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TOPIC: Perin: Mesoblast Delivers Promising CHF Results

Perin: Mesoblast Delivers Promising CHF Results 14 Jul 2015 19:05 #4826

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MACE was impressive but can someone explain whether the explanation of no affect on ejection makes sense?


NEW YORK and MELBOURNE, Australia, July 14, 2015 (GLOBE NEWSWIRE) -- Mesoblast Limited (ASX:MSB; USOTC:MBLTY) today announced that Phase 2 trial results of its cell therapy product candidate for the treatment of congestive heart failure (CHF) have been published in the latest edition of Circulation Research. The results were published as an "online first" article ahead of full print in this peer-reviewed, high-impact journal of the American Heart Association.

Patients with advanced heart failure have a poor long-term prognosis and few therapeutic options. Mesoblast's proprietary Mesenchymal Precursor Cells (MPCs) may offer a promising alternative because of their ability to induce heart muscle repair, stimulate new blood vessel growth, decrease cell death and reduce scar formation.

In the article, entitled 'A Phase II Dose-Escalation Study of Allogeneic Mesenchymal Precursor Cells in Patients With Ischemic or Non-Ischemic Heart Failure', the authors concluded that high-dose allogeneic MPC treatment may reduce heart failure-related major adverse cardiovascular events (HF-MACE) and provide beneficial effects on adverse left ventricular remodelling.
Key results of the 60-patient, placebo-controlled trial were:

Primary Endpoint of Safety
Transendocardial injections of allogeneic MPCs into the hearts of patients with either ischemic or non-ischemic heart failure due to left ventricular systolic dysfunction were feasible and safe, with a similar incidence of adverse events across all control and treatment groups.
Treatment of patients with allogeneic MPCs was not associated with any clinically significant immune response.

Secondary Efficacy Endpoints
Patients treated with the highest dose, MPC 150M, showed the greatest improvement in left ventricular remodeling compared to controls; this was evidenced by significant reductions in Left Ventricular End Systolic Volume (LVESV), p equals 0.015, and Left Ventricular End Diastolic Volume (LVEDV), p equals 0.02, at month 6 post treatment relative to controls.
Parallel improvements in both LVESV and LVEDV in the MPC-treated patients may have accounted for the observed non-significant changes in ejection fraction.
Patients treated with the highest dose, MPC 150M, showed the greatest improvement in functional exercise capacity compared to controls (6MTW: p equals 0.062) at month 12 post treatment.

Major Adverse Cardiovascular Events (MACE)
In a post-hoc analysis after all patients had completed 36 months of follow up, treatment with MPC 150M was shown to be associated with a significantly lower incidence of HF-MACE events compared to the control group (0% vs 33% HF-MACE by Kaplan-Meier, p equals 0.026 by log-rank).
Lead author and investigator Dr Emerson C. Perin, Director, Research in Cardiovascular Medicine and Medical Director of the Stem Cell Center at the Texas Heart Institute, said: "The findings from this trial are very encouraging and suggest that a high-dose of Mesoblast's allogeneic cell-based therapy may decrease major clinical events associated with progressive heart failure for at least three years, including repeated hospitalizations or death.

"These effects appear to be due to the ability of these cells to positively impact on adverse cardiac remodeling associated with chronic heart failure. If these results are confirmed in the ongoing Phase 3 trial currently recruiting at our institution and elsewhere, this new therapy has the potential to change the paradigm for the management of patients with advanced heart failure and a high risk of hospitalization and death," Dr Perin added.

The randomized, placebo-controlled Phase 3 trial using Mesoblast's high-dose MPC 150M is being conducted by Mesoblast's development and commercial partner, Teva Pharmaceutical Industries Ltd., and is actively enrolling patients across multiple clinical sites in North America.

The primary efficacy endpoint for the Phase 3 trial is a time-to-first-event analysis of HF-MACE, the same efficacy endpoint achieved in the Phase 2 trial by the group receiving MPC 150M.
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Perin: Mesoblast Delivers Promising CHF Results 15 Jul 2015 11:15 #4827

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This brings back memories... :whistle: :grin:

I think it was 2011 when these results came out and I had heated discussions with Marty Pfingstgraf and another Yahoo boarder- Florida Joe or something who however lived in maine, since I was in touch with him. :whistle:

Anyway, I have all the Perin slides from his AHA Scientific sessions somewhere on my hard disk and will retrieve the main ones, which explain the results, which certainly did NOT impress me.

Remains to be said at present- I am redecorating and painting etc etc my study, which will keep me busy for another day- that the clinic was SINGLE BLINDED- which has an impact on MACE surely, despite all goodwill and professionalism of the participating doctors and I also found a pathology report from a deceased patient of the trial who had inflammation in the heart from where he got the injections with the cells.

That does not show up in serum values, but-to me- it cannot be good long term, I am sure.... :bye:

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Perin: Mesoblast Delivers Promising CHF Results 18 Jul 2015 11:06 #4837

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Actually this MSB clinic which was reported upon by Emerson Perin at the AHA Scientific sessions in November 2011 is a good example of the issues cell therapy has had and are having with blood flow applications and therefore most of them are turning to autoimmune- whatever "source or type" cells you have at stake.
Personally I think know most of them- and I still like ADRCs the best, although the size (n) of PRECISE and APOLLO (and after wards ADVANCE and ATHENA were abysmal)

So- we will dig into this a bit deeper as usual and start with WST´s rhetorical question:

MACE was impressive but can someone explain whether the explanation of no affect on ejection makes sense?


EF- Ejection fraction- or better LVEF- the one measured on the left ventricle - has from an historic perspective always been the FDA´s first and foremost parameter as it comes to deciding on therapies or drugs for cardiac function. That has changed, since there are several weaknesses in the function. Even some change in heart shape (dilation) might cause a deteriorating heart function to have relatively unchanged or even slightly improved EF results, which obviously is not what is desired. (the dilation of course)

Cytori followed scientific research from Wu et al which showed that saving formerly lost (due to MI for instance) or regained contractile muscle tissue, is a better predictor for morbidity and mortality issues than EF and the FDA simple seems to be focussing in that direction more. That is MACE (Major Adverse Cardiac Events)

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Anyway- back in 2008- things were still EF...and the announcement by MSB was simply MINDBLOWING...... :joy: :woohoo: :really:

Results from the first group of patients receiving the lowest dose of Revascor! (Fas: the 25 Mio cells!) were presented to the American Heart Association by lead investigator Dr. Nabil Dib, Associate Professor of Medicine
and Director of Cell Therapy, University of California, San Diego, and Director of Cardiovascular Research, Mercy Gilbert and Chandler Medical Centers, Phoenix, Arizona.
Patients who received a single injection of Revascor! into damaged heart muscle had significantly improved cardiac function at both three and six months compared with baseline. At six months, a single dose of Revascor! was accompanied by a 22% mean increase in EF, whereas controls had an 18% mean decrease in EF over the same time period. There were no cell-related adverse events. The observed improvement between treated and controlled patients on top of medical standard of care was over two-fold higher than previously reported with existing device therapies.
Dr. Dib said: "The sustained improvement in heart muscle function seen over a six-month period with the lowest dose tested, together with the excellent safety profile, suggest that Revascor!! cell therapy may play an important role in the treatment of heart failure, improving quality of life and even survival."


Question was of course, the 22% increase is great, but what had they done to the poor control patients for them to deteriorate with 18%. The poor buggers. :evil:

Anyway- this announcement was pure sensationalism and not based on scientific facts as we will see later... I will post the slides either tomorrow or later if time permits. :yep:


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Perin: Mesoblast Delivers Promising CHF Results 18 Jul 2015 12:29 #4838

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As an introduction - today just 2 slides- the rest, about 4 , tomorrow, plus conclusion of course.

Here you have the population first of patients in the clinic.




Watch the last line with EF,,, :whistle: These were really really sick patients. The PRECISE patients were at least 8 EF points better off, but than again- that was refractory ischemia and NOT CHF.

But most interesting to note- there were 151 patients screened and eligible for the clinic, however the 60 were selected since the others did not fulfill some or one of the "exclusion criteria"- one of them was....

PRA ≥20% and/or presence of specific antibodies to donor HLA antigens

A PRA number of 20% is quite low- so MSB desperately wanted to avoid anti- immune issues, which however cropped up to a minor degree after all,

What is a PRA (Panel Reactive Antibody) ?

The body naturally produces many different antibodies that help protect against invasion by foreign antigens. Antibodies can also be created by the body to attack tissue, particularly the tissue of another human. In these instances, an antibody called a panel reactive antibody (PRA) is created when foreign tissue is introduced. Blood transfusions, transplants, and pregnancy can trigger production of PRAs. These antibodies target human leukocyte antigens (HLA) that are found in human tissue.

A panel reactive antibody test is a blood test that specifically looks for PRAs. This test measures the levels of PRAs that are in the blood. PRA levels are particularly important to monitor in patients who are waiting for kidney transplants. If these antibody levels are high, matching a recipient with a donor organ can be difficult. Higher patient PRA levels raise the chances that the body will reject an organ that comes from a donor with normal to low PRA levels.

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Perin: Mesoblast Delivers Promising CHF Results 18 Jul 2015 13:32 #4839

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The result.. :whistle: ... not too bad as could have been expected, but as said lesser severe issues are not detected in a living human person. These are are only detected at pathology units, when treated patients do not make it.

There was one at St. Lukes (= Texas Heart Centre) and the abstract of the paper read as follows:

Intense research is under way to determine the optimal stem cell type and regimen for repairing diseased myocardium. Although initial studies in humans focused on the use of homologous stem cells, allogeneic or xenogeneic stem cells have been
studied extensively in experimental work. Clinical trials with allogeneic stem cells are now under way, an approach based on the premise that stem cells and precursor cells are characterized as being immunotolerant. However, evidence indicates that stem cells may gain immune potency in vivo, especially when delivered to inflamed tissue, such as acutely infarcted myocardium.
Histopathologic studies show the presence of a lymphohistiocytic inflammatory reaction at the sites of delivery of allogeneic stem cells, a response that is exaggerated with the use of xenogeneic stem cells. The immune-mediated inflammatory reaction to allogeneic and xenogeneic stem cells may elicit a spectrum of effects, ranging from beneficial (e.g., increased paracrine activity) to detrimental (e.g., accelerated damage and removal of stem cells).
Although the issue of immune-mediated inflammatory responses to non-self stem cells requires further evaluation, non-self stem cells should not be considered as immunologically inert or exclusively immunosuppressive in vivo


The slide from the presentation:


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Perin: Mesoblast Delivers Promising CHF Results 19 Jul 2015 08:52 #4840

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So- today we want to look at the available TWO functional parameters, that is:

LV Ejection fraction- which is well known. A healthy person has an EF of about 65- the patients in the clinic varied from 29 to 34. So very poor and one would think that a 22% increase as per the announcement from 2008 would be feasible. That would bring a 30 EF patient to 37 or so. The control decrease of 18% is baloney of course- a bit of poking around in the myocardium has some positive impact due to the regenerative capacity of humans- even old folks with CHF.

LV End Systolic Volume or LVESV which is the volume of blood left in a ventricle at the end of a contraction, or systole. They measure the emptying of the ventricle with that, which is basically another parameter of the "power" of the myocardium. Clearly- its better for the number to be lower, i.e. at the end of the cycle the blood should be in circulation and not left in ventrice.

First- LVEF:



On the slides in general: the top left hand side. you see the "overall impact" of the treated patients as a GROUP versus placebo as a group broken down for the 3 time points. 3 , 6 and 12 months. In the other 3 slides you see those time points broken up into the "dose groups"- that is 25 Mio cells, 75 and 150 MIO cells.

Firts conclusion- the EF increase in treated (despite the enormous potential) is not 22% - its almost NOTHING. Same for placebo- NOT minus 18% but virtually NOTHING.

The 75 Mio group didnt do anything really, whilst the low dose group (25 Mio) DID have some impact apparently, but was watered down by the 150 Mio high dose group.

Conclusion: these numbers are all over the place- inconsistent and not significant at all, therefore not proving anything.
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Perin: Mesoblast Delivers Promising CHF Results 19 Jul 2015 09:23 #4841

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As a wrote in the prior post:

LV End Systolic Volume or LVESV which is the volume of blood left in a ventricle at the end of a contraction, or systole. They measure the emptying of the ventricle with that, which is basically another parameter of the "power" of the myocardium. Clearly- its better for the number to be lower, i.e. at the end of the cycle the blood should be in circulation and not left in ventrice.





This slide is really something- total chaos if you ask me...

Again 75 Mio does not seem to do anything.

Placebo unexpectedly deteriorates at 6 months and recovers at 12 months...very strange.

The low dose starts off great at 3 months than hits some road bumps apparently and is as bad as control. With the high dose it is kind of the other way round.... seeing this seesaw action, one doubts the expertise of the CRO´s to a great extent.

Totally inconsistent and no trends to be seen anywhere.
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Perin: Mesoblast Delivers Promising CHF Results 20 Jul 2015 08:38 #4842

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Last two slides... :grin:

After the preceding two functional parameters, LVEF and LVESV, you get a parameter which should be the result of the functional improvements in the heart, which so far we really could not see anywhere.

That "result" parameter in the ability to walk extended meters over the baseline for 6 minutes, which was established before treatment. I still do not get it that doctors let a lot of bias (walking thru leg-, lung pain) sneak into this. Just put a mask on the patient and you can measure his MVO², which is scientific and is used for determining whether a patient comes on the transplant list.



Again the numbers are all over the place and at 3 months placebo beat all treated populations by a mile in making more meters in the 6 minute walk.
Makes any sense? Not to me. Interesting to note at 12 months the difference of placebo to the 150 Mio group was almost significant. The P value was 0,062 which was pretty close to 0,05.

Anyway- turning to Cytori i.e. PRECISE- that trial achieved statistical significance on MVO2 and METS which are the comparable (and more scientific) measurements for "performance by patients"- I also recall the percentages on reduction of scarred muscle tissue and general perfusion were certainly better than what we have seen above... :whistle: :whistle: :whistle:
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Perin: Mesoblast Delivers Promising CHF Results 20 Jul 2015 08:49 #4843

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In the end- Emerson Perin called these results encouraging- I guess so, when you get paid very well by MSB a he was by Cytori.

Since the trial was NOT double blinded and the doctors knew who was treated and who had placebo, I do not think you can put great value or trust in the MACE numbers. Doctors protect their patients and believe in what they "do".

Question to you all- would you have put heaps of money into this application by taking it into Phase 3?

TEVA is working since 2014 on a 1730 patients phase III, which to me looks very risky.

Although as mentioned many times- PRECISE looked better to me- it wasnt MUCH better, if you get my drift and should explain to you at the same time why ATHENA wasnt completed and why no BIG Pharma Company has bitten the bait to do this for Cytori, which was the purpose of the exercise.

The present strategy makes sense... :whistle: :bye:

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Perin: Mesoblast Delivers Promising CHF Results 20 Jul 2015 10:40 #4845

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***In the end- Emerson Perin called these results encouraging- I guess so, when you get paid very well by MSB a he was by Cytori.+++

You think ? LOLOL !!!!
Academics are NOT the best place or certainly should NOT be the sole place for research.

There is a reason no one has bitten from the Cytori apple on any indication and I dont believe it is the disruptive tech excuse. Its the trials. Early, small or somewhat lacking on some fronts vs either current tech or reimbursement.

Scleroderma and OA are our chances to change this.
We fail, we're toast !
Just that simple imho.

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