@otherperspective
Would you mind elaborating further on why you think the DREAM-HF trial has a 80% chance of being successful? I've given it a 10-30% chance of success since I view this trial as more of a information gathering exercise rather than a pivotal trial.
I'm of the view that Mesoblast jumped into this trial far too soon without doing the requisite clinical studies to help confirm whether what their post-hoc analysis revealed was real or not. It appears they made this decision because Cephalon/Teva were footing the bill and therefore they decided to fast track the trial, not giving much thought to the totality of evidence normally required before initiating a phase 3 trial. In my view, this trial is essentially being run to test a hypothesis and not to ensure a reasonable level of success. Sure, I accept this trial has been designed (and altered) to help maximise it's chances of success based on the phase 2 results (and failed CHART 1 trial), but even still I only put its probability of success at no more than 30%.
Here is an extract of the two indicators Mesoblast consider to be key for the DREAM-HF trial: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.119.314951
"The recurrent nonfatal HF-MACEs were defined as follows: hospitalization or urgent care for decompensated HF and successfully resuscitated high-grade symptomatic ventricular arrhythmias (eg, ventricular fibrillation)."
How can we reasonably expect MPC's to helpreduce the incidence of decompensated HF and ventricular arrhythmias?
The rationale Mesoblast gives us is they believe their MPC's abrogates further deterioration in heart function. This is different to suggesting it improves heart function, it just stops it getting worse. They mention paracrine factors, but not which paracrine factors. There is very little Mesoblast know about how MPC's work in the heart, but they went 'all in' nonetheless.
There is actually very little evidence to indicate MPC's improve heart function and there is also no biological rationale for this. People have suggested it is through the anti-inflammatory function of these cells, but inflammation does not play a major role in patients who have had heart disease for more than 6 months (part our eligibility criteria). In the context of ischemic heart disease, the damaged part of the heart is becoming fibrotic, and even if our treatment reduced fibrosis, there are a large number of anti-fibrotic treatments being tested to treat late-stage heart disease as we speak.
We do not expect MPC's to become embedded into the heart, but even if they did they don't possess the necessary electrical conductivity potential to help restore heart function to prevent ventricular arrhythmia. MPC's also do not reduce ischemic scar size and may cause patchy fibrosis thereby facilitating reentry, which is one of the main mechanisms that cause ventricular arrhythmia. LVEF was also not significantly improved in the phase 2 trial (except when Mesoblast subsetted the data to look at LVESV >100 mL), so there is still no reliable evidence MPC's will reduce the incidence of decompensated HF.
We have seen improvements in LV diastolic and systolic volumes which holds out hope LV remodeling is taking place, although there is still no biological rationale for why MPC-150-IM would help improve LV remodeling. The LV is usually large following a heart attack because of the infiltrates that enter the heart and also the remaining heart cells being so overworked they become larger to compensate for this. So unless MPC's help stimulate the cKit+ cardiac progenitor cells in the heart, I can't see any real reason for why MPC-150-IM will work based on the information we currently have at hand.
Considering all of the above and the additional complexities that exist between ischemic and non-ischemic heart disease (which has many different causes), and all of the other various complexities associated with this trial (see the inclusion and exclusion criteria above), this helps me to justify the lower probability for success of 10%, and thus the 10-30% probability for success for the DREAM-HF trial.
(20min delay)