3 CIRM challenges: search for new prez, funding, & clinical POW!

The idea of CIRM as a dedicated state stem cell agency was one of the things that got me excited about starting my time as a professor doing research on stem cells in California way back in 2005-2006 on the job hunt. Fast forwarding to today now 11 years later, CIRM is still on the cutting edge, but some major things have changed for California’s stem cell agency and as it looks to its future, the questions and challenges are different too.CIRM 2.0

By analogy, the original CIRM was at first like a stem cell itself navigating its differentiation branches as it went. The new CIRM of 2017, what some call CIRM 2.0, is in contrast more like a developing tissue. It has matured and has a history to build upon as it continues. Today CIRM and its staff aren’t newbies. They were newbies by necessity when I came to California in 2006 because they were literally inventing themselves with no past example to use as a model. Now they are stem cell veterans and CIRM is trying to sort out its fresh path ahead relative to its current path rather than strike a path from scratch.

Three key areas need tackling to navigate the new path for maximum positive impact.

Funding. Does CIRM 2.0 and its backers go for a “Prop 71 2.0” to get another round of California state funding? If so, how much and how to approach the voters? If not (or if “yes”, but the effort isn’t successful), where does CIRM get its funding to continue? Of course, in theory a third option is that CIRM simply ends when its current funding runs out, but to me that’s not a real option. CIRM cannot end because it has so much more to do and it is in some ways just getting to the most exciting part: the bedside part of the bench-to-bedside path. Update: over at California Stem Cell Report, David Jensen has the scoop on an industry-centric stem cell bond proposal idea.

New Prez. CIRM 2.0 President and CEO Randy Mills announced the surprising news recently that he’s moving on from CIRM after a relatively short, but impactful tenure. Who will be the new CIRM President? It’s anybody’s guess at this point, but I’d say that CIRM needs to achieve two things at once here: move very quickly to get a new leader and make that leader be a fantastic choice for CIRM. What exactly do I mean by the latter? The new CIRM President ideally should have impeccable stem cell credentials and also big picture clinical vision as well as strong leadership skills. I asked CIRM where things stand on the President search today and CIRM Sr. Director Public Communications & Patient Advocate Outreach, Kevin McCormack, provided this quote:

“the Presidential Search subcommittee is going to be meeting on July 17th to evaluate the options regarding appointing a permanent President and CEO to replace Randy. They’ll then make their recommendations to the full Board.”

I’m planning a future post to throw some names out on the table for discussion of people who might be considered for the position by CIRM.

Clinical POW! CIRM’s mission is focused on having transformative clinical impact so the agency needs some snap, crackle, and POW! on that front moving forward. It already has provided key support for a number of ongoing clinical trials and the goal moving forward is final approved products that are proven safe and effective. I would call that some stem cell POW! Not everything is going to be a success, but I predict that some will.

I believe that CIRM has the potential to achieve all this. That doesn’t mean it’ll be easy, but what great things have ever been easy?

President Mills Leaving, CIRM Needs New Leader to Navigate Future Challenges

Randy MillsCIRM announced today that its President and CEO, Randy Mills, is soon leaving for a new job as President of the National Marrow Donor Program/Be The Match in Minnesota. Update: Dr. Maria Millan, the CIRM Vice President of Therapeutics, will be its leader starting July 1 until a new leader is chosen.

For this kind of position three years is a relatively short tenure so CIRM will need to scramble a bit to keep continuity and momentum as it searches for and ultimately puts in place a new leader. It’s a critical time for CIRM as it and its allies consider big picture strategy for the future, approaches to future funding such as a possible new proposition for state funding (Prop 71 2.0), and how to continue all those exciting clinical trials and research beyond the current period of its funding.

In general, Mills had a big positive impact on CIRM and helped it go to the next level. About the only thing I wasn’t a fan of in terms of his leadership was my perception of his negativity toward the FDA and toward FDA oversight of stem cells, and how that manifested at CIRM during his time there. But good people can strongly disagree on policy. We’ll have to wait and see how the regulatory experiment of stem cell provisions in the 21st Century Cures Act, which Mills may have helped to make possible, will impact regenerative medicine in terms of changes in FDA oversight. It could also impact CIRM too.

Now CIRM’s Board has an exciting, difficult task ahead. Who do they want as their new leader to tackle CIRM’s challenge? What kind of background and future vision? The priorities, leadership skills, and vision of the new leader are likely to together be a major factor in CIRM’s future success. Who are the top possible candidates out there right now? I’m going to do a follow-up, future post on these questions and CIRM’s future.

The backstory on my opinion piece in SF Chronicle critical of CIRM lobbying

Today an opinion piece that I wrote about CIRM was published in the San Francisco Chronicle. The unusual element here is that the article is critical of CIRM. More specifically I raised concerns about a recent political trend at CIRM under its new President Randy Mills lobbying for dramatically weaker stem cell regulatory oversight. The Chronicle piece was first posted online on Thursday on the paper’s website. I encourage you to read it when you get a chance.

CIRM 2.0

For a decade I have been one of the most consistent voices advocating for CIRM, its future, and all the great things that it does so it wasn’t an easy decision to publicly criticize the agency at this point. I’m still a big backer of CIRM, which made this even harder.

For me the tipping point to action was Mills’ recent opinion piece on Fox News with former Republican Senator Bill Frist that I believe was anti-FDA in tone and utilized hype (e.g. words like “miracles”, “gift”, and “beautiful” medicine) to promote a deregulatory agenda. This extreme plan includes conditional approval of unproven stem cell therapies and elimination of the requirement for Phase III clinical trials in certain cases, which would be very risky to patients and the stem cell field.

Mills also recently gave a speech at a conservative group (the self-styled “Bipartisan” Policy Center or BPC at which Frist is a leader) that counterproductively characterized the FDA as the one big problem for the field. Note that BPC also wants to charge patients to be in clinical trials to get experimental therapies. Historically if anything changed hands in such situations it was patients getting something in return for being so brave to be in clinical trials.

As I pointed out in my opinion piece in the Chronicle, the stem cell status quo is not getting the job done, but this is only in part due to the FDA and the changes that BPC and CIRM are advocating for are too radical. These proposed changes also fit with the REGROW Act, a bill that would codify many of them. REGROW would force the FDA to conditionally approve stem cell therapies that frankly are just not ready for primetime, putting patients at great risk. Note that the big changes being lobbied for in FDA regulations would only apply to adult stem cells. I favor more careful changes at the FDA such as using Breakthrough designation for stem cells, something the FDA has not yet done. They should.

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Stem Cells on the Mesa: Highlights from Heather Main

By Heather Main

Mesa, one of my first Spanish words since moving to California. The isolated flat-topped hill with steep sides where I have just had the pleasure of listening to some of the best basic and applied science. Mountains of various sorts formed the metaphor of CIRM 2.0 with Randy Mills (President/CEO of CIRM) describing the ‘giant boulder of love and happiness’ that academia pushes and industry pulls over the mountain of regulation, safety and efficacy bringing cures to patients. The streamlining of regulation makes the mountain smaller to decrease both the push and pull needed.

The meeting was a nice mix of academic and applied research, highly evident was the drive that CIRM funding has ignited in California. Of interest, after 5 years of 91% academic CIRM funding, the next 5 years is focusing towards critical funding towards industry translational projects…CIRM 2.0

Listening to Elaine Fuchs makes you question your worth in the field and when this woman will get a Nobel Prize for her contributions to stem cell sciences. The number of ‘Cell’ and ‘Nature’ references with her name on it in her talk demonstrate her unique ability to conquer the highest levels of science consistently throughout her career. A career spanning therapeutic skin stem cell application to stem cell niche determination, quiescent stem cell identification and now cancer stem cell quiescence, the lessons outlined by Elaine’s Keynote address form a foundation basis for stem cell sciences in both cellular therapy and cancer applications.

Other highlights for me included:Stephanie Cherqui, Ph.D

Stephanie Cherqui (at right), discussed the nanotubular highways for intercellular organelle transport with HSC cellular therapies that lead to macrophage differentiation and delivery of healthy lysosomes for Cystinosis disease rescue phenotypes.

Samuel Pfaff talked about his lab’s identification of miR218 as the most specific motor neuron marker known to date and the mechanistic possibility of its loss of activity, leading to an increase in gene expression deleterious to motor neuron survival, a possible mechanism for ALS.

Shyni Varghese (at left)Shyni Varhese, gave a great talk on production of bone from endogenously recruited cells using hydrogels engineered to bind minerals. The minerals were sufficient to produce bone in acellular scaffolds, while absence of mineral loading lead to fat formation. There was even novelty in Isaac Newton shaped bone deposit.

Pilar Ruiz-Lozano discussed amazing results using FSTL1 loaded collagen matrix to rescue heart regeneration following infarction, from mouse to pigs. The specific activity of FSTL1 from epicardium was essential to this regenerative function, in contrast to non-regenerative glycosylated FSTL1 produced in response to injury by the myocardium.

Joseph Metzger discussed stabilization of Duchenne Muscular Dystrophy dystrophic muscle membranes. These Poloxamer 188 ‘band-aids’ strengthen weaknesses in dystrophic membranes to avoid catastrophic Calcium entry that leads to cellular death. While super interesting, this is really a band-aid treatment, as Joseph says, just like Type 1 Diabetes, there is still room for gene and cellular therapy based cures.

The most confusing part of the meeting for me was the Thursday night ‘public forum’. I’m not sure what this means in California but the public forums I have attended have a majority of audience members from the public and attempt to pass knowledge and excitement about stem cells to a lay audience. While there was some fantastic science, I don’t think I would have understood a word in regard to ‘The promise of regenerative medicine: are we there yet?’ if I was a member of the public.

As my first time at Stem Cells on the MESA I was really impressed by the attitude I sensed, that solid science combined with effective clinical and commercial translation strategies are essential to successes in our field. That basic research is not enough. Second, it was nice to see an equal and unbiased appreciation for material sciences applications, gene therapy treatments, cellular therapy applications and endogenous repair applications. Whatever gets to the post first should ‘win’ for the sake of the patient.

Radical, Supercharged Vision for Future of CIRM: Interview with New Prez Mills

Randy MillsChange is in the air for the California stem cell agency, CIRM. It has a new President, Randy Mills, and CIRM is soon going to be like a new agency too.

I recently did an interview with Mills that illuminates some of the big changes that are imminent. I also asked him what his favorite type of stem cell is and his view of the regenerative medicine regulatory changes in Japan relative to those here with the FDA.

Paul: Going from the biotech industry to lead CIRM is a big change. What inspired you to make the change?

Mills:  It was actually a two step process. After 20 years in regenerative medicine, the last 10 as the CEO of a publically traded company, I had actually intended to take some time off from work so I could spend more with my wife and children. Perhaps not to permanently retire, but at least take a step back and do more selective things, like sitting on Boards and such.

As my wife says though, I really stunk at that, and quickly became bored.

So when I received a call from CIRM asking if I were interested in the CEO position I gave it serious consideration. Having spent the past 5 years as a grant reviewer for CIRM, I was already quite familiar with the Agency. If you believe in the potential of regenerative medicine and cell therapy as I do, there is no place in the world you could go to have a bigger impact. No company, no other state, not even a country can have the impact California can have in bringing these treatments to patients.

My interest at CIRM isn’t to “stay the course” – it is to be as innovative as possible to make the agency radically more effective and efficient. And so with that, I accepted the challenge.

Paul: You’ve had some time to get settled in at CIRM. What has surprised you most?

Mills: To the upside – without question, the team at CIRM.  They are really a remarkable group of capable and dedicated professionals. They’re not just good at their job, they really care about the work they do and its ability to impact people’s lives. It is such a gift for a new leader to be able to come into an organization and have such talent to work with.  I have challenged the team to rethink the way we do business at CIRM in a really big way and they have responded to the call, producing CIRM 2.0. I am excited that with the rollout of 2.0, people will be able to see just how talented the team is that I get to work with everyday.

Paul: I’ve heard that you plan to extend CIRM funding of new grant proposals to 2020 based on existing funding. Will this mean less funding per year and will that in turn mean focusing more on fewer priorities? For example, one of the questions I’m most asked about CIRM lately by colleagues: will there be another Basic Bio RFA or are those history now given a more translational/clinical focus moving forward?

Mills: It’s funny, I was able to extend the funding life of CIRM until at least 2020 by using a little trick I once learned called “math.” Not to put to fine of a point on it, but I basically looked at how much money we actually had left to spend (approximately $1 billion) and divided it by how much money we actually awarded each year – about $190 million. And there you have it, 2020.

Now what really made the difference in the projection was correcting some of our previous spending assumptions. For example, if a $100 million concept plan was approved by the Board, we would assume all $100 million was spent, when in actuality we typically only spend a fraction of it.

Also built into the previous projections was an assumption that all money we awarded would be spent. However, CIRM awards are milestone driven – meaning that if the project isn’t working as agreed upon by both parties up front, the program is cancelled. Since this is biotech, we know that not all projects are going to work, and thus we will not actually spend all of the money we award.

As for Basic Biology, we fully intend to continue a modified version of the program. The name will be changed to “Discovery” to reflect the new, more active and driven culture at CIRM. We also may go about it in a different manner. We want to have a much more targeted approach, one that asks people to focus on particular problems that are important and partner with us overcome specific obstacles that are holding back the development of treatments.

Paul: What are your top priorities for the near-term future for CIRM?

Mills: Accelerating stem cell treatments to patients in need – that is our primary goal. Everything else we do is subordinate. We have developed a four-part test that the team and I use as a compass.

First, will what we are doing speed up the development of stem cell treatments for patients? Will it increase the likelihood of a successful treatment reaching patients? Is it for an unmet medical need? And lastly is it efficient?

To accomplish this we are implementing CIRM 2.0, the faster, more responsive version of CIRM that will hopefully give us more high quality stem cell programs.

CIRM 2.0 is actually a term I know you first coined Paul. I really liked the symbolism of it. The 2.0 version of something doesn’t imply that the first version was flawed – like the Ford Pinto. Instead it takes a good product and makes it better – like the iPhone! That is what we are doing with CIRM 2.0. Looking at everything in the process and asking ourselves, “how can we make this better?” We plan to launch the first wave of CIRM 2.0 January 1st, and I think stakeholders are really going to like it.

From there, it is on to CIRM 3.0. For me, it is critical that we never stop thinking of ways to get better.

Paul: What about longer term plans for beyond 2020? Will there be a new California Proposition (e.g. essentially Prop 71 2.0)?

Mills: JT (Jon Thomas, Chairman of CIRM) and I are working on some exciting concepts for how to make CIRM the most effective over the long-term. They are still in the early stages of development, so look for more on this later. In the meantime, it is all hands on deck getting ready for the launch of CIRM 2.0.

Paul: We saw just now that ViaCyte got FDA approval for their IND for Type I Diabetes, which is extremely exciting. Are there other similar companies/products funded by CIRM that seem in the pipeline to achieve similar major milestones in the next 1-2 years?

Mills: Oh sure. By the end of this year alone we expect to have ten programs that are approved for clinical trials. This includes research in cancer, leukemia, heart disease, sickle cell disease, HIV/AIDS and blindness. (You can read about those here http://blog.cirm.ca.gov/2014/11/20/10-years10-therapies-10-years-after-its-founding-cirm-will-have-10-therapies-approved-for-clinical-trials/ )

We have many more promising projects in the pipeline that we hope will get approval for a clinical trial within the next year and, of course, we hope that with CIRM 2.0 that will be able to significantly increase this trend.

Paul: Are there ways that CIRM can become even more collaborative with, supportive of, and synergistic with industry? For example, might there be more building of ties to ARM? 

Mills: Absolutely. The first thing we need to do is improve our product. The second thing we need to do is market it. And this goes for academia as well as industry. If we want to attract the best prospects, we need to have a system that is responsive to their needs.

Under our current process it can take around two years for a successful applicant to actually get funded. No company with a promising therapeutic candidate can afford to wait around for two years, they need to get it into clinical trials now. That’s why we are launching CIRM 2.0, so that we have an opened ended application program, one that is available for the researchers as soon as the product candidate is ready.

As for marketing the program, we think the more the word gets out about this and all of the other great features of CIRM 2.0, the more high quality interest we will see from industry and academia alike.

Paul: One of my pet projects yet to get fully moving, but still quite important I think is formal academic training programs (fellowship/subspecialty; http://www.ncbi.nlm.nih.gov/pubmed/23477401) for physicians in cellular and regenerative medicine.  What do see as CIRM’s role in these kinds of educational initiatives? Would you support academic training of MDs of the specific kind I mentioned?

Mills: If it meets the four-part test, sure, we would consider it. But at this time we don’t currently have an approved concept plan for something like that.

Paul: Do you have a favorite kind of stem cell and why?

Mills: It’s a toss up between mesenchymal mint chip and pluripotent pasticcio – they are both delicious!

In reality, no. I am agnostic as to stem cell type. My favorites are the ones that help patients.

Paul: Looking more broadly, what do you see as the top opportunities and also challenges for the regenerative medicine field today and in the near future?

Mills: This single most important thing for us to do in cell therapy is to generate clear and convincing evidence of efficacy in humans. All of the other major issues surrounding regenerative medicine, such as high product cost and scalability can and will be solved once there is obvious and compelling proof of concept data for a product. Looking ahead, I am really excited about some of the things coming down the CIRM pipeline that have the potential to reach this high standard.

Paul: Can you comment on the draft plan for accelerating the process of review and funding applications?

Mills: CIRM 2.0 is a new, streamlined process making it easier and faster to apply for funding from the stem cell agency designed to attract high quality projects ready to make progress quickly.

In the past it could take up to two years to go from us requesting applications for funding to getting the money out the door as part of an approved contract. CIRM 2.0 simplifies and accelerates the process, cutting that two years down to just four months. And if you miss that deadline you only have to wait one month for the next application deadline to come around.

Every application will be reviewed by an expert budget review group to make sure the proposed budget is appropriate for the scope of the work. If not, the budget reviewers will recommend changes. Then it goes to our independent expert scientific review group which can also recommend changes if they feel those would strengthen the application. Only after we have an application that we are really enthusiastic about, do we forward it to the CIRM Board with a recommendation to fund. Remarkably, we can do all of that in just 81 days.

Also, under CIRM 2.0 you only apply when you have a project that is ready to start within 45 days of it being approved for funding by our Board.

Paul: We recently saw the first patient in history administered an IPSC-based therapy in Japan in a clinical study there. Remarkably this occurred just 7 years after the first published report of human IPSCs. Could you comment on the different regulatory framework in place in Japan that made such an acceleration of bench-bedside possible. Do you favor such an approach in the US?

Mills: The approach in Japan has evolved over the past decade. The PMDA (the Japanese version of FDA) was not always so friendly to stem cell therapy. Having been directly involved for the past decade in the development of the first allogeneic stem cell product submitted for approval in Japan, I can tell you that the PMDA has moved a long way in their thinking.

It gives me hope that the FDA might reconsider its approach on certain issues relating to stem cell development.