A California Stem Cell Tale: The Search for a Treatment for Paralyzing Spinal Injuries

Ed Wirth of Asterias, photo by Gabrielle Luri, SF Chronicle 

The San Francisco Chronicle, in a lengthy and dramatic article this week, reported on the story of the first clinical trial in the United States for a human embryonic stem cell treatment, a tale that continues today and well into the years ahead. 

The story involves paralyzing spinal injuries, incurable afflictions, walking rats, Geron, Asterias Biotherapeutics and BioTime and the economics of development of a stem cell therapy. That is not to mention the California stem cell agency, which has pumped more than $20 million into the effort.

The story was written by Erin Allday and is the third installment in a series involving stem cell research and treatments, both legitimate and illegitimate.

Her story began like this:

"Amid the controlled chaos of the operating room, Edward Wirth stood to the side, watching the surgeon slice open the back of the young man on the table....

"The surgeon nudged aside skin and a thin layer of muscle and clamped them out of the way. He chipped away bony vertebrae, exposing the shiny, smooth rope of the spinal cord. His scalpel slid into the membrane surrounding it.

"Wirth stepped forward, just beyond the surgeon’s shoulder, close by for these last steps. The surgical team moved a robotic arm holding a syringe into place. It was loaded with millions of immature support cells that had been meticulously crafted from stem cells, the cells that are the foundation of the human body, able to transform and reproduce indefinitely."

Wirth is a scientist who has been involved with the research since its early days at Geron of Menlo Park, Ca.. He has put in more than 20 years on the effort. Asterias Biotherapeutics of Fremont, Ca., which is associated with BioTime of Alameda, is currently handling the effort to create a treatment for spinal cord injuries.

The $3 billion California Institute for Regenerative Medicine (CIRM), as the agency is formally known, has provided a total of $20.7 million for the effort, first with Geron and now with Asterias.

Allday detailed the ups and downs, financial and scientific, of the research. She peered into the future and wrote that "it will take years to produce a marketable, federally approved therapy -- assuming their research makes it that far."

Nonetheless, she reported,

"Clinical trials like the one run by Asterias are scientists’ most ambitious attempts to harness the potential of what remains an elusive medical marvel. And the work at Asterias exemplifies both the incredible progress that’s been made in stem cell research and the great distance the field has yet to go before life-changing therapies are widely available.

"Riding on Asterias’ success isn’t just the fate of a single company or the careers of scientists like Wirth. Potentially, tens of thousands of patients every year could benefit directly from its therapy — and millions more if its research leads to further advances."

The fourth and final article in the Chronicle series is now scheduled to appear on Sept. 6  and will take a look at the California stem cell agency.

Stanford's Weissman Lauds California Stem Cell Agency For Innovation, Critical Financing

The California stem cell agency has chalked up hearty praise from an internationally known Stanford researcher for its 13-year, $3-billion search for stem cell therapies and cures.

Irv Weissman, Stanford photo

The scientist is Irv Weissman, director of the Institute of Stem Cell Biology and Regenerative Medicine at the Stanford University School of Medicine.  His laudatory reflections on the California Institute for Regenerative Medicine (CIRM), as the stem cell agency formally known, recently found their way to the Oakland-based enterprise. And last Monday the agency posted an item on Weissman's remarks on its blog, The Stem Cellar.  The article began,

"When you get praise from someone who has been elected to the National Academy of Sciences and has been named California Scientist of the Year you know you must be doing something right."

Weissman said the agency has provided the financial support that allows research to bypass "the valley of death," short hand for the stage in which promising research can often die. Plus, he said, CIRM allows the discoverers to guide early stage development rather than diverting it into commercial arena.

Weissman's comments spoke to what the agency calls its "value proposition," a term that is becoming increasingly important as the agency faces its possible demise. The agency expects to run out of cash for new awards by the end of next year. It is trying to raise more than $200 million privately to continue operations until November 2020, when it hopes voters will approve $5 billion more for stem cell research.

CIRM's blog item was authored by Kevin McCormack, CIRM's senior director of communications,  in the context of a $115 million initial public stock offering by Forty Seven, Inc., of Menlo Park, Ca., a company founded on the basis of Weissman's work. Weissman is currently a member of the company's board.

Forty Seven has received $15.2 million from CIRM. Weissman has received $32.4 million.

Weissman said in the statement that CIRM carried,

"The major support (for Forty Seven) came from the California Institute of Regenerative Medicine (CIRM), funded by Proposition 71, as well as the Ludwig Cancer Research Foundation at the Ludwig Center for Cancer Stem Cell Research at Stanford. CIRM will share in downstream royalties coming to Stanford as part of the agreement for funding this development.

"This part of the state initiative, Proposition 71, is highly innovative and allows the discoverers of a field to guide its early phases rather than licensing it to a biotech or a pharmaceutical company before the value and safety of the discovery are sufficiently mature to be known. Most therapies at early-stage biotechs are lost in what is called the ‘valley of death’, wherein funding is very difficult to raise; many times the failure can be attributed to losing the expertise of the discoverers of the field.”

In response to a question from the California Stem Cell Report, McCormack said Weissman's statement came "unbidden" by the agency.  We asked Weissman about what led him to issue the remarks. Weissman said he said he had not seen the CIRM piece, but responded after reading it.

He said in an email, 

"Now that I’ve seen the quote, it is close to what I sent to colleagues at Stanford. I did it so that my colleagues understood the nature of the CIRM experiment in funding research and its translation. One of these colleagues sent it on to CIRM, and I didn’t object.

"I think its very important to know how the original Prop 71 was designed not only to fund stem cell related research, but also to take selected projects competitively reviewed by expert referees to and through phase 1 trials if warranted. The therapy that was developed at Stanford by the team led to the discovery team forming a disease team of experts usually only found in biotechs and pharma, but here led by the discoverers of the leukemia stem cell overexpressed molecule, CD47, which by its ‘don’t eat me’ actions protects the leukemia from removal by scavenger macrophages. The CIRM oversight team helped guide selection of outside advisors, and met frequently with us to monitor our progress, and most importantly, give us advice that led to Stanford filing two INDs on time in the US [FDA] and the UK[MHRA]. The importance of doing high level preclinical testing and toxicity etc without a profit motive allowed the team to keep going when surprising events came up. Many biotechs fail at that point, as the risk starts to worry investors and shareholders. But this went through, and in addition to getting into important phase 1 trials that broadened the potential cancer targets to cancers beyond myelogenous leukemia, the group could see how the therapy needs to be administered to avoid toxicity in patients. By the time Stanford informed us it was time for them to license the ip, many independent companies had formed around the concept discovered by the team, a validation that this could become the second type of checkpoint inhibitor therapy for human cancers, this time for macrophages instead of inhibited T cells. 

"I felt it was equally important to try to get the agency that funded these stem cell related efforts to share royalties with the academic institution that held and licenses the intellectual property; I first raised this issue in 1994 when I was President of the American Association of Immunologists; my article is attached here.

"Most of us hope the discoveries we make can have the potential to help patients with diseases that are only incompletely treated by current medical practice. Very early results of clinical trials reported in the ASCO meeting in early June are consistent with that possibility. 

"I need to make clear that the statement in the blog was written by me, and was not an official document of Stanford University, of Forty Seven, Inc, or from others from the discovery team. If you decide to publish this answer to your question, please either publish it in full, unedited, or don’t publish it at all. I didn’t write this for you to publish, but for you to understand from your question the reason I wrote the original document to colleagues at Stanford."

Stem Cell 'Ethical Tensions,' Recouping the Public Investment, Affordability and Much More

"Staggering" amounts of public money have been spent on stem cell research, and "care must be taken" to assure that commercialization does not exact an excessive "human or monetary price," according to an article this week in the journal Science.

The cautionary note was sounded in the prestigious publication while the world's largest stem cell gathering is underway in Australia with more than 2,500 researchers and others in attendance. Plus next week, the $3 billion California stem cell agency convenes its directors to mull over its own programs and give away more millions. 

Written by Douglas Sipp, a researcher at RIKEN in Japan, Megan Munsie of University of Melbourne and Jeremy Sugarman of John Hopkins University, the Science article said

"Ethical tensions related to stem cell clinical translation and regulatory policy are now center stage...."

They said that expedited government procedures for use of stem cell treatments have been set up in the United States, Japan and Italy. At the same time, they wrote, 

"A staggering amount of public money has been spent on stem cell research globally."

The article declared, 

"The state and the taxpaying public's interests should arguably be reflected in the pricing of stem cell products that were developed through publicly funded research and the regulatory subsidies. Detailed programs for recouping taxpayers' investments in stem cell research and development must be established."

They warned, 

"Care must be taken to ensure that entry of stem cell–based products into the medical marketplace does not come at too high a human or monetary price."

Another journal article this week also sounded cautionary notes. Written by Paul Knoepfler of UC Davis, it was titled: 

"Too Much Carrot and Not Enough Stick in New Stem Cell Oversight Trends"

Knoepfler addressed the Food and Drug Administration's efforts to speed use of stem cell therapies. He wrote in Cell Stem Cell and also on his blog, saying,

"It’s been remarkable to see the FDA approve up to 20 regenerative medicine advanced therapy(RMAT) designations in just over a year. However, I think there’s a strong possibility the agency has swung too far from the too slow review of stem cell and regenerative medicine investigational therapies in the past to now going at warp speed. Since none of the current 20 designated RMAT products had any kind of prior expedited review designation given, is it reasonable to think all 20 now meet rigorous enough standards and all because of new data? It’s hard to say, but there’s likely a spectrum of existing data behind these RMAT designated studies.

"We won’t have an overall RMAT verdict for years as the RMAT trials play out. However, I predict that the agency has lowered the bar too far. There are also concerns that the conditional approval system in Japan is too liberal, as evidenced by discussion over the approval of a recent IPS cell cardiovascular study. Taken together this is what I mean by 'too much carrot.'  Another issue with RMAT is that the criteria by which the designations are given (or not) are not clear." 

Next Thursday, the governing board of California's $3 billion stem cell agency is scheduled to meet to give away more millions for stem cell research in the Golden State. The agency will also be examining the non-scientific considerations that it uses in deciding which applications to fund. It may be that some of the issues raised by these four researchers will also come into play.

Viral Power: California Stem Cell Agency Hits 6K with Cyberspace Event on Stroke Therapy

Here is the Facebook Live event produced by CIRM. The number in the left hand 

corner is not static. It changes as the video is viewed by more persons. 

The $3 billion California stem cell agency last week mounted its first "Ask the Experts" session on Facebook, a look at a stroke therapy that left one patient crying with joy and  researchers "shocked" at the initial, beneficial results.

The Facebook Live event dealt with a stem cell treatment for the most common form of strokes, which claim 750,000 victims annually. It is the leading cause of disability in this country and third leading cause of death.

The webcast at noon last Thursday drew only about 80 viewers, the agency reported. But by late Monday, Facebook statistics showed that it had been viewed more than 6,400 times (more than 6,500 by this morning). The figures demonstrated the viral power of Internet communications in spreading the stem cell agency's message. Not to mention that it could help to stave off the agency's financial demise.

Featured on the webcast were researcher Gary Steinberg of Stanford University, whose work has been supported by $24 million from the agency, and Sonia Coontz of Long Beach, Ca., who said she wept after treatment in the clinical trial as she experienced immediate improvements. Steinberg said his team was "shocked" by the rapidity with which some patients improved from their ischemic strokes.

More than 172 comments were made during the session. Some simply sought more information. Others waxed euphoric. Lisa Bayha Deck, wrote on Facebook,

"I’m a patient of Dr. Steinberg’s and so thankful for his professionalism. He gave me my life back after four strokes and Moyamoya Disease."

The Facebook event was the latest effort by the agency, formally known as the California Institute for Regenerative Medicine (CIRM), to educate the public about the work it is financing. However, the agency expects to run out of cash for new awards by the end of next year. It hopes that voters will provide it with $5 billion more in state bond funding via a ballot measure in November 2020. 

During the event, Lila Collins, a senior scientist at CIRM, provided an overview of key stem cell trials around the country. Kevin McCormack, senior director of communication at CIRM, moderated and produced the session.   

Following the event, McCormack said he thought it went well for an initial effort, although he said he was caught up in the mechanics of handling the session. On Monday, McCormack said, 

"We are going through the stats now and plan on putting together a roundup of views, comments, etc. We are also planning on posting a blog about the event – with answers to questions we didn’t get around to during the hour – so that should be coming in the next few days."

Prior to the webcast, the California Stem Cell Report asked McCormack to elaborate on the agency's Facebook effort. Here is a lightly edited version of that email interview. 

Q: Is this the first such event for CIRM? 

A: It’s the first Facebook Live event we are doing. A few years ago we did a similar series using Google Hangout. We featured a number of our experts in ALS and cancer, heart disease etc. but that wasn’t as easy to do technically. Facebook Live is simpler and because so many more people are on Facebook on a regular basis it will hopefully allow us to reach a wider audience. 

Q: Why is CIRM doing this event? 

A: It’s just part of our outreach efforts to let people know how stem cell research is progressing and the role that CIRM is playing in advancing that. We have been doing similar things for years, reporting back to the people of California on the work we are doing. We do it regularly with in-person patient advocate meetings, and with talks and presentations all around the state so we just wanted to take advantage of this technology to see if we could reach a wider audience.

Q: Will it be saved on the CIRM web site for future viewing?

A: One of the great features of Facebook Live is that it is automatically saved at the end and you can watch them on Facebook again and again. And yes, we’ll be putting links to them on our website but the easiest way to find them is to just go to our Facebook page.

Q: How did this originate?

A: We are always looking for new ways to reach out to a wider audience and let people know about CIRM’s help in advancing stem cell research. We looked at Facebook Live and thought it could be a great tool for us. We are already on Facebook anyway so this was a natural extension.

Q: And, finally, is there anything else you want to say about this event and its significance? 

A: Earlier this year we held a patient advocate event at UC Riverside. It was our first excursion to the Inland Empire and we had a great crowd, more than 100 people showed up on a weekday. But our goal is always to reach as many people as possible, and so we are always exploring new ways, new tools to do that. 

Much as we would like to, we don’t have the staff or budget to travel constantly around the state doing in-person meetings so this is a great way of achieving the same goal in a much more efficient manner. The people of California put a lot of faith in us when they approved $3 billion in funding for stem cell research. As we see that funding really help accelerate the field – we have 49 projects that we funded in clinical trials, we are seeing patients cured of life-threatening diseases – we want to share that news with as many people as possible.

California Stem Cell Agency and First-of-Kind Fetal Transplant for Fatal Affliction

Nichelle Obar and her daughter, Elianna, at three weeks. NYT photo by Bryan Meltz

A uniquely California medical treatment -- the first of its kind in the world -- won national attention today with reports that it could open the door to similar operations before birth for such diseases as sickle cell and hemophilia.

The therapy was developed by a UC San Francisco researcher who treated "the first patient enrolled in the world’s first clinical trial using stem cells transplanted prior to birth," according to a UCSF news release.

Fetal surgery was also invented in California. And the transplant was backed by $11 million from the state's stem cell agency, a $3 billion enterprise that is unique among states in its size and scope.

Missing from the news, however, was any mention of the agency's multimillion-dollar contribution -- a not insignificant matter since the agency is facing its own financial demise in less than two years. The agency hopes voters will keep it alive and approve $5 billion more for stem cell research in 2020. The agency, however, is laboring under a lack of public awareness for its "value proposition." (See here and here.)

The research is being conducted by Tippi MacKenzie, a pediatric and fetal surgeon who has received a total of nearly $15 million from the agency. Her employer, UC San Francisco, has received $169 million in 81 awards.  Various deans of its medical school have also served on the agency's governing board since the inception of the agency, known formally as the California Institute for Regenerative Medicine (CIRM).  

A spokeswoman for UCSF said omission of the CIRM funding in its news release was not intentional. 

The agency was not mentioned also in a lengthy article on MacKenzie's research in the New York Times this morning. The piece was displayed on the front page of the weekly Science section of the Times, a prestigious position available only 52 times a year.

MacKenzie's work involved a family from Hawaii and their child, who was treated in utero for a nearly always fatal affliction. 

In the article by Denise Grady, the Times reported, 

"Elianna, born Feb. 1 with a robust cry and a cap of gleaming black hair, has a genetic disease that usually kills a fetus before birth. The condition, alpha thalassemia major, leaves red blood cells unable to carry oxygen around the body, causing severe anemia, heart failure and brain damage.

"The transfusions in the womb kept her alive, but only treated her illness. The bone-marrow transplant has the potential to cure it. Whether it will succeed is still too soon to tell.

"Elianna and her mother, Nichelle Obar, were the first patients in an experiment that pushes the limits of fetal therapy, a field already known for its daring."

The Times continued, 

"If the treatment works, it could open the door to using bone-marrow transplants before birth to cure not just Elianna’s blood disease but also sickle cell anemia, hemophilia and other hereditary disorders, some so severe that the prenatal diagnosis may lead parents to end the pregnancy.

"Bone marrow is considered a potential cure because it teems with stem cells, which can create replacements for cells that are missing or defective as a result of genetic flaws."

Asked for comment by the California Stem Cell Report, Maria Millan, president of CIRM and a pediatric surgeon, said in an email, 

“The New York Times picture of Nichelle Obar with her 3 week old daughter Elianna shows us something that’s hard to capture in a billion words.(See photo above.)  Elianna is afflicted with alpha thalassemia major, a fatal condition that usually ends up in death before birth.

"It is extremely gratifying to know that CIRM has been instrumental in supporting Dr. McKenzie’s research to develop a treatment for this severe unmet medical need. Dr. McKenzie’s approach combines surgical advances that allow her to treat the baby while still in the mother’s womb; transplantation with the mother’s blood stem cells provides healthy blood cells that the baby needs to survive. 

"We have supported Dr. McKenzie’s research from the early years when she was a new faculty working out the basic science and immunology in the laboratory and we helped her to develop her clinical plan. Most recently, we have partnered with Dr. McKenzie to bring this research to clinical trials. To see Ms. Obar take their child home from the hospital is encouraging. We know that this is just the beginning. This is what the people of California voted for when they approved Proposition 71. They depend on us to boldly partner with Dr. McKenzie to translate the promise of stem cell treatments to patients with unmet medical needs."

The phase one clinical trial, which is aimed primarily at safety, is scheduled to release its preliminary results by February 2022 and hopes to treat another nine patients. The treatment would then face another two phases of clinical trials for efficacy. 

As for the baby, her mother told the Times, 

“Elianna’s doing great. I’m not disappointed at all. If it works, great. If it didn’t, we’re O.K. with it. We’ll celebrate all the little accomplishments. I’m glad we did it."

Here is a UCSF video on the trial.

Incontinence to Cancer: California Kicks in $26 Million for Stem Cell Research

The California stem cell agency this week awarded more than $26 million in its hunt for treatments for afflictions ranging from cancer and incontinence to osteoporosis and eye disease.

The $3 billion agency's board ratified the five research grants in a 30-minute, telephonic meeting on Thursday with little debate. The applications were previously approved behind closed doors by the agency's out-of-state scientific reviewers.

The largest award -- $12 million -- went to a team at UCLA led by Steven Dubinett for a phase one clinical trial. The agency, formally known as the California Institute for Regenerative Medicine (CIRM), said in a news release:

Steven Dubinett, UCLA photo

"The team is using the patient’s own immune system where their dendritic cells – key cells in our immune system – are genetically modified to boost their ability to stimulate their native T cells - a type of white blood cell - to destroy cancer cells. 

"The investigators will combine this cell therapy with the FDA-approved therapy pembrolizumab (better known as Keytruda) a therapeutic that renders cancer cells more susceptible to clearance by the immune system."

The research application approved this week that would likely have the most widespread application involved urinary incontinence. The $6 million award went to a Stanford team led by Bertha Chen. CIRM said,

Bertha Chen, Stanford photo

"Despite being one of the most common indications for surgery in women, one third of elderly women continue to suffer from debilitating urinary incontinence because they are not candidates for surgery or because surgery fails to address their condition. 

"The Stanford team is developing an approach using the patient’s own cells to create smooth muscle cells that can replace those lost in UI. If this approach is successful, it provides a proof of concept for replacement of smooth muscle cells that could potentially address other conditions in the urinary tract and in the digestive tract."

Here is the full list of winners and links to the summaries of the reviews of their applications and their scores. The review summaries other than the one for Dubinett can be found on a single document, which also contains the review summaries of the 10 rejected applications:

• Steven Dubinett, UCLA, $12 million, application number CLIN2-10784, review summary, title advanced non–small cell lung cancer, co-funding not required but $400,000 provided
• Bertha Chen, Stanford, $6 million, application number TRAN1-10958, review summary, title Autologous iPSC-derived smooth muscle cell therapy for treatment of urinary incontinence, co-funding not required
• Cassandra Calloway, Children's Hospital Oakland Research Institute, application number TRAN2-10990, review summary, target development of a noninvasive prenatal test for beta-hemoglobinopathies for earlier stem cell therapeutic interventions. co-funding not required
• Farhad Parhami, Max BioPharma of Santa Monica, Ca., $1.7 million, application number TRAN1-10937, review summary, title therapeutic development of an oxysterol with bone anabolic and anti-resorptive properties for intervention in osteoporosis, co-funding not required
• Magdalene Seiler, UC Irvine, $4.8 million, application number TRAN1-10995, review summary, title morphological and functional integration of stem cell derived retina organoid sheets into degenerating retina models, co-funding not required

Here is a link to an LA Business Journal story on the award to BioPharma.

Alpha Clinic Kickoff: Launch of Capricor Trial for Duchenne in $50 Million California Stem Cell Network

UC Davis this week inaugurated its Alpha Clinic program, part of a $50 million, statewide network created by California's 13-year-old stem cell research agency.

The school kicked off its program with the start of a "HOPE-2" clinical trial for Duchenne muscular dystrophy – a fatal genetic disorder mainly affecting boys and young men. About 200,000 persons worldwide suffer with the affliction. There is no cure. Treatment options are limited.

Craig McDonald
UC Davis photo

The lead trial investigator, Craig McDonald of UC Davis, said in a news release,

"Collaborating with the Alpha Clinic team enables us to capitalize on their research infrastructure and expertise for clinical trials focused on cell-based therapies.

"It complements the skills of UC Davis’ Neuromuscular Research Unit, which is a national leader in conducting Duchenne trials. We believe this unique partnership could be a model for translating stem cell discoveries into meaningful treatments for patients with muscular dystrophy and other serious progressive neurologic diseases.”

The trial will test the safety and efficacy of a therapy developed by Capricor, Inc., of Beverly Hills -- CAP-1002. The state's stem cell agency, formally known as the California Institute for Regenerative Medicine (CIRM), in 2016 awarded the firm $3.4 million, part of a total of $17.8 million that the firm has received from the state. CIRM has also awarded another $7 million to Cedars-Sinai for early development work that led to the creation of Capricor.  

(Here is a link to the summary of the review of the Capricor application, CLIN2-08334, submitted by Deborah Ascheim, chief medical officer at Capricor.)

CIRM governing board member Jeff Sheehy said in 2016,

"This is pretty much a pure CIRM product. They came into our first disease team to develop the product. We've supported two of the three clinical trials. So if this turns out to be a major success, this will be a real feather for CIRM. We've been with them all the way. So I'm optimistic."

Linda Marban, president of the firm, said in a news release that the research is "one of the very few clinical initiatives to focus on helping boys and young men whose ability to walk has been seriously impaired by the loss of muscle function that occurs as Duchenne muscular dystrophy progresses."

Capricor is a publicly traded firm, whose stock closed at $1.32 today. The 52-week high on the stock was $4.25 and its  52-week low 63 cents.

The Alpha Clinics are one of the signature programs of the stem cell agency. In addition to Davis, UC San Francisco, the City of Hope, UCLA, UC Irvine and UC San Diego are part of the network. UC Davis last year received $8 million from CIRM to help create its program. 

California Hits More Than Half-Billion Dollars in Stem Cell Clinical Trials

The stem call agency has an interactive dashboard on its web site, part of which is seen above.

The California stem cell agency this week boosted the number of its clinical trials to 48 -- representing an investment of $553 million -- with the hope of producing its first widely available stem cell therapy and staving off its own demise.

In a 14-minute, telephonic meeting Thursday, directors of the agency ratified three new awards totalling $32 million and increasing its trials from 45. The applications had been approved earlier behind closed doors by the agency's out-of-state reviewers.

The action left the agency, known formally as the California Institute for Regenerative Medicine (CIRM), with $224 million in uncommitted funds, CIRM said in response to a query. The agency was provided with $3 billion when it was created in 2004 by California voters. The $224 million figure could rise $278 million with "recovery" from cancelled grants.

Nonetheless, CIRM expects to run out of cash for new awards by the end of 2019. It is attempting to raise $220 million privately to tide it over until November 2020, the date when voters may be asked to approved an additional $5 billion in bond funding.

Thursday's brief meeting generated no fresh discussion about the financial future of the agency, which is unique in California history and operates with no oversight by the governor or the legislature. Nor was there any discussion of the applications for research funds. 

CIRM said in a news release this morning that while the agency has backed 48 trials, only 42 are active. It has also funded early stage research in 11 additional projects that moved later into the "clinical trial stage" without additional CIRM support. 

The directors made their award decisions Thursday based on a brief CIRM staff presentation and summaries of the reviews of the applications. 

Links to the summaries, the winners and their awards are below. Go to the summaries by clicking on the application number. Updates on the status of CIRM research can also be found as it progresses by searching on the application number.

Sangamo Therapeutics, Inc., of Richmond, Ca., was awarded $8 million to "test a new therapy (phase one/two) for beta-thalassemia, a severe form of anemia (lack of healthy red blood cells) caused by mutations in the beta hemoglobin gene."

The agency said,

Edward Conner
Sangamo photo

"Patients with this genetic disorder require frequent blood transfusions for survival and have a life expectancy of only 30-50 years."

The company, which announced a secondary stock offering of more than $200 million this week, is providing $15 million in co-financing. Its stock closed at $16.75 on Friday. Its 52-week high is $27.50 and its low $4.25. 

The principal investigator is Edward Conner, chief medical officer of the firm, and the application number is CLIN2-11031. 
The company said in a news release that the work also involved Bioverativ.

Stanford University researchers received $12.3 million and provided $2.3 million in matching funds for a a phase one trial for a CAR-T therapy for "patients with B cell leukemias who have relapsed or are not responding after standard treatments, such as chemotherapy."

Maria Millan, president of CIRM, said in the news release,

Crystal Mackall
Stanford photo

“When a patient is told that their cancer has returned it can be devastating news. CAR-T cell therapy is an exciting and promising new approach that offers us a way to help patients fight back against a relapse, using their own cells to target and destroy the cancer.”

The principal investigator is Crystal Mackall and the application number is CLIN2-10846. 

(Here is the link from Stanford on the award. The link was added on April 30 to this item after its initial publication.)

Morton Cowan
UCSF photo

UC San Francisco researchers received $12 million (with no co-funding) for a phase one trial to test a treatment "to restore the defective immune system of children born with severe combined immunodeficiency (SCID), a genetic blood disorder in which even a mild infection can be fatal" and which is often known as "the bubble baby disease."

CIRM said it has"funded two other clinical trials targeting different approaches to different forms of SCID. In one, carried out by UCLA and Orchard Therapeutics, 50 children have been treated and all 50 are considered functionally cured."

The principal researcher is Morton Cowan and the application number is CLIN2-10830.

Weighing California's Stem Cell Trials: An Update from the Golden State's Stem Cell Agency

A sample from the latest information from CIRM on its clinical trial investments. 

California's $3 billion stem cell agency has posted a fresh overview of the 45 clinical trials that it has invested in, ranging from spinal injuries to kidney transplants.

The update is part of the agency's push to better inform the public as well its governing board of the scope and status of its 13-year-old efforts. The clinical trials carry special weight as the agency faces its demise unless it is successful in raising $220 million privately and winning voter approval of a proposed $5 billion bond issue in November 2020.

The Oakland-based agency, formally known as the California Institute for Regenerative Medicine (CIRM), expects to run out of cash for new awards by the end of 2019. Its only funding has been the $3 billion in bonds approved by voters in 2004. The ballot initiative provided no additional source of financing to carry it into the future.

Clinical trials are critical for the agency as it approaches the date when it must ask for more billions. They are the last stage before a therapy is approved for widespread use by the federal government. But even then, a trial can take years. And nine out of 10 proposed, "normal" -- non stem cell -- therapies fail during the clinical trial process, according to studies.  Stem cell trials are so new that their failure rates has not been fully examined.

CIRM is hoping for results in the next year or so that will resonate with voters and lead them to approve additional funding.

The five-page, clinical trial overview sorts the trial information by disease, dollar amount, benefit and date among other things. (See sample of the layout above.) The agency also has additional useful information on its trials on what it calls its clinical trials dashboard, an interactive web page that allows readers to slice and dice the information.

The fresh document on the trials was released as part of the agenda for tomorrow's CIRM meeting during which its governing board is expected to approve $32 million for three additional trials. 

California's $3 Billion Stem Cell Program Partners with BlueRock and Vivo Capital, Looks for More Industry Collaborators

California's drive to produce a stem cell therapy is ratcheting up a notch with announcement of  two new, global industry partners along with a plan to engage more companies and give them "direct access" to hundreds of millions of dollars in state-funded research.

The California Institute for Regenerative Medicine (CIRM), as the $3 billion state stem cell agency is formally known, said the program represents an opportunity "to bring the most promising stem cell, gene therapy and regenerative medicine programs to market where they can help people with unmet medical needs."

The first two participants are BlueRock Therapeutics of  Cambridge, Ma., with offices in Toronto and New York City, and  Vivo Capital of  Palo Alto, Ca., which has offices in Bejing, Shanghai and Tapei. BlueRock was founded in 2016 with $225 million in backing from Versant Ventures and Bayer AG. Vivo has more than $1.7 billion under management, according to the firm's web site.

In addition to venture capital firms, the agency said its Industry Alliance Program (IAP) is looking for pharmaceutical and biotech partners to give them "direct access to CIRM’s growing stem cell portfolio."

Maria Millan, CEO and president of CIRM, said in a news release,

Maria Millan

"The goal of the IAP is to secure industry partnerships and funding for CIRM’s translational and clinical-stage projects. Our agency provides researchers the initial funding to advance promising projects towards the clinic. Now, we’re going a step further by offering a program that facilitates connections between industry partners and our grantees. These companies can offer the support or additional funding needed to give these promising projects the best chance for success and the best chance of helping patients.”

The stem cell agency is nearing its final days and is looking to fulfill promises to California voters who created it 13 years ago through a ballot initiative. The measure provided $3 billion in state bond funding, but no more. The campaign also generated expectations that stem cell cures were just around the corner. The agency has yet to back a therapy that is widely available.

The agency expects to run out of cash for new awards by the end of next year. A $220 million private fundraising effort is being waged to help the agency along until November 2020. That's when CIRM backers hope that the agency's efforts will excite California voters enough for them to approve $5 billion more in funding via another citizen-based initiative.

Deeper involvement with industry is one way to produce quicker results. Venture capital firms are willing to move fast and bet big on research that they deem likely to produce handsome profits.

BlueRock focuses on cell therapies that target severe brain and heart conditions.  According to Biospace, the company expects its most advanced lead therapeutic, a compound for Parkinson’s disease, to begin clinical trials this year.

Vivo focuses on high quality companies in the United States and China but includes building companies from scratch. 

California also brings something to the game.  Karen Ring, the agency's Internet majordomo, noted last week on the agency's blog,

"CIRM is the world’s largest stem cell research funding institution dedicated to helping patients by accelerating the development of quality stem cell treatments. We’re currently funding 244 active stem cell research programs including 39 ongoing clinical trials."

Neil Litman, the agency's director of business development, said CIRM has a "unique vantage point" because of its broad scope. He said the new program is "essentially a built-in concierge service for the stem cell space."

Media Coverage of Stem Cell Therapy for Blindness Loses Sight of California's $36 Million in Support

Dennis Clegg of UC Santa Barbara, one of the leaders in developing a new stem cell treatment for AMD, speaks broadly about the approach in this 2016 video.

The news this week was good for the $3 billion California stem cell agency, which is facing its possible demise in less than two years.

The stories demonstrated what the CEO of the agency, Maria Millan, calls the "value proposition" of the agency's work for the people of California. But only if the agency is mentioned in the news coverage.

Public perceptions are no small matter for supporters of the research agency, formally known as the California Institute for Regenerative Medicine (CIRM).  They wonder as does Millan: How does the agency get real and robust credit for its work, a likely life-or-death question given the agency's hopes to win voter approval of $5 billion more in funding in 2020?

CIRM says it is on track to run out of cash for new awards by the end of 2019 unless its ambitious fundraising plans are successful. And those are only a partial solution until billions more are provided by California citizens.

This week's "good news" stories generated national attention, albeit relatively modest, about CIRM-funded research that has led to to the first-in-human clinical trial for dry, age-related macular degeneration. The treatment uses technology that was described as "very exciting" by one researcher not connected with trial.

The headline on the New Scientist story on Wednesday said,

"Eye implant improves vision in people with age-related blindness"

Reporter Andy Coghlan wrote, 

"A patch implanted at the back of the eye has improved or stabilised sight in four people with severe age-related macular degeneration. The treatment enabled one 69-year-old woman to read 24 letters on a standard eye chart, when she could previously manage only seven.
"The patch is made of eye cells made from human embryonic stem cells, and it has been designed for treating the 'dry' form of macular degeneration, which accounts for 90 per cent of all cases, and affects 1.7 million people in the US."

Nowhere in the New Scientist story was it mentioned, however, that the state of California, through its stem cell agency, has pumped $36 million into the work. 

Likewise for the Los Angeles Times, whose story also did not mention the agency.  And likewise for articles on MIT Review, MedicalXpress, HealthDay, WebMD, US News and World Report, Futurism and FierceBiotech. The list could go on, but you get the idea.

Even the press release from Regenerative Patch Technologies LLC of Portola Valley, Ca., which holds the exclusive license for the implant, buried the Golden State's contribution in the next-to-last paragraph of a nine-paragraph press release.   Plus the company failed to note that the funding was a not insignificant $36 million.

FierceBiotech did mention some private money that was involved in other AMD research, but ignored California's cash.

Readers not familiar with the traditions surrounding news stories about medical research might wonder why the California support received almost no attention. Generally speaking, the amount of cash and the funding source are all but ignored in such stories with some notable exceptions. How that has come about is not clear, but money talks in most circles. The scientist who has lost his or her appointment by failing to bring in sufficient grants can speak to that.

For the California stem cell agency, it is also likely to be a matter of survival. If it fails to receive the widespread public credit for what it believes is a strong and important body of work, it is likely to wither away in very short order. 

$30 Million Cash Infusion for San Diego Firm, On Top of $20 Million from California Stem Cell Agency

A recent recipient of nearly $20 million from the California stem cell agency is on a financial roll this week as it pursues its efforts to translate what it says are "best-in-class gene therapy technologies into lifesaving cell therapies."

The firm is Poseida Therapeutics, Inc., of San Diego. Last October, it was awarded $19.8 million by the California Institute of Regenerative Medicine (CIRM), as the stem cell agency is formally known.

Poseida said yesterday it has hauled in $30.5 million more. The firm said in a news release that the cash will go to "advance a pipeline of autologous and allogeneic CAR-T immunotherapies, as well as gene therapies, using Poseida’s suite of gene engineering technologies."

The firm said its CIRM-backed "P-BCMA-101(product) is a CAR-T therapy currently in Phase 1 clinical development for relapsed/refractory multiple myeloma, with initial clinical data accepted for presentation at the upcoming AACR (American Association for Cancer Research) Annual Meeting." The firm is also tackling prostate cancer.

Jack Murtha of Health Care Analytics News wrote,

"It’s a good day for Poseida Therapeutics, one of the trailblazing precision medicine ventures that aims to transform cancer treatment through cutting-edge gene-editing technologies. But just how good of a day is it? Try $30.5 million good."

Murtha said the company has now raised more than $80 million for its endeavors, including the CIRM award, venture capital of $11.2 million last August and $23 million in 2015. The bulk of today's funding came from Longitude Capital of Menlo Park.

At the time of the CIRM award last fall, Maria Millan, president of CIRM, described the nature of the problem that Poseida was addressing, 

“Multiple myeloma disproportionately affects people over the age of 65 and African Americans, and it leads to progressive bone destruction, severe anemia, infectious complications and kidney and heart damage from abnormal proteins produced by the malignant plasma cells. Less than half of patients with multiple myeloma live beyond 5 years.”

Last fall, CIRM reviewers, meeting behind closed doors, unanimously approved, 10-0, Poseida Therapeutics application (CLIN2-10395), which included Poseida's commitment to provide $8.6 million in co-funding. The agency's governing board later ratified the decision with no discussion.

A public, CIRM-prepared summary of the reviewers' comments said, 

"Reviewers thought that the proposed product has the potential to provide a very high rate of durable response in myeloma patients. There is strong scientific and clinical rationale for targeting BCMA on myeloma cells. Reviewers thought that the proposed improvements to the CAR T cell platform technology are highly innovative and could enhance the efficacy and durability of the treatment. Reviewers unanimously recommended the application for funding."

California's Stem Cell Agency Hits 45 Clinical Trials

Directors of the $3 billion California stem cell agency yesterday added another clinical trial to its portfolio, bringing to 45 the number of its forays into the late stage research that is the most likely to produce a therapy sooner rather than later.

The decision on the $5.7 million award carries more weight in terms of the viability of the agency than might ordinarily be assumed. The agency's cash is running out. It is facing its demise in less than two years unless prodigious funding raising efforts are successful.

One of those efforts involves asking California voters in the fall of 2020 for $5 billion more in bond funding. The California Institute for Regenerative Medicine or CIRM, as the agency is formally known, would dearly love to point to a therapy or cure that would resonate with voters.

Thursday's award went to Joseph Rosenthal, director of pediatric hematology and oncology at the City of Hope and lead investigator on the trial. He told the agency,

"CIRM funding will allow us to conduct a Phase 1 trial in six adult patients with severe SCD (sickle cell disease). We believe this treatment will improve the quality of life of patients while also reducing the risk of graft-versus-host disease and transplant-related complications. Our hope is that this treatment can be eventually offered to SCD patients as a curative therapy.”

CIRM directors also approved a $4 million award to Fate Therapeutics, Inc., of San Diego, a publicly traded firm that is developing a "natural killer" cell cancer immunotherapy derived from induced pluripotent stem cells.

CIRM said that the goal is to treat many patients in an "off-the-shelf manner." The firm hopes to launch a clinical trial in 2019. Fate's stock closed at $10.58 today, down one cent. Its 52-week low is $2.52 and its 52-week high $11.70.

Here is a link to CIRM's press release on the awards. Here is a link to the CIRM blog item on the matter. Here is a link to the Fate Therapeutics press release which the company posted this morning.

Advancing Science, Avoiding Harm: New Fed Rules to Raise Curtain on Clinical Trial Results

The Wall Street Journal today carried a piece about sweeping, new federal research disclosure rules aimed at beefing up the public accessibility of findings of clinical trials backed by billions in public dollars.

The regulations are targeting what Francis Collins, head of the National Institutes of Health (NIH), has called a "disappointing" record of publishing clinical trial results.  He said that "both real and potential harm can result from failure to fully disclose the results of clinical trials."

The regulations are scheduled to roll out somewhat slowly but have been more than 20 years in the works. The Journal reporters, Daniela Hernandez and Amy Dockser Marcus, wrote online today,

"The new rules are part of a push for greater transparency and accountability for the NIH's huge investment in biomedical research. In the past, many organizations have failed to properly register studies and report their findings, actions that NIH officials say result in misspent funds, potential human harm and a lack of public trust in science. The NIH spends roughly $3 billion annually on clinical trials."

Violation of the rules carries the possibility of fines running up to thousands of dollars a day plus endangerment of future funding from the NIH.

Already at one California university, the requirements have increased the workload. The WSJ reported,

"Stanford University School of Medicine is 'adding five or six full-time employees to our overall infrastructure for human research,' said Mark Cullen, senior associate dean for research.

"Dr. Cullen said many of his researchers are still worried and confused about how the new policies will affect their work; the new hires are meant to add to an existing support system made up of roughly 100 staffers."

The NIH is particularly interested in reporting research that has negative results. The WSJ wrote,

"Under the old rules that required publication in journals, negative results often remained undisclosed because journals prefer to publish positive findings.

"'The release of negative results not only prevents duplication and potential unnecessary risk to human volunteers, it also advances our understanding of the science,' said NIH’s Dr. (Carrie) Wolinetz (NIH's associate director for science policy).

In 2015, Collins and Kathy Hudson, then NIH's deputy director for science, outreach and policy and now executive director of the People-Centered Research Foundation, wrote in JAMA,

"If the clinical research community fails to share what is learned, allowing data to remain unpublished or unreported, researchers are reneging on the promise to clinical trial participants, are wasting time and resources, and are jeopardizing public trust.

"The scientific community has a disappointing track record for dissemination of clinical trial results.

A Man Named Lucas and the Future of the California Stem Cell Agency

Lucas Lindner, photo by Cait Covers the Bases

The news last fall from a California stem cell firm was leaden and dense. Terms such as "Phase 1/2a SCiStar study" and "Full enrollment of Cohort 3 (AIS-A; 20 million AST-OPC1 cells)" littered the company's statement. 

Today the state's $3 billion stem cell agency turned the jargon into a heart-warming, human story -- the type that is critical to sustaining the life of the 13-year-old research effort, which is running out of cash.

The story involves Asteria Biotherapeutics, Inc., of Fremont, the California Institute of Regenerative Medicine(CIRM), as the stem cell agency is formally known, a clinical trial for a treatment for spinal injury and a young man named Lucas Lindner.

He is one of the patients in Asterias' clinical trial for a human embryonic stem cell therapy for spinal cord injury.  CIRM has funneled $21 million into the research. 

Writing on the agency's blog, Kevin McCormack, senior director for CIRM communications, said,

"On a Sunday morning in early 2016, Lucas Lindner was driving to get some donuts for his grandmother. A deer jumped in front of his truck. Lucas swerved to avoid it and crashed, suffering a severe spinal cord injury that left him paralyzed from the neck down."

But after the treatment, McCormack wrote,

"Lucas can now type 40 words a minute, use a soldering iron and touch his pinkie to his thumb, something he couldn’t do after the accident.

"In August of last year Lucas did something else he never imagined he would be able to do, he threw out the first pitch at a Milwaukee Brewers baseball game. At the time, he said 'I’m blown away by the fact that I can pitch a ball again.'"

Of course, there are scientific caveats and qualifications in the story. But what the tale really can do is resonate with nearly all California voters if the story ever reaches them.

Those voters are key to continuing the work of the agency, which expects to run out of state funds in 2019 and is hoping that voters will pump an additional $5 billion into the agency through a bond measure on the November 2020 ballot. (A private fund-raising effort is underway to bridge the cash gap.)

The agency has largely functioned in obscurity during the last 10 years or so. Its story is not well known by the public. And it has yet to help finance a therapy that is available to the general public. But CIRM's 44 clinical trials, including the one by Asterias, provide hope for patients and the agency.

The key lies, however, in how the story is told and how well CIRM supporters can turn mind-numbing scientific jargon and public policy issues into compelling yarns that will open both the hearts and purses of California voters.

California Makes a $25 Million Kidney Transplant Wager: Its 44th Stem Cell Clinical Trial

The California stem cell agency this week more than doubled down on its bet on a potentially breakthrough treatment for kidney transplants, raising to $25.4 million its support for a project that is entering its final stages.

The hope is that the treatment will not only improve the success rate of kidney transplants but also lead to use in liver, heart and other solid organ transplants. If successful, the therapy would eliminate the need for immunosuppressive drugs in genetically matched kidney transplant patients.

Maria Millan, CIRM photo 

Maria Millan, president of the agency, said in a news release:

“These immunosuppressive drugs not only can cause harmful side effects, but they are also expensive and some patients lose their transplant either because they can’t afford to pay for the drugs, or because their effectiveness is not adequate."

The award also could help save the life of the stem cell agency, which is facing its financial demise as its funding runs out.

The award brings to 44 the number of clinical trials being assisted by the $3 billion agency, formally known as the  California Institute for Regenerative Medicine(CIRM). Clinical trials are the last stages of research prior to certification by the federal government of a treatment for widespread use.

The stem cell agency is hoping that one of its trials will soon produce a therapy that will resonate with California voters who may be asked in 2020 to provide $5 billion more. The agency expects to run out of state funding next year and is attempting to raise more than $200 million privately to tide it over until a bond election in  November 2020.

Action on the award was swift on Thursday. It took less than eight minutes for the agency governing board to unanimously approve an $18.8 million award to Medeor Therapeutics, Inc., of San Mateo, Ca. The award comes on top of a $6.7 million investment in the firm's research in 2016.

Steven Deitcher, Medeor photo

The vote simply ratified a decision on the Phase 3 trial that was already made by the agency's reviewers, who gave the research strong support during a meeting behind closed doors weeks earlier.

Steven Deitcher, co-founder and president of Medeor, said in the agency's news release,

"CIRM funding accelerates our timelines, and these timelines are what stand between needy patients and potential transformative therapies. This CIRM award combined with investor support represent a public-private collaboration that we hope will make a difference in the lives of organ transplant recipients in California, the entire U.S., and beyond."

$68 Million Saving: California Stem Cell Agency Cuts Size of Clinical Trial Awards

CIRM's new caps on its clinical trial programs

OAKLAND, Ca. -- Directors of the California stem cell agency this morning cut the size of its key awards, saving $68 million that will allow it to support more "shots on goal" as it pursues development of a stem cell therapy available for widespread use. 

The move was made in the clinical trials program of the California Institute for Regenerative Medicine (CIRM), as the agency is formally known. Clinical trials are the last stage of research prior to federal approval of a therapy for general use. 

The unanimous action will allow the agency to continue backing its non-clinical programs as well as generating support for 50 trials by the end of 2019. 

The agency is running out of cash for new awards because of limits in the ballot initiative that created it in 2004. The board will discuss funding for the more distant future at today's meeting. 

California Tightening Stem Cell Research Belt; Size of Research Awards Targeted

The stem cell agency outlined its assessment of its current position
 in this slide prepared for today's meeting. 

OAKLAND, Ca. -- California's $3 billion stem cell agency is preparing to put the squeeze on its research awards over the next two years, cutting the caps on new grants in some areas by 50 percent or more.

It is all part of a strategy to prolong the life of the 13-year-old research effort as it fights to fulfill the expectations of voters who created it when they approved a ballot initiative in 2004. Voters provided only $3 billion in funding, however, and the agency is now expected to run out of cash for awards in 2019 unless it changes its financial ways.

Meeting here today are two key groups, the Transition and Science subcommittees of the governing board of the California Institute for Regenerative Medicine (CIRM), as the agency is formally known.

They are scheduled to wrestle with both the agency's short-term finances and the longer term effort to extend CIRM's life for perhaps an additional 10 years or more via another ballot initiative in 2020. As for next year, based on past discussions and practices it appears certain that the agency's directors will reduce the size of awards to the scientists and businesses who are often hard-pressed to find non-governmental support.

A proposal by the president of CIRM, Maria Millan, calls for reducing clinical program awards by a total of $68 million over the next two years. Here is how the cuts would work compared to the average award this year in each category.

• Phase 1 and phase 1/2 clinical trial grants would see their caps reduced from $20 million to $12 million for nonprofits and $8 million for for-profit enterprises. The average award in 2017 in these categories was $10.3 million. 
• Phase 2 trials would see their caps cut from also $20 million to $15 million for both non-profit and for-profit enterprises. The 2017 average award was $15.3 million. 
• Phase 3 trial awards, which averaged $16.7 million in 2017, would have their caps cut from $20 million to $10 million for both types of enterprises.

Millan's presentation indicated that would her proposals would allow the agency to support 24 new trials and eight trial candidates over the next two years, in keeping with a strategy of taking "more shots on goal" as the agency tries to develop a stem cell therapy for widespread use. Clinical trials, which can take years, are the last stage before a therapy is approved by the federal government. 

Millan's plan would also allot only $10 million for what the agency calls "Discovery" awards (basic research) next year (10 projects) and $9.25 million in 2019 (nine projects). Discovery awards are expected to hit $46 million this year. Education awards are expected to total $1 million this year. Next year they  would receive $750,000 and nothing in 2019. 

Key to the spending plan is the assumption that the agency could raise an additional $220 million from a variety of sources between the end of next year and early 2020. The goal of the fund raising is to bring in $55 million by the final quarter of next year. The rest would be raised between then and the first quarter of  2020. 

CIRM did not release details of its strategy for raising the $220 million. CIRM Chairman Jonathan Thomas, however, has already been on the fundraising trail and reports that he has identified a number of potential donors.

The financial plans and any changes will go to the full board for ratification at a meeting Dec. 14 here at CIRM headquarters.

The California Stem Cell Report will cover today's meeting and file reports as warranted on this web site. Below is another presentation slide from the stem cell agency.