The Final $144 Million and the California Stem Cell Agency's Future

The Golden State's stem cell research program is down to its last $144 million after nearly 14 years of financing searches for therapies for everything ranging from diabetes to bubble baby syndrome. 

Funded with $3 billion in November 2004, California's stem cell agency has yet to back a therapy that is widely available to the public. Its directors are scheduled to meet on Wednesday to approve plans for what could be the last year for new awards. 

Known formally as the California Institute for Regenerative Medicine (CIRM), the agency was created by voters through a ballot initiative. The measure provided $3 billion in bond support but no additional cash beyond that. 

The agency is pinning its hopes for survival on a yet-to-be-written $5 billion bond measure for the November 2020. It is attempting privately to raise $200 million to bridge the gap between the end of 2019 and the election. 

On Thursday, CIRM's 2019 research award budget is slated to come before the Science Committee of its board of directors. The public can participate in the meeting via the Internet and at a number of locations throughout the state. More information about access can be found on the agenda. 

The agency's staff has proposed $123 million in awards for clinical trials during 2019 with another $20 million going for translational research, which is an effort to take basic research and translate it into a clinical application. An additional $600,000 is slated for "educational" awards. 

CIRM documents said there were "insufficient" funds to finance additional basic research. The agency also aims to limit its clinical/translational awards to research that has been previously backed by the agency.

By the end of this year, CIRM expects to have made $2.6 billion in awards. The remainder of the $3 billion has gone or will have gone for administrative expenses, which will continue for a few years as multi-year awards wind down. 

The agency may recover an estimated $30 million in 2019 from research that does not pan out, making those possible funds available for awards in 2020. 

Currently, CIRM is backing 49 clinical trials, the last stage before a therapy is certified for widespread use. But there is no guarantee that any of those trials will generate a treatment prior to the November 2020 election. 

State of Stem Cells: Three-day Conference Opens Today, Includes Japanese Research, Affordability and More

A three-day session to kick around business and scientific developments involving genes and stem cells begins today in La Jolla with live Internet video casts of many of the presentations and panels.

The state of Japanese research, therapies for stroke, commercialization pathways, affordability and much, much more are available. Some samples and times for today for the Cell and Gene Meeting on The Mesa:

7:15am – 8:45am -- Learning Theater, Readiness strategies for cell therapy commercial manufacturing workshop

7:20am – 8:00am -- Ballroom 2, Panel, Session 1: U.S.-based Clinical Programs

7:50am – 8:05am -- Magnolia Room, Development of an “off the shelf” cell therapy for ischemic stroke and other indications under the regenerative medicine regulatory framework in Japan
Speaker: Gil Van Bokkelen, Ph.D., Chairman and CEO, Athersys

1:15pm – 2:15pm -- Ballroom 1, Panel, Navigating acceptance, uptake and affordability across the life cycle 

The full agenda can be found here. The webcasts are available here.  Webcasts can be found by room location. 

Possible Federal Restrictions on Stem Cell Research and the Multi-Billion Dollar California Angle

The recent federal crackdown on the use of fetal tissue in scientific research could well be a harbinger of an effort to revive restrictions on the use of human embryonic stem cells, placing a roadblock in the way of creation of therapies to treat often deadly afflictions that affect millions of Americans.

And it could have an impact on the fate of California's $3 billion stem cell program, which expects to run out of money for new awards by the end of next year.

A leader of the pro-life movement signalled today that anti-abortion groups' next target is likely to be the National Institutes of Health(NIH), which provide billions of dollars in research funding, including use of embryonic stem cells (hESC).

Writing on The Hill web site, Tom McClusky, president of March for Life Action, denounced current federal research practices. His opinion piece was headlined.

"Trump's move on unethical fetal tissue experimentation isn't enough"

McClusky wrote,

"The head of NIH, Frances Collins, has been a long-time supporter of unethical research and has a reputation of disinterest for the countless lives lost as long as it produces results.
"His track record not only includes support for fetal tissue research but also human-embryonic stem cell experimentation, human-animal chimeras and even human cloning. Of the many great nominations made by President Trump, Frances Collins sticks out as a counter to his stated pro-life agenda."

This is a bit of deja vu for the California stem cell agency, whose $3 billion program was approved by voters in 2004. The impetus for creation of the agency, known formally as the California Institute for Regenerative Medicine (CIRM), was generated by then President Bush's restrictions on federal funding for hESC research. State cash, however, was not similarly restricted.

Trump has not yet revived Bush's restrictions, but the issue seems to be increasing in importance for Trump's evangelical political base and at least 102 congressmen. The opposition is based on the belief that using human embryonic stem cells for research is tantamount to murder.

The stem cell agency is hoping that California voters will extend its life in November 2020 by approving $5 billion more for the research. However, the agency has not delivered on 2004 expectations that stem therapies were right around the corner. The agency has yet to finance a therapy that is widely available.

Overcoming voter disenchantment could be difficult. But a Trump crackdown could energize stem cell supporters much as Bush's did in 2004. Scientists, patient advocate groups, venture capitalists and others banded together to win approval of the ballot initiative that created the state stem cell program, using Bush as a handy villain in the argument for more stem cell research.

Ironically, the article by the pro-life group came almost exactly one year after the then president of the International Society for Stem Cell Research,  Hans Clever, wrote on the Stat website that fetal tissue is absolutely necessary to produce cures and therapies. He said,

"The development of vaccines against polio, rubella, measles, chickenpox, adenovirus, rabies, and treatments for debilitating diseases such as rheumatoid arthritis, cystic fibrosis, and hemophilia all involved fetal tissue."

"Fetal tissue has been essential in research used to develop therapies that have saved millions of lives, and it continues to be necessary for the future of medicine."

The Reality of Stem Cell Research vs. Results: A Scientist/Blogger Speaks Out on California's Efforts

A researcher writing on the web site of Science Translational Medicine weighed in last week on California's $3 billion stem cell agency, raising questions about its progress, hype and the fate of the nearly 14-year-old effort. 

In an item Sept. 28 on the blog "In The Pipeline," Derek Lowe said, 

"It’s not like the CIRM money has all been wasted, of course. There’s been a lot of basic research done, and there certainly has been a lot that needed to be done. The amount of brush to be cleared in human developmental cell biology is just monumental. A quick thought the way that all of your body, all the bodies of every human being, comes each from their own single cell will make that clear. If you want stem cell therapies to regenerate organs – as who doesn’t – then you’re asking for a thorough understanding of that process. You may well be asking to do even more than it can tell us how to do."

CIRM is the California Institute for Regenerative Medicine, as the agency is formally known. Lowe's brief bio on the the site says he has worked for "several major pharmaceutical companies since 1989 on drug discovery projects."

The occasion for his remarks was the recent lengthy look at the agency by the San Francisco Chronicle at CIRM and its performance. Lowe wrote, 

"What’s happened? What you’d have expected, if you knew the field at all (or were familiar with basic research in general). None of the bigger promises made during the campaign to fund the CIRM have come true. No approved therapies have come out of the work yet – and that’s one of the class of promises that were most egregious, in California and elsewhere. Just imagine the time it takes from discovery to approval for something like this, and then factor in that the needed discovery hadn’t even been made yet. But if you don’t know anything much about stem cells, or regulatory approvals, or medicine in general, the idea of get-out-of-that-wheelchair cures being just around the corner becomes more plausible."

Lowe also noted that voters may be asked in 2020 to provide more billions for the agency. He said, 

"If you measure it (the agency's work) against what was known and what had been accomplished then versus what’s been done since, you can make a case, for sure. If you measure it against the promises made at the time, though, things look bad. And that informs how you’re going to campaign for renewal: do you point at what’s been done and make the argument that it’s been a success, or do you promise them miracle cures again, because now they just have to be around the corner after all this work, eh?"

Lowe's article received comments from nine readers, who appear also to be researchers. One, who was identified as Miguel Sanchez, wrote, 

"Just at my small CA research institute, the amount of poor science that has been funded by CIRM is staggering. I would say that roughly half the CIRM money we have received has gone to research programs that are prima facie bad science but the PIs are well connected so hey shut up. I don’t think any outright fraud has been published, but the taxpayers of CA are for damn sure not getting their moneys worth on these investments here."

Sanchez did not further identify his employer. The agency's list of grantees did not contain Sanchez's name. 

$10 Million More for Viacyte for a Virtual Stem Cell Cure for Type 1 Diabetes

The San Diego stem cell company that has snagged $72 million from the state of California  announced this week another $10 million infusion from the firm that created the rain gear fabric known as Gore-Tex.

The San Diego firm is Viacyte, Inc., a privately held company that has received more than any other company from the $3 billion California stem cell agency. In 2017, Viacyte became involved with W.L. Gore & Associates, Inc., a materials science company that deals with drug delivery technologies.

Gore is also the enterprise whose Gore-Tex product has shaped the current outerwear industry.

On Tuesday, Viacyte announced the $10 million investment by Gore. The funds are coming in the form of a convertible promissory note.

Paul Laikind, president of Viacyte, said this week that the collaboration with Gore "has been exceptionally productive." He said the use of Gore membranes "has proven invaluable for improving the performance of the PEC-Encap product candidate in non-clinical studies that have been shown to be reflective of the human experience."

He said the additional support "should allow us to resume clinical testing of PEC-Encap as early as the first half of 2019."

California's $72 Million Diabetes/Stem Cell Bet: A New Partner from Massachusetts

CRISPR Therapeutics is the latest firm to become involved in a California-
backed stem cell research effort. It uses gene-editing techniques to devise cures.

The California stem cell agency has invested $72 million in a San Diego firm that is pursuing a a functional cure for diabetes and which announced this week it was moving to dodge a major obstacle facing its potential therapy. 

The firm is Viacyte, Inc., a privately held enterprise that has received more funding by far than any other state-backed stem cell firm. It announced on Monday that it had hooked up with publicly traded CRISPR Therapeutics, Inc., of Cambridge, Mass., to collaborate on a gene-editing treatment that would evade the body's immune response to earlier Viacyte therapies.

In a Q&A with UC Davis researcher Paul Knoepfler, Paul Laikind, CEO of Viacyte, said,

"The advantage of an islet cell replacement therapy that has been gene-edited for immune evasion is simply that patients would not need to take immunosuppressive drugs, which can have side effects. Our main mission is to improve the lives of patients with insulin-requiring diabetes by delivering transformative new therapeutic options. The work we are doing on PEC-Direct, PEC-Encap, and now an immune-evasive approach, known as PEC-QT, are all a part of that mission."

The treatment is principally aimed at type 1 diabetes, which afflicts 1.25 million persons in this country, the stem cell agency said in a piece on its blog about the new collaboration.

Viacyte was one of the earliest firms to receive cash from the agency, officially known as the California Institute for Regenerative Medicine (CIRM). The awards began with only $48,950 in 2008 when Viacyte was known as Novocell.

The arrangement with CRISPR will provide more funding for Viacyte, $15 million from its new partner and possibly another $10 million in the form of a convertible promissory note.

CRISPR's stock closed at $48.99 yesterday, down from $55.36 last Friday. Its 52-week high was $73.90 and its 52-week low $16.16.  The firm announced on Wednesday that it was planning to sell $200 million in common stock.  (Here is a detailed presentation on the firm's strategy and research. Here is a link to one analysis of the firm as an investment.)

In the piece on Knoepfler's blog, Laikind also provided an update on Viacyte's other related research. He said,

"(T)he PEC-Encap (also known as VC-01) product candidate has a bright future! We remain enthusiastic regarding the prospects of PEC-Encap, and are actively working on it. In June, two-year data from ViaCyte’s STEP ONE clinical trial were presented at ADA 2018. Although consistent and robust engraftment has been limited in this study to date, results showed that when engraftment does occur, viable mature insulin-expressing endocrine islet cells can be formed. In some cases, insulin-expressing cells have persisted for up to two years after implantation, the longest time point investigated in the study.

"Building on insights gained during the STEP ONE study, ViaCyte is working with W.L. Gore & Associates, one of the world’s top materials science companies with expertise in medical device development and drug delivery technologies, to modify the Encaptra Cell Delivery System and improve the potential for long-term engraftment. This work has yielded positive results in non-clinical models that, based on clinical experience, have been selected to reflect the response in patients. If the progress continues as expected, we plan to resume STEP ONE trial enrollment in 2019.

"As for PEC-Direct (also known as VC-02), the Phase 1/2 clinical evaluation of that product candidate is also continuing. We are now evaluating patients in the second cohort of the trial. As you know, PEC-Direct has the potential to help the patients with type 1 diabetes with the greatest need."

California's Stem Cell Agency Says It Has Saved Lives and Is Building a Foundation to Save More

Evie Vaccaro, whose life was saved with research backed by the stem cell agency

California's $3 billion stem cell agency took its message this week to the op-ed pages of the
San Francisco Chronicle, declaring that the agency's efforts have saved lives and created a world class network of clinics to develop therapies for all.

Maria Millan, CEO of the agency, and Jonathan Thomas, chairman of its board, said in an op-ed article,

"Have we achieved all we wanted to? Of course not. The first decade of CIRM’s life was laying the groundwork, developing the knowledge and expertise, and refining processes so that we can truly accelerate progress. As a leader in this burgeoning field of regenerative medicine, CIRM needs to continue its mission of accelerating stem cell treatments to patients with unmet medical needs."

The Millan-Thomas article came in the wake of a Chronicle editorial that said the agency, formally known as the California Institute for Regenerative Medicine (CIRM), did not merit additional funding based on its results to date. The Chronicle also carried a lengthy news piece that concluded the agency has not met the expectations of voters who created it through a ballot initiative in 2004. 

The agency expects to run out of cash for new awards at the end of next year. Its hope for survival lie with a yet-to-written bond measure that would appear on the November 2020 ballot. 

Millan and Thomas said the agency is now backing 49 clinical trials and has a host of accomplishments. They said, 

"Today the therapies resulting from the institute’s work are not just changing lives — they are already saving lives.

"Lives like Evie Vaccaro, who is alive today because of a treatment CIRM is funding. Vaccaro was born with SCID, also known as “bubble baby disease,” an immune disorder that often kills babies in their first two years. Vaccaro, now 6, and dozens of other babies were given stem cell treatments thanks to the institute. All are showing improvement; some are now several years past treatment and considered cured. 

"An accident left Jake Javier from Danville paralyzed from the chest down on the eve of his high school graduation. Javier was treated in a CIRM-funded clinical trial. Today, he has regained the use of his arms and hands, is driving a car and is a sophomore at Cal Poly San Luis Obispo. Five other patients treated at the same time as Javier all have experienced improvements meaning that instead of needing round-the-clock care, they can lead independent lives."

California's $50 Million Alpha Network: Managing the Complexity of Stem Cell Clinical Trials

Clinical Leader, an online publication dealing with clinical trials, yesterday carried a piece exploring the $50 million Alpha Clinic program initiated by the California stem cell agency.

Written by Geoff Lomax, a senior officer at the agency for its strategic initiatives, the article discussed the complexity of stem cell clinical trials and the use of a network of high-powered medical centers to support the novel research and treatment, particularly involving the FDA's programs to speed use of some therapies. 

Lomax's concluding statement in the article said,

"(R)egenerative medicine therapies are treating and curing debilitating and deadly diseases. The FDA’s RMAT (regenerative medicine advanced therapy) and breakthrough designations have created a streamlined environment for product sponsors. To effectively leverage this regulatory policy environment, sponsors must conduct high-quality clinical trials that are often operationally complex.

"Clinical trial networks, capable of managing the array of regenerative medicine technologies, are well suited to manage this complexity. The CIRM Alpha Clinic network is a current highly functioning proof of the concept. Patients with unmet medical need and product sponsors will benefit from the replication of this model nationally and internationally."

The agency, formally known as the California Institute for Regenerative Medicine or CIRM, initiated the Alpha network in 2015. It has since enlarged the effort with a total of $50 million and locations at UC San Francisco, UC Davis, UCLA, UC Irvine, City of Hope and UC San Diego. 

The Clinical Leader piece said, 

"Recognizing this operational complexity and limitations in clinical experience, the California Institute for Regenerative Medicine (CIRM) pioneered the development of infrastructure to support regenerative medicine clinical trials. Launched in 2015, the CIRM Alpha Clinics are a network of six California medical centers. The clinics conduct FDA-authorized and IRB approved clinical trials. The aim of the network is to achieve greater and more efficient results than the member organizations could if they acted independently. Each of the Alpha Clinics has formed teams with specialized knowledge and experience with regenerative medicine clinical research involving human cell and tissue products. These teams work across their respective centers. As of September 1, 2018, the network is supporting 49 clinical trials — and has supported 60 clinical trials since 2015 — across a range of indications."

Lomax continued,

"This network model of conducting therapeutically diverse clinical trials lies in contrast to the traditional disease-based clinical trial networks that tend to be located in specific clinical units – oncology, cardiology, neurology, etc. The Alpha Clinic teams are horizontally integrated across the centers, so they can support the diverse range of indications where regenerative medicine therapies are currently being evaluated. This technology-based approach facilitates the conduct of clinical trials, particularly in clinical units that may have limited experience with cell and gene therapy products."

A Global Stem Cell Perspective: CIRM's Accomplishments in a Field Tougher than Rocket Science

The comments below were emailed to the California Stem Cell Report yesterday in the wake of recent news coverage of the California Institute for Regenerative Medicine (CIRM), as the state's stem cell agency is known. 

The author, who asked not to be identified, has followed the field of stem cell research worldwide since its inception. Here is the text of the remarks.

"As you know, I am usually reticent about putting in my two cents worth regarding CIRM and all the politics swirling around the subject. But the recent published items, as well as radio interviews on the subject, have made me quite uncomfortable. I was not in California when Proposition 71 came on the ballot, so I cannot speak to the hype and campaign promises made that swayed the public. But I have to take issue with some of the nonsense that has been reported as news.   

"Here are some relevant facts: 

"1. People forget that in 2004, the NIH, the major agency in the US funding biomedical research, prohibited funding most of the research needed for this field to move forward. Forget about clinical trials, even basic research was severely curtailed based on unscientific premises. This meant that while other countries could move ahead, US scientists could not step into the arena. Prop. 71 was proposed to unshackle Californian scientists so that they could compete in the research arena on a par with UK, Canada, Australia, and many other countries eager to take advantage of this new discovery.

"2. Lest people forget, the NIH rules at that time were so onerous that anything -- buildings, maintenance, and equipment -- partially or wholly funded by the federal government could not be used to conduct human embryonic stem cell research. Hence the need for CIRM to fund the building of labs, infrastructure and facilities early on. This is not an idea to mindlessly benefit academic institutions, but to allow their investigators to conduct stem cells research without using anything (buildings, equipment, personnel) paid for by federal funds. 

"3. Biomedical research is not like rocket science - it is much harder and much less predictable. Twenty years after the big push by Congress to cure Parkinsons’ Disease by building Udall Centers and mandating funding for this effort - PD is still not cured. Alzheimers Disease has been a target of the NIH for decades; just this year, they are increasing funding for this effort. Yet - no cure in sight. Add to the growing list the “War on Cancer” declared by Nixon in 1971. How much progress was made by 1981? Yet look at all the success today? The fact is that biomedical research is much harder than engineering, and we should be patient instead of whining about the slow rate of progress. It behooves the critics of CIRM to remember that success in research requires time and money. Things are just beginning to ramp up exponentially by the end of the first 10 years. 

"4. Finally, taking a world-wide view of the state of human stem cell research, CIRM has to be considered a great success. CIRM supported the first few clinical trials using human embryonic stem cell products. At the end of 2017, there were 17 clinical trials using human embryonic stem cells. Of these 11 are conducted in the US, and all 11 are initiated in California or conducted in California - this is completely due to CIRM. Of the 11 trials, 6 are directly funded by CIRM, and NONE by the NIH. So without CIRM, there will be few or no clinical trials using this new technology in this country!"

(For some of the news coverage, see here and here.)