Silviu Itescu The Legend, page-270

To give reiterate a key point, we are working with biologics here.. which means that it is a multi-faceted chain reaction in the body that actually results in the benefits seen in patients, which is not fully understood. The FDA know how difficult it is, so have special rules to help companies come up with 'proposed mechanism of actions' which do not need to be fully proven, but just 'reasonable'. So the propoed mechanism of action shows that Revascor is responsible for reversing an inflammatory environment by converting damaging macrophages (M1) to beneficial M2 macrophages which not only reduce inflammation, but also results in the secretion IL-10, PDGF and FGF2 which are known to be beneficial to not only the heart, but with all the blood vessels that connect your heart to the rest of the body.

So these are measurable and based on research by others, and used by Mesoblast to derive a proposed mechanism of action. Now the extent by which all this translates to clinical benefit is what Mesoblast are trying to determine through clinical trials, and it seems Mesoblast being held to a very very high standard by these two... in that they are not allowed to make an incorrect hypothesis, and by doing so discredits any other benefits seen in the trial, such as reducing stroke, heart attacks and cardiac death, which by the way are listed as more important secondary endpoints than the ejection fraction ones.

Also, the phase 2 trial showed improvements in ejection fraction.. or remodelling. In lay terms, it showed that Revascor may lead to 'healing' of the heart. That is based on the clinical data generated in a phase 2 randomised trial, which primarily showed benefits in the reduction in hospitilisations, stroke, heart attack and cardiac death as well as the remodelling. The data was very compelling, so much so Cephalon injected US$350m into Mesoblast (US$130m upfront, US$220m in equity).

So what this phase 2 data showed is that Revascor may result in 'healing' of the heart muscle... so they followed the data they had generated and included in secondary endpoints, 11-15 as results that may support their future BLA, but they were not primary endpoints or endpoints which could be used to file a BLA if positive.. rather they were supportive.

So that part is the part-truth, as we haven't seen Mesoblast present data on improvements in injection fraction... we can assume that the 'healing' they saw in the phase 2 trial was not demonstrated in the larger phase 3 trial. Instead, what Mesoblast found was that rather than 'healing', all those beneficial secretions 'preserved' or 'protected' the heart muscle. So the mechanism of action itself is still valid, but the quantam of benefit seen in patients is not as outstanding as 'healing' the heart, but rather 'preservation/protection' of heart muscle that hasn't become scarred/dead.

You can see this with Class II patients performing much better than Class III patients, with strong data showing a strong prevention in disease progression from Class II to Class III/cardiac death. But where there is less healthy heart muscle, the patients have less to preserve, and are too far down the track to prevent a high mortality rate.

In terms of IV vs injection into the heart muscle, this is the type of experiements they would have done at preclinical studies to see which method of administration would be most effective. From what I know, these MPCs need to be injected into an inflammatory environment to be triggered... and you need a lot of them (150m) to see the best benefit. So diluting it in an IV and having it travel around your body, who knows how much will actually get to your heart, and to the inflammed heart muscle where it needs the most help? Also when targeting heart failure, why would you send these cells around your body, potentially have them triggered in other parts of your body where M1 macrophages are lurking, when what you are trying to treat is your heart?

When someone has inflammation in their back, why do they get corticosteroid injections directly into their back.. or if their wrist or shoulder is inflammed why is it injected directly into the site of inflammation and not through IV? Sounds quite logical to inject the 150m MPCs directly to the site of inflammation if you ask me.

You can also see from imaging from Dr Perin's presentation (below) that there are areas in the heart that are normal heart muscle (not inflammed), inflammed heart muscle (i.e. inflammed myocardium) and scarred/dead heart muscle. What they found is that injecting the cells into normal heart muscle, Revascor wasn't as effective as injecting it directly into inflammed heart muscle as those cells were immediately triggered and the mechanism of action is kicked off. When they injected into scar tissue, nothing happens because you need living tissue to preserve/protect.



But I don't think its correct to simply say their goal is to lower CRP levels, their goal is to reduce inflammation in the heart and have the MPCs induce a chain reaction through the polarisation of damaging M1 macrophages into beneficial M2 macrophages, which secrete IL-10, PDGF, FGF2 that benefit the heart and blood vessels connecting your heart to the rest of your body.

I can see @whytee replied after your post with his (more likely borrowed from someone else), which @DocMcstuffins assured was 100% correct. Let me point out firstly that these two are buddies from another thread. So they'll always have each others back... I had some hope for them, but it appears from my latest exchange with whytee that they are only here to cast doubt and spread negativity. I mean I gave @whytee the perfect chance to say something positive, but he simply ignored my questions. If someone was here to genuinely discuss the stock and have a reasonable discussion, they'll acknowledge the good good and the bad... but nope, its all negative and anything positive is ignored.

But although there was no 'healing' of the heart muscle, what they have shown is that it 'preserves/protects' healthy heart muscle. They aimed for the stars and landed on the moon, and these two arm chair warriors think thats a failure. Reducing stroke, heart attack and cardiac death... doesn't matter, something they hypothesised using their phase 2 data didn't translate in a phase 3 trial, ... so their entire phase 3 trial was a failure. That's what they want us to believe.