Apologies for starting a new thread... but the other one discussing CHF seems to have lost direction. Hoping this will summarise the relevant views put forth.. so we can reset and hopefully have a higher quality discussion herein.
Keep in mind that I amnot a medical professional, so my views are that of a typical investor.
Clinicaltrial can be access here:
Phase 3 trial clinical trial.gov link
Theofficial phase 2 dose escalation study paper can be access directly from thebelow link:
CHF Phase 2 dose escalation study paper
Mesoblast’ssummary of mechanism of action
REVASCOR® is designed for local delivery to damaged heart muscle and toallow the MLCs to secrete biomolecules involved in myocardialneovascularization, cardiomyocyte survival, cardiomyocyte precursor migrationand proliferation, and reduction in fibrosis and myocardial scarring.Biomolecules include stromal cell-derived factor 1, Angiopoietin-1, vascularendothelial growth factor (VEGF), hepatocyte growth factor, and matrixmetalloproteinases.
NewYork Heart Association (NYHA) Functional Classification
Class 1:No limitation of physical activity. Ordinary physical activity does not causeundue fatigue, palpitation, dyspnea (shortness of breath).
Class 2:Slight limitation of physical activity.Comfortable at rest. Ordinary physical activity results in fatigue,palpitation, dyspnea.
Class 3:Marked limitation of physical activity.Comfortable at rest. Less than ordinary activity causes fatigue, palpitation,or dyspnea.
Class 4:Unable to carry on any physical activity without discomfort. Symptoms of heartfailure at rest. If any physical activity is undertaken, discomfort increases.
Usefuldefinitions:
LV: Leftventricle is the larger/more muscular side of the heart and services the entirebody, whereas the right ventricle solely pumps blood to the lungs.
LVESV: LVend-systolic volume - lowest volume of blood in the left ventricle at any pointin the cardiac cycle.
LVEDV: LVend-diastolic volume, volume of blood in the left ventricle at end load/filling(diastole).
LVEF: LVejection fraction, this measures the % of blood that is pumped out of a filledheart when it contracts. Studies show reduced LVEF positively correlates withlong-term mortality and LV remodeling.
Myocardialinfarction (MI): Better known as a heart attack i.e. when blood flow decreasesor stops to a part of the heart, causing damage to the heart muscle.
LV remodeling: LV remodeling refers to the change in the structure (size, shapeand function) of the LV. Adverse (larger) LV remodeling can be caused by MI orother heart related diseases, where a larger LV is associated with heart failureprogression.
Positiveindicators:
- Phase2 trial (60 patients), showed that those Class II and III CHF patients dosedwith a single infusion of 150m Revascor (150million) had no HF-MACE events inthree years, compared to 11 in the control group;
- BothLVESV and LVEDV deceased across all 150m dosed patients in the phase 2 trial,which means a beneficial LV remodeling was achieved i.e. a smaller LV;
- Theevent driven trial has run for a lot longer than expected, which implies thatthose participating in the trial (of which 50% are dosed with Revascor), thereis a lower incident of recurring HF-MACE events;
- April2017 futility analysis was performed and was passed i.e. an independent datamonitoring committee (IDMC) reviewed the efficacy and safety data on the first270 patients and recommended the trial to continue. If the IDMC looked at thedata and believed that the results to date were not likely to result inachieving the primary end-point, they would have recommended the trial to stopfor futility.
- InMarch 2020 the lead investigator of our phase 3 trial (Dr Emerson Perrin)sounded very positive about the trial, which should be taken with a grain ofsalt, but nonetheless his face to face interaction with patients across thisstudy and those prior give him an unrivalled insight (although possibly biased)into the trial participants. Of which he said a number of the patients participatingat his study site at Texas heart were doing remarkably well.
Negative indicators:
- The 150m treated patients in the phase 2 trial were mostly Class II (12 or 80%) and Class III (3 or 20%) vs Control of Class II (6 of 40%) and Class III (9 60%). This means the likelihood of HF-MACE events was inherently higher in the control vs 150m dose treated patients;
- ThePhase 3 trial is not going to have the exact same outcome where no HF-MACEevents are recorded for treated patients, as the trial has not been stopped foroverwhelming efficacy and the phase 3 trial is enriched for more severe ClassIII patients with baseline LVESV > 100ml (more than three standarddeviations from normal LVESV levels, and is a predictor of poor long-termoutcomes for CHF patients);
- Nostatistical benefit in 6-min walk test in 150m treated patients vs control inthe phase 2 trial, which is a secondary endpoint as a functional exercisecapacity endpoint in the phase 3 trial. (mostly Class II patients in phase 3150m dosed, so for more progressed CHF patients, there is more scope forimprovement).
- Nostatistical improvement in quality of life questionnaire responses (mostlyClass II patients in phase 3 150m dosed, so for more progressed CHF patients,there is more scope for improvement).
Timingof results/any implication on a positive or negative outcome
Back inearly March 2020, the lead investigator Dr Emerson Perrin said that he expectedthe data to be unblended in May 2020, and if the results were really good MSBwould publish the results in Aug/Sep (i.e. 3-4 months to analyse data as a bestcase), or if the results were not that good – they would be released at the AHA(on 13 Nov 2020). This is in line with what happened with the failed phase 2bLVAD trial, which was not announced early to the market, rather it was delayeduntil the day before the AHA conference.
SinceMarch 2020, the WHO declared COVID-19 a global pandemic and I don’t need toexplain what has happened since. Needless to say, there was severeinterruptions in the US which resulted in the data audit at each study site (52across the US and Canada) – with MSB advising as late as 28 May 2020 that thisprocess was still ongoing. The next update we received on this was in the 27 Augwebcast, where Silviu confirmed all data had been audited i.e. unblinded andanalysis was underway.
If Iassume the data was unblinded in June 2020, then 3-4 months would be September/Octoberread-out. If it was unblended in July, then that would push out toOctober/November.
Keepingin mind that there is the COVID trial, the August ODAC and Ryoncil registrationthat would have taken up a lot of management bandwidth mid-year… in particularJuly/August.
So basedon the above, there is no evidence that management are delaying the release ofthe data because it negative. They are on schedule and if Bell Potter’s latestanalyst report is correct, a release of the results at end of Oct or early Novwould suggest management are trying to get it out as early as possible.
Eitherway management are likely to be prioritising this release anyway given theywant the results to be discussed at the AHA conference on 13 Nov, whether it begreat, good or bad results. This phase 3 trial is the largest stem cell phase 3trial ever run, and has cost hundreds of millions of US dollars to run. Nomatter the outcome, the data generated will be very informative to MSB and themedical community.
Other noteworthyfactors:
- LVEFremained constant for 150m dosed patients as the reduction in LVESV and LVEDVwas consistent i.e. the amount of blood filling and being pumped out of theheard fell inline with each other, meaning the % of blood pumped out remainedrelatively constant.
- Patientsin the treated and control arms are receiving existing HF therapies such as beta-blockers,angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers(ARBs) and/or aldosterone antagonists.
My personal non-medical conclusion
Thephase 2 trial had some eye-catching results, where none of the patients dosedwith 150m Revascor had a HF-MACE event after 3 years of follow up. This haslargely formed the basis of confidence in the read-out due end of Oct or earlyNov, however it should be tempered by the fact that the majority of the 150mdosed patients (12 out of 15) were Class II CHF patients, so the risk ofHF-MACE events is lower compared to Class II patients.
On theother end of the scale, there are those who believe that no statistical benefitseen in the quality of life and functional scores are a sign that there islimited (if any) benefit of this treatment. To balance this out, when themajority of patients dosed with 150m Revascor are Class II, their baselinefunction and quality of life is better than those in Class III, so anyimprovement in function or quality of life will be harder to discern. The phase3 trial is enriched with Class III patients, so that gives the dosed patients apoorer baseline quality of life and function score to start with, and in turn agreater opportunity to see an improvement in those scores in this trial.
It isvery hard to weigh the above up and it is very confusing to think about… bothsides are right. But therein lies the limitation of a small study … and theonly way to know definitely is to run a larger RCT… and here we are. Less thana month away from finding out.
Having saidall that, there is one factor that I find compelling… and that is the beneficial remodeling of the LV, as seen in the decrease in LVESV and LVEDV readings forthe 150m dosed patients. To expect a positive outcome in this phase 3 trial,there has to be a medical rationale for it eventuate… I believe this is clearlyit. A smaller heart means it does not need to work as hard to keep you aliveand functioning, which should ultimately translate to a longer (and hopefully)a better functional and quality of life.
(20min delay)