January 28, 2019; Naples, FL; Highlights – Draft

Hello from Naples, Florida, where JDRF just held its annual Mission Summit. Here is our full report, including additional highlights from fascinating panels on Achieving the Promises of Immunotherapy and Challenges and Opportunities in Regulatory and Health Policy. The gathering convened researchers and donors for a whirlwind tour of the non-profit’s work move the dial in type 1 diabetes. Wow, is this organization truly on fire! Hats off to the organizers and Derek Rapp, Aaron Kowalski, Sanjoy Dutta, Cynthia Rice, and other senior JDRF leaders for an extraordinary set of discussions on the cure for type 1 diabetes. For the first time in Kelly’s 31 years with diabetes, she’s feeling encouraged to think about a cure (not five or even ten years out, but possibly in her lifetime). As JDRF International Board member Ellen Peake said so eloquently, she’d like her granddaughter to see her daughter (who has type 1) “on this side of the cure.” This was eminently relatable.

See our full report below!

Detailed Discussion and Commentary

Dinner Conversation

Drs. Aaron Kowalski and Jennifer Sherr on SLGTs in type 1, Beyond A1c, Value-Based Care/Diabeter, and Clinician Challenges

Aaron Kowalski, PhD (Chief Mission Officer, JDRF, New York, NY); Jennifer Sherr, MD, PhD (Yale School of Medicine, New Haven, CT)

We enjoyed a riveting conversation between JDRF’s Dr. Aaron Kowalski and Yale’s Dr. Jennifer Sherr, covering a variety of critical topics in type 1 diabetes: the FDA Advisory Committee’s split 8-8 decision on Sanofi/Lexicon’s sotagliflozin, the Medtronic-owned chain of Diabeter clinics as a model for value-based care, moving beyond A1c, and more. Read details below!

• On adjunctive therapies in type 1 diabetes: When asked what Dr. Sherr is currently most excited about in type 1 diabetes management, she enthusiastically pointed to adjunctive therapies like SGLT-2 inhibitors. “A multifaceted approach that repurposes some type 2 medications,” she said, will be “essential” in type 1 management. While an FDA Advisory Committee came to a split decision on Sanofi/Lexicon’s NDA for sotagliflozin in adults with type 1 diabetes, Dr. Sherr does not find this discouraging, noting “a split vote is better than being denied.” As she reasoned, the general population is now more open to the idea of using adjunctive therapies – the next step will be to show that they can be used safely. To this end, Dr. Sherr asserted that “the more we can do as a type 1 community to say [SGLT-2s in type 1] are beneficial, the more it will help in the FDA’s decision process.” One attendee wasted no time in heeding Dr. Sherr’s call to action, commenting during Q&A, “SGLT-2s have been the most amazing treatment since insulin. You should really bug your doctor before it is approved because it made a huge change in my glucose control, especially overnight, and with very few side effects.” Dr. Kowalski chimed in, claiming that “the potential is high.” He referenced studies that have shown SGLT-2s to be “tremendously successful drugs” in type 2s, not only in improving glycemic outcomes but also in mitigating cardiovascular and renal complications. Dr. Sherr pointed to her letter to FDA, which can be seen here.
  • Still, Dr. Kowalski underscored the need to ensure safety with SGLT-2 use. He noted that JDRF has helped the FDA “recalibrate what a person with type 1 is willing to take on” and emphasized that the current status quo of treatment is far from ideal. Indeed, Dr. Kowalski pointed out that “patients dose a dangerous drug [insulin] on a daily basis in the wild” and that SGLT-2s “provide another tool” to reduce doses and improve time-in-range. Dr. Kowalski explained that many people think high blood glucose levels cause DKA; in reality, low insulin levels trigger the pathways that lead to DKA. So, as patients on SGLT-2s begin to require less insulin and achieve weight loss and lower A1cs, there is an understandable “temptation” to further enhance these benefits, which opens up the risk for “very serious side effects.” JDRF believes there is a pathway to use the therapy safely, but FDA might want to see more data on the education to reduce risk. According to T1D Exchange data shared by Dr. Sherr, 76% of adults never or rarely check their ketones – something she believes needs to be changed “just at baseline for type 1 care.” The just-published T1D Exchange data also reported that only ~20% of registry members had a ketone meter. Even if 100% of those on SGLT therapies get the meters, the field must be sure that patients are trained properly, particularly to address euglycemic DKA, where the protocol is not always logical.
  • Dr. Sherr also cited pramlintide and Afrezza as two other exciting options. Dr. Kowalski shared his trademark excitement for a mixed pramlintide-insulin solution for hybrid closed loop systems; we hope to see some actual commercial/R&D movement on this front from the pharma side, since the feasibility is clearly there. We saw very impressive hybrid closed loop data  at ADA from a JDRF-funded, 24-hour, in-clinic study using pramlintide on top of rapid acting insulin – time-in-range increased by nearly three hours/day, which adds up to 1.5 months per year! As for Afrezza, Dr. Sherr referenced an ongoing JDRF-funded study looking at Afrezza as a complement to closed loop therapy, building on positive early feasibility data from ATTD 2013! She’s especially interested in investigating how dosing and outcomes might differ for Afrezza use in pediatrics (Afrezza is currently approved for 18-years+).
• On outcomes beyond A1c: When speaking about her own experiences with Medtronic’s MiniMed 670G, Dr. Sherr noted that her son said that she was “nicer” with the system. She explained that the way her 670G “profoundly affected herself and her kids” was “huge.” Dr. Kowalski echoed these sentiments while on a DIY system, sharing that his wife no longer had to wake up repeatedly due to low CGM alarms. (Adam and Kelly have shared similar experience in their Loop test drives on diaTribe – here and here.) Considering these critical quality of life improvements, Dr. Kowalski emphasized the beyond A1c movement, referencing the JDRF consensus statement published in Diabetes Care in 2017. (See our Reflections theme for the latest on this front.) He urged the audience to contemplate “the benefit when you start to lift the burden a little off your shoulders.” To this end, Dr. Kowalski underscored that even advances that might be perceived as incremental – such as bolusing from a smartphone – can “impact life in a major way” by helping to increase discretion.
  • Psychosocial outcomes emerged as a theme during the Q&A portion of the evening, when one attendee brought up the need to increase education surrounding nutrition. Dr. Kowalski joked that “nutrition and diabetes is a much more dangerous topic than politics and religion,” opining that people can be “on polar spectrums” despite limited data on different diets’ relative superiority. On a more somber note, he shared that young females with diabetes have roughly a 5-7-fold greater risk of developing an eating disorder than the general population. He therefore cautioned that the topic must be treated as a “delicate balance” between proper nutrition vs. nutritional extremism. Dr. Sherr agreed, noting that she “walks a fine line,” and tries to reassure newly diagnosed families that “your child is going to have cake on his birthday.”
    • This remains a contentious topic in both the type 1 and type 2 communities; can the field start bringing more data to the discussion? We see a huge upside from studying different diets head-to-head in type 1 diabetes, given the challenging state of care, the obvious potential of CGM to help people personalize their nutrition, and some of the promising outcomes shown with low-carb approaches in type 1. One thing is clear to us: the old narrative of “you can eat whatever you want as long as you take insulin for it” sets many up for challenges.
• On reimbursement and value-based care: Dr. Sherr constantly answers patient questions outside of office visits – substantial time that goes unbilled. As he did at last year’s Mission Summit, Dr. Kowalski pointed to Diabeter, the Medtronic-owned chain of Dutch clinics, as the “holy grail of where we could be” in value-based diabetes management. Diabeter started with just 500 patients in 2006 and as of EASD in October has nearly 2,500 patients and is expected to breakeven financially in the next two to three years. Dr. Kowalski praised Diabeter for “essentially flipping the system” by providing clinicians with dashboards to monitor patients remotely so as to identify those who actually need office visits. By removing payers from each decision, Diabeter clinicians save enormous time previously spent on paperwork like prior authorization requests. Dr. Sherr agreed that if a similar model came to the US, “my life would be a lot better.” In fact, she’s noticed that fewer residents are choosing to go into endocrinology, in part because they think the majority of their days will be consumed with fighting to get patients on pumps. The question, Dr. Kowalski explained, is whether such a system could ever be feasible in the US. He shared that “a number of folks are pushing in that direction” and that “we’re at a pretty critical time.” He noted that JDRF is engaged in a “big project” with the Helmsley Charitable Trust to increase healthcare access in rural communities, acknowledging that it is “the tip of the iceberg” and that “we have to do better.”
  • We have been surprised that Diabeter has moved slowly on the expansion front – Medtronic acquired it to big headlines almost four years ago, but there have been no tangible updates since. Is Medtronic going to invest here and actually expand it globally? Will we ever see a chain of US Diabeter Clinics?
• On clinician challenges: In response to a question from our own Kelly Close on clinicians’ experiences, Dr. Sherr emphasized the need to increase access and education. She acknowledged the privilege of working with diabetes technology and providing tools to her patients, but claimed that more work must be done to ensure that all clinicians, including primary care providers, can easily download and analyze diabetes data. Indeed, given current rates of CGM adoption (~30% of type 1s) at the finest endocrinology clinics in the country, there is a long way to go here. She also wants to make sure that mental health and education surrounding basic topics in diabetes management don’t fall by wayside. As she put it, “we want to make sure we treat the whole patient in the rollercoaster that diabetes is.”

Plenary Sessions

Welcome Address: CEO Derek Rapp: $113.5 million JDRF Research Investment in 2018, Plus $249 million Attracted to the Field from Outside Sources

Ellen Leake (JDRF, New York, NY); Derek Rapp (JDRF, New York, NY)

JDRF’s CEO Derek Rapp kicked off the day with the word impact, highlighting the organization’s financial leverage: in 2018, JDRF investment $113.5 million in research, alongside attracting an additional $249 million from outside sources. Most of the latter is the $150 million Special Diabetes Program, up for renewal by this September – let’s hope Congress does its part here! Relative to the 2018 Mission Summit, JDRF improved both metrics – it directly invested $86 million in 2017 and attracted $214 million in additional investments for type 1 diabetes. Nice!

• As a North Star vision, JDRF BOD Chair Ellen Leake hoped that her grandchild would see their mother “on this side of the cure”, in her daughter's lifetime. Ms. Leake’s daughter was diagnosed at age 10, prompting the family to help found the JDRF Mississippi Chapter in 1998. Assuming that puts her daughter at ~31 years, that leaves several decades for JDRF to get to its goal to cure T1D.

2019 Mission Summit:

Similar Graphic from the 2018 Mission Summit:

Aaron Kowalski: Using the Artificial Pancreas Playbook to Cure T1D?

Aaron Kowalski, PhD (JDRF, New York, NY)

JDRF Chief Mission Officer Dr. Aaron Kowalski covered the non-profit’s drive to cure T1D, with an insightful twist – using the Artificial Pancreas Project playbook. JDRF took a methodical, coordinated approach to driving AP device research and commercialization, beginning with Dr. Kowalski’s landmark 2009 roadmap. The clearly defined milestones – e.g., low glucose suspend, PLGS, hybrid closed loop, fully closed loop, etc. – provided the “specificity and clarity” that opened many doors for the field. Armed with the six-step roadmap, companies could define their pipelines and talk to FDA, researchers could coordinate and do studies to fill in gaps, JDRF could develop and formalize FDA guidance, funding could be directed towards key areas (CGM, algorithms, etc.), work could begin on reimbursement, etc. This kind of “crystal clear” roadmap, Dr. Kowalski emphasized, is now needed in JDRF’s two T1D cure areas: (i) beta cell replacement; and (ii) immunotherapies. Just like automated insulin delivery, Dr. Kowalski believes that “cures” (plural) will take many forms and progress in steps over time. JDRF’s commitment is clear: it invests two-thirds of its budget (~$60 million per year) on cure efforts – this is often misunderstood, given all the progress and headlines on technology. The non-profit has begun meeting with FDA and payers on cure therapies, and it was notable to hear Dr. Kowalski’s sincere enthusiasm on the state of research – “we’re at a pivot point,” “it’s about us filling in the gaps and driving it to the finish line,” and “this stuff is getting real.” He repeatedly noted industry’s cure efforts, including Novo Nordisk, Lilly/Sigilon, J&J, and Viacyte (see our competitive landscape). Dr. Kowalski believes there is “line of sight to disease-modifying therapies,” especially because new biological tools did not even exist five years ago – gene editing technology (see this week’s NYT article on sickle cell anemia), related immune progress in other disease areas (cancer, MS, celiac, rheumatoid arthritis), and even use of immunotherapies in very young children. “Just like we did in artificial pancreas, we are taking a coordinated approach –knocking down gaps and driving this forward to the clinic.”

• “We’re sliding backwards in the US right now.” Dr. Kowalski summarized the concerning T1D Exchange recently-published data: only 17% of youth and 21% of adults are meeting A1c goals. “And this data comes from endocrinology clinics.” He added the still-terrifying stats on hypoglycemia (particularly in seniors), DKA, and depression/anxiety. “We need to do better.”

• Using the Edmonton protocol to transplant cadaver islets, some type 1’s have been off insulin for 17 years now. “Cure is possible,” noted Dr. Kowalski. But there is a two-fold challenge: (i) finding a reliable, renewable source of islets (5,000 human organ transplants per year cannot keep up with 30,000-40,000 new type 1 diagnoses); and (ii) trading type 1 diabetes for chronic immunosuppression. Still, the proof of concept is there: “With a tbsp of cells, [there are] still people who are completely off insulin. If you talk to those people, they will tell you they are cured. Their blood sugars are normal. They have a 5.8% A1c, no hypoglycemia, no dosing – nothing. The potential is real. How do you make this applicable?”

• Dr. Kowalski mentioned his positive experiences on DIY automated insulin delivery (he uses Loop) and the industry’s clear momentum. Alongside Medtronic’s MiniMed 670G, he called out both Insulet and Tandem. One JDRF NY employee is currently in Tandem’s Control-IQ pivotal trial, which is “about to end” (summer 2019 launch expected, per Tandem 3Q18). Dr. Kowalski said this participant “doesn’t want to give the system back” – a common theme in these trials and obviously a good sign it’s delivering value. “These advances are real – better A1c, better sleep, etc. We will not lose sight of keeping people healthy and happy until there are a variety of cures for us to realize. We’ll still fund research on advanced systems.” He then joked (joked!) about pointing out to the employee that he could just “not show up” for the last visit. Laughter ensued – Dr. Kowalski is such a beloved leader and so admired by all for many reasons, but not least of all for all the progress on technology he’s helped create and shepherded in multiple respects.

• There have been many strides in technology in many ways. For example, according to Dr. Kowalski, the UK government has switched its CGM coverage for pregnant women following the JDRF-funded CONCEPTT trial. See our coverage of the positive trial from EASD 2017 – headlined by significantly improved neonatal outcomes. As we noted at the time, this study used an old Medtronic CGM; outcomes would almost certainly be better with more modern devices. Outcomes like this with so much less burden were only dreamed about even five years ago. Massive progress! 

• What is JDRF doing about insulin pricing? Dr. Kowalski: “We’ve had many conversations over the last year – and they are more and more frequent. It’s mission critical. No one should go without insulin – you cannot live without insulin. We’re working with industry and Capitol Hill. There are a variety of problems. The system is not working. There are high-deductible health plans. My brother works at an architecture firm, and his deductible is $14,000 a year. He’s paying list price for these drugs. He’s a successful business guy, but it’s still a burden. We have to fix this problem. We’re all pushing to get it solved. We’re in an unacceptable state. We will be sending out more information for those with Medicare, private insurance, and the uninsured. Anyone with type 1 diabetes should have access to the best standard of care. It’s a top priority of ours.” Added CEO Derek Rapp: “Through our Coverage2Control campaign, we sent letters to CEOs of the 25 largest private insurers. We’ve received several responses, and they’ve said they’re going to make changes. We’ve had some victories, but it’s not nearly all that we want to see happen. But we are seeing some progress.”

T1D Fund: $70 million Raised, 12 Investments – Four New Investments in Cures include Enthera, ImmusanT, Inversago, Pandion

Sean Doherty (JDRF T1D Fund, New York, NY)

JDRF T1D Fund’s Sean Doherty (Executive Chairman) shared an update on the venture philanthropy fund, which has raised $70 million to date and now funded 12 companies – up 50% from eight portfolio companies and $65 million raised as of the 2018 Mission Summit. New investment additions are all in the cure space – Enthera (antibodies that inhibit beta cell death), ImmusanT (peptide desensitization therapy for type 1), Inversago Pharma (oral drug to promote beta cell functional recovery), and Pandion Therapeutics (islet-targeted immunotherapies). See below for the complete list, including those we covered last year. The investment portfolio groups into three categories, in line with Dr. Kowalski’s talk: (i) Improving Lives, with three investments (Bigfoot, Diasome, Glusense); (ii) Beta Cell Therapies, with four investments (eGenesis, Enthera, Inversago, Semma); and (iii) Immunotherapies, with five investments (ImmusanT, Pandion, Provention, SQZ Biotech, TetraGenetics). We appreciated seeing the comparison to other autoimmune diseases – notably, type 1 diabetes and celiac are the only two conditions with zero disease-modifying therapies. For comparison, rheumatoid arthritis and MS have 15 or more disease-modifying therapies! Mr. Doherty urged that it’s “Time to Supercharge” the Fund’s work – including more internal staffing (the team is just eight people!), roadmaps in key areas (see Dr. Kowalski’s talk), defining the financial opportunity in T1D (ongoing work with consulting firms), increasing average investment size from the current ~$3 million to date, exploring pharma partnerships, better collaborating with academic medical centers, and working with VCs to create companies (“a missing link” in the T1D space). Though not mentioned, JDRF has fallen just a bit short of the initial ambitious goal to raise $80 million by the end of 2018; $70 million is certainly closely for this new investment vehicle.

New Investments since 2018 Mission Summit

Investments Covered in 2018 Mission Summit:

Breakout Sessions

JDRF Funding New, Third Trial for Beta Cell Replacement Therapies; Dr. Dutta: Six Months Insulin Independence and Glucose Control “Not Too Far Away”; Dr. Puznansky: Hypoglycemia Unawareness First Beta Cell Target in Next Four Years

Mark Poznansky, MD, PhD (MGH, Boston); Cherie Stabler, PhD (Diabetes Research Institute at the University of Florida, Gainesville, FL); Sanjoy Dutta, PhD (Moderator: JDRF, New York, NY)

Dr. Sanjoy Dutta tempered enthusiasm for beta cell replacement therapies, stating that the first-generation product – one which provides six months of insulin independence and glucose control – is “not too far away …  Definitely not one or two years away, but not far.” This wide-ranging timing prediction is understandable, given the challenging progress to-date in the type 1 cures landscape. There are signs of hope, however – sustained research support from JDRF and recent investments from Lilly and Novo Nordisk (which has an “amazing” new cell therapy facility, according to Dr. Dutta) represent a crescendo in confidence in beta cell replacement. Dr. Dutta shared that JDRF is currently supporting three clinical trials in beta cell replacement: (i) A phase 1/2 study for ViaCyte’s PEC-Direct (encapsulated stem cells requiring chronic immunosuppression) – the furthest along in our landscape; (ii) a study with an “unnamed J&J subsidiary”; and (iii) a third trial that we assume is Sernova’s phase 1/2 cell pouch system. We are curious to know who the unnamed research group is – with only ViaCyte and Sernova in the clinical stage to our knowledge, a third entry is terrific news. Doubtless, many shots on goal will be needed to come up with the first-generation product described by Dr. Dutta. We do appreciate the focus on a target product profile (six months of insulin independence), since “cure” can be amorphous; this specificity builds nicely on Dr. Kowalski’s roadmap talk (see above) and is a lot like automated insulin delivery progress.

• The first target for beta cell replacement therapy, to be strived for in the next few years according to founder and director of the MGH Vaccines and Immunotherapy Center Dr. Mark Poznansky, is hypoglycemia unawareness. Previous studies have shown a profound effect on hypoglycemia awareness with islet transplantation – potentially making it a more realistic first target than replacing insulin.
• What is the greatest hurdle in beta cell replacement therapy? Dr. Poznansky asked for a specific mission statement and timeline (perhaps defined by JDRF) to guide research, while DRI’s Dr. Cherie Stabler wished for a fully functional stem-cell derived beta cell. Those are quite different asks! Currently, beta-cells are derived from a partially mature stem cell, necessitating an immunomodulatory encapsulation device or chronic immunosuppression. Unfortunately, creating Dr. Stabler’s ideal is no small feat. According to Dr. Poznansky, who also works with Semma Therapeutics, the FDA requires six-months of efficacy in an animal model (primate) before even considering an IND for a beta cell replacement therapy. Semma’s stem cell-derived beta cells have remained preclinical since founding in April 2015, despite partnering with pharmaceutical giants AZ and Novartis.
• Below are some of the most meaningful quotes from this session:

• Dr. Poznansky describes what brought him to cell transplantation and why he is very hopeful: “There is a humility from working very closely with the human body. You sit here with trillions of cells, and it’s the most amazing synergy. We are all just massive groups of cells working together, and cells can be organized to replace the function. It’s the humility of having something that’s working in us, and that’s why cell transplantation gives me a great deal of hope.” 

• Dr. Stabler gave an analogy regarding cell therapy: “From my perspective as an engineer, it has always been cell therapy is going to work. The challenge is that it’s all about building a house in a nice neighborhood. You can’t just take these cells, inject them under the skin, and expect them to be happy - you need to create a supportive home for them. You have to have the appropriate protection – the right roof, plumbing, and electricity to make sure food comes in. When you do this,  glucose comes in and insulin goes out of the implant in a very effective manner, while the cells are distributed throughout this 3D home.

The other thing you have to think about is that there is an immune system. It is like building a home in a neighborhood with a lot of break-ins, so you need a really good security system. This is what beta cell encapsulation seeks to do - take these cells and put a protective bubble around them so the immune system can’t get to it. Previous clinical studies have not really lived up to their full potential because the implant environment is not optimal. You wouldn’t build a super security system and then place your house in the middle of the woods with no access to food or water or electricity. Unfortunately, this is what too many encapsulation trials do – they wrap these sensitive islets in a biomaterial bubble and drop them into the peritoneal cavity where access to nutrients is exceptionally poor. They are dying because they aren’t vascularized.

We are trying to take a multi-pronged approach and saying it’s not just about encapsulation, but also finding an ideal location – real estate – of where to put them, making sure they’re vascularized, making sure the home is robust and stable.

What we are also learning from these trials is that even if the security system is perfect, we still have burglars sitting and scratching at the doors. The presence of these immune cells at the edge of the implant can stress the islets, causing dysfunction and death. So, we also need to think of interesting ways to shoo away those burglars. The JDRF Beta Cell Consortium are screening several of these immune cell deterrents with promising results.”

• JDRF is having productive talks, like check-ins, with the FDA, which has increased collaboration among all actors in the field. As Dr. Poznansky said, “My interactions with the FDA have been entirely positive. When you submit an IND (Investigational New Drug Application), the review quality of what you get back is incredible. It is very carefully written, detail oriented, so you know exactly what you’re trying to do.”

Achieving the Promise of Immune Therapies: Panelists Debate Type 1 Etiology (Beta Cell Disease or Autoimmune Disease First?); Tout Incremental Approach Toward Cure and Call for Biomarker Development

Carmella Evans-Molina, MD, PhD (Indiana University School of Medicine, Indianapolis, IN); Eddie James, PhD (Benaroya Research Institute at Virginia Mason, Seattle); Jon Behr, PhD (JDRF T1D Fund, Boston, MA); Andrew Rakeman, PhD (Moderator: Assistant Vice President of Research, JDRF, New York, NY)

Assistant Vice President of Research at JDRF, Dr. Andrew Rakeman framed this immunology-focused session by stating, “Two things go wrong in diabetes, and this sets out the goals for us, there are two things we need to do to get a cure: (i) control the immune system; and (ii) bring back beta cell functioning.” A lively discussing with Dr. Jon Behr, Dr. Eddie, and Dr. Carmella Evans-Molina followed. We’ve picked out some of the most salient points from this panel below, spanning a debate on the root of type 1 diabetes, optimism toward repurposed therapies from other conditions to treat type 1 diabetes, and the importance of developing improved biomarkers in trials.

• JDRF’s Chief Mission Officer Dr. Aaron Kowalski sparked a lively discussion by posing the question of whether “type 1 diabetes is a beta cell disease or an autoimmune disease first?” Answering first, Dr. Carmella Evans-Molina, scientist and endocrinologist noted that although she believes the beta cell “is the most important cell in the body,” she does not believe that the beta cell itself initiates type 1 diabetes. Instead, Dr. Evans-Molina explained that type 1 diabetes is likely driven by a combination of both maladaptive beta cells and autoimmune activation, with beta cells serving to “amplify the disease.” Up next, Dr. Eddie James, immunologist at the Benaroya Research Institute at Virginia Mason, remarked that, “What you’re asking is what’s the trigger for type 1 diabetes. I’m not convinced there is one trigger.” However, he attributed that a big part of the early business in type 1 diabetes is orchestrated by immune responses. Moreover, he noted that it is highly likely that “all people that don’t have type 1 diabetes probably have at some point had some virus or bacteria show up in their pancreas, but their beta cells aren’t as fragile, and their immune system is operating differently.” More provocatively, Dr. Jon Behr of T1D Fund proclaimed that “it really doesn’t matter” in the short term what the true root cause of type 1 diabetes is when trying to get a first drug to market – the distinction is merely “academic.” He pointed toward other diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis, explaining that multiple drugs have been approved for these conditions despite researchers still not pinpointing the cause of these diseases.

• Panelists noted that immune therapies targeted towards treating different conditions, such as Verapamil, ATG, Rituximab, and Orencia, have been moderately to fairly successful in recent type 1 diabetes trials. Very promisingly, a JDRF-funded phase 2 study published in July 2018 (n=32) demonstrated that once-daily oral verapamil promoted endogenous beta cell function while reducing insulin requirements and hypoglycemia in adults with recent-onset type 1 diabetes. As background, verapamil is a repurposed blood pressure medication that was identified to target a specific pathway in beta cells that become activated under inflammatory conditions. Seeing as verapamil is both easily accessible and affordable, we’re highly anticipating future studies in larger cohorts to confirm these promising phase 2 results – the impact of this therapy could be huge. ATG, antithymocyte globulin, Sanofi’s Thymoglobulin for kidney transplant immunosuppression, has been used in at least two studies in kids with type 1 diabetes. There has been evidence that low-dose ATG therapy can prevent or delay the progression of new-onset type 1 diabetes. Earlier this year, Dr. Desmond Schatz noted that “Low-dose ATG, alone or in combination, should be considered as a potential means of preventing T1D.” Nonetheless, Dr. Behr did note safety concerns with ATG, explaining that administering ATG is only advised in in-patient settings. Two additional drugs that were first approved in other diseases but had positive outcomes in type 1 diabetes are Rituximab and Orencia. Rituximab is a drug that depletes beta cells and has demonstrated the ability to slow C-peptide decline in new onset type 1 (four infusions over three weeks), but the effect only lasts to ~six months. Orencia (abatacept) by BMS, was originally used in psoriasis, organ transplant, rheumatoid arthritis, along with other autoimmune conditions. Dr. James emphasizes the overlap between treating diabetes and other autoimmune diseases as he said, “The field is emboldened to try that because we realized that was so much in common between the different diseases.”

  • Individuals responded differently to each of these treatments, but why? The goal has become clearer, which is “to match the right therapy with the right person and figure out who benefits from which drug and why,” along with “sussing out who is going to respond differently.” In the Rituximab trial, the younger patients benefitted the most. The follow-up studies highlighted that younger patients all had B cell signatures that indicated B cell abnormalities. However, the older patients did not have this B cell signature. Panelists concluded that when B cell abnormalities are present, a drug which depletes them helps the disease; however, when B cells are normal, these same drugs do not have much of an effect.

• Dr. Evans-Molina touted the benefits of an incremental approach, saying that although “we are all looking for the homerun, a couple bases along the way are pretty good. Dr. Evans-Molina commented on the progress the field is making, emphasizing that the steps being made forward are more incremental rather than large leaps forward. Elaborating on these incremental steps, she noted, “Doing better can mean a lot of different things. It could be you can achieve a goal A1c easier, you have fewer lows, less chance of having retinopathy down the road because you have some level of insulin secretion, along with many others. If we find approaches that are successful at turning off the immune system and making the beta cell better and we preserve insulin secretion to an extent that people experience less blood glucose and have fewer complications, that’s pretty good.”

• Reflecting his experiences working on the T1D Fund, Dr. Behr highlighted the thought process companies go through when deciding to develop a drug or not: “The three questions a company might ask when developing a drug are: (1) do we have enough confidence in the science? (2) Is it practical to develop this drug? (3) If we think it’s successful and practical to make this drug – will we make money?”             

  • Encouragingly, type 1 diabetes is becoming an attractive market to enter because there is no competition in terms of disease modifying therapies, unlike other autoimmune disease which have more crowded markets. From his perspective at the T1D Fund, Dr. Behr notes they have been looking at companies with new platforms. One example is that they are “looking at companies that have platforms for sequencing the receptors on T cells. This means by looking at each individual T cell, they can pull out a piece of tissue or blood and look at it at an individual cell basis whether it’s a good or bad T cell, what it recognizes, and what it does not recognize in terms of those specific peptides.”

• Support emerged for “shorter trials with a mechanistic focus,” with biomarker development as an enabling factor. Dr. Evans-Molina believes that shorter trials with a combination of using biomarkers as “surrogate endpoints” will help shorten the process and determine positive outcomes. As a result, there have been increased biomarker research, with three major contributions. First, the Critical Path (C-Path) Institute’s Type 1 Diabetes Consortium announced that FDA accepted C-Path’s Biomarker Initiative project into the CDER Biomarker Qualification Program (BQP). FDA’s full response delineates the agency’s belief in the unmet need in type 1 prevention and its support of C-Path’s plan to pursue biomarker validation for a panel of islet autoantibodies. Second, the JDRF Biomarker Working Group aims to identify biomarkers that predict the rate of progression of recent onset type 1 diabetes. The broad goals of the working group are to validate the technical quality of new biomarker assays and eventually to create clinically meaningful predictive models, most likely involving multiple biomarkers. Some examples of biomarkers have been age, various measures of insulin secretion, and measures of immune function. Lastly, type 1 diabetes TrialNet uses biomarkers in clinical trials and screenings to try and identify individuals at risk of type 1 and identify interventions to slow down the process. The organization has a host of ongoing studies to investigate various immunotherapies to sustain insulin secretion over the long term in people at different stages of disease (pre-symptomatic, newly-diagnosed, longstanding, etc.).

  • Dr. Evans-Molina challenged the field to be bolder, noting that “our field gets criticized for being too conservative.” She explained, “We get comfortable at testing things at onset because we can identify those individuals more easily. But we should take a step back to those who have a couple of autoantibodies, and the success we should be looking towards is looking at the population before the onset of diabetes.” Dr. Behr agrees, emphasizing the field’s misperception of risk tolerance: “I think it’s important we’re not trying to find drugs with no risk, but we’re trying to find out what the side effects are. Your [companies’] perception about risk tolerance is wrong, and if there is a real benefit in taking the drug, people are willing to take that risk.”

Health Policy Panel Comments on Rebate System, Biosimilar Insulin Market Entries, and JDRF Integrating Patient Voice

Tanisha Carino, PhD (Faster Cures, Washington, DC); Steven Weisman, PhD (Innovative Science Solutions, Morristown, NJ); Cynthia Rice (Moderator: JDRF, Washington, DC)

We relished a fascinating panel on health policy featuring Dr. Tanisha Carino, Dr. Steven Weisman, and Ms. Cynthia Rice. See below for some of the top highlights from the panel, ranging from commentary on potential changes to rebates, biosimilar insulin market entries, and work JDRF is doing to integrate the patient voice.

• Potential changes to the much-maligned rebate system was a major source of discussion, with several panelists advocating for its elimination. In light of a growing public outrage over escalating prescription drug costs, pharmaceutical manufacturers have pointed toward increasing rebates that PBMs swallow up as the major driver of price increases. In recent times, the Trump Administration has appeared to align with this stance, and has recently pushed forward proposals with the stated goal of eliminating rebates altogether in the hopes of transferring these savings directly toward patients. Ms. Rice underscored that her organization is “fighting for an end to this rebate system which is really driving up prices of insulin and restricting choice.” She also emphasized the twisted incentives that the current rebate system promotes, noting that it “forces manufacturers to compete – which sounds like a good thing – but this is really a competition where the company that pays the most money gets the preferred spot and then that ends up driving up the price because 70% of the list price is made up of the price they had to pay to get that preferred spot.” Dr. Carino aptly noted that this system hurts patients by driving up their end-costs and remarked that “it’s something we should not support if we believe in the patient-centered system.” To this end, we’re hopeful that these recent governmental proposals will be effective in lowering patient costs.

• The dynamics surrounding biosimilar insulin development and market entry remain complex, with Dr. Weisman noting the need for additional biosimilars to drive down costs. FDA has recently taken steps to regulate insulin as a biologic (starting in March 2020), which should theoretically drive competition up and drive prices down, according to Dr. Weisman. Dr. Weisman conceded that this will be a “slow process,” but remains optimistic that “competition will help a lot here…and all these new drugs coming to market – that’s all a good thing.” More biosimilar insulin market entries will be needed to really bring down patient costs – Dr. Weisman explained that “we need second, third, fourth biosimilar to be able to have real competition.” On this note, we’ve seen mixed signals from the industry in the past few months. Disappointingly, Merck announced in October 2018 that it would not commercialize its biosimilar, even after essentially gaining regulatory approval and imminent launch for it. More encouragingly, Novartis recently announced that its generic Sandoz division will partner with Chinese Gan & Lee to develop and commercialize biosimilar glargine, lispro, and aspart.

• Broadly, JDRF remains engaged in a range of activities at the FDA, with the help of allied organizations, Congress, and scientific experts. Bringing “scientific expertise and patient knowledge” to the FDA, JDRF is working with the FDA to advance work in immunotherapy, beta cell replacement, prevention, and complications, while establishing and following FDA guidelines. One notable step was the approval of the 21^st Century Cures Act by Congress at the end of 2016, which provides $6 billion in discretionary medical research funding and proposes a revamp of the FDA approval process to bring drugs and devices to market more quickly. Dr. Steven Weisman highlighted that this bill “mandated that FDA invest more in innovation, more in regulatory science, and to build the necessary teams to be more than just a regulator but to be a partner in developing products.” He continued by explaining that this bill helped “bring the face of the condition to the public to help them understand its importance,” in additional to emphasizing the cross-disease areas where there is overlap between diseases.

  • JDRF also continues to bring experts into the FDA to help educate the agency on the science. Senior Vice President of Advocacy and Policy, Ms. Cynthia Rice, described the two-workshop series that JDRF hosts to educate members of the FDA. The first of the series is on beta cell encapsulation, where JDRF brings in an expert every three to four months to educate individuals at the FDA, who will be reviewing the therapies that will cover them. Similarly, they host immunotherapy workshops, bringing in key scientific experts. Very positively, one other area they are working on is educating on why Outcomes Beyond A1c matter.

• JDRF is also bringing in the patient voice in advocating for improved therapies. Although the field is bringing parties together, collaborating, and focusing resources, JDRF is importantly integrating the patient voice into this dialogue to reveal to lawmakers what’s important to them. Dr. Weisman notes, “The things that are important to people suffering with this condition are not necessarily the things that regulators are thinking about making when they’re making decisions about clinical studies or clinical products.” To push this forward, JDRF has a panel of people with type 1 and family members with type 1 to explain the unmet need in the field to stakeholders. Ms. Rice brings up one example of how these panels impacted regulatory agencies like the FDA: “The voice that made the most impact on the agency was a husband of a type 1, one of his children has type 1 and the other developed autoantibodies. He really made the case that if there was a therapy that could delay his son from having type 1 for at least a few months, even a few months would be a benefit, years would be a great blessing. If you get him through middle school without him needing to do all that everyone else in the family has to do, that would be a tremendous benefit.” Ms. Rice noted that, “you could see the face of the FDA officials change; they had never thought about this before.” We’re thrilled to see JDRF integrate patient voices like this to positively impact how the field moves forward.

--by Peninah Benjamin, Adam Brown, Martin Kurian, Peter Rentzepis, Maeve Serino, and Kelly Close