"disappeared" important data when the company announced results Monday
from a mid-stage study of its stem cell therapy Prochymal in heart
Naturally, Osiris didn't come out and tell investors that it was
issuing a misleading press release on the Prochymal heart attack study.
Instead, the company claimed the study was a success. That's not true.
Figuring out Osiris' deception wasn't that difficult if you know how to
parse the language of clinical trial results and look at independent
sources of information for the truth.
Ride along with me as I pick apart Osiris' statements regarding the Prochymal heart attack study.
Interpreting clinical trial results with a skeptical eye is a crucial
tool for all biotech investors, so apply these skills universally
whenever a drug or biotech company tries to convince you that its drug
works. Hopefully, you'll find most companies are telling the truth, but
sadly and too often, bullish pronouncements about boffo clinical trial
data are just spin jobs ginned up to plaster over problems and bad data.
Here's what Osiris issued Monday:
Osiris Therapeutics, Inc. announced today interim one-year
results from its groundbreaking clinical trial evaluating Prochymal
(remestemcel-L) for the treatment of patients experiencing first-time
acute myocardial infarction. The trial is the largest study of
allogeneic or "off-the-shelf" stem cells ever conducted in heart attack
patients. A total of 220 patients were given a single infusion of either
Prochymal or placebo through a standard intravenous line within seven
days of an acute heart attack.
Not much to quibble with here except it's helpful to know that
Osiris enrolled the first heart attack patient to this study in April
2009, so it took more than three years to complete and report "interim"
[a great, independent source of clinical trial information, by the way]
lists the completion date for this study as December 2011, so Osiris
appears to be reporting results six or seven months late.
Cardiac MRI assessments were conducted for six months following infarct to evaluate cardiac remodeling.
Cardiac MRI is a precise and commonly used method of measuring
cardiac changes in clinical trials. MRI assessments were conducted for
six months after heart attack patients were enrolled and treated with
either Prochymal or a placebo, but Osiris purports to be reporting
interim, one-year results. When were the MRIs conducted in the Prochymal
trial? Osiris doesn't specify, which clouds the reported results,
especially if MRIs were not conducted at 12 months follow up.
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). Cardiac hypertrophy and ventricular arrhythmia are
indicators of pathological remodeling following heart injury and provide
insight into the mechanism by which mesenchymal stem cells attenuate
heart injury following a myocardial infarction.
This is the paragraph where Osiris claims positive results based
on Prochymal beating placebo across two efficacy endpoints. 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.
Again, here is where Clinicaltrials.gov is a good fact checker. The site's listing of the Prochymal acute myocardial infarction (AMI) study
shows left ventricular end systolic volume (ESV) as the primary
endpoint. Secondary endpoints in the study are left ventricular ejection
fraction (LVEF), infarct size and major adverse cardiovascular events
ESV measures the volume of blood in a ventricle at the end of the
heart's contraction -- an important assessment of how well the heart is
able to pump blood to the rest of the body. [More blood left in the
ventricle after contraction signals a weakened a heart muscle.]
Similarly, LVEF measures the percentage of blood that is pumped
out of the ventricle with each heartbeat. A higher LVEF signals a
Osiris designed the phase II study with ESV and LVEF as two key
efficacy endpoints based on the belief that the stem cells contained in
Prochymal would help rebuild heart muscle, thereby lowering ESV and
raising LVEF compared to placebo.
Osiris' silence on the outcomes of these two important endpoints should be deafening to investors -- and not in a good way.
The mechanistic data is complemented by clinical data showing
treatment with Prochymal resulted in 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).
These are interesting observations, but again, largely irrelevant
for the purposes of this study since 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.
"This study is the largest of its kind and provides key insights
into the mechanism of action of mesenchymal stem cells in the setting of
acute myocardial infarction," said Lode Debrabandere, Ph.D., Senior
Vice President of Therapeutics at Osiris. "These important mechanistic
observations are consistent with data obtained from our preclinical
models and from the first placebo-controlled human trial with Prochymal
published in the Journal of the American College of Cardiology. 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."
The canned quote from management: Always positive and optimistic.
I usually ignore this fluff but in this case, Debrabandere reminds me
that Osiris conducted a previous phase I study of Prochymal in patients
suffering from a first heart attack. This study enrolled 53 patients and
randomized them to treatment with either Prochymal or placebo. In other
words, the older phase I study is very similar to the more current
phase II study.
The phase I study, "A Randomized, Double-Blind,
Placebo-Controlled, Dose-Escalation Study of Intravenous Adult Human
Mesenchymal Stem Cells (Prochymal) After Acute Myocardial Infarction"
was published the Journal of the American College of Cardiology in December 2009. You can download the study here for free.
I won't go into too much detail about the results, but suffice to say,
investigators found no statistically significant difference between
Prochymal and placebo in ejection fraction or a six-minute walk test.
Debrabandere's comment that Osiris is extending the current phase
II study to capture the long-term clinical benefit of Prochymal is most
perplexing because the phase I study was notable in that measures of
cardiac improvement between Prochymal and placebo narrowed and in some
cases disappeared with longer follow up. Why results would be different
in the phase II study is a mystery, particularly since patients in the
study are only treated with single infusion of Prochymal.
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.
The trial also demonstrated that treatment with Prochymal was
safe. There were no infusional toxicities observed in patients receiving
Prochymal. Serious adverse events occurred with equal frequency in both
treatment groups (31.8%). To date, there have been 5 deaths in the
trial, 2 in the Prochymal group and 3 in the placebo group.
Prochymal is safe but so is placebo. That's no great comfort.
Deaths in the study are essentially equivalent in both arms, a survival
benefit favoring Prochymal would have been better.
"For interventional cardiologists, keeping our myocardial
infarction patients from progressing to heart failure is central to our
mission," said Mark Vesely, M.D., Principal Investigator on the Study
and Assistant Professor of Medicine (Interventional Cardiology) at the
University of Maryland School of Medicine. "It is remarkable and very
encouraging to see significant changes in clinically meaningful
parameters this early in the study. We look forward to the additional
data that will be gathered as the study progresses, which will help us
to better understand both the magnitude and durability of the benefit to
Vesely's comments were remarkable but not for the reasons he
states. Vesely is the researcher in charge of this phase II study and
sounds encouraged but he ignores the missing data even though endpoints
like EVF and LVEF are more clinically meaningful measures of cardiac
health and progression to heart failure than what Osiris chose to
I tried to reach Vesely to ask him about the study and the
missing data but he didn't respond to my email. Bill Seiler, a
spokesperson for the University of Maryland School of Medicine, reached
by phone, said Vesely's comment included in the Osiris press release was
not authorized or pre-approved by the school.
"I'm just finding out about it this morning," said Seiler adding, "I'm trying to track it all down."
When asked if the University of Maryland School of Medicine agreed
with the conclusions reached by Osiris about the Prochymal study, Seiler
replied via email: "The data has not been reviewed by the university so at this point we cannot
comment on anything in the Osiris news release from this morning."
Asked if the school would make Vesely available to answer
questions about the study, Seiler responded, again by email: "We have
learned that Dr. Vesely is traveling and is not available."
This Phase 2, multi-center, randomized, double-blind,
placebo-controlled study is evaluating the safety and efficacy of
Prochymal (ex-vivo cultured adult human mesenchymal stem cells)
intravenous infusion following acute myocardial infarction. A total of
220 patients were randomized (1:1) at 33 centers in the United States
and Canada and received a single intravenous infusion of Prochymal or
placebo within 7 days following first acute myocardial infarction. In
addition to screening and baseline visits prior to the infusion,
initially follow-up evaluations were scheduled to be conducted through 2
years. Given the encouraging results observed at the one year
time-point, the trial is being extended to include 5 years of follow-up.
Both male and female subjects between 21 and 85 years of age were
enrolled. Patients had to have a left ventricular ejection fraction
(LVEF) between 20% and 45% as determined by quantitative
echocardiography or cardiac MRI at least 24 hours after successful
reperfusion of the culprit vessel. In addition, troponin levels must
have been greater than 4 times the upper limit of normal during the
first 72 hours of hospitalization for the MI.
Here is where Osiris describes the phase II study in detail but
notice what is missing: Any discussion at all of the study's clinical
Osiris had no such trouble describing the study's endpoints on
March 2, 2011 in a press release announcing the completion of patient
Efficacy endpoints determined from cardiac MRI include end
systolic volume, LVEF and the ability of Prochymal to preserve
functional heart tissue and limit scar formation following a heart
attack. In addition, functional and quality of life assessments will be
Osiris did not respond to an email request for the missing data
from the heart attack study. The company also chose not to hold a
conference call with investors following the release of the results
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