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Bio-
I appreciate and thank you for this post. It tells a beautiful story and provides a perspective for us to understand that seemingly impossible things, like a deaf person composing a symphony, are possible. Missling and Anavex are striving to find treatments for diseases that have no cures. ''It is not the critic who counts..." as Teddy Roosevelt said. It is those like Beethoven that repeatedly strive to accomplish great deeds despite hardships, limitations and handicaps. Anavex, compared to Biogen and other major pharmaceutical companies, is handicapped. Its resources are limited. Yet, it seeks to achieve what significant companies have tried for years and failed to execute, which shows that what Anavex is doing is not easy. Nitpickers and faultfinders, please - give Anavex a break. It's trying, and so far it has not failed. It's just running a little late.
There are many potential reasons for the delay in PDD results, but no one knows why PDD data was not available in September. Potential catalysts, however, lie very shortly, including PDD and very likely Rett. PDD is imminent, but Rett data is also due in this fourth quarter based on the early September U.S. Rett trial completion. So, until I hear otherwise, no news is good news. Everything else is mere speculation. Sooner or later, I look forward to: "The thrill of victory and (or) the agony of defeat" (ABC Sports in the old days).
Yes, I hope Anavex accomplishes something with AVXL 2-73, a mixed ligand for sigma1/muscarinic receptors. The "plaque removal" drugs, among other Alzheimer's drug candidates, have consistently proven to be a disappointment over a long time.
Yes, I agree with the 11,000 figure for the U.S.
Baltimore:
Your question is complicated. As you know the FDA must decide on safety and effectiveness of drugs submitted for approval. However, all drugs that are effective are potent compounds. Potency is needed to produce a desired result in the body.
The subject of safety and effectiveness can be complicated. Potency depends on the amount of drug to produce the desired effect. I suppose statins are relatively safe, but it may be that a higher dose is needed by some patients to produce the desired effect of sufficiently lowering cholesterol levels. The higher the dose raises the chance of producing adverse side effects. For example, high dose statin therapy may result in decreased mitochondrial function, muscle pain, etc., which could be serious.
Turning to AVXL 2-73:
“According to a presentation at AAIC 2106, after 31 weeks of dosing in 28 patients, the drug met safety endpoints. Most adverse events were mild or moderate, with headache and dizziness the most frequent. Most people took 20 or 30 mg daily; the maximum tolerate dose was 48 mg.” However, I believe that in the PDD trial and in our AD trial, the highest dose administered is probably 50 mg. Hopefully, we will hear in the next update from Anavex that 50 mg is well tolerated, but note that this article that the above quote was taken says that the “maximum tolerate dose was 48 mg”. See this: https://www.alzforum.org/therapeutics/blarcamesine
It seems though that most patients may benefit from dosages of blarcamesine that are less than 50 mg. Therefore, I believe AVXL 2-73 is relatively safe and may be effective for most patients. Hopefully, it will produce a desired treatment effect that is head and shoulders above any other competitor’s AD, PDD and Rett drug. I also hope that those patients that need a higher dose of AVXL such as 50 mg or more to treat their disease are able to tolerate the higher doses.
Market for Rett
"Prevalence
It is estimated that one in ten thousand girls will be born with Rett Syndrome. This means about 15,000 girls and women in the US and 350,000 worldwide have the disorder.
Rett Syndrome is classified as a “rare disease” (by definition, less than 200,000 affected individuals in the US) by the Office of Rare Diseases of the National Institutes of Health. This designation qualifies the condition for orphan drug status from the FDA which comes with certain perks for pharmaceutical companies like tax deductions and marketing exclusivity on a drug for an extended time period."
https://reverserett.org/about-rett/more-about-rett/
No medications are available specifically for treatment of Rett. Rett patients take a variety of medications that treat Rett symptoms. Here is a medication summary for the treatment of symptoms:
"Medication Summary
No medications are available specifically for treatment of Rett syndrome (RS). Antiepileptic drugs (AEDs) may be prescribed to control seizurelike activity. Antireflux agents may be given to treat gastroesophageal reflux (GER). There is some evidence that levocarnitine may be effective. Sedative-hypnotic agents are used to treat sleep disturbances. Caution should be used if propranolol is used to reduce autonomic tone as paradoxical hypertension is possible."
https://emedicine.medscape.com/article/916377-medication
Potentially, AVXL 2-73 (blarcamesine) could replace multiple drugs that are used to treat Rett symptoms; however, in addition, Anavex's drug may specifically treat the disease. Therefore, if AVXL 2-73 is approved for the treatment of Rett, there is justification for charging a hefty price for the drug.
The higher the benefit the higher the cost of a new drug to treat an unmet need.
https://www.sciencedirect.com/science/article/pii/S2213538315300114
Interestingly, Restasis to treat dry eyes costs over $600 for a 90 day supply. Certainly, the first drug on the market to treat Rett justifies a high cost. Using Restasis is not a good comparable to judge the price that may be charged for blarcamesine if it is proven to treat Rett, but let's use $600 per month (approximately 3 X the price for Restasis).
The potential market in the U. S. Would be 15,000 X $600 = $9,000,000 per month or $108,000,000 per year.
Missling says that Japan and Europe have approximately the same number of Rett patients as the United States. Therefore, the potential market for a drug to treat Rett could be three times $108,000,000 or $324,000,000 based on the price I used above. Personally, I think that the price for a drug to treat Rett would be higher than the price of $600 per month that I have used in this calculation. The economic burden for caring for a Rett patient is difficult to compute; however, it is substantial in deed. Plus, additional factors in pricing the drug may be based on relieving: 1. Misery and suffering for Rett patients; and 2. Emotional and physical toll on the Rett family or caregivers.
Dilution no longer seems to be a big problem for Anavex. Anavex has around $27 million in cash (Duncan interview with Missling). Anavex's burn rate is approximately $18 million per year. There is enough money on hand to fund the company for one and a half years.
I agree with Investor that we should have a pretty good idea where Anavex is headed by the end of this year. Moreover, we should have a good idea about all of Anavex's other clinical trials by September 2021.
I think dilution is no longer a significant problem for Anavex. Anavex could sell additional shares to add one-half year of operating capital, $9 million, to increase its cash to two years of operation, and dilution would amount to approximately 3.5% ($9 million / 255.8 million market cap). Raising $9 million could be spread out over the next year to lessen the dilution impact further. My point is that dilution, a common concern for developmental biotechs, no longer seems to be a concern for Anavex. Of course, additional capital will result from rolling out and marketing AVXL 2-73 if a Rett approval occurs during the next year or so, but that is a good problem.
Anavex institutional ownership increase versus AVXL share value. https://fintel.io/so/us/AVXL
See the chart at that site that illustrates institutional ownership in comparison to share price. Is the share price for AVXL unusually low in relation to the increase in institutional ownership?
Compare the AVXL's chart with Brainstorm Therapeutics chart regarding institutional ownership and share price. https://fintel.io/so/us/BCLI
Great perspective, Bio:
I have been sidetracked because of significant impact from a hurricane and other challenges, but I would like to know what you think about this Bio:
Is "An FDA approval for Biogen Inc's (NASDAQ:BIIB) highly controversial Alzheimer's investigational drug aducanumab .... positive for Lilly'' and positive as well for Anavex? See this suggestion that an aducanumab approval for Biogen suggests a low regulatory bar for Alzheimer's.
'The Lilly Analyst: David Risinger (Morgan Stanley)......
"Lilly's Alzheimer's pipeline represents an inexpensive call option, in our view."
......
An FDA approval for Biogen Inc's (NASDAQ:BIIB) highly controversial Alzheimer's investigational drug aducanumab could be a perception positive for Lilly, as a regulatory nod could suggest a low regulatory bar for Alzheimer's, he said.
Lilly has two Alzheimer's candidates — N3PG and tau antibody — set to report Phase 2 data in 2021, Risinger said.
With Morgan Stanley assuming only 5% odds of success for each, the risk-reward is skewed to the upside, the analyst said.'
https://www.benzinga.com/analyst-ratings/analyst-color/20/09/17371633/why-morgan-stanley-is-buying-the-dip-in-eli-lilly
Doc:
Apparently, you do not base your p value prediction for Anavex's PDD study on the results AVXL has shown so far in the AVXL 2-73 AD trials. Therefore, what is the basis for your prediction "that 2-73 had (or has) a 20% chance of a p value of less than .05 for PDD Phase 2" (BIO568 quote)?
For comparison, this is from a March 2019 regarding a AD Anavex presentation. AVXL 2-73 drug concentration, p values, ADCS-ADL and MMSE performance.
1. Patients Treated with Higher ANAVEX®2-73 Concentration Maintain ADCS-ADL* Performance vs Lower Concentration Cohort
High Concentration cohort shows 88 % difference to low concentration cohort
• High plasma concentration of ANAVEX®2-73 [>4.0 ng/ml] is correlated with the clinically administered dose
• In addition to concentration, the significant covariates identified in MMRM-LME model are:
• SIGMAR1 (p<0.0080),
• COMT (p<0.0014)
(p < 0.0001)?
SLIDE # 12
2. Patients Treated with Higher ANAVEX®2-73 Concentration Show Higher MMSE* Performance Compared to Lower Concentration
High Concentration cohort shows 64 % less decline than low concentration cohort
(p < 0.0008)
• High plasma concentration of ANAVEX®2-73 [>4.0 ng/ml] is correlated with the clinically administered dose
SLIDE # 13
https://www.anavex.com/wp-content/uploads/2019/03/Anavex-Presentation-March-2019-1.pdf.
Why is it likely that your prediction that AVXL 2-73 has a 20% chance of a p value less than .05 in the PDD trial, when the p values reported in the Anavex AD trials are less than .05?
Maybe this or that, but what happened is the Campbell brothers that founded Shake it Up and Shake it Up’s board made a judgment call that this drug had promise, and to put its money where it’s mouth is. Parkinson’s is a horrible disease, and we need doers to get us treatments that are presently unmet. We don’t need the the doubters or slackers that prefer that we not even try or that hope for failure. This is how progress is made by trying and trying again and again.
“It is hard to fail, but it is worse never to have tried to succeed. In this life we get nothing save by effort." Teddy Roosevelt quote. Thank God for Teddy!
The Shake It Up Australia Foundation (SIUAF) is an Australian non-for-profit foundation founded in 2011 by Clyde and Greg Campbell.[1] It is partnered with the Michael J. Fox Foundation (MJFF) to achieve the foundations primary aims of “promoting and funding Parkinson’s disease research in Australia to slow, stop and cure the disease”.[2][3] Together MJFF and SIUAF are the largest non-government funders of Parkinson's research across multiple institutes in Australia.[4] Since its founding, the foundation has co-founded 38 Parkinson's research projects across 12 institutes to the value of over $10.8 million.[3] The foundation's funding model ensures that 100% of proceeds goes towards Parkinson's research in Australia. This is possible due to the founding directors covering all overhead costs and expenses. In January 2019, Shake It Up are one of the partner organisation in the Australian Parkinson's Mission which was awarded a $30 million-dollar grant to test repurposed drugs in clinical trials.[5]
https://en.m.wikipedia.org/wiki/Shake_it_Up_Australia_Foundation
Yes, Missling says that “We have not made a final decision” , I think, meaning a final decision about a partner, which is necessary as Xena points out. Negotiating and drafting a detailed agreement with a partner is an involved process, and Anavex needs to carefully protect its proprietary information, intellectual property rights, etc. The requirement that a Japanese partner must be involved may give Japanese companies a bit of leverage. However, if AVXL 2-73 continues to show potential to treat an unmet need, there may be competition among interested Japanese companies to partner up with Anavex especially with the thought that this one thing, Rett, may lead to other things (AD, PDD, and other CNS disease treatments). Japan, I believe has an early access program. If a drug proves to be safe, obtaining some form of approval should not be difficult as long as AVXL 2-73 demonstrates the necessary benefit as well as safety.
Yes, that is my understanding based on Missling saying that we plan to expand to Japan after the Rett readout. Besides, Missling points out that there are as many Rett patients in Japan as in the United States.
Transcript of conference call re: Japan
Missling commented about expanding RETT study to Asia/Japan:
Yes. Last question is, do you see -- does one see Rett as being a challenge to Asian communities? And is there any corporate strategy to broaden potential access to those countries through maybe partnering or other endeavors?
There is, indeed, the same amount of Rett patients in Asia, especially in Japan and China, but especially in Japan, there's a same amount of patients there than here in the U.S. So it's around about 10,000 to 15,000 patients in Japan alone. And we do plan, after the readout of the U.S. study, which is forthcoming, to then move into the Japanese territory to also continue the study with ANAVEX 2-73 in Rett patients in that regard.
And would those be studies you conduct? Or do you think it may be best to do that in collaboration with a partner?
(Missling) Right. So Japan is a unique market where the entities working has to be local. So there are probably a mix of a local sponsor with us together or to a 0. We have not made a final decision on that yet.
The edited transcript of the August 6 conference call is available here: https://www.yahoo.com/news/edited-transcript-avxl-oq-earnings-065349481.html
Bio - Thank you for the genuine and accurate response to a loaded question.
It is interesting that this FB discussion about Rett makes mention of the SAS authorization for Blarcarmesine for Alzheimer's. See the below Q&A from a webinar on early access medicines. See particularly #10 below about pre-approval access for other indications not tested. You can read more from the website I reference below.
Questions and answers regarding Early Access to Medicines
9. Is that correct that the drug has to compete Phase III, or can also be earlier stage?
Manufacturers can make product available at any stage of development. In rare diseases it is not uncommon to make product available earlier in the development lifecycle. The decision should be driven by the availability of sufficient evidence to suggest a positive benefit-risk profile and/or a well understood safety profile to allow for informed use of the product in a patient.
10. Can pre-approval access be used for other indications not tested?
Yes. It is the prescribing physician’s responsibility to make a clinical judgement as to whether a product may benefit one of their patients, even if that product is not being investigated for that indication. However, the manufacturer decides whether or not to permit access – they are not obligated to.
11.Do healthcare professionals that use pre-approved drugs in their patients, submit any safety reports (SAEs, SUSARs) to local/global regulatory authorities, e.g. FDA in the US?
Yes. Safety reporting is mandatory in all countries under pre-approval access regulations. The specifics of who must be informed and at what frequency is very much country-specific.
12. What is the right and liability of manufacture to patients with such access?
The manufacturer has the right to either grant or deny access, and can make restrictions around which patients, physicians and centres can access a product. Liability, though, lies with the prescribing physician.
https://www.inceptua.com/industry-trends-in-pre-approval-access-to-medicines/
SAS designation of Blarcamesine in Australia is a smart move. Will early access be expanded to Europe? See the below excerpts from 3 articles with references.
1.Early Access Programs
Governments worldwide have created provisions for granting access to drugs prior to approval for patients who have exhausted all alternative treatment options and do not match clinical trial entry criteria, these are so called Early Access Programmes (EAPs) or labelled Compassionate Use Schemes (CUSs). Some markets regulation allows patients to access drugs that are approved outside of the region, but not yet in their home countries. EAPs are governed by guidelines and legislation that vary by country, defining access criteria, data collection, supply and control of the drug distribution. Some countries (e.g. Canada and Australia) have well defined EAP, Special Access Program (SAP) and Special Access Scheme (SAS), respectively. EAPs can be put in place at any stage of development post-phase II and can run in parallel with phase III clinical trials, until market authorisation is granted. Reporting data about efficacy, safety and occurrence of adverse events to the responsible health authority are usually mandatory requirements. Mostly it is the treating physician that is responsible for initiating the request, monitoring and reporting any output coming for the utilisation of the unauthorised drug (in clinical trials, it is the sponsors responsibility). Regulations differ widely among countries, due to differences in national medical practices, resources available, product funding, hospital structures and national insurance systems.
While patients, hospitals and/or national insurance systems bear the costs in some countries, the sponsor is expected to provide Compassionate Use products free of charge. An important consideration is that if a drug is charged for, then the obtained price may be used as future benchmark for pricing and reimbursement committees.
Conclusions
Advances have been made in fast tracking medicines to patients with unmet needs. We have described some evolution by the regulators to create accelerated routes and health authorities allowing patients access to experimental or unapproved medicines. The developer needs to carefully evaluate these options before embarking on any of these routes, all while providing advantages to patients where certain limitations could apply.
Likewise, the decision to implement an EAP should be carefully considered and a sponsor should ask important questions such as when to offer access and for which patients, as there might also be many drawbacks tied to its implementation. Existing regulations do not force companies to offer access to drugs prior to approval or launch.
In addition to providing significant benefit to patients with unmet needs, EAPs can offer important benefits in terms of increased and earlier access to the sponsoring manufacturer. EAPs can be a part of a global market access strategy, generating development strategies that are increasingly innovative and global in scope.
https://www.huronconsultinggroup.com/insights/early-access-medicines-for-unmet-needs
2.Early access programs in Europe: a regulatory tool with pre-marketing impact
EAPs offer real marketing rewards
EAPs are a good means of testing the product in "real life" and convincing prescribers and patients of product efficacy before launch. One advantage is that "real life" data are obtained, reflecting a more clinically and ethnically diverse population than often encountered in clinical trials. This information gained pre-launch can also shape post-launch marketing messages. "Early Adopters" or brand advocates can be identified as a wider group of physicians gain experience with the drug, and physician loyalty may be developed. Furthermore, key opinion leaders often play a major role in discussions with regulatory agencies.
Equally with respect to patients, as well as providing them with access to a potentially life saving medicine, there is the opportunity for feedback, the development of patient loyalty and building relationship with patient advocacy groups and associations.
There is the potential for early revenues in countries where EAPs can be designed as "for-profit" programs, but whether or not a drug is made available free of charge, market penetration can be maximized pre-launch through an EAP, which can then translate to a successful launch and increased post-approval usage. In practice, a good rule of thumb is that first-year market penetration after employing an EAP strategy is equivalent to the second year market penetration of a regular launch.
Even when EAPs run at a loss or neutral returns in stand-alone financial terms, long-term benefits make them an attractive choice for companies. In fact, patient recruitment is generally faster for not-for-profit EAPs, so if these patients keep using the drug when it is sold post-launch, a not-for-profit scenario could in fact provide the most benefit to pharma/biotech firms.
3.Expanded access or compassionate use is the use of an unapproved drug or medical device under special forms of investigational new drug applications (IND) or IDE application for devices, outside of a clinical trial, by people with serious or life-threatening conditions who do not meet the enrollment criteria for the clinical trial in progress.
These programs go under various names, including early access, special access, or managed access program, compassionate use, compassionate access, named-patient access, temporary authorization for use, cohort access, and pre-approval access.
Europe
In Europe, the European Medicines Agency issued guidelines that members may follow. Each country has its own regulations, and they vary. In the UK, for example, the program is called "early access to medicine scheme" or EAMS and was established in 2014. If a company that wants to provide a drug under EAMS, it must submit its Phase I data to the Medicines and Healthcare products Regulatory Agency and apply for what is called a "promising innovative medicine" (PIM) designation. If that designation is approved, the data is reviewed, if that review is positive, the National Health Service is obligated to pay for people who fit the criteria to have access to the drug. As of 2016, governments also paid for early access to drugs in Austria, Germany, Greece, and Spain.
Companies sometimes make use of expanded programs in Europe even after they receive EMA approval to market a drug, because drugs also must go through regulatory processes in each member state, and in some countries this process can take nearly a year; companies can start making sales earlier under these programs.
https://en.m.wikipedia.org/wiki/Expanded_access
It appears that gene mutations likely contribute to fewer than 5% to 10% of Parkinson's disease. Therefore, Parkinson's is mostly not associated with gene mutations. Will AVXL 2-73 benefit most Parkinson's patients similar to AVXL 2-73 benefiting Alzheimer's patients?
1. "During the past decade five genes have been identified that are important in autosomal dominant and autosomal recessive forms of Parkinson disease. The identification of these genes has increased our understanding of the likely pathogenic mechanisms resulting in disease. However, mutations in these genes likely contribute to disease in fewer than 5% of all cases of Parkinson disease."
https://www.nature.com/articles/gim2007120
2.Genetics and Parkinson’s
We do not know exactly what causes Parkinson's disease (PD), but scientists believe that a combination of genetic and environmental factors are the cause. The extent to which each factor is involved varies from person to person. Researchers do not know why some people develop Parkinson's and others do not.
Genetics cause about 10% to 15% of all Parkinson's. In some families, changes (or mutations) in certain genes are inherited or passed down from generation to generation. A handful of ethnic groups, like the Ashkenazi Jews and North African Arab Berbers, more commonly carry genes linked to PD and researchers are still trying to understand why.
Regardless of how a person gets Parkinson's — through genetics or environment or a combination of both — every person with PD experiences a loss of dopamine in the brain, along with symptoms and a progression of their disease that is unique to them.
https://www.parkinson.org/understanding-parkinsons/causes/genetics
4.How Parkinson’s disease causes primary motor symptoms
PD damages the neurons (nerve cells) in the brain, especially an area of the brain called the substantia nigra pars compacta. The neurons in the substantia nigra produce dopamine, a neurotransmitter (chemical messenger) that transmits signals from the substantia nigra to other parts of the brain to produce smooth, purposeful movement. When the neurons in the substantia nigra are damaged in large numbers, the loss of dopamine causes impaired movement and the motor symptoms of PD: tremor, rigidity, impaired balance, and loss of spontaneous movement. Research has shown that people with PD have lost 60-80% or more of the neurons that produce dopamine by the time symptoms appear.
https://parkinsonsdisease.net/symptoms/motor/
5. The Sigma 1 Receptor as a Target for Disease-modifying Therapies in Parkinson's Disease
Objective/Rationale:
The Sigma-1 receptor (Sig-1R) is a protein involved in the transport of lipids and proteins between organelles within the cell. Impairment of these intracellular trafficking processes is believed to contribute to the demise of dopaminergic neurons and other types of neurons in Parkinson´s disease (PD). This project will evaluate the effects of compounds boosting the activity of Sig-1R in pre-clinical models of PD. We hypothesize that these compounds will have neuroprotective, neurorestorative, and anti-inflammatory properties........
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Several mechanisms contribute to the neurodegenerative process in PD, and an ideal disease-modifying therapy should be able to improve more than one mechanism. Based on a vast literature from other disease models, we hypothesize that Sig-1R agonists have the potential to do so. A successful implementation of our project will provide solid support to the idea that Sig-1R should be pursued as a target for disease-modifying therapies in PD.
Anticipated Outcome:
We expect to define at least one Sig-1R treatment regimen that will protect nigral dopamine neurons from 6-OHDA-induced cell death, and/or promote axonal sprouting of their projections to the striatum. We expect these effects to correlate with a reduced activation of microglia in the affected brain regions. .....
https://www.michaeljfox.org/grant/sigma-1-receptor-target-disease-modifying-therapies-parkinsons-disease
6. Questions/comments:
Do most Parkinson's patients possess the wild type gene?
"Wild type (WT) refers to the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard[1] "normal" allele at a locus, in contrast to that produced by a non-standard, "mutant" allele. "Mutant" alleles can vary to a great extent, and even become the wild type if a genetic shift occurs within the population. Continued advancements in genetic mapping technologies have created a better understanding of how mutations occur and interact with other genes to alter phenotype.[2] It is now appreciated that most or all gene loci exist in a variety of allelic forms, which vary in frequency throughout the geographic range of a species, and that a uniform wild type does not exist. In general, however, the most prevalent allele – i.e., the one with the highest gene frequency – is the one deemed wild type."
https://en.wikipedia.org/wiki/Wild_type
Do most Parkinson’s patients in the PDD study carry the wild type gene? Will the PDD patients experience a similar benefit as we surmise to have occurred with patients in the Alzheimer's AVXL 2-73 trials? It has been said that 80% of Alzheimer's patients with the wild type gene benefit the most from AVXL 2-73 as opposed to approximately 20% of Alzheimer’s patients with a gene variant that may interfere with AVXL 2-73. What will the PDD study show a benefit for treating Parkinson’s dementia? Will AVXL 2-73 improve motor function by repairing damage of neurons in the substantia nigra in Parkinson’s patients? The above quote from the Fox Foundation says “an ideal disease-modifying therapy should be able to improve more than one mechanism.” The Fox article also says: “Based on a vast literature from other disease models, we hypothesize that Sig-1R agonists have the potential to do so.”
We will have to wait for the PDD study results and see if the Fox Foundation hypothesis rings true for AVXL 2-73.
It will be interesting to see what happens when trading resumes.
Good point. Could be.
Yes, that makes sense. However, knowing too that generally speaking 80% of the patient population does not have the two variants that interfere with AVXL 2-73, adding 30 patients to the trial raises the possibility that we “swing high enough to reach the required level” that Investor is worried about. This may be especially true if these 30 patients were dosed with 30/50 mg. But, I realize that this is all conjecture for me or anyone at this point because no one knows for certain why or how the additional patients were added - I think I implied as much when answering the question that Generee asked me.
We were commenting about identifying patients that may benefit for AVXL 2-73 after I posted the following article from the LA Times: https://www.latimes.com/science/sciencenow/la-sci-sn-alzheimers-precision-medicine-20180726-story.html
Please read the article I referenced above.
Bio pointed out this quote from the article:
“As the researchers combed through more than 33,000 genes, they had a pretty good picture of what molecular processes (or pathways) Anavex 2-73 worked on. So they knew what they were looking for: gene variations that were likely to interfere with the actions of Anavex 2-73 and make treatment unsuccessful. They found two such genetic variants, present in about one-fifth of humans.”
So, 80% of the patient population should benefit from AVXL 2-73 if we exclude the 1/5th or 20% of the patient population that have the genetic variants that are likely to interfere with the actions of Anavex 2-73. Do please read the entire article from the L.A. Times that I referenced above.
Please also read Bio's posts today, and the responses to his posts. Why would Anavex add 30 patients to a clinical trial, which Anavex did with the PDD trial? We were attempting to piece together why Anavex would add patients to a clinical trial. Anavex did that for some reason, right? We were surmising that Anavex would not add patients to a clinical trial to fail, but would logically add patients to a clinical trial to succeed. Therefore, if you know that 80% of the patient population does not possess the two genetic variants that interfere with AVXL 2-73, it may be likely that Anavex added patients without these gene variants.
We were simply using deductive logic. We do not know for an absolute fact why Anavex added the patients. Therefore, there is no need for anyone to get all hot and bothered about what it is that I am saying except that this is certainly one logical approach to figure out why patients would be added to a clinical trial when, otherwise, there was no need to add patients to the clinical trial. So, if anyone cares to fire away in attempting to destroy this very logical approach, they can have at it and suit themselves.
Lastly, consider all of this in the context that Bio was responding to a post by Investor wherein Investor said that he was concerned that the PDD trial could “not swing high enough to hit the required level”. Investor has a perfectly legitimate concern, of course. However, adding patients that Anavex thinks may better respond to the drug may result in "swinging high enough to hit the required level", and we were having a discussion about that.
Now, that is truly amazing. Good for him.
Yes, we added 30 patients by design to succeed. Therefore, knowing what we know, how would we go about selecting those 30 patients to increase the odds for a successful trial?
BIOMARKERS: This is an older article from the L.A. Times. It is dated July 2018, wherein dementia specialists gathered at the Alzheimer’s Assn.’s International Conference in Chicago to assess Alzheimer's drugs. They discussed Biogen's drug and AVXL 2-73. Here is part of the article about Anavex precision medicine - BIOMARKERS. Missling mentions a swab test that easily and quickly identifies BIOMARKERS."
"In precision medicine (sometimes called personalized medicine), researchers work to identify the genetic factors that drive or contribute to a disease and build medicines that target the downstream effects of those miscreant genes. Then they use genomic sequencing technologies to identify just those patients who bear the distinctive genetic signatures their drug works on.
These drugs tend to be costly, and they don’t work on everyone. But when the right patients get the right medicine at the right time, treatments will be more effective and have fewer side effects.
“If you include a biomarker, which can be detected in a matter of hours or days by a swab test, then you can enrich a study” — enroll just the subjects most likely to respond — “and of course, improve the chances of success,” said Christopher Missling, president and chief executive of Anavex Life Sciences Corp.
Such new approaches to treating dementia could turn the tide in the discouraging search for Alzheimer’s treatments, said Dr. Deepak Bhatt, an expert on adaptive trial designs and precision medicine.
“Identifying which patients might benefit from a novel therapy using biomarkers or genetics will likely be a big part of how medicine is individualized in the future — so-called precision medicine,” said Bhatt, who directs interventional cardiovascular programs at Brigham and Women’s Hospital in Boston.
“This approach may be especially well-suited for therapies that might have side effects or are expensive,” he said. “While further confirmatory studies are needed for this particular Alzheimer’s drug before clinical use, the potential of personalizing care for such a devastating disease is exciting.”'
Note: The specialists at this conference discussed AVXL 2-73 and Biogen's drug. You can read the entire article here:
https://www.latimes.com/science/sciencenow/la-sci-sn-alzheimers-precision-medicine-20180726-story.html
Bio:
Exactly, as per the title of the book Extraordinary Popular Delusions and the Madness of Crowds & Confusión de Confusiones (Wiley Investment Classics) by Charles Mackey.
What was the market saying to “those that care to listen” when Biogen went from a little over $279.17 to $374.99 on February 5, 2020, because Biogen then moved to a low of $257.60 in June 2020 (down $117.99 from this year’s high in February)?
The edited transcript of the August 6 conference call is available here: https://www.yahoo.com/news/edited-transcript-avxl-oq-earnings-065349481.html
Here are some tidbits from the conference call (I may have missed something since I did this quickly):
It sounds like Anavex does not the data from the study yet. Missling in commenting about the PDD study said this, in part: "So I think once we have the data, we'll be able to hopefully be very aware of what's going on in this study."
In reference to the type of PDD study:
Question: "So it's very much a signal-seeking study. You don't have any, call it, biases in terms of effect size or anything that you're thinking about?
(Missling) Right. We just want to see a signal first, and that could be however it is, and that would be then -- certainly, we can move from there by sharing with the regulatory bodies and take it from there since it's a highly unmet need since now almost 80% of all Parkinson's patients develop dementia."
Later Missling said this about Anavex reporting the PDD results/data: "We said this quarter. And also, it will definitely be this quarter. I don't want to go in more specifics. We will report exactly when we have the data."
Missling was vague about what would happen after Phase 2 of the PDD study (whether there would be a Phase 3): In terms of your second question, if the Phase II is positive, we would share it with the FDA and then take the steps from there, what would be the right way to approval or the appropriate next step for seeking approval."
But apparently Anavex has information from whatever is done in any extension of any study"
"So we have, in all our studies, an extension. So both the U.S. Rett syndrome study as well as the Parkinson's dementia study have an extension. And so the extension for the Rett syndrome study is 12 weeks in the U.S.; 1 year, the AVATAR study; and it will be also 1 year in the EXCELLENCE study in Rett syndrome; and it's 1 year in the Parkinson's dementia study; and it's 2 years in the Alzheimer's IIb/III study. All these extension studies have not only the biomarker, but also the underlying randomized, placebo-controlled studies have the biomarker, including the genetic analysis included. So we don't have to wait for readout of the extension study to learn about that."
Missling commented about expanding RETT study to Asia/Japan:
Yes. Last question is, do you see -- does one see Rett as being a challenge to Asian communities? And is there any corporate strategy to broaden potential access to those countries through maybe partnering or other endeavors?
There is, indeed, the same amount of Rett patients in Asia, especially in Japan and China, but especially in Japan, there's a same amount of patients there than here in the U.S. So it's around about 10,000 to 15,000 patients in Japan alone. And we do plan, after the readout of the U.S. study, which is forthcoming, to then move into the Japanese territory to also continue the study with ANAVEX 2-73 in Rett patients in that regard.
And would those be studies you conduct? Or do you think it may be best to do that in collaboration with a partner?
(Missling) Right. So Japan is a unique market where the entities working has to be local. So there are probably a mix of a local sponsor with us together or to a 0. We have not made a final decision on that yet.
Thanks.
Prescriptions can be filled by pharmacies that specialize in Special Access Scheme (SAS) Medicines such as this pharmacy:
“We specialise in the supply of Special Access Scheme (SAS) medicines and have access to a network of Australian importers and also directly source from Europe and the United States where required. If the medicine is not used regularly, it may be difficult to obtain.”
https://swhpharmacy.com.au/services/sas-medicines/
Precisely, thank you Bio.
Frrol: It seems that the patients involved in this scheme/study and their families may communicate about their experience with AVXL 2-73 with any other AD patients or anyone else for that matter. What do you think?
So, it appears there was a poor presentation from all of the angry posts. I was busy today, and have some catching up to do. However, from reading the posts, I see nothing that changes my mind about Anavex's products' potential. Anavex does have its limitations, though. It lacks the art to engage and deliver information to its audience because it is a small company with restraints that are manageable given time. A bad day in a presentation is not the end of the world. Falling on your ass is not a significant event - getting up is! There is only one way to move, and that is forward. Anavex will move forward, and it will get there. It has come a long way with limited resources. Today might have been a step backward, but Anavex has made many steps forward. That is how we make progress.
The TGA approved the Special Access Scheme for AVXL 2-73 may be tantamount to a continuing clinical trial of the drug at little or no cost to Anavex. And, since "...physicians have requested extended treatment of their patients with ANAVEX®2-73 (blarcamesine) beyond these 5 years...", as today's announcement states Anavex already has a number of patients participating.
Additionally, I believe this will lead to new AD patients participating as well. I believe the Special Access Scheme allows any AD patient to apply to use this drug. See this:
"Access Programs and Why We Need to Tell Physicians About New Medicines Available to Patients. When it comes to healthcare, Australians are fortunate.
We have a world-class health care system that includes an amazing government initiated and managed scheme to ensure that new drugs – perhaps already approved internationally -- can be made available in this country, with the approval and supervision of treating doctors.
This scheme is known as the Special Access Scheme (SAS) and was introduced by Australia’s Therapeutics Goods Administrations (TGA) “in recognition that there are circumstances where patients need access to therapeutic goods that are not on the ARTG”. (https://www.tga.gov.au/form/special-access-scheme).
https://www.stabiopharma.com/index.php?q=access-programs-and-why-we-need-to-tell-physicians-about-new-medicines-available-to-patients1.html
Lastly, Australia has a universal healthcare system, and I think that there may be some government incentives for AD patients to have access to a drug that may potentially benefit the patient and lessen the government's burden for having to care for AD patients. For example: The NDSP is an Australian Government-funded program that directly supports people living with dementia and their families and carers.
https://www.health.gov.au/initiatives-and-programs/national-dementia-support-program-ndsp#what-is-the-ndsp
I think it is notable that the AD patients' physicians requested extended AVXL 2-73 treatment of their patients according to today's announcement.
".....the ANAVEX®2-73-003 phase 2a Alzheimer’s disease trial will continue treatment with ANAVEX®2-73 (blarcamesine) via the Australian Government Department of Health - Therapeutic Goods Administration (TGA) compassionate use Special Access Scheme following completion of over 5-years daily dosing of ANAVEX®2-73 (blarcamesine) and recommendation by their physicians.
.....it is pleasing that physicians have requested extended treatment of their patients with ANAVEX®2-73 (blarcamesine) beyond these 5 years.”
Whatever you make of today’s news, I see it as having a foot in the door in the moving forward. Say what you want, I like it! May society one day benefit! Sokol
Yes, Bio. Your exceptional perception/insight is extraordinary as well. Thank you. Sokol
No, Steady T is correct: See this:
Access Programs and Why We Need to Tell Physicians About New Medicines Available to Patients
When it comes to healthcare, Australians are fortunate.
We have a world-class health care system that includes an amazing government initiated and managed scheme to ensure that new drugs – perhaps already approved internationally -- can be made available in this country, with the approval and supervision of treating doctors.
This scheme is known as the Special Access Scheme (SAS) and was introduced by Australia’s Therapeutics Goods Administrations (TGA) “in recognition that there are circumstances where patients need access to therapeutic goods that are not on the ARTG”. (https://www.tga.gov.au/form/special-access-scheme).
https://www.stabiopharma.com/index.php?q=access-programs-and-why-we-need-to-tell-physicians-about-new-medicines-available-to-patients1.html
It may take some time for investors learn about and to digest this, but it is good news to me in any event.