Hitting our Goals: Let’s start at the beginning shall we

Way, way back in 2015 – seems like a lifetime ago doesn’t it – the team at CIRM sat down and planned out our Big 6 goals for the next five years. The end result was a Strategic Plan that was bold, ambitious and set us on course to do great things or kill ourselves trying. Well, looking back we can take some pride in saying we did a really fine job, hitting almost every goal and exceeding them in some cases. So, as we plan our next five-year Strategic Plan we thought it worthwhile to look back at where we started and what we achieved. Goal #3 was Discover.

When journalists write about science a lot of the attention is often focused on clinical trials. It’s not too surprising, that’s the stage where you see if treatments really work in people and not just in the lab. But long before you get to the clinical trial stage there’s a huge amount of work that has to be done. The starting point for that work is in the Discovery stage, if it works there it moves to the Translational stage, and only after that, assuming it’s still looking promising, does it start thinking about moving into the clinic.

The Discovery, or basic, stage of research is where ideas are tested to see if they have any promise and have the potential to lead to the development of a therapy or device that could ultimately help patients. In many ways the goal of Discovery research is to gain a better understanding of how, in our case, stem cells work, and how to harness that power to treat particular diseases or disorders.

Without a rigorous Discovery research program you can’t begin to create a pipeline of promising projects that you can advance towards patients. And of course having a strong Discovery program is not much use if you don’t have somewhere for those projects to advance to, namely Translational and ultimately clinical.

So, when we were laying out our Strategic Plan goals back in 2015 we wanted to create a pipeline for all three programs, moving the most promising ones forward. So we set an ambitious goal.

Introduce 50 new therapeutic or device candidates into development.

Now this doesn’t mean just fund 50 projects hoping to develop a new therapy or device. A lot of studies that are funded, particularly at the earliest stages, have a good idea that just doesn’t pan out. In fact one quite common definition of early research – in this case from Translational Medicine Communications – is “the earliest stage of research, conducted for the advancement of knowledge, often without any concern for its practical applications.

That’s not what we wanted. We aren’t in this to do research just for its own sake. We fund research because we want it to lead somewhere, we want it to have a practical application. We want to fund projects that actually ended up with something much more promising, a candidate that might actually work and was ready to move into the next level of research to test it further.

And we almost, almost made it to the 50-candidate goal. We got to 46 and almost certainly would have made it to 50 if we hadn’t run out of money. Even so, that’s pretty impressive. There are now 46 projects ready to move on, or are already moving on, to the next level of research.

Of course, there’s no guarantee that these will ultimately end up as an FDA-approved therapy or device. But if you don’t set goals, you’ll never score. And now, thanks to the passage of Proposition 14, we have a chance to support those projects as they move forward.

Three UC’s Join Forces to Launch CRISPR Clinical Trial Targeting Sickle Cell Disease

Sickle shaped red blood cells

The University of California, San Francisco (UCSF), in collaboration with UC Berkeley (UCB) and UC Los Angeles (UCLA), have been given permission by the US Food and Drug Administration (FDA) to launch a first-in-human clinical trial using CRISPR technology as a gene-editing technique to cure Sickle Cell Disease.

This research has been funded by CIRM from the early stages and, in a co-funding partnership with theNational Heart, Lung, and Blood Institute under the Cure Sickle Cell initiatve, CIRM supported the work that allowed this program to gain FDA permission to proceed into clinical trials.    

Sickle Cell Disease is a blood disorder that affects around 100,000 people, mostly Black and Latinx people in the US. It is caused by a single genetic mutation that results in the production of “sickle” shaped red blood cells. Normal red blood cells are round and smooth and flow easily through blood vessels. But the sickle-shaped ones are rigid and brittle and clump together, clogging vessels and causing painful crisis episodes, recurrent hospitalization, multi-organ damage and mini-strokes.    

The three UC’s have combined their respective expertise to bring this program forward.

The CRISPR-Cas9 technology was developed by UC Berkeley’s Nobel laureate Jennifer Doudna, PhD. UCLA is a collaborating site, with expertise in genetic analysis and cell manufacturing and UCSF Benioff Children’s Hospital Oakland is the lead clinical center, leveraging its renowned expertise in cord blood and marrow transplantation and in gene therapy for sickle cell disease.

The approach involves retrieving blood stem cells from the patient and, using a technique involving electrical pulses, these cells are treated to correct the mutation using CRISPR technology. The corrected cells will then be transplanted back into the patient.

Dr. Mark Walters

In a news release, UCSF’s Dr. Mark Walters, the principal investigator of the project, says using this new gene-editing approach could be a game-changer. “This therapy has the potential to transform sickle cell disease care by producing an accessible, curative treatment that is safer than the current therapy of stem cell transplant from a healthy bone marrow donor. If this is successfully applied in young patients, it has the potential to prevent irreversible complications of the disease. Based on our experience with bone marrow transplants, we predict that correcting 20% of the genes should be sufficient to out-compete the native sickle cells and have a strong clinical benefit.”

Dr. Maria T. Millan, President & CEO of CIRM, said this collaborative approach can be a model for tackling other diseases. “When we entered into our partnership with the NHLBI we hoped that combining our resources and expertise could accelerate the development of cell and gene therapies for SCD. And now to see these three UC institutions collaborating on bringing this therapy to patients is truly exciting and highlights how working together we can achieve far more than just operating individually.”

The 4-year study will include six adults and three adolescents with severe sickle cell disease. It is planned to begin this summer in Oakland and Los Angeles.

The three UCs combined to produce a video to accompany news about the trial. Here it is:

Prime Time for Rocket

Rocket Pharmaceuticals, a company that specializes in developing genetic therapies for rare childhood disorders, just got a big boost from the European Medicines Agency (EMA). They were given a Priority Medicines (PRIME) designation for their therapy for Leukocyte Adhesion Deficiency-1 (LAD-1).

CIRM is funding ($6.56 million) Rocket’s clinical trial for LAD-I, an immune disorder that leaves patients vulnerable to repeated infections that often results in death within the first two years of life. The therapy involves taking some of the child’s own blood stem cells and, in the lab, correcting the mutation that causes LAD-I, then returning those cells to the patient. Hopefully those blood stem cells then create a new, healthy blood supply and repair the immune system.

The therapy, called RP-L201, is already showing promise in the clinical trial, hence the PRIME designation. The program was set up to help speed up development and evaluation of therapies that could help patients who have limited treatment options. Getting a PRIME designation means it is considered a priority by EMA and could reach patients sooner.

In the US, Rocket has won similar recognition from the Food and Drug Administration (FDA) and has been granted Regenerative Medicine Advanced Therapy (RMAT), Rare Pediatric Disease, and Fast Track designations.

In a news release Kinnari Patel, President and Chief Operating Officer of Rocket, said the designation showed that regulators understand the urgent need to develop a therapy for patients with LAD-1. “More than half of LAD-I patients suffer with a severe variant in which mortality occurs in up to 75% of young children who don’t receive a successful bone marrow transplant by the age of two. Securing all possible accelerated designations will enable us to collaborate with both the FDA and EMA to speed the development and delivery of a potential treatment for these patients.  We look forward to sharing initial Phase 2 data from our potentially registration-enabling LAD-I trial in the second quarter of 2021.”

That trial has now completed enrolling patients (nine altogether) but their treatments are not yet complete. LAD-1 patients with severe disease have low levels of a key protein called CD18, usually less than 2%. Of the first three patients treated in this trial CD18 levels are all higher than the 4-10% threshold considered necessary for these children to survive into adulthood. Another encouraging sign is that there were no serious side effects from the therapy.

Obviously there is still a long way to go before we know if this therapy really works, but the PRIME designation – along with the similar ones in the US – are recognition that this is a very promising start.

Hitting our Goals: Scoring a half century

Way, way back in 2015 – seems like a lifetime ago doesn’t it – the team at CIRM sat down and planned out our Big 6 goals for the next five years. The end result was a Strategic Plan that was bold, ambitious and set us on course to do great things or kill ourselves trying. Well, looking back we can take some pride in saying we did a really fine job, hitting almost every goal and exceeding them in some cases. So, as we plan our next five-year Strategic Plan we thought it worthwhile to look back at where we started and what we achieved. Goal #2 was Expand.

Scientist preparing a sample vial for automated analysis in the lab.

When CIRM first started there was an internal report that said if we managed to help get one project into a clinical trial before we ran out of money we would be doing well. At the time that seemed quite reasonable. The field was still very much in its infancy and most of the projects we were funding, particularly in the early days, were Discovery or basic research projects.

But as the field advanced we got a little bolder. By 2010 we were funding not just our first clinical trial, but the first clinical trial in the world using embryonic stem cells. This was the Geron trial targeting spinal cord injury. Sadly the excitement didn’t last very long. After treating just five patients Geron pulled the plug on the trial, deciding that targeting cancer was a better bet.

Happily, Geron returned all the money we had loaned them, plus interest, so we were able to use that to fund more research. Soon enough we had a number of other promising candidates heading towards a meeting with the US Food and Drug Administration (FDA) to try and get permission to start a clinical trial.

By 2014, ten years after we began, we actually had ten projects either running or getting ready to start a clinical trial. We thought that was really good. But at CIRM, really good is never good enough.

For our Strategic Plan in 2015 we decided to shoot for the moon and aim to get another 50 clinical trials over the next five years. At the time it seemed, to be honest, a bit bonkers. How on earth were we going to do that. But then our Therapeutics team went a hunting!

In the past we had the luxury of mostly just waiting for people with promising projects to approach us for funding. With an ambitious goal of getting 50 more clinical trials, we couldn’t afford to wait. The Therapeutics team scouted around for promising projects, inside and outside California, inside and outside the US, and pitched them on the benefits of applying for funding. Slowly the numbers started to rise.

By the end of 2016 we had 12 new trials. In 2017 we were really cruising along, adding 16 more trials. 2018 there was another 14 and that was also the year we passed the 50 clinical trials total since CIRM was created. We celebrated at a Board meeting with a balloon and a cake (we’re a state agency, our budget doesn’t extend to confetti). Initially the inscription on the cake read ‘Congratulations: 50 Clinical Trails’. Happily, we were able to fix it before anyone noticed. But even with the spelling error, it would still have tasted just fine.

Patient advocate Rich Lajara with the Big Balloon celebration for funding 50 clinical trials

By the time we got to mid-2020 we were stuck on 47 and with time, and money, running out it looked like we might miss the goal. But then our team put in one last effort and with weeks to spare we funded four more clinical trials for a total of 51 (68 since we started in 2004).

So, the moral is dream big but work hard. Now let’s see what we can dream up for our next Strategic Plan.

Going the extra mile to save a patient’s life

You can tell an awful lot about a company by the people it hires and the ability it gives them to do their job in an ethical, principled way. By that measure Rocket Pharma is a pretty darn cool company.

Rocket Pharma is running a CIRM-funded clinical trial for Leukocyte Adhesion Deficiency-I (LAD-I), a rare genetic immune disorder that leaves patients vulnerable to repeated infections that often results in death within the first two years of life. The therapy involves taking some of the child’s own blood stem cells and, in the lab, correcting the mutation that causes LAD-I, then returning those cells to the patient. Hopefully those blood stem cells then create a new, healthy blood supply and repair the immune system.

So far, they have treated the majority of the nine patients in this Phase 1/2 clinical trial. Here’s the story of three of those children, all from the same family. Every patient’s path to the treatment has been uniquely challenging. For one family, it’s been a long, rough road, but one that shows how committed Rocket Pharma (Rocket) is to helping people in need.

The patient, a young girl, is from India. The family has already lost one child to what was almost certainly LAD-I, and now they faced the very real prospect of losing their daughter too. She had already suffered numerous infections and the future looked bleak. Fortunately, the team at Rocket heard about her and decided they wanted to help enroll her in their clinical trial.

Dr. Gayatri Rao, Rocket Pharmaceuticals

Dr. Gayatri Rao, the Global Program Head for the LAD-I therapy, this patient was about 6 months old when they heard about her: “She had already been in and out of the hospital numerous times so the family were really interested in enrolling the patient. But getting the family to the US was daunting.”

Over the course of several months, the team at Rocket helped navigate the complicated immigration process. Because the parents and child would need to make several trips to the US for treatment and follow-up exams they would need multiple-entry visas. “Just to get all the paper work necessary was a monumental task. Everything had to be translated because the family didn’t speak English. By the time the family flew to Delhi for their visa interview they had a dossier that filled a 3 inch binder.”  Rocket worked closely with partners in India to provide the family on-the-ground support every step of the way.  To help ensure the family received the visas they needed, Rocket also reached out to members of Congress and six members wrote in support of the family’s application.

Finally, everything fell into place. The family had the visas, all the travel arrangements were made. The Rocket team had even found an apartment near the UCLA campus where the family would stay during the treatment and stocked it with Indian food.

But on the eve of their flight to the US, the coronavirus pandemic hit. International flights were cancelled. Borders were closed. A year of work was put on hold and, more important, the little girl’s life hung in the balance.

Over the course of the next few months the little girl suffered several infections and had to be hospitalized. The family caught COVID and had to undergo quarantine till they recovered. But still the Rocket team kept working on a plan to bring them to the US. Finally, in late January, as vaccines became available and international flights opened up once again, the family were able to come to the US. One west-coast based Rocket team member even made sure that upon arriving to the apartment in UCLA, there was a home-cooked meal, a kitchen stocked with groceries, and handmade cards welcoming them to help transition the family into their new temporary “home.” They are now in living in that apartment near UCLA, waiting for the treatment to start.

Gayatri says it would have been easy to say: “this is too hard” and try to find another patient in the trial, but no one at Rocket wanted to do that: “Once a patient gets identified, we feel like we know them and the team feels invested in doing everything we can for them. We know it may not work out. But at the end of the day, we recognize that this child often has no other choices, and that motivates us to keep going despite the challenges.  If anything, this experience has taught us that with persistence and creativity, we can surmount these challenges.”

Maybe doing the right thing brings its own rewards, because this earlier this month Rocket was granted Regenerative Medicine Advanced Therapy (RMAT) designation for their treatment for LAD-I. This is a big deal because it means the therapy has already shown it appears to be safe and potentially beneficial to patients, so the designation means that if it continues to be safe and effective it may be eligible for a faster, more streamlined approval process. And that means it can get to the patients who need it, outside of a clinical trial, faster.

Hitting our goals: regulatory reform

Way, way back in 2015 – seems like a lifetime ago doesn’t it – the team at CIRM sat down and planned out our Big 6 goals for the next five years. The end result was a Strategic Plan that was bold, ambitious and set us on course to do great things or kill ourselves trying. Well, looking back we can take some pride in saying we did a really fine job, hitting almost every goal and exceeding them in some cases. So, as we plan our next five-year Strategic Plan we thought it worthwhile to look back at where we started and what we achieved. We are going to start with Regulatory Reform.

The political landscape in 2015 was dramatically different than it is today. Compared to more conventional drugs and therapies stem cells were considered a new, and very different, approach to treating diseases and disorders. At the time the US Food and Drug Administration (FDA) was taking a very cautious approach to approving any stem cell therapies for a clinical trial.

A survey of CIRM stakeholders found that 70% said the FDA was “the biggest impediment for the development of stem cell treatments.” One therapy, touted by the FDA as a success story, had such a high clinical development hurdle placed on it that by the time it was finally approved, five years later, its market potential had significantly eroded and the product failed commercially. As one stakeholder said: “Is perfect becoming the enemy of better?”

So, we set ourselves a goal of establishing a new regulatory paradigm, working with Congress, academia, industry, and patients, to bring about real change at the FDA and to find ways to win faster approval for promising stem cell therapies, without in any way endangering patients.

It seemed rather ambitious at the time, but achieving that goal happened much faster than any of us anticipated. With a sustained campaign by CIRM and other industry leaders, working with the patient advocacy groups, the FDA, Congress, and President Obama, the 21st Century Cures Act was signed into law on December 13, 2016.

President Obama signs the 21st Century Cures Act.
Photo courtesy of NBC News

The law did something quite radical; it made the perspectives of patients an integral part of the FDA’s decision-making and approval process in the development of drugs, biological products and devices. And it sped up the review process by:

In a way the FDA took its foot off the brake but didn’t hit the accelerator, so the process moved faster, but in a safe, manageable way.

Fast forward to today and eight projects that CIRM funds have been granted RMAT designation. We have become allies with the FDA in helping advance the field. We have created a unique partnership with the National Heart, Lung and Blood Institute (NHLBI) to support the Cure Sickle Cell initiative and accelerate the development of cell and gene therapies for sickle cell disease.

The landscape has changed since we set a goal of regulatory reform. We still have work to do. But now we are all working together to achieve the change we all believe is both needed and possible.

A Match Made in Heaven, if heaven were in Oakland!

The Matchmaker – by Gerrit van Honthorst

Throughout history, matchmakers have played an important role in bringing together couples for arranged marriages. Fast forward to today and CIRM is now playing a similar role. We’re not looking to get anyone hitched, what we are trying to do is create partnerships between people we are funding and companies looking for the next hot thing.

So far, I’d say we are doing a pretty decent job. Over the years we have leveraged our funding to bring in some $13 billion in additional investments in stem cell research. But there’s still a lot of untapped potential out there. That’s why tomorrow, March 9th, we’re joining with BIOCOM to host a Partner Day.

The idea is to highlight some of the most promising programs we are funding and see if we can find partners for them, partners who want to help advance the research and ultimately – we hope – bring those therapies to patients.

The webinar and panel discussion will feature a presentation from the CIRM Business Development team about our portfolio. That’s a pretty extensive list because it covers all stages of research from Discovery or basic, through Translational and all the way to Clinical. We’ll show how our early investment in these programs has helped de-risk them and given them the chance to get the data needed to demonstrate their promise and potential.

So, who are we interested in having join us? Pretty nearly everyone involved in the field:

  • Academic institutions
  • Research organizations
  • Entrepreneurs
  • Venture capital firms
  • Companies

And the areas of interest are equally broad:

  • Stem or progenitor cell-based therapy
  • Cell Therapy
  • Gene therapy
  • Biologic
  • Small molecule
  • Medical Device
  • Diagnostic
  • Tools/Tech
  • Other

And for those who are really interested and don’t want to waste any time, there’s an opportunity to set up one-on-one meetings right away. After all, if you have found the perfect match, why wait!

But here’s the catch. Space is limited so you need to register ahead. Here’s where you go to find out all the details and sign up for the event.

A little history in the making by helping the tiniest patients

Dr. Diana Farmer stands with Dr. Aijun Wang and their UC Davis research team.

It’s appropriate that at the start of Women’s History Month, UC Davis’ Dr. Diana Farmer is making a little history of her own. She launched the world’s first clinical trial using stem cells to treat spina bifida before the child is born.

Spina bifida is a birth defect caused when a baby’s spinal cord fails to develop properly in the womb. In myelomeningocele, the most severe form of spina bifida, a portion of the spinal cord or nerves is exposed in a sac through an opening in the spine. Most people with myelomeningocele have changes in their brain structure, leg weakness, and bladder and bowel dysfunction. 

Illustration of spina bifida

While surgery can help, Dr. Farmer says it is far from perfect: “Currently, the standard of care for our patients is fetal surgery, which, while promising, still leaves more than half of children with spina bifida unable to walk independently. There is an extraordinary need for a treatment that prevents or lessens the severity of this devastating condition. Our team has spent more than a decade working up to this point of being able to test such a promising therapy.” 

The team at UC Davis – in a CIRM-funded study – will use a stem cell “patch” that is placed over the exposed spinal cord, then surgically close the opening, hopefully allowing the stem cells to regenerate and protect the spinal cord.

In a news release Dr. Aijun Wang, a stem cell bioengineer, says the team has been preparing for this trial for years, helping show in animals that it is safe and effective. He is hopeful it will prove equally safe and effective in people: “Our cellular therapy approach, in combination with surgery, should encourage tissue regeneration and help patients avoid devastating impairments throughout their lives.” 

Dr. Farmer says the condition, while rare, disproportionately affects Latinx babies and if the procedure works could have an enormous impact on their lives and the lives of their families: “A successful treatment for MMC would relieve the tremendous emotional and economic cost burden on families. We know it initially costs approximately $532,000 per child with spina bifida. But the costs are likely several million dollars more due to ongoing treatments, not to mention all the pain and suffering, specialized childcare, and lost time for unpaid caregivers such as parents.”

Here is video of two English bulldogs who had their spinal injuries repaired at UC Davis using stem cells. This was part of the research that led to the clinical trial led by Dr. Farmer and Dr. Wang.

A word from our Chair, several in fact

In 2005, the New Oxford American Dictionary named “podcast” its word of the year. At the time a podcast was something many had heard of but not that many actually tuned in to. My how times have changed. Now there are some two million podcasts to chose from, at least according to the New York Times, and who am I to question them.

Yesterday, in the same New York Times, TV writer Margaret Lyons, wrote about how the pandemic helped turn her from TV to podcasts: “Much in the way I grew to prefer an old-fashioned phone call to a video chat, podcasts, not television, became my go-to medium in quarantine. With their shorter lead times and intimate production values, they felt more immediate and more relevant than ever before.”

I mention this because an old colleague of ours at CIRM, Neil Littman, has just launched his own podcast and the first guest on it was Jonathan Thomas, Chair of the CIRM Board. Their conversation ranged from CIRM’s past to the future of the regenerative field as a whole, with a few interesting diversions along the way. It’s fun listening. And as Margaret Lyons said it might be more immediate and more relevant than ever before.

Charting a course for the future

A new home for stem cell research?

Have you ever been at a party where someone says “hey, I’ve got a good idea” and then before you know it everyone in the room is adding to it with ideas and suggestions of their own and suddenly you find yourself with 27 pages of notes, all of them really great ideas. No, me neither. At least, not until yesterday when we held the first meeting of our Scientific Strategy Advisory Panel.

This is a group that was set up as part of Proposition 14, the ballot initiative that refunded CIRM last November (thanks again everyone who voted for that). The idea was to create a panel of world class scientists and regulatory experts to help guide and advise our Board on how to advance our mission. It’s a pretty impressive group too. You can see who is on the SSAP here.  

The meeting involved some CIRM grantees talking a little about their work but mostly highlighting problems or obstacles they considered key issues for the future of the field as a whole. And that’s where the ideas and suggestions really started flowing hard and fast.

It started out innocently enough with Dr. Amander Clark of UCLA talking about some of the needs for Discovery or basic research. She advocated for a consortium approach (this quickly became a theme for many other experts) with researchers collaborating and sharing data and findings to help move the field along.

She also called for greater diversity in research, including collecting diverse cell samples at the basic research level, so that if a program advanced to later stages the findings would be relevant to a wide cross section of society rather than just a narrow group.

Dr. Clark also said that as well as supporting research into neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, there needed to be a greater emphasis on neurological conditions such as autism, bipolar disorder and other mental health problems.

(CIRM is already committed to both increasing diversity at all levels of research and expanding mental health research so this was welcome confirmation we are on the right track).

Dr. Mike McCun called for CIRM to take a leadership role in funding fetal tissue research, things the federal government can’t or won’t support, saying this could really help in developing an understanding of prenatal diseases.

Dr. Christine Mummery, President of ISSCR, advocated for support for early embryo research to deepen our understanding of early human development and also help with issues of infertility.

Then the ideas started coming really fast:

  • There’s a need for knowledge networks to share information in real-time not months later after results are published.
  • We need standardization across the field to make it easier to compare study results.
  • We need automation to reduce inconsistency in things like feeding and growing cells, manufacturing cells etc.
  • Equitable access to CRISPR gene-editing treatments, particularly for underserved communities and for rare diseases where big pharmaceutical companies are less likely to invest the money needed to develop a treatment.
  • Do a better job of developing combination therapies – involving stem cells and more traditional medications.

One idea that seemed to generate a lot of enthusiasm – perhaps as much due to the name that Patrik Brundin of the Van Andel Institute gave it – was the creation of a CIRM Hotel California, a place where researchers could go to learn new techniques, to share ideas, to collaborate and maybe take a nice cold drink by the pool (OK, I just made that last bit up to see if you were paying attention).

The meeting was remarkable not just for the flood of ideas, but also for its sense of collegiality.  Peter Marks, the director of the Food and Drug Administration’s Center for Biologics Evaluation and Research (FDA-CBER) captured that sense perfectly when he said the point of everyone working together, collaborating, sharing information and data, is to get these projects over the finish line. The more we work together, the more we will succeed.