Tuesday, January 17, 2017

The $22,000-an-Hour California Stem Cell Story: Rosy Expectations, Fuzzy Future

Evangelina Padilla Vaccaro
CIRM photo
Trump and state bond issue?
More than 60 clinical trials projected
No therapies yet for general public
Siren appeal for reseachers
$2.2 billion out the door

Evangelina Padilla Vaccaro – a pink bow in her hair – was likely the first four-year-old ever to address the leaders of California’s $3 billion stem cell research program.

“Thank you,” she whispered. Her mother said more: 
"Thank you for keeping my family complete." 

Alysia PadillaVaccaro’s voice cracked, and tears flowed on that cool December morning at the meeting at an Oakland hotel.

Evangelina had much to be thankful for. She was born with “bubble baby” syndrome, which meant that she had no functioning immune system. Scientist Donald Kohn of UCLA cured her of the rare affliction by using her own blood stem cells to alter a troublesome gene. It was an experimental treatment not readily available to the public at large. Kohn’s research has been heavily supported with nearly $52 million by the state stem cell agency, known formally as the California Institute for Regenerative Medicine (CIRM) .

Evangelina’s story is just what Californians hoped for when they created the Oakland-based agency in 2004 via Proposition 71. Voters were told that stem cell therapies would ease afflictions found in nearly 50 percent of California families. The agency would create the “cures for tomorrow,” said then Gov. Arnold Schwarzenegger.

Since its first awards in 2005, the agency has given away money at a rate of $22,000 an hour, seven days a week, 24 hours a day. But it has yet to come up with a therapy that reaches the general public despite rosy expectations raised by the ballot campaign.

Today, the future of the program is unclear. The agency calculates that it will run out of cash in just three years. Whether it lives on could depend on the likelihood of another multibillion-dollar bond issue, not to mention the success – or the lack of success – of as many as 60 or more clinical trials and even the policies of the newly elected president of the United States, Donald Trump.

Stem cell therapies, it turns out, are expensive and difficult to bring to market, and their use may be
Shinya Yamanaka, UCSF photo
limited to a handful of diseases. On Monday, Nobel Prize winning stem cell scientist Shinya

Yamanaka said as much in an interview with Wallace Ravven of The New York Times. Because of a wide variety of constraints, he said, 
“We can help just a small portion of patients with stem cell therapy.”
In this context, heartwarming stories of patients such as Evangelina could be some of the strongest selling points for CIRM’s continued existence. They could fire the enthusiasm of voters and embolden businesses to partner with CIRM to bring therapies into the marketplace. The number of these emotional stories is increasing.

Evangelina was not alone at the CIRM meeting last month. Three more patients stepped up during a look at the agency’s performance. They included a 22-year-old man, also with a rare, immune-deficiency disease, a paralyzed 19-year-old man and a 70-year-old cancer patient -- all of whom had experienced major improvements during clinical trials. All told, the agency has pumped $113 million into the research that has benefited the four patients.

Evangelina’s story had special significance for Jan Nolta, head of the UC Davis stem cell program.
Jan Nolta, UCD photo
Nolta began her career working with Donald Kohn at Childrens Hospital in Los Angeles in early research involving the “bubble baby” affliction.

“CIRM has funded Don’s continued work in this area, and he has now functionally cured over 20 children with this disease,” she said in an email. “These kids now need no expensive medicine and treatments to keep them alive. They are functionally cured.” 
In Evangelina’s case, she was able to join her fraternal twin sister, Annabella, in living a normal childhood.

CIRM funding has also fueled the growth of the UC Davis stem cell program, which barely existed prior to creation of the stem cell agency. Today Davis has chalked up $129 million from the agency. “We have 16 stem cell or regenerative medicine clinical trials ongoing or recently completed, with more than 20 in the pipeline,” Nolta said.

Davis ranks as the No. 5 recipient of funds from the agency, trailing only such institutions as Stanford, $314 million; UCLA, $269 million; UC San Diego, $170 million, and UC San Francisco, $139 million.

Nolta is one of a number of researchers attracted by CIRM, lured by the cash and research environment created by the stem cell agency. program. She returned to California from Washington University in St. Louis. 
(See the full text of Nolta's remarks here.)

The appeal of the California largess was highlighted last week by George Daley, dean of the Harvard Medical School.  He was quoted in a lengthy piece about San Francisco Bay Area biotech written by STAT news service editor Charles Piller.
"'I’ve been looking at this from the outside, and franly have been very envious as a scientist based in Massachusetts,' Daley said. CIRM funds have turned many research centers in California, including UCSF, into world leaders in stem cell science, he said, adding: 'I heard the siren song of CIRM early. I considered making a move,' as did more than two dozen of his Harvard stem cell colleagues."
Since CIRM’s inception, it has awarded $2.2 billion to 853 California researchers and institutions. It estimates that it will award another $692 million before money runs out. This year it plans to give away $328 million.  (The awards are separate from the agency’s operational budget, which is capped by the ballot initiative and is about $19 million for the current fiscal year.)

Like most other recipient institutions, UC Davis has representation on the CIRM governing board. The California Stem Cell Report, which has monitored the agency since 2005, has calculated that about 90 percent of the agency’s cash has gone to institutions with links to past or present board members. Those members are barred from voting on awards to their institutions, but they do vote on the nature of the award rounds and approve the rules.

Concerns about conflicts of interest have long been a bugaboo for the agency. Last September,The Sacramento Bee reported that its former president, Alan Trounson, received $443,500 in total compensation after being named in 2014 to the board of directors of StemCells, Inc., of Newark, Ca. Trounson’s appointment to the company’s board came only seven days after he left the agency at the end of June 2014.

Randy Mills, FDA photo
Trounson was replaced by C. Randal Mills, who had been president of Osiris Therapeutics, Inc., of Maryland. Under Mills’ leadership, Osiris was the first company in the world to commercialize a stem cell drug, qualifying it for use in Canada.

Mills and the CIRM team – currently comprised of 48 people – re-crafted the agency’s objectives and established measurable benchmarks for success, winning board approval for what Mills called radical change. The results were summarized at last month’s board meeting and in the 2016 annual report. They included:

  • Over the last two years, the agency has helped to finance 27 clinical trials and is looking for another 40 by 2020. (Clinical trials are the last stage before a therapy is approved by the Food and Drug Administration (FDA) for widespread use. Only one out of 10 conventional drug products emerge successfully from the trials.)

  • More than 250 projects are currently being managed by the CIRM team.

  • Twelve "world-class" research facilities have been created over the last 12 years.

  • Three Alpha Clinics, intended to be one-stop stem cell centers, are in operation. A fourth is scheduled for this year.

  • A $30 million stem cell "pitching machine" to speed clinical trials and help guide development through federal regulations began operations in 2016.

Nonetheless, development of stem cell therapies -- much less cures -- is a risky business and could be stymied by a number of issues. The agency itself acknowledges risk factors that include reluctance by businesses to invest in stem cell therapies and safety concerns, including the possible death of a patient in a clinical trial.

Mills makes a practice of presenting risk, an innovation at the agency, as he offers up new programs to its governing board. In the annual report, he quoted the poet T.S. Eliot as saying,

“Only those who will risk going too far can possibly find out how far one can go.”

The agency has experienced a few hiccups since Mills arrived. He acknowledges he is still working hard on attracting businesses to partner with scientists to turn their research into cures. 

An ambitious effort to create a unique, public-private, $150 million enterprise to develop stem cell therapies and cures stumbled late last year when no qualified applicants surfaced from the private sector. The agency hopes to recast the proposal in such a manner that it will find a partner.

One of those watching the agency since its beginning is Hank Greely, director of the Center for Law
Hank Greely, Stanford Law photo
and the Biosciences at Stanford.

He said in an email,

“CIRM has been spending money from Proposition. 71 for about 10 years. Once initial hopes of finding low-hanging fruit disappeared, this kind of slog toward treatments became inevitable.  (Although, in biomedicine, 10 years is not (Greely's boldface) a long time - see the 35 plus years it has taken gene therapy to get to the edge of an FDA-approved product.)

“The next few years should determine just how good California's investment has been. It is encouraging to see CIRM supporting so many clinical trials; it will be much more exciting when – and I do expect ‘when’ and not ‘if’ – one of those trials leads to an approved treatment.”

John M. Simpson of Consumer Watchdog of Santa Monica, Ca., has also observed the agency for years. He said in an email,

“CIRM’s fundamental problem is that supporters of Proposition 71 wildly oversold what passage of the measure would deliver. Voters were led to believe that miraculous cures were just around the corner if only the proposition passed.

“CIRM-funded research has made important contributions to science, but has yet to deliver what voters were promised,” Simpson said. He added that agency management has improved under the regime of CIRM Chairman Jonathan Thomas and Mills “and the most blatant conflicts of interest were mitigated after the scathing Institute of Medicine report.”

In 2012, the highly respected Institute of Medicine, in a $700,000 report commissioned by the agency, recommended sweeping changes at CIRM to deal with conflicts of interest, its dual executive arrangement and the composition of its governing board. The CIRM board initially greeted the report coldly but made some changes to deal with the critical findings.

California patient advocate Don C. Reed, who campaigned for stem cell research long before CIRM surfaced, however, hailed the agency's work as already saving lives and creating hope for millions. He said in an email it was a "quiet triumph" that can be built on. (See here for full text.)

Simpson, who was heavily involved in development of the agency’s intellectual property policy,
John M. Simpson
 Consumer Watchdog photo
raised questions about the failure of the agency to generate the $1.1 billion in royalties for the state promised by its backers. Simpson said,

“The CIRM annual report cites the number of ‘inventions’ CIRM has funded — more than 180.  What share of royalties have taxpayers received as a result? Anticipated revenue from CIRM-funded inventions was a big selling point for Proposition 71.”

(See here for the full text of Simpson's comments.)

 Ironically, another selling point for the ballot measure came inadvertently from former President George Bush, who had restricted federal funding for human embryonic stem cell research. Backers of the ballot measure said it was needed to compensate for Bush’s action. His restrictions were lifted by President Obama. But many researchers are worried that the Trump administration will once again limit federal support for stem cell research.

Stanford’s Greely said,

“The election of Donald Trump and the continuation of a Republican-controlled Congress could create an increased need for extending CIRM.  If the federal government pulls out of some research on basically religious grounds, California may want to step in again.  It depends both on exactly how restrictive the federal government becomes and, more subtly, on how promising the stem cell trials appear.

“I suspect some federal funding restrictions are inevitable but their scope is unpredictable. As to the trials, if they are tremendously exciting, private funds might take over; if they flop, state funds may not be appropriate.  But if the results are very promising but not spectacular, more state funding might be invaluable.” 

(For more on a possible bond election and Trump's position, see here, here, here and here.)

Simpson has another view. He said,

“No doubt CIRM-funded research has made some important contributions to scientific knowledge. The results, however, in no way justify another bond issue to fund the agency.  If CIRM continues after the current funds run out, it should be financed like any other state agency— out of the state’s operating budget approved by the Legislature on annual basis. CIRM’s operating budget could also be augmented by private contributions.”

Mills avoids public discussion of such things as bond measures. But at a meeting last fall, he likened the research program to a “giant flywheel.”
“It takes a long time to get started, and you move it imperceptibly. Once that thing gets turning, it's almost impossible to stop.”

(Editor's note: A shorter version of this story can be found in the print edition of The Sacramento Bee for Jan. 17, 2017, and also on The Bee's website. The full text of various comments follows this story, which also has links to them. Greely's complete comments were included in the article above.)

(On Jan. 19, STAT news carried a lengthy piece on the agency that said it was slow in financing clinical trials, a major factor that has hampered development of a therapy.)

(An earlier version of this item also incorrectly stated Evangelina's age.)

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