Over the years, clinical-stage stem cell therapies have been credited with repairing damaged cardiac muscle following heart attacks, improving the symptoms of heart failure, and spurring the growth of new blood vessels – and that’s just in the cardiovascular field.
However, new research suggesting that initial studies of stem cells in the cardiac arena were flawed could have far-reaching effects. Companies such as Cardio3 Biosciences, Mesoblast and Shire can trace the scientific lineage of their stem cell therapies back to research that appears to have been discredited. While this does not prove that cardiac stem cells have no therapeutic merit, it suggests that a still-unproven field might be even less proven than thought.
“We did a meta-analysis of all these stem cell trials and we found lots of problems,” says Darrel Francis, professor of cardiology at the UK’s National Heart and Lung Institute. He and his team have systematically detailed many errors in publications describing research into autologous stem cell therapy in patients with heart disease.
Cardio3 in particular is already on the back foot after an investigation into its phase I results (Cardio3 forced to reassure investors after stem cell therapy questioned, July 11, 2013). But Professor Francis and his colleagues have found problems that go much further.
The group looked at 48 reports – a mixture of papers and presentations – describing the research of Professor Strauer, formerly at the University of Düsseldorf, and colleagues, the single most prolific group of researchers in this field, and the pioneers of autologous bone marrow-derived stem cell therapy for cardiac applications.
These 48 reports appear to cover five clinical trials, and some of the errors Professor Francis found are dramatic. For example, he says: “Overall there appeared to be many more patients being treated than bone marrow aspirations actually being processed. That’s impossible to explain.”
He adds: “There are dozens where there are contradictions on factual details – when they were done, how many patients, whether they were randomised or not.”
One of the trials “was described in its first publication as being randomised, in its second as acceptor–rejector, and in its third publication, a poster, the same document describes it both as randomised and non-randomised".
Surfeit of optimism
“Everyone wants this stuff to work,” Professor Francis says, and this is the problem: people are predisposed to look favourably on research that may yield a cure for an as-yet untreatable disease. This can even undermine the peer review process. “Quite a lot of our papers are negative,” Professor Francis says, “and if we say ‘X doesn’t work’ it always goes to experts in X, who are shocked that anyone could ever say it doesn’t work.”
Professor Strauer and colleagues are not maliciously seeking to push fraudulent research, Professor Francis stresses. They are instead suffering from a surfeit of optimism. “It’s inadvertent, innocent self-deception.”
The implications for commercial developers of autologous cellular products for cardiovascular indications are unmissable.
“Strauer was the first to [address] heart attacks and the first for heart failure. As [stem cell developers] are descendants of the original Strauer methodology, let’s hope their trial procedures are more stable than those of Strauer.”
If all the research backing stem cells thus far is questionable, the next clear indication of whether autologous cardiac stem cells are a viable commercial technology will come with the results of Cardio3’s phase III trial, Chart-1, set to report in 2015.
Until then it will be "very challenging to understand how cells taken from the bone marrow can change themselves into properly functioning heart muscle cells”, Professor Francis says. “The missing link is a proper demonstration of the mechanism. I think this might be why there are so many gaps in the trial data that report positive results.
“It may be that we are just too excitable.”
|Selected cardiovascular stem cell therapies|
|Product||Company||Type||Indication||Phase||Trial name||Trial ID||Primary completion date|
|C3BS-CQR-1 (C-Cure)||Cardio3 Biosciences||Autologous||Heart failure||III||Chart-1||NCT01768702||December 2014|
|Vascugel||Shire||Allogeneic||Enhancing blood vessel repair||II||AVG01-SRM003||NCT01806584||December 2013|
|Vascugel||Shire||Allogeneic||Enhancing blood vessel repair||II||AVF01-SRM003||NCT01806545||December 2013|
|Mesenchymal Precursor Cells||Mesoblast/Teva||Allogeneic||Myocardial infarction||II||Amici||NCT01781390||December 2014|
|PLX-PAD||Pluristem Therapeutics||Allogeneic||Pulmonary arterial hypertension||I||-||NCT01795950||September 2015|
All data sourced to EvaluatePharma