Pfizer is going directly after the small molecules secreted by Multistem. They wanted to see if there was a hint of efficacy. If so, they can leave Multistem and synthesize what Multistem produces to sell it as a combo small molecule therapy.
They do not plan to mess around with variable cell cultures that could become infected in bioreactors or deal with batch to batch (donor to donor) variation. I suspect they got what they wanted and will soon cut bait.
By designing trial to fail, they got their efficacy data in terms of a biochemical reponse and can drop Athersys and the patients like a sack of potatoes.
Pfizer screwed Athersys by giving a single dose.
They should have known better based on Osiris results.
Extended Evaluation of PROCHYMAL® Adult Human Stem Cells for Treatment-Resistant Moderate-to-Severe Crohn's Disease
This study has been completed.
Study Start Date: October 2007
Study Completion Date: July 2009
Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)
May 6, 2010
Osiris Restarts Phase III Prochymal Trial in Crohn Disease Following Interim Analysis
"To understand the significance of this trial, it is important to appreciate just how sick these patients were," said Dr. Onken. "On average, they had suffered with Crohn's disease for 14 years and were unable to find relief with currently available therapy. It was in this difficult-to-treat population that we observed clinical improvement upon administration of the stem cell therapy."
Drug: PROCHYMAL adult human mesenchymal stem cells
intravenous infusion four times over two weeks; possibly repeated once
Osiris would never approve a bowel treatment design using a single dose to cure long-term UC patients.
Take a look at the Osiris (now Mesoblast) treatment design from 2007. Four doses.
Pfizer knew one dose of Multistem would not work! What a scam!
Look below, Osiris used FOUR doses minimum to get results.
*****Drug: PROCHYMAL adult human mesenchymal stem cells
intravenous infusion FOUR times over two weeks; possibly repeated once*****
Pfizer set their trial up to fail.
Ohmtaxi and Biospy, use your ignore button if you do not like what you read. The point here is that any buy or sell is likely too early to be based on any insider knowledge. We simply are not far enough along. Insider knowledge is very much possible though as I have explained.
However, the study is grossly under powered, and I have seen insiders with knowledge of failure buy into disaster. So insider buying means "0". It never has, and it never will mean anything. Even total holding means nothing.
This is a risky one, so bet only what you can afford to lose and hope for the best. Disclosure: I am long and have been for longer than most on this board. I assure you this.
Was Pfizer's "impossible to succeed" Multistem phase 2 for UC trial design (as admitted by Gil) an accident?
Key Programs in Registration / Phase 3
Xeljanz® (tofacitinib) – Ulcerative Colitis, Psoriasis (oral), Psoriatic Arthritis
The UC treatments were also double blinded as well, but I suspect they (safety, Athersys, and CRO) could see that nothing was dramatically different across all of the patients weeks or month(s) before the press release. They know the number of patients receiving Multistem vs. placebo, and it is simple enough to do the calculation to determine how many and to what degree of difference is required to meet the primary outcome measure. If there is no way to achieve p 0.05, regardless of knowing the treatment, then there is no difference, and the trial fails. Likewise, a big difference should reveal itself, although because it is blinded one could argue the placebo outperforms Multistem.
Stroke is difficult because of natural recovery, and Athersys really needs to enroll more patients. If they could enroll even 25 more patients in each arm, this might mean the difference in determining if there really is benefit or simply being unable to prove the difference because the design sucks as it did for UC and they were happy to progress this trial under Pfizer. Of course Pfizer has drugs for UC and benefits from a failed UC trial. Go figure. An investment to fail a trial makes perfect sense.
The enrollment number as it stands now for Multistem stroke is razor thin in being able to prove effectiveness, even if it does exist. More likely they will be unable to prove the benefit because of too few patients, which equates to a failure, and it "black lists" Multistem for stroke altogether. No one will want to pay money in the future to do another trial if the first trial fails.
The well will have been effectively poisoned. If Gil wants this trial to work, I suggest prayer. Otherwise the patients numbers are so low, I question the motivation here.
Management and CRO staff should be able to do the math and predict success or failure with a high degree of confidence at about 75-80% patient completion.
Medpace is the CRO.
Docs and staff at each enrolling hospital would have difficulty determining success or failure because of the lack of sufficient data at any one location and the fact that stroke victms do sometimes recover over time.
CRO staff, safety monitoring, and Athersys should be able to determine a trend early based on past history of stroke placebo outcomes. If it is close, it may be difficult to determine, but if the difference are large, the writing will be on the wall...early!
Again people in the know would be:
1. CRO staff
2. Athersys management
3. Safety folks who review data
All would have access to outcome data that could be compared to an established placebo trend to predict success or failure. I would say this data would be availabe by mid November if not before. By then, they should have a clue if the difference is substantial.
Sentiment: Strong Buy
I hope you are right about Japan and looking on the bright side if we miss the primary yet show significance for the secondary outcome measure(s). Missing the primary though would be brand damaging, no more grant money or easy retail money to move Multistem forward.
A failed phase 2 can poison the well, not just for the casual investor, but for the entire company. At some point, the institutional investors pull the plug. A failed strok trail will be the end of the road for Multistem. There are too many other options out there. Expecting second chances is being too optimistic.
Ohmtaxi, where is the money going to come from to keep the doors open? If the stroke trial fails, all confidence will be lost. I doubt Mesoblast is going to buy us out as they did Osiris. Gil does not expect to be successful at everything he does, but come on, how can Multistem survive another failure suggesting it is no better than chicken soup? We must succeed in the stroke trial.
Ah....yes....I know this.
Jakafi is for an entirely different indication.
The Jakafi example was to illustrate the need for multiple doses to affect the spleen.
Most therapies require multiple doses, but Multistem is different, it is "magical" and only takes one dose.
Anyone saying anything different is spreading "misinformation".
Rrrright.....Survtech10.....one dose it all it takes....got it.
Glad we straightend this out.
Sentiment: Strong Buy
Well, no, we lose our money.
Then someone else does another study.
This is interesting and extremely important.
I gave my numerical reference for the mRS as EDISON which includes mRS5 in the inclusion criteria.
However, on the Athersys website they use the NIHSS scale.
Why? Poor correlations between NIHSS and the Modified Rankin Scale.
Here is what they say on the Athersys website:
"The Phase 2 study is a double blind, placebo-controlled trial evaluating the safety and efficacy of MultiStem when administered to patients who have suffered a moderate to moderately severe stroke, as defined by a National Institutes of Health Stroke Scale (NIHSS) score of 8 to 20. Patients enrolled in the study receive a single intravenous dose of MultiStem therapy or placebo in the 24 to 36 hours following the stroke, which is a significant extension of the current treatment window over existing standard of care. The study is currently being conducted at multiple centers throughout the United States."
Again, poor correlations between NIHSS and the Modified Rankin Scale, so is Athersys confused about who is being included????
"For example, in the Phase II stroke study, up to 1.2bn cells can be administered in a single IV infusion, whereas the maximum MSC doses are around 400m cells. Yet even at these high doses, the cells do not appear to become a permanent transplant and are cleared from the body over time."
"Front Immunol. 2012 Sep 26;3:297
Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion.
These results demonstrate that MSC are short-lived after i.v. infusion and that viable MSC do not pass the lungs. Cell debris may be transported to the liver. Long term immunomodulatory and regenerative effects of infused MSC must therefore be mediated via other cell types."
With the current clinical trial design, Gil is assuming that a single dose of Multistem is enough, and he is EXCLUDING the possiblity that multiple doses may be needed. If he is wrong with his single dose hypothesis, we not only lose all our money but also any hope of revealing possible success with multiple doses.
We have here a case of a horrible experimental design that not only excludes multiple doses of Multistem but also excludes 5 to 3 Rankin score successes as well.
This is not a prudent clinical trial design but rather a wildcat design with a very high probability of failure. One has to question:
#1 Why Athersys insists on a single dose to achieve success.
#2 Why Athersys refuses to accept 5 to 3 improvements as evidence of success.
Ok Ohmtaxi, instead of a steroid, compare a single dose of Multistem to Jakafi, as Jakafi is proven to shrink the spleen. Is Jakafi given as a single dose? No, it is not. It is also being argued that Jakafi can extend lives as well, but certaily not as a single dose. You brought it up, this is why I am using Jakafi as a dose/duration example. I do not have any monetary interest in Jakafi whatsoever.
Now back to Multistem, even if Multistem is effective, do you really think a single dose is enough? What if it takes two or three doses? Gil has dosage 'tunnel vision' while totally ignoring duration. He somehow thinks that a single dose is all you need whereas for most therapies this is not the case.
Gil has the bar for success set so high that he is killing Multistem before it even has a chance to prove itself. We might need multiple doses to achieve success. Think about it, what if he is wrong and two or three doses would achieve the outcome needed.
Since Gil said we get an incredible number of doses per donation, multiple doses should not be a problem. I thought this was one of the big selling points of Multistem, that it can supposedly be amplified, but yet Gil limits the Phase 2 clinical trial success to a very confined definition that mandates that a SINGLE DOSE must achieve a modified Rankin score of 2 or less. YEA RIGHT!!!
He has our balls in a vice with this bogus primary outcome that demands that the study IGNORE 5 to 3 successes.
You can worship him all you want. I will continue to question him because we need more patients enrolled to reveal that "2 or less" success can be achieved with 95% confidence. Right now, the patient number are dangerously low to prove this and the single dose duration "crazy ambitious".
"The starting dose of Jakafi is 20 mg given orally TWICE DAILY for patients with a platelet count greater than 200 X 109/L, and 15 mg twice daily for patients with a platelet count between 100 X 109
/L and 200 X 109"/L"
Be advised Allogenie, the Multistem stroke trial is enrolling moderate-to-severe stroke patients with a mRS of 3 to 5. This does include 5 (five).
So, patients with a mRS of 5 ARE INDEED INCLUDED in the Multistem stroke trial, and Gil refuses to accept an improvement from 5 (severe) to 3 (moderate). An improvement from severe to moderate DOES NOT COUNT. An improvement from 5 to 3 is a trial failure based on the primary outcome measure definition. So, if we cannot achieve significant conversions to 2 or less but achieve significant conversions from 5 or 4 down to 3, you lose all your money.
Don't blame me, BLAME GIL!!!
Exhibit 4: Phase II trial design for ischaemic stroke
140 pts; 18-83 yrs; diagnosis of moderate-to-severe ischaemic stroke (8-20 NIHSS; mRS 3-5), occurring in last 24-48 hrs. After low (400m cells)/high (1.2bn) dose cohorts, Cohort 3 will use the highest safe dose, 1:1 randomisation to placebo or MultiStem as single IV infusion 24-48 hrs following ischaemic stroke.
Presence of a lacunar or a brainstem infarct
Reduced level of consciousness
Major neurological event such as stroke or clinically significant head trauma within 6 months of study
"The spleen is believed to play a significant role in the body's immune response to the stroke that can result in additional damage following the primary ischemic event. After administration, MultiStem cells limit the inflammatory cascade that results from the initial stroke, thereby reducing the secondary damage that occurs.
Ok, so within 24-48 hours, patients receive a single high dose of Multistem (1.2 billion cells). These cells are quickly absorbed and the molecules from these cells processed out of the body gradually. However, even with a potenet steroid like prednisone given at high concentration (i.e. 40 mg) more than a single administration is given. It takes a few days of high dose steroids to treat inflammatory responses.
The problem I have here is that a single high dose of Multistem, just like in the UC trial which recently failed, will likely not be enough. Even the best steroids require a multi-dose regimen. This is arguement #1: We need a 2nd or 3rd dose.
The counterargument would be that Multistem is like aspirin following a heart attack and a single dose does make a big difference.
Keep in mind, Gil has set the bar for success very high for this Phase 2 stroke trial. The PRIMARY outcome measure is: The "proportion of subjects with a modified Rankin Scale (mRS) score of less than or equal to 2". This means difficult stroke patients must have a PROFOUND recovery and have only "slight disability; unable to carry out all previous activities, but able to look after own affairs WITHOUT assistance".
Gil buried the much more attainable outcome measure among the secondary outcomes which is, a significant "change in functional outcome THROUGHOUT THE RANGE of mRS scores". In other words, as the trial is designed now, if Multistem achieves a statistically significant improvement from say a score of 5 to an improved score of 3 on the Rankin, this DOES NOT count, and the trial is considered a failure because the primary outcome was not met.