Stem-Cell Therapy Trials Miss Mark but Keep Hope Alive

Patrice Wendling

August 28, 2016

ROME, ITALY — Two stem-cell trials, two negative primary end points, but signals of benefit in each may keep hope alive in patients with heart failure (HF), despite a decade of disappointment in the field.

A phase 2a trial found that IV administration of allogeneic ischemia-tolerant mesenchymal stem cells (itMSC) derived from a single healthy donor did not effect left ventricular (LV) function in 22 patients with nonischemic HF and an ejection fraction <40% (P=0.99)[1].

The single dose of itMSCs, however, boosted 6-minute-walk distances by 36 m (P=0.02) and clinical summary and functional status scores on the Kansas City Cardiomyopathy Questionnaire by 5.22 points (P=0.02) and 5.65 points (P=0.06), respectively, principal investigator Dr Javed Butler (Stony Brook University, NY) reported at the European Society of Cardiology (ESC) 2016 Congress.

Dr Javed Butler

Butler told heartwire from Medscape that this degree of improvement has been associated with better hard outcomes in larger non–stem-cell trials in HF patients, but that the bar has been set so high in HF that anything short of a mortality benefit is not enough for an approval indication.

"This really raises the question that if you don't have mortality, but in a 600-patient trial the results are replicated and are real, shouldn't that be an approval indication for people to feel better, to be able to do more, and have better quality of life?" he posited.

Asked to comment, Dr Frank Ruschitzka (University Hospital Zurich, Switzerland), who was not involved in the trial, told heartwire that the findings should be interpreted very cautiously because of the small patient numbers and said it may be time to stop calling this regenerative therapy.

"At one point we have to ultimately show it does something clinically meaningful and not just pleiotropic effects," he added.

Ruschitzka repeated his call for hard end points in future stem-cell–therapy trials during the hot-line session, while discussant Dr Stefan Janssens (University Hospitals Leuven, Belgium) concluded that the lack of LV benefit "should not deter larger studies in sicker patients with more extended follow-up."

Janssens stressed that future trials should focus on trying to better understand the mechanisms involved in this population, including how itMSCs alter immune response and the role for repeat administration.

During his presentation, Butler reported a significant reduction in natural killer cells after active treatment that correlated with improvement in ejection fraction (P=0.01), raising the question "of whether multiple injections can lead to further improvement, including improvement in LV function."

CHART-1 Trial

The second study, Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1), involved 271 patients, the largest trial to date testing cardiopoietic cells in advanced ischemic HF[2].

After 39 weeks of treatment, all components of the primary composite end point—all-cause mortality, worsening HF events, Minnesota Living with Heart Failure Questionnaire total score, 6-minute-walk distance, LV end-systolic volume, and ejection fraction—favored the bone-marrow–derived therapy, but the difference did not reach statistical significance (P=0.27).

There was, however, a lower incidence of sudden death and aborted sudden death in the active group (hazard ratio 0.16; P=0.04), study cochair Dr Jozef Bartunek (Cardiovascular Center, Aalst, Belgium) said.

Exploratory analyses also suggested the probability of a better outcome with the stem-cell therapy in patients with baseline LV end-diastolic volume between 200 mL and 370 mL, a group that made up 60% of patients (P=0.015), and in those receiving <19 injections (P=0.034).

During a press conference highlighting the studies, Dr Bartunek said the reason that outcomes may be better with fewer injections is unclear but observed that the potency of the cells is hard to predict and that other trials have detected a similar pattern.

Discussant Dr Philippe Menasche (University of Paris Descartes, France) said CHART-1 clearly identified patients who benefit from the therapy and that this should be very helpful for fine-tuning inclusion criteria and delivery modalities in future stem-cell trials. "It's clear that it's not one cell fits all."

He concluded that because of its rationale, design, and way the results were analyzed, "this study is and will remain a landmark in the field."

Session cochair Dr Mariell Jessup (University of Pennsylvania and Presbyterian Medical Center of Philadelphia), however, responded by remarking that "many, many, many people are getting tired of listening to negative trials or neutral trials with stem cells" and asked whether Menasche or Bartunek felt they had the right stem cells, right delivery, and the right patients to launch a 1000- or 2000-patient trial.

Menasche replied that despite the negative primary outcome, the results of the subanalyses "are very inspiring" and that their intention is to take this finding into a larger trial.

Butler reports research support from the National Institutes of Health, PCORI, and European Union and consultancy for Amgen, Bayer, Boehringer-Ingelheim, Gilead, Janssen, Merck, Novartis, PharmaIN, SC Pharma, Relypsa, Z Pharma, and the study sponsor, CardioCell. Bartunek reported being a member of an institution that has been a cofounder of Celyad, the study sponsor. Rushitzka and Janssens reported no relevant financial relationships.

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