Anyone with the fixed idea that stem cells are of no use in heart failure would have found little to dissuade them in two presentations at the European Society of Cardiology meeting in Rome on Sunday. Celyad’s phase III trial Chart-1 was already known to be a bust, and Stemedica Cell Technologies’ phase II study, while certainly not a failure overall, was very small and unable to show a benefit in left ventricular function.
So far attempts to use stem cells to regenerate cardiac tissue that have shown promise in phase II have gone on to collapse in phase III. The results of the Stemedica trial were not so impressive as to suggest that the therapy would buck this trend.
Looking for good news
There was little new to say about Celyad’s now shelved C-Cure cardiopoietic stem cell therapy: the company’s shares crashed in June when Chart-1’s failure emerged (Plan B saves Celyad after heart failure therapy flops, June 28, 2016). Trying to dig something positive out of the data, Jozef Bartunek of OLV Hospital in Aalst, Belgium, spoke of an exploratory analysis that identified a subgroup of patients who might benefit from the therapy.
In patients with severe heart enlargement, defined as left ventricular end-diastolic volumes of between 200ml and 370ml, there was an apparently better outcome (p=0.015). This group made up 60% of patients in the trial. Celyad is aiming to begin another trial, Chart-2, in this population – though not in-house.
“Any resources that will be needed to further develop C-Cure will need to come from an external strategic or financial partner, in the form of a licensing out, an M&A, a joint venture or [another] structure,” a Celyad spokesperson told EP Vantage.
Perhaps this study will hit and Celyad – or the company that buys it – will find itself with a successful heart failure stem cell therapy. But, as one of the panellists, Frank Ruschitzka of UniversitätsSpital Zürich, pointed out, it is unwise to get too excited about subgroup analyses.
Too small for subgroups
Trying a subgroup analysis of Stemedica’s phase II study of its stem cells would be problematic – at just 23 patients in size it would be hard to slice the data into smaller chunks. But the tiny trial was considered a success by investigator Javed Butler of Stony Brook University, New York.
At 90 days, the so-called “ischaemia tolerant” mesenchymal stem cells (itMSCs) showed no difference from a sham treatment on safety endpoints including mortality and hospitalisation. However, there was also no difference between the groups on the secondary efficacy endpoint of cardiac remodelling, assessed by cardiac magnetic resonance imaging.
Two prespecified secondary endpoints were hit: the itMSCs improved patients’ showing on the six-minute walk test, with treated patients managing to go an estimated 36 metres further than placebo recipients (p=0.02). They also showed greater improvements in Kansas City Cardiomyopathy Questionnaire clinical summary score, which Professor Butler said would be considered clinically meaningful. The difference between the two groups on the same scale’s functional status scores just missed significance.
Two key differences exist between the Celyad and Stemedica projects: Stemedica’s cells were tested in non-ischemic patients and were administered intravenously, rather than by catheter into heart tissue.
The latter difference was the subject of discussion around further areas of investigation. Experts speculated that stem cells’ benefit might not result from their regenerative potential but rather their capacity to change cell-to-cell signalling to alter differentiation, called the “paracrine effect”. If this can be accomplished with a treatment administered systemically, it would be less invasive and more tolerable.
However, Stemedica’s project is still a long way from proving that. Experts speaking at ESC acknowledged the existence of stem cell failure fatigue, and the data presented here will do nothing to relieve that.