Dissecting The Press Release For A Failed Stem Cell Trial

–Stem cell therapy supporters can’t acknowledge that it might not work.

Stem cells have never been shown to have any clinical benefit in patients with heart disease. But there is mounting anecdotal evidence that they may have serious adverse effects on the reasoning and objectivity of the medical researchers, biotechnology executives and investors who get sucked into their orbit.

The most recent example is the ALLSTAR trial, which crashed and burned last week. In a press release, Capricor Therapeutics announced that “a pre-specified administrative interim analysis performed on six-month follow-up data from the ALLSTAR Trial, an ongoing randomized, double-blind, placebo-controlled, 142-patient Phase II clinical trial of CAP-1002 (allogeneic cardiosphere-derived cells) in adults who have experienced a large heart attack with residual cardiac dysfunction, has demonstrated a low probability (futility) of achieving a statistically-significant difference in the 12-month primary efficacy endpoint of percent change from baseline infarct size as a percent of left ventricular mass, measured by cardiac magnetic resonance imaging (MRI).”

But in the press release the trial investigators and company officials never even mention the distinct possibility that their product doesn’t work. Instead, they do everything they can to spin all sorts of positive views of the results.

It should come as no surprise that everyone quoted in the press release has a strong motivation for the therapy to succeed.

First, they are all closely connected. There is not even the pretense of an outside, objective perspective. Notice the close connections of everyone involved in the study. Linda Marbán is the president and CEO of Capricor. She is also married to Eduardo Marbán, a prominent researcher and the founder of Capricor. Eduardo Marbán is also the director of the Cedars-Sinai Heart Institute. The two Co-Principal Investigators of ALLSTAR are Raj Makkar and Timothy Henry, both of whom work under Marbán at Cedars Sinai. Makkar is the Associate Director of Interventional Technologies in the Heart Institute and Henry is the Director of the Division of Cardiology.

The conflicts are even more deep rooted. The home institution for Marbán and the other investigators, Cedars-Sinai, has a significant stake in Capricor.

In other words, everyone is highly motivated to see this as a success. They all have rose-tinted glasses. Who among any of these major players has any motivation to view the company, the products, or the underlying science objectively or critically?

For instance, Makkar is quoted in the press release as saying that “we are disappointed that the ALLSTAR six-month data did not demonstrate evidence of scar size improvement with CAP-1002, given the robust findings demonstrated on this measure in the randomized Phase I CADUCEUS clinical trial of cardiosphere-derived cells in a similar patient population.”

But Makar conveniently ignores the fact that the earlier trial missed its most important endpoint, improvement in left ventricular ejection fraction and it was on this basis that infarct size was the main goal of ALLSTAR. In other words, infarct size was a cherry picked endpoint in ALLSTAR only because the preferred endpoint didn’t work out in the earlier trial.

In the press release Makkar tries to explain away the failure: “We believe it is important to note that the observed improvements in scar size in the placebo group are markedly inconsistent with the well-established natural history of this disease process. It is certainly possible that, for a variety of reasons, the greater number of sites involved in the conduct of ALLSTAR contributed to an increase in variability seen in the scar measurements as determined by MRI.”

Makkar doesn’t elaborate on any of the “variety of reasons” why “the greater number of sites” leads to the negative finding. In general, in a well conducted trial more sites and more patients should lead to greater reliability of the finding, not less. Makkar appears to be implying that he and his group are the only ones who are able to see the benefits for which they are looking. This should raise all sorts of red flags.

This is the nearly inevitable danger when there’s no outside critical perspective, and it is especially dangerous in small studies without rigorous controls. The investigators are motivated to grasp at the straws, which in this case means cherry picking their endpoints.

Tim Henry, the other Cedars-Sinai investigator, also sought and found positive signs in the trial. “We are encouraged to see reductions in left ventricular volume measures in the CAP-1002 treated patients, an important indicator of reverse remodeling of the heart. These findings support the biological activity of CAP-1002.” But when you miss your major prespecified endpoint any secondary findings must be considered exploratory at best. Given the dismal results of all previous stem cell trials in cardiology extreme skepticism is warranted in this sort of analysis. But Henry, a veteran stem cell researcher, doesn’t express any such caution.

A New Target

Despite the optimistic spin, in its press release the company indicated it would likely abandon the cardiac indication for CAP-1002 in favor of a new indication in boys and young men with Duchenne muscular dystrophy (DMD). The company recently reported positive interim information from a 25 patient phase I/II trial in this population.

“Although we are disappointed, the favorable safety profile demonstrated by CAP-1002 in ALLSTAR supports the prospect of its chronic, repeat administration in patients with Duchenne muscular dystrophy. Also, the potent anti-inflammatory properties of CAP-1002 may be well-suited to mitigate DMD progression, for which chronic inflammation is believed to play a causative role,” said Linda Marbán.

Given the history, of this therapy in particular and of stem cells in general, extreme caution is warranted.

An important motivating factor for Capricor may well be that the regulatory barrier is much lower for a DMD indication than for a cardiac indication, as demonstrated last year by the approval of Sarepta’s DMD   drug with little or no evidence of clinical benefit. Capricor plans to ask the FDA to grant Breakthrough Therapy or Regenerative Medicine Advanced Technology status for the new CAP-1002 indication.

A String of Failures

Hundreds of millions of dollars have been spent on cardiac stem cell research over nearly two decades now without any sign of success or progress.

Recently, as reported by Retraction Watch, in the latest installment of a long-running scandal, Brigham and Women’s Hospital agreed to give back $10 million to the US government in response to fraud charges against 3 prominent stem cell researchers, Piero Anversa, Annarosa Leri, and Jan Kajstura. Anversa, it should be noted, practically invented the field of cardiac stem cell therapy when he first reported that cardiac cells were capable of regeneration.

I recently criticized another prominent leader in the field, Roberto Bolli, for arguing that the proper response to this dismal record is more stem cell therapy, not less. With absolutely no concrete evidence, he argued that the single dose of cells used in virtually all previous stem cell therapy trials should be replaced with repeated doses of stem cells.

ALLSTAR is only the latest in a string of failures for stem cell therapies. Isn’t it time for people in the field to acknowledge that after decades of failure the field is not going to move forward.

Previous Stem Cell Stories:

• After Yet Another Failure, Stem Cell Leaders Double Down
• Principal Investigator Of Suspended Cytori Stem Cell Trials Remains Hopeful
• Stem Cell Therapy To Fix The Heart: A House Of Cards About To Fall?
• Lancet Editors Raise More Questions About Prominent Harvard Stem Cell Researcher
• Circulation Retracts Paper By Stem Cell Pioneer And Its Own Editor
• Paper Raises Hundreds Of Questions About The Integrity Of Stem Cell Research Group
• Stem Cell Therapy Company Hypes Preliminary Results
• Recent €23 Million Biotech IPO Relied Heavily On Questionable Research