On Job Cuts, Office Closures, and Breakthrough Cures: An In-Depth Discussion with JDRF
By Nena Kotsalidis, Rosalind Lucier, Lorena Bergstrom, Monica Oxenreiter, Cindy Takigawa, Austin Zhang, and Kelly Close
Due to the COVID-19 pandemic JDRF is making some big changes. We interviewed CEO Dr. Aaron Kowalski and Head of Research and Development Dr. Sanjoy Dutta to find out more about their research efforts and downsizing
After 15 years of growth, JDRF fundraising has declined sharply because of COVID-19. The organization plans to shift from a team of nearly 700 to 400, including layoffs of many of the 40% furloughed earlier this year. This comes as part of a larger transition in funding strategy, which streamlines operations.
JDRF goes back to basics. As we wrote when he assumed the CEO position last year, Dr. Aaron Kowalski has tremendous knowledge, an unmatched zeal for helping people with diabetes, and the ability to bring people together. These qualities will all be necessary as fundraising will be more difficult, at least for the next couple years.
We had the opportunity to speak with Dr. Kowalski and his head of R&D, Dr. Sanjoy Dutta, on the strategy at JDRF and the ongoing urgency to drive closer to potential type 1 cures. Our conversation touched on disease-modifying therapies, updated funding strategies, the changing corporate landscape, and more.
According to Dr. Kowalski and Dr. Dutta, JDRF’s new strategy promises to bring more efficient funding and operations, while maintaining its core focus on life-changing T1D breakthroughs. The plan is to become a “volunteer-powered” organization with more emphasis on digital engagement and less on in-person fundraisers. The end goal: a broader impact throughout the T1D community. Additionally, while things will certainly look different in the coming years, JDRF promises to emphasize research that will bring the greatest immediate impact to people with T1D – particularly initiatives to “improve glucose control, reduce disease burden, and support the next generation of researchers and clinicians." Most notably, this includes beta cell and immune therapies.
JDRF announced a major change in its strategy intended to streamline funding, accelerate research, and increase volunteer involvement. While its new approach certainly reflects the impact of the COVID-19 pandemic on development, fundraising, and employment, JDRF maintains its commitment to investing in cutting-edge research. Despite the current challenges, T1D research is advancing faster than ever before – particularly in beta cell and immune therapies, which have seen a series of exciting breakthroughs. JDRF promises to continue supporting key technologies and therapies, albeit with a huge shift in policy.
As its mission, JDRF has chosen to focus on projects with high potential and rapid results. Grants will be larger but fewer, as part of an effort to streamline the research portfolio. Top priority will be given to beta cell replacement strategies and disease-modifying therapies that either delay, halt or reverse T1D development. Most important, JDRF commits to supporting research that leads to concrete results. This policy means “filling the gaps” between research outcomes and real-world applications for people with T1D, including support for drug development, affordability, and health equity. JDRF will continue its commitment to its T1D Fund, which has catalyzed over $250 million in private venture capital. JDRF will also continue to leverage funding from partners in government, academia, and industry, including the Special Diabetes Program, which has provided almost $3 billion in T1D research funding, as well as international governments to advocate for crucial health studies and policies.
As fundraising changes drastically in the wake of COVID-19, JDRF has laid off around 40% of its employees – a tough decision, to be sure. This reflects JDRF’s new funding strategies as in-person events become more difficult in light of the pandemic. The key to this new model is volunteer engagement; JDRF promises to function as a “volunteer-powered organization.” This streamlined system will direct more energy toward individual, corporate, and venture philanthropy. Local chapters will cover larger geographical areas and will focus more on interacting with supporters rather than planning events. The organization hopes to expand its impact within and beyond the T1D community, particularly through digital engagement.
We discussed these changes with two of JDRF’s most influential leaders: President and CEO Dr. Aaron Kowalski, and VP of Research Dr. Sanjoy Dutta. In these exclusive interviews, Dr. Kowalski and Dr. Dutta spoke about JDRF’s strategy, their continued desire to collaborate across the diabetes community, combination therapy, critical areas of JDRF’s portfolio, and more.
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Kelly Close: Thank you for spending time with us, Aaron, at what we know is a challenging time. Can you share more about what it’s like to prioritize the most important thing – finding cures for type 1 – and to have to take on a plan for downsizing JDRF?
Dr. Kowalski: Early on in the COVID crisis, we had to make the really tough decision to furlough a significant number of our staff. And since then, we have been looking at ways to ensure that the organization will be just as strong going forward. We fortunately entered the COVID crisis in a strong financial position. The key principle guiding our pathway forward was that we need to maintain mission momentum. JDRF still has to be to fund research. We’ve got to be able to support our mission. To accelerate mission momentum, we’re going to make a series of fairly significant changes to the organization.
We’re going to reimagine our chapter structure. Right now, we have over 60 chapters. Each chapter has an active volunteer board, In the new structure, we’ll keep all those volunteer boards as “community boards” but will join them together into larger chapter. So, going forward, we will have 29 new chapters that represent larger geographies. For example, instead of an LA chapter, an Orange County chapter, and San Diego chapter, we’ll have a Southern California chapter, with active LA, Orange County, and San Diego communities sharing staff and other resources. The idea is to be as efficient as possible and to support as much research as humanly possible. We are not leaving any communities, rather we are working to ensure our support is distributed more efficiently. Unfortunately, to do that, we are going to have a significant reduction of staff, about 40%, and redeploy staff in these new, larger 29 chapters. The goal is to have a much more efficient organization with shared resources.
Kelly Close: The irony is profound that this shift must come at this point, because there’s never been a more productive time in type 1 cures research. But we see that shifting the model away from live events and crowds is absolutely imperative, for everyone’s safety.
Dr. Kowalski: That’s so true. In early March we held a retreat with our International Board and I said that I’ve never seen so much exciting progress happening across all areas of T1D research and development. We have seen our treatment options improve dramatically with CGM and hybrid-closed loop (life changing for my brother and me) and importantly we are seeing the transition from the lab to companies for disease-modifying therapies – such as stem-cell derived insulin producing cells and immunotherapies that are delaying T1D. It’s a renaissance time for diabetes research.
When the crisis hit, we took a people and science-first approach and you are right, we needed to be safe. Our events can include hundreds and sometimes over a thousand people. Getting together for walks, rides, runs, etc… was not possible and we had to take a strong look at how to move forward to maintain all of the exciting progress that we are seeing.
Kelly: It sounds like a lot of thought was put into this re-structuring of the organization. How do you see volunteers playing a role in this?
Dr. Kowalski: Yes, we are almost going back in time to the older JDRF when volunteers were asked to carry a little bit more weight. As Jim Lurie – son of one our founding Moms - told me this week: we need to go back to the kitchen tables! The plan went through our board approval and showed unanimous support. It is obviously going to be very difficult to bring this up to the staff because we are going to lose a lot of good people. We really try to treat our team as compassionately as possible. We’re just not able to bring most of our furloughed staff back and all of our active staff and that is so tough.
Kelly: Absolutely, it’s a big call to make, and similar to one related to your International board, which sounds like it is also smaller now?
Dr. Kowalski: Yes, we streamlined our board structure from 35 to 15 people. It has worked really well for us; the board is so strong right now. It is definitely a significant change, but I think it has been a huge boost for us. The head of the board now is Joe Lacher. He runs a 9,000-person business and has been an amazing mentor to me. He and his two sons also have type 1 diabetes – I remember you did a great interview with him last year, which I hope everyone has read.
Kelly: Going back to the volunteers, tell us more about what you have in mind. What do you see happening from a volunteer leadership perspective and for future policies going forward?
Dr. Kowalski: I think from my perspective, going forward, we just want to be out in the community even more. We want to rally more folks to get on board and support this amazing cause and help us push for progress.
One way that we’re pointing the ship is to have a clear line of sight toward solutions that improve outcomes. I think the trends of funding has been an amazing example of that. Now, we’re seeing more capital flow into diabetes-related products. For example, immunotherapies or cell therapy, and representation in programs like the Special Diabetes Program. We have a big partnership with the Australian government. Policy will remain a growing part of our strategy. We’ve got to see progress in more than just the United States.
Kelly: You’re exactly right, that’s so good to hear. What do you envision for the Special Diabetes Program?
Dr. Kowalski: Well, prior to COVID, we were very hopeful that we would get a multi-year renewal. In the COVID emergency relief package in March, we got an extension through November and are urging Congress to do more.
Kelly: It sounds like you have been incredibly optimistic about the opportunities for beta cell biology and all of the opportunities for immunotherapy. Can you speak more to your thoughts about that?
Dr. Kowalski: Seeing the data at ADA this year and the investment in stem cell, there’s no doubt in my mind that this is going to play out positively. We launched a big center in Northern California to investigate diabetes cell therapy and immunotherapies at Stanford and UCSF (see “JDRF announces new partnership with Stanford and UCSF to create Center of Excellence focused on stem cell type 1 cures” – September 4, 2019). I went to an FDA event where experts in immunology were talking about disease-modifying therapies. Other diseases like juvenile rheumatoid arthritis use these immunotherapies safely, so I am very optimistic. But it’s a different biology; we know a lot more now, and we have better tools.
Kelly: You are walking through crisis, clear-eyed, and all your care of so many people is so obvious. Making these big decisions is obviously a tough thing to do as a leader. We’re sending you lots of good thoughts at this perilous time in this global health crisis.
Kelly: To start, Sanjoy, the research is at such an exciting inflection point. Perhaps you can share us the background on where we are and how that strategy is going to pivot forward so we can further accelerate?
Dr. Sanjoy Dutta: So, this has been in the planning for a while. And ironically, just before the COVID pandemic hit in New York and we all went on to work from home and lockdown mode, we actually had a board retreat in New Orleans a couple weeks prior to that. And the entire topic of the two-and-a-half-day discussion was JDRF Horizon 2025. And a big component of that is, how can we move things faster into the hands of people modifying the disease, which is essentially to delay, stop or reverse the course of disease. We also want to expand our footprint globally – we are funding in over 20 countries. Historically, we have funded in 35 to 37 countries. But are we truly global? We were challenging ourselves. Do we really have a footprint in reaching people everywhere? Do we understand the heterogeneity of diabetes everywhere? Can we expand to the people without diabetes, and other autoimmune diseases that can benefit from what we are doing? Sticking to our mission, we can still benefit more people. And why aren’t we doing that? So, we challenge ourselves, challenge our board. Coming up on the heels of the board retreat, we were all on a high with this plan in force. And then we had a Research strategy meeting following that, which was super successful. Immediately after that, COVID hit us. So, we were all back home.
So, nothing has changed in terms of our plans with the COVID situation. What has happened is, if there’s any silver lining under the current bleak conditions, it has expedited the way we do things. Our mission will be to find life-changing breakthroughs that really make a difference in people’s lives with type 1 diabetes, and hopefully other people with related diseases. But how can we, moving from a world of prosperity to a world of austerity and to a constricted atmosphere? Let’s face reality right now. We have had five consecutive years of fantastic fundraising and breakthroughs in research. For the first time, we have preventive therapies; we are showing insulin secretion from the cells implanted into the body. We have two closed-loop systems in the market. We have some adjunctive therapies approved in Europe. So, there is movement. And JDRF has fingerprints on all of these things. And how can we continue that momentum in a climate that we are faced with right now without losing sight of the goal we want to achieve
So, the pivot we are going to make is not in mission. The pivot we are going to make is in how we can hone in and get the biggest bang for our buck – whether that is in financial buck or our influence, the regulatory health policy influence, our influence in advocacy across not just the US government, but also in Indian, Australian and European governments, which actually amounts to several hundred million dollars on a per annum basis. And how can we keep that? And how can we change the trajectory of things to now move at a million miles an hour to meet the demand that is ahead of us? So, this is kind of the philosophical pivot that we are making.
Nena Kotsalidis: Thank you again for being with us. Out of all the type 1 areas that JDRF is involved in, including beta cell replacement and immunotherapy, to name a few, which is most impacted by the COVID-19 pandemic and the aforementioned changes to your organization? And are there any pre-clinical projects being affected more than those further along in the R&D pipeline?
Dr. Dutta: Yes. Definitely. So, the good news is that T1D research hasn’t come to a screeching halt – in different parts of the world, of course, they have had different levels of impact. For example, I was on the phone with a couple of Australian investigators this morning. They have been minimally impacted. I was also on the phone with a UK investigator who has gone to their lab every day during this crisis period, pre-clinical work and doing it. So, certainly everything has been impacted, but preclinical work has been impacted to a lesser degree than clinical work.
There have been some clinical trials that are able to conduct remote processes from March till June. And now, they’re all opening up – Barbra Davis is opening up, and I know Minnesota is opening up and several places are opening up in a small way. But yes, pre-clinical work in Melbourne and in some parts of Europe and a few parts in Canada and the USA were not that much impacted. So, we’re very happy – in whichever area of curative therapies that we talked about, that was still ongoing, albeit at a reduced rate because of the limited number of people that could be in the lab at a given point in time. And they did shifts on, “You go on Mondays and I go on Tuesdays,” and so on and so forth. And we were monitoring it very diligently to ensure that we provide the support necessary so that the work is not stalled at this because of our lack of leadership.
Lorena Bergstrom: Thank you. Building on that, we’re just wondering if you could say more about which one particular therapy or intervention you think has the most potential at this moment?
Dr. Dutta: It’s always hard to answer, because you are dependent on the vulnerabilities of typical research and R&D progress, right? I will mention this much, that cell therapy providing – let’s say, hypothetically speaking, six-month of insulin independence, or significant reduction in insulin-dependence – it has its own challenges but probably has a path toward a regulatory decision that is exciting to all of us, primarily predicated on the proof of concept that comes out of transplantation. There is a proof of concept existing. We know there are challenges. We have to overcome some of those through encapsulation of what we call open scaffold with local immunosuppression that’s not systemic and all that. And so, from a scientific angle and the fact that we are in five different clinical studies, it gives me a lot of hope. At the same time, there is also teplizumab – so much excitement around it. It’s sort of a rolling submission with a fast-track designation. It may be a toe in the water. But to me, it’s like man setting foot on the moon because it’s never been done before. I don’t know what will be the decision by FDA, but it’s a big win for humanity, or at least for T1 diabetes.
Kelly: Thank you. Do you think that it can be that you can do this at home, teplizumab, or do you think people will have to go and check in to the hospital?
Dr. Dutta: As a non-clinician, I don’t see it being done at home at the present time. Because it’s an IV infusion. So, as a non-clinician, take it with a bucket of salt, but – I mean, they can probably insert an IV catheter and probably find innovative ways of doing it – you see people with those IVs, and performing dialysis at home. So, I do see it in the future as a possibility. But I don’t know right out the gate that’s going to be a possibility. And that’s just because I’m not a clinician. But I do want to say that – and we were all at ADA virtually. It’s not just limited to Teplizumab although that’s super exciting. There are two additional things I want to mention – you know both of these. One, there’s the golimumabs and the IL-21 plus GLP-1 combination, and there’s probably others coming out of the JAK inhibitors and other classes that are coming. That’s optimism for me, that there’s going to be several options – it’s not a one-trick pony anymore. The second thing is, which I know Kelly will attest to this, the second piece is, five years ago, not even 10 years ago, I did not see this level of momentum from the private sector, from the commercial companies investing in T1D. And the fact that they are seeing the light at the end of the tunnel. And they’re investing and they’re coming to us continuously for advice. In some cases, as a co-funder while in others as advisors on clinical trial design and networks, or community and HCP engagement, depending on which arm of JDRF they’re speaking with. And in many cases, no financial commitment, just for advice on regulatory and health policy, and international clinical networks. I think that is half the battle won.
Even the glucose response of insulin acquisition by Novo Nordisk, and that’s a big investment. Whether or not these succeed, and we know how science progresses, we know the attrition rate in pharma is 90%, and several other impediments. And we know one out of 10 things only work. Still making an investment in T1D and doing this 300 plus patient trials like Novo did, and some smaller trials like Janssen and others did, I think it’s promising. And as JDRF, we need to definitely make sure that we keep removing the barriers of entry. Keep clearing the pathway there. That can go much, much more than our financial funding can do. And so, I’m very optimistic.
But the fact that these companies are thinking about that and engaging with JDRF, the scientific team, the regulatory team and eventually the policy team, is very encouraging for me. And I think the progress in the last 24 to 36 months both on the scientific side and the fact that these companies are there – and look at the successes of T1D Fund, with the amount of investment they have been able to garner for T1D.
The investment that has gone in – I mean, we couldn’t have imagined this, Kelly, you and I, that have been around for longer than some of the others in the call, we didn’t see this kind of movement. So, I call it a movement, actually, almost, in addition to a momentum. So, that’s encouraging to me. And I know we will fail more times before we’ll succeed, but at least the fact that we’ve tried gives me hope.
Kelly: Yes. And do you feel like you have as many of the big Fortune 500 or Fortune 100 companies involved? GSK used to be involved as did Takeda as did BMS and so, there’ve been a lot of exits also.
Dr. Dutta: Right. Well, we are looking at it from a glass-half-full angle, and I will use my career as an example here. When I got out of post-doc, it was a very good job market. There were 14 pharmaceutical giants in diabetes R&D, and not counting the biotechs. And some names that you’ve never heard of, like Pharmacia and others, that were in the diabetes space. Mostly type 2 space. 14 giants. Now, we are down to three to four big pharma companies. Yeah. Exactly. Three to four big pharma companies and if you look at the IMI partnerships in Europe, there are four or five involved already.
Kelly: The IMI. That’s big.
Dr. Dutta: Yes, I see that as promising.
Kelly: Sanjoy, could you talk about some of the principles that are guiding you and the team in terms of the research that’s going to get cures and therapies into the hands of those with type 1?
Dr. Dutta: Sure. So, screening will remain a priority for us – and of course, we’re talking population screening, initially secondary prevention, but eventually population screening for primary prevention, because we will need to identify the level of risk and how many are at risk. And so, we will double down on that. So, TrialNet and several other efforts will double down because we need to identify these people. Screening itself has its benefits which you all know about, and then you also need to have a cohort of people that, of course with consent, can be participating in these clinical trials. More importantly, screening will become the foundation for identifying disease-modifying therapies. And this is true with any disease, certainly with type 1 diabetes. It is always going to be easier to prevent a disease than cure a disease. Not that we’re shying away from cures in any way. But preventing a disease, while still a form of cure, is going to be probably easier from a physiological perspective because the damage is minimal at that stage and time. Followed by screening – and it’s not necessarily always a linear sequence of progression, but followed by screening we will be arresting the disease as early as possible. So, the category of disease-modifying will overlap the stage 2, stage 3, while screening will focus on stage 2 and stage 1 if you go with the type 1 diabetes staging.
So, we will focus a lot on additional immune therapies that are safe and effective, and how can we combine them with beta cell therapies? Right now, we are obviously sitting on essentially one beta cell therapy, Verapamil, which we all know is generic, but we do want to make sure that we have islet targeted beta cell regenerative products coming. We have some promising leads from pre-clinical. And to your earlier question, there are some pre-clinical therapies that are quite promising, but we need to target them to the islet. So, they will be a high priority that we focus on, and of course, cell therapy.
But I want to mention a couple things. One is, we are not getting out of any major area. We will continue to invest in artificial pancreas and metabolic control which is novel insulins and adjunctive therapies). Psychosocial burden of living with the disease is huge for all of us, as well as some effort in diabetic complications. However, that’s an area that we will continue to fund research, probably not to as much a degree as we did in the past, because some of it has, thanks to JDRF and other funders, developed an ecosystem that is self-sustaining, or at least better than the area of cures that needs help. The second and final point is, how will we make these decisions to prioritize? How will we make this decision to work in a climate of austerity? And that will be driven by the guiding principle of productization. So, we will definitely support our basic research and discovery research, but probably ask ourselves and ask the investigator the question, what is this going to lead to or contribute toward a product? Like, I come from a pharma world, where you propose an idea and you’re earlier on the bench top in a test tube, not even in a mouse or a rat. We have to develop a target product. Even if it is going to change 180 degrees by the end of the pipeline, we have to have a purpose to that study.
So, that’s the way I think we’ll approach things – what are we targeting to direct towards the product? So, productization will be a very important focus of ours and covering that pipeline, which includes regulatory approval and beyond that. So, again, those are some of our guiding principles. And throughout this process, we will not lose sight of an important guiding principle that we have kept close to our heart, and continue to fund the next generation of researchers, clinicians, scientists in general, because there is such a dearth of people in type 1 diabetes research due to lack of funding, personal choices, low pay of endocrinologists, etc. And if you look at the ratio of the people with chronic orthopedic disease and diabetes, you will see the huge gap in these two diseases worldwide, number of clinicians to the number of people that require their treatment, some of the widest gaps we have. And so, JDRF will continue to do our best to bridge that gap, knowing fully well that we cannot be the only one trying to do it. So, these are some of our guiding principles.
Monica Oxenreiter: We would love to hear a little bit more about the research on eye disease and kidney disease and cardiovascular risk reduction, where you see those in this era and this environment?
Dr. Dutta: I did not plant that question, but it’s very close to my heart. So, definitely, obviously, from the DCCT days to today, we are doing much better. But we are far from the finish line. To begin with, glucose control is still erratic, even in the US, the leading nation in the world. And so, there will be complications. So, we will have a continued focus in diabetic eye disease and kidney disease. Last several years, and Kelly knows the history, we used to have a very big funding portfolio in complications. We reduced it from a funding, percentage wise, but we always maintained our leadership and our leverage. So, we work very closely with the NIH and its other divisions like NEI and others, and we have partnerships in Europe and in Canada and Australia.
So, we’ll continue to understand more the core differences between T1D and T2D. And we will fight the battle we need to fight to have T1D not as an exclusion criterion in pharma trials for kidney disease. Right now, T1D is an exclusion criterion for most pharma trials for kidney disease, and probably other complications except eye. In eye disease, we want to move beyond VEGF. And VEGF is fantastic, but I think now, it’s in the hands of the manufacturers to make VEGF a better drug, like the less frequent injection, topical, non-invasive injections. So, I think that’s more a role that JDRF doesn’t have to play. We are more looking at, can we reduce the length of the clinical trials through qualification of biomarkers that can read out in six months instead of 24 months? Can we find a new biomarker for kidney disease that’s not creatinine doubling and can be read out early on? So, we will play a role in that, and we are also working with regulators to identify what is required to get a marker, a surrogate marker, qualified so the trials can be reduced in cost and time, and the barrier of pharma entry.
Last, but not the least, diabetic heart disease is not an area we fund directly in, but we definitely collaborate and work with other funders. JDRF is very interested in knowing the differences between heart disease due to T1D versus T2D. The clinical presentation of the two diseases are different. And it is possible, although the data is very limited, that canonical treatments that work in cardiovascular disease for type 2 may not work in people with type 1. So, this has to do with some of the pathologies of the disease and whether it’s affecting more the blood vessels, the heart blood vessels versus inside the heart. And so, you will see a divergence in clinical presentation of heart disease when it comes to T1D versus T2D. And I think it is the responsibilities of JDRF and like-minded organizations to know that and to have drug manufacturers develop therapies that will work for people with type 1 diabetes. And it’s still the highest cause of mortality for people with diabetes, and we need to change that. And we need to change the modifiable factors, the preventable factors. And there will certainly be some non-modifiable factors. But what are the modifiable factors we can change? I hope that answers your question, but that’s the role we’ll continue to play. And as I said, we aren’t getting out of any area.
Monica: Great. Thank you. And to follow up on that, in terms of with the kidney diseases, SGLT2s are approved in the EU for type 1. How are you thinking about that, and how have those programs been affected?
Dr. Dutta: They are definitely affected. Definitely affected with COVID. Not only because COVID has prevented clinical trials in general, but if you look at SGLT inhibitors specifically, they’re asking you to discontinue SGLT if you have COVID infection. This is because of the obvious difficulty in disease management and requirement for insulin doses and type of glucose control. But outside of that, I think GLP-1 and SGLT still hold a lot of promise in T1D. Of course, we have to recognize and mitigate or eliminate the DKA risk with SGLT2. But nonetheless – and Kelly, you know my opinion very well. It’s a very strong opinion. I am not at all belittling the importance of looking at DKA as a risk factor for the person with diabetes, T1D, taking SGLT2 inhibitors. But I feel that there should be a concerted effort in identifying how we could mitigate the risk and have guidelines on the usage in who should be prescribed SGLT and what the other consensus guidelines are that came out in Diabetes Care about a year and a half ago. That’s my goal. So, there are the known SGLTs and GLP1s in kidney and heart diseases, and there are a few others that people are trying to develop, but unfortunately, T1D is an exclusion in most, if not all, studies. And we want to change that. We want to change it.
Kelly: Please talk to us about the cancer therapies like checkpoint inhibitors that have been associated with causing type 1. Very rarely, of course. JDRF, through the T1D Fund, has been investing in some of the companies in hopes of learn more about how T1D might be developed. Please tell us more about where that stands.
Dr. Dutta: Yeah. So, I agree with you that initially we were all surprised. We were all surprised that it was a clustering effect for autoimmune diseases. It was rare. I agree with you. And it was very interesting scientifically to see the clustering of T1D and some related diseases. And then you will see a different cluster here of Hashimoto’s and some other disease coming up. And so, initially, it was not only for scientific curiosity, but to know of the pathways. And this is clearly not a natural process of the immunity coming up and generating autoantibodies, it’s more of a drastic phenomenon, like it figuratively turns upside down. It’s more of a sudden occurrence. It’s like, I don’t mean it literally, that it happens in a days’ time; it’s a very quick occurrence.
So, something is happening in the pathway of these checkpoint inhibitors that probably triggers a particular immune signal here. Initially it was not just a scientific curiosity, but also to understand those mechanisms so we can go back and do the opposite. You activate the immune system so it can destroy the cancer cells. But here, we want to know what are those cells that we can inactivate so you can prevent the beta cell destruction. And so, the Parker Institute and the Helmsley Charitable Trust are in the JDRF collaboration to get to the bottom of it.
But we do have other studies going on here, including the Northern California Center of Excellence, which you are aware about, Kelly, and other immune cell therapy-based approaches that we can learn from. So, am I optimistic that we will learn from this and identify a future risk of intervention? Yes. Am I optimistic whether this will necessarily give us a drug to work with? Not yet. Not yet. Because it has a way to go before we can get there. I’m equally optimistic about learning more about other common mechanisms of autoimmunity and trying to see how we can repurpose a rheumatoid arthritis drug or a psoriasis drug like an anti-TNF. I’m interested to see if we can apply a drug to T1D that has a proven safety track record. And so, that would probably be the lower hanging fruit, if you will. And then, how can we get those in the hands of people with diabetes?
Kelly: Oh, that’s so interesting. I didn’t really realize that this was very sudden.
Dr. Dutta: Yes. So, these people obviously don’t have auto antibodies or diabetes. So, we are going back to these 300 plus patients that were on this and trying to understand their clinical characteristics. They were not checked for autoantibodies because that was not the goal.
So, we’re kind of learning it like a rewind and watch the videotape again. So, we’re going back and looking at them, and prospectively look at other studies that are ongoing with checkpoint inhibitors. These are pretty common these days for multiple cancer indications, not just one. And so, trying to identify what triggered this, and some of them may even be auto antibody negative still, but still have a T1D lighting up.
There is a small subset of people with T1D that don’t have auto antibodies. And this is not an established population. So, they’re more an exception than a rule. And we still don’t understand what that is, and what is it that led to the destruction of beta cells. But the bottom line here is that auto antibody is a biomarker. It’s not a causal link. It’s just a marker that tells you you’re likely to get the disease, but it still doesn’t take you to the pathway of what the causal link is. And that’s relying on the pathways we know. So, I’m positive we will learn a lot from this sudden onset T1D.
And then if I may draw an analogy, although this is more to make a connection here. The new onset diabetes with COVID infection. We’ve seen that in the news. The new one onset diabetes that is concomitant with COVID infection in a few individuals. There are a million questions. Is it T1D? Is it T2D? Is it some other diabetes? And nobody knows. And these are small case studies here and there, but it has a presentation reminiscent of both types of diabetes. People are coming into the clinic with DKA, requiring IV insulin, significant amount of fluids and it reminds you of T1D, yet they don’t have auto antibodies. At the same time, they’re severely insulin resistant. And anecdotal evidence suggests that it’s reversible when the infection is under control, when the insulin levels are high, and glucose is down. Now, we are talking very few case studies here. It’s oranges and apples too, but I drew this analogy right now to tell you what sudden onset diabetes is like and how we can learn from that. But, obviously, COVID and PD-1 inhibitors are very, very different, but they are both causing sudden onset diabetes in small subsets.
Kelly: So, sudden diabetes onset. That’s very important food for thought.
Kelly: You mention that JDRF now has multiple new centers - there is one in San Francisco, there’s a new center in Boston, and there’s a center in Michigan. It sounds like your research is just going to become even more hyper efficient in this new world. Can you talk more about this?
Dr. Dutta: I’m glad you asked the question. I’ll give you at the very highest level first. I’ll talk California and Boston, the two ends of the country first, because they’re both based on a similar theme, but different research on cell therapy. In an overly simplified manner, and there are many nuances to what the Northern California Center is doing, is they’re looking at how can we modify the immune cell. How can we modify the immune cells to not recognize self as an antigen? So, this is more of a gene-editing approach within the immune cell or around the immune cell. And it’s immunology predicated on transplant medicine. And two of the experts there are transplant surgeons.
So, how can we re-teach the immune system to not recognize itself as an antigen? The New England center is trying to look at the beta cell, which Dr. Melton is well known for, looking at the beta cells and seeing how can we use avant-garde technology to modify the beta cell to be not recognized by the immune system. So, there’s a paper in Nature Metabolism that came out today or yesterday from Melton and Stephen Kiessler and others and JDRF has co-funded that study that basically looks at what it is that causes the beta cells to give the immune system a signal that is foreign, but it’s not. And can we have added one, two, three, four, eight genes there? Easier said than done. To now have a decoy. Therefore, the beta cell is no longer recognized by the immune system as being foreign as happens in T1D and other autoimmune diseases. The synergy will come, and both the centers have results, West Coast and East Coast. And hopefully, someday, in an ideal world, the two can be put together. And I don’t mean the centers of the research, but the immune cell modified and the beta cells modified put together.
The Michigan Center of Excellence is working on a different hypothesis. And cell therapy is a part of it, but it’s not the entirety of it. It’s working on a very, very novel concept about a metabolic dysregulation. And what that means is, we know glucose is the key component in diabetes. But they want to look beyond that. So, there hypothesis is based on metabotyping, suggesting that in looking for the trees, sometimes you miss the forest, i.e., there are several other components outside of glucose that go wrong in type 1 diabetes, and we should, in holistically approaching this problem, balance or re-balance the metabolic imbalance. And this is not just from a metabolic control perspective, but also provide a healthy environment, for example when you’re doing a cell implantation. We implant cells for transplantation, encapsulation, etc. Cells don’t survive. There are a million reasons: oxygen supply through blood, vascularization, rejection of the graft, etc. But the point is that also the metabolic environment of the cells is not conducive. It’s hostile. And what can we pick up in metabotyping an individual with type 1 diabetes? Very carefully, using systems biology and differentiating that a person from a type 2 diabetes or a control, and reducing the noise in the background. And so, what is the unique, metabolic signature through system’s biology that leads to complications, that leads to cell therapy rejection, that probably leads to some psychosocial burden. Why are the psychosocial burden and outcomes so much in T1D other than the well-known factors of 24/7 management? Is there a metabolic signature in your blood that we can pick up? People have done that for cognition. People have done that for other diseases. Is there a signature we can pick up in your blood that can then be a diagnostic or prognostic? Eventually develop mitigation therapies based on metabolic fingerprint. It is a very, very novel hypothesis. And we know that at the Michigan center with the different expertise of the different minds to solve that problem rather than an individual investigator. And that’s the Michigan Center’s Central hypothesis.
Nena: That’s really interesting. Kelly and the team and I were thrilled to have the chance to interview Elizabeth Caswell recently, and we understand that she’s now going to be helping lead your research with another brilliant and very influential JDRF volunteer leader Karen Jordan. This is very exciting.
Dr. Dutta: Karen Jordan, from the San Francisco Bay Area, is the Chair of the Research Committee. Elizabeth Caswell, from Michigan – after whom the Michigan Center of Diabetes is named – is Vice Chair. They are both terrific leaders.
Kelly: There has been a lot of talk about beta cell biology, but you implied that you are still supportive of smart insulin and programs going on. Is there anything else you can say about smart insulin?
Dr. Dutta: Right. So, we are obviously going to revisit our strategy with limited funding and what we can do. How can we really move the needle? We were filling gaps in the past, but now we’ve got to pick the gaps we can fill. I’m speaking figuratively now. But the point is, we want to make sure that the research we fund in improving lives area is definitely crucial, and I didn’t mean gap-filling facetiously. Areas where there is limited funding by other funders, there is a gap in pick up the by the pharmaceutical industry, but it has transformational potential.
And I’m a firm believer in glucose-responsive insulins and liver-targeted insulins. I know it’s a highly technical challenge, and I know the insulin challenges in the United States have distracted people. But we don’t want to thwart innovation. It’s going to be challenging. I’ve said this before, Kelly, that no disease has a drug that works automatically in response to a metabolic signal. Taking a cue from the body. People have tried this for pain medication, blood pressure medication, that you have a drug that dials up and down based on your pain or your blood pressure. People have tried and probably are trying. We have tried to do that based on their glucose levels. So, technically, do I think it’s possible? Absolutely. But are there challenges? Of course there are. And so, there are scientific challenges and regulatory challenges we have to overcome. But if we don’t do it, who will do it? So, we will focus on transformative solutions in the future, such as glucose responsive insulin, adjunctive therapies. Closed-loop systems, I think, there is significant room for improvement. So, we will focus more not on the next HCL maybe, but we’ll focus on, what can close the loop? Maybe it is an ultra-rapid insulin, maybe it is an advanced algorithm. And another area we will keep our ears to the ground is miniaturization. Because you know, that’s critical.
And can we have infusion sets that last more than three days? So, extended wear. CGMs have gone so far for 14 days, and why can’t we have infusion sets that last at least seven days? So, those are things that we think will impact people’s lives, but require some level of research. So, we will be very selective in what we do moving forward, Kelly. But it will evolve. It will evolve. And today, I don’t have a crystal ball on what that strategy will be because we’re barely trying to come out of this COVID crisis. All of us really want to put this behind us and look forward to August and onward. And that’s when we will finally get creative into how can we move forward and onward.
Kelly: How is funding distributed?
Dr. Dutta: For the last three, four, five years, all of our funding, almost 70% is in cures. And cures include cell therapy, immunotherapy, beta cell therapies and all of that. So, we have been slowly dialing down in areas of improving lives, which is artificial pancreas, metabolic control, complications. So, we’ve been slowly dialing down because the world has picked up on it, thankfully. And we have been expanding in the area of cures. But in cures is very balanced between cell therapy and immunotherapy, and also screening. We invested a lot in screening. And screening is agnostic to immune or beta cell therapy.
Kelly: Whew! Whew.
We have learned so much Sanjoy, from you and Aaron, even at, especially at, this very challenging time. We can’t help but be very moved by your obvious partnership, along with the rest of your smaller team. Understanding that we have been thrown into such turmoil is very hard, and I know I try to avoid the thinking myself that we have now unmistakably, and so quickly moved right past recession toward depression. I want so badly for the traditional JDRF model, with walks, rides, and large gatherings to be just around the corner. And, I also see for now and clearly for some time, JDRF’s large live events fundraising model could not possibly be sustained, and that JDRF had to make some very hard choices – and, that this leaves you with mission momentum. Thank you for your time, Sanjoy, for your leadership, and for always looking forward.