@DocMcstuffins , likewise thanks for the reply.We agree that...

@DocMcstuffins , likewise thanks for the reply.

We agree that local injections are preferred when inflammation is confined to a local area (i.e. CLBP, perianal fistula etc) and likewise systemic infusions are preferred with multi organ or large areas of inflammation (i.e. aGvHD, some crohn's cases etc). Our point of difference seems to be around CHF patients. You believe a systemic infusion would be preferred (in terms of convenience, safety, and costs). My belief is a local injection is preferred (in terms of getting the greatest concentration of cells to the area in need, safety, and patient outcomes).

Just a response to the above. It is my opinion that the current administration of our cells via a local injection is low risk as it is done by a trained cardiologist (and proven to be safely administered in the DREAM-HF trial) and importantly the current method of administration is proven to improve MACE outcomes. In terms of costs and convenience it may help to consider the bigger picture. Firstly, if the protocol was changed to IV infusions then higher dosages of cells would be required to compensate for the unfavorable first pass effect through the lungs (there are significant increased manufacturing costs with this). To get the same patient outcomes via an infusion (if this is even possible) IMO you would likely need multiple infusions - like with aGvHD - (again increased costs with multiple hospital visits). Secondly, I have no issue with the proven safety profile of local injection as we are not targeting the more advanced Class IV patients, the procedure will be conducted by a trained cardiologist, and the patient may be monitored via an overnight stay. As I have outlined before, even a SHAM procedure was approved by the ethics committee, this speaks volumes. I also do believe that infusions are also safe but they are also not without risks. Thirdly, in terms of convenience, you could argue either way - multiple trips to the hospital for infusions versus a brief overnight stay in hospital. Lastly for now, I just can not get past the fact that a single local delivery will most certainly outperform a systemic approach. This is of utmost importance when calculating the overall cost benefit ratio in terms of improved Quality Adjusted Life Years - therefore for me (and certainly the likes of Dr Perin and the trained cardiologists in the trial) the clear winner is local delivery.

You said : "The problem I have is that the local injection was chosen as suchbecause it was theorised to have a local effect on the inflammatory processesdriving the progression of heart failure. That was not shown to be the case."

I respectfully disagree. Firstly we were not privy as to why a local injection was chosen, but we can be sure there was a very good reason for it.

Agree that Rex-L did not have a meaningful or statistically significant effect on reducing the volume overload and recurrent hospitalisation on top of current standard of care.This is one aspect of the progression of heart failure paradigm and noted it does ultimately decrease Quality of Life (QOL) and is associated with recurrent hospitalisations (and therefore costs of hospital stays). And to be honest this is OK. There are effective drugs on the market today to treat this aspect of CHF.

However Rex-L did have a local effect on halting the local inflammatory processes which drive the progression of heart failure, as evidenced by a clinically meaningful and statistically significant reduction in MACE events, with the most benefit seen from Class II patients with higher levels of inflammation. These results support the mechanism that Rex-L reduces inflammation in the large local vasculature to protect the viable heart muscle from becoming too fibrotic (i.e. preserving heart function which in turn halts the progression of heart failure). This is the other important aspect of the progression of heart failure that has not been adequately controlled by current SOC, which has the FDA's and Cardiologists' attention.

Moving on, like you I agree further trials confirming the excellent MACE outcomes are warranted. I suppose we will know soon enough what that trial will look like. I personally think there is a chance we will be able to treat patients while conducting a Phase IV confirmatory trial (why: MACE is an approvable FDA outcome; significant unmet need for a serious condition; excellent safety profile; may consider a large phase three trial across multiple sites as a series of smaller phase three trials; may be seen as unethical to withhold life saving therapy in order to conduct further trials). Failing this we also have a likely pathway to approval by conducting a second Phase III trial with a surrogate endpoint to considerably shorted the trial length considerably (reduction in CRP? can imaging be treated as a surrogate endpoint?). Failing these accelerated options we will need to conduct another phase III trial in full (you may call me naive or overly optimistic but I believe we will be granted a faster way to approval than this).

Last point, I also value the opinion of independent experts (not junior doctors ). However, the panel I think you are referring to had very minimal time to assimilate Dr Perins' presentation (and of course they would not be privy to review the trial results?) from memory. It will be interesting/exciting when the NEJM Journal Article is finally published (presumably also including later analysis of success with diabeties/ischemia patients with high CRP) - let's see what the panel of experts and cardiologists think then when all is out in the open and has been digested.

I know we are going to have to agree to disagree on many points. That's OK.