US Stem Cell Inc (USRM)

[Dragon Lady]

MARVEL STUDY SUSPENDED 2010 "LACK OF FUNDING":

NEVER WAS RE-STARTED AGAIN, NEVER COMPLETED, NEVER REACHED ITS ENDPOINTS. NOPER. 2010 it was “suspended” at 20 patients “treated” and THAT WAS IT. SHOW OVER, LOL ! Why, why, why would that be I wonder??

IMO, there's some key, likely reasons, IN MY OPINION ONLY, as to why the key Bioheart/USRM MARVEL trial "died on the vine" in 2010, reaching only 20 patients enrolled and treated, then NEVER COULD ATTRACT ANY FURTHER "funding" and has been dead in the water, stalled-out, UNFUNDED through the greatest bull market and "easy money" period in probably ALL WORLD HISTORY. Gotta be some reasons why that happened. I think it's pretty easily explainable. My "theory" is the TRIAL WAS WEAK, WEAK in its early performance and fraught with major problems early on (the need to unblind at only 9 patients, due to serious side effects) among other "issues" as I posit below as nothing but my own "theory" and musings on what I think happened from reading the SEC flings and the FULL HEART JOURNAL trial "results" as published, which only covered 20 patients, then LACK OF FUNDING, never to re-start again:

USRM keeps pointing to the "summary version" of the MARVEL trial as their supposed "hope" for getting the FDA to give them the RAT or whatever it's called, which is NOT "approval" but a "track" to move forward.

However, I personally read the ENTIRE MARVEL STUDY TRIAL RESULTS as published in the heart journal, years ago, and found it personally:

1) Extremely confusing

2) Statistically extremely "weak" and vague as they stopped it way, way early for LACK OF FUNDING so the sample size is tiny, which the authors all point out in their conclusions. Aka known as "WEAK POWERED" or "POWERING" was weak statistically.

3) The study/trial almost immediately had serious adverse event problems (Heart V-tach), causing them to have to "unblind" after only 9 patients were in the "blinding protocol" due to irregular heart beat issues.

4) The author's summary is "vague", stating sorta, "WELL, the study is kinda interesting, but since we never hit anywhere near full enrollment, it's real hard to know exactly what the data means, but it "might" lead to better conclusions if a larger trial could be conducted, AND we're not sure what to make of the number of irregular heartbeat problems, etc" (PARAPHRASING their words)

SO, I just don't see how the freaking FDA is gonna accept that tiny trial, that per it's own design, could NEVER HIT IT'S ENDPOINTS, as they suspended it at only 20 freaking patients when it was "designed" for 330. See, when a trial is statistically "designed", one MUST HIT THE FULL ENROLLMENT NUMBERS, or very close to that number, else, all the end point data is GARBAGE IN, GARBAGE OUT, cause the statistical model is all dependent on initial "assumptions", aka how big a sample size, what end points to test, etc. So in MARVEL, they never remotely came close to that, and again, at only NINE PATIENTS into the trial, they had to "open up the data" and send it to the safety review committee, as they had serious concerns about a high rate of irregular heartbeat problems.

It's NOT a medical problem that HAS NO OTHER "STANDARDS OF CARE" or is a "IMMINENT DEATH SENTENCE" etc. If you look at what the FDA approved per this RAT whatever so far, they have to be real, real, real unique medical problems for which there is pretty much ZERO "hope" and ZERO other "solutions" at this time, that's my interpretation. Well, heart issues are treated and "managed" via numerous methods, many people living well, well past "old age". I had a good friend who's dad had a couple of serious heart attacks, then "managed" his life by reducing stress, using beta-blockers, controlling blood pressure, etc and the dude died at 84 years old, living a full and robust life as many, many "post heart attack" patients do daily (golfed, traveled, continued working till near the end of life, etc). It's NOT A DEATH SENTENCE "medical problem", which is sorta what the RAT thing is about IMO. AND, add to that a "weak" (the author's even state it's WEAKLY POWERED, aka statistically weak as it fell apart in the beginning per LACK OF FUNDING), add in a "weak" study, with a tiny sample size, and I just don't see the FDA tripping over themselves to give this some RAT status or whatever?

SEE THIS, the USRM "PR" we're "working with the FDA" blah, blah, blah. They keep linking to the "Reader's Digest" version of the study:

https://ca.finance.yahoo.com/news/u-stem-cell-inc-working-174500808.html

https://www.ncbi.nlm.nih.gov/pubmed/21982657

SEE THAT, that's the "PubMed" summary, but NOT THE FULLY PUBLISHED STUDY "write up" w/ all data presentations and full study "commentary" by the authors, etc.

READ THE FULL "study" with all conclusions and all "issues" elucidated and it comes up "WEAK" IMO, really a statistical sorta mess to me.

I mean the standard deviations from the mean are so huge as to be hard to get any real meaning from to me, and the authors again, state similar in their conclusion and again "blame" the "WELL, WE DIDN'T REALLY GET TO FINISH ANYTHING CAUSE OF THE FUNDING PROBLEM THING, SO IT'S HARD TO KNOW WHAT IT ALL MEANS, BUT WE "think" IT COULD, MIGHT, MAYBE INDICATE SOME COOL STUFF" (paraphrasing of course, but I'll cut n paste their own words below, and it ain't encouraging if you ask me, at least from a dude like me who's pretty decent at reading and understanding probability and stats. I got a headache just trying to follow their data as presented. Confusing as hell to me as to how many actually got enrolled, then how many were finally blinded and treated, then how many were in the control arm versus the two dosing arms, which is only a handful in each as they only got to 20 patients before it crumbled from LACK OF FUNDING, etc)

What gets me as a KEY POINT, is this study, IMO, as "weak" as it looks to me, would IMO, be a BIG POTENTIAL INDICATOR AS TO WHY USRM/Bioheart NEVER, EVER, EVER attracted or found a "BIG FUNDING SOURCE" to complete this MARVEL trial after it halted at only 20 patients.. I think the data just looks "weak" and maybe that's why no one was willing to pony-up $10 MILLION or more to finish it, maybe as much as $100 MILLION if they went to 330 patients, which I think they later pitched the FDA and got down to 130 or something, but still a large number and very expensive to conduct to FDA standards.

SO, HERE IS THE REAL DEAL, THE FULL TEXT OF THE ACTUAL STUDY. NOT the "short version". THIS, THIS IS WHAT THE FDA will be reading and reviewing among "other" data USRM adds I guess, but again, WEAK LOOKING TO ME. 9 patients into the study, and they had to "un-blind" it and go to a safety committee review on how to proceed, then only got to 20 patients total, I just don't see the FDA buying it. We'll see, but when I read the "data", the probability and stat "data", it's just wide-open to interpretation, cause it swings all over the place on a tiny sample size. HUGE deviations from the mean and outliers, etc

www.medscape.com/viewarticle/751987_2

THE FULL STUDY: (I'll highlight in RED what I "think" just me personally, what I "think" or see in my own lousy opinion, are red flags or "weak statistical problems" or likely FDA type potential "question raisers" etc)

American Heart Journal
A Double-blind, Randomized, Controlled, Multicenter Study to Assess the Safety and Cardiovascular Effects of Skeletal Myoblast Implantation by Catheter Delivery in Patients with Chronic Heart Failure After Myocardial Infarction
Thomas J. Povsic, MD, PhD, FACC; Christopher M. O'Connor, MD, FACC; Timothy Henry, MD, FACC; Andrew Taussig, MD, FACC; Dean J. Kereiakes, MD, FACC; F. David Fortuin, MD, FACC; Alan Niederman, MD, FACC; Richard Schatz, MD, FACC; Richard Spencer, IV, JD; Douglas Owens, RN; Missy Banks, BA; Diane Joseph, BS; Rhonda Roberts, MSPH; John H. Alexander, MD, MHS, FACC; Warren Sherman, MD, FACC
Disclosures
Am Heart J. 2011;162(4):654-662.


Abstract and Introduction

Abstract

Background We sought to determine the safety and preliminary efficacy of transcatheter intramyocardial administration of myoblasts in patients with heart failure (HF).
Methods MARVEL is a randomized placebo-controlled trial of image-guided, catheter-based intramyocardial injection of placebo or myoblasts (400 or 800 million) in patients with class II to IV HF and ejection fraction <35%. Primary end points were frequency of serious adverse events (safety) and changes in 6-minute walk test and Minnesota Living With HF score (efficacy).[color=red] Of 330 patients intended for enrollment, 23 were randomized (MARVEL-1) before stopping the study for financial reasons.
Results At 6 months, similar numbers of events occurred in each group: 8 (placebo), 7 (low dose), and 8 (high dose), without deaths. Ventricular tachycardia responsive to amiodarone was more frequent in myoblast-treated patients: 1 (placebo), 3 (low dose), and 4 (high dose). A trend toward improvement in functional capacity was noted in myoblast-treated groups (?6-minute walk test of -3.6 vs +95.6 vs +85.5 m [placebo vs low dose vs high dose; P = .50]) without significant changes in Minnesota Living With HF scores.[/color]

Conclusions In HF patients with chronic postinfarction cardiomyopathy, transcatheter administration of myoblasts in doses of 400 to 800 million cells is feasible and may lead to important clinical benefits. Ventricular tachycardia may be provoked by myoblast injection but appears to be a transient and treatable problem. A large-scale outcome trial of myoblast administration in HF patients with postinfarction cardiomyopathy is feasible and warranted.

Introduction

Patients with transmural myocardial infarction (MI) are frequently left with considerable myocardial injury due to limitations in the timing and efficacy of thrombolysis and delays associated with primary percutaneous coronary intervention. This has led to increasing numbers of patients with progressive chronic left ventricular (LV) dysfunction and dilation, which accounts for a large component of the growing prevalence of heart failure (HF), one of the most burdensome medical conditions.[1]

Numerous angiogenic and cellular agents have been studied in patients with refractory angina pectoris, targeting regions of ischemic and viable myocardium.[2–4] However, novel regenerative strategies for patients with chronic ischemic HF and scarred myocardium are few. The induction of angiogenesis alone is unlikely to restore function to areas of ventricles depleted of cardiomyocytes.[5] Moreover, vascular progenitors are largely intolerant of the levels of hypoxia found in myocardial fibrosis and do not undergo myogenic transdifferentiation in numbers sufficient to generate contractile tissue.[6, 7] Therefore, myocyte replacement relies on the availability of cell sources with high degrees of myogenic potential.

Few populations of adult stem cells containing a preponderance of myogenic phenotypes are available for clinical study. Resident cardiac stem cells,[8–10] derived from autologous myocardium, are a promising population, although hampered by low cell yields using current isolation and expansion techniques. Skeletal myoblasts, although not cardiomyocyte progenitors, are well suited for large clinical trials, given their ease of procurement and scale-up and intrinsic resistance to hypoxic conditions. In models of chronic myocardial injury, myoblasts form grafts that are fatigue resistant, contribute to cardiac workload, and improve hemodynamics.[11–14] Early-phase human studies of myoblasts have been encouraging with regard to clinical effects and safety.[15–19] [color=red]These studies have been limited by concomitant surgical revascularization[20] or the lack of suitable placebo control groups.[/color][21, 22]

MARVEL was designed as a 330-patient randomized, placebo-controlled, phase IIb to III trial to assess the safety and clinical efficacy and dose response of percutaneous myoblast administration in a population with HF. However, limited financial resources required suspension of enrollment. With enrollment suspended and follow-up on the first cohort of patients (n = 21) complete, the steering committee recommended partitioning MARVEL into a pilot phase, MARVEL-1, with the goal of informing the future design of a larger definitive MARVEL trial.

We report the safety and preliminary efficacy results of the MARVEL-1 population. MARVEL-1 represents the first randomized placebo-controlled trial of catheter-based myoblast administration as a sole intervention in patients with post-MI cardiomyopathy and HF. Although no longer powered to achieve MARVEL's primary outcomes, MARVEL-1 provides important data pertinent to cell-based therapies and offers insights into the conduct of a randomized, blinded, placebo-controlled cell therapy trial.

Methods

Study Population and Design

MARVEL-1 was conducted in 6 US centers between October 2007 and September 2008. Follow-up was completed in April 2009. The protocol was approved by the institutional review board of each institution, and all patients provided written informed consent. The MARVEL trial was funded by Bioheart Inc (Sunrise, FL). In addition, Dr Povsic was the recipient of a Duke Pepper Older Americans Independence Center Research Career Development Program in Aging Research (5P30AG028716) Award.

Eligibility Criteria

Patients aged 18 to 80 years with New York Heart Association (NYHA) class II to IV HF and impaired LV systolic function (ejection fraction <35%) were eligible if they were stable with respect to symptoms (>60 days on optimal medications) and ventricular arrhythmias (>90 days without ventricular fibrillation or sustained ventricular tachycardia [VT]) after insertion of an automatic implantable cardioverter-defibrillator (ICD). Patients were required to have structural characteristics of a chronic infarction on screening stress echocardiography with defined akinetic areas of infarction involving the anterior, lateral, posterior, or inferior walls suitable for transendocardial injections (wall thickness >5 mm). Patients were excluded if their primary symptom was angina, if they had a recent MI or percutaneous coronary intervention (<90 days), if they had recent coronary artery bypass graft surgery (<150 days), or if they had recent cardiac resynchronization therapy (<180 days). Patients with planned revascularization and primary myocardial or moderate-to-severe valvular disease were also excluded.

Required parameters of HF included the following: Minnesota Living With HF (MLWHF) questionnaire score ≥20, 6-minute walk test (6MWT) ≤400 m, and serum brain natriuretic peptide (BNP) levels ≥100 pg/mL.

Noncardiac causes for exclusion included the inability to perform a 6MWT (claudication, pulmonary function, or other diseases limiting mobility); serum creatinine >2.5 mg/dL; anemia, infection with human immunodeficiency virus, human T-cell lymphotropic virus, hepatitis B or C, or active cytomegalovirus; or any illness that might reduce life expectancy to <1 year.

Randomization, Cell Preparation, and Study Intervention

After enrollment, patients were randomly allocated by an interactive voice response system (Interactive Clinical Technologies, Yardley, PA) equally to 1 of 3 groups: placebo, low-dose myoblast, or high-dose myoblast (400 × 106 or 800 × 106 myoblasts). All subjects underwent open surgical biopsies (≥10 g) of the thigh muscle by a surgeon blinded to treatment assignment. Biopsy specimens were sent to a centralized good manufacturing practice facility (Bioheart, Weston, FL) where culture expansion was performed on biopsies from low-dose and high-dose groups only. Study agents consisting of 4 to 5 mL of transport media (Hypothermosol; BioLife Solutions, Bothell, WA) alone (placebo group) or suspensions of 400 × 106 myoblasts (low dose) or 800 × 106 myoblasts (high dose) in transport media were sent to the clinical sites between 16 and 20 days postbiopsy.

All patients underwent electromechanical mapping of the left ventricle[20, 21] and image-guided implantation (NOGAStar and MyoStar, Diamond Bar, CA), consisting of 16 infarct-targeted injections (0.25 mL/injection) of study product. All injections were performed using the MyoStar catheter injected into the LV wall at half the measured thickness as determined by echocardiography. Measured unipolar voltage at the injection site was to be <7 mV. Due to slight differences in turbidity of the 3 study preparations, the operative team had no further contact with subjects after the procedure. A separate blinded investigator team was responsible for all patient contact and follow-up.

Before discharge and at prespecified intervals through 180 days, patients underwent assessments of clinical status, cardiac biomarkers, 6MWT, MLWHF questionnaire, ICD interrogation, dobutamine stress echocardiography, and multiple-gated acquisition (MUGA) scans.

Outcome Measures

The primary safety outcome was the incidence of serious adverse events at 6 months, including death, MI, rehospitalization, and ventricular arrhythmia. All arrhythmic events were adjudicated at the Duke Clinical Research Institute (Durham, NC) by physicians unaware of treatment group.

The prespecified coprimary efficacy outcomes were changes in 6MWT and MLWHF scores between baseline and 6 months. Prespecified secondary outcomes included changes in 6MWT and MLWHF scores at 3 months; NYHA HF classification at 3 and 6 months; resting ejection fraction by MUGA at 3 and 6 months; LV volumes, regional wall motion, and mitral regurgitation by echocardiography; serum BNP levels at 6 months; and readmission and cause-specific readmission rate, time to death or readmission, and total days alive outside of the hospital. Multiple-gated acquisition and echocardiography images were blindly assessed by a core facility (Northwestern University, Chicago, IL), and blood levels (BNP, cardiac enzymes) were assessed at a central laboratory (Esoterix, Austin, TX).

Statistical Analysis

Two-tailed statistical analyses were performed using SAS software, version 8.2 (SAS Institute Inc, Cary, NC). Baseline patient characteristics were summarized using means with standard deviation for continuous variables and frequencies and percentages for categorical variables. All eligible patients received assigned therapy, and an intention-to-treat analysis was used. Comparisons of the 2 study groups with respect to the change from baseline in the primary efficacy end points were performed using Wilcoxon rank sum tests. The prespecified statistical analysis plan indicated that patients lacking follow-up data were to be removed from the analysis; however, sensitivity analyses were performed to determine the effect of an extreme value substitution as well as carried-forward approach on outcomes.

The executive committee was responsible for all decisions regarding study design and conduct. An independent data and safety monitoring board assessed safety data as they became available. After randomization of the ninth subject, unblinded data were provided to the data and safety monitoring board as a result of a perceived excess in VT. Recommendations regarding study continuation, protocol amendments, and methodological changes were conveyed to the executive committee.

Results

Baseline Clinical and Demographic Characteristics

A total of 61 patients (Figure 1) were enrolled in MARVEL; 23 patients were randomized before suspension of enrollment. Of these, 2 did not undergo muscle biopsy (1 death, 1 withdrawal). One randomized patient was excluded due to VT and ICD discharge in the period between muscle biopsy and planned cell administration and was not analyzed as part of the MARVEL-1 treatment group. The remaining 20 patients, randomized between October 2007 and October 2008, formed the MARVEL-1 study population.

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Figure 1.

Patient flow diagram.

Patient characteristics among treatment groups (Table I) were reasonably well matched with respect to sex, race, and cardiac risk factors. The baseline ejection fraction (mean, 25.2% ± 6.4%), 6MWT distance (mean, 307 ± 74 m), and MLWHF score (mean, 50.8 ± 20.3) attest to the significant LV dysfunction and symptoms in these patients. Myoblast-treated patients were older, had a higher degree of prior revascularization, and had more HF symptoms as measured using the MLWHF score.

Successful skeletal muscle biopsies were taken from all patients. Specimens were of comparable weight across treatment groups and gave rise to cell yields that exceeded target doses for both myoblast groups. Cell viability (>99%) and myotube formation (>95%) were uniformly high in all cultures. Catheter-based image-guided study injections were accomplished in 20 patients, each receiving the full 4 mL of product allocated. All patients underwent successful electromechanical mapping using the NOGA-XP system, with delivery of cells using the MyoStar catheter (each patient received all 16 injections of 0.25 mL each).

Efficacy Outcomes

Clinical follow-up was available at 6 months for all 20 patients treated. For evaluation of efficacy, MLWHF scores were available in 19 patients and 6MWT results in 17. One patient (high-dose group) required cardiac transplantation at 3 months, and 2 patients were unable to complete 6MWT due to orthopedic conditions that arose between 3 and 6 months.

The primary efficacy outcome of the 6MWT demonstrated numerical improvement at 6 months (Figure 2A and the online Appendix for individual patient data). Although placebo patients exhibited essentially no change (-3.7 ± 86 m), low-dose and high-dose myoblast groups experienced an increase of nearly 90 m (+95.6 ± 47.2 and +85.5 ± 82.1 m) (Figures 2B and C). Using a repeated-measures test to assess change in walking distance over time, an increase in 6MWT distance of 48.8 m was observed in the combined myoblast group (P < .05, 95% CI 7.06-90.6 m) as opposed to 8.8 m in those given placebo (P = .8, 95% CI -54.2 to 70.6 m), with a difference between the control and myoblast groups of 40.8 m (P = .28, 95% CI -35.7 to 117.4 m). In a sensitivity analysis using a carried-forward (prespecified) or a worst-case approach to determine the effect of the patient in the high-dose group who underwent cardiac transplantation, the results in the high-dose group were more muted (high-dose group +73.3 ± 79.4 m [carried forward] or +31.3 ± 252 [worst case]).

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Figure 2.

A, Six-minute walk distance at baseline and at 3 and 6 months in control, low-dose, and high-dose groups. B, Change in 6-minute walk: cell therapy vs control subjects. C, Change in 6MWT in control, low-dose, and high-dose groups.

Improvements in MARVEL's coprimary end point (MLWHF score) were noted in all treatment groups, with average changes of -22.8 ± 9.7, -17.7 ± 4.3, and -3.8 ± 7.6 points in placebo, low-dose, and high-dose groups, respectively (Figure 3) (P = .6). The combined cell-treated patients showed an improvement of -11.3 ± 16.3 (P = .3 for comparison with control). More than 2 of every 3 patients reported gains in both MLWHF score and NYHA class at the 6-month follow-up, with no difference between the myoblast and placebo groups.

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Figure 3.

Change in MLWHF questionnaire score during the follow-up. Control, low-dose, and high-dose groups.

The effect of myoblast administration on LV function was an important component of the MARVEL study design. Six-month data were available for ejection fraction assessment by MUGA in 17 patients and for ejection fraction, wall motion, and LV dimension evaluation by echocardiography in 16 patients. There were no differences observed among the treatment groups in any of these variables. Brain natriuretic peptide levels were available in 15 patients at the 6-month follow-up. In control patients, BNP increased by 275 pg/mL over baseline measurements, whereas smaller changes were observed in both low-dose (-82 pg/mL) and high-dose (143 pg/mL) myoblast groups.

Safety Analysis

The number of patients experiencing adverse events and the total number of events were similar among the 3 groups (Table II). However, the frequency of VT requiring treatment was higher in the myoblast groups than in the control group, whether categorized by numbers of affected patients (3/7 after low-dose or high-dose vs 1/6 after placebo) or by the total number of treated events (39 vs 18 vs 3 in low dose [7 patients], high dose [7 patients], and placebo [6 patients]). Kaplan-Meier survival curves for freedom from VT reflect the higher level of VT in the myoblast-treated patients (Figure 4). All VT events occurred between 5 and 39 days of implantation, with no events during or within 24 hours of injection of myoblasts. All patients experiencing VT were hospitalized and placed on amiodarone therapy with resolution of their arrhythmias.

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Figure 4.

Freedom from sustained VT according to treatment group.

After a summary of blinded VT events was reported to clinical sites, the use of prophylactic amiodarone was left to the discretion of the investigators. Of 11 subsequently enrolled patients, 8 were placed on amiodarone, although timing and dosing varied. We performed a patient-by-patient analysis to determine the association between prophylactic amiodarone and subsequent ventricular arrhythmias (Figure 5). Among 14 patients randomized to myoblast therapy, 7 received no prophylactic amiodarone. Of those 7, 4 developed postinjection VT requiring ICD therapy. Three patients were either started on amiodarone at the time of cell implantation (n = 2) or discontinued the medication after cell implantation (n = 1). Two of these 3 patients developed VT in the postinjection period. Four patients were started on amiodarone at the time of peripheral muscle biopsy, allowing a 3-week oral loading period before cell implantation. No VT was observed in these patients.

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Figure 5.

Relationship between amiodarone therapy and VT events in myoblast-treated patients.

Discussion

Major Findings

MARVEL is the first blinded placebo-controlled trial assessing the safety and efficacy of percutaneous myoblast administration for patients with advanced symptoms of HF due to transmural infarction. Due to a severe curtailment in enrollment because of financial constraints, conclusions from MARVEL-1 are more limited than initially designed. However, our observations from MARVEL-1 can be briefly summarized: (1) sustained VT requiring intervention was notable and more frequent in myoblast-treated patients, though not statistically significant; (2) enrollment was brisk, even with an invasive control group; (3) logistic problems were very few, despite the complexity of the study; and (4) some improvements in objective functional capacity were observed, although these were not replicated in symptom-driven assessments.

Safety: VT

[color=red]The association of myoblast administration with VT is unresolved, with data from preclinical and clinical studies that support[16, 20, 23] or question[22, 24, 25] a causal relationship. The picture is blurred further by variable application of prophylactic antiarrhythmic therapy before or upon study enrollment.[20] We minimized background noise by excluding patients with recent VT, thereby preselecting a population in whom VT requiring therapy before enrollment was low and to maximize patient safety by requiring prior ICD implantation.[/color]

Ventricular tachycardia (on a per-patient and per-episode basis) was more frequent in the myoblast groups. Among patients randomized to myoblast therapy not treated with prophylactic amiodarone therapy, >50% required automatic ICD therapy. Communication of observed events in the first 9 patients in MARVEL-1 led to institution of empiric amiodarone administration in most patients subsequently enrolled. No ventricular arrhythmias were observed in patients in whom oral amiodarone was begun 2 to 3 weeks before myoblast administration and maintained without interruption for the following 5 weeks. Amiodarone therapy was empirically discontinued after a 3-month period, and no further VT events were noted during the additional follow-up period. Our limited data demonstrating the effectiveness of this strategy and the time dependency (<39 days postinjection) of these events suggest that a focused period of surveillance and treatment with amiodarone may effectively suppress VT during this risk period.

Prophylactic amiodarone may carry some risk. Reassuringly, meta-analyses of amiodarone in this population with advanced HF suggest no mortality risk,[26] and the risks of prophylactic amiodarone in another patient cohort did not appear excessive.[20] In addition, amiodarone might theoretically increase defibrillation thresholds, making automatic ICD therapy less effective. It may be reasonable to exclude patients with known high defibrillation thresholds from such therapy. Whether these safety concerns are outweighed by potential benefits will require adequately powered trials to fully define the risk/benefit ratio of percutaneous myoblast delivery.

Three patients in the myoblast-treated groups experienced worsening HF. We were unable to identify specific causes of these events and can only speculate as to whether disease progression, study injections, or other processes were at play. More definitive trials would be required to do so in this high-risk patient population.

Efficacy

MARVEL-1 is limited from demonstrating significance in original efficacy end points by its small size and wide standard deviations. When compared with placebo, myoblast therapy was associated with sustained (6 months) improvements in 6MWT distance of >90 meters, a clinically meaningful improvement if replicated in larger studies. Subjective quality of life measures improved among all groups with large fractions of control patients reporting beneficial changes in NYHA class (67%) and MLWHF score (83%) after placebo injection. This distinguishes MARVEL-1 from its predecessors, SEISMIC[21] and CAUSMIC,[22] both open-label studies with medically treated control groups, in which fewer control patients (57%-58%) improved with respect to subjective parameters, and suggests that demonstrating improvements in subjective parameters will be difficult in truly blinded studies in this field. Objective changes in 6MWT distance increased in similar numbers of control patients in all 3 studies (~30%), suggesting that functional tests are less likely to be influenced by patient blinding. Findings from blinded placebo-controlled studies in patients with chronic myocardial ischemia[27–29] support observations from MARVEL-1 regarding the benefits of cell administration on objective assessments of patient function.

Dose Response

When MARVEL was designed, there were little data to guide dose selection of myoblast therapy, although the MAGIC trial suggested improved efficacy with higher myoblast dosing.[2] In addition, the reliability of achieving the high dose of 800 × 106 cells was unproven. MARVEL was designed as a phase IIb/III study to determine the relationship between dosing and outcomes in a definitive manner. Unfortunately, given the final enrollment, no conclusions about dose response can be made.

Uniqueness of MARVEL in the Cell Therapy Arena

Previous studies have established the feasibility and potential efficacy of myoblast administration by surgical and transcatheter techniques in low-to-moderate doses for patients with chronic postinfarction HF. MARVEL was designed to advance the strategy of cardiac repair with myogenic precursors to the phase III clinical trial, incorporating design elements relevant to this challenging population of patients. MARVEL attempted (1) to assure blinded enrollment into active agent and placebo groups to allow definitive determination of safety and efficacy, (2) to reveal mechanistic insights through multiple-dose administration and assessment tools, and (3) to provide clinical relevance through the participation of many investigative centers and the uniform application of operational standards (cell production and delivery and outcomes monitoring).

MARVEL-1 achieved several important goals. Recruitment into a blinded, placebo-controlled study testing an autologous cell line requiring harvest was rapid, attesting to the perceived clinical need for therapy for patients with congestive HF due to transmural infarction. In all patients eligible for study injection, cell procurement and expansion and catheter-based intramyocardial delivery were successful and seamless, without untoward procedure-related events. MARVEL is the first study to use high-dose, low-volume myoblast preparations suitable for transcatheter delivery.

The evolution and conduct of the MARVEL trial, its transition to MARVEL-1, and the data derived from this experience are valuable to the progress of stem cell–based cardiovascular repair. Skeletal myoblasts, among the most extensively studied of adult stem cells, are the only myogenic progenitor population targeted to patients with infarcted scarred myocardium. MARVEL was scaled back for reasons highly pertinent to contemporary clinical biosciences—achieving an appropriate balance between the cost of a study and its imperative to incorporate crucial measures of safety and efficacy outcomes. The inability to do so presents a serious obstacle to progress in the still nascent field of stem cell–based repair.

Despite its lack of power to achieve MARVEL's principal goals, MARVEl-1, with its blinded placebo-controlled design, signals the feasibility of performing large-scale clinical trials with autologous skeletal myoblasts. Perhaps more importantly, the MARVEL program set a methodological foundation for the conduct of double-blind, placebo-controlled studies in cardiovascular cell therapy, maintaining a blinded placebo group with the inclusion of cell harvesting and placebo injection procedures.

Conclusions

MARVEL-1, an initial phase of a planned broader MARVEL program, demonstrated the feasibility of conducting blinded, placebo-controlled studies assessing the efficacy of percutaneous implanted cell therapy product (myoblasts) on objective and subjective parameters. Percutaneous myoblast injection was associated with numerical improvements in 6MWT distance but also with a higher short-term incidence of amiodarone-responsive VT. Our results might be used to guide future investigations in cell therapy for cardiovascular disease, especially in those using myogenic progenitors, and suggest that cautious research for patients with advanced symptoms and lacking other approved or experimental options is warranted to improve functional capacity.
"

THAT IS IT. THAT'S AS FAR AS THEY EVER GOT, the SUSPENDED FOR LACK OF FUNDING, NEVER went any further. Again, just me personally, I had a hell of a time trying to follow a lot of their "data" and the statistical conclusions trying to be made (the graphs are confusing as hell in few places to me, again, probably cause they are for such a tiny data set and also the deviations from the mean are enormous with "tails" or outliers that one would seemingly to me, have to toss out, as they make just no sense. The only "outcome" they "promoted" as really improving was the "walk test distance" but the damn standard deviation and variances in the data were HUGE, look at the +/- differences, it's wild swings.

In other words, the placebo dude "might" walk as far as the "treated" dude, but your data size is TWO people. If someone, say and athlete, knows they're running a race, they can beat their own "best time" by a tremendous amount, on shear will power alone and mental "force". So, if a dude is told, THIS IS YOUR WALKING DISTANCE TEST, GIVE IT ALL YOU GOT, then some people are just gonna walk a hell of a lot farther, cause it's a "test", a "challenge" to them. And that's to me, what the data looked like. It's all over the map. And thus easy to "cherry pick" the few people who walked real far, but also, many didn't walk any farther than the placebo dude, who also seems to have walked farther in a case or two. This is real subjective data IMO. Not like a functional MRI or CT scan that shows something like an actual "regenerated" heart via growing new muscle or whatever. It's just people "trying" real hard on a walking test. Again, you see it with runners or athletes all the time, crushing their own best time when you put them "under the test" of race conditions or up against a much fast opponent, etc. Just not a highly credible to me, measure of proving the heart really changed or was magically "regenerated" or whatever.

And that's not even getting into the VT problem, Ventricular tachycardia (V-tach or VT) for which those conducting the trial obviously had great concern, as you can kill a person via VT. They concluded that they didn't really treat enough people to decide what the hell to really make of the V-TACH heartbeat problem, and further, as the treatments took place at different locations, over a long time period, the doses of amiodarone given to try and mitigate the V-tach problem also varied, NOT GOOD, as now there's no known standard for that, which the FDA I'm sure will find "troubling" more than likely. OK, ya got a problem, but WHAT DOES DO YOU GIVE each patient of amiodarone to mitigate it? OH, YOU DON'T KNOW, but want an "approval" or whatever ?

Even in the conclusions, the authors label their own study as "WEAK POWERED" aka statistical-speak for, "WE DIDN'T REALLY TEST ENOUGH PEOPLE TO KNOW FOR SURE WHAT THE HELL ANY OF THIS REALLY MEANS FOR SURE". The FDA has statistical experts on any review panel, they're gonna find that in like 2.3 seconds, like radar lock IMO.

SO, I don't know. I just don't see this as making a "great showing" at the FDA, and the INABILITY TO ATTRACT FUNDING SINCE 2010, TO ME, sorta proves that point IMO. I think the "big money" venture capital folks, who put MEDICAL EXPERTS, M.D. consultants on their "teams", I think they read the study and said PASS, NO THANKS. Not worth plowing $10 MILLION or more into "that", not with that kind of initial data.

That's my 9 CENTS OR SO WORTH, whatever it's doing this AM. My opinion, as a dude who sure as hell ain't an M.D., but who has read and worked on a lot of scientific data and engineering data from a probability and stats viewpoint, to me, it's "WEAK" at best. I think they got an up-hill battle at the FDA, that's what I think.

REMEMBER, Bioheart PUT THIS INFO IN THEIR OWN SEC FILED 10-K:

"https://www.sec.gov/Archives/edgar/data/1388319/000114544314000356/d31044-10k.htm

PAGE 31:

"Our product candidates may never be commercialized due to unacceptable side effects and increased mortality that may be associated with such product candidates.

Possible side effects of our product candidates may be serious and life-threatening. A number of participants in our clinical trials of MyoCell have experienced serious adverse events potentially attributable to MyoCell, including six patient deaths and 18 patients experiencing irregular heartbeats. A serious adverse event is generally an event that results in significant medical consequences, such as hospitalization, disability or death, and must be reported to the FDA. The occurrence of any unacceptable serious adverse events during or after preclinical and clinical testing of our product candidates could temporarily delay or negate the possibility of regulatory approval of our product candidates and adversely affect our business. Both our trials and independent trials have reported the occurrence of irregular heartbeats in treated patients, a significant risk to patient safety. We and our competitors have also, at times, suspended trials studying the effects of myoblasts, at least temporarily, to assess the risk of irregular heartbeats, and it has been reported that one of our competitors studying the effect of myoblast implantation prematurely discontinued a study because of the high incidence of irregular heartbeats. While we believe irregular heartbeats may be manageable with the use of certain prophylactic measures including an ICD, and antiarrhythmic drug therapy, these risk management techniques may not prove to sufficiently reduce the risk of unacceptable side effects.

Although our early results suggest that patients treated with MyoCell do not face materially different health risks than heart failure patients with similar levels of damage to the heart who have not been treated with MyoCell, we are still in the process of seeking to demonstrate that our product candidates do not pose unacceptable health risks. We have not yet treated a sufficient number of patients to allow us to make a determination that serious unintended consequences will not occur."