Thursday, March 05, 2015

Transcontinental Diabetes Duel: The Search for a Stem Cell 'Cure'

Paul Laikind
Doug Melton,

One might call it a California-Massachusetts stem cell face-off. The tussle is over a stem cell cure of sorts for diabetes.

The players are Doug Melton of Harvard and Paul Laikind, CEO of ViaCyte in San Diego.  
Recently in separate forums, the men critiqued each other’s approaches to diabetes.

Most recently it was Laikind three days ago on the blog,, of UC Davis researcher Paul Knoepfler. Laikind was responding in a Q&A carried by Knoepfler.

Knoepfler asked about Melton’s comments in the MIT Technology Review last month. Melton was described in an article as being “worried” that ViaCyte’s technology, now in a first stage clinical trial, would not work. The California stem cell agency has invested $55 million in the firm's approach.

Knoepfler continued,
“(Melton) raised concerns more specifically about the Encaptra capsule, for example, functionally becoming fibrotic and mentioned worries about your cells being immature and taking a long time to mature. Any response on capsule and cells? He also has suggested that his beta cells will be a better option.” 
Laikind replied,  
“Dr. Melton’s work on the beta cell is very interesting. As to the cells, we made the choice to use the pancreatic progenitor cells. An important consideration is that when you first put in cells, they are in a hypoxic environment. Beta cells are sensitive to low oxygen levels, which can negatively affect their survival and function. Beta cells typically exist in a mature highly vascularized organ. The pancreatic progenitor cells that we use undergo an organogenesis-like process, more similar to how they behave in nature, and thus we believe they should be better able to handle low oxygen. They also are believed to release angiogenic and other factors to promote vascularization.
“In regards to the capsule, we do expect there to be a foreign body reaction in patients after implantation, which will generate a fibrotic capsule. In fact, we see a thin fibrotic capsule around the device in mice. But in the mouse model this capsule around the device is very well vascularized. The vasculature is right up against the device membrane on the outside, allowing for oxygen and nutrient diffusion to the cells inside.”
Knoepfler also asked about the diabetes effort in Canada involving BetaLogics Venture, a subsidiary of Johnson & Johnson, which also made a $20 million investment in ViaCyte last summer.

Laikind said situation involving Melton and BetaLogic was “healthy competition.”

He continued,
“There’s room in this area for multiple efforts and we aren’t especially concerned with competition. Yet we do feel we are ahead of others and we have substantial intellectual property that they will need to navigate (~50 patents issued in the United States, and a couple hundred pending patent applications, including international). At ViaCyte we view the real competition as the biology rather than with the efforts of others as we seek to cure this devastating disease.” 
Laikin had more to say about his firm’s product and Melton’s comments.  He also discussed ViaCyte’s clinical trial, which now has four patients with a goal of 40. He said the initial evaluation of efficacy could occur by late 2016. Within five years, he hopes to see “success” with the product and “be moving to market.”

Responding to a question about “product placement,” Laikin said the firm is currently inserting its tiny device in the lower back of patients. Laikin said,
“The reason for that placement is that while the device can withstand the impact of a 60 mph baseball (based on cadaver testing), a needle could go right through it, so we want to put it where patients don’t typically inject insulin.” 
Concerning Melton’s views on ViaCyte, the Feb. 12 MIT Technology Review piece said,
“Douglas Melton, a biologist at Harvard University who has two children with type 1 diabetes, worries that the ViaCyte system may not work. He thinks deposits of fibrotic, scarlike tissue will glom onto the capsules, starving the cells inside of oxygen and blocking their ability to sense sugar and release insulin. Melton also thinks it might take immature cells up to three months to become fully functional. And many won’t become beta cells, winding up as other types of pancreatic cells instead.
“Melton says the ‘inefficiency’ of the system means the company ‘would need a device about the size of a DVD player’ to have enough beta cells to effectively treat diabetes. ViaCyte says it thinks 300 million of its cells, or about eight of its capsules, would be enough. (Each capsule holds a volume of cells smaller than one M&M candy.)    Last October, Melton’s group announced it had managed to grow fully mature, functional beta cells in the lab, a scientific first that took more than 10 years of trial-and-error research. Melton thinks implanting mature cells would allow a bioartificial pancreas to start working right away.”
The Web site, diaTribe, last fall carried an analysis of all three approaches.
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Tuesday, March 03, 2015

$28 Million California Search for HIV/AIDS Stem Cell Cure Advancing to Clinical Trial

The California stem cell agency today announced that one of its multimillion dollar efforts to come up with a cure for HIV/AIDS is moving into the first stage of clinical trials involving human beings.

The effort includes the City of Hope in Duarte, Ca., the University of Southern California and Sangamo BioSciences, Inc., of Richmond, Ca.

John Zaia
City of Hope photo 
The $3 billion agency is pumping $5.6 million into the clinical trial. Overall, the agency has awarded the lead scientist in the project, John Zaia of the City of Hope, $28.2 million for work involving HIV/AIDS. 

The agency, formally known as the California Institute for Regenerative Medicine (CIRM), said the FDA had approved the initial trial to determine the safety of the treatment.

CIRM’s press release said that the plan is to “take blood stem cells from HIV infected individuals, then treat them with zinc finger nucleases (ZFNs), a kind of molecular scissors, to disrupt the CCR5 gene in those cells. The hope is that this will make those stem cells, and their progeny, resistant to HIV. The modified cells will then be reintroduced into the patient with the hope that they will create a new, AIDS-resistant immune system.”

The effort is intended to replicate what occurred with the “Berlin Patient,” a man who has apparently been cured of AIDS as the result of a mutation.

Jeff Sheehy, a longtime CIRM board member and HIV/AIDS advocate, said in the press release,
“This trial is enrolling HIV patients whose immune cells have not returned to normal levels even after success in suppressing the virus with antiretroviral therapy, and even if it doesn’t lead to a cure it could still result in a therapy that offers clinical benefit to patients at risk for opportunistic infections.”

Zaia said,
‘While we have a number of drugs that are effective in holding HIV at bay, we have nothing that cures it. In addition, for many patients, these medications come with significant long-term problems so there is a real need for a therapy that can help eradicate the virus from a patient completely. That is where our work is focused.”  
The agency is also funding a clinical trial involving an alternative approach to HIV/AIDS. That effort includes UCLA and an Arizona company, Calimmune, Inc., co-founded by a former member of the CIRM governing board, David Baltimore. Calimmune also has an address near UCLA in Los Angeles.

CIRM said,
“Calimmune, an HIV gene medicines company focused on developing cell-based therapies for HIV, began its human clinical trial in July 2013 and has already shown that the first group of patients treated did well enough for the company to start treating a second group more intensively.” 
Jonathan Thomas, chairman of the CIRM board, said,
“This kind of work is too important to just try one method at a time and sit back and wait to see if it is effective.”
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Tuesday, February 24, 2015

California's Consumer Watchdog Loses U.S. Supreme Court Challege to WARF Stem Cell Patents

The U.S. Supreme Court yesterday appeared to have put an end to a California’s group nine-year effort to overturn patents on human embryonic stem cells held by the Wisconsin Alumni Research Foundation (WARF).

The court refused to hear the case that was brought by Consumer Watchdog of Santa Monica, Ca., and Jeanne Loring, head of the stem cell program at Scripps. The court issued its decision with no comment.

An article by Lisa Shuchman in The Litigation Daily said,
“The high court's denial leaves in place a ruling last year by the U.S. Court of Appeals for the Federal Circuit, which found that Consumer Watchdog lacked standing to appeal the findings of the PTO's (Patent and Trademark Office) administrative patent review board.” 
While today’s ruling involved relatively technical legal matters, the heart of the challenge to WARF’s patents involves who profits from stem cell research along with whether its patents have or will stifle scientific research.

Royalties from WARF patents in California alone generated an estimated $200 million in 2006 for the foundation. Executives of biotech firms in California have complained that WARF’s restrictions have posed a significant barrier to private investment. 

Asked for comment, Loring said,
"This doesn't mean they believe that human cells can or cannot be patented, but only that they decided that we had not been sufficiently harmed by the patent for them to become involved.
"Even without a Supreme Court decision, we have succeeded.  WARF wanted their patents to include iPS cells as well as ES cells, but they had to narrow their claims as a result of our challenge, and they cannot claim ownership of iPSCs."  
Doing the legal lifting in the WARF challenge was Dan Ravicher, executive director of the Public Patent Foundation of New York. Shuchman carried a comment from Ravicher on yesterday’s ruling. She wrote, 
“Ravicher said Monday that the Supreme Court's decision could impact many would-be patent challengers. ‘This case could have severe consequences for other third parties that challenge patents with IPRs or the other proceedings created under the America Invents Act,’ Ravicher said. ‘Now they will have no right to appeal an adverse decision.’
“But he also said the decision wouldn't preclude individuals who can claim direct harm, such as stem cell research scientists, from challenging WARF's patent—much the same way doctors successfully challenged the Myriad patents.
“Under the America Invents Act, third parties, such as nonprofits, public interest groups and industry organizations, have the right to challenge patents at the PTAB (Patent Trial and Appeal Board). But under the Federal Circuit’s ruling that now stands, they don't have the right to appeal a PTAB decision.”
Shuchman also recounted briefly some unusual history on the federal appellate ruling that declared Consumer Watchdog had no standing to sue. A more detailed account of that hearing can be found here.

The California Stem Cell Report has asked Consumer Watchdog and WARF for comments. We will carry them when we receive them. Here is the full text of what Loring had to say.
"Being involved for nearly 9 years in the challenge of WARF's patent on human ES cells has given me a fascinating glimpse into our legal system. I hoped that the Supreme Court would decide on the patentability of human embryonic stem cells. But ultimately, the Court decided not to take our case.  This doesn't mean they believe that human cells can or cannot be patented, but only that they decided that we had not been sufficiently harmed by the patent for them to become involved. Even without a Supreme Court decision, we have succeeded.  WARF wanted their patents to include iPS cells as well as ES cells, but they had to narrow their claims as a result of our challenge, and they cannot claim ownership of iPSCs.  
"I've learned that the law is every bit as complex as scientific research, and have gained great admiration for people like our attorney, Dan Ravicher, who relentlessly pursue the question of patent ethics - what should and should not be patented in the public interest.  Dan brought the issue of patenting the human genome to the Court, and won (the Myriad Genetics case).  Working on this challenge with Dan and John Simpson (of Consumer Watchdog) has been a joy, and if they ever want my help in the future, I'd agree in a second."
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Monday, February 23, 2015

A Critical Perspective: Klein's $100 Billion Stem Cell/Genomics Plan 'Boggles the Mind'

The San Diego U-T newspaper today reported the first criticism of the $100 billion stem cell/genomics research plan being floated by the former chairman of the California stem cell agency, Bob Klein.

The challenge to the proposal came from John Simpson of Consumer Watchdog of Santa Monica, Ca., in an article by reporter Bradley Fikes.

Simpson, a longtime observer of the agency and once heavily involved in formulation of its intellectual property rules, said the proposal for the international consortium “boggles the mind.”

Fikes reported that Simpson found the international plan flawed on several counts: It would lock money into specific areas of research regardless of the state of the science; it would be cumbersome to run, and it would be expensive because it would use borrowed money.

Fikes wrote,  
"’I don't understand how this could possibly work,’ Simpson said in a Monday interview. ‘The logistics of getting together such a (15 nation) coalition boggles the mind.’”
Simpson said Klein, a real estate investment banker who left the agency in 2011, was peddling illusory benefits. Fikes reported,
"'That's the same premise as he's tried to argue with Prop. 71, and I don't think that's been true at all,’ Simpson said. While the (California stem cell) program has resulted in some major research advances, it hasn't yet generated enough of an economic return and proven treatments to justify it, he said.
"'Pay as you can afford to pay,’ Simpson said. ‘I think that's a better approach to research, generally. That's what democratically elected governments are supposed to do, is come up with appropriate funding for the various things they're faced with. If you had this kind of money to throw at certain problems, it's not entirely clear to me, by any means, that stem cells would have the biggest impact. You might do a hell of a lot more with simple things like malaria eradication.’" 
Fikes wrapped Simpson’s critique into the earlier version of his article on Klein’s plan.
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$100 Billion Stem/Genomics Plan: Borrowing on an International Scale

Bob Klein at UC San Diego last week
Bradley Fikes/San Diego U-T photo
More details are emerging on the $100 billion, international stem cell/genomics research proposal being offered up by Bob Klein, the first chairman of California’s stem cell agency.

Klein’s plan was discussed in a piece by Bradley Fikes of the San Diego U-T, the only daily newspaper in California’s second largest city. The article yesterday also carried videos of Klein pitching his plan.

Klein, a real estate investment banker, cited California’s $3 billion stem cell agency as an example to be emulated internationally. It operates on money that the state borrows (bonds), which roughly doubles the cost of the research because of the interest expense.

He said an international research organization could be supported by bonds which are backed by pledges from 15 countries, including the United States.

Fikes quoted Klein, who left the California agency three years ago, as saying,
"Because the borrowing is so much cheaper than anything a country can do, from the surplus funds we raise, which are about 35 percent to 40 percent more than most countries can raise from the same amount of money, we can have an international pool, where we can collaborate and compete through peer review." 
Fikes continued,
“Klein pointed to the International Finance Facility for Immunization as an international public-private partnership as a financial model. Using long-term government pledges as collateral, the agency can raise capital as needed from the bond markets.” 
Neither the Fikes piece nor an earlier article from the San Diego Daily Transcript carried any indication that Klein’s proposal had the support of major research organizations or governmental agencies.  

Neither article also carried any reference to Klein’s earlier proposal for another $5 billion bond issue to continue the operations of the California stem cell agency, which will run out of money in 2020 based on current spending rates.

Klein and U.S. Rep. Scott Peters, D-San Diego, shared an appearance at a cancer conference last week at UC San Diego. Both extolled the power of using patient advocates as the leading edge of lobbying for research funds.

Fikes wrote,
“Peters…said scientists must broaden their political base beyond their traditional bastions if they wish to become more influential. Patient advocates are key.
"'When we're fighting for NIH funding, a lot of the voices for that come from people who are in universities and in areas of science, and a fairly narrow political spectrum,’ Peters said. ‘Frankly, they tend to be people from Boston, and San Francisco and San Diego, who don't always vote the same way that people from West Texas, or Kansas or rural Wisconsin vote. So patient advocates provide a huge imput for folks from all across the country."
“Klein recounted an example of how that coalition succeeded in keeping diabetes research money flowing in 2002 when that funding was threatened with interruption. He said the bill, which required unanimous consent, got through the House with the support of then-House Speaker Denny Hastert, an Illinois Republican, who had a staff member with Type 1 diabetes."
Fikes continued,
"'Oklahoma is not a hotbed of scientific support, but through a weekend effort, JDRF (Juvenile Diabetes Research Foundation) was able to get 25,000 emails generated,' Klein said. ‘But more importantly, the patient advocates working as informed advocates with the scientists from the Type 1 research and clinical areas got to enough chairmen of the boards and board members and CEOS of major corporations in Oklahoma that they shut down the switchboards of Sen. Nickles' offices in Oklahoma and Washington D.C. with calls.’"
“Nickles released his hold on the bill.
"'We had unanimous consent of the U.S. Senate, two hours before the end of the special session, because scientists informed and teamed up with patient advocates ... ' Klein said."
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Sunday, February 22, 2015

Prodigious Pricing and Stem Cell Treatments: Implications for the California Stem Cell Agency

The most widely read item in the last 10 years on the California Stem Cell Report is one that deals with the cost of a possible stem cell treatment.

Newscom image
The piece contains a $512,000 figure and has chalked up 10,714 page views as of this evening. It deals only with a potential treatment in a fully legal and medically acceptable situation. The item is also nearly two years old. The $512,000 number is likely to have been modified by the researchers involved.

Now comes an item by UC Davis stem cell researcher Paul Knoepfler, who has put together a survey of prices of stem cell “treatments” that are being offered around the world. The costs are for procedures available largely outside established medicine with its accompanying government certification and testing.

Knoepfler reported today on his blog that American clinics – non-FDA approved – run about $10,000 per procedure, with more than one treatment usually described as necessary. Outside of the United States, the procedures run up to $100,000.

Knoepfler wrote,
“Whether inside or outside the US, insurance does not cover the costs of these potentially dangerous, unproven treatments.”
He noted that high profits are associated with the procedures. He said,  
“Part of the way that clinics cut corners to boost their profits is by not following FDA regulations, putting patients in danger. Clinics typically do not do pre-clinical studies to get evidence of safety and efficacy before starting to sell their offerings to patients. Clinics also do not include sufficient follow up in the cost of the treatments. They do not publish their data to get peer review and feedback. They often do not have GMP compliant facilities or devices.”
Knoepfler concluded,
“Of course other costs to patients going to dubious clinics, sometimes not considered, include the price of false hope, potential injury due to dangerous stem cell ‘treatments,’ possibly being excluded from a real clinical trial in the future and injury from deferring other arguably more real treatments.”
The high readership on the 2013 cost item on the California Stem Cell Report is likely due to readers who are considering some sort of stem cell procedure.  Knoepfler will also likely see a similar trend.

The strong interest in stem cell costs is something for the California stem cell agency to consider as it invests in clinical trials. Obviously the expense is of considerable concern to those not ensconced within the stem cell community, where the focus is on a euphemism called "reimbursement," shorthand for making a handsome profit.  Stem cell insiders sometimes shrug off the possibility of a severe, negative kickback on prices. 

But it has already happened in other areas of medicine. A physician protest involving the cost of a particular cancer treatment received national attention in 2013. The article about it in the New York Times received 500 reader comments.  

Obviously no stem cell therapies will reach the marketplace if they do not offer the potential for profit. Nonetheless, if one of the California agency's trials is successful but also carries a prodigious pricetag, California taxpayers who have financed the agency are likely to look askance at the agency’s work.
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Friday, February 20, 2015

California's Bob Klein Proposes $100 Billion, International Stem Cell/Genomics Venture

The man some consider the father of the California stem cell agency has come up with another grand research plan – a $100 billion, 14-nation effort plus California, along with creation of a federal research “trust.”

The proposal comes from Robert Klein, who led the 2004 ballot campaign to create the $3 billion state stem cell agency. He was also its first chairman and a figure revered by some.

Katherine Connor of the San Diego Transcript reported today on Klein’s quest for a “new paradigm in funding scientific research.” During remarks at an oncology symposium yesterday at UC San Diego, Klein said his collaborative venture is needed given the current state of federal research funding. 

Connor wrote,
Robert Klein
“Klein is working on spearheading such a collaboration, where 22 different partners -- including 14 nations, the NIH and the state of California -- commit to long-term funding of scientific research on stem cells and genomics via a World Bank bond. The money invested by each partner would be used to fund work by that entity." 
Connor continued,
“He said if Congress would appropriate a long-term commitment to support this international bond, the research community could leverage it up to a $100 billion program with surplus funds around 35 to 40 percent more than what each individual country or partner could raise from the same amount of money.” 
Klein is a California real estate investment banker who works closely with bond financing. He said his proposed research venture “would go a long way in diffusing the ingrained competitive attitude toward funding.”

Connor continued,
“'The fundamental problem here is that, long term, we have difficulty holding these interest groups together,' Klein said. ‘In California, with Prop. 71, the way it approached that was if you have a unitary decision, you’re either for the bond or against the bond. You can’t go and say 'I want my appropriation,' you have a unitary decision -- it brings all those groups together as a coalition, they have to work together.’”
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Thursday, February 19, 2015

The ViaCyte Diabetes Trial: Clarifying a Patient Matter

The ViaCyte clinical trial is aimed at producing a “virtual” cure for Type 1 diabetes among children, but the first implantation of the device involved an adult man.

That information was reported by the MIT Technology Review and raised a question about whether the article was in error or whether something else was involved.

The California Stem Cell Report queried Paul Laikind, CEO of ViaCyte, which is based in San Diego, about the matter.

Laikind replied,
“This first clinical trial of VC-01, called STEP ONE*, requires patients to be 18 to 55 years old (see  Once we have gained experience with VC-01 and assuming that it is shown to be safe and effective in the adult population we would expect a follow up protocol to include children with T1D.”  
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