Quote of The Day: Noah's Ark and the California Stem Cell Agency

'''CIRM operates at the nexus of the Political (with a capital P), scientific, institutional, and business forces of an aggressive state that views economic development as a priority.' Its organization, (Hamilton Moses) adds, doesn't help. ' 'Noah's Ark' boards, where each member is appointed to represent a constituency, rarely work.'"
 --  Hamilton Moses is a biomedical consultant in Virginia who focuses on non-profit governance, quoted in Nature Reports Stem Cells, from article Sept. 13, 2007, by Monya Baker

Text of Sheehy's comments re Covid-19, CIRM, Its Mission and Other Matters

The discussion at the May 23, 2020, meeting of the governing board of the California stem cell agency ranged from Covid-19 and the agency's strapped financial condition to its mission and priorities. One of the directors, Jeff Sheehy, elaborated on the matters and more when he responded to an inquiry following the meeting from the California Stem Cell Report. 

The California Stem Cell Report has a policy of running verbatim comments from stem cell agency board members and other interested parties.  If other readers would like to submit their comments on this subject or other stem cell matters, please direct them to djensen@californiastemcellreport.com.

Below is the verbatim text of Sheehy's comments.  
"First, I felt a great deal of uncertainty around CIRM proposing a COVID program.  Having worked towards stem cell therapies for HIV since I came onto the board in 2004, I felt some skepticism around stem cell approaches targeting infectious diseases (ID).  Infectious disease has not been a particularly major focus of regenerative medicine efforts and many of the approaches we have tried have struggled.  I think there could be a role, but we have a long way to go.  

"I thought, in general, a focus on ID is a bit overdue, but I was very concerned about taking funds from sickle cell, where I think there is a strong case for believing we are on track for a cure using stem cell technology, and there are well constructed clinical trials such as the one we just funded.  

"Given that CIRM is using its last of its funding, I was also concerned about the funding needed.  One of the most telling moments in Friday's meeting was the descriptions by (CIRM Director) Dr. (Keith) Yamamoto (vice chancellor for science policy at UCSF)  of the ready and ample availability of Covid funding from the NIH and other federal sources, not just in new funds but also the ability to repurpose existing grants towards Covid.

"Btw, I am not alone in my skepticism around stem cells for Covid-19.  I offer first the tweet from Dr. Sean Morrison, former head of ISSCR on March 29:

"'There is no stem cell therapy for Covid19. We would not expect stem cells to have any therapeutic value for people with Covid19.
@ISSCR'"

"Then a couple of weeks ago, Dr. Paul Knoepfler on his blog, the NICHE, offered this:
"'The idea of testing stem cells for Covid-19 may be music to the ears of some folks as an opportunity, but to me from the beginning it sounded mostly like a spaghetti on the wall road to trouble.
"'There is buzz out there that some kind of stem cells or other cells will help with COVID-19. The reality is that that’s probably not going to happen.
"'Even so, a whole range of people and firms are somewhat exaggerating and in a few cases outright hyping the odds of success. That is harming patients and the cell medicine field.'"

"I offer these two comments in support of my doubts.  But, I also feel the urgency surrounding Covid.  This is my second pandemic, having lived through HIV/AIDS and lost and continue to lose countless people that I care deeply about and living with the disease myself, having endured enormous stigma and outright hatred along with indifference from a president, seeing marginalized communities suffering death and disease disproportionately and indifference because people don't recognize the humanity of the populations most impacted, feeling triggered and re-traumatized by this second pandemic and the enormous stupidity from all points in trying to make a disease fit their self described perceptions of reality in the face of what is real and undeniable.

"I voted to support the COVID program despite my doubts due to urgency, but we know what tools work against infectious diseases -- antivirals and vaccines, and I became an enthusiastic and vocal supporter of the vital research opportunity for convalescent plasma.  Convalescent plasma is about as far removed from CIRM as a project could be--a technology at least 100 years old with zero barriers to receiving funding from any source.  But, in the absence of a vaccine or antivirals, it represented to me the best and most rational chance to make a difference in patients now. Plus, Zaia et al at City of Hope have the cell handling and manufacturing ability to address some of the factors limiting use and evaluation of convalescent plasma, e.g. potency and consistency of product to name a couple.

"After having participated in reviews, our two clinical projects are the convalescent plasma one and an ongoing $14 million trial for mesenchymal stem cells for ARDS, the lung complication suffered by critical COVID patients necessitating ventilator support.  That UCSF/UC Davis trial is already treating COVID patients at SF General and in Houston to name a couple of sites, and it was supportable because we were availing more patients of access to that therapy like we are doing with convalescent plasma. But both approaches are well supported outside of CIRM and the $750K we gave each project.  

"The $150K Discovery projects we funded are interesting, but they are very early in development and given the time and money it takes to move from discovery into translation into clinical trials, these antiviral products could likely be superseded by the host of antiviral products in trials around the world.
In that context, we did see a couple of interesting vaccine proposals that were very far afield and did not score in the fundable range.  I had a feeling -- having looked at the vaccine trials underway (and I'm not an expert btw)  -- that they seemed very much based in the most part on proven tech that a far-out, left field approach might be useful to explore.  HIV has been stubbornly resistant to vaccine development, so I'm very cautious about that field.  I was heartened to hear (CIRM Director) Dr. (Kristiina) Vuori from Sanford Burnham opine that she thought that current vaccine approaches were, to paraphrase, following usual pathways, and I thought I heard a suggestion that opening up CIRM to vaccine work might elicit something novel.

"However, the board thought otherwise and I defer to their wisdom.

"I would note that I was intrigued by the discussion around CIRM's mission.  As Dr. (Gil) Sambrano (CIRM vice president for portfolio development)  noted, stem cells are ubiquitous in the body, and I took that to mean that one could either be elastic or inelastic in accepting products.  A vaccine, for instance, would almost necessarily  impact T memory stem cells, which are a crucial part of the adaptive immune response to disease (and a vaccine).  We have begun to recognize the limits of stem cell centric therapies through our VRO for gene therapy.

"I then asked myself, does CIRM hews to its original mission per Prop. 71?  I looked up the original funding mission for the Grants Working Group :

"'(C) In order to ensure that institute funding does not duplicate or supplant existing funding, a high priority shall be placed on funding pluripotent stem cell and progenitor cell research that cannot, or is unlikely to, receive timely or sufficient federal funding, unencumbered by limitations that would impede the research. In this regard, other research categories funded by the National Institutes of Health shall not be funded by the institute....Notwithstanding subparagraph (C), other scientific and medical research and technologies may be funded by the institute if at least two-thirds of a quorum of the members of the Scientific and Medical Research Funding Working Group recommend to the ICOC that such a research proposal is a vital research opportunity.'

"With the federal ban ended, all of CIRM's research is really a vital research opportunity by default at this point.  Per COVID and ample federal funding, any funding in that arena is about as far afield as one could get.

"Even with fetal tissue research, which, btw, has fallen off the radar in the media and with some in Congress and the Administration, I can guarantee no one is talking about banning that.  You simple cannot develop vaccines or antivirals without mice with humanized immune systems created by using fetal tissue.

"To sum up, I'm not really sure what the board is trying to accomplish with its COVID program.  I'm not sure that the board has a clear, coherent view of the scope of CIRM's research.  And I am not sure the board has a clear idea of what the scientific mission of CIRM should be in the event that new funding comes from the voters.

"I would note as an aside that CIRM has never submitted its scientific program, including all grants made and their impact, to a rigorous, independent scientific review.  

"In short, I don't think we really know at CIRM where we've been and where we want to go.  We have anecdotes...."

(Sheehy’s own ellipses in the last paragraph)

California, Stem Cells and the Future of Human Suffering

Has California's $3 billion stem cell research agency "change(d) the future of medicine and human suffering?" 

It's a question and contention indirectly raised very briefly in a news article earlier this week published in the Long Beach Business Journal. 

While the Long Beach weekly does not have the reach of such other Southern California outlets as the Los Angeles Times, the question may well be at the heart of campaign to convince voters to approve an additional $5.5 billion for the California Institute for Regenerative Medicine (CIRM), as the agency is formally  known.  

Robert Klein

CIRM, created in 2004 by voters, is down to its last $27 million. It will begin to  shut down next fall if voters fail to approve the $5.5 billion measure in November. The proposed initiative will labor under a burden created by the ballot initiative campaign 15 years ago that raised expectations that stem cell cures were just around the corner. CIRM, however, has yet to finance a stem cell therapy that is approved by the federal government for widespread use. 

The Long Beach article by Alena Maschke provided a brief overview of the agency and its programs. Right at the top was a quote from Robert Klein, the Palo Alto real estate developer who is leading this year's ballot initiative campaign. He also led the effort in 2004 and was the first chairman of the agency.

Klein was also quoted as saying,

“The scientists and patient advocates in California have proven through the California stem cell initiative funding that they can change the future of medicine and human suffering. California funding has filled the gap of the federal government’s failure to fund this revolution in medicine.”

Mascke's article said Klein's efforts for stem cell research were initially triggered years ago by his concern for his son, Jordan, who had Type 1 diabetes.  The piece said, 

"In 2016, 26-year-old Jordan Klein died of complications related to the disease, two years after scientists first made significant progress on finding a treatment developed with the help of human embryonic stem cells. 

"Klein blames the federal government’s resistance to embracing stem cell research for the lack of adequate treatment options that lead to his son’s death. 'My youngest son died. If they hadn’t held it up in D.C., he would be alive,' he said. 'How many children, how many adults are going to die before they create enough stability to advance therapies that mitigate or cure these chronic diseases?'"

The Long Beach paper also tapped Aaron Levine, an associate professor at the

Aaron Levine, Georgia Tech photo

School of Public Policy at Georgia Tech. Levine was a member of the blue ribbon group that conducted a $700,000 study of the agency's work, an effort that was paid for by CIRM. 

"'CIRM stepped in to fill a gap when the National Institutes of Health was restricting its funding in this space,' Levine said. 'The research that CIRM has supported, as well as the training programs, has had quite a big impact on the field.'"

The article continued, 

"Levine also noted that the program has yet to resolve one crucial question: Who will pay for patients’ treatment with costly stem cell therapies once they’re ready to hit the market? Per-patient costs for stem cell therapies can easily reach several hundred thousand dollars and as research advances, more patients are expected to qualify.

 "'Suddenly, that’s just such a substantial sum of money that it becomes a fundamental challenge to how we pay for healthcare, how we pay for medicine in the United States,' Levine said. Subsidies for California residents, whose taxes helped pay for the research necessary to bring these cures and therapies to market, would be one option, Levine noted.

"Despite these concerns, Levine said he supports the measure to extend the program. 'Even though this is not the perfect measure, I think there’s a lot of value in CIRM and it makes sense to continue it,' he said. In the end, it will be up to California voters to decide. 

"'It largely will rise and fall on whether there’s a motivated campaign for and against it and what people who’ve never really thought about stem cell research as a state ballot issue are going to think about this particular initiative when it comes in the fall,' Levine said."

As for whether CIRM has changed the future of medicine and human suffering, some might argue that it alone has not, that other stem cell researchers around the world have been as instrumental. Others would argue that if revolutionary change has occurred, CIRM has fulfilled its mission and the people of California no longer need to fund it. 

As Levine points out, the voters of California will make the judgment in November. Their decision will come during an election that will focus intensely on presidential politics and much, much less so on the performance of the stem cell agency.  

California's New Stem Cell Initiative and Its $7.8 Billion Cost, Including Interest

The price tag for refinancing California's unique and ambitious stem cell research program could run to close to $7.8 billion, give or take a few hundred million dollars or more. 

So says the state's legislative analyst in a financial analysis of a proposed ballot initiative that is likely to be on next November's ballot. The measure would provide $5.5 billion more for research awards to California scientists by the California Institute for Regenerative Medicine (CIRM), as the state stem cell agency is formally known. 

The increase in the price tag is caused by the fact that the $5.5 billion would be borrowed money -- bonds that would be issued by the state. The legislative analyst estimated that the interest costs could total $2.3 billion, bringing the actual expense to taxpayers to $7.8 billion. 

Significant caveats exist, however. The legislative analyst, who prepares these sorts of analyses for all ballot measures, cautioned that the $7.8 billion estimate could rise or fall depending on how interest rates rise or fall. Another unknown involves the length of the payback period. 

What the legislative analyst has to say is a significant matter for the proposed initiative, whose success will determine the financial survival of the agency. CIRM is running out of cash. It was funded by voters 15 years ago with $3 billion. If the proposed initiative fails, CIRM will wither away over the next two to three years. 

Should the initiative qualify for the ballot, the seven-page financial overview of the measure would be delivered, via the state's official voter's guide, to about 20 million California voters prior to the election. The overview would also serve as the basis for news stories in virtually all of the media, which is always looking for bottom line figures.

Beyond the interest costs, the analysis carried other financial bits of interest. It said that over an initial, five-year period the agency would use some the bond proceeds to pay the interest on the money it is borrowing. The analyst said, 

"Were the state to begin issuing bonds shortly after approval of the measure, CIRM would likely make interest payments totaling in the low hundreds of millions of dollars from bond proceeds by the end of 2025."

The proposed initiative also places a 6.5 percent cap on total funding for certain operational expenses including administration and grant oversight. Other changes would give more freedom to the agency, which originally had a 50-person cap on staff. That cap was later removed by state legislation. The new initiative would set the cap at 70 with a provision for more employees beyond that number, under certain conditions involving, among other things, compensating them with cash raised privately. 

The new initiative stipulates that the agency improve access to stem cell therapies, funding that effort with up to 1 percent of the $5.5 billion, a change from the current law involving CIRM.  Other changes from the current situation: 1.5 percent for starting "community care centers" for new clinical trial sites, $1.5 billion for research into brain and nervous system diseases and up to 0.5 percent for a shared lab program. 

Royalties from any therapies financed by CIRM research would go to the agency and not the state general fund, as currently is the case. So far, royalties have totaled only about $200,000. Larger amounts are likely to appear in the next decade as the therapies emerge from the research that was financed years ago. 

Regarding possible savings as the result of more cost-effective therapies, the analysis said, 

"To the extent the measure results in new treatments that are more cost-effective than existing treatments, state and local governments could experience savings in some programs such as Medi-Cal, the state’s subsidized health care program for low-income people. The magnitude of these and other indirect effects is unknown."

The stem cell agency, which was created by voters in 2004, has yet to finance research that has led to stem cell treatments that are approved for general public use. 

In 2004, the legislative analyst prepared an interest cost estimate of $3 billion on the original amount for awards, also $3 billion. However, the projections did not anticipate the recession of 2008, which resulted in a long-term drop in interest rates. Today, the interest on the original $3 billion is expected to be about $1 billion.

Here are links to more information on proposed initiative and related matters:

SUNDAY, DECEMBER 08, 2019

LA Times: $5.5 Billion Measure for California Stem Cell Agency Could Actually Be a 'Downfall'

FRIDAY, NOVEMBER 15, 2019

$5.5 Billion Stem Cell Ballot Measure: Questions in California but Apparently No Foot-Dragging

MONDAY, NOVEMBER 04, 2019

California Stem Cell Agency Chalks Up its 60th Clinical Trial as Funds Dwindle

LA Times: $5.5 Billion Measure for California Stem Cell Agency Could Actually Be a 'Downfall'

The Los Angeles Times, California's largest circulation newspaper, carried a piece today that called for withdrawal of the proposed, $5.5 billion ballot initiative that would save the financial life of the state's stem cell agency.

The article by Pulitzer Prize-winning business columnist Michael Hiltzik said the measure would perpetuate many of the flaws in the ballot proposition in 2004 that created the agency, officially known as the California Institute for Regenerative Medicine (CIRM). 

In fact, Hiltzik said, the new measure "makes some of them worse."

"That’s dangerous," Hiltzik continued, "because although the measure could fuel the stem cell program for years to come, it might also prompt a repudiation by voters sensitive to its many imperfections. Such an outcome would be tragic for California and the advanced science already supported by CIRM."

Hiltzik's opinion piece was the first extended look at the proposed stem cell initiative by a major media outlet in California. It appeared on the front page of today's business section of the Times. On the paper's web site, the article was featured as a "weekend read" at the time of this writing. 

The Times says it has about 2 million readers on Sunday. It is a go-to source for other journalists when they are researching stories and trying to understand major issues facing the state. 

Hiltzik has followed the $3 billion agency since its inception and has been highly critical. Last spring, however, he wrote that the agency had "proved its value." In today's piece, he had a lot to say about the good work of the agency. 

In his first two paragraphs, Hiltzik declared that CIRM "has made great strides in advancing what’s known as regenerative medicine and placing California at the center of the developing science." Hiltzik also said that CIRM has financed state-of-the-art laboratories, attracted preeminent scientists and "brought scores of promising treatments for severe chronic diseases to the point of clinical trials."

But he also noted that the agency has "has so far failed to yield a single marketable clinical product." He continued, 

"That’s despite the sales pitch for Proposition 71 in 2004 -- that all that stood in the way of 'cures' for Parkinson’s, Alzheimer’s, spinal cord injuries and other maladies was money."

The greatest flaw of the agency, however, has more to do with public policy than science, Hiltzik wrote. And that is the exemption of the agency from the usual oversight by the legislature and the governor, an exemption contained in the measure that created the agency.

Voters provided CIRM with $3 billion in bond funding 15 years ago. 
Today that money has all but run out. Robert Klein, a real estate developer, first chairman of the agency and who sponsored Proposition 71, is now once again sponsoring the latest initiative to give it billions more. 

Hiltzik concluded,

"(Klein) should withdraw his measure, and CIRM’s leadership should write a new one or work with Gov. Newsom and the Legislature to map out the program’s next act. 

"CIRM’s leadership needs to show the public that it’s capable of taking charge of the program’s destiny. If it’s not willing to make its own case for CIRM’s continued existence, how can it persuade voters to give it one cent more?"

Slides from CIRM -- Review of the Stem Cell Agency's Work

OAKLAND, Ca. -- The president of the $3 billion California stem cell agency, Maria Millan, this morning is offering a review of its work over the past year or so. Here are the slides that she plans to use.

Kaiser Healthline: California's Stem Cell Program Short on Cash and Cures

An overview by Kaiser Healthline of California's nearly 15-year-old stem cell research program received attention in California and nationally last month. 

"Despite Failed Promises, Stem Cell Advocates Again Want Taxpayers To Pony Up Billions" said the headline on the article by Ana Ibarra.

Her piece carried both positive and negative comments on the performance of the $3 billion agency, which is running out of cash for new awards. The enterprise hopes voters will approve in November 2020 another $5.5 billion to continue its work.

The article quoted Marcy Darnovsky, executive director of the Berkeley-based Center for Genetics and Society, a longtime critic of the agency, which was created through a ballot initiative campaign in 2004. 

Darnovsky said that if the agency, known formally as the California Institute for Regenerative Medicine (CIRM), is measured against the campaign promises, “then CIRM has been a flop.”  

The agency, however, pointed to its 56 clinical trials, along with the stories of patients who have benefitted from that research, ranging from children who are alive today as the result of experimental treatment to spinal cord injury victims who are seeing their lives improve. 

Ibarra's article was picked up nationally by Salon. Politico noted it in its California newsletter.  The Sacramento Bee, the only daily newspaper in the state capital, published it as well.  

Hard News for Patients, Scientists: California Shuts Down Applications for Its Stem Cell Research Funding

The California's stem agency's rundown on its clinical
trials. Some of the trials have saved lives. 

The $3 billion California stem cell agency today served up the bad news with only a smattering of sugar coating.

No more applications for research funding are being accepted. The cash is running out, perhaps as early as the end of August.

In a posting on its blog, The Stem Cellar, the agency declared,

"It’s never easy to tell someone that they are too late, that they missed the deadline. It’s particularly hard when you know that the person you are telling that to has spent years working on a project and now needs money to take it to the next level. But in science, as in life, it’s always better to tell people what they need to know rather than what they would like to hear."

The news is no surprise to persons who follow the agency. But today brought a more clearly emerging sense of finality.

The California Institute for Regenerative Medicine (CIRM), as the agency is formally known, was created in 2004 by voters who also provided $3 billion in bond funding. However, the CIRM ballot measure also contained the seeds of destruction for the agency. No other cash was provided. No other significant means of funding was laid out.

Today, the agency is pinning its hopes for survival on a yet-to-be-written ballot initiative for the November 2020 ballot. To bridge the gap between now and then, CIRM has been attempting for months to raise privately more than $200 million. So far, no results have emerged publicly. 

As of last month, the agency had in its pipeline applications for $88 million in research funding. But it had only $33 million left for new awards. 

CIRM reports it has enough cash on hand to administer its portfolio of awards, which stretch out a couple of years.

Fifteen days ago the agency quietly announced the application shutdown. Little public notice of the action was taken even in California's stem cell community, which has grown mightily over the nearly 15-year life of the agency. 

During that period, CIRM has helped finance 55 clinical trials targeting diseases ranging from cancer and heart disease to diabetes and arthritis. It has served up 1,015 research awards. The scientists it has supported have published more than 3,000 research papers. 

However, CIRM has yet to fulfill the campaign-generated expectations of the 7,018,059 voters in 2004 who voted to create it and who thought they would see new, widely available, miraculous cures. Impressive results, some of which have saved lives, have surfaced from some of the clinical trials. But the elusive stem cell cure that would be ready for the general public is yet to hit the streets.

The Oakland-based agency is not done yet nor is it out of business.  Its reviewers are expected to meet later this month to make the de facto decisions on some of the pending applications. And then again in August. 

More needs to be done in terms of the private fundraising effort. And more needs to be done in crafting a new ballot measure that would bring $5.5 billion to CIRM.  

In the CIRM blog item today, written by Kevin McCormack, senior director of communications, the agency declared, 

"Over the years we have built a pipeline of promising projects and without continued support many of those projects face a difficult future. Funding at the federal level is under threat and without CIRM there will be a limited number of funding alternatives for them to turn to.

"Telling researchers we don’t have any money to support their work is hard. Telling patients we don’t have any money to support work that could lead to new treatments for them, that’s hardest of all."

Turning Off the California Stem Cell Spigot: Will Private Donors Step Up?

Benchmarks are important to the $3 billion California stem cell research program. When scientists fail to achieve them, the flow of cash from the agency disappears. 

Last week, the stem cell agency quietly announced something of a funding benchmark for its own, 14-year-old efforts.

The bad news? In just six days, the agency will shut off  applications from California stem cell scientists and companies for multimillion dollar awards.

The agency, formally known as the California Institute for Regenerative Medicine (CIRM), last Thursday said that its dwindling finances forced the closure. 

CIRM has only $33 million left for new awards and already has requests in the pipeline for $88 million. Private funding is a possibility, but major donors have not yet surfaced publicly.

Immediate reaction to the announcement was muted but ranged from dismay to tributes to the agency and the work it has financed. 

One scientist, Jeanne Loring, chief scientific officer at Aspen Neuroscience in San Diego, said the action was like "a rug being pulled out from under you." Loring also said in an email that the agency has built an "enormous resource in stem cell expertise in California" and played an important role in her own work at Scripps Research. 

Loring's work has received $17.4 million from the agency since 2005. (See the full text of her remarks here.)

Steve Peckman, deputy director of the Broad Stem Cell Research Center at UCLA, said the agency has chalked up "impressive success" and made California an international leader in the field. (See the full text of his remarks here.)

UCLA has received $289 million from the agency. 

Robert Klein, who led the ballot campaign in 2004 that created the agency, said the application shutdown will create a gap that will hold back development of critical therapies. Klein is expected to lead another ballot initiative in November 2020 to provide $5.5 billion for CIRM. (See the full text of his remarks here.)

Klein is chairman and founder of Americans for Cures of Palo Alto, Ca. He was also the first chairman of CIRM. 

CIRM has provided funds to about 600 researchers and 128 institutions and companies. The researchers run labs that vary in the number of employees, but the total would include  hundreds more stem cell workers. 

The agency is currently trying to raise $200 million privately to continue its awards programs between now and the fall of 2020. No philanthropic gifts have been announced. Queried last week by the California Stem Cell Report, the agency said that it had nothing new to report in the fundraising effort that began last year.  

It is unclear how the application shutdown will affect the fundraising effort. It may serve as a prod, however, for some potential donors and help to crystalize decision-making as CIRM executives stress the importance of the agency.

CIRM's announcement left open the possibility of re-opening applications come September. The agency expects to have a better handle then on how much cash might be returning to CIRM from awards that have missed benchmarks. The amount is not expected to be huge. 

The agency has reported that it has enough money to sustain a wind-down of the agency and to administer remaining multi-year grants, should the yet-to-written ballot measure fail. 

Klein is optimistic, however, regarding the prospects for a bond measure 16 months from now.  He told the California Stem Cell Report that unspecified polls show that 70 percent of voters support re-funding the agency when they learn of the "remarkable progress" that has been achieved as a result of CIRM-backed research. 

Cash and the California Stem Cell Agency: A Critique Notes August Deadline for New Funding Initiative

California's $3 billion stem cell program is facing a cash crunch this year, and the latest commentary on its financial fate raises a host of questions. 

The critique comes from the Center for Genetics and Society, a Berkeley group that has long been critical of the California Institute for Regenerative Medicine (CIRM), as the state stem cell agency is known. 

Writing on the center's blog, Pete Shanks briefly recapped the history of CIRM and its current financial situation. The agency expects to run out of funds for new awards this year and is  trying to raise privately more than $200 million. The cash is intended to bridge the gap between now and presumed voter approval of an additional $5 billion in November 2020. 

Quoting CIRM board transcripts, Shanks wrote: 

"They are still looking for an 'anchor investor,' who might encourage others (as an anchor store draws people to a shopping mall). Which makes CIRM board member Jeff Sheehy (long-term AIDS activist and former San Francisco Supervisor) sound prescient, since in September 2017 he had suggested that savvy voters might say (pp. 78–9 ): 

'So you went to fund-raise. You didn’t get enough to keep you going, so you’re coming back to me with your hand out. So why didn’t you get enough? Why did the people who you’ve been asking for money not think you were a good investment? Why should I?' 

"Good point. Indeed, some of the board members were over-optimistic in that 2017 assessment."

Shanks also raised other questions about the nature of CIRM's private fund raising effort and looming deadlines for qualifying a bond measure, along with a ballot initiative that will likely retool the existing law that created the agency in 2004. 

Shanks concluded,

"Propositions take considerable time to be approved. The deadline for submitting a proposed measure to the attorney general that’s intended for the November 2020 election is August 20, 2019 . In practice, that means that the proposition is probably being written now, or will be completed very soon, and preliminary backers have likely been identified and contacted already. Unless, of course, such funders cannot be found. 

"Will CIRM’s problems be solved? We’ll soon know."

California's Stem Cell Agency Smacks Stanford for Failing to Deliver on Financial Promises

The California stem cell agency today delivered an unusual and sharp rebuke to Stanford University, declaring that it needs to stand by its financial commitments to help back state-funded research. 

The message came during consideration of a request for more research cash from a Stanford researcher, Judith Shizuru. She sought $6 million for continuation of a clinical trial to develop a potentially "transformative" product that would eliminate the toxic impact of chemotherapy for a number of diseases. 

"It boggles my mind," said Jeff Sheehy, a member of the agency's governing board and chairman of its Science Committee, that Stanford, which has an endowment of $27 billion, has not stepped forward to provide the co-funding. 

The amount involved is $1.7 million and is due May 1. It is connected to an earlier $19 million award to Shizuru that kicked off her clinical trial. 

Sheehy noted that Stanford and its researchers have received $379 million from the agency since 2005. It is the top recipient of funds from the California Institute for Regenerative Medicine (CIRM), as the agency is formally known. Stanford also has a member on CIRM's board. 

Steve Juelsgaard, chairman of the board's Finance Committee and a former top executive at Genentech, said that Stanford is "very well taken care of in terms of its economics." 

He said that the agency requires all institutions and businesses to sign agreements to deliver on promises of co-funding. CIRM cannot have two standards for its grantees, Juelsgaard said. 

Today was the first time that the $3 billion research agency has publicly rebuked a grantee on co-funding. Recipients of awards, be they institutions or individual researchers, are generally  treated tenderly in public.  (The full transcript of the meeting is available here.)

CIRM directors did not take issue with the quality of the research, which they described as good. Specifically, today's application sought to advance Shizuru's phase one clinical trial to develop a way to avoid the necessity of chemotherapy in a genetic affliction, popularly known as the bubble baby syndrome.

Nine researchers in the field sent letters to the CIRM board praising the work. Several called it "transformative" and said it could have use in afflictions ranging from blood cancer to diabetes. 

Shizuru applied for $6 million. However, the CIRM board reduced the award to $3.7 million and only on the condition that the previous co-funding be delivered.  

Shizuru told the CIRM board she accepted responsibility for raising the co-funding, which she said has been difficult. Board members noted that agreements on awards are signed by both the recipient researcher and his/her insitution. She said she would discuss today's action with Stanford officials.

Her application came before directors in January with a seal of approval from the agency's reviewers, who make their decisions behind closed doors. Normally, approval by reviewers means a rubber stamp by directors.

Action in January, however, was deferred until this month after directors raised questions about research delays and financial matters. The agency also publicly released a slough of information concerning Shizuru's work, most of which she provided to them.  

Here are links to key documents involving Shizuru application. 

• CIRM's news release on today's action
• CIRM's summary of reviewer comments on Shizuru's application, CLIN2-11431. The agency does not disclose the full application.
• CIRM staff's presentation today concerning the application
• Transcript of the January directors' meeting, including a relatively lengthy discussion and comments by Shizuru
• Today's meeting agenda, which includes links to the letters of support, most of them from prominent researchers in the field
• CIRM award details on the $19 million award, including three progress reports 
• Shizuru successful appeal letter on her 2012 application, which had a median score of 50 and was rejected by reviewers. 
• Clinicaltrials.gov information on Shizuru's clinical trial (start date and last update, both Nov. 15, 2016

(An early version of this item misspelled Shizuru's last name.)

A Peek Inside the California Stem Cell Research Machine: $25 Million, Babies, Bonds and Dwindling Cash

California's stem cell agency this week dished up rare public details of an advanced effort to create "transformative" therapies that would help cure afflictions ranging from diabetes to always fatal immune disorders.

The disclosure involves Stanford University researcher Judith Shizuru, severely ill babies, toxic chemical treatments, delays in clinical trials and stem cell agency board members who are acutely aware of the $3 billion agency's rapidly dwindling resources.

Judith Shizuru
Photo by Flynn Larsen, Ludwig Institute

All this plus more is on the table Thursday at a meeting of the directors of the California Institute for Regenerative Medicine (CIRM), as the agency is formally known. 

The agenda nominally contains one item, an application by Shizuru for $6 million from CIRM. But the issues reach back to 2013 and provide insight into difficult research pathways and how the agency manages its programs. 

At the top of the matter is the fact that the state agency expects to run out of cash for new awards by the end of this year. It is pinning its hopes on a proposed $5 billion bond measure on the November 2020 ballot.  Meanwhile, directors are trying to raise privately $200 million to tide it over until then. 

Avoiding Toxic Chemotherapy

That was the backdrop Wednesday Jan. 30 when directors convened to consider application number CLIN2-11431 by Shizuru for $6 million. She is seeking a way to avoid chemotherapy treatments and their toxic side effects in the case of a rare genetic affliction often referred to as the bubble baby syndrome. 

In December, CIRM's grant reviewers, meeting behind closed doors, approved Shizuru's application, an action that nearly invariably is rubber-stamped by directors. But last month was different, and a bit of CIRM history was brought up.

Shizuru received  a $19 million CIRM award in 2012 which has led to a phase one clinical trial with positive results for her therapy. Cost per each of the six patients so far averages $917,000, according to a CIRM document. 

However, additional patients are needed, along with more funding, before the potential product can reach the marketplace. The average cost of per patient will run about $333,333 during the final portion of the phase one trial.  Her latest application is aimed providing assistance with those costs. 

Questions about Delays and Co-Funding

Last month, questions arose among directors about months of delays in the clinical trial and a current shortfall in co-funding, among other things.

Steve Juelsgaard

Steve Juelsgaard, a former Genentech executive and chair of the directors' Finance Committee, said, 

"It's not clear to me that they're being frugal with the money that they have been given."

Juelsgaard also said,

"Delay doesn't necessarily add up to more money. They obviously spent the money on something that they didn't anticipate or under-budgeted or something. There's something more to it."

Another director, Jeff Sheehy, chair of the board's Science Committee, said,

"Financially, it seems very muddy to me."

Other directors weighed in as well, ultimately leading to a motion to delay action on the application to provide more time to find answers to questions.

At that point, Shizuru, who was in the audience, rose to respond.

"I understand CIRM's concerns, and I can see you're very thoughtful about how this money is being spent," she said, according to the transcript.

 The Sheehy-Shizuru Exchange

The Stanford researcher said that without additional funding the trial would have to suspend enrollment of additional patients, prompting this exchange between her and Sheehy.

"Shiruzu: Budgetarily we're better off using it (the remaining funding) to continue to follow the patients that we've already transplanted. From that budgetary standpoint, we should delay the trial. We should delay treating any more patients on the trial.

"Sheehy: So Stanford won't front you 1.6 million to (treat) patients if we don't give you the money today?

"Shiziru: I hesitate to say what they would do.

"Sheehy: To Stanford...they would actually put patients at risk?

"Shiziru: I'm not at liberty to say what Stanford would do."

Stanford is the No. 1 recipient of CIRM awards, chalking up $379 million over the past 14 years. It also has always had a member on the CIRM board of directors, who is not allowed to speak or vote on awards to Stanford.

Following Shizuru's comments, CIRM directors approved the motion to delay action until this week's meeting. Since the January session, Shizuru has provided the agency with more than five, single-spaced pages of explanation about her research, plus other material that has been kept under wraps for what CIRM has indicated are proprietary and legal reasons.

The information from Shizuru, as well as additional documents from CIRM, provided an unusual, public look into the agency's grant-making process as well as the hurdles encountered in advanced clinical research. In the past, reviews of applications approved by reviewers have received little or no discussion.

Shizuru's Perspective

In her material, which is available on the agenda for this week's meeting, Shiruzu said one, eight-month delay was caused by CIRM itself because of internal concerns. Another nine-month delay was caused by age-restrictions on patients.

"Significant delay" was also caused because of what might be called a supply and demand issue. The bubble baby syndrome is rare. Only one in out of 50,000 to 100,000 births results in a baby with the affliction: severe combined immunodeficiency.

Three other clinical trials are also competing for those rare patients. 

Nine letters of support were received by CIRM supporting the research, with some describing the potential result as "transformative." The letters also said Shizuru's approach could find use in a wide range of other afflictions, an expectation also agreed upon by CIRM. 

Shizuru said she is working on securing the needed co-funding for her first award, which is not yet concluded. As for commercialization, she said she and her colleagues have formed a company, whose name was not disclosed. She said she has a letter of support from one investor regarding "an intention to co-fund pending completion of due diligence."

In a final comment during the vote last month to delay consideration, one CIRM board member, a San Diego patient advocate for Parkinson's disease, praised the board's close examination of the application. David Higgins said, 

"I want to acknowledge fellow board members (for) their continued concern about spending taxpayer's money wisely because I think this is a great example of that."

(The public can listen to and participate in the Thursday meeting via the Internet. Instructions are on the meeting agenda.)