm percentage at day 36. The data shown in Table 2 demonstrate that ANAVEX2-73 administration improves both accuracy and reaction time in subjects performing the target detection task in the ERP study.

[0034] [Table 2]

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

[0036] Figure 8 is a plot illustrating electroencephalogram (EEG) alpha wave peak frequency (PAF) data from 12 patients (at baseline and 36 days after the ANAVEX2-73 on-off-on dosing regimen) compared to a healthy control group. EEG alpha wave peak frequency (PAF) (measured in Hz) is a unique, individual "fingerprint" associated with cognitive performance and reflecting characteristics or states of cognitive readiness. Alzheimer's disease patients have been shown to have lower PAFs compared to controls of the same age. PAF measures the discrete frequency with the highest amplitude within the alpha range. For example, Figure 9 illustrates an EEG power spectrum showing alpha wave peak frequency (PAF). As shown in Figure 8, the measured PAFs in subjects receiving the ANAVEX2-73 dose regimen were higher than baseline PAF measurements. Figure 8 demonstrates that ANAVEX2-73 can shift a subject's PAF compared to the measured baseline PAF. In addition, ANAVEX2-73 was found to improve P300 signaling in 10 out of 12 patients (83%) studied.

[0037] The results of the on-off-on dosing regimen for ANAVEX2-73 in 12 subjects, shown in Figures 5-9, were achieved without any dose optimization. Preliminary measured changes in the Mini-Mental State Examination (MMSE) and Cogstate scales are consistent with the observed trend of 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 are scheduled to be studied during the remainder of the Phase 2a clinical trial. The Phase 2b clinical trial is ongoing with an additional 26-week extension of once-daily oral dose of ANAVEX2-73.

[0038] According to this disclosure, ANAVEX2-73 can be administered according to an intermittent dosing schedule in which the subject receives ANAVEX2-73 for a certain number of days, followed by a period of days during which ANAVEX2-73 is not administered, and then administration of ANAVEX2-73 is resumed. In some cases, the administration period is the same as the non-administration period. In other cases, the administration period may be longer or shorter than the administration period. In some cases, ANAVEX2-73 is administered according to an intermittent dosing regimen of at least two cycles, each cycle comprising (a) a dosing period in which a therapeutically effective dose of ANAVEX2-73 is administered to the patient, and the following (b) a rest period. In one embodiment, the dosing period is 1 to 12 days, and the rest period is 1 to 12 days. In other embodiments, the drug administration period may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In some embodiments, the drug-free period may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.

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

[0040] In one embodiment, the intermittent dose schedule described herein includes an oral dosage form containing about 30 mg of ANAVEX2-73. In another embodiment, the intermittent dose schedule described herein includes an oral dosage form containing about 50 mg of ANAVEX2-73. In yet another embodiment, the intermittent dose schedule described herein includes an oral dosage form containing ANAVEX2-73 between about 30 mg and 50 mg. In yet another embodiment, the intermittent dose 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 forms described herein may range from the lower limit of approximately 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg of ANAVEX2-73 to the upper limit of approximately 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, and 30 mg of ANAVEX2-73.

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

[0043] All figures and ranges disclosed above are subject to some degree of change. Wherever a numerical range with lower and upper limits is disclosed, any number and any range included within that range shall be specifically disclosed. More specifically, any range of values ​​disclosed herein (in the form of “approximately a to approximately b,” or similarly “approximately a to b,” or similarly “approximately a to b”) should be understood to indicate any number and range that are included within a broader range of values.

[0044] The compositions disclosed herein, individually or in combination, are used in combination with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carriers, that do not react adversely with the active composition and are suitable for parenteral, enteral (e.g., oral or inhalation), or topical application. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohols, 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, fragrance oils, fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidone. Pharmaceutical preparations are sterilized and, if desired, can be mixed with adjuvants that do not react adversely with the active composition, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, colorants, flavorings, and / or flavoring substances. These 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 composition. For parenteral administration, there are injectable solutions, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or intracerebral implantation preparations, including suppositories. Ampoules, vials, and injection cartridges are convenient unit doses. "Unit dosage form" means a single-dose entity. Examples include single tablets, capsules, sugar-coated tablets, or lozenges, suppositories, or syringes.

[0046] Furthermore, tablets, sugar-coated tablets, liquids, drops, suppositories, or capsules are particularly suitable for parenteral administration. If necessary, syrups, elixirs, etc., can be used, and sweetened vehicles are employed. Sublingual and buccal forms are also noteworthy.

[0047] Sustained or immediate release compositions can be formulated, for example, as liposomes or those in which the active ingredient is protected by a differentially degradable coating (for example, by microencapsulation, multilayer coating, etc.). Alternatively, the novel composition can be lyophilized, and the obtained lyophilized product can be used, for example, for the preparation of injectable products. [EXAMPLES]

[0048] The following examples demonstrate 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 is showing early signs of Alzheimer's disease is well known in the art. By way of example, the following reference (and all publications cited herein) are incorporated herein by reference in their entireties: 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), S47-50(2014).

[0049] Example 1 A 63-year-old male exhibits 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, each cycle consisting of daily administration for 10 days (dosing period) followed by a 10-day rest period. The patient receives 30 mg of ANAVEX2-73 for 6 months according to this intermittent dosing regimen. The patient's cognitive decline remains stable during this period.

[0050] Example 2 A 58-year-old male exhibits 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 consisting of daily administration for 10 days (medication period) followed by a 20-day rest period. The patient's cognitive decline remains stable during this period.

[0051] Example 3 A 60-year-old woman presents with signs of early-onset Alzheimer's disease. She will receive 3 mg of ANAVEX2-73 intravenously for one year, following an intermittent dosing regimen consisting of daily administration for 5 days (medication period) followed by a 20-day rest period. The patient's cognitive decline will remain stable during this period.

[0052] Example 4 A 55-year-old male exhibits signs of early-onset Alzheimer's disease. This male will receive 5 mg of ANAVEX2-73 intravenously for one year, following an intermittent dosing regimen consisting of daily administration for 14 days (medication period) followed by a 7-day rest period. The patient's cognitive decline will remain stable during this period.

[0053] Example 5 A 64-year-old woman is showing early signs of Alzheimer's disease. This woman will be orally administered a pharmaceutical composition containing 50 mg of ANAVEX2-73 according to an intermittent dosing regimen, each cycle consisting of daily administration for 14 days (dosing period) followed by a 7-day rest period. The patient will receive 50 mg of ANAVEX2-73 for 6 months according to this intermittent dosing regimen. The patient's cognitive impairment will stabilize during this period.

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

Claims

[Claim 1] A pharmaceutical composition for the treatment of Alzheimer's disease, containing a therapeutically effective amount of ANAVEX2-73.

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