Hundreds of California Scientists Eyeing $182 Million from Golden State Taxpayers

Hundreds of California stem cell researchers this week took part in an online exploration of the new, $182 million research plans of the state's newly refinanced efforts to develop therapies for afflictions ranging from cancer to incontinence. 

Their questions ranged from the quite technical to how to comment during the formulation of a new strategic plan for the California Institute for Regenerative Medicine (CIRM), the official name of the stem cell agency. 

CIRM is in the process of figuring out how to spend a total of $5.5 billion approved by voters last fall. The cash will fuel research for about another 11 years. At that point, CIRM funding will terminate unless another source of financing is developed. 

The agency was created in 2004 by voters who allotted it $3 billion in borrowed money. By the time the money runs out, CIRM will have cost taxpayers an estimated $12 billion, which includes interest on the state bonds.  

This week's webinar dealt with the agency's plans to award $182 million -- the first bite into the new $5.5 billion -- over the next six months for basic, translational and clinical research. On Thursday, Gil Sambrano, vice president of portfolio development review, laid out the plans that were approved last month by the CIRM governing board. He answered a number of questions during the session, which was viewed by more than 350 participants. Since then, the recording of the session has attracted an additional, 50-plus viewers.  (To see the session, click on this sentence.) 

CIRM began making awards in September of 2005, and it has delivered cash to more than 900 recipients. Many have received more than one award. 

The first deadline for clinical applications in the latest round of funding is the last business day of this month. The deadline for translational applications is 2 p.m. PST Feb. 18. The deadline for the basic research "Quest" round is 2 p.m. PST March 18. 

Needs of the Underserved: California Scientists Seeking Millions for Stem Cell Research Will Need to Measure Up

Directors of California's $12 billion stem cell agency tomorrow are expected to require scientists seeking hundreds of millions in research dollars to specifically address the needs of underserved communities.

If the researchers fail to do so, their applications will receive a score that reflects that shortfall. The immediate impact will fall on scientists who apply for funding from the $182 million expected to be handed out during the next six months.

Below is language from a "concept plan" before the board. This particular version comes from the plan that applies to basic research applications. Nearly identical language is also contained in plans for the translational and clinical rounds.

All of the concept plans can be found on agenda for the meeting, which also contains instructions for participating in the online meeting, which is open to the public. Written comments are always useful as well as oral presentations. Written material can offer needed backup for the briefer oral comments and are directly in front of CIRM directors and staff. Comments should be emailed to kmccormack@cirm.ca.gov.

The new language is in red. The strike-throughs indicate language to be removed. 

“Addressing the Needs of Underserved Communities

in CIRM-Funded Projects

“All applicants for the DISC2 program will be required to provide a statement describing how their overall study plan and design has considered the influence of race, ethnicity, sex and gender diversity. 

"Applicants should discuss the limitations, advantages and/or challenges of their research proposal in developing a product or tool that addresses the unmet medical needs of the diverse California population, including underserved racial/ethnic communities. Examples include use of models and tools that account for population diversity (e.g. HLA types, gender, genomics data, cell models). 

"Applicants should also address how the research team has or will incorporate diverse and inclusive perspectives and experience in the implementation of the research project. 

"The GWG and CIRM’s governing board will evaluate consider these statements as a review criterion in their evaluations and in making funding recommendations. Priority will be given to projects with the highest quality plans in this regard."

California's $40 Million Stem Cell Genomics Center: Its Fate and Outcomes

California's stem cell agency hit something of a milestone six years ago when it approved $40 million to create a genomics center that was aimed at positioning the state as a global leader in stem cell genomics. 

The round triggered complaints about irregularities, unfairness, score manipulation and the role of its then president, Alan Trounson. The $40 million, at the time the largest single research award by the agency, was ultimately divided three ways and now has been spent. 

The California Stem Cell Report queried the agency this week about the award, its status and results. Here is the response in Q&A format.

Q: How was the $40 million shared and with which institutions?
A: The genomics grant was split into three awards: $22.7M to Stanford (GC1R-06673-A), $13.2M to the Salk Institute (GC1R-06673-B), $4M to UC Santa Cruz (GC1R-06673-C). (The application numbers carry links to the progress reports on the CIRM website.) 

Q: Is there any requirement for the grantees to come up with a plan for continued funding? 

A: There was no requirement for the grantees to come up with a plan for continual funding in the concept RFA.  Stanford and Salk provided co-funding to support the centers during the award period.

Q: If not, what prevents the doors from closing at the genomics center(s) in the next couple of years?

A: The Stanford sequencing center established by the genomics awards continues to operate with other sources of funding.  The Stem Cell Data Hub established by UCSC continues to be supported.  UCSC has no plans to shut down the site even though its CIRM award has ended. 

Q: How much time remains on the grant(s)? I See there was at least one extension given, but it is unclear why there was delay.

A: All three genomics grants have ended as of May 31^st.  The sequencing centers at Stanford and the Salk were given six month award extensions to continue supporting projects with technical delays in sequencing activities.  The data hub at UCSC was given a 12 month extension to process data generated by the sequencing centers.

Q: What else do readers need to know about this award? 

A: A number of outputs were generated from genomic center projects, including:

• 60 publications connected to CESCG funding
• 10 data analysis/visualization tools created
• 1 new sequencing technique developed
• 300 new iPSC lines created
• Central online data hub created with standard metadata, analysis pipelines, restricted access
• Data repository of human single cell global transcription in heart, pancreas, blood, brain, brain
• 84TB data generated from sequencing activities across projects

*********

​Read all about California's stem cell agency, including Proposition 14,  in David Jensen's new book. Buy it on Amazon:  California's Great Stem Cell Experiment: Inside a $3 Billion Search for Stem Cell Cures. Click here for more information on the author.

Covid Research Backed by California's Stem Cell Agency: 15 Awards, Including Help with Three Clinical Trials

The California stem cell agency is down to its last $272,357 in its special, $5 million effort to help finance research involving Covid-19.

The research round began in May and has approved 15, fast-track research projects, including participation in three clinical trials. The latest awards were approved last Friday by agency directors. 

• Evan Snyder of Sanford Burnham Prebys Medical Discovery Institute received $250,000  to create lung organoids to test two drug candidates for treatment of the virus.
• John Zaia of the City of Hope received an additional $250,000 for his previously approved study dealing the use of convalescent plasma treatments. 
• Steven Dowdy at UC San Diego was awarded $150,000 to study a more effective way of delivering a genetic medicine, called siRNA, into the lungs of infected patients.

Summaries of the CIRM application review on the grants can be found here, including the six rejected.  

Approval of the latest awards came as a New Jersey firm that two weeks ago received a $750,000 award still has not disclosed the location of its clinical trial site in California. By law, the stem cell agency can only finance work within California.

The awardee is Celularity, Inc., a business whose proposed therapy is backed by Rudi Giuliani, the president's personal lawyer, who has also touted other possible Covid therapies, including one that has been rejected by the Food and Drug Administration.

In creating the Covid round, CIRM said award winners must be "ready to start work within 30 days of approval and propose achieving a clear deliverable within six months." It has been 16 days since the Celularity award was approved. 

The California Stem Cell Report has asked the firm repeatedly for the location of the California site but it has not responded. The agency itself also has not disclosed the location and defers to the company.

Celularity and $750K from California Stem Cell Agency: Where is the Money Being Spent?

The New Jersey firm that was awarded $750,000 by the California stem cell agency to help finance a Covid-19 clinical trial has four trial sites in two states, but has not identified any in California. 

State law requires that awards from its taxpayer-funded stem cell agency be spent for work in California. 

The firm is Celularity, Inc., which is developing a product that has been fast-tracked by the federal government and which has the support of President Trump's personal attorney, Rudy Giuliani. 

According to the National Institutes of Health website this morning, Clinicaltrials.gov, Celularity has three clinical trial sites in its home state of New Jersey and one in Washington state for the Covid therapy. The information shows that all of those sites are currently recruiting patients. The estimated primary completion date of the work is Nov. 30, 2020.

Although the stem cell agency said on Sunday that a trial site existed in California, it declined to disclose the location. The agency referred questions about a site in California to the company, which has not responded to three requests yesterday and today for information.

Corey Casper, interim president of the Infectious Disease Research Institute in Seattle, is listed as the principal investigator for the trial by Celularity. Casper spoke to stem cell agency directors on May 15 on behalf of the application. Casper also did not respond to inquiries about the location of the California work. 

Six weeks ago, when Celularity's application first came before directors of the California Institute for Regenerative Medicine (CIRM), Casper said the treatment "has a biologic plausibility for being very important and very unique in its treatment for Covid disease."

He continued,

"I think that we have adequate safeguards that have been put into the trial to really assure the safety of the participants."

Safety concerns have been raised by CIRM's grant reviewers as well as by other scientists. The reviewers, who are from outside California, originally rejected the application, giving it a score of 84, one below the cutoff point. After Celularity addressed reviewers' concerns, it scored 85 and was sent to directors who approved it last Friday with no debate.

It is CIRM's 64th clinical trial.

The Covid-19 Fight: $1 Million Awarded by California Stem Cell Agency for Research

The California stem cell agency this morning awarded $1 million to three researchers for work aimed at battling the coronavirus, which has taken more than 1,500 lives in California and nearly 45,000 nationally.

The grants are the first coronavirus research to be funded by the agency, formally known as the California Institute for Regenerative Medicine (CIRM). Maria Millan, CEO and president of CIRM, said in a news release,

“We are in the midst of very challenging times where there is not yet an approved treatment for COVID-19. In response to this, CIRM launched and executed an emergency COVID-19 funding program, which was made possible by our board, patient advocates, California scientists, external scientific expert reviewers and our dedicated team."

Millan cited one application in particular.  She said,

“With CIRM funding, the City of Hope COVID-19 Coordination program will tap into CIRM’s network of researchers, physicians, and our Alpha Clinics to deliver this treatment to patients in need.  It will also serve the critical role of gathering important scientific data about the plasma, safety, and clinical data from treated patients.”

The City of Hope application received the most funding in today's round, $749,999. It went to a team led by John Zaia.

The proposed research would involve development of a program in California to identify potential blood plasma donors who could take part in a Covid-19 treatment program. A summary of the reviewers' comments on the Zaia application (Clin2dovid19-117) said,

“This will help develop a new screening tool for the California public health arsenal by identifying what patient and (plasma) donor factors predict clinical benefit.”

The other two awards went to Gay Crooks of UCLA, $150,000, (Disc2covid19-11817) and Brigitte Gomperts, also of UCLA, $149,998 (Disc2covid19-11764).

Crooks is seeking to enhance the ability to generate specialized immune cells in the lab and use them to discover viral antigens that have the highest potentcy for vaccines.

Gomperts is aiming identifying a federally approved lead compound that could be repurposed for Covid-19 infection.

CIRM's out-of-state reviewers had questions or concerns about each proposal, which can be found in the summaries of reviewer comments. Zaia wrote a letter dealing with some of the reviewer comments, noting that the application was prepared on a short timeline and more work had answered some of the key questions.

CIRM directors gave higher prior to plasma applications that had strong plans for "outreach and study participation by under-served and disproportionately affected populations." Zaia's three-page letter devoted full page to an outline of that effort. Other applicants did not submit a letter to the CIRM board.

Nine applications were rejected by reviewers, whose decisions are nearly invariably rubber-stamped by the board. The board continued that longstanding tradition today. 

CIRM has speeded up its normal processes to gather applications and act on them. Winners are expected to begin work 30 days from today. "Deliverables" are expected in six months. 

The applications considered today were among 19 submitted April 7, the first deadline for the $5 million round. The seven not reviewed did not meet the eligibility criteria.  Sixteen more applications were received last Tuesday. The next deadline for applications is May 5.

Directors expect to act in the middle of next month on more applications. 

California Stem Cell Agency Set to Award Millions on Friday for Coronavirus Research

The California stem cell agency is moving with dispatch to approve millions of dollars for stem-cell related research that would assist in the battle to fend off Covid-19 and ease the coronavirus crisis.

Meeting behind closed doors yesterday, the agency's reviewers  evaluated 12 applications seeking $2.7 million in total funding, including one proposal at a clinical stage. The proposals were received about two weeks ago and were the first in the agency's special Covid-19s round. 

It is standard practice for the reviewers to meet privately when considering applications. 

The reviewers' decisions, still undisclosed, are expected to be ratified by the agency's governing board on Friday. The researchers are expected to be ready to begin work 30 days later. 

Also yesterday, the agency received 16 more applications in the $5 million, rolling, coronavirus round. Four involved clinical applications. Three came from businesses and the rest from non-profits, including academic institutions. 

The board's meeting is open to the public via the Internet. Instructions are available on the agenda of the meeting, which begins at 11 a.m. PDT. 

Covid-19 and California Stem Cell Agency: Plasma Research to be Funded in $5 Million Round

California's stem cell research agency, in an "emergency" move this morning, joined the search for a plasma treatment for Covid-19, stressing the importance of extending access to minority communities. 

It was only the second time in the 15-year history of the agency that its governing board invoked its "vital research opportunity" clause, which gives it authority to divert funding from stem cell research to other purposes.

Maria Millan, CEO and president of the agency, said in a statement,

“The intent behind this amendment is to be responsive to this COVID-19 crisis by leveraging CIRM’s funding programs, processes and infrastructure within the scientific ecosystem that it has supported to date.

"By providing an opportunity for the medical and scientific community to gather important data while using convalescent plasma treatment protocols on an emergency basis, CIRM is joining the global effort to  expedite treatments to patients in need in the midst of this global pandemic."

This morning's action, approved unanimously, adds plasma research to a $5 million grant round aimed at the coronavirus.  The round has rolling application deadlines. The first was last Tuesday and drew 19 applications. The next deadline is expected in about two weeks.

The board unanimously added a provision to the plasma proposal aimed at ensuring that it would reach into minority and medically under served areas of the state. 

The agency, formally known as the California Institute for Regenerative Medicine (CIRM), is speeding its award process and expects winning applicants to be ready to begin their work within 30 days of approval of an award.

The use of plasma in treating Covid-19 has attracted international attention as well as here in California.   

CIRM directors also approved additional members to its panel of grant reviewers, all of whom come from out-of-state. The agency selects reviewers from the panel depending on the nature of their expertise. 

Here is a link to the CIRM news release on the action today.

$5 Million Allotted: California Stem Cell Agency Receives 19 Applications for Research Targeting Covid-19

Nineteen scientists seeking to crush the coronavirus submitted applications this week for research grants from the California stem cell agency, which has set aside $5 million for the job. 

Details on the nature of the proposed work were not disclosed by the agency, known formally as the California Institute for Regenerative Medicine (CIRM). That's in keeping with its usual practice concerning applications that are yet to be reviewed or approved. 

The research must involve a stem cell or a drug or antibody targeting stem cells. The agency said that only research involving "development or testing of a treatment for Covid-19 (is) eligible."

The "emergency" coronavirus round was established by the agency just two weeks ago. CIRM plans to deliver funds quickly to the winning applicants. The researchers are expected to be ready to begin work within 30 days of approval of the awards. 

The agency allocated the $5 million on March 27. Yesterday was the first deadline for applications. The next is expected in about two weeks.  The agency has said it would fund all stages of research from basic to clinical. Maria Millan, president and CEO of the agency, said earlier in a statement, 

“These are clearly extraordinary times and they require an extraordinary response from all of us.... California researchers have made us aware that they are pursuing potential stem cell based approaches to the COVID-19 crisis, and we felt it was our responsibility to respond by doing all we can to support this research and doing so as quickly as we possibly can."

Some scientists have expressed doubt that a stem cell approach can generate the results needed. In posting Sunday on The Niche stem cell blog, Sean Morrison, chairman of the Public Policy Committee at the International Society for Stem Cell Research and director of Children’s Research Institute at University of Texas Southwestern, responded to a question that asked about "potential roles for cellular therapies for COVID-19? Is there something unique they might be able to achieve that other approaches like anti-viral drugs could not?"

Morrison replied,  

"I’m afraid I’m skeptical about cellular therapies for Covid-19. Some have suggested that transplantation of immune effector cells, such as NK cells, into patients might promote a more effective immune response. I worry it will take too long for the transplanted cells to engraft and mount an effective immune response against a virus that often kills patients within days of hospitalization. 

"Others have suggested that mesenchymal stem cell (MSC) transplants might provide a benefit by attenuating the hyper-inflammation that occurs in late stage patients. While there has been some evidence that MSCs can attenuate pathological immune responses in some contexts, most clinical trials that tested this strategy failed. The other red flag is that all of the cell therapies I have seen proposed for Covid-19 have been repurposed from very different indications.

"To some extent that’s to be expected when dealing with a novel pathogen. However, it gives one pause when a cell therapy under development for cancer is suddenly touted as also having anti-viral activity. Immunologically, these are two very different problems that require very different kinds of pre-clinical testing."

The next step in CIRM's Covid-19 round is for the agency to convene a panel of scientists from out-of-state to review the applications behind closed doors and make the de facto decisions on whether to fund them. Their decisions then go to the CIRM governing board for ratification. 

At that point, summaries of the anonymous reviewers' comments on the applications become public. 

Five of the applications were from private companies and the rest from nonprofits. 

The reviewers do not publicly disclose their financial or professional conflicts of interest. Members of the governing board are barred from voting on applications involving their institutions. The research is required to be performed in California. 

Bloomberg News: $191 Million Payout for Stanford Researcher in Immunotherapy Deal

Renowned stem cell scientist Irv Weissman of Stanford University stands to gain $191 million from the sale of a Menlo Park, Ca., immunotherapy firm that he co-founded to develop a cancer treatment, Bloomberg News reported this afternoon.

The firm is Forty Seven, Inc., whose scientific underpinnings were developed in Weissman's lab. Gilead Sciences, Inc., of Foster City, Ca., announced Monday that it is buying Forty Seven for $4.9 billion which amounts to a price of $95.50 a share.

Weissman serves on the company's board and holds 4.2 percent of the company's stock, according to the article.

Weissman was not immediately available for comment on the report.

The article by Devon Pendleton said,

"Stanford’s payout from the sale is $67.1 million. Other winners from the deal include billionaire Stanley Druckenmiller’s Duquesne Family Office and the Rockefeller family’s venture capital firm Venrock Associates. The entities, which own stakes of 0.8% and 1.2%, respectively, acquired their holdings in the last quarter of 2019, filings show, when the shares traded for as low as $5.53 and as high as $45.39."

Pendleton wrote that Weissman "credits the support of the nonprofit Ludwig Institute for Cancer Research and the state-funded California Institute for Regenerative Medicine (CIRM) with funding Forty Seven’s early clinical research and development."

CIRM, commonly known as the state stem cell agency, awarded Forty Seven directly and Weissman $30 million for earlier research. The agency does not stand to benefit from the sale unless the proposed therapies reach the marketplace and generate a profit. That could trigger royalties to the state.  However, the agency has said that the deal validates its efforts to successfully stimulate research that leads to a product and fills an unmet medical need.

Bloomberg said,

"Biotechs saw it as too dicey to invest in at an early stage, Weissman said. So he and (Ravindra) Majeti formed Forty Seven, with Stanford getting an equity stake and future royalties that it agreed to share with the state."

Majeti is a professor of medicine at Stanford, a director of Forty Seven and also held stock. The Bloomberg piece did not identify his gain.

(A slightly earlier version of this story attributed the initial report to the Los Angeles Times. It was a Bloomberg News story that was picked up by the Los Angeles Times.) 

Whoopee Time at the California Stem Cell Agency: Celebrating a $4.9 Billion Deal

The California stem cell agency this afternoon burst out with an exuberant cheer, declaring that a huge financial deal announced just yesterday gave its research program a $4.9 billion seal of approval. 

If you missed it, the deal involves the $4.9 billion purchase of Forty Seven, Inc., by Gilead Sciences, Inc., two companies nestled only 20 minutes apart on the San Francisco Bay peninsula. 

Writing on its blog, The Stem Cellar, the agency all but said, "WHOOPEE!"  Not that that would have been inappropriate. The agency declared, 

"It’s not every day that a company and a concept that you helped support from the very beginning gets snapped up for $4.9 billion...CIRM has supported this program from its very earliest stages, back in 2013, when it was a promising idea in need of funding."

CIRM, of course, is the official name of agency, the California Institute for Regenerative Medicine. 

Maria Millan, CIRM photo

The blog item continued with this from Maria Millan, CEO of CIRM:

“To say this is incredible would be an understatement! Words cannot describe how excited we are that this novel approach to battling currently untreatable malignancies has the prospect of making it to patients in need and this is a major step. Speaking on behalf of CIRM, we are very honored to have been a partner with Forty Seven, Inc., from the very beginning."

The Forty Seven tale originated in the Stanford University lab of Irv Weissman. CIRM quoted him as saying,

Irv Weissman, Stanford photo

"The story of the funding of this work all of the way to its commercialization and the clinical trials reported in the New England Journal of Medicine is simply this: CIRM funding of a competitive grant took a mouse discovery of the CD47 ‘don’t eat me’ signal through all preclinical work to and through a phase 1 IND with the FDA (Food and Drug Administration). Our National Institutes of Health (NIH) did not fund any part of the clinical trial or preclinical run up to the trial, so it is fortunate for those patients and those that will follow, if the treatment continues its success in larger trials, that California voters took the state’s right action to fund research not funded by the federal government.”

Ingrid Caras, CIRM photo

Ingrid Caras, CIRM senior science officer, who was on the agency team that provided assistance to the academic researchers, said,

“I had the pleasure of working with and helping the Stanford team since CIRM provided the initial funding to translate the idea of developing CD47 blockade as a therapeutic approach. This was a team of superb scientists who we were fortunate to work closely with them to navigate the Regulatory environment and develop a therapeutic product. We were able to provide guidance as well as funding and assist in the ultimate success of this project.”

McCormack concluded, 

"Forty Seven Inc. is far from the only example of this kind of support and collaboration. We have always seen ourselves as far more than just a funding agency. Money is important, absolutely. But so too is bringing the experience and expertise of our team to help academic scientists take a promising idea and turn it into a successful therapy."

CIRM did not mention the amount of money provided to support the research. But it has awarded $15 million directly to Forty Seven. Weissman has received $30 million, much of which has played a role in Forty Seven's products.  

'Getting Stanford's Attention:' The Transcript of a $1.7 Million Matter

The California stem cell agency has posted online the 24-page transcript from last week's meeting during which the agency's governing board raised sharp questions about Stanford University and its obligation to provide co-funding on a $19 million award to one of its scientists.

The board voted unanimously last Thursday to condition additional millions for the research on receiving by May 1 the co-funding, which totals $1.7 million.

Just before casting his vote, Art Torres, vice chairman of the board and a former longtime state lawmaker, said, 

"I do think that we have put forward this motion in order to get Stanford's attention as to what their commitment has been in the past, and what it will continue to be given the nature of the arrangement that we made with them."

Stanford researcher Judith Shizuru sought $6 million for continuation of a phase one clinical trial to develop a potentially "transformative" product that would eliminate the toxic impact of chemotherapy for a number of diseases. 

The $3 billion agency reduced the amount that would be given to Shizuru to $3.75 million along with imposing the deadline for co-funding. 

The agency expects to run out of money for new awards by the end of this year. 

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.) 

California Stem Cell Agency Approves Assault on "Terrorizing" Affliction: Huntington's Disease

Frances Saldana, at a stem cell agency meeting last year, spoke emotionally about the loss of her three children to Huntington's disease. 

Directors of the California stem cell agency this morning approved $18 million in clinical stage research awards, including a "high risk" plan to tackle a degenerative brain disease for which there is no treatment.

Action on the proposal to create a therapy for the genetic disorder, Huntington's disease, came after a woman who lost all of her three children to the affliction said it has "terrorized my family for generations."

Frances Saldana of Fountain Valley, Ca., wept as she pleaded for approval of the $6 million effort to treat the disease that  lingers in her family. 

Another patient advocate, Bill Waddington, whose mother died from the affliction, told the agency in a letter, 

"Huntington’s disease isn’t just death.  It’s complete and utter devastation to families."

Maria Millan, president of the stem cell agency, said later in a news release that children born to parents with Huntington's have a 50/50 chance of getting the disease.

Huntington's affects 30,000 persons with another 200,000 at risk. It  progresses slowly. Symptoms are unrelenting and include inability to control movement and declining cognition leading to dementia, according to experts. Affected persons usually die within 15 to 20 years after diagnosis,. 

The applicant for state stem cell funding, Leslie Thompson of UC Irvine, told the board in a letter,

Leslie Thompson
UC Irvine photo

"Given the relatively slow progression of HD, care-giving stretches over 10 years or more after the patient loses independence. Patients become completely dependent on family and caregivers, who in turn have an emotional and debilitating economic burden managing the physical, cognitive and psychiatric manifestations of the disease.  

"HD can lead to catastrophic events such as homelessness, prolonged hospitalization awaiting placement, or long-term psychiatric placement. The length and severity of the disease has a profound financial and emotional impact on families and health systems. The direct medical costs and costs of disability and care giving for each patient are substantial and pass from one generation to the next."

Members of the governing board of the agency, formally known as the California Institute for Regenerative Medicine (CIRM), discussed the application at some length because of a split involving the application reviewers. The summary of comments by reviewers said,

"Reviewers disagreed on whether the treatment offers a significant value to the patients and caregivers. Some reviewers thought the immunosuppression and surgical risk that is required for this cell therapy may outweigh any potential therapeutic benefits given that there are other less invasive treatment options being tested. Others thought that despite the stated risks, any potential treatment for slowing down disease progression is worth pursuing as current alternative therapeutic approaches are still many years away from commercial use."

Last month, the agency's reviewers, meeting behind closed doors, approved the award on an 8-1-5 vote with five against funding, eight for funding and one saying the application needs improvement and could be resubmitted. The latest application was, in fact, a resubmission after changes were made to deal with reviewers' concerns.  The summary of the latest version described the effort as "high risk."

In one of the six letters of support for Thompson's research, Michael West, CEO of AgeX Therapeutics, Inc., of Alameda, Ca., said the work could have application in treatment of other neurodegenerative diseases such as Alzheimers and Parkinson's.

Six is a relatively high number of letters for the board to receive on an application.  Advocates dealing with Huntington's have been active in the past, appearing before the CIRM board on a number of occasions.

The second award today went to Everett Meyer of Stanford and totalled $12 million. It involves a clinical trial for renal failure. 

Here are links to review summaries for each application considered today, the principal investigator, institution and other information. 

Application number, CLIN1-10953; amount, $6.0 million; title, "An hESC-derived hNSC Therapeutic for Huntington’s Disease;" principal investigator, Leslie Thompson; institution, UC Irvine; review summary; letters of support, letter to the board CLIN1-10953, letter to the board #2 CLIN1-10953,​ letter to the board #3 CLIN1-10953, letter to the board #4 CLIN1-10953, letter to the board #5 CLIN1-10953, letter to the board #6 CLIN1-10953, letter to the board CLIN2-11431, other CIRM funding for the PI, $12 million.

Application number, CLIN2-11400; amount, $12.0 million; title, "Induction of Tolerance by Combinatorial Therapy w/ Donor Stem Cells and Expanded Recipient Treg cells in HLA-mismatched Kidney Transplant Recipients;" principal investigator, Everett Meyer; institution, Stanford; review summary; letters of support, none; other CIRM funding for the PI, none.

Action on the following application was put off until Feb. 21 to provide time to answer financial questions raised by board members today: 
Application number, CLIN2-11431; amount, $6.0 million; title, "A monoclonal antibody that depletes blood stem cells and enables chemotherapy free transplants;" principal investigator, Judith Shizuru; institution, Stanford; review summary; one letter of support; other CIRM funding for the PI, $20.4 million.