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Like many of the smart science types on the board, I am extremely pleased with what the company disclosed today. What's not to like about:
- Confirmed safety & dose-dependent target engagement with SIGMAR1 using PET
- Exome sequencing showed response-linked gene variants using formal concept analyses (FCA)
- Identified SIGMAR1/COMT variants shown to be linked to limited clinical response
- Targeted therapy benefit on WT variants is expected for about 80% of patient population
- Confirmation through high SIGMAR1 RNA expression levels linked to clinical response
- Results consistent across cognition (MMSE) and activities of daily living (ADCS-ADL)
- Identified actionable genetic variants support enrichment with genetic biomarkers in the
clinical development of ANAVEX®2-73
I had no expectation of significant market reaction, up or down, thus no disappointment for me with today's price action. Actually, I see the drop to $2.65 and subsequent recovery to 3 as a bullish signal going forward. Relatively low volume attributable to momentum traders expecting a pop bailing out disappointed, and, unfortunately, some fellow retail longs also taken down by MM's scooping up stop loss positions. No material institutional participation today in my opinion.
The reaction to BIIB after hours (following presentation at AAIC) confirms what many here have pointed out as not impressive results with their/Alsai's drug.
The safety and efficacy of Anavex 2-73 continues to be verified. Meaningful, positive or negative, PPS will only come with further trial results being released or announcement of partnership consummation.
Make your own judgement and GL whichever road you travel.
Lima,
Your girls will not have to worry about money for life if you hole what you currently have in AVXL. I have my money where my mouth is. Confident for long-term, not worried about immediate return In fact I expect that price will linger ~3 to 5 until trial results or partnership announcement.
GL
"The trial of drug Anavex 2-73 has already had some success with patients’ personalities restored, skills they had not been able to use for years returned and many of the memories that had been locked away, now remembered.
On average the group remained stable and did not decline, which was expected with a group of 32 Alzheimer’s patients.
Anavex 2-73 is a drug designed to not only relieve the symptoms of Alzheimer’s Disease, but also slow the progression. It works by blocking proteins in the brain, which prevents the oxidative stress and cell death seen in the brains of people Alzheimer’s Disease.
The Phase 2 trial has assessed 32 people with mild to moderate Alzheimer’s Disease, with some very positive results. One of the test participants can now play piano again, while another – award-winning artist Valerie Lynch, says the drug has allowed her to be able to paint again. Others experienced an improvement in memory, mood and humour.
The goal of this particular trial was to determine the maximum tolerated dose of the drug, while also assessing participant’s resulting cognitive skill, blood results, and brain scans
Quote:
"It is interesting to me that one poster is up on the AAIC website for AVXL and the other one is to be released on the day of the conference"
Late breaking information cannot be made public prior to being presented at the conference. If so, it no longer qualifies as late braking. Make your own conclusion.
This comment was posted after the article in AU this morning. Could Robert have direct contact with the patients?
Robert July 13, 2018 at 12:43 pm #
This drug is going to revolutionize the way we treat and cure Alz. How do I know? To give a hint: The piano player and the painter. Comparing the before and after personality is like living in the dark and looking at the early morning sunshine. Get ready for some real thrilling results mid way during the trial, especially as the participants are going to be selected and targeted by the drug using precision medicine.
Thank you!
Thanks for the write up. It all makes sense and lays out the case for why this should not be viewed as a negative.
What remains now is successful trials execution and hopefully results that lead to commercialization, which may still require additional capital through share sales or partnership.
GLTA
To hopefully end this silly discussion. I admit it, the pro-Anavex cabal paid for it. There you have it. Report us.
For those who might have missed it, here is the full article from down under. I bolded some of the key points which I found different than in previous company PR's or comments from those associated with the story. The statements from Dr.McF appear to me more assertive (less legally cautious) than they, Anavex and the lead researcher, have previously made.
Obviously there are not gurantees but approval to proceed with this phase of the trials is a giant step in the right direction. Results do not need to be perfect for A-273 to become the new SOC for AD, but, as many of the science savy posters here have been telling us about, also likely to become the magic pill to be used as a profilactic and treatment for many other neroulogical disorders.
As a human being, I hope this comes to fruition for the health benefit of us all. As an investor, I am betting big on riping the rewards of being early to the table to what could become the Amazon of bio investmens.
GLTA longs. For those on the other side, it is still time to change your position and join the winning team. We welcome you.
-----------------------
ALZHEIMER’S DRUG HOPE
Local Alzheimer’s trial
Herald Sun4 Jul 2018BRIGID O’CONNELL brigid.oconnell@news.com.au VISIT anavexaustralia.com PHONE (02) 8437 7355
VICTORIAN Alzheimer’s sufferers will be hand-picked to trial an experimental drug that has already “woken up” some patients with dementia.
Genetic testing will be used to select 450 people to trial the drug, Anavex 2-73, which has led to dramatic improvements patients.
GENETIC testing will be used to select Victorian Alzheimer’s disease sufferers to take an experimental drug that has already “woken up” some patients with dementia.
The Melbourne-led international trial will give the drug, Anavex 2-73, to 450 patients who have the disease in a mild to moderate form and who are believed likely to best respond to the treatment.
The cognition of most of the 32 patients who took part in the most recent trial of the drug remained stable, when it had been expected to decline.
But there were dramatic improvements in the mood and memory of a group of six “super responders”, some of whom were able to play the piano or take up golf again, or resume painting.
At their request, the drug trial was extended for a further two years.
Lead researcher Associate Professor Steve Macfarlane, of HammondCare’s Dementia Centre, said the pharmaceutical company that made Anavex 2-73 had spent the past year working out why some people had a better response to the drug.
He said genetic analysis predicted that patients who received a higher dose and who had a particular common gene variant would respond well.
“The big change, since a lot of Alzheimer’s trials have failed, is that the industry has started to look at subgroups of people with Alzheimer’s,” Prof Macfarlane said.
“They all have the build-up of the two proteins, amyloid and tau (that are associated with the disease).
“But there is lots of variation in the inflammation, disruption to the waste cells functions and calcium imbalance.
“Recruiting the right people into the right trial for a particular drug is going to be more and more important, and that’s the step we’re taking with this current trial.”
Associate Prof Macfarlane said it was believed the drug, which is about to be tested in Parkinson's patients with dementia, worked not only by removing the build-up of abnormal proteins but by addressing other damaging processes in the brain.
“It doesn’t buy into the old argument, that has been around in the field (of research into Alzheimer’s disease) for years, as to whether it’s the amyloid or the tau that’s the cause,” he said.
If the latest drug trial is successful, researchers say it would lead the case for the treatment’s approval by the US drug agency, which could then lead to its being approved for use worldwide.
Investor, good find. Thanks for sharing.
For the scientists, details about the patent narrative. Thanks for providing interpretation/translation for the rest of us.
Claims
1 . A pharmaceutical dosage form of T Anevex2-73 substantially free of Anavex2-73 © .
2. The pharmaceutical dosage form of Claim 1 comprising from about 0.5 to about 100 mg of ©Anevex2-73.
3. The pharmaceutical dosage form of Claim 2 comprising from about 1 to about 20 mg of ©Anevex2-73.
4. This invention further includes a method of therapeutic treatment of a subject in need of enhanced stimulation of sigma 1 receptors by administering a therapeutically effective dose of pharmaceutical preparation comprising T?2-73 substantially free of ©A2-73.
5. The method of Claim 4 wherein said therapeutically effective amount comprises about 0.5 to about 100 mg of ©Anevex2-73.
6. The method of Claim 5 wherein said therapeutically effective amount comprises from about 1 to about 20 mg of ©Anevex2-73.
7. A method of treating Alzeheimer's disease in a subject in need of such treatment by the method of administering a therapeutically effective amount of ©A2-73 substantially free of ©A2-73.
8. The method of Claim 7 wherein said therapeutically effective amount comprises about 0.5 to about 100 mg of ©Anevex2-73.
9. The method of Claim 8 wherein said therapeutically effective amount comprises from about 1 to about 20 mg of ©Anevex2-73.
10. A method of classifying cells as to sigma receptor type by the method of exposing said cells to a detectable amount of ©A2-73 substantially free of ©A2-73 and determining the level of sigma receptor binding.
Description: ENANTIOMERS OF TETRAHYDRO-N,N-DIMETHYL-2,2-DIPHENYL-3-FURANMETHANAMINE (ANAVEX2-73) AND USE THEREOF IN THE TREATMENT OF ALZHEIMER'S DISEASE AND OTHER DISORDERS
MODULATED BY THE SIGMA 1 RECEPTOR
Field of the Invention
A pharmaceutical preparation comprising ©A2-73 substantially free of © A2- 73. This invention further includes a method treating Alzheimer's disease in a subject in need of such treatment by the method of administering a therapeutically effective amount of ©A2-73 substantially free of ©A2-73.
This invention yet further includes a method of classifying cells as to sigma receptor type by the method of exposing said cells to a detectable amount of ©A2-73 substantially free of ©A2-73 and determining the level of sigma receptor binding.
Background of the Invention
Two sigma receptor subtypes have been identified based on their
pharmacological profile. The sigma-1 (s-1 ) receptor has been cloned (Hanner et al., 1996). The sigma-2 receptor has been reported as a separate molecular entity (Langa et al., 2003). The sigma-1 receptor has been reported as having high affinity for positive isomer of bezomorphas such as (+)-pentazocine and (+)-SKF-10,047. The sigma-2 receptor has been reported as having a high affinity for ibogaine (Vilner and Bowen, 2000). In particular, sigma 1 receptor agonists have also been has been reported as having antidepressant effects. In this regard, Sigma 1 receptor ligands show clear antidepressant effects in several animal models. By way of example, the selective sigma 1 receptor agonists (+)-pentazocine, (+)-SKF-10,047, igmesine, OPC14523, DTG or SA4503 reduce the immobility time in the forced swim test or are active in the tail suspension test (Ukai et al. 1998, Matsuno et al., 1996, Tottori et al. 1997, Kinsora et al. 1998). U.S. Pat. No. 5,034,419 describes N-cycloalkylalkylamines, which is also reportedly a sigma 1 receptor agonist.
The sigma-1 receptor, first reported cloned in 1996, is a single polypeptide transmembrane protein comprising 223 amino acids. It is mainly located on the endoplasmic reticulum membrane. The sigma-1 receptor is reported to be expressed in ocular tissues including the cornea, lens and retina. It has also been reported to play a role in cell survival (Wang et al., Exp Cell Research, Vol. 312(8):1439-1446, 2006); Hayashi et al., Cell, Vol. 131 (3):596-610, November 2007; Jiang et al., IOVS, Vol.
47(12):5576-5582, 2006). Sigma receptor ligands have been reported to be neuroprotective. The sigma receptor ligand opipramol was reported as protected against ischemia in gerbils. In addition, other sigma ligands, including BMY-14802, caramiphen and haloperidol, exhibited properties in in vivo models that are consistent with protective effects
(Pontecorvo et al., Brain Research Bulletin, Vol. 26:461 -465, 1991 ). Several sigma ligands were reported to inhibit ischemia-induced glutamate release from hippocampal slice preparations in vitro (Lobner et al., Neuroscience Letters, Vol. 1 17:169-174, 1990). It has also been reported that the Sigma-1 receptor agonist (+)-pentazocine can protect the retinal cells against stress (Dun et al., IOVS, Vol. 48(10):4785-4794, 2007; Smith et al., IOVS, Vol. 49(9):4154-4161 , 2008).
Ihiguez et al., has reported that treatment of Jurkat T cells with sigma-2 (s-2) agonists decreased the induction of the expression of Interleukin (IL)-2, Tumor necrosis factor (TNF)-a, and Cyclooxygenase (COX)-2 by activated T cells in a dose-dependent manner. ("Inhibitory effects of sigma-2 receptor agonists on T lymphocyte activation," Front. Pharmacol, 13 March 2013 j doi: 10.3389/tphar.2013.00023.) Reported effects take place at the transcriptional level since s-2 agonists BD-737 and CB-184 diminished the activity of the promoters of those genes. Those immunosuppressive effects could be attributable to interference with transcription factor activation. Induced transcription mediated by Nuclear factor (NF)-KB or Nuclear Factor of Activated T cells (NFAT) was inhibited by s-2 agonists. The authors suggested that these effects were specific for s-2 agonists as no significant effects on T cell activation by s-1 ligands PRE-084 [2-(4- Morpholinethyl)1 Phenylcyclohexanecarboxylate] and BD-1063 were found. By way of non-limiting example, reported s-2 agonists include CB-64D, CB-184, BD-737, and haloperidol.
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens agonist-mediated responses rather than provoking a biological response itself upon binding to a receptor. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active (orthosteric = right place) site or to allosteric (= other place) sites on receptors, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist-receptor complex, which, in turn, depends on the nature of antagonist-receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptor.
Competitive as to an agonist or antagonists (also known as surmountable) reversibly binds the agonist or antagonist to receptors at the same binding site (active site) as the endogenous ligand or agonist/antagonist, but without activating the receptor. Agonists and antagonists "compete" for the same binding site on the receptor. Once bound, an antagonist will block the opposite functioning molecule from binding. The level of activity of the receptor will be determined by the relative affinity of each molecule for the site and their relative concentrations. High concentrations of a competitive agonist or antagonist will increase the proportion of receptors that the that molecule occupies, higher concentrations of the molecule will be required to obtain the same degree of binding site occupancy. In functional assays using competitive antagonists, a parallel rightward shifts of agonist dose-response curves with no alteration of the maximal response is observed.
The term "non-competitive" (sometimes called non-surmountable antagonists) can be used to describe two distinct phenomena: one in which the agonist or antagonist binds to the active site of the receptor, and one in which the agonist/antagonist binds to an allosteric site of the receptor. While the mechanisms are different in both of these phenomena, they are both called "non-competitive" because the end-results of each are functionally very similar. Unlike competitive, which affects the amount of agonist or antagonist necessary to achieve a maximal response but do not affect the magnitude of that maximal response, non-competitive agonist or antagonists reduce the magnitude of the maximum response that can be attained by any amount of agonist or antagonist. Sigmal - Without being bound by any particular theory it is believed that Sigmal receptors regulate neurotransmission via the NMDA receptor and the release of neurotransmitters such as dopamine and acetylcholine. It is thus proposed that the sigmal receptors play a role in learning and memory as well as in certain
neuropsychiatric disorders.
Antagonists - Sigmal antagonists are believed useful in treating schizophrenic associated symptoms of blunted affect, anhedonia, avolition or apathy, and alogia.
Sigmal antagonists are also believed useful in attenuating orofacial dyskinesias and dystonic reactions associated as side-effects of physochotropic drugs. Sigmal antagonists are also believed useful as cancer anti-proliferatives.
Agonists - Sigmal agonists are useful as antidepressants. Particular note is made of the utility of a Sigmal agonist with low Sigma2 affinity in treating ischemic brain/neuronal injury such as from focal ischemia. Sigmal agonists are also believed useful in improving cognitive impairment such as exhibited with impaired
neurotransmitter function {e.g., acetylcholine) as well as age associated cognitive impairment, and anxiety associated impairment (including pregnancy stress resulting in learning deficits of offspring).
Sigma2 - Sigma2 receptors are believed useful as a target for motor function and cancer treatment. Sigma2 receptors are expressed in high densities in rapidly proliferating cancer cells.
Antagonists - Sigma2 antagonists are useful in the treatment of irreversible motor side effects such as those reported after the long-term administration of typical antipsychotic drugs. Reference is made to Sigma Receptors: Chemistry. Cell Biology and Clinical
Implications, Eds Matsumoto et aL, Springer; 2007 edition (November 16, 2014). The teaching of this publication and all references cited herein are incorporated by reference in their entirety. Additional reference is made to:
Nguyen et ai., "Role of sigma-1 receptors in neurodegenerative diseases," J
Pharmacol Sci. 2015 Jan;127(1 ):17-29; Guo et al., Sigma-2 receptor ligands: neurobiological effects," Curr Med Chem. 2015;22(8):989-1003;
USSN 62/065,833 entitled "A19-144, A2-73 and Certain Anticholinesterase Inhibitor Compositions and Method for Anti-Seizure Therapy," filed October 20, 2014;
Crawford et al., "Sigma-2 Receptor Agonists Activate a Novel Apoptotic Pathway and Potentiate Antineoplastic Drugs in Breast Tumor Cell Lines," Cancer Research, 62, 313-322, January 1 , 2002;
Rossi et al., "A step forward in the sigma enigma: a role for chirality in the sigmal receptor-ligand interaction?" Medicinal Chemistry Communication (Impact Factor: 2.63). 09/2014; 6(1 );
U.S. Pub. No. 201 10206780 entitled "Morphinan modulators of nmda receptors, sigmal receptors, sigma2 receptors, and/or a3b4 nicotinic receptors," to Gant et al., having a priority date of January 6, 2010.
WO2013008044 to Vamvakides et al. entitled "SYNTHESIS OF (+) AND (-) 1 - (5,5-DIPHENYLTETRAHYDROFURAN-3- YL)-N,N-DIMETHYLMETHANAMINE, (+) AND (-) 1 -(2,2-DIPHENYLTETRAHYDROFURAN-3-YL)-N,N- DIMETHYLMETHANAMINE AND (+) AND (-) 1 -(2,2-
DFFHENYLTETRAHYDROFURAN-3-YL)-N-METIHYLMETHANAMINE" sets fort chiral separatory methodology.
U.S. Patent application entitled "ANAVEX2-73 FOR THE TREATMENT OF
ALZHEIMER'S DISEASE" and filed on date even herewith.
U.S. Patent Application entitled "CRYSTAL FORMS OF tetrahydro-N,N-dimethyl-
2,2-diphenyl-3-furanmethanamine hydrochloride, PROCESSES OF MAKING SUCH
FORMS, AND THEIR PHARMACEUTICAL COMPOSITIONS" and filed on date even herewith.
Summary of the Invention
A pharmaceutical preparation comprising ©A2-73 substantially free of ©
A2-73.
This invention further includes a method of therapeutic treatment of a subject in need of enhanced stimulation of sigma 1 receptors by administering a therapeutically effective dose of pharmaceutical preparation comprising T A2-73 substantially free of
©A2-73. Particularly noted is the pharmaceutical preparation of ©A2-73 substantially free of ©A2-73 of from about 0.5 to about 100 mg ©A2-73 and particularly 1 -20 mg.
A method of treating Alzeheimer's disease in a subject in need of such treatment by the method of administering a therapeutically effective amount of T A2-73 substantially free of ©A2-73.
Further noted is a method of classifying cells as to sigma receptor type by the method of exposing said cells to a detectable amount of ©A2-73 substantially free of © A2-73 and determining the level of sigma receptor binding
Detailed Description of the Invention
This invention will be better understood with reference to the following definitions: A. ANAVEX2-73, or A2-73 shall mean tetrahydro-N,N-dimethyl-2,2-diphenyl-
3-furanmethanamine hydrochloride. This is listed in some of the test data as AE 37. A2-73 is a compound which is believed to bind to muscarinic acetylcholine and sigma-1 receptors with affinities in the low micromolar range.
B. ANAVEX19-144 or A19-144 shall mean 1 -(2,2-diphenyltetrahydrofuran-3- yl)-A/-methylmethanamine hydrochloride. A19-144 is a compound which is believed to bind to muscarinic acetylcholine and sigma-1 receptors with affinities in the low micromolar range.
C. ANAVEX1 -41 or A1 -41 shall mean tetrahydro-N,N-dimethyl-5,5-diphenyl- 3-furanmethanamine hydrochloride. This is listed in some of the test data as AE 14. A1 -41 is reported in Villard et al., "Antiamnesic and Neuroprotective Effects of the Aminotetrahydrofuran Derivative ANAVEX1 -41 Against Amyloid b25-35-lnduced
Toxicity in Mice," Neuropsychopharmacoloqy, 1 -15 (2008). D. The term "enantiomer" or "enantiomeric" refers to a molecule that is nonsuperimposeable on its minor image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction and its minor image rotates the plane of polarized light in the opposite direction. E. "Substantially free" as to defining enantiomers ^form absent ^ form or T form absent ©form shall mean less than about 2% (w/w) of the excluded form and preferably less than about 1 % and more preferably less than about 0.5%, and in some cases less than about 0.1 %.
F. "Classifying" cells as to the s 1 or 2 receptor populations shall mean determining the presence and or density of either s 1 or 2 receptors on cell surfaces in a given cell population. Classifying takes advantage of the differential populations of sigma receptors used as biomarkers. Biomarkers are useful as a means to define cell population propensities such as the likelihood of proliferation as to breast cancers. Testing methodology is more fully set forth in the following:
Hashimoto et al., "Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals," Curr Pharm Pes. 2006;12(30):3857-76;
Mach RH et al., "Sigma 2 receptors as potential biomarkers of proliferation in breast cancer," Cancer Res 1997; 57: 156-61 ;
Al-Nabulsi, I et al., "Effect of ploidy, recruitment, environmental factors, and tamoxifen treatment on the expression of sigma-2 receptors in proliferating and quiescent tumour cells," Br J Cancer 1999; 81 : 925-33; and,.
Wheeler KT et al., "Sigma-2 receptors as a biomarker of proliferation in solid tumours," Br J Cancer 2000; 82: 1223-32.
A2-73 T is a selective noncompetitive agonist for s1 receptors and a significantly stronger agonist than A2-73 © .
The pharmacologically active compositions of this invention can be processed in accordance with conventional methods of Galenic pharmacy to produce medicinal agents for administration to subjects, e.g., mammals including humans. Studies were conducted to on the effects of several compounds in various in vitro receptor binding and isolated organ assays.
1. MATERIALS AND METHODS
? ? . ?? VITRO PHARMACOLOGY: Binding Assays
1.1.1. General Procedures rioin
1.1.2. Experimental Conditions
As a general statement, in vitro results showing an inhibition (or stimulation for assays run in basal conditions) higher than 50% are considered to represent significant effects of the test compounds. 50% is the most common cut-off value for further investigation (determination of IC50 or EC50 values from concentration-response curves).
Results showing an inhibition (or stimulation) between 20% and 50% are indicative of weak to moderate effects (in some assays, they may be confirmed by further testing as they are within a range where more inter-experimental variability can occur).
Results showing an inhibition (or stimulation) lower than 20% are not considered significant and mostly attributable to variability of the signal around the control level.
Low to moderate negative values have no real meaning and are attributable to variability of the signal around the control level. High negative values (> 50%) that are sometimes obtained with high concentrations of test compounds are generally attributable to non-specific effects of the test compounds in the assays.
1.1.3. Analysis and Expression of Results
The specific ligand binding to the receptors is defined as the difference between the total binding and the nonspecific binding determined in the presence of an excess of unlabelled ligand.
The results are expressed as a percent of control specific binding and as a percent inhibition of control specific binding obtained in the presence of the test compounds. Individual and mean values are presented in the results section.
The IC50 values (concentration causing a half-maximal inhibition of control specific binding) and Hill coefficients (A?H) were determined by non-linear regression analysis of the competition curves using Hill equation curve fitting. The inhibition constants (K,) were calculated from the Cheng Prusoff equation (K, = IC5O/(1 +(L/KD)), where L = concentration of radioligand in the assay, and
KD = affinity of the radioligand for the receptor).
1.2. IN VITRO PHARMACOLOGY: Isolated Organ Bioassav 1.2.1. General Procedures
1.2.2. Experimental Conditions
Prostatic segments of rabbit vas deferens were suspended in 20-ml organ baths containing an oxygenated (95 % O 2 and 5 % CO 2 ) and pre-warmed (30 °C) physiological salt solution of the following composition (in imM): NaCI 1 18.0, KCI 4.7, MgSO 4 0.6, CaCI 2 2.5, KH 2 PO 4 1 .2, NaHCO 3 25 and glucose 1 1 .0 (pH 7.4).
Yohimbine (1 µ?) and naloxone (1 µ?) were also present throughout the experiments to block the a 2 -adrenergic and opioid receptors, respectively. The tissues were connected to force transducers for isometric tension recordings. They were stretched to a resting tension of 1 g then allowed to equilibrate for 60 min during which time they were washed repeatedly and the tension readjusted. Thereafter, they were stimulated electrically with square wave pulses (submaximal intensity, 1 msec duration, 0.1 Hz) delivered by a constant current stimulator. The experiments were carried out using a semi-automated isolated organ system possessing eight organ baths, with multichannel data acquisition.
1.2.3. Experimental Protocols
Test for agonist activity
The tissues were exposed to a submaximal concentration of the reference agonist
McN-A-343 (1 µ?) to verify responsiveness and to obtain a control response. Following washings and recovery of the initial twitch contractions, the tissues were exposed to the test compounds or the same agonist which were left in contact with the tissues until a stable response was obtained or for a maximum of 15 min. If an agonist-like response (inhibition of twitch contractions) was obtained, the reference antagonist pirenzepine (0.1 µ?) was tested against the test compounds to confirm the involvement of the M receptors in this response.
Test for antagonist activity
The tissues were exposed to a submaximal concentration of the reference agonist McN- A-343 (1 µ?) to obtain a control response.
After stabilization of the McN-A-343-induced response, the tissues were exposed to the test compounds or the reference antagonist pirenzepine which were left in contact with the tissues until a stable response was obtained or for a maximum of 15 min. If it occurred, a recovery of the twitch contraction amplitude by the test compounds indicated an antagonist activity at the M receptors.
1.2.4. Analysis and Expression of Results
The parameter measured was the maximum change in the amplitude of the electrically- evoked contractions induced by the compounds.
The results are expressed as a percent of the control response to McN-A-343 (mean values).
COMPOUNDS 1.3. Test Compounds
From: EURO GENET Lab A.E.
1 .E-02 M 1 .E-04 M
9327-1 (+) A1 -41 318.00
DMSO H2O
1 .E-02 M Direct DMSO
9327-2 (-) A1 -41 318.00 1 .E-02 M 1 .E-04 M CEREP ^ , , _ Reference Submitted .., intermediate oompouna l.D. , biocK solution t .
1.E-02 M Direct DMSO
1.E-02 M 1.E-04 M
9327-3 (+) A2-73 318.00
DMSO H2O
1.E-02 M 1.E-04 M
9327-4 (-) A2-73 318.00
DMSO H2O
5.E-02 M Direct DMSO *
1.E-02 M 1.E-04 M
9327-6 AdPhAE/C6 compound 6 376
DMSO H2O
1.E-02 M 1.E-04 M
9327-7 AI142Me/C8 compound 8 332
DMSO H2O
1.E-02 M 1.E-04 M
9327-8 Ad2PhPZMe/C3 compound 3
DMSO H2O compound ? -, ? ?? 1.E-02M 1.E-04M
9327-9 AdPh3/VC7 374.00 DMSO H20
F.W.: Formula Weight
* : for the isolated organ bioassay
RESULTS
1.4. IN VITRO PHARMACOLOGY: Binding Assays The mean values for the effects of the test compounds are summarized in table 1 - 1 . The individual data obtained with the test compounds are reported in table 1 - 2.
The IC 50 and R values for each reference compound are indicated in table 1 - 3. Each is within accepted limits of the historic average ± 0.5 log units.
1.5. Reference Compounds
In each experiment, the respective reference compound was tested concurrently with the test compounds in order to assess the assay suitability. It was tested at several concentrations and the data were compared with historical values. The assay was rendered valid if the suitability criteria were met, in accordance with the corresponding Standard Operating Procedure.
Table 1 - 1
Summary Results
Test
Assay ^ ,. , , , ... , . % mniomon of
? « , ~ uient compound ,?. concentration „ , , . ,. oerep compound .u. 1 oontro bpecmc bmdina
9327-1 (+) A1 -41 1 .0E- ¦ 06 66
9327-2 (-) A1 -41 1 .0E- ¦ 06 65
9327-3 (+) A2-73 1 .0E- ¦ 06 19
9327-4 (-) A2-73 1 .0E- ¦ 06 50
9327-6 AdPhAE/C6 1 .0E- ¦ 06 97
9327-7 AI142Me/C8 1 .0E- ¦ 06 63
9327-8 Ad2PhPZMe/C3 1 .0E- ¦ 06 81
9327-8 Ad2PhPZMe/C3 1 .0E- ¦ 05 95 Test
Assav , % nhibition ot
, , ^ client Compound LD. Concentration ? , , cerep compound ?. oontroi ¾pecmc Binatnq
9327-9 AdPh3/VC7 1 .0E-06 95
9327-1 (+) A2-73 1 .0E-06 42
9327-2 (-) A2-73 1 .0E-06 59
9327-3 (+) A2-73 1 .0E-06 14
9327-4 (-) A2-73 1 .0E-06 -13
9327-6 AdPhAE/C6 1 .0E-06 78
9327-7 AI142Me/C8 1 .0E-06 17
9327-8 Ad2PhPZMe/C3 1 .0E-06 -9
9327-8 Ad2PhPZMe/C3 1 .0E-05 57
9327-9 AdPh3/VC7 1 .0E-06 84
Table 1 - 2
Individual Data
Assay X/¾ct % of Control Specific
Client Compound
Cerep Compound cScentration Bindin 9
I.D. Test
Assav , % nhibition ot
, , ^ client Compound LD. Concentration ? , , cerep compound ?. oontroi ¾pecmc Binatnq
Oi (h)
9327-1 (+) A1-41 1.0E-06 35.0 32.9 34.0
9327-2 (-) A1-41 1.0E-06 35.7 33.3 34.5
9327-3 (+) A2-73 1.0E-06 81.5 81.1 81.3
9327-4 (-) A2-73 1.0E-06 50.7 50.0 50.4
9327-6 AdPhAE/C6 1.0E-06 4.3 1.9 3.1
9327-7 AI142Me/C8 1.0E-06 46.2 28.1 37.1
9327-8 Ad2PhPZMe/C3 1.0E-06 22.1 15.1 18.6
9327-8 Ad2PhPZMe/C3 1.0E-05 5.0 5.7 5.4
9327-9 AdPh3/VC7 1.0E-06 7.5 2.6 5.0
9327-1 (+) A1-41 1.0E-06 60.0 56.8 58.4
9327-2 (-) A1-41 1.0E-06 41.0 40.3 40.7
9327-3 (+) A2-73 1.0E-06 88.9 83.2 86.1
9327-4 (-) A2-73 1.0E-06 126.1 100.6 113.4
9327-6 AdPhAE/C6 1.0E-06 19.6 24.6 22.1
9327-7 AI142Me/C8 1.0E-06 84.0 81.0 82.5
9327-8 Ad2PhPZMe/C3 1.0E-06 103.7 113.9 108.8
9327-8 Ad2PhPZMe/C3 1.0E-05 45.2 40.5 42.9
9327-9 AdPh3/VC7 1.0E-06 1.6 30.2 15.9
Table 1 - 3
Reference Compound Data
haloperidol 1.3E-08 1.1E-08 0.8
haloperidol 1.5E-07 1.3E-07 1.1 haloperidol 1.0E-07 8.6E-08 0.6
1.6. IN VITRO PHARMACOLOGY: Isolated Organ Bioassav
The effects of (+) A1-41 , (-) A1-41 and (-) A2-73 investigated for agonist and antagonist activities at the muscarinic Mi receptors in the rabbit vas deferens are presented in table 2 - 1 where those of the reference compounds are also reported.
In the field-stimulated rabbit vas deferens, the M receptor agonist McN-A-343 induced a concentration-dependent decrease in the twitch contraction amplitude which was reversed by the antagonist pirenzepine in a concentration-dependent manner.
In the untreated tissues, (+) A1 -41 , (-) A1 -41 and (-) A2-73 did not decrease the twitch contraction amplitude but caused a slight to moderate increase.
In the tissues previously depressed with McN-A-343, (+) A1 -41 , (-) A1 -41 and (-) A2-73 produced a concentration-dependent and almost complete recovery of the twitch contraction amplitude.
These results indicate that (+) A1 -41 , (-) A1 -41 and (-) A2-73 behave as antagonists at the Mi receptors. Table 2 - 1
Effects of (+) AE 14, (-) AE 14 and (-) AE 37 investigated for agonist and antagonist activities at the muscarinic M receptors in the rabbit vas deferens
Test for agonist activity
Compounds Control response to Responses to increasing + pirenzepine concentrations
McN-A-343 (1 .0E- of the compounds (1 .0E-07 M) 06 M)
1 .0E-06 M 1 .0E-05 M 5.0E-05 M
(+) AE 14 100 - 16 - 31 not tested
(-) AE 14 100 - 5 - 8 not tested (-) AE 37 100 - 20 - 33 not tested
1 .0E-07 M 3.0E-07 M 1 .0E-06 M
McN-A-343 100 29 67 99 - 5
Test for antagonist activity
Compounds Control response to Responses to McN-A-343 (1 .OE-06 M) in the presence
McN-A-343 (1 .0E- of increasing concentrations of the compounds 06 M)
1 .OE-06 M 1 .OE-05 M 5.0E-05 M
(+) AE 14 100 13 1
(-) AE 14 100 20 9
(-) AE 37 100 16
1 .OE-08 M 3.0E-08 M 1 .OE-07 M pirenzepine 100 72 43
The results are expressed as a percent of the control response to McN-A-343
(decrease in twitch contraction amplitude) (mean values; n=2) Example 1
Neuroprotection against beta amyloid A 67 year old male diagnosed with early stage Alzheimer's dementia is treated with 10 mg of ©Anevex2-73 substantially free of Anavex2-73 © , once per week for three years. His mental function is tested quarterly and does not decrease over the period. On autopsy, his brain is found to contain senile plaques but very low content in amyloid peptide oligomers.
Example 2
Neuroprotection against oxidative stress A 29 year old female balloonist, anticipating anoxic stress, is orally administered
10mgs of oral ©Anevex2-73 substantially free of Anavex2-73 © daily for 5 days preceding a balloon ascent. The balloonist ascends to 6,000 meters without oxygen assist and suffers no anoxic damage. Example 3
Neuroprotection against neurotoxicity
A 37 year old male hazardous materials engineer, anticipating neurotoxic stress, is orally administered 1 mg of ©Anevex2-73 substantially free of Anavex2-73 © , daily for 5 days preceding exposure to tetanus toxin. The engineer is exposed 0.1 ng/kg of said neurotoxin and suffers no damage.
Example 4
Neuroprotection in stroke patient
A 57 year old male enters the emergency room and is diagnosed with an ischemic event involving the middle cerebral artery, with symptomatology onset being less than 1 hr. Immediately, the patient is administered an i.v. supplemented with 1 mg of ©Anevex2-73 substantially free of Anavex2-73 © while blood supply to the restricted area is restored. Daily testing of cognitive and motor systems show no deficits in physical or mental capacities. In addition, CT/MRI imaging shows no signs of lesioning in the affected region, immediately following recovery and that this was maintained and confirmed by follow-up imaging and behavior testing. Example 5
Neuroprotection against amyloid
An 80 year old female patient is diagnosed with AD and treated with 10 mg of T Anevex2-73 substantially free of Anavex2-73 ® daily for 3 yrs. The patient's cognitive score stabilizes and then increases slowly and regularly over the following months.
Dosing information/dosage forms:
For ©Anevex2-73 substantially free of Anavex2-73 ® dosages of about .Ol 100 mg/daily, preferably 0.5-10 mg/daily, more preferably 0.5-2 mg/daily are noted.. Dosing once every two days (3 times a week) is noted. AD is a chronic disease, so staring treatment promptly with diagnosis is preferred.
Particular attention is drawn to the method of this invention comprising T
Anevex2-73 substantially free of Anavex2-73 ® administration. In some instances therapeutic treatment includes administration of at least one cooperating
acetylcholinesterase inhibitor (donepezil, galantamine, rivastigmine, or memantine), wherein at least one of said therapeutically effective amounts of either or the dose of cooperating acetylcholinesterase inhibitor is sub-therapeutic (sub-MAD) as compared to the active dose when used alone. Either the T Anevex2-73 substantially free of Anavex2-73 ® or the cooperating acetylcholinesterase inhibitor is used. In this regard, reference is made to USSN 13/940,352 to Vamvakides et al entitled "ANAVEX2-73 AND CERTAIN ANTICHOLINESTERASE INHIBITORS COMPOSITION AND METHOD FOR NEUROPROTECTION" the teachings of which are incorporated herein by reference. 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.
For parenteral application, particularly suitable are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. Ampules, vials, and injector cartridges are convenient unit dosages.
"Unit dosage form" shall mean single drug administration entity. By way of example, a single tablet, capsule, dragee, or trochee, suppository, or syringe. Also for parenteral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules. A syrup, elixir, or the like can be used wherein a sweetened vehicle is employed. Sublingual and buccal forms are also noted.
Sustained or directed release compositions can be formulated, e.g., liposomes or those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc. It is also possible to freeze-dry the new compositions and use the lyophilizates obtained, for example, for the preparation of products for
Just a reminder to keep it real
AAIC - Wed, July 25th.
Sigma-1 Receptor Target Occupancy Study with Dynamic PET Scan Analysis of ANAVEX®2-73, a Clinical Candidate for Neurodegenerative and Neurodevelopmental Diseases
------------------------------
Full Genomic Analysis of ANAVEX®2-73 Phase 2a Alzheimer’s Disease Study Identifies Biomarkers Enabling Targeted Therapy and a Precision Medicine Approach
-----
Systematic Processing of Full Genomic Analysis of ANAVEX®2-73 Phase 2a Alzheimer’s Disease Study Identifies Biomarkers Enabling a Precision Medicine Approach
------------------------------
Latest PR:
Phase 2 Study of Potential Oral Therapy for Parkinson’s Dementia, Anavex 2-73, Planned
parkinsonsnewstoday.com/2018/04/20/anavex-planning-phase-2-trial-of-potential-parkinsons-dementia-oral-therapy/
Jose Marques Lopes, PhDApril 20, 2018
Phase 2 Study of Potential Oral Therapy for Parkinson’s Dementia, Anavex 2-73, Planned
Anavex Life Sciences is planning to open a Phase 2 clinical trial testing Anavex 2-73, a potential oral treatment for patients with Parkinson’s disease dementia (PDD), this year.
Anavex 2-73 aims to treat PDD by binding to the sigma-1 receptor, located in a cellular structure called the endoplasmic reticulum and important to protein production and transport.
The proposed double-blind, placebo-controlled trial will evaluate Anavex 2-73’s ability to ease both cognitive and motor difficulties in Parkinson’s patients. A trial application is before European regulators, with plans to start this study in the second half of 2018.
According to the Parkinson’s Foundation, around 50 to 80 percent of Parkinson’s patients will develop disease-related dementia. Parkinson’s is characterized by the loss of neurons in a crucial brain area that controls movement, the substantia nigra. This loss, in turn, lowers brain levels of dopamine, a key player in nerve cell or neuronal communication.
With disease progression, these changes spread to other areas of a patient’s brain, affecting memory, attention, and thinking and reasoning.
“As many as 80 percent of people with Parkinson’s will experience Parkinson’s disease dementia and treatment options are limited,” Christopher Missling, president and CEO at Anavex, said in a press release.
Results of preclinical work, fully funded by the The Michael J. Fox Foundation for Parkinson’s Research, show that treatment with Anavex 2-73 was able to restore function to damaged nerve cells in mouse models of Parkinson’s disease. Data also demonstrated that it targets misfolded proteins and poorly working mitochondria — a cell’s energy source — to prevent oxidative stress, inflammation, and cellular stress.
“We are excited to progress our program to Phase 2, with a focus on the many patients with Parkinson’s disease dementia, and we remain focused on the discovery and development of potential treatments for neurological diseases with unmet needs, including Alzheimer’s disease and Rett syndrome,” Missling added.
Anavex filed an updated investigational new drug application to the U.S. Food and Drug Administration (FDA) earlier this year for a double-blind, Phase 2 study evaluating Anavex 2-73 in Rett syndrome. If approved, this trial is also expected to open in late 2018.
The company plans to open a Phase 2/3 trial of Anavex 2-73 in up to 300 people with mild-to-moderate forms of Alzheimer’s disease. A Phase 2a dose-escalating study (NCT02244541) involving 32 people with probable Alzheimer’s was conducted at sites across Australia.
I took advantage and further lowered APS. Gift!!
I don't agree that the trading action (volume) today is related to upcoming announcemt. Today's is the last day of the Russell rebalancing and it looks like AVXL has been deleted from the Index. I hope this is the case and with this event behind us we should be in a position to resume the upward trend in expectation of news prior to or at the upcoming AAIC.
Just an opinion and not intended to be taken as fact.
GLTA longs. Our time is coming.
The other side of the story:
https://fintel.io/sob/us/avxl
https://seekingalpha.com/news/3356305-oryzon-genomics-commences-mid-stage-study-alzheimers-candidate
Oryzon Genomics commences mid-stage study of Alzheimer's candidate
May 14, 2018 12:27 PM ET|By: Douglas W. House, SA News Editor
Spanish biotech Oryzon Genomics announces that enrollment is underway in a Phase 2b clinical trial assessing ORY-2001 in patients with mild-to-moderate Alzheimer's disease (AD).
The 90-subject trial, ETHERAL, will be conducted in Spain, France and the UK. The company plans to launch a twin study in the U.S. as soon as feasible.
Orally available ORY-2001 is a selective inhibitor of enzymes lysine-specific demethylase (LSD1) and monoamine oxidase B (MAOB) and is able to penetrate the blood brain barrier. MAOB breaks down dopamine so inhibiting its action prolongs the action of dopamine in the brain. LSD1 inhibition is an approach to treating certain cancers because it increases the expression of tumor-suppressor genes. The company says the molecule acts on several levels, reducing cognitive impairment, memory loss and neuroinflammation and may act as a disease modifier. It is also being evaluated for the treatment of multiple sclerosis.
AD-related tickers: VTVT, BIIB, TNXP, ACAD, AXSM, ACIU, DNLI, WVE, OTCPK:TKPHF, VYGR, ABBV, MRK, AVXL, OTCQX:IGXT, AMGN, OTCPK:ESALY, IONS, AXON, BHVN
Previously: Oryzon Genomics on go with mid-stage study of Alzheimer's candidate ORY-2001 (April 4)
Just a reminder of why some, if not most, of us who follow this MB and remain faithful to our belief that we are in the cusp of something very special.
Can a Sigma-1 Agonist Stabilize Cognition and Function in Alzheimer’s Disease?
A novel drug appeared to benefit patients in a phase IIa trial.
Neurology Reviews. 2017 February;25(2):46
SAN DIEGO—A novel Alzheimer’s disease drug candidate appeared to stabilize cognition and function over 57 weeks in a small, early-phase, open-label trial.
Patients with mild to moderate Alzheimer’s disease who took ANAVEX 2-73, an agonist of the sigma-1 receptor, experienced virtually no decline on the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Cooperative Study–activities of daily living (ADCS-ADL) functional scale. These findings correlated with significant improvements in the P300 evoked potential test, an electrophysiologic measure sometimes used to approximate synaptic connectivity and cortical processing speed.
ANAVEX 2-73 (Anavex Life Sciences, New York) also conferred an unexpected benefit upon subjects with insomnia. “Any patient who scored on the insomnia measure [of the Hamilton Depression Rating Scale] at baseline had no sleep disturbance at all by weeks 12 and 26,” Stephen Macfarlane, MBBS, said at the Clinical Trials on Alzheimer’s Disease conference.
Stephen Macfarlane, MBBS
The findings must be interpreted cautiously. The phase IIa study was designed to assess safety and tolerability; cognitive and functional end points were secondary. It comprised 32 patients at baseline, 25 of whom completed both a five-week, randomized, dose-finding, crossover trial and a 52-week, open-label, extension study. There was no placebo comparator. Instead, researchers used three different sets of historical control data.
Investigators will continue to treat and follow the extension study cohort, and plan to launch a placebo-controlled study in 2017, said Dr. Macfarlane, Head of Clinical Governance for the Dementia Centre in Melbourne.
The five-week, randomized, dose-finding, crossover trial started one group of patients on 30 mg/day or 50 mg/day oral ANAVEX 2-73 for 11 days after an initial two-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 11 days of 3 mg/day or 5 mg/day intravenously. A second group first received 11 days of 3 mg/day or 5 mg/day ANAVEX 2-73 intravenously after an initial 2-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 30 mg/day or 50 mg/day oral ANAVEX 2-73 for 11 days. This trial was followed by a 52-week, open-label, extension trial of 10-50 mg/day orally, titrating each patient to the maximum tolerated dose. The extension phase was originally planned to last six months, but patients and caregivers wanted to continue on the medication, so the company extended it to 12 months. It is ongoing.
An Attractive Drug Target
The sigma-1 receptor targeted by ANAVEX 2-73 is found on neurons and glia in many areas of the CNS. It modulates a number of processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke.
The sigma-1 receptor also appears to play a role in helping cells clear misfolded proteins—a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.
In preclinical testing, ANAVEX 2-73 seemed to enhance cognition in wild-type and Alzheimer’s disease–model mice.
The mean age of patients in the extension study was 71. The median MMSE score was 20.5. Most patients (78%) were taking a stable dose of an acetylcholinesterase inhibitor. During the extension phase, they were titrated to the maximum tolerated dose; 14 mg was the minimum dose necessary to achieve a therapeutic effect and keep the MMSE stable.
The primary end points were safety, tolerability, and pharmacokinetics. The exploratory measures included the P300 electroencephalogram, MMSE score, the Computerized Cogstate Alzheimer’s Battery, and the ADCS-ADL. The Hamilton Depression (HAM-D) Scale was also employed as a neuropsychiatric symptom measure.
The cohort had low baseline depression scores, with a mean score of 2 on the HAM-D. By the study’s end, it had decreased to a mean of 1 point. Patients also reported improvements in their ability to work or do other activities, and in anxiety, agitation, hypochondriasis, and insight.
Electrophysiologic Measures
The P300 wave amplitude showed a small initial increase from about 6 microvolts to 7 microvolts by four weeks, and then returned to about 6 microvolts until about week 32. Thereafter, it steadily improved to about 8 microvolts by 57 weeks—a level usually seen in healthy age-matched controls. There was a significant separation from the P300 decline seen in a matched historical Alzheimer’s disease cohort, which decreased to about 4 microvolts over a 52-week period while patients were taking donepezil.
Researchers used a second historical control group to assess changes on the Computerized Cogstate Alzheimer’s Battery. All subjects in a large Australian prospective cohort study, called AIBL (Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing), were taking standard of care Alzheimer’s drugs. Compared with that cohort, the ANAVEX 2-73 group experienced benefits in processing speed, attention, and working memory, which became statistically significant at week 31 and continued to improve.
At 57 weeks, patients’ mean MMSE score was near the baseline mean score of 20. ADCS-ADL scores declined slightly, from a mean of about 70 to approximately 65.
Finally, the investigators used another historical cohort to assess projected cognitive and functional benefit. Compared with a pooled, placebo-arm, cohort study conducted by the Alzheimer Disease Cooperative Study Group over 12 months, ANAVEX 2-73 would have been associated with 1.8-point benefit on the MMSE and a 4-point benefit on the ADCS-ADL.
“The MMSE declined 45% less and the ADCS-ADL declined 56% less than what we would have expected from the historical control data,” Dr. Macfarlane said. “This is not only statistically significant, but clearly clinically meaningful for patients.”
Nearly all patients (98%) experienced an adverse event. Most events were mild, transitory dizziness or headache; 76% of the events were grade 1, and 2% were grade 2. There were no serious adverse events. Three subjects dropped out of the trial because of adverse events (ie, delirium, dizziness, and a combination of confusion, disorientation, and lethargy). There were no problematic interactions between the study drug and any standard of care Alzheimer’s disease medications.
—Michelle G. Sullivan
BIO International Convention - Jun 4-7
https://mybio.org/event/member?item_id=7687772
Bourbon,
Best not to engage them. They move on.
Bourbon,
Thanks for the nice summary. I was able to grab another 10K shares at the discounted price -this is it for me, although I have said that before.
I continue to believe that our patience will be handsomely rewarded. It may take a couple of more years but it all will be worth it in the end.
GLTA who believe.
Thanks for the advice. Just bought another 5k.
I am with you and added a few today. This can all turn in a hurry with a PR. I expect it.
Anyone with a Schwab account? Have you received proxy material? I have not.
Thank you.
He said nothing that it is not public. Some just don't want to accept facts.
Anavex 2-73 And The Stabilization Of Alzheimer's Disease $AVXLhttp://www.seekingalpha.com/article/4155507
With some modifications, this could easily be an Anavex PR.
https://www.telegraph.co.uk/science/2018/03/06/alzheimers-disease-will-become-manageable-like-hiv-say-award/
Alzheimer’s disease will become manageable like HIV, say award-winning scientists
People will be able to take drugs to prevent Alzhiemer's, scientists believe
Sarah Knapton, science editor 6 MARCH 2018 • 7:04PM
Alzheimer’s sufferers may be able to live with the disease without the devastating symptoms within the next few decades, scientists said as they were awarded the Brain Prize for their work fighting the illness.
Professor Michel Goedert, of Cambridge University, who discovered the importance of tau protein in Alzheimer’s said he could see a time when dementia became a chronic illness like HIV.
Prof Goedert who shares the one million euro Brain Prize with four colleagues, said: “Alzheimer’s will become something like HIV. It’s still there but it has been contained, or whittled down by drug treatments.
“It will disappear as a major problem from society.”
Prof Goedert was awarded the prize alongside Professors John Hardy and Bart De Strooper of University College London who developed the hypothesis that Alzheimer’s is caused by a build-up of amyloid protein in the brain, and Professor Christian Haass of Ludwig-Maximilians-University of Munich.
Prof Hardy said in the future, treatments for Alzheimer's would be taken before the disease developed to prevent symptoms rather than trying to reverse them. He said may drug trials had failed because they had started when the disease was too well established.
“The mistakes we have made is the trials is that treatment has been given too late,” he said.
“It’s like popping a statin to stop a heart attack.
“But when we first started we knew almost nothing about Alzhiemer’s and now we understand a huge amount.”
Prof De Strooper added: “In 10 years we will have a completely different picture.”
The Brain Prize organisers said the winners had made essential contributions to the genetic and molecular knowledge of Alzheimer’s disease ‘which are the foundations for finding new ways to diagnose, treat and possibly even prevent it and other devastating diseases of the ageing brain’
Professor Anders Bjorklund, chairman of the Lundbeck Foundation Brain Prize selection committee, said: “Alzheimer´s disease is one of the most devastating diseases of our time and the remarkable progress that has been made during the last decades.
“These four outstanding European scientists have been rewarded for their fundamental discoveries unravelling molecular and genetic causes of the disease that have provided a basis for the current attempts to diagnose, treat and possibly even prevent neurodegenerative brain diseases.
“The award recognises that there is more to Alzheimer´s disease than amyloid, and that the field of dementia research is more than Alzheimer´s disease alone.”
Not much to be said other than with this credentials you join because you believe that the odds for success are very high.
https://www.linkedin.com/in/stephan-toutain/
Ditto.
https://seekingalpha.com/news/3334878-celgene-minus-8-percent-fda-turns-away-multiple-sclerosis-drug-application
Celgene -8% after FDA turns away multiple sclerosis drug application
Feb. 27, 2018 5:19 PM ET|About: Celgene Corporation (CELG)|By: Carl Surran, SA News Editor
Celgene (NASDAQ:CELG) -7.8% after-hours on news the U.S. Food and Drug Administration rejected its new drug application for a multiple sclerosis treatment, a surprise that likely will delay the entry of one of its most important pipeline assets.
CELG says it received a "refusal to file" letter from the FDA for the company's drug ozanimod for the treatment of patients with relapsing multiple sclerosis because of insufficient data.
CELG says it will "seek immediate guidance, including requesting a Type A meeting with the FDA, to ascertain what additional information will be required to resubmit the NDA."
Parkwest owns 2,712,858 (6.1%) shares. 13G required when >5% <10% ownership is established.
https://www.sec.gov/Archives/edgar/data/1314052/000090571818000242/anavexlife_13gam1dec2017.htm
I suspect Mr. West might know a little more than we do, without violating SEC rules.
Unless they do a PR pre-market open, or halt trading and disclose to general public, no material information can be presented.
Thanks for posting.
Associate Professor Stephen Macfarlane
Australia
Stephen Macfarlane is Head of Clinical Services for Dementia Support Australia (DSA).
He became a psychiatrist in 2003, Deputy Chief Psychiatrist for Victoria in 2008 and Associate Professor and Director of Aged Psychiatry at Alfred Health. Alongside DSA he now leads an Alzheimers’ disease clinical trials unit. The conference provided delegates the opportunity to learn from the DSA program, as the largest global program of its kind seeking to understand and support people with dementia with changes in behaviour.
Like you, long and undeterred.
For what it is worth and only sharing with the intent to inform.
Had a lengthy call with IR today. I expressed my (our) shared frustration about the company's failure to initiate trials as affirmed and re-affirmed by the CEO.
IR spokesperson acknowledged that he understood why investors would be disappointed. Proceeded to tell me that he could not say more that has already been disclosed but reassured me (more than once) that nothing has materially changed, or else it would have been disclosed; rather the company is being extremely diligent in continuing to analyze the data to ensure that they recruit the right trial participants to significantly increase the probability of success.
I acknowledge that I (we) believe that this is the right approach and rather be slow and successful that fast and failed. However, we believe that a bit more transparency would be welcomed by us, retail investors, and institutions.
Expecting SOP I asked:
Q: Is the Rett trial delayed for the same reason? A: Could not say.
Being cautious about what is said as advised by legal counsel (SEC concerns).
Q: Has anything changed from what was communicated on last investors' call? same as above but added, nothing material has changed or else it would have been disclosed to the general public.
Q: Can we expect to hear news within days? weeks? months? A: Could not say (SEC).
Q: Is Dr. Missling at the JPM Healthcare Conference in SF? A: Yes. Not presenting but meeting with potential institutional investors.
In closing, I told him that I would share a brief summary of our discussion (we talked for about 20 minutes), and that my main take away is that we remain on track for trials to commence in the near future and that nothing has drastically changed from what is already know by all. He said that that was a fair assessment and thank me for the support and look forward to our next conversation from a more positive stand point.
I asked him to relay the message to Dr Missling that I (some of us) are generally pleased with the progress he has made but we also expect a bit more transparency and solid planning and execution.
GLT all longs.
LTB, I am also a long-term-believer. Locked and loaded and looking forward to 2018.
ANAVEX®2-73 Program Update:
The Company filed an IND for ANAVEX®2-73 in Rett syndrome, for which the Company received orphan drug designation by the FDA, and is expecting feedback from the FDA to finalize the clinical trial protocol for this study. As start-up activities with clinical trial sites have been underway, the Company anticipates dosing the first patient in due course following FDA approval of the IND. January in my opinion.
With the integration of genome sequencing information from ANAVEX®2-73-treated patients, the Company is now able to enhance the planned Alzheimer’s Phase 2/3 study. It is expected that incorporating this novel precision medicine approach as well as including comprehensive fluid-based biomarkers and multimodal neuroimaging, will enable a more robust regulatory submission, anticipated within the upcoming quarter. The randomized, double-blind, placebo-controlled study will be aimed at evaluating the safety, tolerability and efficacy of ANAVEX®2-73 in Alzheimer’s disease patients and will be conducted in both Australia and North America. Further details of the study will be shared in upcoming announcements. Q2 in my opinion.
Due the strength of the preclinical Parkinson’s disease data on ANAVEX®2-73 from a collaboration with Michael J. Fox Foundation, Anavex plans to file an upcoming clinical trial application (CTA) with European regulatory authorities to conduct a Phase 2 trial for ANAVEX®2-73 in Parkinson’s disease patients. Q2 in my opinion.
My opinion is a valid as that of many who predict nothing will happen in 2018. As an investor, I have to believe or I would have moved on.
Happy New Year to all who believe!
While the news was not all bad, we must admit that it was disappointing that Dr. M. waited this long to update us about trial time lines. The market does not take lightly to missed guidance and MM always always ready to take advantage and sweep those juice stop loses. I see this as an opportunity and picked up a good batch of cheap shares.
If you take away the trial delay it is all good news. Fundamentals have not changed. Pleased to hear about global approach for trials.
As far as the CEO, I still believe he is doing the right things to do what ultimately matters most, get the drug to market.
If you are a long term investor, today's news should make you feel believe more that we are on the right track. Looking forward to today's call.
"The stock market is a device for transferring money from the impatient to the patient".
Excellent! Thank you.