When things do not go as planned..it is best to step back and take stock of the situation.
Have you been led down the garden path ? Is @Gan_Gans a visionary...or @Sector the chosen one ? Well time will tell. I certainly have not covered myself in glory. I was always taught that a broken clock tells the correct time, twice a day and Captain Hindsight and his enthusiastic detractors have been lavishing corrective advise/punishment to all and sundry. Whilst mainly undeserved, because I question both their motivation and the fact that Mesoblast is working at the leading edge of new science so they are making cheap shots , I felt these lashings as a sort of penance to be endured...after all we did not meet the primary endpoints in our flagship trials.
But when I see @col69, the epitome of decency, cordial manners and fair play, being a realist and contemplating accepting cheeky low bids for Mesoblast ,I have to return to the inflammatory milieu. After all poor@Lopez must be about to pass out having held the fort so admirably. I must also commend the excellent@Cooper111 who has made some particularly astute observations. Our usual fact-checking prefects@Zenox,@stockrock and@bedger have rightly shown caution after a run of nasty surprises...but deep down I hope they still believe the science works...
HAS EVERYONE LOST LEAVE OF THEIR SENSES ?
The Revascor trial design may have proved hapless ...the phase 2 results which helped to formulate the primary endpoint, were later shown to have further compounded an inaccurate understanding of how our cells actually operate. It appears that there is a sweet spot when our cells achieve unbelievable efficacy which does not necessarily correspond to when the inflammation has reached its peak (unlike our excellent results in Grade D srGVHD). We have learnt that when a patients innate immune system has deteriorated and the left ventricle is too damaged there is little chance of remodelling the left ventricle to correct the effects of volume overload . We knew that we could not totally rely on our Phase 2 CHF results because of the small sample size ...but lets not forget that the 150m dosing arm did achieve a p value of 0.001 against the control . We got a hint that things might not be perfect when it emerged that only 18 patients with a baseline of over 100ml, generated any meaningful data in the phase 2 trial. Indeed it was because of the small sample sizes that I was told by the company not get too hung up about the contradictions which emerged from some of the data in the different dosing arms . They were of course, correct, to make that point, because small sample sizes are likely to throw up disparities... but when looked at, in the round, the data showed that something meaningful was being achieved. Let’s not forget, that even the Godfather of stem cell therapy , Arnold Kaplan , has dramatically revised his understanding of the mechanism of action of mesenchymal cells in the last decade.
Listening to a recent webcast from Emerson Perin we were told that ejection fraction was not likely to be changed in patients over 60....when the mass of heart muscle in the left ventricle finally capitulates to the mechanic stretch and volume variability of a heart pumped full of anti diuretic therapies trying to mediate sodium levels, we cant do much to mitigate that ...and yet ...
HOW DID WE REDUCE HEART ATTACKS AND STROKES FOR BOTH CLASS 2 AND CLASS 3 PATIENTS !
Yes, it would appear Mesoblast might have got something spectacularly right in thinking that we help regulate production of endothelial nitric oxide synthase. The role of mesenchymal cells in reversing endothelial dysfunction and arteriosclerosis would appear to manifest itself in much lower incidence of strokes and heart attacks . We already know from the LVAD trials that our cells have an effect on dysplasia in the GI tract and epistaxis in the nasal cavity when they were injected into the heart. I believe these cells affect both autocrine as well as paracrine signalling pathways . I also believe that our therapy has proven to stimulate the growth of new small diameter blood vessels, or arterioles, “ which help regulate intravascular pressure (myotonic response ). These vessels, dilate with local reduction in oxygen tension and release various mediators during increased metabolic activity of the parenchyma.”
WHAT DID WE EXPECT..from the first major five year study of Mesenchymal stromal cells ? Perfection ?
Well we almost got it . I cannot overemphasise the fact that the Revascor trial was groundbreaking...a new Paradigm in CHF therapy according to Mesoblast management, which might even surpass the achievements of statins as a new frontline therapy in the management of CHF. BUT WE MUST ADMINISTER THEM AT THE SWEET SPOT IN THE PROGRESSION OF THE DISAESE...which we now how reliable biomarker assisted evidence is in Grade 2B HYHA patients. I am looking forward to the full data set being released shortly and the inevitable bidding war breaking out between every global Pharma for access to our IP. Don’t believe me ? Watch this space ! We are told by the current team in CEBR that Mesoblast should master its knowledge of the interoperability of 600-700? activated localised proteins, amino acids, micro vesicles and a host of immunomodulatory signalling pathways which help bring the body back into homeostasis, before having the temerity to request a regulatory approval....yet over a decade later they are still working out the shortcomings of statins ...what a cheek !
Before, you all start bleating the new mantra of rigorous designed RCTs are the only way forward ...just consider how Japan has learnt to safely and quickly fast track orphan designation treatments by using common sense for conditions such as GVHD. If a therapy has an almost unblemished safety record and is treating an unmet need in a high mortality condition ...having a more flexible system is both preferable, effective and humane . The advent of the “Right to Try” legislation has failed to be embraced by the FDA ...The European Medicines Agency has already approved Temcell ...which is a mesenchymal cell therapy which is based around Mesoblast IP. Far from becoming the gold standard , I think the FDA, is an obstructive and bureaucratic organisation .. and i can supply a whole list of scandals and bad decisions for anyone who is interested...but we will have to bend to their hand.
Moving forward..because we must face up to realities.. The failure to reach a number of important primary endpoints in successive trials has consequences. Milestones will not be triggered pressuring cash flow and exacerbated by bloated inventory (even though prudent accounting will most likely have written that off until FDA approval when it will be categorised as stock ) Novartis is free to walk away should it so choose and we will need further guidance from the FDA before we can make the appropriate strategic decisions. That is quite a setback....so why am i not rushing for the door ?
...because the Revascor trial result has achieved a major reduction mortality and in three point MACE. This was thought to be so difficult, that no one...not even the Professor, ever thought he could achieve in his wildest dreams . How do I know? ...because he told us on the webcast. More importantly, having spoken to him over a number of years, I knew that he had not ever made such an optimistic claim, which we now see backed up by a rigourous and carefully monitored clinical randomised controlled studies.. I believe any confirmatory CHF trial will need to involve about 500 patients and take about 4 years in to total to read out. However, the process of partnering with a major should ensure that shareholders can enjoy as major rerating during that time. In the meantime, the FDA may decide to grant accelerated approval for Revascor. In the light of recent hiccups and the 206 trial size, it might be a tall order...but the massive scale of improvement in mortality and morbidities mean that it has a pretty decent chance . That will screw the shorters .
I believe we are one of the hottest properties in town right now...and Revascor’s real value , will, in my opinion, justify a major partnership deal with past costs refunded with a global partner . I would guess that a deal will take about 3-4 months max to conclude. It may be a bumpy ride but as our current valuation sinks below US $1bn...i would be surprised if it had not recovered substantially by the next six months.
As to CLBP readout. I think we will show decent efficacy. Will it be enough in pain and function ? ...have not got a clue...but i think we will find out in the next few days. If we get lucky we can revisit new highs ...otherwise another leg down is in prospect ...until long term institutions relieve the retail investor of their burden....
Good luck to all.
Oh Merry Christmas
Please do not rely on the opinions or facts in the above post when making an investment decision . OP
(20min delay)