Don't remember saying that I did "know more than anyone else".
Here, I presented facts with very specific references.
You can take them as positive, negative, or neutral.
I see that you have taken them as negative, but the important point of your post is that it is 100% void of any contribution to the discussion/debate.
I am not responsible for your gamble on this stock. You placed the bet, you ride it. You have entrusted management and purchased their wares. If you have a beef, take it up with those from who you gave your money. If you expect everyone to toe the line so that you may execute some self serving monetary end, then you are in the wrong Country my friend.
Regarding the Athersys/Pfizer failure to release the full UC trial results.
This is exactly what Osiris Therapeutics did after their Prochymal myocardial infarction trial. They released very limited information, inspiring Adam Feuerstein to write TheStreet article, "How to Tell When A Drug Company Fibs About Clinical Trial Results".
Actually the information that Osiris did release was good...
Nevertheless, Mesoblast followed this "Fib" with a total Prochymal transaction worth up to $100 million in initial consideration and milestone payments. Additionally, Osiris will receive royalty payments on sales of Prochymal and other products utilizing the acquired ceMSC technology.
So, this lack of information to "shareholders" is par for the course, but remember Osiris's Prochymal was already approved in several countries for GvHD (first to market) before the Mesoblast deal.
However: "So far, in vitro studies showed comparable suppressive effects for hMSCs and hMAPCs, although the broader expansion capacities of hMAPCs make them more attractive for clinical use."
Immunol Cell Biol. Jan 2013; 91(1): 32–39
So, is ATHX worth about 1.28 PPS at the local pawn shop if the Stroke trial fails? Is Osiris supernatant extraction technology capable of negating the broader expansion capacities advantage of Multistem? Keep in mind that the environment inside the damaged body does promote the cells to produce some of their "goodies"...
Place your bets, and let the games continue lads!!!
How can supernatant contribute to scalability?
As Gil has said, Multistem does not engraft to any meaningful extent. The cells die and are absorbed over the course of about three days. Two days after infusion, the Multistem population will be about half, and at the end of three days, almost entirely absorbed. Absorption occurs primrily in the lung, liver, and spleen. The benefit of molecules secreted by Multistem over these three days must maintain benefit for the therapy to succeed.
Prochymal is not as scalable as Multistem, but like Multistem it can be maintained in culture for a prolonged periods of time. Unlike the hostile environment of the host, optimal culture conditions can maintain the cells over time, allowing them to essentially serve as factories secreting active molecules into culture to be harvested and concentrated over time in the supernatant. In this way, cells that cannot be easily multiplied or die quickly in the body can be maintained in culture to generate high concentrations of compounds that, in this way, achieve virtual scalability. This is perhaps even superior to scalability because a billion Multistem cell may not be able to carry or produce this much active ingedient once infused. In fact Athersys may need to consider supernatant spiking of their cells.
As for the current Athersys trial, Gil should have found a partner like Mayo Clinic to conduct an Institutional Sponored Trial (IST) so that a recognized expert in the field could try multiple doses or even add supernatant to define what works before diving headlong into a high risk phase 2 trial with only a single dose. Make no mistake about it, Gil's single dose trial is high risk because what if it takes three doses to succeed? We would never know it. Gil is definitely going double of nothing on the stroke trial. They recently saw the light with their last minute global assessment changes, but this only let us know they know there is a problem.
I agree with this and moneygrubber13's comment in that both a secondary endpoint success would be a Multistem win as well as your comment that possible inhibition of further damage may make room for natural recovery and a possible successful primary outcome measure. But, I would be giddy with anything successful in the secondary. This would be enough for me.
But what you point out as the primary benefit of Multistem is measured in the secondary outcome measures rather than the primary which is "recovery" based on global test analysis.
We really need to examine this some more.
I think at the time Randy Mills and Peter Friedli of Osiris knew Multistem was more scalable and possibly more effective. Gil often attempted to drive this point home when he and Randy attended the same meetings.
But, Osiris made a good move, they leveraged GvHD as their first indication and got regulatory approval in several countries outside the USA. They then sold Prochymal for $100million plus royalties to Mesoblast to focus on wound care which was already on market.
Essentially Randy thought stem cell regulatory approval in the USA would be a nightmare, so Osiris walked with the Mesoblast deal. Why Mesoblast bought Prochymal knowing Multistem could possibly be more effective is two-fold: 1. Supernatant could be used to compensate for scalability and 2. First to market, especially for GvHD in Europe. We all know first to market is key.
Meanwhile, Athersys is not first to market with GvHD, so they chose to roll the dice on high risk indications of inflammatory bowel disease, heart, and stroke. Inflammatory bowel crashed and burned, so now all the focus is on stroke. Myocardial infarction is extremely crowded and the Cedars-Sinai autologous heart stem cell transplant results look better than any bone marrow results.
So, stroke HAS to work.
It is the key indication where Athersys Multistem scalability really has a distinct advantage. For GvHD, there are so few cases, scale is not important unless physicians want to start all transplants with a dose of stem cells to ward off GvHD which could happen.
Regardless, for Athersys, all the chips are now on the table for the stroke trial.
The stakes could not possibly be higher. GLTA and hoping for any possible "signal of efficacy" as they say.
Multistem cells should be present in patients for 3 days, with a rapid decline from day 1 to day 3. Cells persist throughout this treatment window, and we hope during this time the cells continue to secrete beneficial factors into the spleen and less in the brain.
Interestingly, Osiris (now Mesoblast) has some patents for using purified cell factors collected from cell culture supernatant, essentially to spike their cells with their own product. Athersys could do this with Multistem as well. Instead of relying on Multistem cells to secrete beneficial compounds, simply collect the cell factors secreted into culture, concentrate it, quantify it, and use this to spike cells before administration the dose to patients. This would then be billions of cell equivalents in terms of "active ingredients". There are these options on the table.
All Athersys has to do is show any significant outcome, either primary or secondary. They can then make adjustments to maximize efficacy.
For the AIIMS trial, cells were given at a median was 18.5 days after stroke onset...too late.
They used autologous stem cells from the patients averaging 50 years of age. This is too old. Multistem is from a young donor. Osiris prefers 24 yrs or younger for Prochymal now owned by Mesoblast. So, the AIIMS study is not good because they wait too late to treat, and they treat with essentially old cells that do not produce sufficient beneficial factors. Osiris worked this out a long time ago.
Finally, and importantly, dose. AIIMS says its not that much of a factor, but it is. They used 280 million cells. Athersys is using billion+. If you look at Figure 2 of the AIIMS paper, the spread between the cell therapy arm and control arm is best at 90 days which is when the Multistem trial comes off.
Unfortunately, the lines are pretty tight for the AIIMS study, but with their bogus trial design all they did was muddy the waters of using stem cells for stroke. They gave too few stem cells, too late, and worst of all old cells harvested from dying patients. The whole thing is #$%$. I don't trust it, but its out there, so we have to deal with it.
Still what concerns me is Multistem dose frequency. One dose is probably not enough. And I wish they had limited the study to 24 or less of having the stroke. 48 hours is too risky because often the stroke is preceded by mini strokes and occurs at night so 48 hours may be even longer in reality.
This Multistem stroke trial is very much clinical research. We have a long way to go.
What is this, sarcasm?
Now, if we had only left Saddam alone maybe we would not have ISIS and 3 trillion in debt for WMDs we have gave Saddam to use against Iran. But now we do have ISIS and the debt clock keeps ticking. Jeb will make it all good I am sure. In the meantime, invest in military contractors, right Ohmtaxi???
Ohmtaxi, basically the only evidence we have that Multistem works is animal models. We can only guess the possible mode of action via the spleen, but these are only guesses, wild gueses, WAGs. Gil has no more clue than we do other than to change stroke treatment as we know it for an unmet medical need with potential billions in profit.
We have the animal models, that's it. The dose, frequency, and timing are still very much up in the air. The results will speak for themselves.
According to the video, the 66 year old male patient featured in the video had a stroke 5 years ago, and now they are seeing improvement in 5 days? He is also receiving intense physical therapy. I attribute any improvement to the physical therapy alone. This phase 1 trial being conducted in India has been ongoing since 2010. The inclusion criteria are questionable.
An AIIMS found: New Delhi: Researchers at AIIMS have found stem cell therapy offers no additional benefit over conventional treatment for stroke.
The researchers said of the 120 patients, 60 patients were assigned to receive conventional treatment and the rest were assigned to bone marrow stem cells treatment besides the conventional treatment. They were assessed at an interval of three, six and 12 months and the difficulties they experienced doing various daily activities were measured using two scales—safety and benefits.
"During a stroke, some part of the brain is damaged irreversibly but there are neurons surrounding the affected portion of the brain which are sleeping even while some are inactive, energy-less and at the risk of death. It was believed that stem cells help wake up the sleeping cells, activate the inactive ones and save the dying ones thus accelerating the recovery. But the new findings do not give enough proof of that," said Dr Prasad. He added that the pilot study, conducted between 2006 and 2008 where 12 stroke patients were infused with bone marrow stem cells, had indeed shown some hope.
-Times of India
There are many things happening after stroke. Some in the spleen, some in the brain, and some between the brain and spleen and elsewhere...
"Spleen-derived cells, including neutrophils, lymphocytes, and monocytes/macrophages, are known to contribute significantly to ischemic brain damage."
CNS Neurosci Ther. 2014 Dec 5
Meanwhile in the brain:
UCLA researchers found that a rise in a chemical system known as "tonic inhibition" immediately after a stroke causes a reduction in this level of excitability.
But while this "damping down" initially helps limit the spread of stroke damage, the increased tonic inhibition level and reduced brain excitability persists for weeks, eventually becoming detrimental to the brain's recovery.
"It was surprising to find that the level of tonic inhibition was increased for so long after stroke and that there was an inflection point where the increased level eventually hindered the brain from recovering," said Dr. Tom Carmichael, associate professor of neurology at the David Geffen School of Medicine at UCLA and a member of the UCLA Stroke Center.
In short, we know that the brain is damaged within minutes following a stroke. Multistem likely prevents further damage and allows for repair by modulating the spleen response. How this may also modulate tonic inhibition, if it does at all, is not known. But Multistem seems to work in animal stroke models, so we think it might reduce tonic inhibition.
More info can be found at carmichaellab
Management already said this:
"If MultiStem is safe and there is a SIGNAL OF EFFICACY, a late stage phase IIb-III trial is planned." Int J Stroke. 2014 Apr;9(3):381-6
Gil has said and The University of Texas Health Science Center at Houston has published that the primary mode of action is PREVENTION OF FURTHER DAMAGE:
"The spleen seems to play an important role in some neurological disorders by contributing, for example, to ongoing inflammation and brain injury AFTER stroke. We're finding these stem cells are working on dampening inflammation involving the spleen."
-The University of Texas Health Science Center at Houston
"Most strokes happen suddenly, develop quickly and damage the brain within minutes."
Multistem is primarily for prevention of further damage. This is a secodary outcome measure. It will succeed on this basis which is ok.
Yes, I addressed why I deleted the post already.
The spinal cord injury treatment candidate mentioned in the Nature paper is protected by preliminary patent application (61/621,623) which is NOT shared with Athersys even though the PI of that lab does share other patents with Athersys.
Yes, the prevention of additional damage may afford some recovery, but the primary benefit is prevention of additional damage, and this is what we need to look at to succeed here. The decision makers are looking primarily at prevention of further damage which possibly aids some recovery. Regardless, if we can prove prevention of further damage, it is a technical failed trial but a long term winner. This is life my friend.
No, the Multistem stroke trial is designed to wait 24-48 hrs to eliminate the "30-40% of them that 'recover' on their own".
Second, you fall into a category of being "grossly overoptimistic in your expectation of treatment effect." You state that Multistem "works not just by limiting damage due to post stroke inflammation but also helps the brain 'recover'".
I understand what you are saying, but lets face it, single high dose Multistem by IV is much better at preveting additional damage than it is at brain recovery simply because most of the cells on target end up in the lung, liver, and spleen. Your suggestion that the primary benefit is brain damage recovery rather than prevention of further damage is incorrect based on where the bulk of the cells end up.
Mode of action and pathophysiology are aligned for prevention of further damage not recovery and this falls in the secondary outcome measures. I look there for success and expect any neuro remodeling to be buried by statistical noise among the placebo and treatment arms.
I could go on and on, but if you had to pick one, you would pick prevention of further damage over Multistem directly impacting neuro remodeling. If anything, the prevetion of further damage simply allows the neuro remodeling to occur. Any "factors" that directly benefit the brain are in too low a concentration in the brain by IV, so I give you neuro remodeling only as a benefit of the reduction of the spleen's response.
The success of this trial will be prevention of further damage, and this wil show up in the secondary measures. Prepare for a likely failed primary. The upside is, those in charge expect this.
Ohmtaxi, we are in the same boat. The difference is, I do not fear debating and probing and asking the hard questions. I think Multistem is likely a good medicine, but proving this is not going to be easy. Management would be happy with a signal of efficacy, and I would be too. If this comes from the secondary rather than the primary outcome measure, so be it. The PPS would drop like a rock until Pfizer jumps in for a phase 2b or phase 3. In this case, Athersys may not even release all the results as Osiris often used to do. But, I fully understand where you are coming from with your investment. If this works out for you, I hope you diversify into more conservative investments if this is not mad money for you already.
Stroke damange is done within minutes following the stroke.
Multistem is not going to change this at 24 or 48 hrs after a stroke.
What Multistem is expected to do is prevent ADDITIONAL brain injury following the initial stroke.
So if Multistem works by prevention of additional damage, patients on Multistem will not "recover", they just won't have the additional damage. So a placebo and Multistem patient could be given the same score and the placebo patient gets worse wherease the Multistem patients stays the same but does not "recover".
As I understand, prevention of additional damage (but no recovery) is measured by the secondary outcome measures including proportion of patients with a lower score.
I predict a failed primary outcome. Multistem patients will not improve so much as not get worse. A successful secondary outcome is likely because of prevention of further damage rather than "healing" or "recovery".
Nevertheless, I think a successful secondary outcome would be taken as a success, but we have to prepare for a failed primary because I do not think Multistem is capable of putting Humpty Dumpty back together.
JCC, take a look at this journal article on PubMed: Int J Stroke. 2014 Apr;9(3):381-6
They state in their conclusion: "If MultiStem is safe and there is a SIGNAL OF EFFICACY, a late stage phase IIb-III trial is planned."
Athersys management is saying all they need is a: "SIGNAL OF EFFICACY"
This means that if the primary outcome measure is missed slightly or the secondary outcome measures provide a "SIGNAL OF EFFICACY", there will likely be a phase IIb.
I suspect Athersys is already in negotiations with a big pharma (Pfizer) because Mesoblast (Teva) has already made their move by buying Osiris's bone marrow stem cells "Prochymal" for stroke. Teva market cap is 54.75B, so the big boys are in play. Trust me, Athersys is in negotiations.
I do not expect gangbuster results from the current phase 2 Multistem stroke trial. What I expect is a "signal of efficacy", and I suspect this is what Athersys' big pharma stroke partner is looking for. The trial is underpowered. So, in this case, a failed trial with a signal of efficacy is expected because of insufficient patient numbers. Athersys and their partner know this.
The current phase 2 Multistem stroke trial is very much tasting the stew before the main course so to speak.
The next step will be to take these results and re-tool for another phase 2b to nail down dose frequency and timing. It could very well be that 24 hrs post-stroke it works, but 48 hrs after a stroke is too long. Also, we likely need a second or third dose and markers to guide this. There is still a lot of work to do here.
Bottom line: A "signal of efficacy" would mean that we do not lose all our money. We have some cushion for success...we have some wiggle room to put Multistem for stroke on the market. The reason we know this is because management said it. They said all we need is a "signal of efficacy". I take this as very rational thinking for this very small trial.