January 18, 2018; Full Commentary; Draft

Greetings from downtown San Francisco’s historic Palace Hotel and the JDRF Annual Mission Summit. More than ever, this year’s gathering reminded us of just how much JDRF is doing to propel the field of type 1 diabetes – from basic research to policy to commercialization.

The focus on the entire T1D pipeline began in CEO Derek Rapp’s opening one-hour talk, covering the organization’s broad focus on Research (basic, translational, and commercialization), Advocacy (legislative, regulatory, health policy), and Community Engagement (volunteerism, awareness, and outreach). In one of our favorite slides, Mr. Rapp highlighted the organization’s “leverage” – for every $1 that the JDRF invests in type 1 diabetes research, more than $2.50 of additional investments are made to the field. Last year, for example, the nonprofit allocated $86 million in research, which led – according to the JDRF – to an additional $214 million from other contributors. Even if Mr. Rapp’s estimates are overstated, his larger point about the financial sway of the JDRF rang true, and it clearly impressed everyone in the room.

This idea of multiplying impact was a theme throughout the day, especially in the inspiring dinner discussion between Helmsley Charitable Trust’s David Panzirer and JDRF Chief Mission Officer Dr. Aaron Kowalski. The discussion touched on their incredible partnership, technology (including how both are using the DIY Loop system), Helmsley’s big push on primary prevention ($54 million), the challenging type 1 diabetes commercial environment, the inefficient and frustrating care many with type 1 diabetes receive, and how access to insulin is an enormous issue in many developing countries – Rwanda was just one example. This discussion, during which both leaders received standing ovations, represented a major highlight of the packed day, covered in detail below.

Creating leverage also came up in multiple discussions on JDRF’s T1D Fund. Chairman Sean Doherty delivered a compelling message on the need for the fund, its ability to validate companies and catalyze further investment, and how it will bring in incremental funding to JDRF; Managing Director Dr. Jonathan Behr shared illuminating examples, adding significantly to the discussion. Notably, the fund has now invested in eight companies – Bigfoot Biomedical, GluSense, Semma Therapeutics, Egenesis, TetraGenetics, SQZBiotech, Proventionbio, Diasome – with ~$65 million raised of the initial $80 million goal. The Fund expects to invest in six to eight companies per year, deploying on average ~$3-$5 million in capital over the lifetime of the investment.

Our coverage below also includes a terrific plenary with USC’s Dr Anne Peters on SGLT-2 inhibitors in type 1 diabetes and outcomes beyond A1c (some compelling graphs in people without diabetes) and UCSF’s Dr. Jeffrey Bluestone on the intersection between cancer and autoimmunity.

The day was unquestionably inspiring, full of good news; at the same time, Mr. Panzirer and Dr. Peters were unrelenting in stressing that the type 1 diabetes community has an access and care “crisis” on its hands. Even as the field looks to next-gen therapies and technology to further improves lives, so much remains to be done on basic things like access to insulin, CGM adoption, and adequate care delivery. JDRF’s job gets harder every single year, especially in determining the right portfolio mix to help the most people with type 1. Where can it do the most good? How should it balance short-term technology-driven wins with longer-term cure research – and where does prevention fit in? What is the right time horizon to invest for? Overall, we were incredibly impressed with discussions around the T1D Fund and love that it, itself, has inspired greater investment than the JDRF would have alone.

Detailed Discussion and Commentary

Dinner Conversation: Envisioning Our Future

David Panzirer (Trustee, Helmsley Charitable Trust) and Aaron Kowalski, PhD (Chief Mission Officer, JDRF)

Dr. Kowalski: David and I have been good friends over the years. I always say this is the club we don’t want anyone to join, but when you’re in it, you meet amazing people. We’ll talk about JDRF and the Helmsley Charitable Trust partnership.

At JDRF, Helmsley is our #1 partner. David is the energy that powers that. When David and I first met, his daughter had just been diagnosed with type 1 diabetes. We set up a meeting at the Helmsley Building. For those of you not in NYC, that sits just above Grand Central Station. David, I remember going into your grandmother’s office, with a picture of the famous dog. Your grandmother had a huge personality and a reputation. Can you talk about your connection and the Helmsley legend?

David Panzirer:  My grandmother has a tough reputation, some of which was certainly earned.  My grandmother did two amazing things for me: Introduced me to my wife and gave me this opportunity to impact my children’s disease. Five months after my daughter was diagnosed, my grandmother passed away and named me as one of the executors of her estate and a trustee of the Helmsley Charitable Trust. I knew nothing about medical research or how to get a drug or device to market. I went on a learning tour, and spent the better part of 18 months living out of a suitcase. I got a pretty good education on the landscape of what we’re trying to impact.

We became a $2 billion foundation almost overnight, and by the rules, you have to spend 5% every year. We were five trustees with absolutely zero foundation experience. I was the very squeaky wheel at the beginning, since I knew what I wanted to tackle. My daughter’s diagnosis and grandmother’s death happened within five months of each other – I took that as a sign. I’ve now been at this for almost 11 years.

My second daughter Caroline, who has all four antibodies, was diagnosed in August. We caught her really, really early. She’s in TrialNet, and at 14 years old, she said, “Dad, I’m done with TrialNet.” I said, “That’s fine, but you have to wear a sensor once every couple of months so that we know what is going on.” I’ve heard that in pediatrics, the first blood glucose that gets compr0mised is your postprandial after dinner. Caroline was wearing CGM over the summer, and we watched it go to 200, 220, 240 after dinner. I’m a huge believer in trying to mimic normal as much as possible. She was quickly put on short-acting insulin for dinner and a little more right before bed. After a few weeks, she started going low. We backed off insulin slowly but surely and she’s now been insulin-free for the past four months. I’ve talked to immunologists, who say the autoimmune response waxes and wanes. We may have temporarily tipped her back. But if I could do a few weeks of insulin every once in a while to keep her from full blown type 1 diabetes, that would be a good tradeoff. For now, I’m running my own n=1 clinical trial. [Applause]

Dr. Kowalski: There are not a lot of $6 billion charitable trusts out there. Talk about Helmsley and how you’ve championed type 1 diabetes – with other trustees there, how does it work?

Mr. Panzirer: Well, I was the very squeaky wheel at the beginning. But when my grandmother was alive, she gave some money to diabetes and to JDRF because of Morgan’s diagnosis. It wasn’t hard after that, and I got the buy-in from the other trustees. Helmsley’s philanthropic giving is focused almost exclusively on helping to advance health and medical research. In fact, we’ve been winding a couple of programs down to narrow that focus further. I was lucky enough to meet with the first CEO of the Bill and Melinda Gates Foundation Patty Stonesifer, and she told me two things I’ll never forget: (i) We are the Gates Foundation, and even with our resources, we can’t truly solve anything. I thought, “jeez, you’re 10-times the size of us, I might as well go home.” (ii) With each dollar, you have to be laser-focused; ask yourself what the impact will be. It was really humbling to hear this. So we’re in the process of narrowing our focus, and we’ll probably be there in the next four or five months.

Dr. Kowalski: When David and I first met, Dana Ball worked with David at Helmsley. And you helped JDRF significantly with a number of projects. Helmsley was an important initial investor in our automated insulin delivery project. Dr. Sanjoy Dutta and Campbell Hutton (who helps lead JDRF’s regulatory affairs) were brought in because of support from Helmsley. To date, we’re probably approaching $100 million that JDRF and Helmsley have co-funded together. Talk about the decision to keep your type 1 program separate from JDRF.

Mr. Panzirer: I started out really naïve and really cynical, now I’m less naïve and still really cynical. My cynical thought was that JDRF should be working towards a goal that would put themselves out of business, and if they haven’t done that yet, then they must be doing something wrong. As I said, this is a completely naïve and cynical point of view. Clearly I was wrong. As I began to study the landscape and understand it, at the end of day, if  Helmsley and JDRF have two separate funnels of ideas, each with its own separate staff to compare and contrast, that’s got to be better. We have our own, they have theirs, and we compare and share ideas. Talking to Derek [Rapp], earlier I commented on how different things are between our organizations compared to seven or eight years ago we used to say we’re frenemies. Gina and I were talking last night and Gina made a comment that the vibe here is so much better amongst us and the leadership of JDRF, our collective teams versus the tension even five years ago. Now we work seamlessly as important partners collaborating together, thanks to Dr. Kowalski, Derek Rapp, Mark Fischer-Colbrie, John Brady, and everyone else as I don’t want to exclude anyone...

Dr. Kowalski: Let’s talk about technology. Helmsley played such an important role in moving this field forward, starting with the team at JDRF. JDRF and Helmsley funded multiple things together, now including in health policy. I mentioned today that I was Looping; can you talk about Morgan’s experience on Loop?

Mr. Panzirer: Aaron turned me on to Loop 14 months ago. Having a 16 year-old daughter – she is pretty damn responsible – but she’s still 16. I hear they turn into a human again around 24. [Laughter] Loop is not for everybody; you have to be a bit of tinkerer. But I believe that to be impactful in type 1 diabetes, technology is the way. If you asked me what the single biggest advancement in diabetes is, I would say it’s CGM. If we could only have one tool to work with, it’s CGM. The way I see the future, automated insulin delivery is going to be important, and hopefully it will catalyze more people to get on pumps. But there is going to be a group that says ‘I don’t want both devices on my body.’ When you pair form factors like Libre and the future Dexcom/Verily sensor – the sensor that looks like an M&M, which is pretty damn compelling – and you couple that with connected insulin pens, you begin to see the pathway clearly towards decision support/AI. What decision support or AI means to me is: Let’s take all this data and turn it into something actionable. That is not that far off. I don’t believe in putting time frames on things, because I will most definitely be wrong. But there are major players in this space – beyond just the regular diabetes companies.

Dr. Kowalski: You and Helmsley have been amazing at ‘go big or go home.’ One of the areas I’m most fond of is prevention. Obviously I want my brother and me to be cured, but I worry a lot about my kids getting diagnosed. They’re at genetic risk, at about 15 times the risk of the general population. I’m proud of the role JDRF has played in prevention. Helmsley just announced a massive investment in prevention, can you talk about that?

Mr. Panzirer: Like anyone, I’d cut my right arm off to get a cure for my kids, but that’s not happening anytime soon. As a private foundation that does not have to fundraise, we believe we have an obligation to think differently and take more risk and fund longer-term projects such as primary prevention. Simply put, primary prevention would be to vaccinate against type 1 diabetes.  Gina and I, along with our team, spent a lot of time in Europe and we just launched a very large primary prevention program over in Europe. It’s general population screening, and we’re going to screen about 300,000 newborns. We will start in Germany, then add four other countries. The goal is to see who has the genetic risk for T1D and intervene prior to autoimmunity. For kids like my daughter with four auto-antibodies, it’s not “if,” but “when” you’re getting diabetes. Almost all of the interventions tried today are on people who already have autoimmunity. Once you have autoimmunity (more than two antibodies) I would argue you already have the disease. If this were cancer, we would begin treatment at the onset of autoimmunity. In T1D, (a) There’s nothing to treat it with and (b) there’s a stigma to diagnosing early, especially a child. Helmsley believes we have to intervene prior to autoimmunity. We’re trying large doses of oral insulin in people who have no autoimmunity. The endgame will be to delay or prevent diseases, and more importantly, maybe understand how it starts. [Applause]

Dr. Kowalski: You didn’t mention how big the grant is: $54 million. [More applause] It’s amazing how powerful Helmsley is. You can see David has conviction, you can see we’re not afraid to share our opinions. In that sense, I think we should also go after people with two auto-antibodies. Adults progress slowly, so we could intervene there. What do you think about biological cures, smart insulins, and other things?

Mr. Panzirer: If I knew which one to bet on, we’d be done. We have made a strategic decision to focus on primary prevention. We have funded Dr. Bob Langer’s lab (encapsulation, smart insulin, and smart glucagon), but our major focus is on primary prevention, and then tools to ease the burden of managing disease. We still do some of the biologic and immune tolerance stuff, but you have to focus. My motto is “go big or go home.” I don’t believe in tickling the problem.

Dr. Kowalski: Both organizations are very closely linked on all the problems we’re working against. ADA, NIH, the companies, FDA – we want to figure out who is doing what. Where are the funds best dispensed? So when Helmsley puts a $54 million push on primary prevention, we may be supplementing in another area or prioritizing something else. There is still a big focus at JDRF on smart insulin and encapsulation. On a weekly basis, David and I are talking and discussing what to prioritize and what the gaps are.

Q: We’ve heard a lot about where Helmsley and JDRF’s roles and techniques are aligned, but are there any examples where Helmsley is doing something totally different?

Mr. Panzirer: I have an obligation not just to my kids but to everyone living with type 1 diabetes. I became acutely aware of this when Gina and I last year went to Rwanda and saw the situation there and acknowledged just how much more access we have to experts and options than in other regions around the world. I think what we lack here in a room like this is perspective, and I lacked that perspective a year and a half ago before I went there. If you have blood running through your veins and you go and see this, it is gut wrenching stuff. Kids, if lucky enough to get diagnosed, will still likely not live long with diabetes. Their biggest problem is not diabetes, but poverty. We sit in our bubble here, I do too, but I think we all have an opportunity to branch out a little more. Relatively little money can literally save lives. Take a step back, and think what are our obligations as a fiduciary? We’re not all fiduciaries, but we all have a voice. It’s not a knock on JDRF, just a revelation we had and something we should all remember.

Dr. Kowalski: This is an area that is going to be discussed more at JDRF. We’ve waited a little, but we’re partnering with ISPAD (International Society for Pediatric and Adolescent Diabetes) and funding fellows from developing nations to train up and better take care of type 1. Another area is diabetes complications – an area that JDRF funds and Helmsley hasn’t traditionally. A portion of our budget, 5%, goes to retinopathy and diabetic nephropathy. We did a very extensive analysis of that area when Jeffrey Brewer was CEO – should we even be there anymore? It was clear that while the complication risk has dropped dramatically, the risk is very, very low. That said, lots of people out there who have had diabetes a long time, they’re still at risk. So we’re still working on it, and as we set priorities each year, we communicate these things, and David weighs in as a member of our research committee.

Ms. Margaret Anderson (Deloitte Consulting; Former Executive Director, Faster Cures): Can you talk about the creation and launch of the JDRF T1D Fund? It seems significant not just for type 1 diabetes, but for the entire ecosystem? This comes from the perspective in my former role at Faster Cures.

Dr. Kowalski: One of the biggest concerns is that the type 1 diabetes marketplace is not very healthy. It has dramatic impact on our ability to move programs forward. The dissolution of Animas should be concerning for everyone in this room. It’s a huge problem that no pump company has ever turned a profit besides Medtronic. Before the JDRF T1D Fund, support and a pathway was very, very difficult. This gives us an additional funding mechanism, plus leverage on funding – you heard today how other syndicates are coming in who were on the fence. Now de-risking is happening. JDRF has been funding companies since I’ve been here – almost 14 years now. But this additional vehicle – providing equity and expertise – is massive. It’s game-changing. I commend John Brady and Sean and the team. And then we had Helmsley coming in and providing additional hustle.

Mr. Panzirer: We sometimes hear the T1D market described as the valley of death. If we don’t pave the way, companies are not incentivized to play. This is another vehicle to pave the way. We deal with a bunch of VCs, and we get calls all the time asking, “Why aren’t you guys investing in this? We have had companies say, “I just need you guys to give a little bit of money.” Both JDRF and Helmsley have a little bit of a halo effect – that gives investors a degree of confidence. It’s immeasurable how valuable that is.

Dr. Kowalski: I also want to thank the folks on the JDRF Research team. John Behr’s team works hand in hand with the JDRF team. Many things funded by the T1D Fund percolated up through work that’s happened over a number of years at JDRF. David, how do you think about philanthropy and people supporting the Fund and JDRF Research?

Mr. Panzirer: I come from the business world – it’s the only world I understand. I think of this as a business. We want to deliver a drug or device or therapy to people. In order for that to happen, the FDA must approve it, a payer must pay for it, and a company has to believe it will make them money  so they can do the manufacturing and distributing of it. I’ve met with tons of philanthropists. They want what all of us want. But I’ve seen people write seven-figure checks, and then they say, “What do you think about so and so?” I’ll say, “That’s an interesting project, but I’m not sure I would have written a check that way.”

Philanthropists have an obligation to do the same amount of diligence they did to make their money when they give it away. Don’t just write the check and trust the guy in the white coat; there are plenty of charlatans out there. If you are not as fortunate as Helmsley, where we could build our own team, JDRF and the T1D Fund have a team that can do the diligence for you in the right way. So you can write a check with more confidence.

Dr. Kowalski: David mentioned his wife Karen. What also makes me happy is that Karen has run a number of races for team JDRF and been supportive that way. David always says he has chicken legs, not built for running. It’s about how different people can be impactful.

Q: I love Derek as a leader. He did a pretty good job of introducing you, but I really want to hit home for the audience for those who don’t get it. There’s the government, JDRF, and there’s you – that’s how I see funding for type 1 diabetes. As a father of a son with type 1, all we’ve been through, I cannot thank you enough because the work you’re doing is unbelievable, and I’m sorry if words fail me to thank you enough. [Standing ovation]

Mr. Panzirer: Thank you for that. The way I look at it is everyone in this room would do exactly what I’m doing if given the same opportunity. I made a very simple promise to my daughter at diagnosis that was: I would do anything I could to help her with her diabetes. Five months later, I was named a trustee of what is now a massive charitable trust. I’m not the most religious guy, but these two events, five months apart made it pretty clear what I had to do. You’re all doing the same thing I’m doing, I just have a bigger toolbox.

Ms. Kelly Close (The diaTribe Foundation, San Francisco, CA): I haven’t had diabetes as many decades to remember when there wasn’t a JDRF. But I know there are people in the room who do and thank you to all of them for creating JDRF. I do remember JDRF pre-Aaron, and no matter how great JDRF was leading up to this moment, your impact on the organization since you joined has been profound. I remember really well the moment that Jeffrey Brewer introduced me to you, and it’s just incredible to see your impact. And I remember diabetes really well before the Helmsley Charitable Trust entered, and thinking about all of that, I worry the most about the doctors and nurses trying to take care of all of us with diabetes. How do you think about this important population, healthcare providers, and what might be possible to help them be more successful, perhaps partly with digital health and telehealth?

Dr. Kowalski: To start, a lot of people said they loved hearing from Dr. Anne Peters earlier today. She is a super doc. If we could clone her and put her all over the world, the world would be a better place. She has a house in Montana, and told me last night that there are no other endocrinologists in Montana dealing with diabetes. We have a massive problem looming in the US with a lack of endocrinologists, pediatric endocrinologists, diabetologists, and funding for folks – the pipeline and resources to help them do their jobs. This is why the policy work we’ve been doing with Helmsley and NIH and everyone is so important. I think you’re right, it’s a really, really big problem. Gina, David, and I were talking about this yesterday, and we need to get our arms around it.

Mr. Panzirer: It’s like a train wreck happening in slow motion. We need to get the clinician out of the middle – the majority of clinicians are actually a barrier to the adoption of technology. With the endocrinologist shortage, most patients see a PCP who doesn’t know anywhere near enough about type 1 and has no incentive to learn due to the of a lack of reimbursement. We’ve piloted health models to get doctors to see more people – telemedicine, group appointments, the easy layups. But in the long term, we see the need for a different model, one in which the CDE, who does 95% of the heavy lifting in a clinic anyway, writes the prescription and becomes the core of the care team. It’s easier said than done to get that accomplished.

I think about a model like Best Buy’s Geek Squad. Imagine a dedicated team of professionals to help people get on diabetes technology. We’re talking to the three CGM companies to see if there is an appetite for this concept. How could we get people with diabetes straight to the Geek Squad (company agnostic) to help them with technology? We need a new model; the current model is failing.

Sean Doherty (Chairman, JDRF T1D Fund): David and I first got to know each other a couple years ago. When we started working on the T1D Fund, I thought, “If David doesn’t think it’s a good idea, it’s not going to work.” It used to be once a week or so, as we were trying to develop fund, we’d talk. I knew that David’s involvement was critical. David, thank you for your generous gift.

Mr. Panzirer: It’s not a gift, it’s an investment. [Laughter]

Mr. Doherty: David, how can people think really, really big in type 1 diabetes? What we’ve learned from over the past few years is that there are a lot of people who are willing to contribute and think big – if they know where the money is going. This is a moonshot question. We don’t have the benefit of Helmsley. But for us at the T1D Fund, if we were able to decide to raise an extra $100 million, what should this organization do over the next 1-3 years? Where should JDRF take it?

Mr. Panzirer: If you’re following the mission as published – to help the most people with the most impact as soon as possible – it’s access to insulin. That will have the most impact on the most people – keep people alive. It’s probably not what most people think of in this room, but my perspective got adjusted after my trip to Rwanda. If you had an extra $100 million, you might also be able to do something else.

Mr. Doherty: Yes, we talked about this point on insulin access last night. You could probably address that for less than $100 million. So what next?

Mr. Panzirer: I believe in primary prevention. And then I believe in coming up with tools to reduce the burden. We need to keep our kids healthy until a cure comes. If they have crappy care and are dealing with stuff that’s not so great, I think we’ve failed. Let’s take this disease and make it easier to manage. I truly believe CGM is the star and the key component, and then we add on decision support – and whatever else people will tolerate. It’s a different equation as to what people want to deal with. The Dexcom/Google (Verily) partnership is going to dramatically shrink the size, and with Abbott returning to the market and coming with Bigfoot with a true CGM, that’s going to drive the price down.

Mr. Doherty: If it was about a cure, what would your vote be?

Mr. Panzirer: You’re asking an impossible question. If I knew, I’d be all in. I don’t know if it’ll be stem cells, microbiome, regeneration, combo therapy…I think all of it is interesting. We’ve pivoted to primary prevention, that’s not to say cure’s not interesting, but I couldn’t look you in the eye and say this is the right horse to bet on, and I’ll tell you that anyone who does is full of it. [Laughter]

Dr. Kowalski: This is where David and I diverge a little bit. If you look at stem cell research right now…One of my friends in the Diabetes Online Community was giving JDRF a little razz over the last week or so, pulled out an ad from Countdown saying that “a cure was in the bag” – from 1984. I empathize with folks from JDF (at that point), because islet transplantation did look like a cure back then – it needed chronic immunotherapy – but it looked like a cure. When we talk about expectations management, it wasn’t a malicious forethought, just a lack of appreciation for immunotherapy. That said, if you look how we chart out time horizons – we can do it very well for devices, plot trials, etc. Look at cell therapy, and where that is, and you hear ViaCyte, Semma Therapeutics, work going on materials science combined with the truth that you can make cells that make insulin – you can make a product there. I’m not sure when it will come to market, but I’m sure that the next few years will show us what the path looks like toward a marketable product. We focus on devices, but as I always say, ‘no one without diabetes wears an insulin pump.’ I still don’t like the tube coming out of my pocket, ripping out on a door, the rash on my arm, I don’t like any of that, but we need to push. I love prevention, but I’m still in this for my brother and me too. We will not lose sight of that. Glucose-responsive insulin, cell therapy, microbiome, we’re going to push like hell on them and try to figure it out.

David: Obviously, I hope you’re right.

Q: In endocrinology and the relative paucity of providers, that’s partly driven by health economics. Cancer therapy makes a lot of money. Endocrine loses money in every hospital. When people decide on what field they want to go into, they understand the job market. I’m heartened to see the movement away from just A1c, and also the move to primary prevention. But how do you turn that into billing codes? That’s the fundamental problem in the field.

Dr. Kowalski: One of the discussions that I have been noodling – and this is going to sound crazy – is whether Helmsley and JDRF went after taking care of people with diabetes. What’s really motivated me over the past 10 years is the model for what I think is the future: Diabeter. This is a center in Holland. The word means “better diabetes” in Dutch. Hank Veeze had this idea to go to the payers. He said, “I want reimbursement for X% less than you pay per year, wherever and whatever you’re paying. For example, I’ll take 75% of what you’re paying, and then get out of my way. He then completely flipped the model. Right now in the US, the people coming into the office are people like me. I take up 30 minutes, and I really just need a prescription for my insulin. But the people who need the most care don’t get seen at all, and then they rack up expensive bills. The Diabeter model is the opposite – for the people doing well, they never come to the office. It’s all electronic. The people who want a sensor get a sensor. The people who need psychosocial care get it. What if we could change the way we manage people with diabetes? Let’s eliminate all this billing, coding, and wasted time. This speaks to an aspiration, but you’re right – we have to fix this problem. One of my favorite doctor friends in Southern California says he spends 60-70% of his time on paperwork. Pre-auths, things like that. This guy is a genius with patients. But you’re exactly right. For the future of JDRF and Helmsley, the ecosystem and marketplace is fundamentally broken in the US and we’ve got to fix it.

Mr. Panzirer: I went to that Diabeter clinic. We compared/contrasted it to a city clinic in Amsterdam run by Dr. Hans DeVries. This Diabeter clinic, which is now owned by Medtronic, receives 2-3 times the amount of reimbursement of the city clinic that is a 40-minute train ride away. When patients do better at Diabeter, they get more reimbursement. That is a model we need to follow here in the US. Let’s go at-risk. If you give the right care, put your money where your mouth is. The current path is not sustainable. We’re beginning to see these at-risk contracts now.

(Editor’s Note: We thought this discussion was fascinating and it reminded us of another possible fix: diabetes companies taking on patient care more directly. We’re seeing this trend in the early stages with Medtronic acquiring Diabeter, Onduo (Sanofi/Verily), Virta, and a slew of diabetes coaching products and pilots coming online. Will industry start to replace some/much of the traditional, inefficient diabetes care system? This has the benefit of aligning incentives for chronic care, which would be compelling in diabetes. Of course, it could also reduce patient choice, reduce the role of HCPs, and shrink the market to only the largest companies with big infrastructure and payer relationships… Interestingly, the Diabeter clinic was acquired back in April 2015, but Medtronic has not given a material update or firm expansion plan since then. When will we see it move further on scaling Diabeter?)

Q: In the state of Ohio, we’re trying to get a hold of a diabetes registry. Do you see the value of that, and why is there such a struggle to get it done?

Dr. Kowalski: We didn’t talk about this tonight, but one of the most important things to happen to diabetes in the past 10 years was the formation of the T1D Exchange. Every scientific talk cites that data, it changed the game in discussions with FDA. In a lot of discussions with the device group at FDA, they’d say “people are doing fine, insulin is a great tool.” Sure insulin is great, and I can go in and say that people are still not doing well, but with a 27,000-person registry, it’s different. The fact we can’t do it in the US is another big problem. How do you track progress and manage outcomes? The UK, Scotland, Australia, and Denmark can all do it; but the US can’t do it.

Mr. Panzirer: I remember having a conversation with FDA – they thought T1D was a safe and  managed disease. We had 5,000 people in the T1D Exchange at that point, and showed Dr. Jeff Shuren and his team that the average A1c was 8.4%, and ~10% of people had had a severe hypoglycemic event in the past 12 months. And that’s at the best clinics in country. Chins were on the floor. The problem is it (the T1D Exchange) costs a boatload of money to build. We had to pay docs to enter the data. You’d think you could pull it out electronically. Nope. Manually. The EHR systems in this country it’s pathetic. But data is king, at the end of the day.

Q: What I’m hearing is the #1 priority in diabetes is saving lives, as evidenced by your experience in Rwanda. #2, what I’m hearing, is the delivery of healthcare services, particularly for diabetes in America, is poor. Is that right? From the research committee, it sounded like only 35% of people with type 1 have CGM in America.

Mr. Panzirer: That number is high. (Editor’s Note: As of a Fall T1D Exchange update, CGM penetration in the Exchange stood at 24%; broader penetration outside of Exchange clinics is likely lower.)

Q: Even if it’s that high, it’s woefully low. We come in here with a heavy bias. It’s personal. Most of us have kids with diabetes. But what you’re saying is the policy issues are what matter – #1 is save lives, #2 is make them better. And if we get a cure, that’s okay too.

Mr. Panzirer: I agree with that.

Dr. Kowalski: It’s all interrelated. To get to a cure, you have to have an ecosystem that incentivizes companies to go after it. We’ve learned this in the JDRF artificial pancreas project and some of the other work we’re supporting: all of these pieces have to be aligned. If one is out of place, it doesn’t move. What we have to struggle through is resource allocation across different barriers and opportunities. That’s one of our hardest jobs. These are really hard discussions to wrestle with. We have a research committee, and a Board, who govern this and wrestle with it. We agree, we disagree, and then we make the best decisions we can. It’s folks just like you. We’ll all be sitting around come June, asking, “How do we deploy our resources most effectively against the different priority areas?” It’s a really good process; it’s not perfect, but I think it’s really good. I wish we had more money so we could solve more problems.

Mr. Panzirer: You cannot end on that – it’s depressing! I want to thank all of you for what you do.

Derek Rapp: They say “of those to whom much is given, much is expected.” David, on behalf of all of us, I cannot tell you how grateful I am for handling things as you have. You’ve become a real champion for the type 1 diabetes cause. You’re an awesome partner for us. [Applause]

And Aaron, you are loved by everybody, and rightly so. You lead our mission efforts, and you do it with a wonderful combination of intelligence and heart. You have great passion for the mission and we’re all so grateful. [Applause]

I was doing a radio interview, and someone asked me for my favorite quote: “Never doubt that a small group of committed citizens can change the world. Indeed, it is the only thing that ever has.” That is Margaret Meade.

The opportunities that lie before us are tremendous. None of us signed up to be in this room, and we would be delighted never to have had type 1 diabetes enter our lives. But it did. I commend you all for being in this room and saying, “This is something I’m going to take on.” On behalf of myself and my loved ones, thank you. You’re in this room because you care. You have a chance to change this world. 47 years ago, two families came together and said they were going to do this (JDRF). They did not have a scientific background. They were laughed out of the room at the idea of bringing scientists together to advance research that would ultimately cure this disease.

Now the mantle is with us. Mark Fischer-Colbrie talked about passing the mantle. It’s up to you to continue. It’s up to us to continue an incredible, audacious mission to create a world without type 1 diabetes. I know you’re all up for it.

Thank you for spending the time with us. In doing so, you will return more invigorated, more informed, more connected, and better able to recruit others to our mission, and perhaps more willing to support our mission. I look forward to seeing you during the year. As Turner’s dad, and a representative of this community, I thank you for all you have done and will do as we create a world without type 1 diabetes. Thank you all, and safe travels home.

Plenary Sessions

Welcome Address

Derek Rapp (CEO, JDRF, New York, NY)

JDRF CEO Mr. Derek Rapp’s welcome address served as a reminder of JDRF’s outsized impact on type 1 diabetes – particularly in attracting outside dollars. One slide said it all: “For every $1 JDRF invests in research, an additional ~$2.50 is brought into the field. The pyramid graphic below shows that while JDRF directly invested $86 million in 2017, it estimates it attracted $214 million in additional investments for type 1 diabetes – $12 million from NGOs and other funding, $36 million in industry partnerships, an $166 million in US and international government funding (much of that from the Special Diabetes Program, which it strongly advocates for). In total, that’s $300 million funneled into type 1 diabetes that would likely not otherwise be available. The idea of drawing external dollars into the field is perpetuated by the T1D Fund (see elsewhere in this report). Hats off to the Foundation for making so much amazing advocacy, research, and collaboration possible – indeed it has pushed the field in so many ways. Mr. Rapp showed the classic black and white picture of Dr. Arnold Kadish and his backpack insulin pump, with an arrow pointing to Medtronic’s MiniMed 670G hybrid closed loop system: “Sometimes it’s hard to appreciate progress. We get caught up where we are, and don’t stop to look back and forward. We need to stop and reflect at where we are now vs. where we were many years ago. And this will only continue to improve. One day, the 670G will seem old and outdated … A word without T1D – I feel like closing my eyes, picturing that, it would be so phenomenal. And we’re working on it.”

• Mr. Rapp’s lengthy remarks went well beyond the financials, as he delved into a few of the areas where JDRF’s Dr. Aaron Kowalski-led team of >20 PhD scientists has focused over the past year:
  
  • On JDRF-catalyzed research, he highlighted advances both in the basic and translational veins. He reminded the audience that it is incumbent on JDRF to fund basic efforts such as nPOD (Network for Pancreatic Organ Donors with Diabetes) because they are often “not economically interesting.” That said, in the ten years since nPOD was launched by JDRF, 40,000 samples have been collected, 179 articles have been published, and samples have been sent to 19 countries around the world – this quickly became the single largest funded area of research for JDRF as it affords access inside the pancreas of a person who lived with diabetes. Helmsley is now co-funding the nPOD program. He also discussed work in retraining the microbiome and large-scale studies (TEDDY, Fr1da, TrialNet, ASK – Autoimmunity Screening for Kids), which will all feed data into IBM Watson to make sense of the data and answer elusive questions: Are there different versions of type 1 diabetes? Are there clear risk factors? Will multiple cures be necessary? [At this point, data has not yet been fed into Watson, as JDRF is conducting a demonstration project to see if it can build a progression model.] On the translational side, the clear victory from the past year came in the form of Medtronic’s MiniMed 670G, of which JDRF not only helped stimulate the development (via FDA guidance), but also whose advocacy and FDA communication likely helped speed regulatory review. Both of these efforts were crucial, and Medtronic announced yesterday that 99% of Priority Access Program orders have been fulfilled, implying that ~35,000 people will soon be on the 670G hybrid closed loop system in the US. Of course, JDRF’s translation portfolio also encompasses therapeutic approaches that hope to cease the destruction of and replace lost beta cells. In fact, >50% of JDRF grants involve beta cell replacement or restoration, “because we recognize that this area holds so much promise.”
  • In advocacy, the top item on the agenda was the Special Diabetes Program, which started with JDRF 20 years ago but is now in jeopardy of not being renewed. The program has allotted $2.5 billion to date for type 1 diabetes ($150 million per year), said Mr. Rapp, and is “somewhat on the ropes,” as it hasn’t been renewed by Congress. We know that JDRF has continued to drum up support and advocate on Capitol Hill for full funding in early 2018 – fingers crossed they are successful so the unparalleled funding can continue! Elsewhere on advocacy, Mr. Rapp pointed to numerous meetings with FDA on pushing toward the acceptance of outcomes beyond A1c (see our extensive coverage of one such meeting from the past year here). Finally, Mr. Rapp overviewed JDRF’s efforts in policy (namely, pushing for the classification of CGM as “durable medical equipment” to open the door for Medicare coverage) and the #Coverage2Control campaign, which garnered ~52,000 signatures in favor of access, choice, and coverage for people with type 1 diabetes.
• With regards to community engagement, JDRF made meaningful strides in 2017, and boasts one million supporters (those who are actively involved), not to mention more passive supporters. This past year, JDRF activated the community through the creation of an insurance toolkit (tips and tricks for choosing plans, help with costs, how to apply for an exception, etc.) and through hurricane relief via a partnership with Insulin for Life, to name just a couple.

Panel Discussion: Accelerating Life-Changing Breakthroughs Across the Pipeline

Anne Peters, MD (USC, Los Angeles, CA) and Aaron Kowalski, PhD (JDRF, New York, NY)

In an insightful lunchtime panel, JDRF’s Dr. Aaron Kowalski and USC’s Dr. Anne Peters highlighted JDRF’s remarkable role across the pipeline, touching on basic research, human research, clinical adoption, and advocacy/policy. We loved hearing Dr. Peters’ views on SGLT-2 inhibitors in type 1 diabetes, which have been a life-changing tool for many of her patients, though DKA risks must be managed – she shared her SGLT-2/DKA-prevention protocol in Q&A, which naturally drew a lot of audience interest. (Tidepool’s Brandon Arbiter added that he’s using a combo of DIY closed loop and an SGLT-2 inhibitor, which has put him into DKA four times.) Both Dr. Peters and Dr. Kowalski persuasively covered outcomes beyond A1c, including early results from a new Helmsley study of CGM in people without diabetes – we had not been aware of this trial, but boy were the FreeStyle Libre Pro traces paired with A1c data compelling. Dr. Kowalski added insight throughout, notably mentioning open protocol AID systems (he uses Loop), JDRF’s critical advocacy work (outcomes beyond A1c, Coverage2Control, Special Diabetes Program), the fragile type 1 diabetes commercial environment (e.g., Animas closing), and lessons from nPOD.

In one of the panel’s most poignant moments, Dr. Peters shared her gratitude, along with a reminder of how far we have to go: “JDRF and Helmsley changed my life... [But] I’m constantly reminded that there is so far to go in just getting the basic things to people. For some of my patients, the only place where they can manage diabetes is in jail. They get food and insulin. That’s a really sad situation if you have to go to jail to manage your diabetes.”

On SGLT-2 inhibitors in type 1 diabetes

• Dr. Peters shared a compelling before-after glucose trace from a type 1 on an SGLT-2 inhibitor – she experienced far lower variability and fewer highs and lows, equating to an A1c drop from ~9% to ~7. “What does she say? ‘I feel my diabetes is more predictable and less variable when I give a dose of insulin. I know that within 2-3 hours, I’m going to end up between 120-180.’”
• Dr. Peters was clear about the DKA risk in type 1, but now that she has a protocol in place, the risk is manageable: “We can largely prevent DKA, after I figured out how to prevent it and have a protocol. Now, I’ve had zero cases of DKA, except one woman who refused to follow my instructions. All drugs have risks and benefits, and in type 1 diabetes, we have to study and prevent the risks. The reason I fought so hard for SGLT-2s in type 1 is because my patients love them. They can go into DKA, get over it, and they still want to be on them. It’s not the cure, but if it makes things easier to manage with less variability, patients are willing to accept risk. If they do what I say, they work.”
  
  • Dr. Peters’s SGLT-2 in type 1 protocol is roughly as follows:
    • Measure ketones in blood at baseline (“It turns out, a lot more people than you think have elevated ketones. Patients check at baseline to understand where they usually are.”) Dr. Peters does not have people routinely test ketones except when starting. She added that “every person has a ketone threshold, which you need to establish in the first month or two.”
    • In type 1, start at ~ 25% of the normal SGLT-2 dose, raising the dose over time. Doses may vary between patients – one of her type 1s cannot get on more than half a pill without getting ketotic.
    • Make sure not to reduce insulin too much!
    • If experiencing DKA, eat carbs and take insulin. (Feeling ill is often an indication of high ketones.)
    • For anything that causes out-of-the-ordinary stress, Dr. Peters recommends cycling off the SGLT-2.
• “We did the sotagliflozin study in out of control adolescents with type 1. I thought it was the bravest study in the history of studies. The problem is – and this is where JDRF could help – is clinicians have used SGLT-2s in adults. There has been some use in adolescents, but no one has gotten a best practices guide for how to do that. I have my protocol, but we need to get together and publish it. These expert clinicians can do this safely. I’m afraid they (FDA) are going to damn the drug. People are using it off label. I want physicians to feel comfortable. I want pharma to talk about DKA in type 1. If there is not an indication for type 1, I cannot teach about it. If you could gather people and publish best practices, it would make a difference.”
• Tidepool’s Brandon Arbiter brought up an interesting point in Q&A – he’s on a DIY hybrid closed loop AND an SGLT-2 inhibitor [Jardiance]. He’s now been in DKA four times. “I’ve never been hospitalized. However, like some of your patients, I refuse to go off of it – it makes a difference. I’m also running a closed loop system. I’ll go to bed and think I’m fine. However, the closed loop system sees I’m at 90, decides to temp basal to 0 to get me back up to 100. Then the SGLT-2 kicks in and brings me lower. That results in the closed loop system keeping basal off for 8-12 hours, so I wake up in DKA. It’s the perfect storm of an SGLT-2 and the closed loop system. Do any of your patients on an SGLT 2 run closed loop? Could it magnify the risk of euglycemic DKA?”
  
  • Dr. Peters: “I haven’t had that experience, but since you’re on Jardiance, I think it is too long acting; you should be on dapagliflozin. Just email me. [Laughter]”

On Outcomes Beyond A1c

• Dr. Peters shared preliminary results from an under-the-radar Helmsley-funded study testing CGM in people without diabetes. The goal, shared Dr. Peters, is to define “What is “normal” glucose tolerance. Clinicians have no clue what to do with CGM. They can barely understand fingersticks. This is an educational gap. People have no idea what CGM is, what it means, how to use it. Even most endos don’t do this. We have to educate clinicians and physicians. In this study we’re doing, we’re trying to define ‘what is normal.’ If I cannot teach a clinician, what is normal, we have a problem.”
• Dr. Peters showed several Libre Pro CGM traces from the study – even people with near-normal A1c’s (5%-6%) have significant glucose spikes. Dr. Peters did not share when these results would be presented/published, but there were some fascinating takeaways. For instance, comparing profiles for an A1c of 5.0% vs. 5.3% vs. 5.6% vs. 6.4% vs. 7.2% showed a clear progression – more glucose spikes as A1c rises, particularly after breakfast and in older individuals. Even those with an A1c in the 5%-range has glucose levels rise up to 200 mg/dl after high-carb meals. “This is why we have so much illness in modern society,” noted Dr. Peters. We LOVE this research and the implication – we can treat people earlier and earlier, as CGM can identify glucose tolerance issues far before A1c can pick them up. With CGM, Dr. Peters said, “everyone could improve their health habits and end up with better health outcomes.” YES!
• Dr. Peters also showed some traces in people with type 1 diabetes, where similar A1c’s drove remarkably different glucose profiles – one had an A1c of 6.8% with low variability and high time-in-range, while a same-aged comparator treated identically (A1c: 6.9%) had very high variability and far less time-in-range. “She feels like diabetes is ruining her life, with high variability and lots of hypoglycemia. I cannot tell you how different this person’s existence is…”
• “A1c is one poor single measure of how people are doing – you must understand time-in-range and variability, which you cannot get as a clinician unless you understand CGM. Clinicians are a slave to A1c’s. We have to teach them that this woman (A1c of 6.9% and very high variability) is someone who needs a lot of help.” – Dr. Peters

On Using DIY Closed Loop and Open Protocol Systems

• Dr. Kowalski shared that he uses the DIY Loop system, and added that JDRF’s work on open-protocol systems is a “big effort.” He diplomatically added that these open protocol systems are “outside the box” and “FDA doesn’t know what to do with them.” JDRF is now working with both Helmsley and FDA to figure out the pathway forward. “A hybrid closed loop that is on your iPhone is not a traditional regulatory pathway. How do you do that? We have a team working on that.”
  
  • We can’t wait to see some progress here – when this effort was announced last October, it was a major victory for the DIY movement. We hope to see pump and CGM companies apply and regulatory path develop. To date, there has not been details from specific companies sharing plans to apply, possibly because applications are not due until January 31.
• Dr. Kowalski alluded to some of the challenges he’s seen closed loop: exercise and breakfast. Dr. Kowalski still runs a lot, but turns off closed loop during exercise – otherwise, hybrid closed loop turns basal insulin too low for too long, making him ketotic over the course of a 90-minute run (even with decent blood sugar levels). And for breakfast on a hybrid closed loop, Dr. Kowalski has had to do bigger boluses – his basal rates going into breakfast are now lower than they used to be on open-loop, meaning more bolus insulin is needed to compensate. Before he made this change, breakfast was “a rocket ship,” even if he pre-bolused. Dr Kowalski framed these as “interesting new challenges” for researchers to investigate. We’d echo both sentiments in our experience on DIY hybrid closed loop. These comments also align with early clinical commentary on the MiniMed 670G – Dr. Rich Bergenstal and others often tighten insulin:carb ratio at meals.

On JDRF’s Advocacy and Work to Expand Access

• Dr. Kowalski on JDRF’s Coverage2Control campaign: “I cannot overstate how important this is. And it’s some of the hardest work I ever done. In the last year, we’ve been on the phone with the Chief Medical Officers of the top 20 plans, advocating for lower copays for insulin pricing, access to devices, CGM, pumps, and automated insulin delivery. If you don’t have access, we haven’t succeeded. There also a cycle: companies don’t invest or are less incentivized to invest if there is not a pathway to get advances into people’s hands. We’ve made amazing progress on AID, but in the same discussion, many people used Animas pumps at some point. Animas just went out of business. We don’t have a perfect ecosystem, and that inhibits better outcomes and future R&D. I mentioned sleeping, which is one of best things about closed loop – we need to capture that outcomes. One of the other things you notice on closed loop is you still have challenges at mealtime. With fast-acting insulin or a co-formulation of insulin and amylin, perhaps we can help with mealtime. That would be the biggest advance in hybrid closed loop. But who is going to do that? If the companies don’t see a pathway to put in the R&D to get next-gen stuff – because they are already getting pulled back on the formularies – it’s a tight rope we’re walking here. Helmsley has a huge grant with us on this. We’re developing cost-economic models that quantify the cost of ambulance visits, the cost of missing work, and that show the value proposition of advances.”
• “This is a huge healthcare crisis and we have to fix this. I see all sorts of young people who cannot even afford their insulin.” – Dr. Peters
• On the regulatory front, the FDA artificial pancreas pathway was a big success. That pathway enabled the Medtronic 670G and others in the pipeline – the speed of reaching the market was due to advocacy. We’ve also been working with the FDA on what is the pathway in type 1 diabetes for an SGLT-2 or 1/2 inhibitor. We also have a team working on beta cell initiatives and immunological initiatives. This is a really critical part of what we’re doing.”
• Dr. Peters also shared two education/access efforts she’s been working on: The Type 1 Diabetes Self-Care Manual and low-literacy diabetes technology educational guides. The former covers type 1 diabetes from babyhood to old age, including patient voices in each chapter; it sold out on Amazon in paperback, but is available on Kindle and from ADA. Dr. Peters also just finished creating a set of low literacy tools in English and Spanish “for anyone who doesn’t want to struggle through 11^th grade reading materials” to learn how to use devices. The tools cover everything but CGM, which Dr. Peters hopes to get funded. The unbranded, non-copyright tools incorporate over 100 illustrations and sound very exciting. Dr. Peters did not say when they would launch, but said the printed books just “arrived last week.”

On nPOD

• Filling in for Dr. Mark Atkinson, Dr. Kowalski covered some of the myth-busting learning from the important nPOD project:
  
  • Dogma: type 1 diabetes is a singular disorder. Reality: Type 1 diabetes is a syndrome of disorders having various pathways that eventually culminate in a symptomatic disease. The nPOD project has revealed type 1 diabetes is “probably a diverse set of pathways” that drive “different forms of type 1 diabetes.”
  • Dogma: the symptoms of type 1 diabetes occur with 85-95% of beta cells are destroyed. Reality: the disease can appear with as little as 40% loss of beta cells.
  • Dogma: beta cells are eventually gone/destroyed in type 1 diabetes. Reality: almost every type 1 diabetes patient retains some beta cells (longest identified is 78 years).
  • Dogma: type 1 diabetes is just a disease of beta cells. Reality: the exocrine pancreas is involved, since it is 1/3 to ½ size of the normal pancreas in type 1 diabetes.

Hacking Diabetes Through Cancer Research and Philanthropy

Jeffrey Bluestone, PhD (President & CEO, Parker Institute for Cancer Immunotherapy, San Francisco, CA)

Dr. Jeffrey Bluestone from UCSF and the Parker Institute for Cancer Immunotherapy delivered the day’s keynote on the complexities of the immune system, and how breakthroughs in cancer and autoimmunity feed into research in the other – a fortunate realization for Dr. Bluestone, since he spends his time working on both! He first simplified the immune system’s function into “gas pedal” (immunity) and “brakes” (tolerance), a framework he referred to throughout the remainder of the talk. It is the prime balance of the gas-brakes seesaw that allows the immune system to function properly: too much gas begets autoimmunity, and too much braking begets cancer. His narrative began in 1992, when his group showed for the first time that it is possible to block a gas pedal – a signal necessary to activate the beta cell-destroying T cell – with a modified antibody, resulting in permanent acceptance of an allo-islet in a mouse following just two weeks of treatment. This drug, Abatacept, went on to be branded as Orencia by BMS and is used today in psoriasis, organ transplant, rheumatoid arthritis, and other autoimmune conditions. Two years later, Bluestone’s lab demonstrated that another related target molecule called CTLA-4 served as a checkpoint inhibitor that acts a brake to prevent T cell-mediated cellular destruction. Soon after, scientists across the bay in Berkeley hit a homerun in cancer treatment by showing that an anti-CTLA-4 drug, ipilimumab, inhibits the checkpoint inhibitor, releasing this brake in humans. The results showed marked improvements in the survival of metastatic melanoma patients. Ipilimumab treatment allowed T cells to recognize and destroy the cancer cells. As people are highly heterogeneous both in genes and environment and there are many gas pedals and brakes in the immune system, there are responders and non-responders to pulling certain levers, and tweaking multiple can result in combinatorial effects. The combinatorial effect was evident in a study in which patients received CTLA-4 blockade, PD-1 blockade (inhibition of another checkpoint inhibitor), or a cocktail of the two. In an early clinical trial, patients who received both drugs had increased survival as compared to either of the drugs alone. Checkpoint inhibitors have exploded commercially in oncology and have made for potent anti-cancer warriors.

What does this have to do with type 1 diabetes? Tampering with the immunity seesaw can have unintended effects: Following similar observations from other scientists, Dr. Bluestone shared that about 20 people at UCSF and Yale had developed type 1 diabetes due to beta cell destruction after taking checkpoint inhibitors. That is, taking the brakes off of the immune system had resulted in the seesaw tipping too far toward autoimmunity – and therefore causing collateral damage. These patients had beta cell loss and subsequent hyperglycemia appeared to begin rapidly after checkpoint inhibitor treatment (not necessarily the first) as opposed to a gradual decline, as is typical for patients who develop Type 1 diabetes. About a third of the patients (in a small sample) developed auto-antibodies. A prospective study is now underway, since it’s impossible to know if these patients had auto-antibodies before taking the checkpoint inhibitor, and many characteristics of type 1 diabetes are present (detection of T cells targeting proteins in the islets, beta cell death, inflammation that led to expression of the checkpoint that the drug is blocking).

Dr. Bluestone listed a number of key questions: Why do immune-related adverse events occur? When do they occur? Why do they occur in some patients and not others? Why do different drugs induce disease in different patients? Are anti-islet T cells directly affected by checkpoint inhibitors? Are they present before treatment? Is a disturbance of normal mechanisms of tolerance involved? Moving forward, a priority will be answering these questions, and more generally we imagine, figuring out which pedals to press, when, and in whom. This is no trivial task, but as JDRF Prevention and Cures lead Dr. Andrew Rakeman told us, we are in the golden age for immune therapies. The crosstalk between cancer and diabetes research affords a roadmap for moving forward.

• Dr. Bluestone provocatively asked, “Can the success of cancer immunotherapy be replicated for type 1 diabetes?” His position at the helm of the Parker Institute for Cancer Immunotherapy – the center forged from a $250 million donation from the co-creator of Napster and the 1st President of Facebook, Sean Parker – gives him among the best visibility into this question. From a purely scientific perspective, he believes the cancer field has been much more successful venturing into combination therapies, and also at targeting both the tissue and its environment. At a higher level, Dr. Bluestone thinks the cancer field has done an exceptional job exploiting new partnerships across disciplines and challenging the models of philanthropy. Still, cancer research is somewhat disorganized and bubble-like. There are now over 1,500 clinical trials mixing and matching immunotherapeutic drugs together, many without thinking deeply about the underlying biology. Dr. Bluestone estimates that there are currently 24 almost identical checkpoint inhibitors in development, which frustrates the research community and FDA, and siphons valuable patients off the clinical trial free agent list. “Smart” immunotherapy is the next step, in his mind. Of course, we’re dying to see the Parker Institute model applied in diabetes in a big way. The Institute has partners in UCSF, Memorial Sloan Kettering, MD Anderson, Penn, UCLA, Dana Farber, and other top centers, more than 60 labs, 40-plus industry and non-profit partners, and more than 300 of the nation’s top researchers, and a highly-specific strategic plan to focus on: (i) checkpoint blockade response; (ii) tumor antigen discovery; (iii) best-in-class T cells; and (iv) the tumor microenvironment (which affects a person’s ability to respond or not respond to checkpoint inhibitors). Encouragingly, the Institute already has a partnership with the Helmsley Charitable Trust, and hopefully JDRF will come on board soon!
• Dr. Bluestone expertly floats back and forth between cancer and diabetes work, sometimes to the point where his friends ask him why he is getting out of diabetes. Fortunately, he clarified that this couldn’t be farther from the truth: “Diabetes is a hard disease to think about how to cure, because the immune system is hard. It spends a lot of time figuring out the balance between tolerance and immunity. I’m always thinking about how we take the immune system, so important in just about every disease, how do we understand it well enough so we can cure a disease. When I ran the Diabetes Center or Immune Tolerance Network, it’s always been the sense that as we think about underlying mechanisms of disease, if we can find commonalties in immune system, then we can learn about all of them. No fear, Tuesdays and Thursdays I’m in my lab and all I think about its type 1 diabetes and autoimmunity …. To be clear, I’m a type 1 diabetes guy and I really appreciate all the help I’ve gotten from JDRF.

Questions and Answers

Q: It sounds like there are a number of brakes and a number of gas pedals?

A: Yes. We block a brake in cancer, it works permanently in some patients but for others, after a while the cancer gets around the treatment. So yes, the immune system, by redundancy, has lots of brakes. We need to figure out the best one in the best settings. I don’t think with autoimmunity we have to get rid of everything – if we turn on one dominant brake, we believe it’ll work. But the complexity of this should not be underestimated.

Q: Comment on development and advancement in biomarkers?

A: The biggest challenge in diabetes is that we believe all of the action is in the pancreas, yet the only thing we can easily monitor is the blood. Biomarkers are very hard; easy in dermatitis or cancer, because you get biopsies. Type 1 diabetes is hard because you’re monitoring the immune system at a distance from where the action is. But there are ways of monitoring in the blood what’s happening in the pancreas. There’s an assay [developed by Kevan Herold at Yale University], where you can see beta cell death in blood by looking at insulin gene DNA in blood, which is really exciting. The next key question is can we get biomarkers that inform whether an individual can or can’t respond to a drug. We’re not there yet, and there is a lot of work to be done. Who’s likely to respond or not? In the cancer field, we’ve made a lot more progress in the last year. You have both blood and tissue, so based on the tissue, here’s what’s going on. You can now see based on blood and stool who’s likely to respond to a checkpoint inhibitor. I’m afraid to say we’re not there yet in diabetes.

Q: I think you said it’s easier to do human research than mouse model work … is that because of FDA, safety, what?

A: I want to be careful. Doing good science in humans is the future, but it’s not an experimental, geeky thing. It’s really thoughtful studies that allow you to examine the immune system in the patients with the disease. If you perturb the normal situation with a drug treatment, you can see how that perturbation effects the system. Human research is the driver of future research because we have assays in place in many cases to monitor perturbations very well. Second, animal systems, incredibly important, are different – different molecules determine brakes and gas, and they have different genetics. We work in inbred mouse, they’re all the same, genetically and live together in one cage. But humans are diverse, live all over the world. Humans eat different things. Humans have diversity. The tools are in place so that we can take the diversity into account and make broader conclusions. In this way, human research is more robust than that in animals. Scientists are now doing experiments in mice they got from pet stores because they have more diversity in their immune systems, because they have more genetic and environmental diversity, like humans. In the end, I think it will take a combo of both animal and human research to move the field forward.

Close Concerns Q&A with Dr. Jeffrey Bluestone

Close Concerns: Please share with us your view about the state of immunology research in type 1 diabetes. 

Dr. Bluestone: I strongly believe that with knowledge comes advances, so what you heard today is great. With increased knowledge from programs like nPOD, we’re learning about what’s going on at the site of diabetes pathology. There’s a lot of great clinical work being done to look at the effects of disease on people over time. There have been a lot of fits and starts in this field – the disease is complicated, diverse, and hard to predict in any individual. Stop and look where we’ve come from. We now understand a lot more about fundamental elements of disease, from the contribution of immune system, effector cells, regulation, to beta cells themselves. Frankly, the advances in human immunology have made that easier. Still I’m very optimistic that we’re not stuck. It takes a long time, but we’re not stuck.

Close Concerns: Who are some type 1 researchers that you think the field should be watching closely?

Dr. Bluestone: I’m really impressed by the current generation of researchers. Obviously, the particular impact of Dr. Todd Brusko (University of Florida Diabetes Institute), researchers from the Benaroya Institute like Dr. Alice Long and Dr. Dan Campbell – the way they build their program is exceptional, young people in various different places making contributions. It’s such a big field. Some of the people most likely to make big contributions may not be viewed as type 1 diabetes researchers. They may do work in autoimmunity, genetics. There’s a group of young people out there – UCSF’s Dr. Alex Marson, he works on gene editing in T cells… a process that is currently be adopted for clinical treatments. Biomarker studies [by] Dr. Garry Nolan at Stanford, incredible work. There are so many other young people, supported by organizations like JDRF, I’m amazed by all of it.

Close Concerns: What would you say to draw more people into the diabetes field?

Dr. Bluestone: I don’t worry about that. The immunology community is very sensitive to the broad-based nature of research. There’s always a sense that what we learn in one area can have an impact in others. Don’t worry too much about pigeonholing people. JDRF, NIH, other large organizations, it’s our responsibility to be aware of the broader landscape so we can tap into folks doing great work in other areas. Frankly, the more money there is in cancer immunology, the more advances that can be brought back into the diabetes arena.

At least in the last year or so, there’s been so much more attention being paid to collateral damage – the opportunity seen by way of untoward aspects of drugs. Companies are interested. Helmsley Charitable Trust almost immediately gave us money to support this study. There’s quite a bit of interest. One-and-a-half years ago, it was hard to convince anyone to be working in this area, but now it seems like everyone understands the opportunity. I’m pretty excited about the generation of interest in this for both the cancer patients and the opportunity to gain knowledge that will impact on our understanding of type 1 diabetes.

The other thing that’s prompted that shift: awareness. In the early days, the industry was not so focused on defining immune response-related adverse events. Two things: One, we get a big enough set of data from the patients treated with the drugs, and two, as we have gained more experience with the therapies, they are used in earlier stages of disease on healthier immune systems, so the adverse events are becoming more prevalent. We’re seeing increased appreciation that it’s not just general inflammation. Experience, numbers and the patient population are changing. So we’re starting to see awareness in the immunology community to consider studying this area. When you’re treating 100 people and 2 develop Type 1, it’s hard to study, treat one million people and have 2% occurrence, it’s more real and more easy to study. Drug companies are now very interested in trying to figure out the mechanism, Bristol-Myers Squibb in particular. We have a great relationship with them. We’ve begun working with some of other companies as well.

Close Concerns: What is your dream trial?

Dr. Bluestone: I believe at the end of the day, a combination therapy will hold the key. Some drug that effectively debulks the autoimmune T cell response combined with a drug that promotes regulation, and then some beta cell replacement/rejuvenation. I’m not dogmatic about which combination plays out. It will be interesting to see how genetics plays out. The perfect trial is to take a couple therapies we know are working in type 1 diabetes or other autoimmune diseases, T effectors or Tregs, a combo, and induce tolerance. Since we’re trying to induce tolerance, it’d be a short-term treatment. Couple that with beta cell replacement therapy. The barriers are not trivial and doing it in kids is essential, which we can’t conceive of now. Early after diagnosis is critical, but maybe not if we have a good beta cell replacement therapy. Being able to do good biomarker studies [is vital] so we can identify responders and non-responders. When we do studies, younger people are often better responders.

Close Concerns: Could that get funded?

Dr. Bluestone: Well, it would be high cost. Convincing someone else to spend $50 million is not easy. Anti-CD3, a top candidate in my mind, is a drug that’s been around for 25 years. People are always looking for the next shiny drug. It’s hard to convince people to fund that. When you have a drug that, for reasons that aren’t clear to me, that have to do with misinformation or maybe other members of the class, perception of side effects – it makes it difficult. Really simple things like the way we developed anti-CD3 as a two-week treatment – others wish we had tested a four-day treatment early on but I am convinced that two weeks of therapy is important mechanistically.

The biggest barrier to seeing an inflection point in type 1 research? Having an approved drug for the immune system. If we had one that really had a dramatic effect, for instance is 5%-10% of patients were able to go off insulin, that would allow us to have an anchor, something to build off of. We could look at elite responders, it would allow us to do combination therapies, get into kids easily, perform innovative mechanistic studies. A good drug that could be a standard-of-care, that’s the inflection point.

I’m optimistic that if we could raise money and do one more phase 3 trial, anti-CD3 could be the first winning immunotherapy. We need just one success. Once companies see a path forward, they will hop on. There are so many great scientists now who five years ago wouldn’t have touched cancer. Now, there’s money there, excitement. Joe Biden, Jimmy Carter – as a researcher, my family and friends ask if I’m working on cancer now. It’s a snowballing effect. I do worry about a bubble, what’s going to happen in the next few years when not everything works. There are surfers and swimmers – surfers ride a wave and move on to the next wave, while swimmers are in it for the long haul. I do think, even if the bubble pops and the surfers move on, swimmers will stay committed, just like they have in T1D work over the past decades …but success will bring in enthusiasm, press and more resources. I’m most disappointed that we’ve never had that transformative success. If we just get over the finish line with one drug we’re working on, that’d be something. The good news is T1D researchers are extraordinary swimmers who keep plugging away.

Close Concerns: Is anti-CD3 the one?

Dr. Bluestone: Hard to say, but it’s really the furthest along. There are a lot of barriers. I don’t know, a shiny object may actually do a lot of the same things but anti-CD3 has worked in many patients.

Close Concerns: What are your second and third options to form a trial around?

Dr. Bluestone: There’s a lot of great stuff out there. There is research in antigen (insulin) immunotherapy that might be promoting regulation. There are opportunities in the IL-2 area, to promote immune regulation… with new alternative IL-2s on the horizon. [I’ve done] a lot of this type of work in my lab, so I’m biased. I believe in regulation, growth factors, antigen therapy, that’s a big change from 20 years ago. It’s reverse from in cancer. In cancer, it’s undoing regulation, in diabetes, it’s increasing regulation. Lot of drugs fall in that category. The other category is to shift the balance by reducing T effector cells to give regulatory cells a chance. Those are the areas I’m most excited about. You can list any drug, there are probably 20 out there, and any can fit the bill. I’m prejudiced towards ones already being developed, because it’s easier to get into a combination if one of the treatments is an approved drug, but there’s no single magic bullet. Even anti-PD-1, anti-CTLA-4, they’re not mild therapies in cancer, but they were just enough to get us to the inflection point. You have to be bold enough in diabetes. It’s easy to be bold if the alternative is death, like in cancer. It’s harder to be bold in diabetes. You’re not going to put people at risk if the drug’s not safe. Even when the drug is 100% safe, you still have to convince and persuade and balance the risk/benefit of a given therapy.

Close Concerns: Thanks so much for your time Dr. Bluestone!

Breakout Sessions

JDRF T1D Fund – Vision, Strategy, and Status

Sean Doherty (Chairman of the Board) and Jonathan Behr, PhD (Managing Director, JDRF T1D Fund)

Charismatic JDRF T1D Fund leaders, Sean Doherty and Dr. Jonathan Behr, provided an outstanding update on the ~one-year-old JDRF “venture philanthropy” investment vehicle. Since the 2017 Mission Summit, progress has been impressive – the fund has now invested in eight companies, up from only one as of its January 2017 launch (Bigfoot Biomedical). All eight companies are discussed in more detail below, including Dr. Behr’s comments and rationale: Bigfoot Biomedical, GluSense, Semma Therapeutics, Egenesis, TetraGenetics, SQZBiotech, Proventionbio, and Diasome. Fundraising progress has been impressive: the fund has raised ~$65 million from 39 donors (minimum: $500,000 investment), up from last August’s $55 million, nearly doubling JDRF’s initial $32 million seed investment (covering overhead for four years), and close to the two-year goal to raise $80 million.

Dr. Behr covered the fund’s deal flow and tight selection process – the eight portfolio companies were chosen from 200+ bona fide investment opportunities, with many whittled down at each stage of diligence. Moving forward, the T1D Fund anticipates 6-8 investments per year, each averaging ~$3-$5 million over the lifetime of the investment (~$25 million deployed each year) – this was the most specificity we’ve ever heard on investment size. Funding has been pretty split between the different areas of JDRF’s portfolio, a trend Dr. Behr and Mr. Doherty expect to continue. In Q&A, both emphasized that the fund is not just moving money around – it is designed to be an incremental source of capital for JDRF to deploy towards its mission.

• As hoped for, JDRF’s investments have also served as an important catalyst for the field – validating early-stage companies, convincing investors to come on board (either co-investing or lining them up as a follow-on investor), and even convincing new players to move into type 1 diabetes from other areas. The fund has also allowed JDRF to fund opportunities that previously did not have a home in its funding universe – e.g., Semma Therapeutics. There was significant audience excitement and many “congrats” during Q&A, and we’d guess raising the full ~$80 million will be very doable for the high-powered team. The biggest uncertainty, of course, will be showing success from some of these investments, which are inherently risky given the early stage of some companies.
• Both leaders emphasized that beyond JDRF/T1D mission fit, the fund is built on tried-and-true VC metrics – e.g., each company’s leadership team, an investable business model, a pathway for liquidity event (funds reinvested in the Fund), frequent contact with companies, quarterly donor updates, etc.

Building a Path to a Cure

Stephen Gitelman, MD (UCSF, San Francisco, CA) and Andrew Rakeman, PhD (Assistant Vice President, Research, JDRF, New York, NY)

UCSF’s acclaimed Dr. Stephen Gitelman presented already-published compelling data on autologous Treg therapy to preserve beta cell function soon after diagnosis, and informed attendees that a new phase 2 pediatric study (n=~110) has enrolled quickly and should read out in about a year. He explained that some T cells are autoreactive and attack beta cells, while others, Tregs (regulatory T cells) are essentially the police of the immune system who decide when the immune system should stop or slow down an assault. The diseased state in autoimmunity is reflected by a relative excess of autoreactive cells vs. Tregs. So why not simply fix this imbalance by supplementing the individual with more Tregs? Researchers first found this to effectively reverse diabetes in a mouse, so it was moved onto a clinic. A unit of blood is taken from the individual, Tregs are purified, stimulated with factors over a period of two weeks to promote 1000x growth, and they are ready to be re-infused. Fascinatingly, people with type 1 often have dysfunctional Tregs, but after this process, the purified cells grown in a dish appear normal. Dr. Jeffrey Bluestone et al. published phase 1 results of the therapy in adults ages 18-45 years, and within two years of diagnosis, had measurable C-peptide. The Tregs were safe and well-tolerated (self-donation precludes need for immunosuppression or fear of graft vs. host), and at lower doses, it appeared to preserve C-peptide secretion for a year (and two-year data looks pretty good, he added). According to Dr. Gitelman, the preliminary study was “a great joy for all of us” and the results “very exciting and promising.” The next step is the Treg Expansion study (“T-Rex”) with partner Caladrius in a phase two study for 8-17 year-olds within three-months of diagnosis (n=~110). We eagerly await results in ~a year!

• Dr. Gitelman also presented the Gleevec data we covered at ADA, showing treatment with the tyrosine kinase inhibitor (commonly used to treat leukemia and other cancers) to apparently preserve C-peptide secretion and lower required insulin dose. This was an early stage study, but Dr. Gitelman and team are enthused about the signal and are proceeding with a pediatric trial. He reminded attendees that Gleevec may exert protective effects by reducing stress on overworked beta cells, preventing them from being subjected and succumbing to the unfolded protein response (aka, apoptosis). 
• According to JDRF Assistant Vice President, Research Dr. Andrew Rakeman, there has been tremendous progress across the JDRF portfolio, as evidenced in the below photo showing that immune therapies, survival therapies, and regenerating therapies are all in the clinical stage. It is of course highly encouraging and promising that (i) there are so many irons in the fire and that (ii) they all seem to be moving along, but Dr. Rakeman pointed out that success brings new challenges. Human trials are long and costly, so JDRF has to be more selective moving forward. Combining therapies will likely be necessary, but there is “no paradigm about how to do that in a smart way at this point.” Lastly, research gets more expensive at later stages. He estimated that two to three clinical studies would cost $3-$10 million! Even work aimed at streamlining these long and costly trials is estimated to set JDRF back $3 million over the next three years, though it will hopefully serve as an up-front investment to reduce the cost of future trials. 

JDRF Training Programs in Action

Everett Meyer, MD, PhD (Stanford, Palo Alto, CA) and Julia Greenstein, PhD (VP, Discovery Research, JDRF, New York, NY)

Stanford’s Dr. Everett Meyer overviewed the bleeding edge work at the intersection of bone marrow transplantation and complex cell therapy for type 1 diabetes treatment enabled by his JDRF Career Development Award. Dr. Meyer studies immune tolerance induction via hematopoietic stem cell transplantation as well as Treg cell immunotherapy, hypothesizing that combining the two approaches could result in targeted immunosuppression and islet protection – possibly a cure cocktail for type 1 diabetes. Bone marrow transplantation has been shown to eliminate insulin dependence for extended periods of time in Brazilians with newly-diagnosed type 1 (JAMA 2007; this procedure is viewed as too risky for the US), and to even remove the need for immunosuppression when accompanying a kidney transplant. Tolerance is induced through “mixed chimerism,” whereby the recipients lymphohematopoietic system consists of a mixture of host and donor cells, allowing the donor cells to “train” the hosts’ immune response. On the other side of the equation, Dr. Meyer et al. have shown in a proof-of-concept rodent study that they can engineer Tregs to express chimeric antigen receptor (CAR), resulting in the protection of allografted islets. Dr. Meyer noted that it was still a “rough” system – islets are still eventually lost – but this a solid start. Dr. Meyer believes the two-pronged approach could be tested in patients within the next three to five years. Initially, the treatment would be reserved for those with “high-risk” diabetes who may have gone through transplant procedures prior, and could eventually move into a more general population within “5, 10, 15 years.” In an alternate application, Dr. Meyer pointed out that countless companies are on the brink of, if they aren’t already there, generating competent islets, and a big hurdle to commercialization is having those islets accepted. These early-stage approaches could hold the key. 

• In introducing Dr. Meyer, JDRF’s Dr. Julia Greenstein shared that since 2005, JDRF has awarded >$85 million to nearly 400 trainees. Crucially, surveys show that >87% of the trainees remain in type 1 diabetes research. This latter metric is a firm indicator that the training program is meeting its goal of attracting talent: “Once you get a grant for research in one disease, it’s easier to get another grant in that disease. So we bring people, MDs and PhDs, into type 1 diabetes early on, and it appears that they’re staying.” There are now four different grant opportunities for young scientists at different stages in their careers: (i) Postdoctoral Fellowships offer a yearly budget of $53,000-$64,000 (stipend) plus $5,500 for research allowance. There are currently 45 grants in total (15 international, 30 in the US). (ii) Advanced Postdoctoral Fellowships offer a yearly budget of $95,000/year for individuals transitioning from a fellowship to an independent faculty-level position. Dr. Greenstein noted this grant gives applicants a leg up in applying for their first jobs, since they come with some research funding and proof that they have already emerged successful from a competitive applicant pool. There are currently 14 active Advanced Fellowships (9 in the US, 5 international). (iii) Career Development Awards provide $150,000/year for individuals early in their faculty careers for up to five years. There are 12 active in the US (including Dr. Meyer) and nine outside of the US. Drs. Matthias Hebrok (UCSF) and Seung Kim Stanford) are both well-known former recipients. (iv) Finally, the Early Career Patient-Oriented Diabetes Research Award is the newest on the roster, designed for physician-scientists who generally don’t have enough bandwidth to work as clinicians and also conduct research up to the par of full-time researchers (Dr. Meyer is a notable exception – a physician-scientist who earned a Career Development Award). There are four active recipients of this award in the US (including Yale’s Dr. Jennifer Sherr) and one active internationally. We’d love to see the training program – budgeted for $5 million for 2018 – to expand and draw even more talent into the diabetes field. 

Diabetes Everyday: Challenges and Strategies to Live Well

Jill Weissberg-Benchell, PhD and Nicole Johnson, Dr. PH, MPH

In a heartwarming breakout session, Drs. Jill Weissberg-Benchell (Northwestern University) and Nicole Johnson (JDRF) discussed the emotional and behavioral challenges of living with diabetes and the non-profit’s exciting new efforts in this area. It was striking to hear that in ADA’s registry, there only around 50 diabetes-focused clinical psychologists in the US. Yikes! (According to this ADA page, the browsable directory is not yet available.) Through the new JDRF National Diabetes Psychologist Fellowship Program, eight new diabetes psychologists will be trained by 2020, adding a very meaningful number of specialized professionals into the field. Each fellowship costs just $60,000, and offers fellows clinical care, research, and local JDRF chapter opportunities. Dr. Jill Weissberg-Benchell shared sincere pride for her fellows (one of whom just presented at ISPAD), and Dr. Johnson emphasized that JDRF is the “only organization anywhere” doing this kind of program. JDRF also just announced a Students with Diabetes internship program for young professionals with type 1 – in the past eight weeks, 144 applicants with type 1 have applied to work in type 1 diabetes (for-profit, non-profit) and give back to the community. “This says a lot about our young people,” noted Dr. Johnson. In 2019, JDRF plans to add a specific young adult summit program for the organization’s regional TypeOneNation meetings – these will be “made for young people, by young people.” Amazing! We also loved seeing JDRF CEO Derek Rapp in the audience during this talk, a reminder of how important this area is to JDRF’s mission. Indeed, we can think of few other areas that could have such an immediately positive impact on patients’ lives, especially those who are having a hard time. See below from some excellent quotable quotes and tips from the first part of their talk, which focused on the psychological and emotional burden of diabetes and what families can do about it.

• “Most people with diabetes who are struggling are not depressed – they are distressed. If we nip that distress in the bud, we can prevent depression.” – Dr. Weissberg-Benchell
• “Finding positives is really important: ‘Tell me something positive that came out of having diabetes, whether it’s big or small.” – Dr. Johnson
• “When I start with parents who are frustrated, I say, ‘Tell me about some of the things about your adolescents that you adore.” – Dr. Weissberg-Benchell
• “Just because diabetes is sometimes hard does not mean there is psychopathology.” – Dr. Weissberg-Benchell
• “Distress is a better predictor of glycemic control than depression in the pediatric literature. High levels of distress are associated with worse adherence in adults and in teens. Treating distress improves diabetes outcomes.” – Dr. Weissberg-Benchell
• “Because of the unpredictable hormones and social pressures, the hardest time to have diabetes is during puberty. Imagine – you are starting to give your children independence at exactly the same time as no human being can keep tight blood sugar control.” – Dr. Weissberg-Benchell
• “High levels of distress are associated with high levels of diabetes-specific family conflict. When parents are very distressed, their children’s A1c’s tend to get higher. Parent distress and teen distress are also strongly correlated.” – Dr. Weissberg-Benchell
• “We as a society believe that when you’re 18, you’re a grownup – you can smoke, join the military, etc. But that’s at the point when the frontal lobes are still not developed enough to accurately assess risk and harm. That doesn’t happen until the mid-20s. Kids cannot biologically recognize the importance of adherence. The only organization in the US that recognizes this (how brain development influences risk taking) are the people that rent cars. [Laughter]”

What You Might Not Know About JDRF

Alisa Norris, Cynthia Ford, Jim Lurie, Margery Perry, Emily Spitzer

In a trip-back-in-time panel, JDRF’s Chief Marketing & Communications Officer Alisa Norris led a discussion with JDRF Chancellors Cynthia Ford, Jim Lurie, Margery Perry, and Emily Spitzer. See some of our favorite quotes below!

• On the power of JDRF Advocacy at the White House: “There was an issue about stem cell research a few years ago – it was being banned. Our volunteers literally shut down the White House call system. The White House staff called us, ‘Call off the dogs, we get it.’ So when you get an email from Cynthia Rice now, click the link below and send the letter in. Do it. They remember us. When I go into Kathleen Rice’s office once a year, she remembers me. I feel empowered. We have a legitimate conversation. JDRF means something in Washington.” – Jim Lurie
  
  • “Everyone yesterday should have gotten an email about the special diabetes program. Please reach out regarding the importance of SDP. Tell your personal story and pass it along.” – Alisa Norris
• On the move to strategically guide research: “JDRF envelops people. So when I was given the opportunity, I immediately got very involved. At the time, JDRF would receive applications from scientists, other scientists would review them, and we had lay review committee. I became head of research, and I was spending more and more time on it. I remember this moment where my daughter turned to me and said, ‘Mom, you spend all that time at the computer, but when is my life going to change?’ I realized then that we were not being proactive in guiding the research. We needed to make it patient-centered. If pharma could figure out a path for a drug, we could do so as well. So we put together a roadmap and identified who was best able to fill those gaps. We put out RFPs, and we started to direct the research.” – Emily Spitzer
  
  • “What this lady did with the roadmap and guiding research was one of the seminal moments in the history of JDRF.” – Jim Lurie
• “JDRF entices researchers to come into our area. One example is Dr. Doug Melton, who was an embryologist with no connection to type 1. But he was a super star. Once his son was diagnosed, he changed his lab – basically from one night to the next morning to work on type 1 diabetes. He was funded by JDRF and is the founder of Semma, one of the companies we fund. He has taken this field of developing beta cells and become one of the leaders. He went to JDRF, we grabbed him, and we moved him forward.” – Margery Perry
• “JDRF started nPOD. That was revolutionary. For the first time, we could see human tissue that had type 1 diabetes. It showed us things that we believed were completely wrong. We still don’t know what causes type 1 diabetes, and there is no way to prevent or cure it. But nPOD is a very, very important thing.” Margery Perry
• On rebranding: We started out as JDF, but since our focus was on research, we eventually felt that ‘JDF’ didn’t tell the full story. It was going to cause some disruption, but we wanted to get across the point that were a research organization. That was the decision to go from the “Juvenile Diabetes Foundation” to the “Juvenile Diabetes Research Foundation.” Then we made another decision a few years ago to drop “juvenile.” So we changed again to “JDRF International” – that’s our technical legal name. We had to get the focus on juvenile out of it, since most people with type 1 diabetes are adults.” – Jim Lurie
• On the creation of JDRF chapters: I want to dispel everyone’s notion that there was a plan and a roadmap. There were originally two chapters: one out of NY, where my parents lived, and one out of Philadelphia where the Ducats lived. My father did a lot of traveling, as did the Ducats. My father would go to a city and ask people to start a chapter. There was not a great plan. I remember getting a call once from a JDRF chapter, who was looking for a certificate of authority. I said, ‘What’s that?’ There was nothing formal about the process. Dad or Lee said, ‘You’re our chapter.’” – Jim Lurie

Replacing the Missing Beta Cell Function: Overcoming Hurdles in the Cure and Treatment of T1D

Kevin D’Amour, PhD (VP of Research/CSO, ViaCyte, San Diego, CA) and Esther Latres, PhD (Director, Translational Development, JDRF, New York, NY)

ViaCyte VP of Research/CSO Dr. Kevin D’Amour shared that therapeutic dosing has been initiated in the second cohort of the Phase 1/2 PEC-Direct trial (stem cell-derived beta cell replacement involving immunosuppression). We first heard at JPM that therapeutic dosing in the first cohort had begun – study completion is expected in December 2020, with completion of enrollment expected in December 2018. Dr. D’Amour also reviewed the status of the company’s other two bets, PEC-Encap (stem cell-derived beta cell replacement with an updated device that eliminates the need for immunosuppression) and the newest and most exciting prospect, PEC-QT (immune-evasive beta cell replacement therapy). He noted that PEC-Encap is making preclinical advancements and is “headed back towards the clinic.” No time frame was specified, though we take the optimism to be a good sign since results from PEC-Encap engraftment have not been as robust or reproducible as expected, related to technical challenges around the Foreign Body Response to the implant. The company has since partnered with Gore to improve the membrane system, and is “getting never-before-seen levels of function with the new membranes in rats.” Dr. D’Amour confirmed that before the modified system enters another human trial, it will have to undergo “just a couple more” safety and efficacy studies to satisfy FDA’s IND criteria. There was no news on PEC-QT, in which ViaCyte hopes to genetically modify cells to make them invisible or defensive to the immune system – preclinical research is ongoing, and Dr. D’Amour echoed CEO Dr. Paul Laikind’s JPM sentiments that PEC-QT could be the ultimate islet replacement product. See our JPM coverage for a deeper dive on all three products and comments from Dr. Laikind.

• According to JDRF Director of Translational Development Dr. Esther Latres, the Foundation currently supports 77 active grants in the area of beta cell replacement. The total budget allotted to this area for 2018 is $13 million.  

-- by Adam Brown, Brian Levine, and Kelly Close