Below are some of my thoughts on the 90 day ARDS results.
I've incorporated a more detailed rebuttal of Prof Paul Knoepfler's piece (first link below) in which he said it would be difficult to 'tease apart' the benefits of MSCs from the steroid benefits.
Re. steroids, I've mentioned in previous posts that 'regardless of the cause' has been debated for decades in ARDS and I found a meta analysis that examined just that.
Prof Knoepfler also raised a potential problem with MSCs in the presence of virus. I think the effect of MSCs on the virus could be important because of the change in focus I see in this most recent presentation.
@Southoz raised the issue of adjusting for multiplicity. This is a very smart poster and I appreciate the value of a strong opposing view that makes me look and think. I've looked and thought and I'm not concerned about this criticism for common sense reasons.
I think this is far from a failed trial. I'm less concerned now about whether we have enough good data because there's the potential to use the whole cohort.
Please note I have a confirmation bias. This is by far my largest holding and there are two MSB candidates i have a personal interest in. Feel free to make corrections. I think this forum is an important place to learn both for my investment and personal reasons.
DEXAMETHASONE
"Dexamethasone did not Reduce Mortality in Controls on Invasive Mechanical Ventilation with Moderate/Severe COVID-19 ARDS"
I believe the above statement to be an accurate reflection of Dex's general performance in Covid ARDS. The statement is particularly important IMO because mechanical ventilation is where Dex had the most benefit in the Recovery Trial. This was an open label trial with important information about patients missing.
When steroids became SoC I was very surprised. I've been through meta analyses and studies that I referred to in previous posts that show no mortality benefit in ARDS:
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Caroline L. Hough MD asks if we should ever give steroids to ARDS patients. She reviews the clinical trials:
"The first randomized controlled trial of corticosteroids for decreasing mortality in patients with established ARDS was conducted in the early 1980s... the hypothesis that this treatment would reduce 45-day mortality30. This study was stopped early for futility, with 60% mortality in the methylprednisolone group and 63% in control, after enrolling 99 patients".
On the rigorous ARDS Network NIH:
"The primary outcome was 60 day mortality. It was estimated that the intervention would decrease mortality from 40% to 20%, with a sample size of 180 and 85% power. Sixty day mortality was lower than anticipated—29%—and was equal in both study groups.There were interesting differences between the treatment groups, however. Patients randomized to steroids liberated from mechanical ventilation sooner than those on placebo (14 days versus 23 days, p=0.006) and had significantly more ventilator free days at both 28 and 180 days. Yet, there was no difference in ICU length of stay between the groups, and return to mechanical ventilation was significantly more likely among patients randomized to steroids (20 versus 6, p=0.008)."
I found a meta analysis on Regardless of the Cause. Chaudhuri et al (2021) examined corticosteroids in Covid ARDS and non Covid ARDS. The meta analysis included 18 RCTs enrolling 2826 patients.
"In keeping with GRADE methods, we use terminology consistent with the overall certainty of evidence. This includes stronger language for high certainty evidence, and less certain language (‘probably’ or ‘may’
for moderate or low certainty evidence."
"The use of corticosteroids probably reduced mortality in patients with ARDS of any etiology (2740 patients in 16 trials, RR 0.82, 95% CI 0.72–0.95, ARR 8.0%, 95% CI 2.2–12.5%, moderate certainty). Patients who received a longer course of corticosteroids (over 7 days) had higher rates of survival compared to a shorter course."
"Corticosteroid use may reduce ICU mortality (RR 0.61, 95% CI 0.38–0.99, ARR 18.6%, 95% CI 0.5–29.6% reduction, low certainty, e-Fig. 8) and probably reduce hospital mortality (RR 0.67, 95% CI 0.46–0.96, ARR 16.6%, 2.0–27.2% reduction, moderate certainty, e-Fig. 9) in critically ill patients with ARDS."
"The use of corticosteroids may lead to fewer days of mechanical ventilation (MD 4.04 days fewer, 95% CI 2.53–5.53 days fewer, low certainty, e-Fig. 18) and a shorter hospital length of stay (MD 8.05 days fewer, 95% CI 3.12–12.98 days fewer, low certainty, e-Fig. 10). There was an uncertain effect on ICU length of stay with corticosteroids (MD 0.78 days more, 95% CI 4.11 days more to 5.68 days fewer, very low certainty, e-Fig. 1"
Investigators used 28 day mortality as a PE, which is not the best indicator. You'll note the P values for under 65s in our trial have changed from 0.048 to 0.038 in just in a month for sad reasons that I mentioned before.
The criticism of the ARDS trial not meeting the PE of 30 days is the most disingenuous thing I ever heard. It was clear to me right in the beginning from a basic perusal of the ARDS literature that mortality benefit is clearer over time. I thought benefit would be clearer after 6 months, continuing up to a year, even two.
OP has pointed out the word "discharge". I'd have overlooked such a simple and important thing. In the Recovery Trial which had 28 day mortality as a PE, it wasn't clear how many patients remained in ICU or hospital. I've been unable to find 6 month follow-up data.
The synergy with Dex I view as a double-edged sword. On the one hand Dex has become SoC, which is convenient for us; however, I was worried that our therapy would be overshadowed by a cheap anti-inflammatory (Knoefler's piece illustrates this) and my biggest concern was that Dex would abrogate the benefits of our cells.
Before the ARDS results were reported, what I saw as bad luck I thought might somehow work in our favour. My hope, though, was that it would be more cut-and-dried. My concern about our therapy being tied to Dex is that best mortality benefit is ahead of ventilators where Dex benefit was even more modest and in patients not requiring supplemental oxygen harm couldn't be ruled out.
I know this is not a scientific thing to say, one I've mentioned before, and I admit my bias against steroids in this condition (and also GvHD.) I think medicine works best in an acute setting and ARDS is the pointy end of that. I have a particularly high opinion of Mount Sinai who are doing cutting edge work with predictive and response biomarkers. What I know of clinicians in acute medicine is that they're not easily impressed.
The EAP results were outstanding. The doctor interviewed appeared to be in awe. I inferred that biomarkers showed those patients were going to die but they didn't.
I just don't understand how Remestemcel-L +Dex could be more effective than Remestemcel-L on its own.
MORTALITY
The issue of adjusting for multiplicity has been addressed by experts on this forum. Mortality is, of course, the most important outcome but it's important to consider other factors when you assess if a therapy works.
While short-term mortality in ARDS has improved, longer-term mortality hasn't, as I provided evidence for in a previous post
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Secondary endpoints, such as ventilator-free days, are often considered more meaningful
A major issue is bad survival and those survivors being relatively young, as I also provided evidence for in the above post and this one
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The placebo-controlled RCT is considered the gold standard. Such a trial denies treatment to some who might benefit and gives treatment to some who might not, yields an average result when people are not average, particularly not in a heterogeneous condition such as ARDS.
I see a movement into an era of personalised medicine simply because of improved imaging, where we can see exactly what a therapy is doing:
I watched Dr Matthay's presentation on YT. Removal of VEGF abrogated MSCs' ability to remove edema from the lungs. Putting VEGF back in and the cells could do it, even the conditioned medium. Effect was achieved within 24 hours.
The respiratory improvement reported in our trial is also supported by the pre-specified endpoint of ventilator-free days, We can maybe use the whole cohort If we know why the improvement wasn't sustained in over 65s. I recall that SI said in that over 65s had higher viral loadings. I don't know what happened to the 'use early' because it's now about the age of the patients but I've read that SoC changed to delaying ventilators and giving multiple therapies. I still think the viral loading might have been less if patients had received our therapy earlier.
Then there are objective results such as change in biomarkers CRP, IL-8, IL-6. Perhaps IL-6 will be particularly important because I've read that high IL-6 correlates to severe Covid and I referred to a study reported in Nature that Dex didn't have a positive effect on this.
Then there are CD4 and CD8 levels. The China study I referred to by Shi et al (Nature, 2021) found that "UC-MSC infusion did not result in a significant reduction in the duration of oxygen therapy, mMRC, cytokine, or chemokine levels, which might be in part attributed to the status of the enrolled population, as most of them were not in the acute progressive stage." There was also no difference in CD4 and CD8 levels between groups.
Perhaps this is the study Prof Knoefler refers to whose results were inconclusive? MSCs are not drugs but respond to existing signals in this acute condition. The failures therefore reinforce their MOA.
Then in treated under 65s in our trial, there could be things not happening. Not returning to hospital or ICU. Not having secondary infections such as pneumonia. Not surviving with organ damage (Josh Farkas, whose blog is Pulmcrit, says survival but with end stage kidney failure would not be considered a good result) and it takes time to show that things haven't happened. A therapy against fibrosis, aberrant scarring, is the holy grail of inflammatory conditions and it can take time to show itself.
ANTIVIRAL EFFECT OF MSCs
Prof Knoefler also comments on MSCs in the context of a virus:
"A more serious, but perhaps less likely, risk is that these approaches could harm people with Covidf-19. For example, if the rationale that stem cells might treat Covid-19 by reducing immune system activity has any chance of being correct, then such a treatment could overshoot. Stem cell therapies could reduce immunity too much, leading to greater spread of virus from cell to cell, or cause other harm in unexpected ways"
Dr Matthay addressed this concern in his YT presentation on MSCs' ability to clear bacteria and endotoxins through direct and indirect mechanisms. (Prof Caplan also confirms this in his YT lecture). Dr Matthay says there were concerns that the MSC treated mice might have a worse host defence against bacteria because the MSCs are immunomodulatory but surprisingly they found the opposite was the case.
There's less research on MSCs' antiviral effect but they've been studied in HIV and Hep C. MSCs got good results in clearing HIV in an animal model. (SI has also published work on HIV).
Weber et al (2021) say:
"Our findings suggest that MSC treatment produces an immunophenotype resembling some of the characteristics of long-term HIV-infected non-progressors. HIV controllers have highly effective HIV-specific CD8+ and CD4+ T cell responses compared with HIV progressors and are reflective of GC integrity and function (9, 39, 40). Regulation of GC homeostasis and function is important for effective antiviral immunity and better clinical outcome in HIV infection".
'GC' stands for Germinal centres where B cells evolve and produce antibodies.
(Another finding of this study, which supports our findings in MPCs, indicates MSCs could deliver the other holy grail in inflammatory conditions - the restoration of gut barrier integrity - which in my view is the key to switching off the cytokine storm and the only way to make the microbiome work against disease)
From the report on the above study by UC Davis Health:
“Stem cells are good synergistic partner components with drugs. The antiretroviral drugs can stop the fire of the viral infection but cannot restore the forest of the lymphoid tissue compartment. The MSCs would rejuvenate the field and bring back immune vitality,” Dandekar said.
"Even without the use of antiviral drugs, MSCs were able to increase the host’s antiviral response by repairing the lymphoid follicles, restoring the mucosal immunity and reviving what has been targeted by the virus very early on".
Perhaps there could even be a "synergy" with Merck's new antiviral drug for Covid which it's seeking approval for?
Re. Prof Knoefler's suggestion that the cells could boost what you don't want them to such as viruses, the evidence IMO is pointing the other way. If the cells boost the good (acute) inflammation that prevent and can cure chronic inflammation (provided organ damage hasn't occurred) but don't let it overshoot then I think the same logic applies to their effect on viruses.
MSCs as a VACCINE
As far back as 2012, Tomchuck et al proposed that MSCs could serve as an "unconventional but innovative, vaccine platform" and refer to reports that MSCs promote adaptive immunity.
There was concern early in the pandemic about the type of vaccines being developed that focused on antibodies. The rationale is that Covid-19, being an intracellular pathogen, T cell response is more protective. Those who recovered from SARS1 and MERS had broad protection that lasted for 18 years shown by CD4 and CD8 levels.
Robert Sanders reports on research by Marc Hellerstein of the University of California, Berkeley. Professor Hellerstein has studied the birth and death rates of T-cells in HIV/AIDS patients over 20 years ago, using sophisticated mass spectrometric techniques designed by his laboratory.
"Hellerstein points out that antibodies are not the primary protective response to infection by coronaviruses, the family of viruses that includes SARS-CoV-2. Indeed, high antibody levels to these viruses are associated with worse disease symptoms, and antibodies to coronaviruses, including SARS-CoV-2, don’t appear to last very long".
Hellerstein refers to the concern of Antibody Dependent Enhancement (ADE). Of ADE, Lee et al (Nature, 2020) say:
"SARS-CoV immunization studies in animal models have thus produced results that vary greatly in terms of protective efficacy, immunopathology and potential ADE, depending on the vaccine strategy employed. Despite this, vaccines that elicit neutralizing antibodies against the S protein reliably protect animals from SARS-CoV challenge without evidence of enhancement of infection or disease71,72,73. These data suggest that human immunization strategies for SARS-CoV-2 that elicit high neutralizing antibody titres have a high chance of success with minimal risk of ADE".
Regarding protection, from Hellerstein's review article in Vaccine:
"A key early question for any candidate vaccine for COVID-19 will therefore be whether it induces durable, high quality T-cell protective immunity. A theoretical advantage of mRNA vaccines, for example, is that antigens are synthesized in the cell cytosol where they can be processed and bound to MHC-class I molecules on the cell surface for recognition by CD8 T-cells. But it is not known whether the absence of SARS-CoV-2 antigens such as M or N will mimic the functionality of T-cell responses from natural infection or what the durability of induced T-cells will be. The same uncertainties hold true for any spike protein based COVID-19 vaccine".
Hellerstein says that "whoever is paying for or approving the vaccine trials has the obligation to make sure that we look at the quality and durability of the T-cell response".
I've found a couple of studies on CD4 and CD8 levels after mRNA vaccines but they were small.
We've read about the problem of emerging variants in the pandemic. Heide Leford (Nature 2021) reports on the race to develop next-generation vaccines. Such vaccines would stimulate T-cells which could be more resistant than antibodies to threats posed by emerging variants.
ADE is not a theoretical concern, which is why data from Israel is being closely watched. It could perhaps be due to waning vaccine efficacy. We know a third dose is now being recommended for over 50s. There's also growing anger at the lack of focus on therapeutics. Either way, I think Rememestemcel-L has to be widely deployed this autumn/winter in the northern hemisphere. It's the ONLY therapy left standing and also IMO the ultimate Covid vaccine.
ALL IMO Good luck to all holders
https://www.statnews.com/2021/06/25/for-now-stem-cells-for-covid-19-are-mostly-a-shot-in-the-dark/https://pubmed.ncbi.nlm.nih.gov/33876268/
https://www.nature.com/articles/s41392-021-00488-5
https://insight.jci.org/articles/view/149033https://www.sciencedirect.com/science/article/pii/S2590136220300231?via=ihub
https://www.nature.com/articles/d41586-021-00367-7
https://www.frontiersin.org/articles/10.3389/fcimb.2012.00140/full#T1
https://health.ucdavis.edu/health-n...ource=biweeklyupdate&utm_content=20210623
https://news.berkeley.edu/2020/09/0...id-vaccine-look-beyond-antibodies-to-t-cells/
https://www.nytimes.com/2021/08/18/...ons-booster.html?referringSource=articleShare
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