A few home truths to finish 2018.. not to be taken too...

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A few home truths to finish 2018.. not to be taken too seriously.

1) A little knowledge is a dangerous thing....this especially applies to me !

2) The arrival of Google, made us all armchair medical experts...we tell our GP's what wrong with us..and they normally tell us to keep to our day job.

3) Confirmation bias is very amusing in the rear view mirror.

4) NEVER, I REPEAT NEVER, get carried away with a Phase 1 clinical trial results. In a sample size of only 16 patients split into 2 dosage groups, achieving an 88% success rate ( Cynata) vs about 75% for the very old MSB result, does not mean you are home and dry. Welcome to the world of biotech where you have earned a seat at the table to spend a great deal of money (even if its Fuji Films)and several years of testing to find out if you have anything worth marketing. In the meantime, expect to be lectured by posters from other websites how they have the next big thing is stem cell science.  

Don't forget MSB was in the same position and we lost our free carry when Cephalon was acquired by Teva (see previous posts from me)

https://stemcellres.biomedcentral.com/articles/10.1186/s13287-018-0988-9 pfeifer1982  Post #: 34440015

1. Originally posted by Sector  ↑

   If that is gen 2, then you'll be excited to hear that they are currently working on a gen 3 version of our MCA-MSCs in Ireland:
   
   "An understanding of how MSCs enhance phagocytosis would help us develop a next generation cellular therapeutic."

From what I can gather Cynata does appear to be at an inflection point because it is highly likely that Fuji will have to exercise their option by the end of March 19, resulting in milestone payments and Cynata will effectively get a free carry on clinical development. This will be a very good result for the Company in terms of future funding. Fuji has been trying to navigate a way through the patent obstacle path because it has arrived late to the party.  

 5) Try not to be late to the party:                                                                                                                                      and have to rely on non exclusive IP licences for your contract manufacturer.

Non exclusive licence agreement for CDI (Fujis manufacturing company for stem cell facility) https://www.sec.gov/Archives/edgar/data/1482080/000148208013000014/a1041warflicenseagreement1.htm

When achieving a safety certification and spending a $1bn in the process on approvals, it is best not to switch processing methodologies half way through because an improved method of culture harvesting is in the horizon.

 When ARM Holdings dominated the 32bit RISC market  by being first to market by a matter of months the competitors know they would be frozen out so they had to wait to challenge them in the 64bit year later which was the next major change in the silicon roadmap. When Boeing receives a product certification for a new airliner, it does not make alterations to the design, when better solutions are available because it will invalidate the product certification. When P&G wants to change the flavour of its toothpaste it knows that more than a 1% percentage change in the formulation will mean it will have to seek new product approvals etc etc. This is especially true in the biotech world where the gold standard FDA approved treatment is prioritised and usually patients who do not respond are then given the opportunity to use experimental technologies. The latter companies miss out on all the real market share. Hence, everyone will probably use MSB as the gold standard therapy and Cynata will picks up the remaining market share, until it has an  FDA approved product. This is especially true where there is marginal differences in efficac(since 2012 in Canada). Furthermore, Cynata stockholders will also have to hold their breath for Regeneus clinical trials relating to CLI where they are more advanced I believe in their clinical trials pathway and already have a credible partner who is funding them. CLI is a bigger market opportunity for Cynata than aGVHD. 

https://unauthorised investment advice/columnists/tim-boreham-whats-next-for-stem-cell-play-regeneus-as-it-waits-for-japan-deal/

6) Do not use block capitals on website as its rude

7) By early to the party. You cover yourself with patent protection to keep your options open for the future. 

8) We should use the Christmas period to spend time with our families not websites

9) Our understanding of science is still rudimentary.

10) Virtually everything we thought we know about MSC cells has been turned on its head in the last few years. (see rule 7).  To quote the great Arnold Caplan of Osiris Therapeutics in a November 2018 research paper (link below)

"Based on the above false assumptions, the dogma of the day was that the MSCs were vital to the bone marrow stroma and that for bone marrow transplantations, the addition of exogenously provided MSCs would strengthen the marrow scaffold to enhance the engraftment of the hematopoietic progenitors and to speedup recovery of the hematopoietic system, thus de‐risking the patient from infections or graft‐versus‐host disease. The first‐in‐man trials of exogenously expanded autologous MSCs added to bone marrow transplantations was started by us and it was proved to be highly successful . This led others  in adults and especially at Osiris to provide data that allogeneic MSCs could be used quite spectacularly in children who were on death's door with graft‐versus‐host disease  We now know that the mechanism for these very positive results had nothing to do with the marrow stroma and were attributable to the intense paracrine properties of the MSCs with especially potent immunomodulating components. With this clinical experience, it was soon established that MSCs had strong immunomodulatory and trophic activities that had medicinal effects. This challenged the multipotentiality logic and suggested that the MSCs had a strong paracrine activity but not stem cell activity in vivo."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216418/

The article is very thought provoking. It is a well known result of gene therapy, that results can be improved by personalising medical treatments for each individual ( although this must prevent a nightmare for the FDA). My take is that conventional clinical trials are wasting an inordinate length of time and expense in the approval process (which is completely unfair to placebos and non responders), because allogenic stem cells appear to have few adverse affects (other than raised antibodies from not filtering out impurities completely which SI has made great progress with recently) . He makes a valid point that the CLBP treatment in a previous MESOBLAST clinical trial ,was shown to be relevant ,to a very large sub set of the cohort group (50%) but irrelevant to the non responders. The FDA need to rethink the merits of "stabilisation" of degenerative diseases as opposed to "improvement" ( in other words preventing a disease from getting worse, could be considered an endpoint in itself). 

https://research.monash.edu/en/publications/optimization-of-alginate-purification-using-polyvinylidene-difluo

9) When achieving a safety certification and spending a $1bn in the process, it is best not to switch processing methodologies half way through because an improved method of culture harvesting is in the horizon. 

10) Protect yourself by registering patents so these young upstarts can't steal a march on you later

11) Drive down relentlessly the cost of production so the cost of replicating feedstock becomes a side issue. SI has issued research papers this year which show a continuous improvement in manufacturing processes are paying off...for example better filtering of cell material and consumables, which may have an antigen response? improving batch consistency, the use of proprietary 3D scaffolding for cell harvesting etc.

https://research.monash.edu/en/publications/optimization-of-alginate-purification-using-polyvinylidene-difluo

 I am pretty confident that neither myself or any poster on the Cynata forum, has a clue what those efficiencies represent in production costs and scalability yet as it is a proprietary product...so to be lectured about cost of production is a bit rich...having said that I do acknowledge the major benefit of pluripotent production is its limitless scalability....this does not stop MSB commericalising its technology much earlier and using advances in cell production for a future generation of  products...for example ,it announced only in June 2018, an agreement with Cartherics to combine its pluripotent treatment with our technology to lower costs:

Mesoblast Partners With Cartherics to Develop ’off-the-shelf’ Cell-based Immunotherapies for Solid CancersRelapsed Ovarian and Gastric Cancers Initial Targets for Allogeneic CAR-T Cells                                                                                                                                         Combining technology platforms from Mesoblast and Cartherics aims to facilitate large scale production of allogeneic CAR-T cells from induced pluripotent stem cells (iPSCs)². Clinical-grade manufacturing and banking methods will be used to convert gene-edited iPSCs to potentially limitless numbers of killer T cells, eliminating costly resources required to produce autologous (patient’s own) CAR-T cells. This could provide large numbers of cancer patients with access to cost-effective ‘off-the-shelf’ CAR-T therapies.

Mesoblast Chief Executive Dr Silviu Itescu stated, “With our combined technology platforms and expertise, we are ideally placed to greatly increase accessibility to this very promising new field of cancer therapeutics through the development of highly-scalable, allogeneic cellular immunotherapies.”

12) There was a reason why SI did not use iPS technology years ago. It was not safe at the time. It has been around since at least 2008 . Note also that three different labs have IP over the discovery.                                                                               .http://stemcell.childrenshospital.org/about-stem-cells/pluripotent-stem-cells-101/

Induced pluripotent cells (iPS cells):
Scientists have discovered ways to take an ordinary cell, such as a skin cell, and “reprogram” it by introducing several genes that convert it into a pluripotent cell. These genetically reprogrammed cells are known as induced pluripotent cells, or iPS cells. The Stem Cell Program at Children’s Hospital Boston was one of the first three labs to do this in human cells, an accomplishment cited as the Breakthrough of the Year in 2008 by the journal Science.

Because iPS cells are derived from skin or other body cells, some people feel that genetic reprogramming is more ethical than deriving embryonic stem cellsfrom embryos or eggs. However, this process must be carefully controlled and tested for safety before it’s used to create treatments. In animal studies, some of the genes and the viruses used to introduce them have been observed to cause cancer. More research is also needed to make the process of creating iPS cells more efficient.

                             

13) Expect a longer approval process when your technology no longer addresses an unmet clinical need. MSB have been marketing a solution for aGVHD (then Prochymal TM Osiris which was purchased by MSB in 2013) in Canada. The idea that Cynata will be a competitive threat, outside possibly Japan) in the next 4 years is highly unlikely in my opinion. I do note however, that our licensee can withdraw from its agreement if a better proven technology is available).

Conclusion.

There is nothing wrong with Cynata...it has interesting IP in the early stages of commercialisation. A deal with Fuji film looks pretty slam dunk, but as an investment for me, it is far too early stage for my taste. I am more concerned about disbursement criteria for insurance companies for approving C-ART and stem cell products, than I am about feedstock production methods . I believe MSB  is making good  progress with its own proprietary technology right now...which will all help in attracting the elusive Global marketing partnerships in due course. It also has its own IP for pluripotent production.

PRODUCTION OF REPROGRAMMED PLURIPOTENT CELLS

Publication number: 20170037377

Abstract: The present invention provides a method of producing a reprogrammed cell, said method comprising exposing Stro-1+ multipotential cells and/or progeny cells thereof to one or more potency-determining factors under conditions sufficient to reprogram the cells. The present invention also provides cells produced by such a method and cells differentiated therefrom in addition to various uses of those cells.

Type: Application

Filed: October 20, 2016

Publication date: February 9, 2017

Inventor: Silviu Itescu

If anyone is in doubt about the challenges that lie ahead for Cynata I thought I would post an extract from an article  which was first posted by the very diligent  Pfiefer1982 who is flying the kite? or flag?, on the "other" thread.

https://www.fightaging.org/archives/2018/12/the-current-state-of-therapeutic-development-involving-induced-pluripotent-stem-cells/

Merry Christmas everyone....seasonal greetings to the non believers !  I have just wasted a day of my life writing this so I hope it benefits someone. I will not be replying to comments for a little while so I can spend time with the kids! Last minute shopping to do ...Bugger,.I am late...no time to check post for errors so apologies for typos etc, in advance.