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Sanofi Message Board

scistats 6795 posts  |  Last Activity: Apr 30, 2015 1:04 AM Member since: Apr 5, 2009
  • Answer: The spleen starts to dump pro-inflammatory cells at ~6 hours. Cerebral ischaemia induces release from bone marrow at ~4 hours. Microglia contribution to inflammation is even sooner. This all lasts ~22 hours.

    So what is the best time to give Multistem?
    A nice round number to administer Multistem would be ~10 to ~14 hours post-stroke but no later than ~22 hours post-stroke.

    Waiting 30-36 hours post-stroke to administer Multistem is ASKING for major trouble in the next trial. This will clearly contribute to a lack of significance.

    Sentiment: Strong Buy

  • It looks like a rapid phase 2b-3 will happen.
    Rapid because:
    1. With the current results, patients and doctors want Multistem.
    2. In-hospital cryo storage now allows more centers around-the-clock access to Multistem.

    Sentiment: Strong Buy

  • scistats scistats Apr 29, 2015 12:55 PM Flag

    36 hours is too long. The very highest end is ~22 hours for optimal results, and ~22 is pushing it if you want to get ahead of the spleen.

    I think this is what Athersys has to accept. The reality is that stroke is extremely time sensitive, and Multistem adding 17.5 hours to the treatment window is the best we can do. But adding this time is a major advance.

    I am concerned about starting at 0 hour because the signal needs time to get to the spleen from the brain and the response to manifest. Giving Multistem as early as possible seems intuitive, but it may be most needed around hour 6. For all real world purposes though, unless someone is in a hospital, giving Multistem as soon as possible is probably going to be the right thing to do because chances are they are in the window.

    Those receiving Multistem should have a more rapid recovery rate even with spontaneous recovery. Multistem should help everyone to some degree so measure this by progress over time and look for a correlation .

  • Next trial:

    Multistem vs. Placebo

    1. Multistem given within 6-22 hrs (0-6 hrs should not be given Multistem; tPA up to 4.5hrs)
    2. Primary outcome measure: Global recovery RATE over 90 days.

    Exclusion criteria: patients given tPA + mechanical clot removal
    Total enrollment : 500 (250 Multistem; 250 placebo)

  • Imagine this label coming soon:

    "Multistem may be administered within 6 to 22 hours following a stroke to help prevent infection, neurological disability, and death."

    Why?

    Ischemia causes the brain to release signals that activate the peripheral immune system, causing the spleen to "shrink" within 6-22h. During this period, the spleen releases neutrophils, lymphocytes, and monocytes/macrophages that produce pro-inflammatory cytokines contributing to further brain damage.

    Occurring even more rapidly (before 6 hours) following a stroke is activation of microglia, the major resident immune cells in the brain itself which can also contribute to inflammation.

    In addition, stroke influences leukocyte responses in the bone marrow. So, the spleen is not the first player in response to stroke, nor is it the last responder that can contribute to inflammation.

    Multistem can reduce inflammation inducing respnoses from the spleen and perhaps other sources (microglia and bond marrow) of inflammation as well. The sooner you get Multistem, the better.

    Within 6-22 h is ideal, and Gil et al. need to embrace this time frame as a medical fact.

    Sentiment: Strong Buy

  • Reply to

    ATHX was doing it right in the beginning ...

    by dr_sumitchawla Apr 27, 2015 2:29 AM
    scistats scistats Apr 27, 2015 3:07 AM Flag

    24-36 hours post-stroke to administer Multistem to those not responding to standard of care would have been better. This time would have proved Multistem a significant contributor to a positive outcome. But, is 24-36 hours post-stroke ideal? Not by a long shot.

    If you or I are the patient, we need to be given Multistem ASAP. At minimum, we need Multistem within 6 to 22 hours when we know the spleen is reacting to the stroke.

    To make Multistem work, we need markers and a formula to predict which patient will fail standard of care without waiting 24 hours. There are some marker for those predisposed to stroke, perhaps these could be combined with age, infarct location, etc. Some formula to tell us which patients need a $20,000 boost.

    Otherwise, we find a way to make Multistem cheap, and everyone gets it, standard operating procedure (SOP). Say, $2500 per dose. Can it be done? Yes.

  • scistats scistats Apr 27, 2015 2:56 AM Flag

    Ideally, we would know which patients will not respond to standard of care so that Multistem can be given immediately without waiting 24 hours to use lack of improvement as a diagnostic.

    Chugai is likely probing this possibility, " They found...an ALDH1L1 gene variant..strongly associated with stroke." If such a gene marker can be linked to lack of response to standard of care, these patients can be selected for Multistem immediately.

    Perhaps a formula would capture most of these patients say: age + ALDH1L1 gene variant + location of infarction + etc. etc. If such a group is compared, Multistem vs. placebo, this would demonstrate the maximum possible potential of Multistem for stroke.

  • Ischemia causes the brain to release signals that activate the peripheral immune system, causing the spleen to "shrink" within 6-22h. During this period, the spleen releases neutrophils, lymphocytes, and monocytes/macrophages that produce pro-inflammatory cytokines contributing to further brain damage.

    However, occurring even more rapidly (before 6 hours) following a stroke is activation of microglia, the major resident immune cells in the brain itself which can also contribute to inflammation.

    In addition, stroke influences leukocyte responses in the bone marrow. So, the spleen is not the first player in response to stroke, nor is it the last responder that can contribute to inflammation.

    Indeed, Multistem must play "catch-up" not only with the spleen but with other sources of inflammation as well. So, the sooner you get Multistem the better. Within 6-22 h is a minimum.

    Athersys needs to enroll more folks and administer Multistem ASAP but no later than 22 hours.

    Sentiment: Strong Buy

  • Reply to

    I think I know what Chugai is doing...

    by scistats Apr 26, 2015 4:04 AM
    scistats scistats Apr 26, 2015 4:29 AM Flag

    Highlights
    •MSCs exert stimulatory or inhibitory effects on tumor growth and invasion through direct or indirectinteraction with tumor cells.
    •MSCs may be involved in many aspects of regulating immune surveillance, apoptosis, and angiogenesis during tumor development as a source of soluble factors.
    •hMSCs home to sites of tumorigenesis, where they inhibit tumor cell function.
    •The potential role of MSCs in cell-based anti-cancer therapy: (1) as a vehicle for therapeutic drug and (2) as a vehicle for prodrug gene therapy.

    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
    Volume 768, October 2014, Pages 98–106

  • It is becomming standard procedure to scan the genome sequence of trial patients.

    It would take about 3-4 months to get this done for the Multistem stroke trial participants.

    What would Chugai be looking for?

    "Scientists studying the genomes of nearly 5,000 people have pinpointed a genetic variant tied to an increased risk for stroke...They found...the ALDH1L1 gene was...strongly associated with stroke...When the gene is not working properly, it has been associated with a breakdown in a normal cellular process called programmed cell death, and cancer cell survival."

    "The protein encoded by ALDH1L1 converts 10-formyltetrahydrofolate to tetrahydrofolate and is an essential component of the FOCM pathway. These results provide a new and significant link between the FOCM pathway and risk of initial ischemic stroke."

    So Chugai could be looking to see how patients with this genetic variant responded. They could also correlate ALDH1L1 activity following Multistem in Gil's Christmas Tree experiment.

    If Multistem regulates some genes associated with cancer, it could be interesting:

    METHODS OF TREATING CANCER AND PREVENTING DRUG RESISTANCE
    WIPO Patent Application WO/2014/128235
    Abstract: Provided herein are pharmaceutical products comprising therapeutically effective combinations of ALDH inhibitors (e.g., disulfiram and/or derivatives thereof) and targeted therapeutics, as well as methods of using said combinations for the treatment of cancer.

    Assignee:
    F. HOFFMANN-LA ROCHE AG (Grenzacherstrasse 124, Basel, CH-4070, CH)
    GENENTECH, INC. (1 DNA Way, South San Francisco, California, 94080, US)

  • Chugai analysts seem to know its coming.
    Athersys analysts are out right saying it, e.g. Kolbert.
    Athersys management and experts are convinced.
    The ~24 to 30 hour time frame is the correct window for Multistem.
    You can tell...its happening.

    Sentiment: Strong Buy

  • scistats scistats Apr 25, 2015 4:43 AM Flag

    Actually, it is best to have the data that defines the time frame.
    Now we know.

  • 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

  • scistats scistats Apr 24, 2015 8:09 PM Flag

    Excellent point.

    Sentiment: Strong Buy

  • They did not take "no" for an answer for a reason.
    They know the new 24-36 hr time frame as well as we do.

  • scistats scistats Apr 24, 2015 2:45 AM Flag

    To answer the question:
    Department of Stroke Medicine, Kawasaki Medical School

  • Chugai is a multi-billion dollar big pharma in Japan.
    Nevertheless, analysts at the FY 2015.12 1Q meeting tried hard to get more information about Multistem because they obviously know the Multistem story is not over. Likewise, Chugai did not say the Multistem story is over. We now have to wait on a decision about the earlier-time-frame application of Multistem.

    Q&A Session 4:
    I have three questions on Multistem.
    The first question is about your decision and future policies.
    When do you expect to make that decision? Is there any timeline?
    We are now in the process of gathering and analyzing detailed data.
    Our target is to decide within 3 to 4 months.
    Thank you.
    In Athersys conference, it was said several times that they are consulting with PMDA (Pharmaceuticals and Medical Devices Agency) with Chugai involved as well if I remember correctly. With the result of the phase 2 study based on which you are going to make a final decision, are you in a position to file for approval in Japan?
    To give you the conclusion first, though we did sign an agreement the other day, we have not participated in the consultations with PMDA. As for submission, as you know, unfortuntely the primary endpoint was not achieved, and therefore, we will need to see and analyze the details before we make any decisions.
    Thank you. My last question. If and when you perform a clinical study on Multistem in Japan, do you already know which hospitals are qualified as site for the study?
    I hope you will understand that we are not in the position to share any details on that yet.

  • scistats scistats Apr 22, 2015 1:19 AM Flag

    I agree.

    You nailed it with this statement: "other patients make no or little recovery regardless of however much time passes because the brain tissue that infarcts is significant"

    These patients that do not respond cause variation in data. We have to deal with this variation by enrolling more patients.

    Larger numbers are needed to clearly demonstrate the full potential of Multistem. What we have now is a great phase 2, but with a larger number of patients at the 24-36 hour time, the benefits of Multistem will be clearly seen.

  • Reply to

    When do brain cells die?

    by survtech10 Apr 22, 2015 12:17 AM
    scistats scistats Apr 22, 2015 1:08 AM Flag

    TACKLE THE INFLAMMATORY CASCADE, yes.

    But this is not all it does, remember, dr_sumitchawla imparted this knowledge on us: Multistem, "helps in remodelling by releasing trophic factors that help in neurogenesis & angiogenesis among others".

    This is why Multistem works so well after 36 hours. It remodels the brain by the birth of new cells, neurogenesis. I am so confident of dr_sumitchawla that Athersys should forge ahead and focus on the 48 time point.

SNY
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