NeoStem Sees Whopping Jump in Stock Price on $18 Million Backing from California

A graphic depiction of trading on NeoStem stock last week.
Google chart

The stock price of NeoStem, Inc., shot up 28 percent in one day last week after the California stem cell agency approved a nearly $18 million grant to the firm for a potential therapy that “teaches the immune system which cells to attack and kill.”

The governing board of the state research effort awarded the funds on Thursday May 21. The grant is to assist in a third stage clinical trial involving a treatment for metastatic melanoma, the most deadly form of skin cancer. Following the approval, NeoStem’s stock soared from $2.30 to close at $2.95.

The California Stem Cell Report first disclosed the agency’s virtually certain action on Tuesday May 19.

It was an obvious boon for the New York-based company whose CEO, David Mazzo, told the board that the award would help to raise more cash to finance the trial which is expected to cost $45 million to $51 million, according to analyst Yi Chen of H.C. Wainwright.

For the California Institute for Regenerative Medicine (CIRM), as the stem cell agency is formally known, it will be the first time that it has plunged into a stage three trial and the closest it has come to actually bringing a therapy to market.

Jonathan Thomas, chairman of the $3 billion agency, told the board on Thursday that the NeoStem project has “the greatest chance of success for the people of California that we have funded.”

The agency was created in 2004 when voters approved a ballot initiative whose backers raised expectations of quick development of stem cell therapies. The agency has committed more than $1.9 billion for research. Its money for new awards is expected to run out in 2020.

NeoStem, which has operations in Mountain View and Irvine in California, issued a press release hailing the award. The company called the action a “significant endorsement” of its approach which it said has potential application in other types of cancer.

  

The release quoted Randy Mills, president of the agency and former head of Osiris Therapeutics of Maryland, as saying cash would start flowing to NeoStem in 45 days. He continued,

“But that's just the start. We are not just providing financial support; we are also partnering with these groups to provide expertise, guidance and other kinds of support that these teams need to help them be successful.”

Under a new scoring system introduced by Mills, the agency’s blue-ribbon reviewers voted 6-3-5 to fund the program with the three saying the application needed improvement. That action occurred behind closed doors weeks before last Thursday’s meeting when the board ratified the reviewers’ decision on an 11-0 vote. One CIRM board member, Leon Fine of Cedars Sinai, said that one perspective on the reviewers’ voting could be that eight persons thought the application needed more work or should be rejected.

Board member Steven Juelsgaard, former executive vice president of Genentech, raised questions about what might happen if the board rejected the NeoStem application, given that it has only $19 million on hand at last report. Juelsgaard said that was not sufficient to complete the trial.

Mills declined to speculate on what the company might do.

Juelsgaard returned to the subject a few minutes later when Mazzo addressed the board and asked Mazzo about the company’s “Plan B.” Mazzo said the company could go to the “capital markets.” He also said the company had recently negotiated a $30 million equity line of credit.

Mazzo said that the firm is constantly looking for funds and that the CIRM grant would go “a long ways to advancing the trial.”

The vagaries of the marketplace do, however, play a role in the investment community’s view of the company. After the stock jumped 28 percent on Thursday, it dropped 2 percent on Friday.

The 52-week low for the stock is $2.15 and the high is $7.23.

The trial is currently seeking enrollees worldwide, including at seven sites in California. 

UC Davis Stem Cell Program Cited in Sacramento Bee

Here is one of the photos run by The Bee today with a story
about the UC Davis stem cell program.

The Sacramento Bee today published an article on the rise of UC Davis as a major stem cell research center, largely with a $130 million assist from California’s stem cell agency.

The news article was written by the editor of this blog, David Jensen, on a freelance basis. At the time of this writing, the article ranked No. 1 out of 81,000 results on a Google news search using the term “California stem cell.” 

While the piece focuses on UC Davis, a similar impact has been felt at UC Santa Barbara, whose stem cell program has also benefited greatly from CIRM largess.

CIRM Directors Coverage Delayed

Today's meeting of the directors of the $3 billion California stem cell agency will not be covered live by the California Stem Cell Report. Look for a reprise of the session in the coming weeks.

NeoStem Up For $18 Million Melanoma Award from California

California's stem cell agency is expected to make an $18 million bet this week on a treatment by NeoStem, Inc., for a skin cancer that kills 10,000 persons a year in the United States alone.

Up for approval on Thursday is the company's application for an award to assist in a late stage trial that could produce a commercial product before the agency is expected to run out of money in 2020.

NeoStem is based in New York city but has operations in Irvine and Mountain View in California. It acquired California Stem Cell, Inc., in Irvine in April of 2014 for $124 million. California Stem Cell was founded by Hans Kierstead of UC Irvine, who is now president of NeoStem Oncology.

The $3 billion agency did not disclose the name of the company in keeping with its longstanding practice of concealing the identity of applicants.

However, company documents and SEC filings indicated that NeoStem was the applicant. It would be the first award by the agency to Neostem, which is a publicly traded firm.  

The summary of the agency's review posted on its Web site said the funds would go for completion of a stage three trial for a tumor stem cell-targeted immunotherapy for metastatic melanoma, which accounts for 20,000 new cases annually.

The review cited "compelling results" from the phase two stage of the trial. NeoStem has reported separately that its stage two trial had a 72 percent survival rate after two years compared to 31 percent for the control group.

NeoStem said in SEC filings that the treatment is for the most lethal form of skin cancer and has estimated market size of $1 billion.

Helping to develop a marketable product would be a big score for the agency, which has yet to fund a commerical therapy after 10 years and $1.9 billion.

Its money for new awards will run out in 2020 at its current spending rate. No additional funding sources for the agency have surfaced at this point. Being able to cite development of a commercial therapy would be likely to generate considerable enthusiasm for the agency's continued work.

Both reviewers and the CIRM staff recommended approval of the NeoStem application at the CIRM governing board meeting on Thursday.

The action came on a split vote among reviewers, 6-3-5, with six recommending funding and five against funding, according to a CIRM document.. Three reviewers said the application needed improvement.

The CIRM summary of the review said,

"Reviewers considered the lack of mechanistic data and inadequate plan to gain understanding of therapeutic mechanism of action to be a major weakness and expressed concern regarding the ability of the applicant to enrol the proposal pivotal Ph3 (phase three) study as projected."

CIRM said, however, the vote and staff recommendation to fund the research "reflects both the high risk and the clear potential to impact unmet medical need."

The CIRM governing board almost never overturns approval of an award by its reviewers and staff.

The award would be one of the two first approved in CIRM's 2.0 program to fast-track cash to researchers, speed development of therapies and improve the quality of grant applications. The second award  -- $5 million -- is for work immediately leading up to a clinical trial for a therapy for retinitis pigmentosa. Shaomei Wang and Clive Svendsen at Cedars-Sinai in Los Angeles are the likely key figures in that research. Reviewers voted 15-0 to fund the work.   

California Stem Cell Audit: Praise for Mills but More Work Needed on IP, Conflicts of Interest

The California stem cell agency this week received good marks for changes made by its new president, but it is also being told that it needs to improve how it tracks potential royalties and how it prevents grant reviewer conflicts of interest.

A "performance audit" by Moss-Adams, a Seattle business consulting firm, made 12 recommendations for the $3 billion research enterprise. One of the 12 was to implement the unfulfilled recommendations made by Moss-Adams three years ago.  Seven of the 24 from that audit still need more action, the firm said.

On Thursday, the agency's governing board is scheduled to discuss the latest audit at a meeting in Berkeley.  The study is required by state law every three years. The agency's scientific performance, however,  is specifically excluded from being examined. Moss-Adams is scheduled to receive $230,000 from the agency for the audit, which was for the 2013-14 year.

On Sunday, the California Stem Cell Report covered the deficiencies involving disclosures of the financial interests of grant reviewers.

Other areas of concern included the need for better tracking of intellectual property that could mean royalties for the state, more timely review of progress reports from grantees, more timely, formal evaluation of employees and keeping up-to-date on technology related to grant management and agency efficiency.

Under the subject of "commendations," Moss-Adams said that CIRM had "many strengths."  The consultant said the agency has made "significant strides" in three areas: the grant management system, grants process improvements and "organizational culture."

The grants process comment referred to CIRM 2.0, the fast-track funding program initiated by Randy Mills since he became president a year ago. The organizational culture commendation also involved Mills' efforts, but touched indirectly and delicately on the resignation of Robert Klein as chairman and the election of Jonathan Thomas to replace him in June of 2011. 

Moss-Adams reported "enhanced seamlessness" between the president's and chairman's offices. Proposition 71, which created the agency, dictated a controversial dual executive situation that has troubled the agency since its inception.

The audit found significant deficiencies involving the treatment of CIRM employees, some of which have been addressed in a positive way already by Mills. One example cited by the audit involved performance evaluations that are tied to pay increases. It said that evaluations that were scheduled to occur in 2013-14 did not actually take place until January of this year.  

Moss-Adams said the agency also needs to do better in monitoring and protecting its intellectual property (IP), which could generate royalties. Without tight tracking of the IP and inventions funded by CIRM research, the state could lose out on revenue. Backers of Proposition 71 told voters in 2004 that the state could receive more than $1 billion in royalties from CIRM research. So far, none has resulted. 

Moss-Adams said that royalties are now more possible because the agency is backing late stage research that is more likely to make it into the market place. 

Moss-Adams said more work was needed on implementing the seven recommendations from three years ago, including those involving IP, the transition plan to deal with the possible demise of the agency and a grants outcome database. 

Five Public Sites Set for Thursday's Board Meeting of the California Stem Cell Agency

For those who want to participate in this Thursday's meeting of the governing board of the California stem cell agency, five public locations are available.

The actual meeting will be in Berkeley beginning at 9 a.m. PDT. Oher public locations will be in San Diego and Danbury, Conn., and at UC Irvine and Cedars-Sinai in Los Angeles.

Specific addresses can be found on the agenda for the meeting along with instructions on how to listen in on an audiocast. However, the audiocast does not provide the opportunity to comment.

Written comments to the board for the meeting can be emailed to mbonneville@cirm.ca.gov.

Conflict-of-Interest Failings Reported in Application Reviews at California Stem Cell Agency

Conflict-of-interest issues have dogged the $3 billion California stem cell agency since its inception, and they are surfacing once again this week in a report commissioned by the agency itself.

This time the matter is being brought up by Moss-Adams, LLP, of Seattle, a business consulting firm that is being paid $230,000 by the agency to conduct a "performance audit."

In a report to be discussed at a CIRM governing board meeting on Thursday, the firm said it discovered serious problems dealing with the reporting of the interests of the agency's blue-ribbon reviewers.

The reviewers make the de facto decisions on the applications from researchers for millions of dollars from California taxpayers.  Their reviews are conducted behind closed doors. The identities of the specific reviewers and applicants are not publicly disclosed.

The California Institute for Regenerative Medicine (CIRM), as the agency is formally known, requires the reviewers to fill out forms about their financial and professional interests as part of the review process.

However, those disclosures are withheld from the public and from applicants whose proposals are being assessed.  The agency's basic position has been to say "trust us" to monitor the conflicts.

Moss-Adams said, however, it "found that CIRM did not fully meet its compliance requirements regarding financial disclosures" during 2013-14. It also said that it could not verify that CIRM staff had actually checked for unreported conflicts.

Moss-Adams examined 40 applications and pre-applications and did not mention specific instances, such as the 2013 case involving a reknown scientist from Washington state, Lee Hood, and Stanford researcher Irv Weissman.  The matter was first reported by the California Stem Cell Report.

The audit said,

"Specifically, we found that of the 25 pre-applications we tested, three reviewers were missing Financial Interest Disclosure Forms in connection with the review of applications submitted in response to a particular RFA. These three reviewers participated in the review of four of the 25 pre-applications. Similarly, for the 15 applications we tested, which related to five different RFAs, we found that Financial Disclosure Forms were missing for eight different reviewers. For each of the 15 applications, we found that CIRM was missing a Financial Disclosure form for one or more reviewers who participated in the application review process for a particular RFA. In each of these cases, however, the reviewers completed their Conflict of Interest Form for that review."

The audit, which is required by state law, continued,

"Unlike the Conflict of Interest Form, which had already become an integrated element in the GMS (grant management system) in fiscal year 2013-14, no system restrictions were in place to prevent participation in reviews prior to the receipt of Financial Interest Disclosure Forms. Without these system restrictions, compliance with this requirement lapsed and reviewers with missing Financial Interest Disclosure Forms were allowed to review and score pre-applications and applications."

Moss-Adams said the agency took steps to correct the situation in July of last year. However, it told CIRM that  it should continue those procedures to ensure compliance on conflict of interest matters.

The audit also said it could not verify that CIRM had actually followed its process for determining whether unreported conflict of interests existed on the part of reviewers.

The audit said,

"Currently, there are no written policies or procedures outlining this process. While CIRM regulations define what constitutes a financial conflict of interest, the Grants Review Staff does
not have additional written guidance to follow when performing these reviews. Moreover, because the Grants Review Staff does not document the performance of these reviews, we could
not verify that these reviews were performed or assess the manner in which they were performed. Without procedures that formalize this process or internal records that document
the performance of these reviews, CIRM cannot fully demonstrate its performance of due diligence to ensure the financial independence of reviewers."

Moss-Adams told the agency that it should develop detailed procedures for examining the disclosure forms and document the work via the automated grants management system.

The agency's response to the concerns raised in the audit, which covered a wide range of issues beyond conflicts, did not specifically mention the disclosure and conflict matters.

The California Stem Cell Report will have more on the findings of the audit during the next few days. Specifically excluded from the audit is the performance of the agency's scientific portfolio.

California Stem Cell Agency to Hire Top VP

Randy Mills, who enters his second year this week as president of the California stem cell agency, is looking for a vice president for the $3 billion research enterprise. 

The salary for the new executive ranges up to $375,524. He or she would be the only vice president in the organization.  

The new position oversees three key areas of research with a budget of more than $600 million and 75 active programs at the California Institute for Regenerative Medicine, as the agency is formally known. 

Mills this month added the VP position to his official organization chart. In a memo to the governing board of the agency, he noted that some members of the board had expressed concern about the number of persons reporting directly to him.  Mills said that "upon further reflection" he determined that adding a VP would mean more efficiency and effectiveness. 

Also unfilled are the high-level slots for senior directors of the areas that the new VP would oversee: organ systems, neuro/ocular therapies and blood and cancer. 

The three senior director openings were first posted in January, reflecting Mills' new structure at the San Francisco agency and his emphasis on speeding development of therapies.

They are among seven job openings at the agency including project manager for clinical advisory panels, web and social media manager and grants management specialist.

The media manager position came open this month when Anne Holden left after about a year on the job and completing an overhaul of the agency web site. 

See here for access to all the job postings. 

Business-friendly Changes in California's $500 Million Stem Cell Loan Program

The California stem cell agency is set to overhaul its $500 million loan program, acknowledging that it has been far less than successful.

The change would allow companies to accept a multimillion dollar grant and then convert it to a loan. The process would enable a firm to escape paying royalties on a lucrative product that might be developed partially as a result of CIRM funding. Royalties are required under the terms of a grant but not on a loan.

Backers of Proposition 71, the ballot measure that created the Callifornia stem cell program, touted the promise of royalties to help convince voters to approve the measure.

A memo by James Harrison, general counsel to the agency, said the loan program failed to meet its objectives. Only two loans are currently outstanding. They are to Viacyte of San Diego and Capricor of Beverly Hills.

The original intent of the 2008 program was to generate additional cash through interest on the loans to help with research funding.

Harrison said,
"Under this proposal, recipients of CIRM’s clinical stage project awards (PA 15-01, 15-02 and 15-03) would have the option to elect to convert their award from a grant to a loan within the earlier of marketing approval by the Food and Drug Administration or seven years from the effective date of the award. Unless the parties agreed to different terms, the awardee would be required to repay the loan balance within ten days of making the election to convert from a grant to a loan at a rate that would escalate based on the date of repayment. Conversion from a grant to a loan would become final only after the awardee has satisfied the terms of the conversion."

The proposal is scheduled to be heard Monday by the agency's intellectual property subcommittee and finalized May 21 by its full board.

Here is the link to the subcommittee agenda where Harrison's full memo can be found. It also shows locations in San Francisco, San Diego, Irvine, Napa and Redwood City where interested parties can listen in and participate in the proceedings. https://www.cirm.ca.gov/agendas/05082015/ip-subcommittee-meeting

Here is a link to an item about the history of the program, which was originally scheduled for change in March. http://californiastemcellreport.blogspot.com.es/2015/03/500-million-stem-cell-loan-effort-klein.html

Fast-Track Stem Cell Grants and Big Boost in California Stem Cell Agency Budget

Directors of the California stem cell agency will meet May 21 to make their first award under the agency's new, fast-track grant program and to approve an $18.7 million operational budget, up $2.8 million from this year's estimated spending.

The award will come in Randy Mills' CIRM 2.0 program as he begins his second year as president of the $3 billion state research effort. He initiated the program with intention of dramatically speeding cash to researchers.

The agenda for the directors' meeting in Berkeley does not specify how many awards are likely to be considered, but the number is expected to be very small. More details are likely to be posted on the agenda prior to the meeting.

Mills plans to extend the CIRM 2.0 speed-up to all of CIRM's award cycles, including basic research.

Also expected to be approved is the operational  budget proposed by Mills for the fiscal year that begins July 1. The spending plan is up substantially from actual spending for the current fiscal year largely because of increases in personnel costs. Mills expects to fill a number of high-level slots in the organization that will help boost employee costs from $11.3 million this year to $12.7 million. The agency is expected to be $815,000 under budget for employee expenses for the current fiscal year because positions were not filled.

Mills also plans to update the agency's strategic plan during the next few months. A discussion of that effort is on the meeting agenda. Such matters as spending on basic research vs. clinical funding are the sort of topic for strategic planning. A few years ago, a shift away from basic research triggered some public concerns among researchers, who said the field was too young to push heavily on the more costly clinical funding.

The agency has committed $1.9 billion so far and estimates it will run out of cash in 2020 for new awards.

No plans for public input concerning the strategic plan have been announced, but they have been a component of previous efforts.

Directors are additionally expected to hear a report on a "performance audit" of the agency. The agency commissioned the $230,000 audit, which is required by state law. The last such audit in 2013 made 27 recommendations for improvements at the agency. An evaluation of the agency´s scientific portfolio was specifically not included in the audit.

Look for more details on matters to be considered by the agency on the California Stem Cell Report over the next 10 days as more information becomes available.

jCyte to Conduct Clinical Trial on Stem Cell Therapy for Retinitis Pigmentosa

More information is emerging today on the clinical trial for a retinal eye disease supported by the California stem cell agency, which has already committed $20 million or so to the project.

Henry Klassen and Jing Yang

The trial will be conducted by jCyte, Inc., of Newport Beach, Ca., close to UC Irvine where the principal investigator, Henry Klassen, works. The firm was founded by Klassen and Jing Yang, also of UC Irvine.

The jCyte Web site is a bit thin, but it did say it hopes to "leverage national qnd international partnerships."

Klassen wrote on the site;

"Please bear in mind that this is just the beginning. Not the beginning of our labors, certainly (which go back decades), but the beginning of the clinical undertaking. The whole project remains experimental, yet all of our hopes are running high. So, while this does not translate immediately into a treatment, it opens the door to that possibility." 

The CIRM Web site also has a progress report from Klassen on his research plus more details of the science.

CIRM said in its press release yesterday that the agency had provided $21 million for Klassen's research. However, its Web site today shows only $19 million, We are asking CIRM about the difference,

The jCyte team, photo from jCyte

12th Clinical Trial For California's Stem Cell Agency

The California stem cell agency today announced its 12th clinical trial, one that deals with retinal eye problems and and research that has already seen $21 million in state funding. 

The trial involves work by Henry Klassen of UC Irvine, where the treatments will be carried out pending final approval by the school's insitutional review board. Today's announcement came as the result of FDA approval. 

The agency said in a press release that Klassen and his colleagues "have developed the therapy to treat retinitis pigmentosa (RP), which erodes the cells in the retina, the light sensitive area in the back of the eye that is crucial for vision."

The agency continued, "The clinical trial will involve enrolling up to 16 patients who will get a single injection in the eye of stem cells known as retinal progenitors. It’s hoped these will help protect photoreceptors that are not yet damaged by the disease, and even replace those that are already lost."

Jonathan Thomas, chairman of the agency's governing board, said, "RP affects about 1.5 million people worldwide and is the leading cause of inherited blindness in the developed world. Having an effective treatment for it would transform people’s lives in extraordinary ways.”

The goal of the initial trial is to test the safety of the treatment.

California's 'Incredible' Stem Cell Invention

C. Randal Mills - CIRM 2.0. Building a better stem cell agency (Part 2) from MCC Industry Relations on Vimeo.

Randy Mills, the president of the $3 billion California stem cell agency, was selling hard a couple of months ago in San Diego.

Animated and gesticulating, Mills said,

"There's nothing like CIRM.  It's an incredible invention that probably only could have taken place in California."

But he said the agency was on its way to being better and faster, delivering cash to researchers in 120 days instead of the previous average of 22 months.

"We are an accelerating agency. We are in the time business. So we can't be slow...Urgency matters."

Mills' comments were made to a symposium at the Moores Cancer Center in San Diego Feb. 19. But his full remarks surfaced recently in a video posted on Vimeo(see above).

Mills took only a little more five minutes in his presentation about CIRM 2.0, his radical overhaul of the agency's grant-making process. He is seeking higher quality applications, higher success ratios and stronger partnerships with researchers and patient advocates.

CIRM  2.0 is still in the process of being fully implemented in all of the agency's award efforts. Mills said there will be bumps.
"Buckle up. It's going to be a wild ride."

'Born in Hype:' The California Experiment and Stem Cell Research

A California newspaper with a daily readership of 1.5 million this week thrashed the field of stem cell science, declaring that it “is slathered with so much money that immoderate predictions of success are common.”

“Infected with hype” is the way the headline put it on the March 31 piece in the Los Angeles Times. The paper has the largest circulation in the state and is an agenda-setter for much of the state’s mainstream media.

The comments came in an article by Pulitzer Prize-winning columnist and author Michael Hiltzik, who holds the California stem cell agency in low regard.

Kalina Kamenova
 U. of Alberta photo

Timothy Caulfield
U. of Alberta photo

His starting point was a study in Science Translational Medicine by Timothy Caulfield and Kalina Kamenova of the University of Alberta law school.  Their content analysis research focused primarily on newspaper coverage of timelines for stem cell therapies before and after Geron bailed out of the first clinical trial for a human embryonic therapy in the United States. They did not have warm words for scientists as public communicators.

Neither did Hiltzik, but he also faulted the media. He wrote, 

“The authors mostly blame the scientists, who need to be more aware of ‘the importance of conveying realistic ... timelines to the popular press.’ We wouldn't give journalists this much of a pass; writers on scientific topics should understand that the development of drugs and therapies can take years and involve myriad dry holes and dead ends. They should be vigilant against gaudy promises.”

Hiltzik then took on the California Institute for Regenerative Medicine (CIRM), as the stem cell agency is known.  He wrote about the cash that was "slathered" about. He said,

“The best illustration of that comes from California's stem cell program -- CIRM, or the California Institute for Regenerative Medicine -- a $6-billion public investment (including interest) that was born in hype. 

“The promoters of Proposition 71, the 2004 ballot initiative that created CIRM, filled the airwaves with ads implying that the only thing standing between Michael J. Fox being cured of Parkinson's or Christopher Reeve walking again was Prop. 71's money. They commissioned a study asserting that California might reap a windfall in taxes, royalties and healthcare savings up to seven times the size of its $6-billion investment. One wouldn't build a storage shed on foundations this soft, much less a $6-billion mansion.”

 He wrote about how CIRM played a dubious role in funding the Geron clinical trial only a couple of months before the company pulled the plug for financial reasons, something that the California Stem Cell Report has dealt with as well.  The $26 million loan to Geron involved a major departure from the agency’s normal procedures.  Abandonment of the trial also raised ethical questions that should be of continuing concern to the agency and its ethical advisors who are meeting today and tomorrow in Los Angeles.  

Caulfield’s views on stem cell hype are well-known in the small stem cell research community. But rarely does his sort of perspective, which is shared by others in the field, reach a mass audience such as the 1.5 million readers of the Los Angeles Times.

All of which poses a challenge for the California stem cell agency whose finite amount of cash is now expected to run out in 2020. As Hiltzik noted, the overblown expectations led voters to believe that miraculous cures were just around the corner.

Today, more than a decade after creation of the agency, the promised cures have not materialized and none are likely for some years. The agency has undoubtedly made a major contribution to stem cell science. But the unfulfilled promises of the campaign hype gave its foes the kind of tools they need to battle any efforts to provide more state funding for the agency.  How CIRM deals with that scientific and PR challenge will be one of the major tests for it over the next several years.

Moratorium on Possible Genetic Alteration of Human Race on Agenda Tomorrow at California Stem Cell Agency

The select panel that helps the $3 billion California stem cell agency set  research standards meets tomorrow and Friday in Los Angeles, its first session since 2013.

The agenda appears modest but it does include a discussion involving possible genetic modifications to the human race and the germ line letter signed by Nobel prize winner David Baltimore, among many others.

The starting point for the discussion is a statement by the International Society for Stem Cell Research that said,

“The International Society for Stem Cell Research calls for a moratorium on attempts at clinical application of nuclear genome editing of the human germ line to enable more extensive scientific analysis of the potential risks of genome editing and broader public discussion of the societal and ethical implications.” 

Scientist Paul Knoepfer of UC Davis has an ongoing look at the issues on his blog, ipscell.com. The latest is a March 29 piece headlined “Genetically Modified Humans Now Inevitable?” Knoepfler wrote, 

“Rumors are swirling that upwards of four papers reporting production of GM(genetically modified) human embryos are in various stages of review at high-profile journals, sparking a sense of urgency for some kind of steps to deal with this new reality. Could these papers report germ line correction of the CTFR mutation in cystic fibrosis or of a BRCA1 mutation? Were these GM human embryos used to make embryonic stem cell lines or are they cryopreserved?

“The prime concern now is that GM human embryos could in principle be rather simply turned into GM humans at any one of thousands of IVF clinics around the world with a surrogate mother. That simple technological step of going from GM human embryo to GM human being of course invokes incredibly complicated, thorny legal, bioethical and societal issues.”

Although Baltimore once served on the stem cell agency’s governing board and the agency has been active with the international stem cell research group, it is not clear that it will do anything in regard to a moratorium.

The agency board has shied away from such matters since 2011, when Robert Klein left as its chairman. He often pressed for the agency to take on legislative and other policy matters during his tenure.

The moratorium is not scheduled to be officially voted on so legally it would difficult for the standards panel to do anything significant. But the group could make an expression of sentiment and ask that the full board consider the matter.

The standards group’s last meeting was Oct. 1, 2013, according to the CIRM Web site. However, it was quite active in the early days of the agency when it was formulating the first comprehensive stem cell research regulations in the country. 

The public can attend tomorrow’s session, which beings at noon PDT in Century City in Los Angeles, and speak to the committee on any matter. 

Here is a link to a list of its members. Its chairman is Bernie Lo of UC San Francisco. 

California's Stem Cell Bank and Its Fujifilm Moment

A CIRM slide from last week on the Cellular Dynamic stem cell bank project.

Remember the “Kodak Moment?” California’s $3 billion stem cell agency yesterday experienced a “Fujifilm Moment.”

It came when the Japanese firm announced it was buying Cellular Dynamics International (CDI) for $307 million. That doubled the price of the company stock overnight, probably leading to moments of ecstatic celebration in some circles. The stock closed at $16.43 today, well above its 52-week low of $4.72.

The purchase was part of what FierceBiotech today called a “fresh frenzy of biotech-related buyouts.”

Cellular Dynamics is a Wisconsin firm that has a $16 million grant from CIRM, as the stem cell agency is known, to create what could be the world’s largest bank of induced pluripotent stem cells (iPSCs). The firm was founded by noted University of Wisconsin researcher Jamie Thomson. The bank is located at the Buck Institute in Novato, north of San Francisco. The 155-employee CDI is also the prime subcontractor on a related $10 million award to the Coriell Institute.

At the CIRM board meeting last week, Uta Grieshammer, a science officer at the agency, gave an update on the $32 million project that directors approved in March 2013. From the tenor of her briefing, the effort seems to be on track. (Here is the CIRM-CDI contract dated Oct. 25, 2013.)

It is not entirely clear what, if anything, the Fujifilm purchase means for the CIRM contract with CDI.  Sometimes new owners have different views of previous business arrangements and seek modifications. The Fujifilm press release said CDI work will continue in California and Wisconsin. But the release also said Fujifilm will “seek synergies and efficiencies,” which can be industry-speak for cutbacks and layoffs.

The California Stem Cell Report yesterday queried the agency about its thoughts but no response has been forthcoming.

In June 2014, Kerry Grens of The Scientist magazine wrote about the stem cell banking business. The article said,

“The California Institute for Regenerative Medicine (CIRM) has the ambitious goal of creating the world’s largest iPSC bank. This will include cell lines from people with cardiomyopathy, blinding eye diseases, and Alzheimer’s, among other things. Michael Yaffe, the associate director for research activities at CIRM, said it was important not to duplicate the efforts of other iPSC banking initiatives. In planning the program, Yaffe explained, 'We wanted to make as many [cell lines] as possible. Then it became an economic argument: How many could we afford and how much could we push a deriver to handle?' 

“CIRM settled on a goal of 9,000 lines derived from 3,000 individuals. Yaffe said he anticipates that the first of these will be available for distribution by the end of the year or early 2015. What’s still unsettled, however, is the cost. It’s a tricky calculation, given that the utilization of the lines is unknown. 

“'If a few large pharmaceutical companies buy a complete set of all the lines, that would keep the bank established and running for many years,’ Yaffe said. ‘If academic researchers are going to buy a few lines at a time or a few lines each, it will create some challenges for the sustainability of the bank.’”

In December 2013, CIRM’s staff recommended a $2 million addition to the stem cell banking program. The CIRM governing board rejected the proposal after one board member called the plan dodgy. Jeff Sheehy, who serves on the grant review committee, said it needed to be peer reviewed and competitive.

The Fujifilm purchase attracted considerable news coverage but little mention of the CIRM connection. Here are links to some samples: Madison.com, ipscell.com, xconomy. Here is a link to CDI’s one-year progress report with CIRM.

Three-Month Birthday: California Dances Forward With its Fast Track Stem Cell Plan

Randy Mills' chart last week on changes coming as a result of CIRM 2.0

On New Year’s Eve, the California stem cell agency and its relatively new president, Randy Mills, kicked off a radical and fresh way to hand out money to researchers and speed development of therapies.

Today, nearly three months later, the agency is still wrestling with some key issues, including virtual termination of its old, $500 million loan program.

Nonetheless, at a meeting last week in Berkeley, the governing board of the agency did put behind it many aspects of implementation of what it calls CIRM 2.0, a term drawn from its official name, the California Institute for Regenerative Medicine(CIRM).

Approved were new rules involving administration of grants and beefed up oversight of the research -- with the agency as an ever more engaged partner with researchers, some of whom may not care for more suggestions from the back seat.

Background checks will be required on recipients. Budgets that are out of whack will not even be submitted to agency’s application reviewers. Much paperwork will be eliminated. The out-of-state researchers who approve the grants will now also scrutinize progress and make recommendations. That’s on top of clinical advisory panels that will be created to monitor research progress on a quarterly basis.  Researchers will be encouraged to save money and will have more freedom to spend surplus cash. (For more details, see here and here.)

The goal says Mills, who has been in place only since last May, is to send checks to researcher 120 days after they submit an application instead of the previous average of 22 months. New clinical stage projects are now being accepted every month instead of only once or twice a year.

Most of the CIRM 2.0 matters are much too granular to impress the public, which really only cares about production of useful therapies. But if Mills is successful, it will likely mean speedier development of the treatments that were promised 10 years ago ago when voters created the stem cell agency. Researchers and stem cell firms, as opposed to the general public, need to pay close attention, however, to the details, which can mean millions of dollars for them.

Another stem cell filip is coming up this spring: the agency's strategic plan, which appears ready to be revised as a CIRM 2.0 document. Mills avows his continued support for basic research, strongly favored by board members from academia and research institutions. But heavy pressure exists to bring a product to market quickly or much closer to market. Without such a demonstration, the agency will find it tough to secure additional funding after 2020, the latest estimate when its cash will run out. 

Still hanging out there are the details of what will be left of the agency’s once ambitious, seven-year-old loan program, which was a favorite of the agency’s first chairman, Robert Klein.

Only five loans were made. Only two are still active. In a memo to the board, Mills said the program was “overly complex, administratively burdensome, and, as reflected in the number of loans issued, it does not appear to be attractive to industry.”  He told the board last week that small companies balk at the loans because they do not want the debt on their balance sheets. Grants, however, carry royalty requirements that companies also dislike.

Mills said,

"If we can't make it better, maybe it shouldn't exist."

The board’s intellectual property committee was scheduled to act on a new loan policy in January but that meeting was cancelled with no public explanation. Again this month, a meeting was scheduled but postponed with no immediate explanation. The link to the proposed policy was removed from the CIRM Web site, although the document can be found here. 

 CIRM spokesman Kevin McCormack, in response to a question from the California Stem Cell Report, said,

“The meeting was postponed so we could work on the proposal some more before bringing it to the subcommittee. The document was removed from the Web site because it was actually the wrong document. It was an earlier, outdated version of the proposal and didn't reflect many of the changes that were made.”  

Last week's action directly involved only the first stage of CIRM 2.0, but Mills plans to extend the process to the entire portfolio, making adjustments as necessary. The rules are officially interim. The state’s official regulation adoption process is much lengthier and will provide more opportunity for the public to comment.

Mills has told the board that implementation of his changes will not necessarily be smooth. He also said the effort is likely to be modified as CIRM 2.0 progresses.

CIRM chart on status of CIRM 2.0 applications

Mills has now scheduled the first, closed-door review session for a CIRM 2.0 application, one of two received in January. The 90-minute telephonic meeting is set for tomorrow. The second application from January was sent back to the applicant for re-working. The agency received two CIRM 2.0 applications in February. One was sent back to the applicant. The other is expected to be reviewed and scored April 27.

More CIRM 2.0 applications are expected at the end of this month, next Tuesday.

The public can address tomorrow's meeting from CIRM's headquarters in San Francisco during the public portion of the session.  As usual, however, the name of the researcher and the target of the research are being withheld from the public.

See here, here and here for the text of key documents on CIRM 2.0 approved at last week's meeting.

California's Stem Cell Directors Adjourn, More News Coming up Tomorrow

The directors of the California stem cell agency have adjourned their meeting in Berkeley. We do not expect additional stories today but will have more tomorrow including an update on the agency's search for a new home and an overview of the progress on CIRM 2.0. We call your attention to the item below that involves a flap over the agency's grant review process, which its president calls "sub-optimal."

(The progress report on CIRM 2.0 can be found here. The update on the search for a new CIRM home has been delayed.)

$25 Million for Stem Cell Research Plus Sharp Criticism of California Stem Cell Board

The California stem cell agency today approved $25.2 million for preclinical research aimed at speeding development of therapies for afflictions that include arthritis, Alzheimer's and “bubble boy” syndrome.

The action came during an agency governing board session that was marked by sharp criticism from an executive with a La Jolla firm associated with one of the rejected grant applicants, Jill Helms of Stanford. The executive, Sanford Madigan of Ankasa Regenerative Therapeutics, told the board he was "disturbed by board members not willing to do their jobs."

Sanford Madigan, LinkedIn photo

Several board members said they were offended by Madigan's remarks, although he later apologized. He appeared to be irritated by the reluctance of the board to override its reviewers. Five board members subsequently abstained from voting to overturn staff and reviewer rejection of Helms' application. The motion that would have funded her proposal failed on a vote of 5-1-5.

The public flare-up involving the board and a member of the public was unusual, although comments such as Madigan's are sometimes heard in private.

His remarks came at the end of a discussion about the weaknesses of the agency's closed-door review process. The discussion involved other applications in addition to Helms' proposal. Randy Mills, president of the agency, acknowledged the review process was "sub-optimal" and was being replaced by new procedures he has dubbed CIRM 2.0.

Ankasa was created by Avalon Ventures, which is raising $16 million to help commercialize Helm's work to develop a stem cell therapy to improve skeletal healing of elderly people.

The governing board of the agency handed out awards to seven scientists with the goal of moving their research closer to federal approval for a start of a clinical trial. The board approved applications from two researchers who made special appeals to the board after reviewers and staff nixed their proposals.

Prior to the vote on her application, Helms was told that she could revise her $7 million application and submit it for later consideration. She said the soonest that would occur would be in about 10 months, given the agency's timetable. By that time, she said the research team would be disbanded through lack of funding and the effort would "disintegrate." 

CIRM has already put $7 million into Helms' research. She has been something of a bright star for the agency, which has featured her on its Web site and asked her to appear on its panels.

The rejection of the Helms proposal highlighted some of the vagaries of the agency's longstanding review process.  She received an average scientific score  of 72 which knocked her out of the funding category(tier one). However, her median score was 75, a figure that two reviewer-approved grants received. What skewed the average figure was a low score of 45. No other grant in the top 10 received that a ranking that low. Eight reviewers recommended funding the proposal, Four did not with three recommending it be placed in "tier two," a grey area for applications.

No reviewers were listed as having conflicts of interest on the Helms proposal. However, their finanicial and professional interests are not disclosed to the public. Nor are they identified to the public.

On another proposal, John Cashman, CEO of Human BioMolecular Research Institute of San Diego, asked for a re-review of his firm's application for a treatment involving spinal fusion. He said that his firm has worked with CIRM for several years to make changes that the agency had requested. Nonetheless, he said reviewers do not seem to agree.  Cashman said,

"Certainly the system is broken."

The board did not act on Cashman's request for a re-review.

Here is the roll call vote on the Helms' application: Yes -- David Higgins, Steve Juelsgaard, Kathy LaPorte, Lauren Miller, Art Torres. No -- Jonathan Thomas. Abstain -- Francisco Prieto, Robert Quint, Al Rowlett, Jeff Sheehy, Diane Winokur.

Summaries of the reviews of the winning applications can be found on this 90-page document.

(Editor's note: An earlier version of this item did not contain the two paragraphs that deal with the vagaries of the grant review process and conflicts of interest.) 

California Stem Cell Awards $7.7 Million for Therapy to Alter Arthritis Progress

The governing board of the California stem cell agency today approved $7.7 million to develop the first therapy that would alter the progression of osteoarthritis.

The action came on a proposal by Daryll D’Lima of Scripps Health, whose application was rejected earlier by reviewers of the agency and its staff. 

D’Lima told the board that arthritis is the No. 1 cause of disability in the nation. Annually, arthritis has a more than $120 billion economic impact, which exceeds 2 percent of the gross domestic product.  D’Lima’s research has already received $3.1 million from CIRM.

California Okays $1.7 Million for Alzheimer's Treatment

Directors of the California stem cell agency today all but approved a $1.7 million award to a Salk researcher to develop a therapy that would alter the progression of Alzheimer's Disease.

The action came on a 11-1-1 vote.

Researcher David Schubert of the Salk Institute appealed to the board to overturn rejection of the proposal by reviewers and CIRM staff.  Schubert was told that the application needed to be improved.

Schubert appeared before the board today and sent a letter to the board earlier this month. He said the proposed treatment was “highly effective at reversing the memory deficits” in mice. His proposal, he said, could move very quickly into clinical trials under new federal regulations.

The vote came on a motion to move the application into a category that will be approved by the full board later today. 

Voting Conflict List on California Stem Cell Preclinical Awards

Here is the list of California stem cell agency directors with conflicts of interest on today's preclinical research awards. The list comes from the stem cell agency. The directors on the list are not allowed to vote on the applications in question.

  Voting Conflict List Preclinical CIRM Awards

$32 Million or $16 Million for California Preclinical Stem Cell Research?

The California stem cell agency board has begun discussion of the preclinical awards to be approved today. Reviewers approved five grants totaling $15.8 million. Three rejected researchers are asking the board to approve another $16 million. The board budgeted $40 million for the effort. At least one rejected researcher, Jill Helms of Stanford, is expected to address the full board.

Four Applications Submitted Under CIRM 2.0 Fast-track Plan

CIRM President Randy Mills has begun his update on the status of CIRM 2.0 and has even mentioned the possibility of CIRM 2.1 in the not too distant future. His slides can be found here.

He said the first application under CIRM 2.0 will be sent to the full board on April 23. The second application that came in during January has been sent back to the reviewer for revision.

Of the two applications that came in during February, one is going to application reviewers. The other has been sent back to the researcher.

California Stem Cell Board Begins Meeting

The governing board of the California stem cell agency opened its meeting at 9:07 PDT this morning with its usual pledge of allegiance and roll call. The meeting in Berkeley was scheduled to start at 9 a.m

An Update on California's New Fast-Track Stem Cell Research Plan

This morning's session of the governing board of the $3 billion California stem cell agency has not yet begun but the agency has just posted the presentation slides to be used by its president, Randy Mills. 

Most of Mills's presentation deals with the progress of CIRM 2.0, his plan to speed cash to researchers and improve the quality of the applications. He also offered up the above slide concerning the end of the existing, $500 million loan program.

Coming Up This Morning: Gavel to Gavel Coverage of California Stem Cell Meeting

The 29-member governing board of California's $3 billion stem cell research effort, the only such organization of its size in the nation, meets at 9 a.m. PDT in Berkeley to award millions of dollars and to ratify radical changes in the way it operates.

The California Stem Cell Report will provide live, day-long coverage and stories as warranted from its perch in Mazatlan, Mexico, based on the Internet audiocast of the session.

For those would like to follow directly all of the meeting, the agenda contains instructions for dialing in. For those who have not used the process, it is helpful to begin setting it up about 15 minutes before the meeting.  To view the presentations as they are being made, log into the WebEx url.

Correction

The "arthritis, alzheimer's" item earlier today incorrectly said that researcher Jill Helms had already received $11 million from the agency, based on figures on the CIRM Web site. However, Helms said the correct figure is $7 million.

Arthritis, Alzheimer's, Healing: California Stem Cell Agency Urged to Help Elderly

Three California scientists are asking the state’s stem cell agency to come to the aid of tens of millions of elderly persons and provide $16 million to develop therapies to treat Alzheimer’s and arthritis and to speed skeletal healing in the elderly.

The researchers have asked the governing board of the $3 billion agency to overturn at its meeting tomorrow the rejection of the proposals by both scientific reviewers and the agency staff.  All of the potential therapies are close to moving into clinical trials.

Jill Helms, Stanford photo

One of the scientists, Jill Helms of Stanford, said in a letter to the board that her team is addressing healing issues -- “an unmet medical need in an under-served and often overlooked patient population, namely, the aged….Elderly patients are entitled to the same level of healthcare afforded to younger patients.”

The California Institute for Regenerative Medicine (CIRM), as the agency is formally known, has already pumped $7 million into Helms’ research. She is seeking another $7 million to advance the potential therapy closer to clinical trials.

The two other researchers are Daryll D’Lima of Scripps Health and David Schubert of Salk.

D’Lima is seeking $7.7 million to develop the first therapy that would alter the progression of osteoarthritis, which is the No. 1 cause of disability in the nation. Annually, arthritis has a more than $120 billion economic impact, which exceeds 2 percent of the gross domestic product.  D’Lima’s research has already received $3.1 million from CIRM.

Schubert has applied for $1.7 million for work on an Alzheimer’s therapy that he said was “highly effective at reversing the memory deficits” in mice. His proposal, he said, could move very quickly into clinical trials under new federal regulations.

The researchers’ rejected applications were scored at either at an average of 71 or 72 by the agency’s blue-ribbon scientific grant reviewers, who do their work behind closed doors. The reviewers approved five grants with scores ranging from 89 to 76. Two of the approved grants had the same median score of 75 as the three rejected grants.

During public sessions in the past, a number of board members have said that a few points difference on scores is not statistically significant.

In a memo to the board, Randy Mills, president of the agency, recommended rejection of the applications. He said the applicants could re-apply next summer under the agency’s new CIRM 2.0 program or possibly under the preclinical round that is now open.

Mills’ memo also includes the range of scores and summaries of reviewers' comments. The agency does not identify applicants by name until after the board acts and then only the winners. However, Helms' application is 08105; D’Lima’s is 08128, and Schubert’s is 08086. 

The CIRM board originally budgeted $40 million for the research to be approved tomorrow. Only five applications were okayed by reviewers for a total of $15.8 million.

Helms noted in her March 20 letter to the board that CIRM has been a big supporter of her research since 2009.  The agency has also considered her something of a bright light, using her on panels and presentations.

About the review of her application, she wrote,

“Reviewers had nothing negative to say about the proposed product, the preclinical data, the approach, the veracity of the indications, the MOA, the proposed plan of action, or the milestones.”

Helms said that Avalon Ventures is backing her research to the tune of $16 million, including creation of a new firm, Ankasa Regenerative Therapeutics of La Jolla, to push it forward.

Daryll D'Lima, Scripps photo

In his March 19 letter, D’Lima said his research has demonstrated “very convincing proof" that his possible therapy was “very successful in repairing osteochondral defects (a major factor leading to osteoarthritis)." 

Schubert said in his letter that “there are currently no drugs that halt (Alzheimer’s) progression so the potential benefits of moving CAD- 

031(the name of the treatment) into human trials are enormous."

David Schubert, Salk photo

Schubert’s letter was dated March 16 but was only posted on CIRM Web site within the last two days as were the other letters(dated March 19 and

March 20). The delay in posting makes it difficult for patient advocates to attend the board meeting tomorrow to express directly to the board their opinions about the proposals.

The D’Lima and Schubert applications also involve organizations that do not have seats on the agency’s governing board. D’Lima’s is the only award to Scripps Health. Schubert works at Salk which has not had a representative on the CIRM board since 2011. Salk has received $50 million from the agency.

About 88 percent of the funds that the CIRM board has awarded have gone to institutions with ties to persons who have been members of the board.

(Editor's note: An earlier version of this item said that Helms had received $11 million from the agency, based on information on the CIRM Web site. She said, however, the correct figure is $7 million.)

California's Stem Cell Grant Reviewers Set for More Oversight on Research Awards

The California stem cell agency today moved forward on creation of new rules for its research awards, ranging from more fiscal scrutiny to elimination of paperwork.

The aim of the move is to improve the quality of the research and speed development of stem cell therapies by the $3 billion agency.

The Science Subcommittee of the agency’s governing board, as expected, unanimously approved the rules, which are nearly certain to be ratified Thursday by the full board at its meeting in Berkeley.

The proposals are part of CIRM 2.0, a major change at the agency initiated by Randy Mills, who became president of the agency last May. 

In addition to the grant regulations, the subcommittee unanimously approved changes in procedures involving the conduct of the closed-door grant review meetings. 

The grant reviewers, formally known as the Grants Working Group, make the de facto decisions on all applications. The agency’s board has legal authority to accept or reject applications, but has almost never rejected a positive recommendation from its blue-ribbon scientific reviewers.

One change involving the scientific reviewers, all of whom come from out-of-state, calls for them to exercise oversight on the progress of the research and on “continued funding.” The reviewers would report their findings to the full CIRM board or the agency’s president. That would be in addition to CIRM staff monitoring and quarterly reviews by new panels of advisors.

Another change in the review process calls for a patient advocate member of the review group to be more actively involved in the review of applications. One advocate would be asked for his or her views on an application but would not score the application. All of the patient advocate members of the review panel are also members of the agency board.

In addition to the seven members from the agency board, including its chairman, each group of reviewers for a particular award round includes 15 scientists from outside California. They are drawn from a list of more than 100.  Their financial and professional interests are not disclosed to the public. Applicants are not notified which researchers review their applications.