Replies to post #74467 on Amarantus Bioscience Holdings Inc (AMBS)

[zoomboom]

Wrong again on MJFF and AMBS

[blackhawks]

MJFF is firm with their notion that NFs have to go through an alpha syn model. That said, Jason has not considered this in his evaluation.

I hightly doubt that you can cite a quote from the MJFF that they are 'firm with their notion....' as they are a science-centric/driven organization where 'notions' cannot by definition be held firmly.

Considering the thoroughness/comprehensiveness of Jason's analysis I'd say that it is highly unlikely that he did not consider "that NFs have to go through an alpha syn model". (Perhaps you could email him with YOUR notion?)

Equally unlikey that Amgen missed it too. And of course Gerald, his father and every one on his board of advisors would have to have missed it as well.

However, all of the research regarding MANF treating chemically induced PD is obsolete now that we know how PD is caused.

Can you furnish a link from either the MJFF web site, or any other source, that confirms that "we now know how PD is caused"?

I myself am having difficulty finding certitude on that point.

[expediter13]

However, it is reasonable to test MANF in primates to see what will happen. It is also reasonable to test it against Alpha syn. To that end, it will get research dollars.

Hopefully you will be available when the time comes.

[Old Hillbilly]

This thread was broken and some replies can be found here:
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=88250742
Glad to help new readers get all views.
It was a former "Sticky" as well but was replaced with current newsworthy info.

[joboggi]

MJFF is firm with their notion that NFs have to go through an alpha syn model. ( Email correspondence )

This has not been considered in the many writings of JN from Seeking alpha. This impacts the market value of MANF as it pertains to PD. MANF in PD has been tested on the chemical model of PD, not the alphasynuclein model of PD. This is becoming the accepted model of PD.

PD is an alphasynucleopathy. Now, it is not known, in all cases, what causes this pathology, but there are a number of similar diseases that share a similar pathology.

http://www.ncbi.nlm.nih.gov/pubmed/14502652

"
The term synucleinopathies is used to name a group of neurodegenerative disorders characterized by fibrillary aggregates of alpha-synuclein protein in the cytoplasm of selective populations of neurons and glia. These disorders include Parkinson's disease (PD), dementia with Lewy bodies (DLB), pure autonomic failure (PAF), and multiple system atrophy (MSA). Clinically, they are characterized by a chronic and progressive decline in motor, cognitive, behavioural, and autonomic functions, depending on the distribution of the lesions. Because of clinical overlap, differential diagnosis is sometimes very difficult. Parkinsonism is the predominant symptom of PD, but it can be indistinguishable from the parkinsonism of DLB and MSA. Autonomic dysfunction, which is an isolated finding in PAF, may be present in PD and DLB, but is usually more prominent and appears earlier in MSA. DLB could be the same disease as PD but with widespread cortical pathological states, leading to dementia, fluctuating cognition, and the characteristic visual hallucinations. The deposition of aggregates of synuclein in neurons and glia suggests that a common pathogenic mechanism may exist for these disorders. Even though synuclein may play an important role in disease development in these disorders, in light of the different symptom complex and prognosis and management issues that characterize each disorder, we think that the term synucleinopathy has little practical value as a diagnostic term for the clinician. Clinicians should attempt to reach standard clinical diagnosis on patients, such as PD, PAF, or MSA"



"
Alpha-synuclein is a 140 amino acid neuronal protein that has been associated with several neurodegenerative diseases. A point mutation in the gene coding for the alpha-synuclein protein was the first discovery linking this protein to a rare familial form of Parkinson's disease (PD). Subsequently, other mutations in the alpha-synuclein gene have been identified in familial PD. The aggregated proteinaceous inclusions called Lewy bodies found in PD and cortical Lewy body dementia (LBD) were discovered to be predominantly alpha-synuclein. Aberrant aggregation of alpha-synuclein has been detected in an increasing number of neurodegenerative diseases, collectively known as synucleopathies. Alpha-synuclein exists physiologically in both soluble and membrane-bound states, in unstructured and alpha-helical conformations, respectively. The physiological function of alpha-synuclein appears to require its translocation between these subcellular compartments and interconversion between the 2 conformations. Abnormal processing of alpha-synuclein is predicted to lead to pathological changes in its binding properties and function. In this review, genetic and environmental risk factors for alpha-synuclein pathology are described. Various mechanisms for in vitro and in vivo alpha-synuclein aggregation and neurotoxicity are summarized, and their relevance to neuropathology is explored."

http://www.ncbi.nlm.nih.gov/pubmed/15737408
http://www.ncbi.nlm.nih.gov/pubmed/11193145
http://www.ncbi.nlm.nih.gov/pubmed/14502650
http://www.ncbi.nlm.nih.gov/pubmed/15094295
http://www.ncbi.nlm.nih.gov/pubmed/12794302


So while we do not know what causes the alpha syn difficulty in all cases, this is associated with PD, and it is thought to be the

No one has attacked those mutant forms of alpha syn yet, and I am expecting them to do so at some point. That may or may not work but it certainly needs to be tested. Now, since they do not know what causes the alpha syn in all cases, there may be another agent or process that causes that pathology to ensue.

So, in that sense, they do not know what causes PD, but in a more general sense, they have known for some time a lot of what causes PD in the human body, and it has nothing at all to do with the chemical model induces in rats.

I would submit that is why ALL of the NFs have failed in Humans.

As best as I can evalutate, after reading enough of the literature to make a reasonable assessment, MANF is a reactant to the inflammation and death caused by the mutant alpha syn. As it helps with cell death in the ER in other processes, it does so in PD, but it ultimately fails.

That means it helps a little in delaying the onset of PD, but ultimately fails because it does not attack the root cause. Difficulties with delivering MANF will more than likely keep it from being a disease modifier for PD.

However, it is reasonable to test MANF in primates to see what will happen. It is also reasonable to test it against Alpha syn. To that end, it will get research dollars.

We've known about alpha syn for more than 10 years but for some reason the main focus of research has NOT gone through alpha syn. That has wasted a lot of money on GDNF and Neurturin.

RP - is terribily indolent. Given that MANF shows improvement in the pathology in RP I suspect that it will work in humans here, because the damage is not yet done in RP. In Parkinson's and in Wolframs, the damage is already done by the time you find the patient. In RP, while the conclusion is inevitable, blindness takes decades to develop.


Wolfram's THis is a genetic disease. While MANF does show improvement in the ER in the pancreas that may delay the DM, there are standard treatments, that are not expensive for DM. A biologic llike MANF would be very expensive treatment. It would have to cure the DM in Wolfram's which is caused by the genetic disorder that causes Wolframs in the first place, and so I doubt that a cure would ensue.

Regarding Lympro
1. Before they bought Lympro they had 98 and 95 % sen and spec
2. Results from the Phase 1 study show the scoring model was able to differentiate between AD subjects and other demented subjects (e.g. with PDD or MCI) with co-positivity (sensitivity) up to 91% and co-negativity (specificity) up to 92% relative to the clinical diagnosis of AD.

Between AD subjects and non-AD subjects we found a co-positivity of 88% and a co-negativity of 82%. The separation between AD and OD was particularly apparent, with a SI score at 0.55. This can be seen in the graph below where red bars represent patients with probably AD and the blue bars represent patients with another form of dementia (in this case Parkinson’s disease dementia). The study investigators also found a 95.6% correlation on AUC relative to clinically diagnosed AD compared to OD. Source: Stieler at el; Neurobiology of Aging 33 (2012) 234–241

http://finance.yahoo.com/news/meeting-amarantus-confirms-fundamental-turnaround-160000478.html

This says two things.

a. Lympro could differentiate between AD and other dementias with a sen os 91% and spec of 92%.
b. Lympro was able to differentiate between AD and Non AD with a sensitivity of 88% and a specificity of 82%.

3. In October the company did not release any numbers even though they announced that the test had been verified. This is never done. The sen and spec for that study need to be released before you can judge anything. Not releasing that data, and just SAYING that it is great is totally laughable.

4. The company did just announce that MemoryDx may have come up with a better assay. There are no numbers published yet, and certainly no peer reviewed data.
http://ir.stockpr.com/amarantus/company-news/detail/1254/amarantus-acquires-additional-rights-to-lympro-test-from-memory-dx They are calling this Version 2. During a study, you are supposed to be blinded, so you should not be able to say that the version 2 lympro is going to be

"Assuming Lympro's Phase II success, which would clear the way for CLIA approval and commercialization in 2H2014, investors will have to wait until the completion of Eli Lilly's solanezumab Phase III trial on Autosomal Dominant Alzheimer's patients in December 2016 to see if these asymptomatic patients respond to it, as signified by delay in the disease. If they do, LymPro could prove to be a lot more crucial to the Alzheimer's world than we all thought."

This is a way of saying until there is a treatment for patients who do not have the disease but are destined to get AD, there will be no market for a test given to patients who do not yet have AD. Since this article was written we found out that the Sen and Spec was 81 and 82% for figuring out amongst all comers who would get AD.

now, in that setting, you would actually DO the Lympro and then figure out where Lympro failed so that not all would get treated by doing LPs, PET scans which would take care of things.

However, "investors will have to wait until the completion of Eli Lilly's solanezumab's phase III trial on Autosomal Dominat Alzheimer's patients in December 2016 to see if these assymptomatic patieints respond to it, as signified by a delay in the disease."

And there is absolutely no guarantee that essentially 2017 is the date when Lympro will be used in this very small group of patients. All other treatments for AD have failed, and there are somewhere around 100 compounds that have not worked so far.

Note that these patients have a genetic predisposition to AD ( a rare case ) And so that will decrease the population that gets a lympro test for this reason.

http://seekingalpha.com/article/1773372-amarantus-lympro-may-be-more-crucial-for-alzheimers-treatment-than-we-think

Again, I realize that the SA writer used diplomatic speak, but he DID say that the pertinent study that could result in the use of Lympro will come out in Dec 2016. Essentially 2017.

Again, I would say that is a very generous estimate, and by then the Georgetown test will be close to approval. That is two and a half years away.

Note, like JN, the target of .20 for AMBS by the end of the year, 2014 is repeated by this writer. .20 with a billion shares out there then a 1/25 RS takes you to $5.

That is the data. I say that #1. the .20 is arbitrary, and at around $200 million dollars for a company with no revenue and no clinical studies, is about three times too much in terms of valuation. Remember that JN put on that price target for the end of 2014.

#2, the need for the test, based on the Amvid experience is not as high as you might think.

#3 The consideration that this test will cost $1000 + makes this a pie in the sky effort. In one presentation from last year, GC noted costs would be $70 and priced the test at that time between $300 and $500. Now they want more money for a test that will only do one thing.

Tell far too many people who are not going to get AD that they are going to get AD.


Regarding Eltoprazine

1. The Primary reason this is not a likely candidate for LID Rx is that it makes the PD worse.

2. It did seem to work better for LID when combined with Amantidine in the study. However, Amantidine is the standard, and so you would have to prove that Eltoprazine did something on top of Amantidine to alleviate the LID.

Taking all of this and more in consideration, and looking at comparable companies who have no products and no clinical trials, the market cap should be 60-80 million.

Now, PRs are the bread and butter of penny stocks. and so, I would not be surprised to see this stock go to 25 cents.

I will be modifying this post again soon. That will put more data in this post. It will not change the overall perspective.