Levine-Riggs Diabetes Research Symposium 2016

March 6-9, 2016; Long Beach, CA; Full Report – Draft

Executive Highlights

Our team recently headed to sunny Long Beach, CA to attend the annual Levine-Riggs Diabetes Research Symposium. This report contains our compiled coverage from the four days of the conference, held from March 6-9. In addition to the signature basic science offerings, this year’s agenda included heated debates on the use of non-insulin therapies in type 1 diabetes, updates on the cutting edge of digital health and beta cell encapsulation, and perspectives on industry investment in novel type 1 diabetes therapies and cures. We always appreciate this conference for its curated peek at what’s to come in the diabetes and obesity world – see below for our themes and full coverage of these excellent presentations!

Themes

  • Interest in non-insulin therapies for type 1 diabetes is gaining further traction. Dr. Anne Peters (USC, Los Angeles, CA) strongly argued in favor of a role for SGLT-2 inhibitors in the type 1 diabetes treatment armamentarium. Several pharmaceutical giants (Sanofi, Janssen, and Novartis) presented their takes on industry investment in non-insulin treatments, cures, and preventive therapies for type 1 diabetes. We welcome more alternatives for type 1 patients as long as they have full education and knowledge on the importance of ketone testing and understanding of euglycemic DKA. We continue to believe that many type 1 patients (as well as type 2 patients, for whom the risk is lower) know very little about ketone testing – ketone meters and test strips are also expensive and not well reimbursed at this stage.
  • While Levine-Riggs has typically been a basic science-focused conference, several new technologies for diabetes therapy were highlighted in this year’s agenda. Boston-based Intarcia was represented with a presentation discussing the impetus behind development of its ITCA 650 implantable exenatide mini-pump. We also received a glimpse of UMass’ Get In Touch trial of Livongo’s cellular-enabled blood glucose meter in type 2 diabetes and heard pipeline updates from Tidepool CEO Mr. Howard Look. We were heard an update from ViaCyte; two more patients have been implanted with the company’s beta cell encapsulation system since its last update at JPM 2016, bringing the total number of patients to 14 – even more recently, we’ve heard it is up to 16.
  • We also heard plenty of new insights on mechanisms behind diabetes and its associated complications. These presentations were on the cutting edge of basic science research in diabetes, and they also served as a reminder of how much we still have to learn about both type 1 and type 2 diabetes and obesity. Several presentations hinted at potential new therapeutic targets for diabetes and obesity treatments, and while most of this research is at a very early stage and years away from any kind of clinical application, the more promising findings piqued our interest and are discussed below.
Table of Contents 

Detailed Discussion and Commentary

Debate: Pharmacological Approaches for Glycemia Management in T1D is No Longer Limited to Insulin Alone

Position 1

David Nathan, MD (Massachusetts General Hospital, Boston, MA)

Dr. David Nathan (Massachusetts General Hospital, Boston, MA) argued that improvements in type 1 diabetes treatment should focus on innovations in insulin therapy rather than the inclusion of additional drug classes. He acknowledged that more options for type 1 diabetes care are needed, as many patients on standard insulin therapy currently are not at goal, struggle with hypoglycemia, and have fairly significant dosing and financial burdens. That said, he argued that we should look to more physiologic insulin analogs and innovations in pumps and CGM to improve therapy. He agreed that addressing patients’ needs should be the highest priority and argued that patient-centered outcomes need to be studied with the same rigor as other endpoints. Regarding his point that “Nobody has ever shown that glucose variability has been able to improve outcomes,” we would point out that until recently, there were no reliable tools to even measure glucose variability (the Dexcom G4 was the first) and that CGM has certainly shown a reduction in severe hypoglycemia but to show improvements in long term outcomes would likely require a ten-year trial or more – much easier said than done!

Position 2

Anne Peters, MD (USC, Los Angeles, California)

Dr. Anne Peters (USC, Los Angeles, CA) countered Dr. Nathan with the stance that type 1 diabetes is not a one-hormone disease and that while some patients have success on insulin alone, many others struggle to maintain good control. She explained that SGLT-2 inhibitors in particular have had profound effects for many of her patients, including quality of life improvements that are difficult to assess in clinical trials. One of those patients (a college debater no less!) then delivered a compelling testimonial about the impact J&J’s Invokana (canagliflozin) has had on her diabetes management. She suggested that clinicians don’t always fully understand the importance to patients of improvements like weight loss, modest insulin dose reductions, or reductions in glycemic variability. As one example, she noted that her blood sugar will now rise only to 170 mg/dl after a meal instead of 250 mg/dl, and “the difference between 170 and 250 is being able to move your legs.” Stories like these illustrate the enormous gaps between clinical trial results and the complexities of living with diabetes in the real world – we wish this sort of patient perspective could be on the agenda at every diabetes conference and we salute the organizers in making it possible for more researchers to better understand patient perspectives.

Panel Discussion

After the debate, both speakers concurred with the room’s anger around rising insulin costs and pointed to the usability of older insulins as an imperfect solution. Specifically, Dr. Nathan expressed confusion around rising insulin costs, noting that competition doesn’t seem to be driving down prices. In fact, the opposite has occurred: prices have consistently gone up, even for “the same insulins that were sold 20 years ago.” Dr. Peters shared that while it’s not her “favorite,” she can effectively manage patients without insulin analogs, referring to the lack of affordability of such options in East Los Angeles. Notably, she emphasized that it is important to not communicate negatively about the use of older insulins with patients, stressing that “you don’t ever want people to feel they’re getting second-rate insulin.” We can see the truth of this although it’s likely at least some patients will get the perspective through other means (blogs, etc.).  The discussion around insulin pricing and whether the clinical benefits of analogs are worth the cost is certainly controversial and we were glad to hear Dr. Peters’ insights on how these issues are impacting the most vulnerable communities. Check out the NYT’s recent opinion piece on the high cost of insulin and responding letters to the editor (including one by our own Ms. Kelly Close) to read more about the perceived pros and cons of the more expensive, but hypoglycemia-reducing newer insulins. Dr. Irl Hirsch also delivered a very passionate and comprehensive talk on this topic at ADA Postgrad last week, echoing his memorable presentation at ADA 2015. We are slightly troubled by how reductive this issue seems to be – from our view, vilifying any one part of the ecosystem is not particularly productive. Reimbursement absolutely must improve; we also look to systems improvements and much greater transparency.

Rebuttals

Dr. David Nathan (Harvard University, Boston, MA): Individual tests are incredibly powerful and listening to patients is obviously critical. But show me the money – I need to see studies that demonstrate it. There are different flavors of type 1 phenotypes that look like type 2. The problem with empagliflozin is that the company is going to push for it to be used in everyone with type 2 but it shows benefit only in a small high-risk population. In type 1 diabetes, absolutely if we have trials showing a benefit. Nobody has ever shown that glucose variability has been able to improve outcomes. The data Anne presented at ADA showed an increase in patient satisfaction and that definitely means something. But I need to see clinical benefit because this comes at huge financial cost – it tacks on $5,000 to $8,000.

Dr. Anne Peters (USC, Los Angeles, CA): From the patient perspective, the sole reason I’m giving my patients an off-label drug is because of what I’ve found in patient after patient. It’s anecdotal, but I’m not sure if studies will show a full benefit because variability is hard to relate to outcomes. But it’s about what makes the patient feel better. What price would you pay to feel better? I want to stress that I’m not using this cavalierly; I’m not saying everyone should be on it. I’m agreeing more than disagreeing – we need big trials and we need more data to look at risks and benefits. If I use it off label, I use it with very adherent patients and carefully. I have them do ketones, and I start with one quarter of a tablet and go up slowly. If they get sick, they know to stop it. The real part of this is if the therapy can help the patient, it’s great. We have to look at mitigating risks. A lot of stuff isn’t cost-effective. The pump is a big expense. It doesn’t improve A1c, but it’s a quality of life issue.

Dr. Nathan: If it’s right for the patient, you should be able to prove it. For quality of life, there are metrics. We want them to feel better and do better overall – that’s no question. In terms of approving or suggesting it’s effective based on anecdotal evidence, I have a problem with that.

Dr. Peters: What we need is CGM data. We need the FDA to accept CGM data as an endpoint. You can look at variability, time in high or low range. You can pick up hypoglycemia you might not already know, which could lead to hypoglycemia unawareness down the road.

Questions and Answers

Q: I don’t think A1c is as valuable as it was 30 years ago; we’re more interested in beta cell function. I think we can’t tell whether something works after one year. We don’t know what the effects of some interventions are until five, ten, or 30 years later. It’s a new insight in diabetes. So far, we’ve been discussing the consequences and symptoms but not the cause. Virtually all patients have remaining beta cells, and we may have drugs that can get people out of senescence.

Dr. Nathan: I wasn’t addressing the potential for waking up beta cells. I was looking at glucose lowering drugs. Would I say we shouldn’t do transplants? That’s lots of extra drugs.

Q: What about sulfonylureas? Once we stop inflammation, they might have a place.

Dr. Nathan: Maybe, if you have beta cell mass, but the data in type 2 diabetes suggests that it works against beta cell survival.

Q: Could some long-term effects of these drugs be dismissed?

Dr. Nathan: There’s no business model for any pharma company to do anything other than short-term investment. These studies are 24 or 26 weeks, maybe a year, and they maybe unmask it and do another year. That’s something I think is unrealistic. Although A1c not quite as useful, it still represents what we understand as a chronic measure of glycemia that is most tightly linked with outcomes.

Q: Can any of you think of new developments in pump therapies that actually make pumps more cost-effective to justify being the standard of care? We also keep having more new products including new insulins that bring minimal clinical improvement. What we face in everyday practice is a large number of patients who cannot afford new expensive versions of insulin. There was a NEJM editorial on why we don’t have cheap insulins anymore – should we consider using older insulins on the basis of cost?

Dr. Nathan: These are the same insulins that were sold 20 years ago. These are going up and up and up; they’re charging whatever the market will bear. I don’t understand it. Competition doesn’t have an effect – Levemir and Lantus have been raised in lockstep.

Dr. Peters: I spend half my time in East LA. I can still manage patients with no analogs – it’s not my favorite but I can do it. Many patients can’t afford analogs. It’s important not to forget how to use old insulins. I shouldn’t spend hours every day trying to beg for my patients to get the right insulins, but I think we can use non-analogs too. Never say to patients this is a worse insulin; it’s a different one. You don’t ever want people to feel they’re getting second-rate insulin.

Pumps and sensors and newer pumps have lots of benefits in terms of turning off. I have learned to have my patients do a lot of basal rate adjusting. Technology will allow patients to get better control. It’s going to help people way at the top – the highest income patients at most modern facilities. There’s a whole world of patients with type 1 diabetes who can’t even get the basic care. I’m interested in also applying care that we already have to the many, many who don’t have it.

Q: Thank everyone for bringing up cost. We’re not going to solve it tonight. For me, it comes down to on the one hand, insulin works and it’s the best we have now. You’re right – we can’t justify adding anything routinely now. But it’s hard to discount people living with it who tell us things about a drug impacting their life. Variability is something we don’t usually look at, but we should. If we’re using things off-label, we owe it to ourselves to keep track of what we’re doing and do some form of clinical study so we can either say we have evidence or there’s lots of anecdotal stuff but it doesn’t help. If we’re not doing it in a careful, monitored way, we lose track of adverse events. It’ll come back and bite us.

Dr. Nathan: I certainly agree. I would guess for a moment that Anne’s report at ADA won’t show a difference in quality of life.

Dr. Peters: There are no tools that actually are good for assessing variability and its effect on quality of life. What my patient is saying about how she feels, there is no scale for that. I’ve looked hard to find a scale. One thing I can say is that I wrote the first big case series of euglycemic DKA with SGLT-2s. It had 12 patients. Nine had type 1 and all were in the ER sick with DKA. Every single one of those people has begged to go back on an SGLT-2. Even after having that bad outcome, they liked the benefits enough. My n is small but it’s in the order of several hundred now. And I am following them.  If I had gone into DKA that badly, I would never want to take the drug again, but they do. I’m just telling you that the patient voice here is stronger than for anything I’ve done in diabetes.

Q: I would think that the economics of metformin use are quite strong. If you assume everyone is on analogs, which I acknowledge isn’t the case, you can save possibly $200-$300 billion a year if you’re using metformin and getting a very mild 10% reduction in insulin requirements. Statistically, it doesn’t seem like a lot, but if you extrapolate it out to the population and think globally, this is huge savings in diabetes management.

Dr. Nathan: Metformin is always a drug people look to in economic analyses because it’s pretty much free. To save a couple of units (like 5%-10%), I guess you could do the math, but to put someone on another substance that they have to take to save a few units, it doesn’t compute. I’d have to think about it.

Comment: A couple units a day as a patient is incredibly important. I pay $350 for insulin every few months, so $10-$20 savings is huge. It doesn’t look like anything in a study but it’s actually a large amount.

Q: You do not need other drugs. You could try a gluten-free diet, which is a wonder drug. It’s known to depress inflammation and to increase insulin sensitivity. It doesn’t even have to be 100% gluten-free, but maybe 80% or 90%. The problem is what company is going to start a trial. But these are minor things that could be tried.

Dr. Peters: Patients benefit from various kinds of diets. Some of the patients who don’t need anything but insulin adhere strictly to a low-carb diet. Some people do amazing regimens. But it’s also hard to have a regular life. My patient who spoke, I used to worry about her. She was my realtor and she would come over late in the day and I’d want to ask is your sugar low. I don’t worry about that anymore.

Comment: That’s why I said 80-90%, not 100%. It’s not that difficult to be 80-90% gluten-free.

Dr. Nathan: My experience in my patients is that when they go on diets, they reduce carb intake dramatically, their glucose stabilizes, and I’m not sure about inflammation but dietary changes predictably do lead to improvements. Most of my patients stay on the diet only for a brief time. Being on a gluten-free diet is difficult.

Q: SGLT-2 inhibitors are probably a more promising class of drugs. At least one CVOT looks promising, but I’m really concerned about diabetic nephropathy in the drug with its direct effects on the kidney. I need more data to be confident that it doesn’t cause more serious problems.

Dr. Nathan: The EMPA-REG group showed kidney data at ADA – it’s not only reassuring but very exciting. I’m not excited about the drug at all, but I’m excited by the kidney data.

Comment: On another note, I would urge us to stop talking about metformin being so cheap before some company buys its rights and multiplies the price.

Diabetes Technology

Electronic Communication Systems to Energize the Patient with Diabetes to Engage in their own Health Care

Michael Thompson, MD (University of Massachusetts, Worchester, MA)

UMass’ Dr. Michael Thompson briefly introduced the ongoing 120-patient, 12-month Get In Touch trial of Livongo’s cellular-enabled blood glucose meter in type 2 diabetes (baseline A1c ~10%). The year-long, randomized, controlled crossover Get In Touch trial (n=120) is investigating the acceptability, clinical efficacy, and patient-reported efficacy of the Livongo system in comparison to “usual care” (which, at University of Massachusetts, includes meter downloading and uploading to the MyCareTeam web portal). Baseline A1c was a very high 10.3% in the Livongo intervention group and 10.0% in the control group. Of the 120 participants who initially enrolled in the trial, 96 are currently active at the six-month mark (47 in the Livongo group and 49 in the usual care group). Halfway through the study, about half of the participants in the Livongo group (n=23) have been contacted by a CDE in response to a high or low blood glucose and 11 participants have had CDE coaching. In the usual care control group, only two participants (!) have downloaded their meter data at home through MyCareTeam, suggesting (as expected) that the cellular-enabled Livongo system facilitates better remote care through zero-hassle data downloading. Dr. Thompson emphasized the “teachable moments” offered by the real-time CDE responses: participants are able to better understand what exactly precipitated the high or low by talking with a CDE about it immediately. This is the first trial of Livongo’s system we’ve heard about and we’ll be curious to see the impact on A1c and how patients react to the more hands-on, real-time monitoring approach to diabetes data. Scalability is always a big question for diabetes coaching, and we wonder if the company can drive significant uptake vs. established players (e.g., Roche and J&J, who are now actually moving on connectivity with Accu-Chek Connect and Verio Flex), and serious strides in mobile CGM (Dexcom G5, upcoming Medtronic Guardian Connect). The meter launched in 2014, though we have not heard a company update in some time. We also wonder what Telcare is up to, who pioneered the cellular-enabled meter approach but has been quiet recently. More details below from this talk include Dr. Thompson’s depressing perspective on electronic visits, praise for MyCareTeam, and a wish list.

  • Dr. Thompson also highlighted a phase 1 pilot program for electronic visit (e-Visit) reimbursement with the University of Massachusetts health system and Massachusetts-based insurer Harvard Pilgrim. The trial hoped to show that e-Visits could reduce the need for in-clinic care, the type of efficiency that technology has brought to other therapeutic areas (e.g., Doctor On Demand, MD Live). Unfortunately, enrollment in the trial was even tougher than anticipated and identified a host of barriers to greater uptake of the e-Visit model. On the patient side, barriers included a lack of computer access, trouble logging on or uploading to the portal, trouble connecting devices to the computer, and general hassle. On the provider side, billing for e-Visits in practice was actually fairly rare because it felt like “extra work” to the providers. Dr. Thompson likened telehealth to where online banking was in the early 2000s. In 2000, only 18% of customers used online banking features and the number had jumped to 61% by 2013. Dr. Thompson sees uptake of telehealth following a similar trajectory in the coming years. We certainly hope so – diabetes care has to go in this direction if the tiny sliver of providers has any chance of caring for the tsunami of patients. That said, this trials brings up a disturbing number of barriers, and we wonder who will blaze the remote care delivery trail forward. 
  • Dr. Thompson praised the MyCareTeam software for its ability to interface directly with a wide variety of EMR systems, including Epic and AllScripts. From a patient’s file within the EMR system, Dr. Thompson can press a single button to reach the patient’s glucose readings. In addition, MyCareTeam creates a “diabetes scorecard” for each patient that integrates patient data it pulls from the EMR file. Furthermore, Dr. Thompson praised the online communication portal that facilitates HIPAA-compliant asynchronous communication (in contrast to logistically difficult phone calls or the universally hated faxes). Despite the benefits, Dr. Thompson acknowledged that some providers have avoided integrating self-management technologies into their practice, largely due to the lack of reimbursement for the care provided through these technologies.
  • Dr. Thompson concluded with his wish list of goals for each aspect of the diabetes communication process. At the interface of the patient with the diabetes device, he praises “effortless connectivity” through cellular, Wi-Fi, and/or Bluetooth connectivity. Dr. Thompson’s ideal diabetes management application would be able to interface with all devices and contain a host of diabetes self-management tools. The ideal EMR system would be able to interface with a variety of management apps. As a provider, Dr. Thompson wants a single sign-on to access all of a patient’s diabetes data and the need for systemic support for remote care (e.g., reimbursement!.)

Open Data. Open Source. This is Medical Software?

Howard Look (CEO, Tidepool, Palo Alto, CA)

Tidepool CEO Mr. Howard Look shared two pieces of pipeline news: (i) that the company hopes to release its Nutshell app “within the next month or two”; and (ii) that the launch of partnerships with Animas and OneTouch are also on track for the near future. The timing on Nutshell is consistent with the guidance laid out at ATTD; as a reminder, the app is currently in beta testing and delivers insights that can help users make more informed bolusing decisions for future meals by logging and integrating mealtime data (bolus, correction, pre- and postprandial blood glucose values). Mr. Look walked attendees through a live demo of the app, illustrating how the tool can help individuals move away from “carb guessing” to really understanding the ideal bolus dose for different meals. In addition, he noted that Tidepool will be officially launching its partnerships with Animas (Ping, Vibe) and OneTouch (VerioIQ, Ultra2, Ultra Mini) within the next couple months, building on compatibility with Dexcom, Insulet, Tandem, Abbott, and Bayer. Notably, Medtronic and Roche have still not authorized Tidepool to read data from their devices though Tidepool can import data from Medtronic’s CareLink Personal. We continue to be so impressed with Mr. Look’s passion and energy (he lit up the room here at Levine-Riggs) and we applaud his team’s unwavering commitment to incorporating the patient perspective into Tidepool’s products. For more of our commentary on Tidepool, please see our coverage from ATTD and the White House Precision Medicine Initiative Summit that featured Mr. Look in conversation with President Obama.

A Sub-Dermally Placed Osmotic Mini-Pump in the Treatment of Type 2 Diabetes

Brian Schwartz, MD (Senior Medical Director, Intarcia Therapeutics, Boston, MA)

Dr. Brian Schwartz (Intarcia Therapeutics, Boston, MA) provided an overview of Intarcia’s ITCA 650 (implantable exenatide mini-pump) and delved into the impetus for its development. Dr. Schwartz emphasized that despite the broad range of available treatments, type 2 diabetes remains a large and growing problem with many patients still not at goal. Dr. Schwartz identified challenges with patient adherence as one of the main barriers to glycemic control in type 2 diabetes. He emphasized Intarcia’s belief that releasing another pill or injection into the diabetes market would do little to change the number of patients not at goal. Instead, the company aims to take patient adherence out of the equation with a therapy placed directly under the skin of the patient’s abdominal wall. He underscored that the mini-pump would continue delivering the GLP-1 agonist exenatide 24/7 without the patient needing to remember to take any pills or injections – the patient could even travel with the mini-pump without any additional planning. This echoes Intarcia CEO Mr. Kurt Graves’ previous commentary on Intarcia’s goals of improving the accessibility and uptake of GLP-1 agonists. We wonder whether this could have price implications, though Intarcia has not made any definitive comments on pricing to this point. Dr. Schwartz also reviewed the impressive FREEDOM-1 and FREEDOM-HBL phase 3 clinical data for the program in his presentation and explained the placement process for ITCA 650. In a conversation following his presentation, Dr. Schwartz shared that the CVOT for ITCA 650 (FREEDOM-CVO) is ongoing (Mr. Graves indicated at JP Morgan that results will be available in 2Q16). Dr. Schwartz stated that while the positive LEADER results for Novo Nordisk’s Victoza (liraglutide) are certainly encouraging for the GLP-1 agonist class, ELIXA for Sanofi’s Lyxumia (lixisenatide) was neutral. In our view, it is possible that the long-acting vs. short-acting distinction could be a factor in the difference between the LEADER and ELIXA results, which could cast doubt on exenatide’s potential for cardioprotection. On the other hand, ITCA 650’s built-in adherence makes it one of the more likely GLP-1 agonist products to demonstrate cardioprotection.

Islet Cell Encapsulation: Progress in Clinical Trials

Jeremy Pettus, MD (UCSD, La Jolla, CA)

Dr. Jeremy Pettus (UCSD, La Jolla, CA) shared updates on the ongoing phase 1/2 trial of ViaCyte’s VC-01 islet cell replacement therapy. After reviewing the concept and preclinical data for VC-01, he shared that the clinical trial is progressing well and that safety and tolerability results have been promising thus far. 14 patients in the first cohort have now been implanted with the device, up from 12 as of the company’s JP Morgan presentation in January. Dr. Pettus noted that an analysis of a sentinel device removed from one of the participants after 12 weeks demonstrated robust vascularization and cell survival. This is strong proof of concept data, though our impression from the JP Morgan presentation was that the outcomes have not been as positive in every patient. Dr. Pettus did not provide any more specifics on the timeline for the rest of the trial. The company’s goal for this first cohort is to demonstrate that VC-01 is viable in humans. That data will then be used to optimize the therapy for the second half of the study, which will evaluate efficacy and safety in a separate cohort of 36 patients. During Q&A, Dr. Pettus emphasized the dedication of the participants in this first cohort, who have committed to a fairly rigorous protocol with almost no likelihood of personal benefit at this stage.

Lowering the Barrier of Entry and Long-Term Commitment of Pharma in Type 1 Diabetes

Challenges of Conducting Type 1 Diabetes Clinical Trials: Industry Perspective

Marjorie Zakaria, MD (Novartis, Cambridge, MA)

Dr. Marjorie Zakaria (Novartis, Cambridge, MA) highlighted the challenges of conducting type 1 diabetes clinical trials, touching on the importance of incorporating patient-specific outcomes in the regulatory framework as well as the collaboration between industry and research institutions. Dr. Zakaria first reviewed what it takes for entry into type 1 diabetes, noting challenges of meeting safety requirements and identifying optimal doses. Notably, when discussing regulatory guidance around type 1 diabetes, she emphasized that the endpoint of C-peptide is difficult to assess due to its slow rate of decline, thus implying the need for long clinical trials. Dr. Zakaria therefore supported Dr. Anne Peters’ argument from day #2 that patient-specific outcomes on quality of life can be very valuable in this regulatory framework, commenting that, “health authorities do listen to patients.” We would agree that the FDA has recently made greater strides in taking the patient perspective into account in its work – see our coverage highlighting the Agency’s Patient Preferences Initiative for more on this. Regarding the conduct of clinical trials, Dr. Zakaria highlighted the immense time (up to two years) that can be required by the facilitation of contractual agreements between industry and type 1 diabetes consortia, government-funded institutions, and academic sites, thus encouraging the field to better facilitate these discussions. Ultimately, we find it notable that many of Dr. Zakaria’s outlined challenges were often related to the separation among different stakeholders (whether that be researchers, regulatory authorities, or patients), thus calling for the need for greater collaboration across sectors. As Dr. Zakaria eloquently concluded, this cooperation across the field is critical as “our patients are waiting.”

  • In discussing targeted therapy and early decision making within clinical trials, Dr. Zakaria heavily emphasized the importance of identifying biomarkers. Specifically, she called for the need to identify early response biomarkers along with clinically relevant and prognostic biomarkers. She stressed that as the type 1 diabetes population is very heterogeneous, selecting the right patient population for trials is challenging but incredibly important in targeting the appropriate treatments for the right patients at the right time.

Research and Development of Disease Modifying Drugs for Type 1 Diabetes: Challenges and Gaps

Philip Larsen, MD, PhD (Sanofi, Bridgewater, NJ)

Dr. Philip Larsen (Sanofi, Bridgewater, NJ) emphasized the need for more research to develop a rational approach to type 1 diabetes therapies centered around combination therapy. We aren’t able to hear Dr. Larsen speak and this was a terrific opportunity. Dr. Larsen pointed out that the root cause and triggering event for type 1 diabetes is still a mystery, as is why beta cell decay progresses much further and faster in some people than others. Dr. Larsen suggested that type 1 diabetes might be a syndrome of multiple conditions, meaning a rational therapeutic intervention would combine immune suppression and modulation therapies with beta cell restoration. He pointed out the fairly disappointing history of monotherapy immunosuppressive approaches that only transiently preserve beta cell function and highlighted promising combination therapies such as ATG/GCSF (currently being investigated by TrialNet in new-onset type 1 diabetes). However, Dr. Larsen feels that a greater understanding of the etiology of the disease is needed to develop a truly comprehensive cure approach. He suggested that such an approach could combine (i) an anti-inflammatory agent (such as etanercept or anakinra), (ii) immunomodulation (with alemtuzumab), (iii) mobilization of stem cells for beta cell repair (with plerixafor), and (iv) preservation of beta cell health (with a GLP-1 agonist such as liraglutide). This is consistent with statements from a number of leaders in the field (including Dr. Carla Greenbaum and Dr. Jay Skyler) that combination therapies are the future of disease-modifying type 1 diabetes interventions.

  • Dr. Larsen also highlighted the EU-based INNODIA consortium of industry (Novo Nordisk, Lilly, Sanofi, GSK), nonprofit (Helmsley Charitable Trust, JDRF), and academic partners. The group plans to build an infrastructure to recruit, phenotype, and collect biosamples from a large cohort of newly-diagnosed patients with type 1 diabetes and at-risk family members. The goal is to discover and validate biomarkers for type 1 diabetes and maintain integrated databases containing phenotype, genetic, immune, beta cell, and metabolic information and more. The group will solicit input from patients and families with type 1 diabetes and will focus on mechanistic, exploratory, short-duration clinical research rather than full-blown clinical trials. Dr. Larsen was careful to emphasize that the collaboration is not competitive and is aimed at advancing the general understanding of type 1 diabetes etiology. Such an innovative partnership model that combines top-notch researchers with substantial resources and investment could make significant strides in our understanding of type 1 diabetes and improve the chances of developing successful cure therapies. We hope the reach of this consortium extends beyond the EU in a meaningful way – Dr. Larsen emphasized during a panel discussion following the presentations that the initiative is not restricted to Europe.

How can Academia Help Accelerate the Development of Commercial Products to Prevent and Intercept Type 1 Diabetes

Joseph Hedrick, PhD (Janssen, Raritan, NJ)

Dr. Joe Hedrick (Janssen, Raritan, NJ) discussed Janssen’s efforts to shift the paradigm from treatment to prevention of type 1 diabetes through the Disease Interception Accelerator program. He explained that type 1 diabetes was an ideal initial area of focus for the program because of the combination of high unmet need and a fairly deep understanding of the root causes and early biomarkers of the disease. There is also a clear window for intervention in type 1 diabetes, as the disease process begins long before the onset of symptoms. Dr. Hedrick believes that a successful approach to type 1 diabetes prevention will include three components: rebalancing the immune system, maintaining beta cell health, and addressing environmental triggers. He also emphasized the importance of biomarkers, which he believes is an area with plenty of opportunity for increased cross-sector collaboration. For example, the diabetes community could agree on a list of five key biomarkers that would be included as endpoints in every clinical trial of a potential intervention, and the aggregated data would be freely available. Dr. Hedrick argued that while there is a genuine desire for collaboration from both industry and academia, there is a lot of room to make the communication more effective and transparent, and to share information earlier in the process. He listed several components of what he views as a “critical path” approach to research, including (i) defining priorities for limited research resources; (ii) asking “what will I do differently based on these results?” before every study; (iii) defining a core team focused on the question at hand; and (iv) thinking of drug development as a relay race rather than assuming one person needs to retain ownership throughout the process. We have been very impressed with the mission and progress of the DIA program, which announced its first research collaboration last June. We hope Janssen and others can serve as role models and inspire a similar emphasis on prevention from other manufacturers.

Panel Discussion

A panel discussion following the industry presentations drilled down into some of the practical hurdles to more effective cross-sector collaboration. While there are clearly good intentions on both sides, there is also frustration with the bureaucratic hurdles that often arise. For example, several academics in the audience expressed frustration at how difficult it often is to obtain drugs from companies for clinical trials, while the industry representatives noted that much of the holdup is due to FDA regulations around their interactions with HCPs. On a more uplifting note, there seemed to be a strong consensus around an effort to enable the use of autoantibodies as endpoints in clinical trials for type 1 diabetes therapies. We hope these sentiments can be translated into organized action and ultimately a change in regulatory policy in the future. See below for a full transcript of this informative discussion.

Questions and Answers

Q: It’s great that you talked about collaboration. Are there any specific initiatives from Janssen you can cite?

Dr. Joe Hedrick (Janssen, Raritan, NJ): There’s the RFA we put out with JDRF earlier this year funding biomarkers in the interception space. We haven’t put any restrictions on the availability of that data because it’s so important for our initiative and our community. That’s the clearest example. Keep in mind I’m a one-year-old organization at this point.

Dr. Carla Greenbaum (Benaroya Research Institute, Seattle, WA): You all mentioned challenges and you all talked about how we can work together. What does that mean in reality? How can we have more effective, faster cooperation? What can we do so we as academics don’t have to talk to each of you separately? We’re working hard on centralizing IRBs and contracts. What’s happening on your end?

Dr. Philip Larsen (Sanofi, Bridgewater, NJ): INNODIA is not restricted to Europe. It reaches out to the entire globe. The idea is to build, over a seven-year period, substantial translational medicine to understand type 1 diabetes. It involves biomarkers, preclinical models – it’s not restricted. There are other initiatives within individual companies. There’s also a huge appetite to engage in more basic and clinical research. We can make great use of TrialNet and other vehicles. Now we have reached an inflection point where we think we can do something more proactively, not just treat people when the damage has happened. I encourage you to reach out to industry, and we reach out to academic groups. We’re reaching the point where we’re in a more collaborative mode.

Dr. Hedrick: One example is that we’ve alluded to the fact that once you’re multiple-autoantibody positive, you’re on the path to type 1 diabetes. Why aren’t autoantibodies qualified as a biomarker for trial selection by the FDA? That’s an easy one where industry and academia can come together. That says that the FDA or another authority has examined the data and acknowledged that these are biomarkers of risk, which enables us to use them as criteria for enrollment in registration trials. It sends a clear message to physicians and payers that the disease doesn’t start with insulin dependence. It starts earlier. I think this is a huge sea change in how we think about type 1 diabetes relative to every autoimmune disease. That is a catalyst for moving forward.

Dr. Marjorie Zakaria (Novartis, Cambridge, MA): I totally support that. We need to work together to have a conversation with health authorities that can change medical practice and diagnostic criteria for type 1 diabetes. That’s an area where we can work together and engage regulators. If we change our position and approach, we can enroll patients early and have a benefit.

Dr. Hedrick: We’re much stronger as a community of academics, patient advocacy groups, and industry. Patients themselves should argue for the need for this change. Any one of us alone would be subject to some suspicion, particularly industry.

Dr. Greenbaum: My talk tomorrow is on this topic. It’s important to keep a sober perspective on this. Yes, the disease starts earlier. That’s not going to make the trials shorter at the moment. Another question is that academia has a longer time frame in some ways. We’re ok saying it takes a year to get to an endpoint. My question is how can we get better access to therapies that come from industry?  

Dr. Larsen: If it’s a drug that’s already registered it’s very simple – just reach out to the company and ask for a supply. We’re usually quite open. For compounds that are still experimental, there needs to be a solid rationale. If it’s a good rationale, you can assume that most companies will be interested in exploring new molecular entities in disease areas where it makes sense. If they’re as committed to make a difference as we are in type 1 diabetes, all good, creative, rational suggestions are welcome.

Dr. Zakaria: There is also a mechanism for investigator-initiated trials. You can submit a proposal to Novartis with a solid scientific rationale and a request for support with a specific molecular entitity. That goes through an internal approval process and a review for scientific merit. So there is that conduit.

Dr. Charles Mackay (Monash University, Melbourne, Australia): Is there a role for JDRF as a go-between?

Dr. Richard Insel (JDRF, New York, NY): Absolutely. JDRF wants to be viewed as the honest broker. That’s absolutely critical for interacting with regulatory agencies. Qualifying autoantibodies is something under active discussion at JDRF. If we go down that road, we would welcome all companies to join with academia, and with the NIH if possible, or at least with data generated from NIH funding, on behalf of the effort. JDRF does this in concert with the ADA and other foundations.

Q: What about the cell products coming down the pipeline? Sanofi has a relationship with Evotec and Novartis with Semma. Those will go to clinical trials, so what will the regulatory environment be for that? Do you have advice for people thinking about those trials?

Dr. Zakaria: I would say it’s an evolving field. Obviously with cell therapy it depends on the source of the cells; embryonic stem cells have different requirements than induced pluripotent stem cells. It’s also a question of how you deliver the cells, through encapsulation or immune suppression. I don’t have direct interactions with health authorities, but we’re thinking about it.

Dr. Hedrick: There are also challenges about how the product is defined. How do you ensure that lot to lot, you’re getting the same thing to your patients? That’s another challenge in that space. It’s certainly an evolving area. I wish there were easy answers, but there aren’t at this point.

Dr. Larsen: I don’t have concrete experience with beta cell replacement, but we have experience with other cell therapies. I think the field is in full-blown development, and we’ll have to have a dialogue as the products mature and we test them out. I don’t think the regulatory agencies have a crisp understanding either. We’ll have to shape our views in collaboration.

Q: Almost everyone probably came in knowing the goal was to move the starting point back before diagnosis. If you look at the regulatory environment, there’s resistance to doing immunotherapy trials even in children already with the disease. How can we move that back? I think it’s wonderful to say we want to work together, but a lot of times when I’ve tried to go through the process, it’s a black hole. We’ve heard for several years about the importance of combination therapy. Each of you had the idea of combining immunomodulation with beta cell support. How do we help you to play together when I say I want to combine this with another drug but no one wants to take the risk?

Dr. Hedrick: One thing I keep saying in my company is that if a product is on the market, there’s nothing to stop anybody from buying the molecules they want to buy and putting them into the clinic. Money is a challenge, but if they really want to do it, they’ll do it with or without us. I’d rather be involved than let them just go ahead, even if at this point the only thing I can do is get the drug supply to you. We have finite resources, but part of it is just having a conversation and being open about the internal pressures acting against this or for this. We’ve had recent conversations explaining a lot of this process at the companies. We’re really risk-averse. A lot of that is imposed. We face hefty penalties if we’re not careful about how we interact with providers. There are some unintended consequences of some of that legislation. I may really want to do the study but there could be specific requirements that have nothing to do with me. If you don’t know that, you’re thinking why are they taking so long? If we can provide more clarity and come at this as partners, that will start to move the needle. All I can say is we’re involved with a study now that came about as part of a casual conversation at a meeting like this.

Dr. Larsen: You may not realize what compliance requirements are in place before we can respond to an investigator-sponsored trial request. If we want to do this as a constructive two-way dialogue, that usually means we end up as the sponsor. Then that trial is competing with everything else we do. We want to make sure we get the most out of our resources. I have my biased preferences – I want to promote diabetes – but I also have colleagues that care for people with other diseases. That’s part of the internal prioritization. It’s much easier if it’s an investigator-sponsored trial wanting access to drugs.

Dr. Matthias von Herrath (La Jolla Institute for Allergy and Immunology, La Jolla, CA): If we’re talking about adults, the idea of combining things has moved ahead. We have started a trial with a GLP-1 agonist and anti IL-21 at Novo Nordisk. But there are other challenges. Recruiting is hard, and you need large numbers. Our trial is four arms and 380 people. So there are statistical significance challenges, but there is general willingness around the idea of combining things. You have to have a dialogue; you can’t just say we’ve made up our mind. The pharma company might say we disagree, these drugs won’t work together. You need data on what could be combined. With dialogue, it’s an obvious way to go. I’ve written about this for 10 years. The issue is that you have too little effect with monotherapy. I think we’ll see more, maybe collaborations with larger pharma companies. There’s not as much space for competition here as in type 2 diabetes.

Comment: One thing I believe is very important is reflecting on things beyond registration. I think we’re notoriously bad at doing that early. Here we have a clear medical need and a relatively small population. That should make the business case quite challenging. There’s an obvious need to look at what it takes to access the market and the payer perspective. That is the next step to take. It’s sensitive stuff and not everyone likes it, but it’s something we really have to face.

Dr. Hedrick: Again in the interception space, I don’t think the models we have will work.

Dr. Insel: You all talked about biomarkers and called for us to come together as a community and prioritize which are most useful. We have multiple people in the academic sector working on this. What are your thoughts about bringing the community together around biomarkers?

Dr. Hedrick: There’s no question. All you need to do is sit down at PubMed and look for biomarkers in type 1 diabetes; you’ll be buried. None of us can know the breadth of the space individually as well as we can as a community. Don’t let the perfect be the enemy of the good. We have to start somewhere. If we can get 80% alignment, we can move forward. Investigators can still ask the questions they want to ask, but as long as they’re going to the trouble, why not look at those additional five biomarkers and make the data available as soon as possible. That goes for industry and academia. These are the kinds of things you need to commit to in advance. It would be a good subject for a consortium or a brokered meeting.

Dr. Larsen: There are two approaches. One is addressing existing disease, and those people are much easier to access. If you believe we have a prodromal phase in type 1 diabetes, those are not people you normally jab needles in. We need a different approach to understanding type 1 diabetes development at a population level, including reaching out to pediatricians and other networks that are not normally thinking about type 1 diabetes. That calls for a societal initiative that goes far beyond what the people in this room can do. We can fortunately access huge cohorts that were sampled for different reasons. That needs to be spread out to other regions for the sake of validation.

Dr. Bart Roep (City of Hope, Duarte, CA): What we really need is a biomarker that shows efficacy. When we’re talking about two autoantibodies, they rarely say anything about the success of an intervention. I had biomarkers that predicted with 100% specificity when not to transplant islets, but no surgeon asked me for them. If I had a biomarker that defines 10% of people at onset, would you develop a drug for them?

Dr. Larsen: Sure, it all depends on the response rate. If there’s 100% certainty those patients will benefit, it would make good sense.

Dr. Hedrick: That’s one of the very first questions we raised. If we can intercept the disease in 10% of subjects, that’s an important victory because it says it’s possible. So yes, at least in the first instance it would certainly be possible.

Q: If I’m someone with strong preclinical data, what key questions should I ask before approaching industry?

Dr. Hedrick: There’s a lot of work done on how therapies can work and what is the benefit. There’s often little thought given to the potential downsides and how to assess them. People don’t do those experiments. That’s my first question when someone brings me a new pathway or molecule. I say that’s great, there’s evidence that it might work, but safety is a big question. What have you done to address the potential risks? And how do I prioritize that against the other 20 opportunities I’m trying to juggle?

New Concepts in Natural History of Disease

Naming and Stages of T1D: What and Why?

Carla Greenbaum, MD (Benaroya Research Institute, Seattle, WA)

Dr. Carla Greenbaum (Benaroya Research Institute, Seattle, WA) outlined several practical benefits of the new ADA/JDRF staging system for type 1 diabetes. The main conceptual change under the new system (which arose out of an October 2014 workshop and was published in Diabetes Care in September 2015) is the definition of multiple islet autoantibodies as the starting point for the disease. Stage one is defined as the presence of multiple autoantibodies with normal glucose tolerance, stage two as multiple autoantibodies and glucose intolerance/dysglycemia, and stage three as symptomatic type 1 diabetes. Dr. Greenbaum reviewed clinical data on the rate of progression in different subgroups at each stage. Her main conclusions were that once someone has multiple autoantibodies, it is a matter of when, not if, they will progress to full-blown diabetes, and that the rate of progression varies dramatically by age at all stages. The latter point was the main impetus for the Consensus Conference Dr. Greenbaum co-chaired in January 2015 aimed at defining distinct regulatory pathways for pediatric type 1 diabetes. Dr. Greenbaum outlined several reasons why this new staging system has so much practical importance: (i) it shifts the mindset from treatment to prevention; (ii) it should facilitate shorter clinical trials with intermediate endpoints; (iii) it provides a framework for better understanding mechanisms and biomarkers of the disease; and (iv) it could facilitate better communication with industry, regulators, funders, and patients. We agree that if widely adopted, this system could create a much more favorable climate for development of much-needed early interventions. Clinically, this system could also potentially help identify at-risk patients earlier and smooth the transition into symptomatic type 1 diabetes, though this would require much more widespread screening than is typical today.

Debate: The Beta or Not the Beta

Summary

Debbie Thurmond, PhD (City of Hope, Duarte, CA) and Bart Roep, MD, PhD (City of Hope, Duarte, CA)

A debate on “the beta or not the beta” as the root defect in type 1 diabetes produced more consensus than disagreement. Dr. Debbie Thurmond (City of Hope, Duarte, CA), filling in for Dr. Mark Atkinson, took the position that type 1 diabetes is primarily a beta cell defect. She pointed to several pieces of evidence that bring the autoimmune explanation into question: (i) beta cell dysfunction precedes and possibly predicts type 1 diabetes, (ii) type 1 diabetes is associated with defects in beta cell insulin release, (iii) beta cell preservation or recovery interventions are most effective in patients with the most residual insulin production, (iv) beta cell function in established type 1 diabetes is associated with improved clinical outcomes, and (v) there is evidence that exocytosis proteins STX4 and SNAP25 may regulate insulin secretion and beta cell apoptosis. Furthermore, Dr. Thurmond noted that proteins that have been associated with type 1 diabetes susceptibility are mostly beta cell function gene products. Dr. Thurmond argued that type 1 diabetes therapies should both increase beta cell mass and improve beta cell function. Dr. Thurmond listed a host of potential therapies that address these goals, including islet transplantation/beta cell replacement, reduction of beta cell stress, beta cell proliferation increase, beta cell transdifferentiation, beta cell apoptosis prevention, and immune response prevention. Dr. Bart Roep (City of Hope, Duarte, CA) argued that the immune system, not the beta cell, is the primary culprit, though he hinted that his true views are more nuanced. He noted that research on nPOD tissue samples has revealed islet abnormalities that are not confined to beta cells, and that most of the known genetic risk variants for type 1 diabetes are linked to the immune system, not to beta cell function. He also suggested that the selectivity of beta cell killing is consistent with autoimmunity as the primary defect, and noted that therapies like bone marrow transplantation that only affect the immune system can lead to remission in a significant percentage of cases. As is often the case in these debates, we suspect that the truth lies somewhere in the middle; as one attendee suggested during Q&A, it is also possible that the primary defect is different in different patients. We also agree that targeting both defects at once with combination therapy may be more effective than addressing either one alone.

Insulin Resistance/Insulin Secretion

Hepatic Mitochondrial Uncoupling to Treat Diabetes and NASH

Gerald Shulman, MD, PhD (Yale University, New Haven, CT)

Dr. Gerald Shulman (Yale University, New Haven, CT) presented intriguing early data on the use of a controlled-release mitochondrial protonophore (CRMP) to treat metabolic disease. He presented studies from his lab showing a number of favorable metabolic changes in rodents (increased lipid oxidation, reduced hepatic fat, protection from hepatic insulin resistance) with the mitochondrial uncoupler DNP. However, DNP can lead to dangerous increases in body temperature, as its mechanism of action (uncoupling the mitochondrial proton gradient from oxidative phosphorylation) leads to greater dissipation of energy as heat. Dr. Shulman hypothesized that a liver-targeted mitochondrial uncoupler could produce the favorable metabolic effects without the systemic toxicity. He was proven correct, as an altered form of the compound that remains inactive until it enters the liver produced reductions in plasma glucose and insulin in rodents with no effect on body temperature. Based on this research, Dr. Shulman’s lab developed CRMP, an oral mitochondrial uncoupler that leads to a small (60%) increase in mitochondrial oxidation in the liver. He presented promising data of the compound in three rodent models of metabolic disease showing a favorable safety/efficacy profile: reductions in triglycerides, insulin resistance, hyperglycemia, hepatic steatosis, and other hepatic defects with no systemic toxicity. CRMP also reversed NASH and liver fibrosis in rodent models of NASH. These changes were independent of changes in body weight or food intake – the drug essentially produces a metabolically healthy obese phenotype. Dr. Shulman indicated that his group is gearing up to test CRMP in a diet-induced obese non-human primate model of NAFLD and metabolic syndrome for safety and efficacy. The FDA is likely to take a conservative approach to a class associated with such serious toxicity in the past. If the safety profile checks out in humans, we imagine that the candidate’s ability to address multiple metabolic defects would be quite appealing to many companies, especially as NAFLD/NASH becomes an increasing area of interest.  

Boosting Insulin Secretion and Insulin Action to Promote Healthspan

Debbie Thurmond, PhD (City of Hope, Duarte, CA)

Dr. Debbie Thurmond (City of Hope, Durate, CA) offered an intriguing look at exocytosis proteins Syntaxin 4 (Syn4) and Doc2b as potential targets to improve insulin secretion and insulin sensitivity simultaneously. On the insulin secretion front, Dr. Thurmond implicated Syn4 and Doc2b in the final stage of the exocytotic process that brings insulin molecules to the beta cell surface for secretion. Dr. Thurmond highlighted data in mouse models that suggested mice with lower levels of Syn4 were more susceptible to streptozotocin-induced glucose intolerance and impaired insulin secretion. Excitingly, replenishment of Syn4 levels in these mice resulted in a complete restoration of insulin secretion and normoglycemia. Doc2b, which binds and activates endogenous Syn4, had a similar effect on insulin secretion. Furthermore, Dr. Thurmond noted that Syn4 only becomes active in response to an external glucose-mediated stimulus, suggesting that a Syn4-based therapy would carry a lower risk of hypoglycemia since the Syn4-boosted insulin secretion would slow as blood glucose levels fall. On the insulin sensitivity side, Syn4 and Doc2b are involved in the transport of GLUT4 vesicles to the skeletal muscle cell surface, mediating glucose uptake.  Dr. Thurmond showcased mouse data demonstrating that enrichment of Syn4 and Doc2b leads to an increase in GLUT4 on the surface of skeletal muscle cells, an increase in glucose uptake, and an increase in peripheral insulin sensitivity. This one-two punch boosting insulin secretion and insulin sensitivity is promising in its own right, but Dr. Thurmond took it a step further with data suggesting that enrichment of Syn4 or Doc2b can actually extend longevity overall – transgenic mice with overexpression of Syn4 lived 33% longer. Looking to humans, Dr. Thurmond offered a peek at data suggesting that boosting Syn4 in human islets led to an increase in beta cell survival and an improvement in both beta cell function and functional beta cell mass.

New Trend Lecture

Microbiome Metabolite Approaches to Treat Type 1 Diabetes and Other Western Diseases

Charles Mackay, PhD (Monash University, Melbourne, Australia)

Dr. Charles Mackay (Monash University, Melbourne, Australia) discussed the potential of short-chain fatty acids (SCFAs) produced by gut microbiota to protect against type 1 diabetes. He explained that it is clear that high-fat, highly processed Western diets alter the composition of the microbiome, leading to decreased production of SCFAs and other healthy metabolites. He presented data showing that SCFAs and the receptors that bind them (such as GPR43 and GPR109A) play an important role in gut homeostasis in mice. Dr. Mackay then discussed what he described as a very surprising finding: raising the levels of SCFAs by knocking out the gene MYD88 completely protected NOD mice from type 1 diabetes, but that protection was lost in germ-free mice, clearly implicating the microbiome. Similarly, Dr. Mackay’s lab demonstrated that transferring the microbiota of male NOD mice to females led to increased levels of SCFAs (specifically acetate and butyrate) and greater protection against type 1 diabetes (female NOD mice are normally at higher risk of type 1 diabetes than males). Dr. Mackay then presented results from several experiments using the HAMSA/HAMSB technology to deliver large amounts of SCFAs to the colon. Results showed that the technology led to impressive (~80%) protection against type 1 diabetes in NOD mice, mediated through effects on regulatory T cells (Tregs) and antigen-presenting cells. He suggested that this could be a very promising approach to reducing diabetes incidence using essentially natural products, albeit at higher doses and in a more targeted fashion. Dr. Mackay closed by raising questions about the impact of SCFA exposure during pregnancy on the offspring’s risk of type 1 diabetes, noting that such an approach has shown promise in mouse models.

Plenary Lecture

Adiponectin and its Receptors: Implications for Obesity Associated Diseases

Takashi Kadowaki, MD, PhD (University of Tokyo, Japan)

In an evening plenary lecture, Dr. Takashi Kadowaki (University of Tokyo, Japan) presented on the preclinical data of the drug candidate AdipoRon, an adiponectin receptor agonist, for obesity-associated diseases. He first illustrated the pathways involved in adiponectin, touching on adiponectin receptors AdipoR1 and AdipoR2 and discussing how adiponectin levels decrease with obesity and insulin resistance. Specifically, he demonstrated that reduced adiponectin levels in the plasma lead to down-regulation of adiponectin in target tissues, leading to negative impacts on the liver, muscle, blood vessels, adipose tissue, and endothelial cells. Regarding treatment options under this paradigm, Dr. Kadowaki then introduced AdipoRon, an AdipoR1/R2 agonist. In preclinical data in the rodent model, the drug was shown to reduce insulin resistance, oxidative stress, inflammation, and oxidative stress while increasing fatty acid oxidation, energy dissipation, and endothelial function. Notably, Dr. Kadowaki also showed that AdipoRon largely restored the shortened lifespan of mice with high-calorie, high-fat diets, even with the consumption of similar diets. Looking forward, he highlighted that it will be important for ongoing clinical development to better understand how AdipoRon interacts with the human adiponectin receptor and what the 3D structure of that receptor is for optimization of AdipoRon’s structure. We have heard recent work understanding the role of adiponectin in obesity and how lifestyle intervention can play into this, but not so much regarding pharmacotherapy options in this realm. While this candidate remains preclinical, we see this approach as an exciting one, especially since its effects appear to directly impact many organs and can thus positively influence many disease areas even outside of obesity.

Aberrant Regulation of Glucose Homeostasis in Metabolic Disease

Juleen Zierath, PhD (Karolinska Institutet, Stockholm, Sweden)

The impressive Dr. Juleen Zierath (Karolinska Institutet, Stockholm, Sweden) delivered a plenary lecture focused mainly on epigenetic contributions to metabolic disease. She presented preclinical and clinical data showing that obesity and other metabolic derangements can alter the DNA methylation profiles of genes that control oxidative metabolism, leading to impaired insulin action and metabolic processes. These changes can be passed down through multiple generations. Dr. Zierath shared data showing that dietary patterns in male rats altered the metabolic status of offspring two generations later, mediated through changes in the sperm epigenome. She also presented data suggesting epigenetic contributions to fatty liver disease. Her lab has demonstrated that people with obesity have altered DNA methylation of genes associated with increased hepatic glycolysis and lipogenesis. Her hypothesis is that the additional pyruvate produced by increased glycolysis is converted to fatty acids rather than being used for ATP production, thereby leading to increased liver fat. Finally, Dr. Zierath presented clinical data demonstrating that high-intensity exercise leads to immediate changes in DNA methylation and gene expression, leading to increased synthesis of enzymes that support higher metabolic rates. She also shared preliminary data identifying several microRNAs that are upregulated in obesity and type 2 diabetes and downregulated after exercise, suggesting clear implications for metabolic regulation. These specific results strongly support the use of exercise as a way to alter the underlying pathophysiology of metabolic disease. More broadly, all of these experiments underscore why epigenetics is such an up-and-coming field in metabolic disease – see our Rachmiel Levine 2015 report for more intriguing findings in this area.

Obesity

Novel Therapeutic Targets for Obesity and Insulin Resistance

Alan Saltiel, PhD (UCSD, La Jolla, CA)

Dr. Alan Saltiel (UCSD, La Jolla, CA) presented promising early data on amlexanox (marketed for asthma in Japan) as a treatment for obesity. Amlexanox inhibits IKKe, an enzyme overexpressed in high-fat-diet-fed animals that leads to decreased energy expenditure and increased inflammation, insulin resistance, and steatosis. Experiments in high-fat-diet-fed mice showed that amlexanox reversibly reduced body weight, improved glucose tolerance and browning of adipose tissue, and increased energy expenditure. The effects were not seen in mice fed a normal diet. Amlexanox also corrected adipose tissue resistance to catecholamines, which is compromised in obesity. Dr. Saltiel closed by sharing results from a very small (n=6) open-label clinical trial of amlexanox in patients with obesity and type 2 diabetes. While the broad conclusions from such a low-powered trial are limited, it is promising that amlexanox led to weight loss in five out of the six participants. The response to the drug was also correlated with the expression of genes involved in fat browning – an intriguing hint of the possibility of personalized medicine to predict individual responses to drugs.

Role of Gut Adaptation in the Potent Effects of Bariatric Surgeries on Obesity and Diabetes

Randy Seeley, PhD (University of Michigan, Ann Arbor, MI)

Dr. Randy Seeley (University of Michigan, Ann Arbor, MI) suggested that an increase in bile acids, mediated through the farnesoid X receptor (FXR), is responsible for the metabolic and weight improvements of bariatric surgery. Dr. Seeley argued that the effects of sleeve gastrectomy and Roux-en-Y gastric bypass surgery are similar and cannot be explained by the conventional restriction vs. malabsorption distinction. Thus, he embarked on a search for a potential molecular mechanism that could explain the impact of bariatric surgery on weight and glycemic control. GLP-1 and ghrelin were both initially identified as promising targets (as GLP-1 increases and ghrelin decreases following surgery), but GLP-1 and ghrelin knockout mice undergoing bariatric surgery responded similarly to wildtype mice. Surgery also increases plasma bile acids (due to an effect on liver bile acid reuptake) and bile acid effects are mediated through FXR. In FXR knockout mice, there was no reduction in body fat or food intake and no improvement in glucose after surgery. Dr. Seeley found that it is possible to recapitulate the effects of bariatric surgery in mice by redirecting the bile acids only, suggesting a potential avenue for a less-invasive metabolic surgery in the future. Furthermore, FXR has been implicated in regulating the microbiome and Dr. Seeley suggested that future studies can investigate FXR-dependent changes in the microbiome following surgery.

Beta Cell Transcriptomics, Epigenetics, and Targeting

Beta Cell Targeting of Estrogens with GLP-1

Franck Mauvais-Jarvis, MD, PhD (Tulane University, New Orleans, LA)

Dr. Franck Mauvais-Jarvis (Tulane University, New Orleans, LA) discussed the potential of GLP-1 and estrogen (E2) conjugates in improving beta cell function, demonstrating that conjugates of inactive GLP-1 and E2 can help protect islet survival. He opened his presentation by illustrating the benefits of estrogen therapy in glycemic control (referring to the Women’s Health Initiative hormone therapy trials), but noted that one concern is the challenge to solely target estrogen to beta cells without also binding to receptors in the breast or uterus, which can have oncogenic potential. Dr. Mauvais-Jarvis then referenced research of the highly regarded Dr. Richard DiMarchi (Indiana University, Bloomington, IN), as his team created fusion peptides of E2 and GLP-1 in one molecule, which were demonstrated to not show uterotrophic action. In the mouse model, GLP-1-E2 conjugates were found to reduce fat mass and leptin; however, this conjugate did not show superior efficacy regarding insulin sensitivity. Surprisingly, Dr. Mauvais-Jarvis presented data showing that conjugates of inactive GLP-1 and E2 better helped protect islet survival and improved insulin sensitivity, compared to conjugates of active GLP-1 and E2. Thus, he concluded that while active GLP-1 conjugates help decrease body weight, GLP-1 reverses the protective effect of E2 and is deleterious to islet function/survival in insulin deficient states. Ultimately, while these findings suggest that active GLP-1 counters the beneficial effects, they demonstrate that inactive GLP-1 can provide efficient targeting of estrogen to beta cells and may protect islet survival, which Dr. Mauvais-Jarvis noted is now being investigated in non-human primate models. This approach is certainly intriguing to us, highlighting GLP-1 as a promising vehicle for targeting beta cells rather than its agonists’ impacts and we will be curious to see how this research can enhance further understanding around the GLP-1 agonist class.

Dinner Lecture

History of the Nobel Prize in Physiology or Medicine

Juleen Zierath, PhD (Karolinska Institutet, Stockholm, Sweden)

Dr. Juleen Zierath presented a fascinating look at the history and selection process of the Nobel Prize in Physiology or Medicine during a dinner lecture. For the last three years, Dr. Zierath served as the chair of the Nobel Committee, and since 2006 she has been a member of the Nobel Assembly, a committee of 50 professors from the Karolinska Institutet that are responsible for selecting the Nobel Laureates in Physiology or Medicine each year – she is the first American and the first woman to hold the position. In her talk, Dr. Zierath gave a brief history of the prize and the selection process from nomination to award. In particular, Dr. Zierath emphasized that the prizes must be awarded for a specific discovery and cannot be considered lifetime achievement awards. Dr. Zierath concluded her presentation with a tongue-in-cheek set of tips for budding researchers aiming for a Nobel: (i) make an important discovery, (ii) be prepared to fight dogmas, (iii) there is no requirement to publish in a high-profile journal, (iv) train in excellent laboratories, (v) personal background is irrelevant, (vi) be patient. Best of luck to any aspiring prizewinners out there!

 

-- by Melissa An, Helen Gao, Emily Regier, and Kelly Close