Yor, Perhaps the question should be applied in a broader...

Yor, Perhaps the question should be applied in a broader context, since FDA rules must be uniformly applied. Until regenerative medicine came along, many drugs even after receiving marketing authorisation, have subsequently been found wanting in post confirmatory trials... (as seen recently with Entresto narrowly missing its primary endpoint for HFpEF ) Occasionally after long term use in the general population, serious side effects have emerged as we have seen now with opioid addiction epidemic. Indeed it is safe to say that the FDA has saved many lives in protecting people from cowboy practioners, incorrectly labelled and marketed medications and unnecessary patent extensions...so lets be fair. In relation to clinical trial success rates, researchers at MIT Sloan School of Management led by Charles E.and Susan T.Harris and Professor Andrew Lo, published their findings in Biostatistics. Based on their analysis, the overall probability of success (POS) for industry sponsored drugs entering Phase 1 trials to obtain FDA approval was 13.8%. Not surprisingly the highest POS was for drugs moving from Phase 1 to 2 (66.4%) while the lowest was for drugs moving from Phase 2 to Phase 3. With such low percentage approval rates it is difficult to argue that the system is failing, but obviously the use of double blinded randomised clinical trials often leaves its fair share of victims who participate in the control group.

Until the FDA manage to conduct a strictly observed doubled blinded randomised data set over a longer duration as evidence of the efficacy of MSCs, they presumably had no choice but to approach the Revascor phase 3 clinical trials with conservatism and caution. Where I tend to agree with you, is that after 20 years of clinical studies and in relation to salvage therapy, where fast-tracking treatment is not only desirable, but essential, the FDA might be more pragmatic. With all the clinical data for Remestemcel from the Expanded Access Programme and the patient use in Japan , if a parent is willing to agree to an indemnity waver for an “experimental” therapy (for conditions such as Grade 3/4 Liver & Gut srGVHD, where there are no real treatment options) it should be allowed. If I was an American right now, whose child was suffering from such an orphan disease, I would be on a plane to Japan, where Temcell represents the gold standard treatment option for both paediatric and adult acute categories of sr GVHD referenced above. Sadly it is not a real option for an immune compromised child from a low income family with no hope of insurance reimbursement. The FDA have recognised this shortcoming in the system...and now even offer help with preparing BLA applications ...but they could do better. The US has a blame and litigation culture which sadly leaves the regulators having to comply with some of the strictest regulations in the world.


Having said all that , stem cells have had there fair share of controversies over the last 20 years or so...in fact it has to be remembered that there have been some tragic cases...for example in pancreatic cancer.

https://www.ncbi.nlm.nih.gov/pubmed/19609435

For a less rose tinted view of the sector there is a recent review highlighting many of the issues but acknowledges at the end recent trials may be about to change all that :
https://www.hindawi.com/journals/sci/2019/9628536/
When therapeutic stem cells first arrived on the scene, it was often embryonic or umbilical cord therapies which were expected to have the greatest therapeutic benefit until it was noticed that abnormal clotting factors were present in pregnant women, which was natures way of preventing haemorrhage during natural birth . At the other end of the spectrum we had the problems of amplification and senescence in older donors which were vulnerable to a whole host of conditions many of which are highlighted in the link below :
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222976/

This caution relating to even mesenchymal cells still continues to this day, although the focus is now slowly moving to commercialisation issues such as GMP ( Good Manufacturing Practice) to ensure consistency, efficacy and potency of donor batches, as people start to recognise the indisputable advantages of allogenic versus autologous donation. As Dr. Jacques Galipeau, Chair of the ISCT MSC Committee attests in the link below:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434696/

“Admittedly, the use of pre-banked allogeneic MSCs is the only feasible deployment strategy for use in acute tissue injury syndromes like stroke, sepsis, or myocardial infarction, where the delays in manufacturing autologous MSCs would forfeit their utility in affecting outcomes. Independently from biological concerns for immune compatibility, a business case can be made that only mass produced allogeneic MSCs will ever sustain a margin driven marketing model where cost of goods is the main headwind to commercial success”

Ironically I have been told by one industry expert that, in his opinion, Dr Galipeau originally favoured the cause of “fresh autologous therapies” which wrong footed many people both the industry experts and investors alike. At least he now acknowledges the superiority of Mesoblast’s allogenic cryostored production techniques . On Page 829 he concedes :
“The TiGenix-sponsored trial, NCT01541579, was completed in 2015 and represents the first unambiguously successful use of MSCs and/or ASCs in an advanced clinical trial.”

https://www.cell.com/cell-stem-cell/pdfExtended/S1934-5909(18)30222-4

It is the rigorous FDA testing procedure, which I believe has left Mesoblast, as the real contender in the short term for a successful mesenchymal cell therapy for CHF. At one stage it might have looked a close run thing with another Company Celyad . Their autologous therapy for CHF patients with a low ejection fraction failed a 9 month clinical trial in Europe which you can find reviewed on Page 828 of the same research paper . Galipeau observes the differences between Celyads and Mesoblasts IP and production methods and recognises the superiority of the latter. Bearing in mind that both Mesoblast and Celyad administer dosing via a cardiac catheter it is an interesting case study which examines potential damage to the myocardium from 18 different endoventricular injections , with some counter intuitive conclusions on dosages:

“...there is concern that the injections are concentrated in areas of good myocardium that may increase the risk of disruption of the tissue and worsening outcomes. Indeed, post hoc analysis of ventricular remodeling 52 weeks after treatment of NCT01768702 study participants revealed that the largest reverse remodeling was evident in patients receiving a moderate number of injections (i.e., <20). These data suggest an inverted U-shaped dose/response curve with worse outcomes at higher dose delivery attempts. This counterintuitive observation informs that the number of injections may well be an important factor in improving outcomes because more injections may cause potential myocardial damage through multiple mech- anisms, both mechanical and biological (Teerlink et al., 2017 “


The failure of the Celyad trial and their subsequent withdrawal from the cardiac therapy space had another unexpected benefit for Mesoblast. In 2018, MSB was able to negotiate exclusive rights to use their proven percutaneous catheter technology for an initial payment of just $800,000....a point which few have noticed buried away in the 6K filings. Below is an abstract from the marketing literature for C-Cathez :

C-Cathez ® is C3BS’ steerable percutaneous catheter. With its nitinol-based curved needle and side holes, this new generation of percutaneous injection catheter for myocardial delivery has been designed and developed to elevate the standard of care to clinicians and patients by focusing on three key features: local drug concentration, safety, and ease of use.

With C-Cathez ® , Cardio3 BioSciences provides the clinician with a catheter which can be safely steered to reach target sites within the heart left ventricle. C-Cathez ® permits stable contact with the beating myocardium without generating additional tissue trauma and diffuses the therapeutic agent over a bigger target area to obtain both a higher concentration and a wider tissue exposure

This is just another example of the huge barriers to entry for any other competitor to Mesoblast other than J&J , who already have the gold standard mapped cardiac catheter in this space. Amazingly, a large sub group of the Celyad trial relating to ischemic heart patients was later shown to have been more successful than first thought and Post hoc analysis demonstrated that LVEDV and LVESV of treated patients decreased by 17.0 mL and 12.8 mL greater than controls (P=0.006 and P=0.017, respectively at 1 year. (Teerlink et al., 201 Of particular interests to Mesoblast shareholders was the absence of any patient mortality in the ischemic sub group compared to the control . By the way, I have been advised that Celyad’s technology would probably still have breached at least one of MSBs patents with regard to targeted patient profiling using mesenchymal cells of patients with heightened baseline LVESV. ( I have not been able to verify this yet ).
I found the cell.com paper particularly helpful as it gave a comprehensive review of the main stem cell treatments, as of 2018, in the clinical development stage. This can be found in the Appendix with the Celyad results in Section 9.

DREAM 1 started enrolment in 2014 after being delayed by over a year by Teva. We know that by June 2016, 230 ‘enriched patients” had been enrolled, split between Class 2 and Class 3 CHF Hence when our interim futility test was undertaken in April 2017 on 270 patients, many may have been experiencing MACE as a precursor to a TCE. We know from meta analysis (which i have provided a link to in a previous post) that patients suffer on average 3-4 MACE before death mainly in the last decile of their lives post confirmed diagnosis.

The observations above led me to conclude, that there were enough MACE events to accurately calculate a PPOS which predicted an outcome that was at least 25% more favourable in comparison to the control group...which is why I believe Mesoblast continued with the trial after passing the interim futility test. Whilst there were probably enough MACE events to indicate an accurate assessment of the prospects for our Revascor trial, there may not have not have been a conclusive of TCE to get the FDA to call off the trial at the time even if there was no pre defined rule to that effect. After the April 2017 test, all parties to the have remained blinded so there are none of the ethical issues which require the trial to be halted.

Lastly in relation to our own Revascor trial ...I thought it might be useful to mention something relevant to the interim futility test that will disappoint the shorters amongst us (you know who you are) . When I mentioned in a previous post that Mesoblast inferred in a webcast Q&A that it had insisted on a “high bar” for the powering of the primary endpoint in the trial ...they have on many occasions refused to discuss the precise details. Don’t forget that calculations such as the Posterior Probability of Success has to be set prior to the trial starting ...which is why I was surprised to see the precise level for the powering of the Revascor trial mentioned in an article by Robin Davison (link below for Gan_Gans) published on the 25th August 2015 by a respected industry publication , in relation to our clinical trial NCT 02032004 :

“The basic design of the new trial remains the same: recruiting patients with NYHA class II or III systolic heart failure, who will receive a single injection of CEP-41750 (Rexlemstrocel-L ) directly into the left ventricle or undergo a cardiac catheterisation involving a sham cardiac mapping and cell delivery procedure.

The primary endpoint remains a time-to-event analysis of heart failure-related major adverse cardiovascular events, or HF-MACE (since changed to number of MACE events) The study was originally powered to show a 25% relative reduction in HF-MACE versus control.

An interim analysis is expected later this year, but the key will be the second analysis, which Teva has changed to a combined interim efficacy/futility analysis now triggered at 50% of the HF-MACE events, and which could occur in mid-2017.

Mesoblast said use of recurrent HF-MACE as primary endpoint was supported by a new analysis of the completed phase II trial, where patients treated with CEP-41750 had no HF-MACE over 36 months' follow-up, compared with 11 (of 15) recurrent HF-MACE in the control group (p<0.001).

https://www.evaluate.com/vantage/articles/analysis/tevas-phase-iii-rejig-leaves-some-unanswered-questions

In general, targeted therapies to prevent HF after MI have lagged behind advances in reperfusion, with Entresto (valsartan/sacubitril) the only novel pharmacotherapy for HF to enter the mainstream market in over a decade. Despite the evident burden of HF, many MI trials have predominantly focused on thrombosis, bleeding and composite endpoints [e.g., major adverse cardiac events (MACE)] rather than HF events specifically.

So, in my opinion, Mesoblast appears to have set a high bar for powering its MACE interim futility test compared with the published trial results of some of the major heart trials for CHF by the global pharmas which I referred to in my previous post which showed a 13-17% reduction in MACE . So what gave Robin Davison, who is a specialist biotech analyst at Vantage, such an insight into our Dream 1 clinical trial ? It so happens that he was previously Head of Biotech at Edison Research who I believe acted in some capacity for Mesoblast in the past. It may not be his most discreet revelation but it is of public record.
https://www.edisongroup.com/wp-content/uploads/2019/02/HealthcareQuart_28May.pdf

Lastly , with regard to the protocol for stopping rules, I actually agree with Gan_Gans that the FDA will probably require a further confirmatory trial for Revascor ....UNLESS there is overwhelming evidence of a substantial reduction of TERMINAL CARDIAC EVENTS (TCE) compared to the control group...in which case I believe Revascor will be fast tracked and we can all get very excited. Let’s wait and see....I think we will see a major reduction in TCE and MACE , because there is research showing the two are correlated.
Interestingly the size of the trial was reduced by Teva, from the originally proposed 1165, to 600 patients, back in August 2015 which in theory reduced the statistical power of the trial. IT IS THEREFORE VERY INTERESTING THAT THE DMC ALLOWED OUR TRIAL TO BE FURTHER REDUCED TO 566 PATIENTS AND KEPT THE 540 MACE NUMBER THE SAME. I wonder what they have observed to date that made them do that ?




(Sorry to be so long winded, but it is important to back up my observations when I am being accused to being a “siren voice”.)