July 5th, 2012
Stem Cell Therapy Company Hypes Preliminary Results
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 (MSC) therapy called Prochymal, which is being studied in a phase 2, placebo-controlled trial 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. 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).
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. 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 trial’s 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.
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 multicenter 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.