The biggest concern I had was even though LVESV and LVEDV were both reduced in the Phase 2 study, there was no improvement in LVEF. However, LVEF was approaching significance despite the trial not being powered for efficacy. If LVEF is not improved then we shouldn't expect major functional improvements, such as for the 6 minute walk test or quality of life questionnaires.
However, when Mesoblast subsetted their data into <100 ml and >100 ml groupings, they started to see statistical significance for LVESV, LVEDV and LVEF. I agree with the approach to enrich for NYHA Class III patients, since this will increase the probability of enrolling patients with LVESV and LVEDV > 100 mL and should increase the probability the trial will be successful.
I'm still sitting on the fence on whether MPC-150-IM improves ventricular remodeling or abrogates further deterioration . There is some evidence LVAD patients had some improvement in heart function as indicated by temporary weaning from the devices. There is also evidence of reduced infarct size and improved ventricular function in sheep (https://pubmed.ncbi.nlm.nih.gov/23658436/). An interesting question is it only the paracrine factors that help improve heart function or do at least some of these cells become embedded in the heart? And if so, what cell types do they become?
Here are also some of my responses:
The Phase 3 trial is not going to have the exact same outcome where no HF-MACE events are recorded for treated patients, as the trial has not been stopped for overwhelming efficacy
My suspicions are the pre-specified test for overwhleming efficacy was likely complicated by the change in primary endpoint and trial size changes. - Initial endpoint: Time to first heart failure (HF)-related major adverse cardiac events (HF-MACE) [ Time Frame: 5 Years ] - Current endoint: Time to recurrent non-fatal decompensated heart failure major adverse cardiac events (HF-MACE) that occur prior to the first terminal cardiac event (TCE). [ Time Frame: 6 Month minimum ]
"This compositeconsisted of the following prespecified positively adjudicatedHF-MACE:1. cardiac death or2. hospitalization for decompensated HF or3. successful resuscitation of documented ventricularfibrillation.Inherent in the TTFE primary end point methodology isthe convention that once a patient experiences one of the endpoint’s component events, all other forward-looking eventscontained in the composite end point are censored. "
"This approach,however, has major limitations: • Recurrent HF hospitalizations and terminal cardiac events(TCEs), defined as cardiac death, heart transplant,or LVAD implantation, are not independent. • Patients with prior HF hospitalization are more likely tobe readmitted for decompensated HF events. Therefore,in the TTFE analysis, the HF hospitalization is a maskingevent for subsequent decompensated HF admission(s),as well as subsequent TCE. • Death and HF hospitalization are assumed to have equalimportance and to occur independently of each other.However, clinically, this is not the case. • TTFE analyses ignore the fact that across a study, patientshave different risks of TCEs and decompensatedHF hospitalizations because of between-patient variabilityin the severity of their underlying clinical frailty. • With this approach, ≈60% of recurrent nonfatal HF hospitalizationevents would be ignored in the TTFE analysis.Ultimately, ≤80% of TCEs could be masked whena decompensated HF hospitalization or successfully resuscitatedventricular fibrillation event occurs before aTCE."
"Figure 4 illustrates how a recurrent events analysisprovides a more comprehensive assessment of a patient’sHFrEF-related healthcare journey.At the time that DREAM-HF was being initiated, therewas growing recognition of the benefits of strategies thatcapture recurrent nonfatal HF-MACE in studies focused onpatients with advanced chronic HFrEF. This alternative statisticalapproach (which may be implemented using variousstatistical recurrent event models) appeared to address manyof the inherent limitations of the traditional TTFE methodology.157,158"
"Extensive discussions were conducted with the Foodand Drug Administration (FDA) on modifying the study’s primaryefficacy end point from a TTFE composite to one usingrecurrent events with the analysis based on the joint frailtymodel (JFM). The recurrent nonfatal HF-MACEs were definedas follows:1. hospitalization or urgent care for decompensated HF and2. successfully resuscitated high-grade symptomatic ventriculararrhythmias (eg, ventricular fibrillation). The TCEs were defined as cardiac death, LVAD implantation,heart transplant, or placement of an artificial heart. Onlythe first TCE was taken into account in the primary and keysecondary analysis."
"This modification was ultimately supported by the FDA ata time when <10% of the estimated planned randomized patientshad been enrolled into the trial and only 3.2% of the prespecifiednumber of primary TTFE end points had occurred.Importantly, according to the adaptive design FDA guidance,since blinding was unequivocally maintained, this primaryend point modification did not impact study integrity."
"It is important to emphasize that throughout the entire conductof the DREAM-HF trial, the baseline NYHA class II andIII patients were randomized separately for appropriate treatmentbalance. The patient enrichment and replenishment adaptationdid not change eligibility criteria for the trial (beyondfuture enrollment of only baseline NYHA class III patients).All baseline NYHA class II patients who were randomizedbefore the adaptation will be included in the final intent-to treatanalysis. Because all details of this patient adaptationwere prespecified before the beginning of its implementation,this planned adaptation adhered to FDA recommendations."
"Finally, the hypotheses being tested in the DREAM-HF trialand the primary end point were unchanged and continue asprespecified previously. Based on the specifics of this blindedadaptation, we believe that the type 1 error rate was not affectedand no α-level adjustment will be required."
...and the phase 3 trial is enriched for more severe Class III patients with baseline LVESV > 100ml (more than three standard deviations from normal LVESV levels, and is a predictor of poor long-term outcomes for CHF patients)
In the limitations section of the Dose escalation study paper you attached it says:
"Also, there were baseline differencesin subjective assessments of functional class, with more NewYork Heart Association class III patients in the control groupthan in the 150 million cell group. However, there were nodifferences in the objective measurements for LVEF, brain natriureticpeptide, or 6MWT distance at baseline."
Even though there were more NYHA class III in the control group (60%) vs MPC-150-IM group (20%), there were also 5/15 (33.3%) in the MPC-075-IM group which had 9 HF-MACE events.
Second, the results were more remarkable for MPC-150-IM group for patients with baseline LVESV > 100ml
(20min delay)
