MSB’s announcements (and their respective conference calls) of three interim analysis results and headline results together indicate that external changes that have occurred over the course of the trial, and that these appear to have materially affected Rem-L’s apparent efficacy. Most recently, the aging of trial population and dexamethasone have been raised. On 18 December 2021, MSB ALSO described
that numerous changes in the treatment regimens for COVID-19 patients occurred, including both prior to and while on mechanical ventilation that may have an effect on the mortality endpoint in the trial.
These include extended management of patients prior to ventilator support… IMHO, changes to ventilation practices, and an associated tendency to delay commencement of ventilation, are likely to have confounded MSB’s trial results.
This post puts forward a thesis that Rem-L is indeed very effective, and that elevated and rapidly rising CRP biomarkers may be a more appropriate criteria for commencing dosing with Rem-L, as opposed to commencing based on respiratory symptoms of moderate-severe ARDS (i.e. requiring mechanical ventilatory support with low PaO2/FiO2 ratios) which were inclusion criteria for this trial. The following research / reasoning supports this position, most of which is new information or learnings that have arisen about COVID and Rem-L over the last year and after the trial began. I invite comment from others on this thesis
1. Rem-L ‘appeared’ to be efficacious in the initial phases of COVID outbreakMSB have revealed that the COVID ARDS trial was aiming for, and was powered for, a (quite ambitious) target of reducing overall mortality by 43%. The first two interim analysis were passed by the DMSB which indicate that the trial (across all ages)
was showing substantial trends towards this high level of efficacy. However, something seemed to happen over the course of the trial which reduced apparent efficacy by the third interim analysis.
An aside observation might also be made regarding apparent speed of recruitment for the trial. Those on HC who were following (and predicting) recruitment rates may have made an observation that recruitment seemed to be comparatively rapid in the earlier phases (to get to first and second interim analysis points) but them seemed to slow down. This could be for a whole host of practical reasons; one possible cause of this was that changes in Standard of Care affected the rate at which patients met the trial inclusion criteria.
2.Ventilation practices have changedNIH’s updated guidance for critical care of COVID patients (updated Dec 2020) identifies a number of strategies for treatment of hypoxemic respiratory failure. This includes oxygenation, use of a high-flow canula oxygen, non-invasive positive pressure ventilation and prone positioning prior to proceeding to positive ventilation. These guidance procedures have developed in the first few months / waves of COVID and may affected the ‘Berlin’ criteria (PaO2/FiO2 ratio <200mm Hg) which was what MSB used to recruit participants.
https://www.covid19treatmentguidelines.nih.gov/whats-new/ Tobin (Jan 21) puts a case that PaO2/FiO2 is a mismeasure of oxygenation in COVID-19 and presents why this particular measure is problematic for randomised clinical trials. He explains that the PaO2/FiO2 ratio has a curvilinear relation with the concentration of inhaled oxygen (FiO2) which distorts who is categorised as having ARDS.
In patients who fulfil all ARDS criteria, administration of 100% oxygen for 30 min caused PaO2/FIO2 to increase such that 58.5% were no longer categorised as ARDS.https://erj.ersjournals.com/content/57/3/2100274Meanwhile, Torgensen (Jan 21) has undertaken studies of ventilation practices (albeit in Britain) which identified that
during the first wave of the covid-19 pandemic, almost three quarters of patients who were admitted to critical care received invasive ventilation, and one in two received it within 24 hours of admission. Now the numbers are around half that. If this occurred similarly in the US, it is significant.
https://www.bmj.com/content/372/bmj.n121A likely trend that may have occurred through MSBs trial is that patients in the latter phases of the trial were not diagnosed with moderate/severe ARDS and put onto ventilators, as early as they might otherwise have earlier in the pandemic, and therefore did not receive Rem-L until later in the course of the progression of their disease. This may have occurred after inflammation had done its damage and rendered Rem-L less effective in its immunomodulatory action.
3. C-Reactive Protein (CRP) strongly predicts mortality in COVID ARDSWang (June 2020) identified early in the pandemic that CRP was correlated with lung legions and disease severity.
https://www.sciencedirect.com/science/article/pii/S0399077X2030086XManson et al. (August 2020) published information in the Lancet which showed elevated,
rising CRP levels predicted 28-day mortality. I have previously commented on this paper, and provided graphical extracts at:
https://hotcopper.com.au/threads/msb-trading-2021-paradigm-shift.5840628/page-1285?post_id=50622516R. Smilowitz et al (Jan 2021) presented an analysis that elevated and rising CRP at hospital admission has a strong association with adverse outcomes and mortality. Data was presented that showed CRP concentrations of CRP rising in excess of 150mg/L was a significant predictor of mortality (p-<0.001). It recommended that
CRP-based approaches to risk stratification and treatment should be tested. https://pubmed.ncbi.nlm.nih.gov/33448289/Mueller et al. (Oct 2020) particularly identified that
rapidly rising CRP during the first 48hrs of the disease is a particularly strong predictor of respiratory decline and that there is a potential role for targeted immunomodulation in a subset of patients early in hospitalization.(my emphasis)
doi.org/10.1016/j.xcrm.2020.100144Edy Yong Kim MD, PHD cited this study in Science Daily (Nov 2020) stating that:
a single CRP lab value from hospital admission wasn't very practical as a predictor of who might get sicker, tracking the rate of change from Day 1 to Day 2 or 3 was a very powerful and very clinically predictive test. Even though all of these patients looked clinically similar upon admission, as early as 24 hours after hospitalization, the immune systems of patients who would go on to the ICU multiple days later were already inflamed, as measured by these biomarkers."“Even if you gave immunomodulatory drugs, which reduce rising inflammation, as early as Day 3 -- which is pretty early for a clinical trial -- that may already be too late," "But here we have some evidence that a rise in inflammation directly drives respiratory failure, which implies that the immunomodulatory drugs might be able to prevent respiratory failure if given very, very early -- as early as hospital Day 1 and 2"This study related to Tocilizumab, which is
now recommended by NIH to be used in combination with dexamethasone.https://www.sciencedaily.com/releases/2020/11/201105112947.htm4. Dexamethasone is efficacious and has synergies with Rem-LThe RECOVERY Collaborative Group (Feb 2021) have shown through a trial of 2104 patients that Dexamethasone (Dex) has been shown to be efficacious (albeit to a minor degree) to reducing mortality in COVID 19. The eligibility criteria for this trial included diagnosis with COVID-19 and did not require moderate – severe ARDS and so this treatment would be unaffected by ventilation practices and could be administered early in this trial.
https://www.nejm.org/doi/full/10.1056/NEJMoa2021436Dex has the same immunomodulatory mechanism of action as is proposed for Rem-L. It may be able to be administered early in the disease progression (prior to ventilation) where it is effective.We have learned that, like Tocilizumab, Rem-L appears to be very effective when used with Dex. The two may be complimentary or synergistic. One explanation might be that patients who had Dex may have had inflammation ‘held at bay’ so that overwhelming damage had not been done by the time Rem-L was eventually administered.
5. Rem-L demonstrated to work better on other indications when CRP levels are highSince the trial commenced, MSB have announced on 7 December 2020 that Rem-L reduces inflammatory biomarkers in AGvHD.Just 4 days ago Daniel Weiss at al. (8 May 2021) published a paper identifying that Rem-L’s efficaciousness in COPD was significantly more when patients were stratified by CRP levels.
https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-021-01734-86. We are generally learning that stem cells beneficial impact may be more prophylactic that regenerativeWhilst Rexlemestrocel-L is a different product used for different indications, the results from chronic heart-failure and chronic lower back pain seemed to have common themes that there is a ‘sweet spot’ in terms of timing of administration relative to the course of the disease. It would not be inconsistent if Rem-L also had a ‘sweet spot in acute settings.
CONCLUSION
When all of this new information is pieced together, it seems that there is a strong probability that Rem-L does reduce mortality and indeed did reduce mortality for COVID ARDS early in the trial. If the detailed analysis of the COVID trial identifies supporting temporal trends between inflammatory biomarkers, dosing and efficacy, this would be highly material to establishing Rem-L’s mechanism of action, setting up a confirmatory trial to succeed, securing the Novartis partnership and possibly EUA approvals from FDA for COVID ARDS and possibly for paediatric AGvHD.
(20min delay)