Stem Cell Therapy To Fix The Heart: A House Of Cards About To Fall? Reply

For more than a decade cardiac stem cell therapy has attracted an enormous amount of attention, promise, and research dollars. Now an original and important new study published in BMJ finds that many of the most promising results in the field are illusory and that the potential benefits of stem cells to treat heart disease are probably far more modest than we’ve been led to believe. The study also raises disturbing questions about ethics and research conduct (and misconduct) in a high-flying field.

Researchers in the UK, led by Darrel Francis, closely scrutinized 133 reports from 49 different clinical trials testing autologous bone marrow stem cells in patients with heart disease. They found an astonishingly large number  of discrepancies in the reports– altogether more than 600  discrepancies, ranging from minor oversights to serious unexplained errors and apparent deceptions. Many errors were mathematical or statistical errors while others were more general, such as conflicting descriptions of studies as either a prospective randomized trial or a retrospective observational study.

The key finding of the study is that there was a very strong correlation between the number of discrepancies in a study and the reported improvement in heart function as measured by left ventricular ejection fraction(LVEF)…

Click here to read the full post on Forbes.

 

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Recent €23 Million Biotech IPO Relied Heavily On Questionable Research 2

A successful €23 million initial public offering  (IPO) last week was based on highly questionable research, according to a group of UK physicians who have scrutinized the available data. In addition, one of the researchers, a prominent European cardiologist, failed to disclose in a key paper that he helped to start, and held a significant interest in, the company, Cardio3 BioSciences.

On July 4 Cardio3 BioSciences, a biotechnology company focusing on cardiac stem cell therapy, said that it had raised €23 million in an IPO on the NYSE Euronext Brussels and NYSE Euronext Paris. The company’s main product is called C-Cure, which it defines as “a unique cell therapy aimed at repairing damaged tissue and improving heart function, clinical outcomes and quality of life.” C-Cure uses uses pre-programmed cardiac progenitor cells to treat heart failure. As described by the company, “the supporting science is the result of Mayo Clinic innovation leading to advanced product development, manufacturing scale-up, and clinical trial execution by Cardio3 BioSciences catalyzed by ongoing collaboration facilitated through Mayo Clinic Ventures.”

The company plans to use the IPO money for a Phase III trial, following what the company describes as “positive Phase II results, recently published in the Journal of the American College of Cardiology.”

But the phase II results are a bit more complicated, according to Darrel Francis and colleagues (who last week published a paper highly critical of a different stem cell group). Francis et al have identified numerous errors in the paper which raise serious questions about the validity of the data and whether any useful conclusions can be drawn from the paper.

One striking finding– obvious once it has been pointed out– is that the authors report at different times different number of patients enrolled in the trial. The text of the paper says 48 patients were randomized, Figure 1 lists 47, and Table 1 lists 45 (42 men and 3 women).

Click here to read the full story on Forbes.

 

 

Stem Cell Therapy Company Hypes Preliminary Results 3

Update (July 6)–  I have heard from several investigators in the trial that the Osiris press release was issued without any input or consultation from the site investigators. In fact, the site investigators, including several who are  extremely experienced clinical trialists, have expressed frustration and disappointment because their input has not been sought at any point during the trial. In most multi-center trials it is common practice to consult with the sites, and in particular the top-enrolling sites. In this case, the highest enrolling sites have had no significant involvement in the trial design or conduct. One investigator said he “had never worked with a company like this.”

Another member of the steering committee told me that the committee had not met in a long time and has not seen the trial data. In fact, steering committee members were not even aware that Mark Vesely, an assistant professor at the University of Maryland, was the principal investigator of the study. One steering committee member said he’d never heard of him before reading the press release.

A biotech company has been accused of releasing preliminary and misleading information about a clinical trial. The company, Osiris Therapeutics, is the manufacturer of  a cultured mesenchymal stem cell therapy called Prochymal, which is being studied in a phase 2, placebo-controlled study in post-MI patients. Earlier this week Osiris issued a press release announcing preliminary results from the trial, in which 220 patients have been randomized, claiming that Prochymal “significantly reduces hypertrophy, arrhythmia and progression to heart failure in patients suffering a heart attack.” But Adam Feuerstein, a veteran biotech reporter for The Street, accuses the company of distorting the truth about the trial.

Osiris “disappeared” important data in its press release, Feuerstein writes in his detailed analysis of the press release. He quotes the press release:

Patients receiving Prochymal had significantly less cardiac hypertrophy, as measured by cardiac MRI, compared to patients receiving placebo (p [less than] 0.05). Patients treated with Prochymal also experienced significantly less stress-induced ventricular arrhythmia (p [less than] 0.05).

Feuerstein comments:

Sounds impressive except none of the Prochymal benefits disclosed by Osiris are predefined endpoints in the phase II trial.

Osiris appears to have thrown out the real endpoints called for in the phase II trial and replaced them with new endpoints which just happen to show Prochymal in the best light. Why would Osiris do this? Perhaps the pre-defined endpoints in the study all failed? That’s a pretty safe assumption when companies decide to swap out trial endpoints with no disclosure or explanation.

Feuerstein points out that the primary endpoint of the trial, as listed on Clinicaltrials.gov, is left ventricular end systolic volume (ESV), while the secondary endpoints are  left ventricular ejection fraction (LVEF), infarct size and major adverse cardiovascular events (MACE). Writes Feuerstein: “Osiris’ silence on the outcomes of these two important endpoints (ESV and LVEF) should be deafening to investors — and not in a good way.”

The Osiris press release also claims “a statistically significant reduction in heart failure”:

In the study, seven patients who were treated with placebo have progressed to heart failure requiring treatment with intravenous diuretics, compared to none of the Prochymal patients (p=0.01). Furthermore, patients receiving placebo tended to require re-hospitalization for cardiac issues sooner than the patients receiving Prochymal (median 27.5 days vs. 85.5 days).

However, as Feuerstein writes, “these weren’t predefined endpoints”:

Importantly, Osiris doesn’t disclose the time point at which these purported benefits occurred, nor does the company tell us anything about the number of patients analyzed. How was heart failure defined? Osiris doesn’t say. What was the baseline incidence of heart failure in the study? Osiris doesn’t say. The study only allowed for a single infusion of Prochymal or a placebo immediately after the first heart attack but patients were followed for six months or a year, so how do follow-up therapies in each arm of the study compare? Were they balanced? Again, Osiris doesn’t say.

In the press release a company official announces an extension of the trials duration:

Given the quality of the data and highly encouraging results observed thus far, we are extending the trial’s duration to capture a better understanding of the long-term clinical benefits of MSCs.”

But the company offers no explanation for the extension. Writes Feuerstein:

Perhaps Osiris is extending the phase II study to delay the reporting of negative results? Again, that’s a pretty safe assumption absent a better explanation.

Note: I’ve requested comments from Osiris and from several trial investigators.