Thursday, December 8, 2011

An Era Ends Before It Even Begins

To paraphrase an oft-cited verse of T.S. Eliot’s, “this is the way the experiment ends.  Not with a bang but a whimper.”

The experiment was Geron’s highly touted clinical trial using human embryonic stem cells (hESCs) to treat patients with spinal cord injury (sci), for which the FDA gave approval in January, 2009.  The experiment certainly began with a bang, arriving with the usual media hype that human embryonic stem cell research (hESCR) has enjoyed over the years. 

Some people think this is the dawn of a new era,” ABC’s Diane Sawyer gushed on Good Morning America.  The Los Angeles Times agreed with Sawyer’s talking points, similarly gushing that the trial was “ushering in a new era in medicine.” 

Well, that “new era” in medicine lasted not quite two years, which must be some sort of record for brevity in defining an “era.”  On November 14th of this year, Geron announced it was shutting down its human embryonic stem cell program.  During this brief “era,” 5 sci patients received infusions of hESCs (Geron originally intended to treat 10 patients total for the trial).  While there were no serious adverse side effects, there has been no evidence of any benefits to the patients either. 

Geron cited financial difficulties as the reason for shutting down the program.  So how did market watchers react to that?

The Street.Com reacted by selecting Geron’s announcement to terminate its hESCR  program as one of the “Five Dumbest Things on Wall Street” for the week of November 18.  It deserves to be quoted in full:

“3. Geron's Bluto Moment
You think John "Bluto" Blutarsky from Animal House had it bad? He saw only seven years of college go down the drain. Biotech bust Geron squandered 21 years of shareholder hopes, dreams and dollars on a wasted education. Shares of Geron fell 21% to $1.74 Tuesday as a result of its decision to shut down its embryonic stem cell research program in order to focus on its experimental cancer drugs. John Scarlett, Geron's newly appointed CEO, insisted in interviews Monday that the company's decision to exit the stem cell business was not an indictment of the entire field but was more a company-specific business decision. Frankly, Scarlett, we don't give a damn how you spin it, but Geron will always be an embryonic stem cell company. For more than two decades, Geron has been sucking money from investors' wallets like a Hoover vacuum with the sole intent of turning embryonic stem cells into new tissue or organs. And now you want to drop it like a bad habit? And after all that preaching about how this technology will help paraplegics walk, cure diseases like diabetes and Parkinson's and prevent heart attacks -- not to mention an accumulated deficit of nearly $700 million -- now you want to try something new? No way, dude! You can't simply change your major like an aimless college student trying to delay graduation. Your parents -- or in this case, your shareholders and investors -- deserve better. Not that they have seen much of a return on their money so far. To date, only four paralyzed patients have received injections of embryonic stem cell-derived nerve cells into their spinal cords. And while no safety problems have been reported, Scarlett admitted that there were "no signs" the stem cell therapy was helping patients either. Still, that's no reason to abandon hope and to change course after all these years of trying. Remember, Bluto spent all those years in a filthy, idiotic fraternity and then went on to become a member of the U.S. Senate. Wait, maybe that's not the best analogy.  But you know what we mean.”

For years, Geron cynically manipulated investors with carefully timed but nonetheless deceptive media announcements that its hESC clinical trial for spinal cord injury was imminent.  Here’s a partial chronology of how Geron did this, as compiled by DNH founding member David Prentice, PhD: 

18 March 2002
University of California, Irvine Prof. Hans Keirstead announces he will ask university officials to seek the U.S. Food and Drug Administration's approval to test human embryonic stem cells on human patients with spinal cord injuries. Initially, Keirstead said he might be ready to take this step in about a year.

22 February 2004
"The company believes it will be cleared to start the first stem-cell therapy in human tests next year, possibly for spinal-cord injury."

1 December 2004
According to Geron CEO Thomas Okarma, the company is aiming to file an investigational new drug application with the U.S. Food and Drug Administration (FDA) requesting permission to begin clinical trials using glial cells derived from embryonic stem cells to repair damaged spinal cords in 2005 or early 2006.

5 February 2005
"Next year [Hans Keirstead] and his corporate partner, Geron, plan to try treating people who have recent spinal cord injuries, in what would almost certainly be the first human trial of any therapy derived from such cells.

19 April 2005
Thomas Okarma, Geron's CEO, is even less convinced that larger animal studies are necessary before testing Keirstead's technique in humans. During an interview at a conference, he said he believes the clinical trial could begin in mid-2006.

9 September 2005
"Geron plans to begin clinical trials on acute spinal cord injury treatment in early 2006, according to chief executive officer Tom Okarma."

7 November 2005
"[R]esearchers at Geron of Menlo Park want to take the next step - in people. They hope to get federal permission to inject those cells into damaged spinal cords. The procedure - which Geron intends to do next year - would be the first human tests of a treatment derived from human embryonic stem cells, the highly versatile body cells that can be coaxed into becoming almost any tissue in the body."

29 March 2006
Tom Okarma: We will complete our IND-enabling studies, which are now in process and still on track, and file our IND during the fourth quarter of this year, assuming the preclinical data continue to go well. That starts a 30-day review clock by the FDA, who then has 30 days to either accept our IND and allow us to proceed or, at that point, they have questions that we must answer before we can begin. We are on track for that. So, assuming they bless the IND, we would hope to be in the clinic in the first quarter of (2007).

17 June 2006
"I'm confident that we will be in the clinic next year with the first human ESC-derived product," said Tom Okarma, chief executive of Geron, at a conference in London last week.

27 July 2006
The company will apply for approval to start US clinical trials in 2007, using glial cells derived from human embryonic stem cells to treat spinal injuries.

4 August 2006
One company, in particular, Menlo Park, CA-based Geron, is taking the lead in developing experimental embryonic stem cell therapies and hopes to begin human trials next year.

9 May 2007
"The first clinical trial of embryonic stem cells is on track to start early next year on patients with spinal cord injury. Geron, the California-based biotechnology company, will carry out the study on accident victims in six trauma centres across the US."

20 July 2007
"Geron Corporation in Menlo Park, California, expects to start clinical trials of a therapy for spinal cord injury early in 2008, according to spokesperson David Schull."

31 October 2007
Geron, based in Menlo Park, Calif., has been using rats in its experiments of a potential treatment for spinal cord injuries. Geron has already met with the FDA and will submit its plans for human testing to the agency by the end of this year, according to Sion.

13 November 2007
Geron's development plan for the product calls for the filing of an Investigational New Drug (IND) Application with the U.S. Food and Drug Administration and, pending the agency's review, initiation of human clinical trials in 2008.

13 November 2007
Geron's development plan for the product calls for the filing of an Investigational New Drug (IND) Application with the U.S. Food and Drug Administration and, pending the agency's review, initiation of human clinical trials in 2008.

15 May 2008
The Geron Corporation announced Wednesday that its plans to begin the first clinical trial using embryonic stem cells had been delayed by federal regulators. While companies typically do not announce when they submit an application to begin a trial for an investigational new drug, the F.D.A.'s action means Geron must have submitted its application in the last 30 days, Mr. Benjamin said.
17 October 2008
But the FDA is nearing the end of its review process and may lift the hold and allow clinical trials to commence within the next three months, Okarma told The Scientist.
20 October 2008
A clinical trial that would test the use of embryonic stem cells to treat spinal cord injury could begin within three months.

In sum, Geron’s behavior over the years is emblematic of the way hESCR proponents have tried to advance their cause: year after year after year, promise major medical breakthroughs with, in the end, little or nothing to show for it. 

In addition to the market, other observers saw other forces at play in the demise of Geron’s hESC trial.  According to Datamonitor Expert View: “Although many would say that Geron's decision reflects the worsening economic environment, in which biotechnology companies are increasingly struggling to raise capital investment, Datamonitor believes that the underlying reasons for the announced divestment actually relate to clinical and intellectual property roadblocks facing Geron's stem cell programs... Geron's divestment highlights the potential pitfalls associated with specific types of stem cell technologies - namely, embryonic stem cells (emphasis added).”

In marked contrast, Datamonitor went on to observe, “adult stem cell therapies continue to race ahead.” 

As Geron’s great new era of medicine was closing with a (media) whimper, the Discovery Institute’s Wesley Smith noted the media’s double standard in the way it covered Geron’s failure vs. advances with adult stem cells.

“You would think Geron’s failure would be very big news,” Smith wrote in the Weekly Standard.  “Instead, it turns out that the mainstream media pay attention only when embryonic stem cell research seems to be succeeding—so far, almost exclusively in animal studies.  When, as here, it crashes and burns, it is scarcely news at all.”

Citing, for example, the attention the Los Angeles Times gave to the FDA’s approval of the Geron trial in January 2009, and then again when the first patient actually received a transfusion of hESCs in October, 2010, Smith noted: “During the same period, however, the paper did not report the encouraging results of early human trials of treatments for spinal cord injury developed using adult stem cells.”
On that Good Morning America show cited above, Sawyer asked Sean Morrison, PhD, a researcher at the Howard Hughes Medical Institute: “What about it, Dr. Morrison? Do you think it could have been done with adult stem cells?”
Morrison replied: I don't think there's any adult stem cell that's ready for use in clinical trials that could be used to do what Geron is doing with these [embryonic] cells.”

How to explain such a remark?   Ignorance?  A willingness to mislead?

In 2005 – four years before the FDA approved Geron’s trial – Dr. Carlos Lima of Portugal published a report in the peer-reviewed Journal of Spinal Cord Medicine showing positive results from a “pilot clinical study” that used adult stem cells derived from olfactory mucosa to treat sci patients  (Lima subsequently published a second study on the use of olfactory mucosa derived stem cells to treat sci patents in the peer-reviewed Neurorehabilitation and Neural Repair, 9/30/09). 

Even earlier, in 2002, reviewing the positive results of using such stem cells in animal models, the Federation of American Societies for Experimental Biology declared : “These results are the most dramatic functional and histological repair yet achieved after complete spinal cord transaction in mammals, and they open new avenues in the search for treatment of spinal cord injuries in other mammals, including humans.”

Finally, and perhaps most important, a word about the patients.  They are the ones who have been the most ill-served by all the media hype surrounding Geron’s “new era” of medicine and hESCR in general.  They have also been ill served by the corresponding willingness of the media and even many researchers to downplay the very real and ongoing advances with adult stem cells.   

There is still great hope and promise for stem cell research to help patients. 

As the Geron example shows, don’t go looking for human embryonic stem cell research to fulfill it.  That hope and promise are being realized with adult stem cells.

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