Cell Therapy News/Articles, page-1941

Don’t believe this has appeared on HC .......This is from Left-e ,a quality poster on Yahoo, and should spell the end to all discussions about the other two companies we are comparing to (copied verbatim)...

First of two parts: An unusual situation is brewing for investors. All three major players - and some smaller ones - in the cell-based therapeutic space have plans to focus their research efforts on the same illness, Covid-19 ARDS at the same time. It's a rare head-to-head match up and this new illness may prove to be the final arbiter on who has the best stem cells. As potential patients we want them ALL to succeed. But as investors where should we place our cash? I spoke earlier about “risk” based on a comparison of financials. Now I'll say a few words about risk based on the science. Here are a few reasons why I choose to invest big in Mesoblast and not Athersys or Pluristem. As of the end of 2018 over 900 clinical trials have been performed using MSC's according to Dr Martin Grumet at Rutgers. A number of the studies have been done at leading universities by scientist physicians like Dr Matthay or Dr. Weiss, who appear to have pure academic rather than commercial aspirations. Their results, not always “miraculous”, have been published in peer-reviewed journals and serve to pave the way; giving a broad scientific foundation for which mechanism of action in various illnesses, dose-response curves, and blind alleys to be avoided have been established – for MSC's. Moreover, the FDA maintains a lab that studies MSC's, which I interpret as an advantage for companies seeking FDA approval. It's more difficult to find independent scientific info on MAPCs. And if we look at total number of trials documented on the clinical trials website, MESO has sponsored 36 trials, Athersys 10 trials, Pluristem 9. Recall that Athersys has been in existence about 25 years, Pluristem 20 years and Mesoblast 15 years. Looking at results, Athersys has had trouble getting past phase 2. Yes, they are doing a phase 3 in stroke but it's based on tweaking the entry criteria and the dosing after their phase 2 study in stroke failed on efficacy. Perseverance may pay off we'll see, but it gives me pause as an investor. A major concern is their cells, described as MAPC's, which are a type of “Progenitor” cell, less differentiated than an MSC. These have not been studied much by academics or other entities – other than their commercial partner in Japan, Healios. No published university research or independent studies. I raise it because there's something that really stands out with these Progenitor cells: the dose. Look at just about any paper on MSC's and you'll find the dose is in the range of 75 to 200 million cells for an adult. Mesoblast/Osiris used 100 million cells in the COPD study that showed suppression of inflammatory cytokines. The studies out of China on Covid-19 and avian flu were all in that dose range. Hope Biosciences is testing three doses ranging from 50 million to 200 million cells per injection, Dr Cordi at U of Miami is using 200 million cells, and the list goes on. There's evidence in the literature of a dose-response curve – don't give enough cells OR give too many cells and the response is worse than with the “Goldilocks” dose of around 100 million cells. In other words, it's just as possible to over-modulate the immune system as it is to under-modulate it. Now look at the doses used by Athersys. In their phase 1 / 2 ARDS study they started with a dose of 300 million cells and ended up using 900 million, which they'll probably use if they get to phase 3. In their phase 3 stroke study they are giving 1.2 billion cells per dose. That's over 10 times the typical dose of MSC's... Why so many cells?? Speculation on my part but could they be less effective than MSC's? Is that why Athersys has barely limped past phase 2 in 25 years? Something to recall is that we all start out as a solo stem cell, which is good at one thing - dividing into two stem cells. Eventually as the embryo develops, some cells give up their ability to divide by differentiating into cells that can do metabolic or synthetic or secretory or immunologic work in the various tissues and organs. MSC's can still divide but they've differentiated far enough along the mesenchymal lineage that Arthur Caplan, a founding father of the field, says we should no longer call them stem cells (he proposes the term Medicinal Signaling Cells instead, because they are able to secrete signaling molecules that influence nearby host cells, ie they're able to do some work. Others call them Mesenchymal Stromal Cells). We know that indeed MAPC's are less differentiated. For starters they're better than MSC's at dividing, as would be expected from something that's closer to being a pure stem cell. MAPC's can go through 60 doublings without senescence, whereas for MSC's it's 38 max. That's a tremendous difference since 60 and 38 represent exponents. But can MAPC's do any metabolic/secretory/immunologic work in the body after injection? Can they treat an illness? Is that why Athersys has had trouble limping past phase 2?? Part 2 to follow.


Part 2 of 2: What about PLX cells? There's also something there that really stands out. To the extent Pluristem PLX cells are true MSC's (they describe them as “mesenchymal-like, whatever that means) derived from placenta, I would favor them over MAPC's for therapy, all else being equal. Of course, all else is never equal and we really don't know for sure how these companies are tweaking, priming or even engineering their cells. So, let's keep an open mind. But as investors we have to decide based on what we do know or can know. Pluristem has done a number of phase 2 trials. In terms of dosing they're in the range on Mesoblast in terms of number of cells, but what really stands out is the way they administer the cells. It's by intramuscular injection – as opposed to Mesoblast and the large bulk of university studies where the cells are given IV directly in to the circulation. OK, why the IM route? In some of their trials they're acupuncturing the patient with 8 IM injections into an ischemic leg. Ouch. Some speculation that it may be to avoid IP issues. Some of their animal studies seem to have given better results with IM over IV. Maybe IM injections are ok for the indications they've studied to date, but it's hard to imagine that patients with diffuse bilateral lung infiltrates on a ventilator are going to be treated by IM injection. Is that why Pluristem claims they plan a trial in Covid-19 ARDS but have apparently not yet obtained approval to do one? If they want to give their cells by any route other than IM they would be starting from scratch on dosing. They have limited experience with IV dosing, so almost back to phase 1. Which is why I anticipate they may try something totally different. Like intra-bronchial administration which has been discussed in the literature as a theoretical approach to ARDS. Let's see what happens, such a novel approach might prompt me to take a second look at PSTI. If they simply switch to IV admin or even continue with IM I see little advantage over Mesoblast and potential IP infringement if they're ever successful with any program. Looking at what both Athersys and Pluristem were doing prior to Covid-19, in terms of their phase 3 programs they were barking up some very tall trees: ischemic stroke for Athersys and ischemic limb disease for Pluristem. Variations on the same theme – impaired blood flow in large arteries. Color me skeptical for a home run treatment with stem cells. Yes, you have a secondary inflammatory component with those two, but the big problem is a macro-mechanical one. An artery is blocked. No cell can survive total ischemia for long. Maybe stem cells can help preserve tissue in the outlying hypoxic areas, but strikes me there's a high risk for failure, especially if your cells are only good at dividing, not doing work. Those patients are usually older, harder to treat and likely to have other problems. So, it's very noble but as an investor I'm more comfortable seeing a stem cell company start with problems that are primarily inflammatory. Relatively low hanging fruit. Start with GvHD, Crohn's disease, then maybe some post-op inflammatory conditions or inflammation in joints and disk spaces, RA, etc. Or show you can treat ARDS (credit to ATHX there) or do something to influence the tumor micro-environment. Then try to have your cells lift the heavy boulder of blood-clotted and cholesterol-clogged arteries in diabetics and hypertensives and heavy smokers. And not too surprisingly, that's the route the first products have taken to market. It's the route taken by Mesoblast. For investors it's a question of the odds of success vs the risk of failure. Advantage Mesoblast based on what we know so far about their cells, approach to illness, manufacturing capability and history of regulatory approvals. I expect the knowledge and experience gained there to carry over to Covid-19. I suspect the NIH felt the same when they chose a partner.