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I appreciate this feedback and it makes sense. I guess what I am thinking is that some sort of animal study needs to show histologically that new myelin is appearing. Thx.
They will speak to the issue of differentiation but I am not sure they will say anything about remyelination at this point in their research.
Sorry remyelination
That is exciting news to me because actually demonstrating demyelination as opposed to just differentiation is akin to a holy grail for MS.
It's important in that A2-73 causes oligodendrocyte precursor cells to differentiate into mature oligodendrocytes. It takes a mature oligodendrocyte to create myelin. DM does not do this. I don't know of any other drug besides A2-73 that does this. Someone correct me if I am wrong. I suspect that BIIB is now working on finding out if these mature oligodendrocytes stimulated by A2-73 actually create new myelin. If they do, this is a big deal.
I am hoping soon to see that the company is actually making money. In other words signing actual contracts with hospitals and, even better, hospital systems.
Sorry, they have not actually verified remyelination.
My understanding of the WSU data is that A2-73 was shown to cause differentiation of OPC's into oligodendrocytes. Although these are the cells that bring about remyelination, they have not actually verified demyelination. If I am wrong, I would appreciate a link to that data. Thx.
S1 agonism coupled with agonism of various muscarinic receptors does appear to be unique to A2-73. No?
Good question. I don't have a specific reference, just what I have read on this board over that past couple of years and Anavex's web site. I have in my notes, however, that A2-73 has specific preclinical validation in 10 different neurodegenerative diseases. These include Alzheimer's, Parkinson's, depression, epilepsy, anxiety, infantile spasms, Rett Syndrome, Fragile X Syndrome, MS, and Angelman Syndrome.
A2-73 has already been successfully tested and validated in animal models of MS.
The company stated that there are 100 million surgeries performed yearly in the US. Do you have a sense as to how ORHB is going to charge for its software service, i.e., so much per surgery or so much per month? Also, it seems to me that the demand for this service would be large considering that companies that own hospitals such as HCA, Tenet, Lifepoint, etc. all have declining revenues.
Randy--I have a question regarding how a software-as-a-service company is valued. I have read that Wall Street values these companies on the basis of revenue generation. In other words, the market cap would be a certain multiple of revenues. Some people call this the price/sales ratio. Adobe, for instance, has a P/S ration of around 11. Salesforce has a P/S of around 8. Legacy software companies, such as Oracle, are valued lower, having a P/S ratio of 3-6. How do you think ORHB's valuation would fit into this valuation model given that it is on the pink sheets and has no "track record"? Also, do you know of any particular compettition for ORHB in this space?
They may be but their parents won't. The Duchenne Muscular Dystrophy parents spoke loud and clear.
The success rate of AD drugs that make it to P3 is 20%
I agree with you. I was merely trying to counter F1ash's statements regarding A 2-73's chance of success based on the overall statistics for AD drug candidates. My post was an argument that there are different ways to look at statistics.
I would say that 100% of drugs that targeted amyloid plaque failed. To my knowledge, none of the 4 drugs approved by the FDA for AD targeted amyloid plaque.
As has been posted before, 99.6% of all drugs tested for AD have failed. This means that 0.4% of these drugs were successful and were FDA approved. According to Missling and others, only 4 drugs have ever been approved by the FDA for AD. So 4 drugs represents 0.4% of all drugs tested. This means that only about 1000 drugs have been tested. It has also been posted a number of times that only 2% of incepted compounds made it to P3. So, 2% of 1000 is 20 compounds that made it to P3. Of these 20 compounds, 4 were FDA approved. This is an approval percentage of 20% for those drugs that made it to P3.
Alzheimer's, Parkinson's, MS, Huntington's could be considered "subtypes" of neurodegenerative disease.
I suspect Rett parents will voice their opinions in an equally strung way if they see clear benefit to their girls from 2-73.
Eteplirsen treats Duchenne Muscular Dystrophy which, like Rett's, is a rare disease.
Sarepta Therapeutic's drug eteplirsen was approved by the FDA a year ago based on a 12 patient trial with no placebo arm.
I suspect that PFE misses the $3 billion it used to make from Aricept.
One thing I might add in regard to the upcoming Rett trial. Rett's is a rare disease. Another rare disease is Duchenne muscular dystrophy. Last year the FDA approved Sarepta's drug eteplirsen for that disease after a 12 patient trial which did not have a placebo arm. Vocal parents who could see firsthand the beneficial effects of the drug had a lot to do with that.
I agree with you. DMD is a rare disease with no or minimally effective therapy and the parents were committed and vocal. I hope the RETTs parents are the same.
Eteplirsen was approved last year by the FDA for Duchenne muscular dystrophy based on a 12 patient trial with no placebo arm. No secret sauce was mentioned.
In regard to the upcoming RETT trial as well as A2-73's safety record and preliminary efficacy results, it might be useful to review the events leading up to last September's FDA approval of Sarepta's Duchenne muscular dystrophy drug, eteplirsen. Most of this information comes from an article written by Ed Silverman, a senior writer for Pharmalot, who covers the pharmaceutical industry.
The approval of this drug was very contentious. The decision came after months of debate about whether Sarepta had provided enough evidence to demonstrate that eteplirsen had a meaningful impact on patients. "A key issue was whether the drug can sufficiently produce higher levels of a protein called dystrophin. Without this protein, muscle fibers degenerate and voluntary movement becomes impossible. The FDA also raised doubts about the results of a small, 12-patient clinical trial that Sarepta relied on to make its case....Moreover, the company failed to conduct a larger trial involving the use of a placebo, as the FDA had requested. In light of these concerns, an FDA advisory panel in April (2016) voted that the drug not be approved and, by a narrow margin, also agreed that the drug does not appear to be effective. Those decisions were made at a day-long meeting that was punctuated by a parade of emotional pleas from parents and children, some of whom appeared in wheelchairs. Despite the outcome, the agency appeared to signal that parents should not lose hope. In remarks designed to appease the crowd, Janet Woodcock, who heads the agency division that approves drugs, said that "It's possible to reach different conclusions based on the data presented today...Failing to approve a drug that actually works in devastating diseases--these consequences are extreme." And so, the FDA made an unexpected request for Sarepta to provide more data about muscle biopsies from 13 boys who participated in the ongoing trial in order to determine the extent to which the medicine may produce dystrophin. THE MOVE SUGGESTED THAT THE FDA TRIED TO FIND OTHER WAYS TO APPROVE THE DRUG."
Five months later, in September, 2016, the FDA approved the drug. "In reaching its decision, the agency essentially overruled its own medical staffers, who earlier in the year questioned the effectiveness of the drug, which was tested in a small clinical trial. The wrangling raised still larger questions about standards for approving a drug, especially when it's intended for patients with a rare and deadly disease and no other treatment options." "In rare diseases, new drug development is especially challenging due to the small numbers of people affected by each disease and the lack of medical understanding of many disorders," said Dr. Janet Woodcock. As a condition of the approval, Sarepta will have to conduct a two-year randomized control trial to verify the clinical benefit of the drug.
The approval delighted a frazzled, but vociferous community of parents, whose determined lobbying efforts were reminiscent of the movement three decades ago to force regulators to green light AIDS treatments."
"The fate of the Sarepta drug has been closely watched as a litmus test for an intensifying struggle between the FDA and patient groups that want the agency to take a more expansive view toward approving medicines for unmet medical needs. In this instance, patient advocates hoped the FDA would use the accelerated approval process to endorse eteplirsen. This approach relies on a substitute outcome in a clinical trial to suggest a drug may have, but does not guarantee, a benefit."
Subsequent to all of this, as we all know, the Twenty First Century Cures Act has been passed. Part of the drug approval process under this act is the patient's and caregiver's perspectives on how the patient is responding to the medicine. The FDA stated that "Real world evidence and the stronger inclusion of patient perspectives on endpoints are two examples of the shifts that will impact therapy development." In this regard it seems significant that RETT parents are extremely involved and, in regard to A2-73, all patients wanted to continue the medicine after the end of the trial. Also the Australian media exposure supports very strong patient and caregiver responses. Additionally, in regard to potential accelerated approval and substitute outcomes, the impressive EEG/P300 results could qualify for that as, according to MacFarlane, "these are the kinds of studies that got donexepil approved by the FDA." Moreover, a positive outcome from Biogen's remyelination tests on A2-73 might also qualify, particularly in the context of A2-73's safety record.
Appreciate your opinion. The Rett Foundation's funding of A2-73's Rett trial has been stated I believe to be a "minimum" of $600K. This will likely be the shortest trial, stated to be 3 months, with potentially early read-outs for certain end-points such as seizures. If positive this may "move" the stock and make funding easier in various ways. However I realize that my opinion at this point is based on hope, not fact. Probably why I'm not the best investor.
It may not be insufficient if you factor in the Australian government, the RETT foundation and MJFF.
Where and when did he say that? Can we have a link?
Missing said he would partner for commercialization.
How would you know this prior to a dose-optimized P3 trial?
Frrol--I may be wrong, but I have in my notes that A2-73 has positive dose response at 5 and 31 weeks for Alzheimer's in 2 independent cognitive markers (MMSE and ERP/P300). It also has a positive dose-response curve in preclinical for Rett Syndrome.
This is a great question. How do you partner for one neurodegenerative disease when the drug could be used off-label for the other CNS diseases? This would make the negotiating process for partnering very complicated.
Missling has stated that they would need to partner for commercialization. He has not stated that they need to partner for anything else.
Thanks for the unsolicited advice. Can you direct me to an Anavex SMB where the "good sense" is better? I find Anavex's planned "multiple regulatory filings" by a 24 year FDA veteran to be intriguing.
Emmanuel Fadiran, Anavex's new hire from the FDA, is said to be in charge of regulatory filings. A company statement said that Anavex has a number of upcoming regulatory filings. Does anyone have a good sense of what these regulatory filings might be?
My point was that A2-73 has been shown not to be sedating. Nevertheless, 8 out of 8 patients who had symptoms of insomnia improved relative to those symptoms. This suggests that it does not have to be sedating to have efficacy for insomnia.
It is incorrect to say that if A 2-73 were effective in treating insomnia that it causes somnolence. In fact it has been shown to be non sedating.
Let's talk again after we get some data from the Retts P2 Trial.
Yes that's OK.