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.
We have been informed by Dr. Tefferi that he has submitted data from the Myelofibrosis IST as an abstract to be considered for presentation at the American Society of Hematology or ASH annual meeting to be held in San Francisco in December. The abstract contains safety and efficacy data from patients with MF which have been updated since his presentation at ASH 2013.
Unfortunately, updated data sets from the MDS-RARS and blast phase MF patients were not available to Dr. Tefferi at the time of the ASH abstract deadline and as a consequence he did not submit abstracts to ASH regarding the treatment outcomes in these IST cohorts.
These data sets were not available because of the extensive data entry and analysis required to update the MF IST cohort data sets in order to support the preparation of this complete response to the FDA partial hold as well as the activities required to prepare for the transfer of the IND and study sponsorship for Mayo Clinic to Geron.
We look forward to the data from the patients with MDS-RARS and patients with blast phase MF being presented or published by Dr. Tefferi at a future venue.
This year we have also initiated collaborations with a select group of academic investigators who are looking into the effects of the imetelstat in non-clinical models of MF and other myeloid malignancies such as AML.
From these studies we may gain insight into the potential mechanisms of action of our drug in these malignances as well as non-clinical data to support broader clinical development of imetelstat. We’re pleased to report that our collaborators have submitted some of these data as abstract for ASH 2014. In keeping with standard ASH embargo policy, I will not be making any further comments on any of the submitted data from the collaborators.
Sentiment: Strong Buy
We will have some competition from Mesoblast and the like, but the key feature of Multistem is ability to expand for cost-effective, off the shelf therapy.
Taking into account the competition and a conservative market penetration of 20%. Lets cut the market size on the low end by half (see below) to $7 billion. That would be 1.4 billion per year or 350 million per quarter until something better comes along.
This puts us at 33 PPS as a very conservative estimate relative to PCYC as a reference for a company with similar total shares. The maximum high end would be no more than PCYC at around 100 PPS.
"As a consequence of an aging population, recent forecasts from the American Heart Association project that the prevalence of stroke will increase by 25% in the next twenty years, and the total estimated annual cost for treating and caring for stroke survivors in the United States will skyrocket from $64 billion in 2010 to $140 billion in 2030, representing a substantial increase in costs to the healthcare system. The company believes that the market for a safe and effective therapy for stroke that could be administered within a clinically reasonable time frame could represent a $15 to 20 billion annual market opportunity."
Sentiment: Strong Buy
No, I decided not to waste my time emailing Athersys. Instead I have focused on crunching the numbers for the phase 2 stroke trial that is underway using the method that I outlined in detail above.
During the next Q&A, an analyst could ask the question: Why are the 5 to 3 Rankin score improvements in the Multistem stroke trial being moved to the secondary outcome measure where these case improvements do not count?
Patients who do not improve within 24-48 hours are the only ones being enrolled, and while they are less likely to spontaneously improve and inflate the placebo response, these patients are also the most challenging for Multistem and may, at best, only achieve a 5 to 3 Rankin score improvement for many cases. Still, this would hint that a large Multistem trial would identify a sufficient number of cases moving from 4 to 2 which is our definition of success. The problem is, the number of patients needed to statistically prove this in the current Multistem stroke trial are most likely insufficient. Plug in the numbers as I have described above.
So, will the same excuse be used for the stroke trial failure that was used for the UC trial failure? "We enrolled the most difficult stroke cases, those that did not improve within 24-48 hours, and because of this, one dose of Multistem was simply not enough to meet the primary outcome measure of a Rankin of 2 or less, but we did see some secondary measure improvements that we hope to follow up over time. Thank you for your money. Good day. Sorry for losing all your money. Thanks for the big salary."
My Long-Term Sentiment Disclosure: A very prudent strong buy with an urgent warning to invest absolutely no more than you and your family can afford to lose. If Multistem has the potential that Gil has stated, even a very small investment will yield well without the risk exposure.
Sentiment: Strong Buy
"Give it up shortie?"
Nice, thought provoking response Ohmtaxi.
Anyway, try the calculator and see what you come up with.
Maybe I will agree with you, but try to at least back up what you are saying.
"Give it up shortie" does not cut it. Nor does "real deal" with exclamantion marks.
Sentiment: Strong Buy
There may be others, but sealdenvelope has a sample size calculator that everyone can use. Tell us how you get your numbers and plug them into this calculator. Provide some dicussion relative to the following reference Stroke 2004 May 351216-24. In terms of the success of this trial you have to look at the normal recovery and reduce it a bit to account for the 24-48 hour observation period to select those patients who do not improve during this time frame and consider that these patients may never make it back to 2 or below. But, go ahead and give you your numbers a shot, and we can all cuss and discuss what you find.
We are sampling the stroke population for a binary response to Multistem or placebo. The binary outcome is either 2 or less (success) or, alternatively, more than 2 (failure) on the Rankin scale.
The more patients we evaluate, the more likely we are to reveal a differene, if one exists. Whether you call it larage number or more patients, the bottom line is the same. The more numbers we have the more power we have to reveal the true average response in the population. The fewer patients we have, the more likely we are to be unable to prove the benefit of Multistem, even if it does exist, because of error and other factors.
When I get time, I will try my hand at running some number through the calculator too.
Sentiment: Strong Buy
We need MORE patients enrolled to prove significance, not FEWER.
Multistem has to have more recoveries (2 or less on the Rankin scale).
To prove Multistem successful, we have to beat standard of care 'natural recoveries' which occurs at a high rate, as much as 40% but perhaps 30% in our case because they are enrolling only cases showing no improvement at 24-48 hours.
However, enrolling these difficult cases is risky!
Multistem has to really work well because some of these risky cases are Rankin score 5 have underlying health conditions, and improvement from a score of 5 down to a much less severe score of 3 DOES NOT COUNT. 5 to 3 conversion is a secondary outcome measure which means nothing if we cannot meet the primary outcome measure of reducing severity to 2.
If placebo and standard of care achieve 30% of recoveries from say 3 to 2, we have to have large numbers to prove statistical significance for Multistem. It is going to be touch and go as Gil has put in the secondary outcome measure what should be in the primary outcome measure.
Gil has set the highest bar possible and demands success with an absolute minimum number of patients enrolled. If I wanted a phase 2 to fail, I would design it just like this, push reason down into the secondary outcome measure and put out a one liner of did not meet primary outcome on judgement day.
Sentiment: Strong Buy
8 people received Multistem.
Do the math. Gil knows the results.
Furthermore, if a safety committee knows the results, a lot more people know.
Unless you still believe in the tooth fairy.
Third, the study is now a balanced design between placebo and Multistem.
Moderate to severe stroke is scored 3-5 on the Rankin scale.
We already know the outcome for standard of care in terms of the proportion to expect converting to less than or equal to 2, which is the primary outcome measure. So, once again, if you do the math with knowledge of the collective patient outcomes after 90 days, its not too difficult to determine if Multistem is working as the study progresses.
As the trial moves toward completion of enrollment and more patients complete their 90 day period, the writing will be on the wall for those in the know.
Sentiment: Strong Buy