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Analysis of the EAP

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    Goodmorning Australia, Left-e from the USA posting here for the firsttime under the handle LeftYahoo, chosen to poke a stick at therestrictive nature of that board which has been blocking many of myin-depth posts. A pleasure to be on the same forum with ecool2, TheYankee and other dedicated MSB and MESO longs. Thoughts expressed onthis board are respected and get wide circulation in the States. Icome to make a small contribution from an American perspective, myapologies if I duplicate any ideas already presented.

    So,shackles off, I thought I'd start with some thoughts about the12-patient EAP done at Mt Sinai Hospital in NYC. I agree witheverything ecool2 and others have said, but to round out theperspective: First, some are rightly concerned by the small size ofthe study because up to 50 patients were authorized by the FDA. But,more than 12 weren't needed. We are given a lot of additional ofinformation about the 12 patients based on posted entry criteria forthe study and facts we know about the situation in NYC in April,which has been carefully studied. Selected NYC patients may indeedserve as unblinded “controls” so to speak. That allows us tomake perhaps a stronger initial assessment regarding remestemcel-Lefficacy than might otherwise be expected with just 12 patients. TheFDA guidelines for designing Covid-19 clinical trials are a startingpoint. Patients with “severe Covid-19” who might have beencandidates for C-19 experimental medications such ashydroxychloroquine or remdesivir or leronlimab or Kevzara, would NOThave been eligible for rem-L at Mt Sinai hospital in April. Not sickenough. To be a candidate for rem-L patients had to enter into the“Critical Covid-19” category, which essentially means they had todeteriorate to the point of requiring intubation and a ventilator. One of the criticisms of the EAP by the uninitiated has been, “Aha,rem-L patients also received other experimental medicines, no wonderthey got better!” Wrong. No ICU doctor is going to start a secondexperimental med on a patient getting better on a first experimentalmed. The correct interpretation is that rem-L took on patients whohad already failed essentially everything else that could be tried. So that tells us something.

    Nextwe can look at how ventilator patients are classified. Once apatient is intubated, the widely-used Berlin Criteria for ARDS allowfine-tuning of severity based on P/F ratios. That's a ratio thatmeasures the Pressure of oxygen in the blood divided by the Fractionof oxygen in the air (room air =21% or 0.21) A normal P/F on roomair is in the 475 range. As patients become ill, go to the ER, andare placed on supplemental oxygen, the P/F ratio drops. When apatient is intubated an effort is made to adjust FiO2 and ventilatorsettings to bring the P/F ratio into the high 200 to 300 range. Thepatient has “mild ARDS” under Berlin, but is “critical” underthe FDA Covid-19 classification. Important not to mix the twosystems. Many patients linger in the mild ARDS category, some evenget better. A point to remember. If the lungs worsen the P/F ratiodrops despite the doctor's best efforts. At a P/F of 200 the patientcrosses into the “moderate” ARDS category and becomes a candidatefor rem-L. We know that from the posted EAP entry criteria. Mostpatients this ill are already excluded from entering other trials. CYDY/Leronlimab will enroll some patients down to a P/F of 150. rem-L takes patients all the way down into the “severe” category,which is a P/F ratio below 100. Excepting other stem cells(MultiStem, PLX) no other experimental medications enroll patientsthat ill. The key point is these patients follow a downward curvethat can accelerate suddenly. Almost like a 737 max in a nosedive, aLOT is being asked of these cells and they must work quickly. Timingbecomes important. My impression: rem-L was reserved in the EAPessentially as a medicine of last resort for patients felt to besalvageable based on vital organ function (brain, kidneys, liver),but who were clearly dying from their lungs. So, that tells ussomething.

    Third,in the press release we are given some statistics about ventilatorpatients and mortality rates in New York City during the same March -April time period. 88% mortality rate, only 9% could be liberatedfrom their ventilator. We know that as the virus swept from Chinatowards the west, ER protocols slowly began to change. Some hardlessons were learned in Europe in early March, especially in Italy,and Italian docs got on the internet to share knowledge. Followingstandard protocols they intubated patients, but it turned out theywere intubating too early. Way too early. Bad for patients whomight linger for weeks on a ventilator, might suffer lung damage fromthe ventilator (VILI), might end up with a tracheostomey... and badfor ICU's which over-flowed. It became clear that Covid-19 ARDS is“different”. Many ER and ICU docs say it. It causes a bilateralperipheral pneumonia, yes, and patients have fever, cough and rapidbreathing, yes. That's why they go to the ER. What's different formany is the “flexibility” of the lungs. They remain remarkably“compliant”, and don't become so stiff as in classic ARDS. Sopatients breathe shallow and fast but they don't tire out as easily. Meanwhile blood oxygen levels can go to frighteningly low levels.Patients who would have been intubated in Italy in early March arenow treated with high-flow oxygen at tank-depleting rates up to60L/min. (standard use is 2-6L/min). A new jargon has emerged. These “happy hypoxemics”, also referred to as “L-phenotype”patients, scare their doctors a-plenty, but they actually do prettywell without intubation and represent 70 to 80% of serious cases. These are the Boris Johnson type patients who are too ill to beadmitted to hospital – that would be dangerous. But they can't stayin the ER for days. So they get admitted to the ICU for carefulmonitoring on high flow O2 by mask or nasal cannulae. And thedoctors now hold off intubating, hoping they'll get better onwhatever non-rem-L experimental medicine is tried. And often they doget better. Mr Johnson received no particular VIP treatment. ICU orstep-down care for happy hypoxemics is the norm for Pauper, Princeand Prime Minister alike. So, that tells us something.

    Sometimesthe doctor's hand is forced by factors not related to blood oxygenlevel per se and intubation must be done to save a life. Thesepatients have often progressed to a more classic type of ARDS withstiff lungs (also referred to as “H-type”). That's one reasonthe mortality rate for ventilated patients has risen so high in NYC. Of course, both H and L types may be intubated depending on otherfactors. But lessons learned from Europe mean that only the sickestin NYC were getting intubated in mid-April, those who could survivewithout intubation were winnowed out. So, that tells us something.

    Fourth,we should look at the FDA response to all this. To do that we haveto compare what's happening with rem-L's closest competitors, whichare MultiStem bone marrow derived MAPCs from Athersys and PLXplacenta derived “mesenchymal-like” MSC's from Pluristem. I haveno particular interest in those products which are probably steppingon Mesoblast IP, only the FDA response. As far as we can tell, whenMesoblast completed its 12-patient EAP the FDA gave a green light toproceed directly to a full phase 3, controlled, 300-patientmulti-center trial. It means the 12-patient EAP functioned as a phase2 in a disease for which the company had no prior direct experience. That's huge in terms of saving time and represents a big vote of FDAconfidence, imo, even in the Age of Covid-19 where “expedite” isthe new mandate and rules are meant to be bent. Let's look at theothers. So, Pluristem which has been developing its cell line for 19years also ran an EAP and recently reported results at 28 days on 8patients: 7 were in ICU's in Israel and 1 was a ventilator patient inNJ who had been intubated 3 weeks. We are told 87.5% of patients (ie7) survived at 28 days, 75% (6) were liberated from ventilators and62.5% (5) were discharged from hospital. Pluristem cites statisticsfrom NYC for March-April showing only 3.3% of NYC patients onventilators were discharged alive (from a study also cited byMesoblast, therefore useful for rem-L). So, it all looks good on thesurface, but digging a bit deeper, one might ask why didn't they waita few days longer and allow a few more (American) patients to reach28 days. No public updates are planned now till after their fulltrial. It would also be good to know P/F ratio entry criteria forthe EAP. Unfortunately, those data aren't given publicly because thePluristem EAP isn't registered. So, we can't tell how many “mild”ARDS cases there were. Likewise, given the changing protocols is itaccurate to apply NYC statistics to patients far to the east inIsrael who may have been intubated following a more classic protocol? Finally, did the NJ patient survive? I haven't seen confirmation ofthat other than a newspaper report proclaiming “100% survival”(in 1 patient!) 4 days after the cells were injected (IM). We knowfrom the Mesoblast EAP that MEAN time to extubation was 10 days forsurvivors, so a report at 4 days in a patient weakened by nearly amonth of ventilator care could be, well, premature. Most importantthough is the FDA response to Pluristem: Go Find Dose. Pluristemwhich has phase 3 trials running for its product was sent back tophase 2 and will begin a 140-patient dose-finding study. Wow. Inquiring minds might wonder why an EAP, smaller yes, but givingpretty comparable results for a company older than Mesoblast led toa very different FDA response? How about Athersys? Athersys electednot to put its cells on the line and opted not to do an EAP. They'vebeen considered the leader in investigating classic ARDS, having runa phase 1 / 2 study from 2016 to 2019, They reported safety andpromising efficacy results, however the 36-patient trial was notpowered for efficacy. Still 36 is 3 times 12... Moreover, theirpartner in Japan is also collecting phase 2 data with the sameproduct in ARDS. Isn't that enough to find dose? No, says the FDA,like Pluristem Athersys is required to do a phase 2 in Covid-19 ARDS,which they will conduct as an open-label lead-in to theirFDA-approved pivotal phase 3 trial. Essentially an EAP but morehidden inside the envelope of a larger trial – maybe saferreporting-wise if you're not convinced of the efficacy of your cells. So, the FDA response to competitors tells us something.

    Finally,Mesoblast is partnered with the NIH, another big vote of confidencethat these cells are capable of getting the job done. The leadhospital for the study is again Mt Sinai, which remians in anepicenter for the illness in the US. The trial coordinator seems tobe very engaged with frequent updates to the site as reported on HC. They've seen many patients not make it. They want this trial to succeed. That tells us something.

    Myfinal impression is that remestemcel-L is still flying under theradar of the American press, but is one of the leaders in the racefor an approved FDA therapeutic. There are none yet. Hydroxychloroquine is approved for other indications and has an EUAfor C-19, remdesivir has an EUA but is unapproved... and may not getapproved, data are pending. It means there's still an outside chancefor rem-L to capture bragging rights as the world's first FDAapproved C-19 therapeutic. Important thing is to let the trial playout and post solid incontrovertible, hopefully jaw-dropping numbersno matter how long that takes. All of these companies MUST do trialsto get over the finish line. We're leaders in the race, mostcompetitors are bogged down in phase 2 dose finding. Keeping the barhigh and the moat wide eliminates the weak and is the best strategyfor now, though investors are impatient. Comparing the rem-L phase 3to other trial designs shows this cell-based therapeutic is beingpositioned to occupy a most special niche: medicine of last resort. It's a great place to be: give us the patients who have failed yourvaccines, anti-virals, convalescent plasma, IL-x Inhibitors,monoclonal antibodies, JAK inhibitors, nitiric oxide, HCQ, zinc,Super Factor XYZ, or combinations of any or all of the above,whatever. Try those first and when they're stopped due totoxicities, drug interactions or side effects - or when they fail tocure - give us those patients. That's all we need for now. It's agreat starting point for this cost-effective ICU medication seeking acceptanceacross a wide swathe from patients to doctors to insurance. Get anapproval in adults for that niche. As doctors gain experience withthe treatment in the clinic that niche can only expand. But startthere. No need to go after hay fever or toe nail fungus this firstyear. As for children, a BLA for SR-aGvHD is sitting on the FDA'sdesk. Now that children are suffering from a variant Kawasakisyndrome officially labeled Pediatric Inflammatory Multi-systemSyndrome (PIMS), that has some inflammatory marker similarities, whatwill the response be? I don't see anyone stepping up to the plate (anAmericanism) to take on this horrible complication when it progressesto the killing of some innocent children. And leaves others withcoronary aneurysms that might rupture at any moment. Will the FDAmove the BLA to the top of the stack? Might we see something in Japanwhere rem-L has approval and where Dr. Kawasaki first described thiscomplication? Might the company file an IND to do a trial for thatindication?

    Excitingtimes ahead. glta, All IMO, Left-e

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