It’s all about the data stupid !
https://www.nature.com/articles/s41422-021-00573-y
Abstract….
“The infusion of coronavirus disease 2019 (COVID-19) patients with mesenchymal stem cells (MSCs) potentially improves clinical symptoms, but the underlying mechanism remains unclear. We conducted a randomized, single-blind, placebo-controlled (29 patients/group) phase II clinical trial to validate previous findings and explore the potential mechanisms. Patients treated with umbilical cord-derived MSCs exhibited a shorter hospital stay (P = 0.0198) and less time required for symptoms remission (P = 0.0194) than those who received placebo. Based on chest images, both severe and critical patients treated with MSCs showed improvement by day 7 (P = 0.0099) and day 21 (P = 0.0084). MSC-treated patients had fewer adverse events. MSC infusion reduced the levels of C-reactive protein, proinflammatory cytokines, and neutrophil extracellular traps (NETs) and promoted the maintenance of SARS-CoV-2-specific antibodies. To explore how MSCs modulate the immune system, we employed single-cell RNA sequencing analysis on peripheral blood. Our analysis identified a novel subpopulation of VNN2+hematopoietic stem/progenitor-like (HSPC-like) cells expressing CSF3R and PTPRE that were mobilized following MSC infusion. Genes encoding chemotaxis factors — CX3CR1 and L-selectin — were upregulated in various immune cells. MSC treatment also regulated B cell subsets and increased the expression of costimulatory CD28 in T cells in vivo and in vitro. In addition, an in vivo mouse study confirmed that MSCs suppressed NET release and reduced venous thrombosis by upregulating kindlin-3 signaling. Together, our results underscore the role of MSCs in improving COVID-19 patient outcomes via maintenance of immune homeostasis.”
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@LearningEachDayThank you for assiduously posting links to several peer reviews regarding the mechanism of action of mesenchymal cells. All of the reviews broadly support the weight of evidence in favour of the FDA /OTAT allowing us to resubmit a BLA for full approval for paediatric acute srGVHD. More importantly perhaps, the data should also greatly encourage Novartis to fund a further Phase 3 trial in ARDS.
One such peer review, link shown above, was under the purview of one Prof Georgina Ellison Hughes whose work at Kings in London is highly regarded and closely followed. In fact , if you expand the list of reviewers on the link , you will see a decent representation of other Western reviewers to the latest research.
It should be remembered that not all these peer reviews have access to the same priming, tissue source, harvesting techniques as Mesoblast’s own IP utilises …but the biomarker panels and supporting diagnostics show compelling evidence. Look at the
evidence… NOT the pathetic whining of the downramping contributors who do not further debate. It’s there in black and white. Read it ! Chest x rays showing much
improved lung scans in a randomised controlled study,
shorter hospital stays,
fewer adverse events and some compelling data regarding NET formation and a biomarker panel showing
key inflammatory cytokines heavily suppressed like for IL1RA, CRP, TNF-alpha and IFN-gamma with
supportingpvalues .
Remembering that the majority of the placebo cohort received a standard of care which
includedcorticosteroids… then look at IL5 suppression in the MSC group in comparison. This augurs well for treating a whole host of respiratory disorders.
What I love most of all about MSCs is that time and time again , provided they are administered at the correct time in disease progression, they appear to help maintain immune homeostasis, without many of the crude repercussions of most single monoclonal antibody treatments. There are limitations of course in relation to treating acute versus chronic conditions as we have seen from the CLBP and CHF trials.
The latest peer reviewed research showing mesenchymal cells having greater efficacy in severe Covid as opposed to mild, is just another reminder of the importance of the in vivo activity of the cells…who respond to the inflammatory milieu they encounter.
I can understand Silviu’s predicament with the original FDA review of the BLA application for Ryoncil . Should Mesoblast stick with potency assays in his submission which were well understood and widely used at the time his last phase 3 trial was designed and agreed with the FDA, or move to assays such as IDO or CD4/CD8 activation as others had proposed ? Mesoblast would also need to try to patent this potency assay process if possible, to create further barriers to entry for those seeking authorisation later. Meanwhile Peter Marks at the FDA was telling the press, just pick something where you can make a reasonable case…Such are the pitfalls of being a first in class therapy ! The FDA is essentially making up the guidance as it goes along throwing a proverbial spanner in the works to slow things down while it tries to establish a regulatory framework. Progress has been made in autologous and CAR-T therapeutics but they are going to have to be dragged kicking and screaming over the line in allogenic. Hopefully the penny is finally dropping in CBER that autologous therapies often DO NOT HAVE COMPARABLE EFFICACY in compromised or dysregulated immune systems , especially in older people or for long term chronic sites of inflammation . What is especially frustrating for Silviu is that he needed to reference consistent potency assay data from all his acute srGVHD trials to help verify how process improvements had improved potency in his phase 3 results. Mesoblast documented at the ODAC meeting they had previously consulted the FDA who had approved the phase 3 trial design and their behaviour at the subsequent ODAC hearing was a total disgrace in my opinion. Remember, with steroid refractory aGVHD we are talking about an
orphanindication with no approved therapy for children under the age of 12. Whilst i am critical of the FDA, it must be acknowledged that as far as in vitro activity is concerned, there is a case for
upgrading potency assays …but to deny treatment to patients where there is no real hope , leading to almost certain death in most with Grade D category , is akin to murder …especially now the expert panel of practitioners on the ODAC committee have opined in favour of Ryoncil .
The key to understanding efficacy in srGVHD is to understand that most RCTs are not worth the paper they are written on because the two clinical grading systems currently used to evaluate the severity of the disease are essentially
flawed… particularly in grade C patients where retrospective analysis using ST2, resulted in a massive
regrading of disease severity at virtually ALL stages of disease progression . It is now so bleedingly obvious (appropriate metaphor) we should be hounding journalists to expose this sh+tshow. There is overwhelming evidence that ST2 is a far more accurate prognostic biomarker of disease severity and the latest review of efficacy of our treatment using ST2, shows indisputable evidence that we have
tremendous efficacy in the “
nonresponders” whose mortality rates using all other standards of care are shameful. I suppose the FDA will exalt themselves for making us prove the golden link which allows them to judge other therapeutics in the future….but prove efficacy we have.
https://www.globenewswire.com/news-release/2021/10/18/2315632/0/en/Remestemcel-L-Improves-Survival-of-Children-With-Biomarkers-for-Highest-Mortality-in-Steroid-Refractory-Acute-GVHD.htmlSilviu sounds confident about our new potency assays to be submitted to the forthcoming scheduled OTAT meeting …which presumably is a result of
guidance he has received from OTAT about what it is they want us to demonstrate….and the fact Mesoblast have been running trials for a good six months? to prove that they are capable of delivering consistent potent batches, regardless of donor variability and traceable by individual cell lot.
Like everyone else I have been extremely frustrated about the delays in obtaining authorisation…the blame lies at many doors …the FDA are under extreme pressure from the Covid pandemic and it has been widely reported that they have not been able to meet their normal timeline guidance for reviewing documentation in cell and gene therapies. We are lucky in that all our phase 3 trials were finished when the outbreak started.
Most people forget that some of the biomarker data needed by Novartis is provided by the NIH …and the Company has little control over how quickly this information is provided. Many of the longer term holders will remember that this was a problem affecting analysis of the LVAD trial a few years back. Silviu can hardly come out and bollock the NIH, who have been superb in helping to fund his Covid ARDS trial in the first place.
Where I am very disappointed with the Board, is this ridiculous “secret squirrel” approach to informing shareholders of continually changing regulatory timelines. I can just imagine the conversation at board level. “Mesoblast cant give a running commentary on changes…. and the shorters would have a field day”…might be a typical riposte to my criticism. The failure to be forthright with shareholders on a timely basis has eroded trust….leaving a market capitalisation which, in my opinion , is effectively a joke. Why not tell your shareholders the date of the forthcoming OTAT meeting if you have one ? I do accept these meeting dates change, but many shareholders are growing weary of flaccid comments like “short term’ or a “few weeks” which have proven very misleading.
@madamswer is perfectly correct to make his point about a forthcoming
need to
strengthen the balance sheet... a point made on several occasions over several years. It is a point made by many shorters who attempt to push down the share price on such occasions to try to dilute shareholders. History has shown that our secured lenders have shown great flexibility in extending credit facilities or Silviu has been able to pull a rabbit out of the hat when it counts with fresh equity . The secured creditor “waterfall “ essentially has Hercules at the apex…so they have to decide whether the combined IP and clinical trial data combined with existing royalties are worth a few hundred million before rolling over the facility . If Hercules flinch there should be a whole host of alternate funders who I think would be happy to replace them. Let’s not forget that the funding gap will be comparably modest, IF we receive US$50m as expected from Novartis on deal
confirmation and when manufacturing
milestones are reached, this triggers much larger payments, provided for in the agreement . I acknowledge of course that Novartis could pull out..but it appears to me they just want to get comfort we will pass the OTAT scrutiny first. Cant blame them really .
The
upcoming presentation at this months AHA conference by the eminent Emerson Perin M.D. PHD, of the Texas Heart Institute , followed presumably by the publication of an
embargoed peer reviewed article in the NEJM ? should finally put paid to the primary endpoint junkies who are incapable of understanding
clinicaldata arising from the rigorous Phase 3, double blinded RCT trial of Revascor in CHF. I will go out on a limb and say there must be a very realistic chance that the FDA will want to fast track Mesoblast’s therapy and may even allow them to propose a
suitablesurrogateendpoint for a further phase 3 trial, such as ejection fraction, systolic/diastolic pressures or levels of NT Pro BNP which would have the potential effect of dramatically
speedingup the
approval timetable . If that does occur, i think global pharmas would get their cheque books out in a heartbeat because the discounted cash flow valuation of future revenues would equate to potentially tens or even hundreds of
billions depending on the scope of treatment ! …that is where so many shorters get it wrong…the
industry will presumably validate our treatment and then the stock market will completely rerate the investment opportunity. The Phase 3 data from the Revascor and CLBP trials is already outstanding. The MACE and mortality benefits as a combination therapy in the Class 2 ischemic subgroup, which historically show the highest hospitalisation costs and reduced life expectancy, dwarf the efficacy shown in Phase 3 trials by either Entresto or the SGLT2 inhibitors alone. Why is Emerson so fired up ? Oh well…not long to wait to find out ! Personally, i think feedback form one of the worlds premier cardiology conferences this month and commentary arising from a peer review in the NEJM ?, should provide quite a fillip to the shares. I believe a positive OTAT meeting for GVHD with follow shortly after….assuming we are allowed to file for full approval, we may well then hit an all time high especially if Novartis has choosen to jump on board.
To think, our little darling shorters think they have us trapped. Maybe they do, maybe they
don’t. It’s trick or treat time ! OP
Please do your own research and do not rely on the facts, opinions or speculation expressed in the above post. Remember it is the opinion of the FDA which ultimately matters. God help all the patients needlessly dying in their hospital beds because of the ineptitude of regulatory bodies in approving a perfectly safe therapeutic for an orphan indication …..which has already been approved and used to save hundreds of people in Japan over the last five years.
(20min delay)