MAPC's contribution to recovery, if any, could be very complex, or it could be one component from the cells that is responsible for the majority of the benefit. It is so complex, no one really knows what is going on.
The collective evidence from MAPC, MSC, and neural stem cells suggests that there is some benefit in model systems, including primates which is encouraging. We all know why MAPC has advantages over MSC and NSC.
However, teasing the truth of efficacy away from the noise of natural recovery and high variability associated with stroke is a tall order.
Gil and company are already in high cotton and eating gravy. First, they have lucrative salaries, second, win or lose in the stroke trial, the general consensus is that these cells do indeed have value. As seen with Osiris, even though Prochymal failed its heart attack primary outcome, Mesoblast was ready to pony up 100M. Pfizer will take MultiStem. It is just a question of, on what terms?
When we have a no lose scenario for management. A trial that fails to prove what is actually real benefit is not a problem for anyone...except shareholders. Hence, the sinking ship warning is to make only a prudent investment in ATHX.
Some have admitted on this board that they are way overextended in ATHX. I am not trying to influence anything, just calling the science and odds as I see them.
It is a big gamble with big potential. Management's position though, based on what happened at OSIR, is something to keep in mind. I would like to hear from Pfizer about the Crohn's BEFORE the stroke trial results. Right now, I feel like if the stroke fails but Pfizer actually likes the Crohn's data, they could clear the table for almost nothing upon stroke fail news and walk with all the marbles, giving Gil a position in ATHX/Pfizer. Just like the Icagen deal.
"In conclusion, human MSCs participate in the innate immune response against Gram-negative bacteria through the secretion of the antimicrobial peptide, LL-37. The secretion of this peptide is inducible with prior bacterial stimulation and has antimicrobial effect both in vitro and in vivo. Thus, human allogeneic human MSCs may be beneficial in bacterial infections because of their antimicrobial properties as well as their immunomodulatory effects."
Stem Cells. 2010 Dec; 28(12): 2229–2238.
What about lysozyme?
Are you limiting the definition of antibiotic to those compounds produced by bacteria?
Then what about penicillin which comes from a eukaryote?
Mesenchymal stem cells (MSC) have direct antimicrobial activity mediated in part by secretion of human cathelicidin hCAP-18/ LL-37. Arnold Caplan at Case Western Reserve has discussed this at many lectures. This has also been published.
Through this antimicrobial secretion, "Mesenchymal Stem cells synergizes with conventional antibiotic therapy and enhances clearance of chronic bacterial infections. The use of activated Mesenchymal stem cells enhances the effectiveness of conventional antibiotics in treatment of antibiotic-resistant microbial infections and may also help prevent the development of new antibiotic-resistant strains."
So, you are saying that Prochymal, which is MSC, has the distinct advantage of antimicrobial activity that MAPC (MultiStem) do not have?
I am betting that MAPC has similar function...Dude.
Splenic contraction and a potential release of red and white blood cells (Stewart and McKenzie, 2002). This contraction causes a release of proinflammatory immune cells, which are attracted to the brain by chemokines induced by the stroke. These peripheral immune cells could then act to increase neuroinflammation and subsequently neurodegeneration (Hausmann et al., 1998; Abraham et al., 2002).
Human bone marrow-derived MSCs possess direct antimicrobial activity, which is mediated in part by the secretion of human cathelicidin hCAP-18/ LL-37.
Stroke is associated with splenic atrophy and the release of monocytes and macrophages that make their way to the brain. Some of these monocytes are PRO-inflammatory such as Ly-6C(high), but some are ANTI-inflammatory such as Ly-6C(low).
What is the outcome of PRO + ANTI inflammatory immune response?
Pennypacker and Offner (Journal of Cerebral Blood Flow & Metabolism (2015) 35, 186–187) argue that the overall outcome of spleen removal is neuroprotective.
Kim et al. (Journal of Cerebral Blood Flow & Metabolism (2014) 34, 1411–1419) state that spleen monocytes and macrophages do not significantly contribute to acute infarct development.
In response to Kim et al., Pennypacker and Offner (2015) suggest that their splenectomy experiments conducted immediately before stroke does not allow the body time to adapt or equilibrate. However, removing the spleen two week before stroke, you can see the benefit.
WHEN DOES THE SPLEEN SHRINK?
"The spleen was found to significantly decrease in size from 24 to 48 h following middle cerebral artery occlusion (MCAO) in rats compared to sham operated controls. By 96 h post-MCAO the spleen size returned to levels" -J Neuroimmune Pharmacol, 2012 December; 7 (4):1017-1024.
So Athersys is in the ballpark in terms of timing with their design, but we have to HOPE FOR MORE PATIENTS AT 24 HOURS THAN 48 HOURS.
NEWS FROM HARVARD
Ischemic stroke leads to higher BONE MARROW output of inflammatory Ly6C(high) monocytes and neutrophils.
So, perhaps MAPC (Multistem) can assist in a global inflammatory response?
In addition, MSC have been show to produce antibiotics. Perhaps MAPC does as well? If so, Multistem may help because, "Stroke-induced immunodeficiency promotes spontaneous bacterial infections" J Exp Med. 2003;198:725–736. As Gil has mentioned in the Nov.13th London talk, secondary infection (pneumonia) is a high cause of stroke mortality.
The evidence we have so far comes from model:
J Exp Stroke Transl Med (2010) 3(1): 34...
Refractory Crohn's is at the top of Mesoblast's pipeline.
Mesoblast has an advanced program to develop Prochymal® (remestemcel-L, human mesenchymal stem cells for intravenous infusion) for the treatment of patients with refractory moderate to severe CD.
Prochymal® has demonstrated immunomodulatory properties to regulate T-cell mediated inflammatory responses by inhibiting T-cell proliferation (demonstrated in a mixed lymphocyte reaction2) and down-regulating the production of the pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interferon gamma.
More critically, mesenchymal lineage stem cells have been shown to be capable of effective down-regulation of Th17 cells, reduction in IL-17 levels, and induction of FoxP3 regulatory T cells.
A Phase 3 multi-centered, double-blind, randomized, placebo-controlled trial is evaluating the safety and efficacy of Prochymal® in moderate to severe CD in patients who are resistant to steroid, immunosuppressant and a biologic therapy. The primary endpoint is the proportion of patients experiencing disease remission within 28 days of treatment with Prochymal®, compared to those patients receiving placebo.
Preliminary data from two interim analyses planned under the protocol has provided encouraging results. The Phase 3 trial is ongoing.
Is Pfizer watching Big Daddy Teva (Mesoblast)?
Market cap 54.81B
Mesoblast is partnered with Teva Pharmaceutical Industries Ltd. for the development and commercialization of its Mesenchymal Precursor Cell (MPC) products
Mesoblast pushes hard into Crohn's with Prochymal.
Maybe Pfizer is still watching??????????????????????????
Evaluation of PROCHYMAL® for Treatment-refractory Moderate-to-severe Crohn's Disease
This study is ongoing, but not recruiting participants.
Safety and Treatment Outcome Study of PROCHYMAL® (Remestemcel-L) Intravenous Infusion in Subjects With Treatment-resistant Crohn's Disease
This study is ongoing, but not recruiting participants.
Evaluation of PROCHYMAL® Adult Human Stem Cells for Treatment-resistant Moderate-to-severe Crohn's Disease
Borrowed this from brother Ozark on the OSIR board.
Recap of the Osiris/Mesoblast deal
Osiris sold their Therapeutics products, Prochymal and Chrodrogen to Mesoblast on December, 2013 in a deal worth up to $100 million. $35 million cash was payable upfront and another $15 million payable after delivery of assets and another $50 million is contingent upon certain Mesoblast milestones. Total, up to $100 million.
The upfront cash of $35 million has already been received by Osiris.
The $15 million was also received, but in Mesoblast stock and presumably sold in December 2014. The price guarantee money was payable in December 2014 in either cash or more Mesoblast stock, which also has an additional 1 year lockup clause, but with no price guarantee. Details of this should be reported in next annual report.
Mesoblast will also pay Osiris the following milestone payments for the remaining $50 million:
First marketing authorization received in the U.S. $20 million.
First marketing authorization received from France, Germany, or European Union. $10 million.
Completion of the enrollment of the Phase 3 Crohn’s Trial or Mesoblast’s election to discontinue the trial $10 million.
Receipt of final data for the Crohn’s trial or first marketing approval for Crohn’s. $10 million.
Note: All milestone payments may be paid with Mesoblast stock in lieu of cash.
Total Mesoblast milestone payments to Osiris is worth $50 million in cash or stock equivalency.
Grand total of all upfront and milestone payments is worth up to $100 million.
Plus....Osiris will still receive Sales Royalties from Mesoblast once their Osiris derived products go to market. Osiris is entitled to earn single to low double digit cash royalties on future sales by Mesoblast of Prochymal and other products utilizing the acquired ceMSC technology.
Clot-removal device paired with drug shows benefits for stroke patients
Surgeons who operate on blood vessels in the brain are hailing new data that suggest many more patients would survive strokes if they were treated with removable stents in ADDITION TO DRUGS.
That’s partly why they say the findings — first reported in December and confirmed in three publications in the New England Journal of Medicine this week — will ultimately lead to changes in national treatment guidelines for some types of stroke.
EXPECT NEW TREATMENT GUIDELINES TO INCLUDE:
1. Clot removal if possible.
2. Drug/stem cells (if found to be effective)
-Within 5 years of a stroke, 24% of women and 42% of men will experience a recurrent stroke.
-Recurrent strokes often have a higher rate of death and disability because parts of the brain already injured by the original stroke may not be as resilient. [Would Multistem make the brain more "resilient" so that a recurrent stroke is not as deadly?]
-Risk factors of stroke in general:
1. High blood pressure
2. Cigarette smoking or exposure to secondhand smoke.
3. High cholesterol.
5. Cardiovascular disease, including heart failure, heart defects, heart infection or abnormal heart rhythm.
6. Being age 55 or older.
7. Race — African-Americans have a higher risk of stroke than do people of other races.
8. Gender — Men have a higher risk of stroke than women.
Yes, timing ATHX for a spike sell and re-load upon a successful phase-2a is folly.
You can't time this bull/bear.
Selling into a March madness pre-announcement run-up is also folly.
You could miss the big moment.
There is only one way to invest in Athersys, and that is a prudent charge to take the hill.
This is not for mutual fund money.
"I have over 50k shares and my average is a little over $3"
Did you double down and plan to sell some during the March madness before results?
Yes, I would obviously want clot removal + Multistem too, but because of Gordie Howe we now have to also consider intrathecal neural stem cells as well. Do they play a role? If so, how much relative to MAPC/MSC?
As for clot removal:
"53% of 120 patients who had clot removal via a tube fed into a blood vessel of the brain were functionally independent 90 days later. Of the 118 who received only the standard clot-busting drug, 29% were."
That's a ~24% difference.
"While 19 percent of patients receiving drugs alone died within three months, only 10.4 percent of those whose clots were removed died."
So the death rate was cut in half.
There is still room for improvement for the other 47% of patients who are not functionally independent by 90 days and 10.4% who died even after having clot removal by stent.
There is daylight for Multistem.