"Ischemic stroke is associated with a systemic increase of blood mononuclear cells expressing interleukin-8" But what Chugai is not going to get with an antibody for IL-8 are the antibiotics produced by MSCs.
You mean did Athersys obfuscate the post hoc data interpretation.
I am confident the numbers/data were not transformed or changed in any way.
dr_sumitchawla is focusing on whether individual patients should have been included or removed from the analysis based on treatment time or others treatments received in addition to Multistem.
Obviously the treatment time was wrong. In my opinion the data is now falsely supporting treatment out to 36 hours post stroke. Gil has admitted 48 hours was too long. The argument of too early, such as administration of Multistem within minutes following a stroke, may also be true. There is animal model data to perhaps support this and a 24 hour cut-off.
The phase 2 data has to be taken as a whole, not only stroke scale but all of the other variables, including infection. The inclusion or exclusion of individual patients due to time or other treatment can surely pass or fail the study because of its small size, but when you look at all the variables measured, there is a collective trend in favor of Multistem.
Splitting hairs over which patient should or should not have been removed is folly. There is no right answer for such a small study with the wrong time. What we do have a right answer for is the biochemical mechanism of Multistem's mode of action. There is a strong underlying biological rationale.
If you take this data and combine it with the overall positive trend seen in the phase 2, the time post stroke for infusion should be adjusted toward 24 hours and the patient numbers increased to statistically overcome spontaneous recovery. It will be Chugai's call. But remember, Chugai does have their own antibody stroke patent, and they may be simply sizing up Multistem by paying to get closer to the data only to pivot and use their antibody therapy. This would explain a lot.
Cerebral stroke/cerebral edema preventive or remedy containing IL-8 binding inhibitor as active ingredient
European Patent EP1854481
Gil participated in sponsoring a talk there with Pete Petit. This tells me he is talking to Pete about stroke. Also Pete has his eye on oncology. As I have detailed, Celgene is bullish MSCs for certain oncologic diseases with Mesoblast. Mimedx has interest in this as well. Multistem can home in on cancer and deliver therapeutics in a very targeted way, especially lung and liver cancer. Besides this, Pete is looking for an injectable that is minimally manipulated. Multistem qualifies.
We have to look at Prochymal to answer this and think about Multistem costing less.
Prochymal® has already received conditional approval in Canada and New Zealand for the treatment of children with acute GVHD, and is available in the United States under an Expanded Access Program for treatment of acute GVHD in children. Prochymal® has also generated promising Phase 3 data in adults with acute GVHD at high risk of death due to inflammatory gut or liver complications.
Mesoblast intends to seek FDA marketing approval for use in both pediatric and adult patient populations. Additionally, JCR Pharmaceuticals in Japan is aiming for product launch of its MSC-based product for steroid refractory GVHD in children and adults in Japan
A peer-reviewed article in the November 2013 issue of the scientific journal Biology of Blood and Marrow Transplantation reported that use of Prochymal® resulted in a significant survival benefit among responding pediatric bone marrow transplant recipients with refractory acute GVHD. Of the 75 children with acute severe GVHD, 61% responded to Prochymal® and 76% of these were alive at day 100.
In patients with liver GVHD, Prochymal® improved response by 76% versus 47% in controls (p=0.026, n=61) and durable complete response in 29% versus 5% (p=0.046).
GlobalData estimates that the global GVHD therapeutics market was worth $261.6m in 2010 and is forecast to grow at a Compound Annual Growth Rate (CAGR) of 11.3% to reach $615.1m by 2018.
Molecular Therapy accepted article preview 28 July 2015
T-cell depletion therapy is used to prevent acute allograft rejection, treat autoimmunity and ‘create space’ for bone marrow or hematopoietic cell transplantation. The evolved response to T-cell loss is a transient increase in IL-7 that drives compensatory homeostatic proliferation (HP) of mature T cells. Paradoxically, the exaggerated form of this process that occurs following lymphodepletion expands effector T-cells, often causing loss of immunological tolerance that results in rapid graft rejection, autoimmunity and exacerbated GVHD. Whilst standard immune suppression is unable to treat these pathologies, growing evidence suggests that manipulating the incipient process of HP increases allograft survival, prevents autoimmunity and markedly reduces GVHD.
Multipotent adult progenitor cells (MAPC) are a clinical grade immunomodulatory cell therapy known to alter gamma-chain cytokine responses in T-cells. Herein, we demonstrate that MAPC regulate HP of human T-cells, prevent the expansion of Th1, Th17 and Th22 effectors and block the development of pathogenic allograft responses. This occurs via IL-1β-primed secretion of PGE2 and activates T-cell intrinsic regulatory mechanisms (SOCS2, GADD45A). These data provide proof-of-principle that HP of human T-cells can be targeted by cellular and molecular therapies and lays a basis for the development of novel strategies to prevent immunopathology in lymphodepleted patients.
The way ahead is like Icagen, and the estate is worth 5 to 6 PPS until proven otherwise.
Gil is milking the runway to what appears and inevitable low-level buyout.
That's because Vladimir will be paying good money to Greece to make it a Russian naval base that will project power over Germany soon.
I just did a quick search for the PR and grabbed what I thought was the whole opt-in description simply to make the point that opt-in is on the table and potentially favorable for GERN.
I did not claim to post the unabridged SEC filing description, and the part I pasted gets the point across.
Regardless, Janssen is not going to pay any royalties when they can just buy Geron and also pursue imetelstat combinations showing promise in the literature for other indications. Royalties on MF are not that big a deal, but if Janssen has other indications in mind, a buyout is most likely.
"In addition, if we exercise the U.S. Opt-In Rights, we will also have a separate co-promotion option, or the U.S. Co-Promotion Option, to provide 20% of the U.S. selling effort with sales force personnel, in lieu of funding 20% of U.S. promotion costs, upon regulatory approval and commercial launch of imetelstat in the United States. Such co-promotion would be conducted under a Janssen prepared promotion plan, and in accordance with a co-promotion agreement to be agreed by us and Janssen at the time of our exercise of the U.S. Co-Promotion Option. We would be responsible for all costs associated with establishing and maintaining our sales force in any conduct of such co-promotion. All product sales would be booked by Janssen. If we do not exercise the U.S. Opt-In Rights upon an affirmative Continuation Decision by Janssen, then all further development and promotion costs beyond the Initial Phase 2 MF Study or Initial Phase 2 MDS Study will be borne by Janssen, we will receive a $65 million milestone payment at the time of the Continuation Decision plus a $70 million payment for Janssen's retention of full U.S. rights, and will be eligible to receive additional potential payments of up to $415 million in development and regulatory milestones, up to $350 million in sales milestones, and tiered royalties ranging from a double-digit up to a mid-teens percentage rate on worldwide net sales in any countries where regulatory exclusivity exists or there are valid claims under the patent rights exclusively licensed to Janssen."
Chugai is an oncology company. They have now dropped Athersys for stroke like a hot potato. Get over it.
Athersys now needs to think strategically which DOES NOT mean going it alone with a second phase 2. This would be pure stupidity.
Gil can learn a lesson from Geron who had Mayo Clinic run their imetelstat trial first as an IST that was then picked up by Janssen when Mayo proved authoritative efficacy.
This is how you do it!
Let Erlanger run the damn stroke trial as an IST until they nail down the early infusion efficacy. This would be both cost effective and definitive. Then, a big dog in cardiovascular, like Abbott, will launch a world-wide phase 2 with hundreds of patients to get orphan status and early market approval.
Athersys has no money, and the Chugai stroke deal is an absolute stinking pile of #$%$. They are not interested, so get over it. Chugai is not taking this forward. As I said, they are a freaking oncology company that is just going to give Multistem a bad name with their short sighted all or nothing hege bet they just took. They are not the least bit serious about seeing this through.
What Chugai can do, if they have the sense, is use Multistem for oncology per the systematic review I have posted following Celgene's lead.
If Athersys had maintained infusion at 24-36 hours following ischemic stroke, "we'd still be waiting for results".
What does this say about enrolling the next trial, even with cells available 24/7 and focuing on the 24-36 hour group? Will we still be waiting?
Erlanger, and other major stroke centers, have rapid response telestroke and very efficient clot removal teams. With this strategy in place, they are eliminating the need for Multistem BASED ON THE STUDY STROKE SCALE CRITERIA because more and more patients are recovering within 24 hours and fewer patients are available that have exceeded the 24 hour mark.
Multistem has to be given to ALL patients no later than 24 hours, and the enrollment size has to be larger to distinguish that the subgroup that normally does not recover with standard of care alone recovers with Multistem. Or that Multistem enhances recovery of the majority of all patients beyond standard of care.
Multistem is an insurance policy for stroke victims:
Then, we have to get dose costs down to below 5 thousand USD to justify dosing everyone who has a stroke.
Doing this may be justifiable considering the cost burden of taking care of one incapaciated person runs into the millions. We need economies of scale here, and this means everyone gets a little Multistem to make it work. Think of Multistem as an insurance policy that cannot survive if standard of care recovery pateints do not also enroll. If Japan gets this and all patients undertand they may be the ones who need it, Athersys might just pull this thing off. But, it is going to take a collective effort on the part of Japan. In this sense, Japan is the best place in the world to achieve this.
There are two sides to Athersys management, greed and pride. Greed pays inflated salaries and bonuses while pride actually wants to make a medical contribution.
Perhaps is was greed that resulted in a change in the protocol to speed things up ? The extension to 48 was the kiss of death, but even 36 hours is too long.
As far as needing to increase enrollment numbers for stroke, I already gave references about stroke variability and samples size calculations. Because of this, a small trial, even dosing at less than or equal to 24 hours, could eat ATHX's lunch. With stroke, you either go big or go home. I hope Chugai gets this and understands that 36 hours is too long.
Lonza will take care of cell expansion, and the MAPC advantage will make it rise to the top for oncology applications. Apceth's dose was not high enough, as seen in their ASCO abstract. I think they will need Athersys' Multistem in addition to tweeking their system.
Biggest mistake Athersys ever made...
Before (Updated 2011_09_16)
single infusion 24-36 hours following ischemic stroke
After (Updated 2011_10_24)
single infusion 1-2 days (24-48 hours) following ischemic stroke
SCALING UP AND MANUFACTURING CHALLENGES
Overcoming Comparability and Scale-Up Challenges in Cell Therapy Production
Robert DeansRobert Deans, Ph.D., EVP, Regenerative Medicine, Athersys, Inc.
Advancing cell therapeutics to commercialization requires adapting early pilot scale clinical manufacturing to a scale meeting commercial expectations. Improvements and scaling cell processing can involve radical shifts in bioreactor format, often moving from 2D planar culturing to microcarrier based bioreactor formats. A case study will be presented for comparability analysis involving MultiStem®, an adherent adult stem cell product, in commercialization for cardiovascular and CNS indications.
Mesenchymal stem cells as vectors for lung cancer therapy.
Lungs for Living Research Centre, University College London, London, UK
If Chugai and Athersys really are ignoring oncology...we have a major problem.