Adipose Tissue Derived MSC's used in Spain to treat C-19-related Pneumonia
Some observations on the "Proof-of-Concept" study (essentially an EAP) out of Spain just published in The Lancet. The study was conducted back in April at essentially the same time Mesoblast was running its EAP in NYC using remestemcel-L.
I guess what strikes me the most is that we again see MSC's taking the position of "medicine of last resort" in critically-ill ICU patients... and again showing great promise, which reinforces the investment thesis for remestemcel-L. Patients in Spain were first treated with hydroxychloroquine... with steroids (like Dexamethasone)... with anti-virals... with severeal monoclonal antibody anti-ILx inhibitors... and... their lungs continued to fill with fluid. They failed on all of those medications, and progressed to intubation and mechanical ventilation. Informed consent was obtained from "the family" (ie patients were out of it) to bring in life-saving MSC's. Eleven of 13 survived in Spain and of those 11 there were 9 who definitely improved. Ten of 12 survived in New York and of those 10 there were 9 who definitely improved. Both studies were done against a background of C-19 ventilator mortality rates typically much higher.
So, Spain reinforces with surprisingly comparable percentages what we already know from Mesoblast's EAP in NY. Both studies serve as the basis for conducting larger randomized and controlled trials.
It's always a challenge to compare small studies like this. While Spain took cases with P/F ratios as high as 300 (ie easier to treat) compared to Mesoblast's 200 (harder to treat), Spain took on patients who had been intubated longer. Median time to first MSC infusion in Spain was 7 days after intubation, while Mesoblast set an entrance criterion of less than 72 hours after intubation for all patients. As the Spanish doctors point out, better outcomes are observed in terms of time to recovery when patients are treated with MSC's sooner after intubation rather than later. From the paper:
"Whenwe examined the time from intubation to administration of
AT-MSC,we observed that patient successfully extubated had
receivedthe cells earlier than patients that were not extubated
(median5 days... versus 10 days...)."
And one of the striking findings in Spain was indeed how long it took some of these patients to come off the ventilator... if we start to give MSC's "late" when the patient has progressed to heavy, sponge-soaked, fluid-filled, ventilator-damaged lungs where fibrosis has perhaps already started to set in, we shouldn't be surprised to see patients sometimes needing over 2 weeks to come off the ventilator... even though other parameters like oxygenation, lab values, and x-rays are showing improvement.
But at least they manage to come off the ventilator. Patients 1, 2 and 4 in the Spain study at good examples of slow recovery times. C-19 patients weakened after days on a ventilator don't get an infusion and jump right out of bed. Despite expectations and fantasies often expressed on message boards. It takes time for cells to heal soggy damaged fibrosing lungs... but with MSC's they do tend to heal.
Another aspect of note is dosage of cells. Spain used 1x10^6 cells/kg per dose. Mesoblast 2x10^6 cells/kg per dose, so twice as many. Spain gave second doses as soon as 2 days after the first, so a bit earlier than Mesoblast... and Spain also gave a third dose in one patient. Looking at the graphs they provide, one has the impression that some of their other patients might have benefited from a third dose... or a higher initial dose at the outset. The authors provide no information on how they arrived at that dose or whether dose-ranging studies were done previously with their adipose-derived formulation.
In terms of side effects, the study from Spain reported no issues directly attributable to MSC's, always reassuring. The authors make this point about Covid-19, just one of the things that makes it an illness that is "different":
"Inaddition, the presence of a progressive endothelial thrombo-inflammatory syndrome (with elevated D-dimer) not described in otherviral infections adds differential features and aggravates the disease's prognosis" (emphasis added)
In other words, C-19 can cause inflammation in blood vessels throughout the body leading to clotting problems. So, injecting foreign cells into the circulation should give us pause... could we be provoking blood clots or blockage of the micro-circulation? So far, no evidence for that and this study gives further reassurance in that regard. Quite the opposite, we see D-dimer, fibrinogen and C-reactive protein levels generally decreasing after treatment with MSC's, along with improving X-rays. There have been no reports of pulmonary hypertension, decreased oxygen levels or shunting at the time of infusion, which one might expect if MSC's were "lodging" in the lungs and blocking circulation. In fact, they home to the lungs (an important distinction) or other areas of inflammation where they are able to exert a therapeutic effect without blocking circulation. I mention it because one of our competitors (Athersys) likes to imagine that MSC's being larger than MAPC's causes them to become mini emboli somehow blocking the micro-circulation of the lungs. It's true that MSC's have a larger diameter under the microscope, perhaps because they carry a larger payload of cytokines and exocrine factors in their cellular medicine cabinets. But MSC's are not rigid like a B-B. They can easily deform or elongate to pass through a normal capillary if there's no work to be done at that site.
There's another point the authors don't discuss. Two of the 13 patients in their study were above the age of 70. And those were the two patients who happened to die. Coincidence? The next closest male patient was aged 64. Of the patients who died, one had a massive upper GI bleed and the other a fungal pneumonia. The authors attribute the GI bleed to mucosal irritation/ulceration from the patient's NG tube. I'm more skeptical given that the other patient died from a fungal pneumonia. Both upper GI bleeding and fungal infection are know complications of steroids... From a large meta-analysis:
"Corticosteroids increased the risk of gastrointestinal bleeding or perforation by 40% .... The risk was increased for hospitalised patients." And we might add that the risk also increases with age. Simply to point out that the 100% use of steroids reported by the doctors in Spain seems higher than what was being used in other countries, including the US, prior to the RECOVERY trial results out of the UK. Another reason it would be interesting to see publication of the Mesoblast EAP in a scientific journal. Bottom line: care needs to be taken in the use of steroids and we might be heading into a period of "over-exuberance" in that regard.
Finally, I find it curious that this "proof-of-concept" study discloses "Funding: None". Takeda seems not to want to associate itself with the study, which clearly involves the use of "Alofisel-like" cells and involves at least one of the company's long-standing investigators, Dr. Damian Garcia-Olmo - who is a surgeon not a pulmonary specialist. So, it will be interesting to see how this plays out as the product goes through further testing. The authors point to a planned BALMYS-19 phase 2 study and provide its listing on clinical trials dot gov. However, a review of that reference says "not yet recruiting" and the study was last updated on April 16. Perhaps a small EAP could be accomplished with resources from a consortium of universities... a 100-patient phase 2 trial generally needs a sponsor and funding to get accomplished. Are they foot dragging a bit now knowing they're well behind in the race for FDA approval, or are they just not keeping the trial web site up to date? The treatment vista certainly looks different now than it did back in February/March when they planned this "proof-of-concept" study.
All in all I found the write up of the study to be very well done. The results are nicely presented with detailed graphs and tables. Two sets of X-rays are given showing definitive improvement following MSC treatment. Definitely a positive addition to the medical literature on C-19 pneumonia. And it bolsters my investment thesis for remestemcel-L, because adipose-derived MSC's are more similar to rem-L than they are different. If Alofisel works in C-19 I would expect rem-L to work as well or better... and rem-L is closer to the FDA finish line, much closer.
"First-mover effect" will be huge for a therapeutic able to treat advanced cases of the illness of the century: "A first mover is a service or product that gains a competitive advantage by being the first to market with a product or service. Being first typically enables a company to establish strong brand recognition and customer loyalty before competitors enter the arena".
There are two races that concern us. One is to become the "First FDA-approved product for Covid-19". Remdesivir is the favorite there, has an FDA-authorized EUA, but has yet to cross the finish line for full approval. Dexamethasone has FDA approval for the general treatment of "inflammation", not specific to C-19 or ARDS. The second race is to become the "First FDA-approved product for Covid-19 ARDS". Among the products in the latter race, remestemcel-L stands out as the leader, certainly among cell-based products where the two closest competitors are still trying to find dose.
The first interim read out at the "90-patient, minimum 30 days after enrollment" mark could come at any time now, and could have a big impact on how both races play out. Awaiting news, glta
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