The California stem cell agency has decided to put more manpower behind its push to drive therapies into the clinic.

The agency this week posted an opening for a senior development officer, who would be paid up to $226,108 annually.

The new hire would have a strong background in industry and an advanced degree. The job posting calls for a minimum of 10 years experience and expertise in "in developing, designing and assessing preclinical and early clinical safety and efficacy, within regulatory framework."

The position reports directly to Ellen Feigal, CIRM's VP for research and development. The job description says the person would "directly interact with investigators on CIRM’s clinically applicable research programs to help provide product development guidance from preclinical, manufacturing, and first in human to early phase clinical regulatory perspectives."

The $3 billion agency, which has yet to produce the cures promised to voters in 2004, is re-examining its strategies, particularly with an eye to backing a product that would actually be used on patients.

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It was not exactly a case of "Back
to the Future," the hit movie starring Michael J. Fox,
but it did offer a reflection on the past.

Fox's 2004 Ad

 "It could save the life of someone you love."

“It’s not so much that [stem cell
research has] diminished in its prospects for breakthroughs as much
as it’s the other avenues of research have grown and multiplied and
become as much or more promising. So, an answer may come from stem
cell research but it’s more than likely to come from another area.”

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The California Stem Cell Report will
provide live coverage of tomorrow's meeting of the governing board of
the $3 billion California stem cell agency. Directors are expected to
make major decisions about the agency's future direction, hear the results
of the first-ever performance audit and award about $95 million in
grants or loans.

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It was brief but pointed comment on the differences in the stem cell world of 2004 compared to the stem cell world of 2011.

Larry Ebert, a patent attorney, made the remark on his blog, IPBiz. He was writing about an observation on this website that without George Bush and his restrictions on federal hESC research, there would have been no California stem cell agency.

Ebert said,

"IPBiz notes that when the California voters voted Prop. 71 in, scientists thought Huang Woo Suk's work on hESC was real. In 2011, the current state of the art is still not up to what Huang Woo Suk falsely reported in the journal Science. Californiastemcellreport should give Huang Woo Suk some credit for the passage of Prop. 71."

Consider Woo Suk duly credited.

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From Canada last week came a stem cell "reality check" that pulled together a professional football quarterback, a Yankee baseball pitcher, a Republican presidential hopeful and Geron.

Timothy Caulfield, U. of Alberta Photo

What do they all have in common? Stem cell therapy, answered Timothy Caulfield, a Canadian academic, writing on the Canadian version of the Huffington Post. Declaring that stem cell treatments are being ballyhooed as a "miracle cure" and "elixir of life," Caulfield wrote,

"But does it actually work? I think not -- at least not yet."

Caulfield is not one of your stereotypical opponents of stem cell research. In fact, he describes himself as a "believer" in the likelihood of development of effective stem cell therapies. Caulfield also springs from a deep academic background. He is research director of the Health Law Institute at the University of Alberta and has published a plethora of scholarly articles related to stem cell research.

Caulfield wrote that Geron's abandonment of hESC research "underscores the cavernous gap between the well-publicized (and completely legitimate) promise of stem cell research and actual, efficacious, therapies."

He said the California company's decision "generated both shock and anger. And for the patients hoping for a near-future cure, it was nothing less than heartbreaking."

Caulfield continued,

"Not only did the company decide to stop this particular trial, it decided to get out of the field of stem cell therapies altogether. So definitive was the decision that Geron gave back millions of public research dollars(to the California stem cell agency)."

Caulfield warned, however,

"We need to be careful not to over-interpret the Geron pull out. This is one company and one trial. There are now a few other clinical experiments in the pipeline (emphasis on a few), such as one to treat a form of blindness. And we must remember that not all things that are called 'stem cell therapies' are the same. "

Caulfield continued with his "reality check,"

"First, ignore the hype. I believe there is little evidence that any of the often advertised stem cell therapies, embryonic or otherwise, work. Yes, there are a handful of decades-old treatments ….

"(Peyton) Manning, (Bartolo) Colon and (Rick)Perry may have had a positive experience (the placebo effect is a powerful thing, after all), but, to date, I believe good clinical evidence simply does not exist.

"Second, despite the hope of many, it isn't going to be easy to make money off stem cell research -- at least with a treatment that is scientifically legitimate, appropriately tested and approved by the relevant regulatory agencies (three characteristics missing from most of the stem cell therapies currently offered in clinics around the world). "Economic growth has often been one of the ways that the huge public investment in stem cell research has been justified. Just a few weeks ago, for example, the UK government announced that it was committing millions in a stem cell research centre with the hope that it will help drive the UK economic recovery.

"But the ability of emerging stem cell technologies to stimulate the economy and create jobs is far from certain. Indeed, economics is the explicit reason for the Geron pull out. The company press release stated that the decision was made after a strategic review of the costs, timelines and 'clinical, manufacturing and regulatory complexities associated' with this kind of research. In other words, stem cell research is not, from the perspective of this company, worth it."

Caulfield concluded,

"I don't mean to be a downer. In fact, I believe that stem cell research holds tremendous potential. I remain fully confident that, one day, therapies will emerge. But the inappropriate hype associated with this area hurts policy debates, leads to unmet expectations, and has the potential to mislead the public about the actual state of the science. The Geron story is a sober reminder that promise is not reality, even in a field as exciting as stem cell research."

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The $3 billion California stem cell agency has confirmed that it is looking for companies to take over Geron's hESC business, but remained vague on the details of just what it is proposing as well as any financial incentives.

A certain ambiguity may appropriate because Prop. 71, the ballot initiative that created CIRM seven years ago, constrains the state research effort, which is engaged in an aggressive push to bring stem cell therapies into the marketplace.

After last week's New Scientist article in which CIRM President Alan Trounson said he was talking to at least three companies, the California Stem Cell Report emailed this inquiry to the agency:

"Re Trounson's comments about CIRM trying to find an enterprise to pick up the Geron hESC business, what form is that taking? Are CIRM officials contacting companies, asking them to consider the Geron business? Are promises being made that Geron's loan would be passed along to a new company? Are CIRM officials giving any sort of assurance that the new enterprise would be looked on favorably in terms of possible CIRM financing help, even a wink or some such thing?"

In response, Maria Bonneville, executive director to the CIRM board, said yesterday,

"Dr. Trounson is encouraging companies to take a hard look at the potential of this project. If any companies express a solid desire to continue the project, they would be thoroughly vetted through CIRM's existing procedures."

The stem cell agency is limited by law in what it can do encourage a deal for Geron's orphan business. Nonetheless it will have to move quickly if it wants to keep Geron's hESC team intact. Otherwise, those folks will be heading for more secure employment.

With some crafty lawyering, however, CIRM might be able to move its $25 million Geron loan over to a some sort of new entity if the clinical trial remains virtually identical.

The agency might also find a way to use a newly created $30 million "strategic partnership" program to support a deal involving Geron's stem cell program. CIRM's new program is industry friendly and aimed at early stages of clinical development.

However, by law, only a public vote of the 29-member board of directors can approve a loan or grant. That vote is taken in what is supposed to be a blind process in which the names of the applicants are not known. However, it is clear from last May's approval of the Geron loan that the directors knew the identity of the applicant although it was not announced publicly until after the formal 16-1 vote. The agency's procedures also call for action prior to the board vote by its grant review group, which makes the de facto decisions on grants.

The timeline on normal award rounds is lengthy – more than a year from concept to finish – and may not be appropriate in this case. Plus the rounds are open to more than one applicant.

CIRM's current award rounds for business involve loans not grants. The loan policy was developed, in part, because businesses objected to the financial hooks in grants. Originally, the loan program was created to fund business projects that otherwise could not find funding. The program was originally slated to run as high as $500 million. The interest was expected to finance additional research.

The agency also has geographic constraints. It cannot pay for work outside of California. So that would mean that a potential buyer probably would need a substantial presence in California unless the agency could put together a deal in which Geron is still in the game and doing some of the work.

The agency can receive warrants in loan deals but does not make stock investments. It probably cannot legally directly buy a stake in a company and thus provide a cash infusion.

A new arrangement for Geron's hESC business would need some likelihood of a substantial stream of cash over the next several years, based on what Geron said last week. But the current environment for early stage biotech investment is quite difficult. And then there is the FDA, which authorized the clinical trial and is likely to have something to say about who operates it.

Whether CIRM can overcome all these obstacles would seem to be problematic. But, of course, Geron is also shopping its business around. And some buyers might be attracted by a bargain basement price enhanced by the expectation of continued cash from the California stem cell agency.

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The $25 million loan that the California stem cell agency awarded to Geron was the largest ever made by the research enterprise.

Directors approved the loan last May during a hearing that was a major departure from its usual procedures. The loan agreement was signed Aug. 1., about three months before Geron announced that it was abandoning the hESC business.

Geron last week repaid the $6.42 million that it had received from CIRM up to that point. Geron also paid the agency $36,732.33 in interest. CIRM additionally received 537,893 warrants to buy Geron stock at $3.98, CIRM told the California Stem Cell Report. Geron closed at $1.50 yesterday. The warrants expire in 10 years.

Last summer the California Stem Cell Report requested copies of the loan documents, which can be found at the end of this item, although the agency blacked out much of the information.

In a note accompanying the documents, Ian Sweedler, deputy legal counsel to CIRM, said,

"Geron requested and justified redactions to the milestone document, to those parts that describe specific activities, plans and data within the overall project.  Geron asserted and justified a claim that these details meet the legal standard for trade secrets that are exempt from production.  For the milestones, Geron agreed to leave enough unredacted to give a sense of the intent, at a level of detail that is not confidential.  For example, it will be possible to see that a milestone refers to enrolling a certain number of patients, but not what that number is, or other specifics about that stage of the project.  There are also accompanying comments with technical details and alternative approaches considered.  For these comments, we were unable to find a way to leave any meaningful text that would not disclose trade secret information.  The comments have therefore been completely redacted.

"Geron similarly justified redaction of information about how it will divide funds among different aspects of the project.  They explained that their internal costs, processes, and sequences are confidential, competitive trade secret information.  The redacted versions therefore show the amount of funding CIRM will provide, but not when and how Geron will allocate that to different activities."

Here are the loan documents.
CIRM-Geron 8-1-11 Loan Agreement

CIRM 7-28-11 Geron Loan Term Letter

Geron-CIRM Loan Agreement Appendix B

Geron-CIRM Loan Timetable Appendix C

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The president of the $3 billion California stem cell agency, Alan Trounson, says it is in talks with at least three firms in an effort to salvage Geron's orphan stem cell business.

Andy Coghlan of New Scientist magazine reported Trounson's remarks in an article on Friday headlined, "Is there life for stem cells after Geron."

The Menlo Park, Ca., firm last Monday abandoned its stem cell therapy development program and terminated a much-heralded clinical trial that was the first-ever in the nation for an hESC therapy. The California stem cell agency loaned the firm $25 million just last May as part of its push towards bringing therapies to market. Geron last week paid back the $6 million of the loan that it had received up to that date.

Details were sketchy in New Scientist about CIRM's attempt to serve as a stem cell matchmaker. Coghlan had only this to say,

"Alan Trounson, the institute's president, told New Scientist that CIRM is now talking to at least three other possible backers to take over the spinal trial. 'We'll have to wait and see, but it's important that it happens in a short time [because] once it gets beyond a couple of months, it gets very difficult to hold people together,' he said."

Coghlan noted that Geron, in addition to the spinal therapy clinical trial, had three other hESC possible trials lined up for diabetes, heart disease and arthritis.

Last week, several names surfaced in the media of a number of possible buyer/partners/backers for Geron's stem cell business. They included Pfizer, which is involved with Peter Coffey of UC Santa Barbara in another possible hESC trial; BioTime of Alameda, Ca., which has a number of Geron alums, and Teva Pharamaceutical of Israel. UC Irvine researcher Hans Kierstead, whose work led to the Geron spinal trial, was also in the mix, according to a report in the Orange County Register. Pat Brennan, who interviewed Kierstead, wrote that the researcher said "he is exploring alternative funding to continue the trials." Keirstead, who is on the scientific advisory board of California Stem Cell of Irvine, Ca., also said the trial may well go overseas.

The California Stem Cell Report queried the firms identified last week concerning their intentions towards Geron. All declined to comment specifically. Michael West, CEO of BioTime, also said,

"I think the commentary you heard was a deduction based on my prior role at Geron, our being so geographically close to Geron, and, of course, our entire focus on hES cells and reprogramming. I will only add that I continue to believe passionately in the cause. More than ever, we have an historic opportunity to impact the practice of medicine. That is about as far as I can go."

West founded Geron and has served as president of Advanced Cell Technology of Santa Monica, Ca., which is conducting an hESC trial at UCLA involving eye disease.

Brokering a deal for Geron's stem cell business places the California stem cell agency in a novel position and will test its business skills. CIRM's activities have been largely devoted to awarding grants and loans. Its loan to Geron was only approved by directors just six months ago. The loan agreement was not actually signed until August.

Under CIRM's procedures, companies receiving loans are supposed to be vetted during a private due diligence process. However, one might question the quality of that due diligence given Geron's withdrawal from the business only three months after the loan was finalized.

The key question, in trying to attract buyers for Geron's orphan stem cell project, will be not so much about whether it is good science but whether it is a good business.

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Two-Drug Phase I Trial Shows Promise in Treating Late-Stage Ovarian Cancer, ScienceDaily, June 13, 2010. Excerpt:

"Our hypothesis is that decitabine isn't just targeting active ovarian cancer cells, but also cancer stem cells that seem to survive the first treatments," [Kenneth] Nephew said. "By keeping tumor suppression genes from being methylated, carboplatin and other platinum-based treatments for ovarian cancer have a better chance of success in the late stages."

This news release is about the publication entitled: A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum-resistant, epithelial ovarian cancer by Fang Fang, Curt Balch and 9 co-authors, including Kenneth P Nephew and Daniela E Matei, Cancer 2010(Jun 8) [Epub ahead of print].

Oxygen in Stem Cell Biology: A Critical Component of the Stem Cell Niche by Ahmed Mohyeldin, Tomás Garzón-Muvdi and Alfredo Quiñones-Hinojosa, Cell Stem Cell 2010(Aug 6); 7(2): 150-61. Review. [PubMed citation][FriendFeed entry]. Via Twitter @CellStemCell: Access [to the full text] is free in August worldwide so readers can try out new enhanced online format.

Abstract:

The defining hallmark of stem cells is their ability to self-renew and maintain multipotency. This capacity depends on the balance of complex signals in their microenvironment. Low oxygen tensions (hypoxia) maintain undifferentiated states of embryonic, hematopoietic, mesenchymal, and neural stem cell phenotypes and also influence proliferation and cell-fate commitment. Recent evidence has identified a broader spectrum of stem cells influenced by hypoxia that includes cancer stem cells and induced pluripotent stem cells. These findings have important implications on our understanding of development, disease, and tissue-engineering practices and furthermore elucidate an added dimension of stem cell control within the niche.

The chairman of the $3 billion California stem cell agency has made his second entry into the blogosphere, this time adding a bit more on Geron's abandonment of what would have been its historic hESC clinical trial.

Jonathan Thomas, a Los Angeles bond financier, wrote yesterday on the CIRM research blog, which has recently been the site of more spritely and relevant items.

Geron's action has particular relevance for CIRM, which awarded the company a $25 million loan last May to help with the clinical trial.

Thomas said CIRM's "immediate concern" when officials heard the surprise news was for the patients and the families involved in the trials. Thomas continued,

"However, Geron is a business. The company decided that their cancer therapies were farther along than the stem cell trial and when they held the stem cell program against the prism of economic reality they made a business decision to end the trial."

Thomas also minimized the importance of Geron to CIRM. He said,

"CIRM’s award to Geron was just one of the 44 projects in 26 disease areas that are in various stages of working toward clinical trials."

It was a somewhat different story last May when former stem cell agency chairman Robert Klein said in a widely distributed CIRM news release,

"Supporting the Geron trial is a landmark step for CIRM."

Regardless of the spin on Geron from either CIRM or others who are more skeptical, Thomas' entry into the world of electronic media is to be applauded as is what appears to be a new direction in the research blog.

The CIRM blog is now newsier, more lively with more variety and more voices. All of which should redound, albeit modestly, to CIRM efforts to improve its communications with the public and opinion makers. The difficult thing about blogs, however, is the time and effort required to sustain them, and the task could be something of a communications test for CIRM. Blogs constantly need to be fed. Indeed, blogs are voracious, sort of like the carnivorous plant called Seymour in "The Little Shop of Horrors." As many of you may recall, Seymour had a simple but insistent refrain, "Feed me, feed me, feed me."

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Medical Hypothesis: No small matter: microRNAs - key regulators of cancer stem cells by Qing Ji, David Karnak, Ping Hao, Rongquan Wang and Liang Xu, Int J Clin Exp Med 2010(Mar 12); 3(1): 84-7 [FriendFeed entry][Full text via PMC]. PubMed Abstract:

Emerging evidence demonstrates that both tumor suppressor and oncogenic miRNAs play an essential role in stem cell self-renewal and differentiation by negatively regulating the expression of certain key genes in stem cells. It seems logical that they may also be critical players in cancer stem cells. Though small in size, miRNAs play a key role in the epigenetic regulation of cancer stem cells. Specifically, the imbalance of oncogenic vs. tumor suppressor miRNAs may lead to dysregulation of cancer stem cells, thus causing excessive self-renewal and survival of cancer stem cells, and resistance to chemo/radiotherapy. We postulate that restoring the balance of miRNAs will correct this dysregulation via the direct and simultaneous modulation of downstream stem cell pathways involved in cancer stem cell self-renewal and/or differentiation. The resultant restoration of key regulatory pathways could improve therapeutic response. Restoring tumor suppressor miRNAs and/or inhibiting oncogenic miRNAs may provide a novel molecular therapy for human cancers, potentially via modulating cancer stem cells.

Directors of the California stem cell agency today approved a $30 million program that could generate "disease-in-a-dish models" that "have the potential to make drug discovery faster, more efficient and more personalized to individual patients."

The "human pluripotent stem cell (hPSC) initiative" is aimed at generating high quality stem cell-based tools for use by the researchers and drug developers.

The proposal includes four elements, one of which is a $300,000 collaboration with the NIH to develop cell lines from patients with Huntington’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis. The plan includes a $4 million disease line award round, a $16 million core hiPSC derivation round and a $10 million stem cell bank round. The RFAs would go out in May of next year with funding expected early in 2013.

The initial staff memo on the initiative did not mention human embryonic stem cells, but a spokeswoman for the agency said they were not excluded from the effort.

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In an overview of the $3 billion California stem cell agency, the San Jose Mercury News says that CIRM "still has no treatments on the market and is at a critical juncture that could determine how much longer it stays in operation. "

The story is the second significant piece about CIRM this week in a major California newspaper, which has not received much coverage in the mainstream media in the state in the last year or so. The Los Angeles Times earlier this week carried a column that raised questions about the "Geron fiasco" involving CIRM and the conduct of the agency's business.

The San Jose article yesterday by Steve Johnson said that voters "may not be as enthusiastic" about providing several billion dollars more to finance the agency as they were when they created it seven years ago.

The newspaper, located in the heart of California's Silicon Valley, quoted John Simpson, stem cell project director of Consumer Watchdog of Santa Monica, Ca., as saying,

"I think it's crazy. The state's economy is in a far different position now. We're not even able to provide adequate funding for education."

Johnson also reported that former CIRM Chairman Robert Klein, who led the 2004 Prop. 71 campaign, is raising or intends to raise funds for another bond issue, perhaps in 2014. The agency will run out of cash in about 2017, according to its projections.

The article noted that CIRM has awarded only $83.4 million to 15 businesses, which are the key to pushing research into the clinic,  out of the $1.3 billion it has handed out. Johnson wrote,

"Many businesses have been deterred from even trying to make stem-cell treatments because of how long it might take.

"'It's a challenge,' said Rodney Young, chief financial officer at Newark-based StemCells, which hopes early next year to obtain a $20 million institute grant to determine if a type of adult stem cell can slow the loss of cognitive function in Alzheimer's patients. 'It's an expensive, uncertain and long process.'"

Johnson additionally noted that CIRM has received criticism for the high salaries it pays its top executives and for conflicts of interests.

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Just a few days ago, the California Stem Cell Report carried an item about the state's stem cell agency and its supporters' mantra that the agency has a mandate from voters albeit one that is seven years old.

We mentioned that Robert Klein, the former chairman of the agency and head of the 2004 ballot campaign that launched CIRM, is one of those fond of citing voter mandates with great regularity.

Indeed, Klein found shelter again this week under a voter mandate, but this time it was a moral one.

Klein popped up in a San Jose Mercury story about the status of the stem cell agency. Writer Steve Johnson said that Klein declared that he quit as chairman last June in part because he wants to raise money for a campaign for another multibillion bond measure for CIRM. Johnson quoted Klein as saying,

"It would be a huge failing in meeting our moral mandate" to let CIRM die. "We can't afford to break the momentum."

As we noted on Dec. 6, mandates come and go, as another multibillion California bond program, high speed rail, has discovered.

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