The annual JDRF Mission Summit was held late last month (January 26-27) at the Westin San Francisco Airport. We were lucky to be included in the intimate gathering, during which attendees were treated to fantastic talks pertaining to the theme of “Investing in New T1D Advances.” Perhaps the most relevant development from the meeting was the launch of the JDRF T1D Venture Philanthropy Fund, which has already raised over $40 million and is looking to fund the best “early-stage high impact” type 1 opportunities in partnership with other investors. We got to hear from Chair of the Fund’s Board, Mr. Sean Doherty, as well as its Managing Director, Dr. Jonathan Behr, and learned that Bigfoot Biomedical is its first investment. Bigfoot Biomedical CEO Mr. Jeffrey Brewer also spoke about FDA submission, launch timing and pivotal trial of its smartloop automated insulin delivery service, as well as plans for a Series B raise next quarter. The rest of the two-day meeting was filled with JDRF-funded researcher presentations on topics from prevention, to big data, to smart insulin, to beta cell biology, and beyond. See below for our top five highlights, followed by detailed discussion and commentary from the Summit.
Top Five Highlights
1. In a very confidence-inspiring presentation, Bigfoot CEO Jeffrey Brewer shared expectations for an FDA submission of the smartloop automated insulin delivery service in 2018, enabling a potential launch in early 2019. The pivotal trial is still currently slated for mid-2017, and in new news, is expected to occur at 12+ centers and enroll a “few hundred” adults and pediatrics.
2. Dr. Jonathan Behr, an MIT engineering alumnus who has been running the T1D Fund since late last year, publicized the Fund’s first investment: an equity investment in Bigfoot Biomedical (which we previously reported on). He said that the Fund has a “rich” pipeline of potential and diverse deals and that the Fund has already begun to deliver on its promise to leverage JDRF’s strategic know-how and relationships. Dr. Behr noted that the Fund is currently in diligence with 10-20 opportunities, and hopes to eventually evaluate hundreds of deals per year.
3. The always-insightful Dr. Atul Butte delivered an engaging talk on the incredibly effective tactic of utilizing the enormous amount of public data in free, online databases such as PubChem and other National Center for Biotechnology Information (NCBI) resources to conduct scienctific research. “It’s like a bank where everyone knows how to deposit, but no one knows how to withdraw the money.”
4. The brilliant Dr. Zhen Gu shared a high-level view of the work going on in his iMedication laboratory, including that on glucose-responsive microgels, a glucose-responsive nano-network, and smart insulin and cell patches. He hopes to bring the most promising technology formulation to clinical trials ASAP.
5. According to Dr. Matthias Hebrok, the field is getting very, very close to replicating and regenerating insulin-producing beta cells. He described the roadmap to functional beta cells using an east coast to west coast United States road trip as a metaphor – New York is the stem cell, Chicago is the endoderm, Denver is the pancreas, San Francisco is the near-beta cell, and UCSF is the true beta cell. Two years ago, he said, researchers successfully generated the immature beta cell, placing the field at the Embarcadero on the analogous US map, just five miles from UCSF. Today, he set out to convince attendees that we are knocking on UCSF’s door, with essentially fully functional mature beta cells.
Detailed Discussion and Commentary
Presentation by Bigfoot Biomedical
Jeffrey Brewer (CEO, Bigfoot Biomedical, Milpitas, CA)
In a very confidence-inspiring presentation, Bigfoot CEO Jeffrey Brewer shared expectations for an FDA submission of the smartloop automated insulin delivery service in 2018, enabling a potential launch in early 2019. The pivotal trial is still currently slated for mid-2017, and in new news, is expected to occur at 12+ centers and enroll a “few hundred” adults and pediatrics. (We’ve since learned that the pivotal timing hinges directly on a commercial agreement with Dexcom, which still has not been signed. According to Bigfoot, selecting a CGM partner for the commercial system is a top priority.) Mr. Brewer also confirmed that Bigfoot will pursue a Series B round of ~$30-$5o million in 2Q17, quickly following the $35 million Series A round in October and an investment this week from JDRF’s brand new T1D Venture Philanthropy Fund (size not disclosed, but it was significant and strategic). Having Mr. Brewer on stage at the Mission Summit was an incredible vote of confidence in Bigfoot from JDRF, particularly because no other companies pursuing closed-loop devices presented. Obviously Bigfoot can start from scratch and leverage a lot of what Mr. Brewer learned as CEO of JDRF and getting the AP project off the ground a decade ago. See below for more details and some very compelling quotes from this talk.
- Enthusiasm for the Bigfoot system was palpable in the room following the presentation. Attendees swarmed Mr. Brewer and Bigfoot CTO Mr. Bryan Mazlish with questions after the presentation. We overheard a woman saying to another that her 13-year-old son was in the feasibility study and “it was great,” to which the other responded “Oh my god I want my daughter to do it!”
- Mr. Brewer commented that achieving the early 2019 launch timing is entirely dependent on funding and execution – “I don’t think the FDA is the problem anymore.” We would agree with that statement, given the remarkable three-month FDA review of Medtronic’s MiniMed 670G. Mr. Brewer’s comments today confirmed the October expectation for a PMA submission in “early 2018,” enabling an early 2019 launch if all goes well at FDA and other things fall in place. The timing puts Bigfoot’s market entrance obviously behind Medtronic’s MiniMed 670G (full launch this May-September); possibly behind Tandem/TypeZero’s system (2018 launch; pivotal study starting in the coming weeks), and roughly on par with the most recent timing for Beta Bionics’ insulin-only iLet, Animas device, and Insulet (see our automated insulin delivery competitive landscape). We think this field will be more about product form factor, ease of use, and reimbursement than launch timing, since pumps are not particularly fluid (four-year warranty) and expanding the market will require much less costly products delivered in a more consumer-friendly business model.
- Series B financing discussions to raise another ~$30-$50 million are already underway. This would put total funds raised up to ~$70-$90. A year ago, Mr. Brewer estimated that $80 million would be sufficient to commercialize the planned product pipeline, but today he amended this number meaningfully to $120 million. Things always take longer and are more expensive than imagined, so this is not surprising to us. We also wonder if Bigfoot still has a broader insulin delivery scope in mind, as there was mention of a smart pen a year ago at JPM.
- The pivotal trial will take place at over 12 geographically diverse locations and enroll “a few hundred people split between adults and pediatrics.” Mr. Brewer couldn’t offer any more specifics, just adding that “we’ll make sure people know when and where the trial will commence.” We have no doubt this will enroll very quickly. In July, Bigfoot started enrolling patients in its first clinical trial of the smartloop automated insulin delivery system, which has since completed. We’re not sure if results will be shared publicly. The 48-hour in-clinic feasibility study enrolled “up to 50” participants across three study sites (Stanford, Sansum, Barbara Davis Center). We love seeing the pediatric focus from the get-go, as the study’s inclusion criteria go down to age seven years.
- The charismatic Mr. Brewer had a number of notable quotes pertaining to the current state of diabetes management and the Bigfoot proposition:
- “As I said, today you can have 10 different prescriptions when you go to the endocrinologist – pumps, reservoirs, infusion sets, BGMs, lancets, strips, CGM receiver/transmitter/sensor – all of these today are fulfilled at different places, some at the pharmacy, the company, mail-order pharmacy, and co-pays are different for everybody. And everybody that lives with this disease has a closet at home where you keep inventory management of all this stuff. People laugh because it’s true. It’s tremendously inefficient, burdensome, and we actually think that’s part of the burden we want to alleviate. The emotional and cognitive burden is not just about dosing insulin, it’s about all of the management tasks necessary in order to use a system. If we can take some of those away, we think we’re clawing some life back for people with type 1 diabetes. So it’s going to be one prescription for the doctor, one co-pay for the user, one predictable payment for the payer, and that’s the business that we’re building.”
- “Current devices are not getting it done. They’re too complicated and require too much training. If the tools don’t work for the average person treated by a doctor at a distance, then they don’t work at all. People with type 1 are not one, heterogeneous group. But they all want things that reduce burden and that they can trust.”
- “Things have moved fast, and things never move this fast in the medical field. We’ve been in business two years and three months. We have a Series B funding next quarter. With FDA submission in 2018, we can be on the market at the beginning of 2019. It’s too slow to me, but as fast as it’s ever moved.
- “Care should be more about choice and wrapping technology around people’s lives, not making people be a pump person or a shots person. Why can’t I be what I want to be when I want to be it?”
- “The healthcare system pays $33,700 per hypoglycemia-induced ER visit. $25,980 is the average cost of a hyperglycemia-induced ER or hospital visit. We can build a nice business keeping people out of the hospital. At the end of the day this is about access. We won’t be a business for people who will self-pay. The only way to build a business is to make sure everyone can get it, and everyone needs it.”
- “We were tremendously fortunate that Asante ceased operations. It’s why Bryan and I are in Silicon Valley. It’s the best deal we’re ever going to get.”
- “Moving the system to the interface of a smartphone seems like an obvious win, but you have to make some fundamental changes and investments in order to do that. It has to be secure. Our company was founded and inspired by hackers, so we know how they think. Our system works more like a Tesla. It has a crypto chip in it that authenticates in the cloud devices that talk to it. This is a secure system that leverages over-the-air firmware updates. In a world where security is constantly evolving, you need to have something that is dynamic. Every current insulin pump has been hacked, and now we have the technology to protect against that.”
- “Onboarding consists of one question: “How much Lantus did you take yesterday.” Within 7-10 days, you’ll have the most amazingly configured pump you’ve ever had. And if you get sick or pregnant or go through puberty, settings change, and they never result in a doctor’s visit.”
Questions and Answers
Q: What issues do you see in the future?
Mr. Brewer: Two things – getting the money – we’ve reached a tipping point, proved that we can do this, and the market is shaping up to show the merits of our approach, but we need $120 million all in all. We’re $40 million there and hoping for a Series B of $30-$50 million. It’s still a risk. The other thing is that we have a lot of work to do. It’s a complicated system, we have a lot of blocking and tackling to execute. But I feel good about raising the capital, and the world is coming our way. If we can raise the money and execute, we’ll be there in 2019. I don’t think the FDA is the problem anymore.
Q: Amazing, crisp, and thoughtful way of analyzing the problem. Isn’t this sort of a prototype for things that should be attracted by the T1D fund?
Mr. Brewer: This is a very challenging space in which to raise capital. It’s not popular. For us, devices and diabetes and clinical trials equals death for most VCs. We had to go far and wide to find non-traditional investors. The further you get, the more traditional players you want to get in. I’m sure there’s an analog in drug discovery. It’s a tough space, which shows the absolute need for the T1D Fund. There are a lot of research opportunities, but the thing that remains to make the most progress is the capital to fund businesses to take it across finish line.
Q: Can you comment on pivotal trial details?
Mr. Brewer: We plan to have over a dozen sites geographically dispersed. Jen Block did all of these trials at Stanford and knows the players. We will do a trial with a few hundred people split between adults and pediatrics. We can’t be more specific about that. We’ll make sure people know when and where the trial will commence.
Mission Summit Fund Launch
JDRF T1D Fund
Sean Doherty (Chairman, T1D Fund Board of Directors)
Mr. Sean Doherty, Chairman of the new JDRF Venture Philanthropy Fund, introduced the $40 million plus investment fund for type 1 diabetes, sharing that he’s never had more conviction about anything in his life. Mr. Doherty, himself, and his wife have already contributed to the cause. As we previously wrote the day of the announcement, the Fund is looking to invest in the best “early-stage high impact” type 1 opportunities in partnership with other investors. The JDRF expects to raise over $80 million by 2018 through individual “venture philanthropy” donations. At this point, over $40 million has already been raised, with $32 million coming from JDRF. The Fund will make a number of investments in the coming years that will be equity- and royalty-based, which could potentially yield large sums for this fund and the broader JDRF global organization if the investments go well. The Fund was setup with two central tenets in mind: First, bring private venture and pharma dollars into the type 1 diabetes space. From 2009-2013, $17 billion was invested in biotech by venture capital firms, but a minute fraction actually went to type 1 diabetes. By leveraging JDRF’s extensive expertise and resources, the Fund hopes to de-risk investments. Said Mr. Doherty, “it is incumbent on us to make a case that this is a pool worth jumping into.” Second, the Fund will serve to help early-stage companies navigate the canonically underfunded valley of death, when great science leaves a lab for translational research and development. See our day-of report for more context for the fund’s formation, along with quotes from JDRF VP of R&D Dr. Aaron Kowalksi and International Board member (and father of a woman with type 1 diabetes) Mr. Doug Lowenstein.
- Mr. Doherty emphasized the attractive donor model of the Fund. While acknowledging that this will be risky investing (as is most in early stage biotech), the maximum donor efficiency is 100%. The minimum donation is $500,000 (over four years), and JDRF will cover up to $2 million per year in overhead, as well as providing shared resources including research diligence, transparency, reporting and access through a donor advisory council.
JDRF T1D Fund
Jonathan Behr, PhD (Managing Director, JDRF T1D Fund)
Dr. Jonathan Behr, an MIT engineering alumnus who has been running the T1D Fund since late last year, publicized the Fund’s first investment: an equity investment in Bigfoot Biomedical (which we previously reported on). He said that the Fund has a “rich” pipeline of potential and diverse deals and that the Fund has already begun to deliver on its promise to leverage JDRF’s strategic know-how and relationships. Dr. Behr noted that the Fund is currently in diligence with 10-20 opportunities, and hopes to eventually evaluate hundreds of deals per year.
- While exact terms were not disclosed, we understand the Bigfoot investment was significant and strategic. Bigfoot still expects a pivotal study of its smartloop automated insulin delivery service in mid-2017. This new financing adds to the company’s impressive $35.5 million Series A round last fall, giving the company 12 months of runway, including some recently obtained non-dilutive funding sources. Discussions are already ongoing about a Series B (possible as soon as Q2), which would take the company through to commercial launch. As we understand it, a commercial agreement with Dexcom has still not been signed. According to Bigfoot, selecting a CGM partner for the commercial system is a top priority.
- In contrast to the traditional JDRF model of spreading funding wide and thin, the Fund will concentrate its investments on a select few promising opportunities every year. The downside of this strategy is that makes for riskier investing since the diversity of the portfolio can’t be as great. On the other hand, it gives the selected companies a better chance of surviving the valley of death, and also communicates to the private sector that a firm who is very smart about type 1 diabetes is all in, and perhaps they should be too. In Q&A, Dr. Behr drove this point home, saying he’d be surprised if the Fund had an investment where it wasn’t investing with someone else with deep pockets.
- We wonder what kind of impact the Fund’s investment will have on the size of Bigfoot’s impending Series B. Investors have already shown that they have confidence in this company ($35.5 million Series A last fall), but we have to think that being the recipient of the T1D Fund’s first investment would grab the attention of other firms.
- How will the Fund measure success in the near-, medium-, and long-term? In the near-term, the Fund Board is hoping to see a dramatic increase in pharma and venture capital funding in the type 1 space. Medium-term, the goal is to see acceleration and expansion of a transformative clinical trial pipeline. And in the long-term – no surprises here – the Fund would like to see the delivery of outcomes to patients with type 1 diabetes and their families. As of Day #2 of the Summit, 13 individual donors (~$8.5 million total) had already bought into this mission, and Mr. Doherty said that many other attendees had expressed interest in contributing as well.
- The Fund has learned about best practices via a partnership with Harvard Business School. Members have studied the venture philanthropy space and the perceptions and expectations of venture capital and pharma. The collaboration will continue into 2017 as the Fund probes the space further.
Questions and Answers
Q: Recycling returns, partnerships, it seems like you want to provide gap financing, then get out. What’s the philosophy? To help companies get on their feet or to stay invested in firms over the long term? What kind of investments are you making? Low interest, no interest, loans? How do you get the money back, because the mission is to keep investing in more and more organizations?
Dr. Behr: We have flexibility in structuring investments, but when we’re talking about equity, we expect to invest on the same terms as other investors, thereby aligning incentives. We don’t want to be cheap money. We want people coming to us because they think we’re the best partner to work with.
Q: How early-stage investing are we talking about? How mature?
Dr. Behr: Early stage opportunity. We will make seed investments, A rounds, perhaps later stages as well. We’re less sensitive about time in market and time to exit as transitional investors. Gap funding is good, but the bridge has to be built to somewhere. The goal is to leverage private capital – I’d be surprised if we had an investment where we weren’t investing with someone else with deep pockets.
Mr. Doherty: The research developments are extraordinary, and it’s time to start taking risk. This is a vehicle that is attractive to those who understand that. We will certainly make mistakes; just as other life science venture capital firms do. Over the long term, if we’re not making investments and attracting private capital, we will get swallowed by the valley of the death.
Q: How big is the landscape?
Dr. Behr: In the long run, if we’re using the same metrics as venture capital (deal flow), we hope to be looking at hundreds of deals per year, leveraging partnerships and relationships. Currently, we have between 10-20 opportunities that we’re in diligence with, investment committee is very generous with time, meeting bi-weekly, we do see a lot of opportunity with volume.
Mr. Doherty: The pipeline in front of us greatly exceeds our current capital, so we need to raise and attract private capital.
Q: You mentioned the FDA approval process – how do you see that influencing investments?
Dr. Behr: There’s a lot of uncertainty in regulatory landscape. That is a compelling reason to have this fund and for people to work with us. We have people on Capitol Hill working to solve that problem for this condition. The T1D Fund is therefore advantaged.
Q: Can you give an example of why a company would prefer equity vs. a research grant?
Dr. Behr: Companies like non-dilutive capital. When an opportunity comes to JDRF, we will decide the best mechanism. There are different value propositions for both. Governance, milestone-based nature, new companies pivot sometimes, we’ll put the right governance in place for equity, but more flexibility. There are advantages to equity. It’s up to us to determine which mechanism will be most effective to support opportunities.
Q: Will there be a used funds restriction, if a company pivots and isn’t focused on T1D? What kind of restrictions will be in place?
Dr. Behr: Governance will be on a deal-by-deal basis. Bigfoot won’t pivot, so we’ll put much less governance on them than a platform company. We’ll do what’s appropriate.
Q: Tax-advantaged for individual donor, 100% tax deductible?
Mr. Doherty: That’s correct.
Q: What’s the nature of existing VC partnerships with JDRF?
Dr. Behr: JDRF has been collaborating and making investments in companies for ~10 years. Those are co-investors in companies. We’ve learned a lot over 10 years (better structure investments, real needs of partners) and have the foundation. We’ll continue to have relationships with corporations beyond the T1D Fund.
Q: In constructing the typical venture portfolio, if you make 10 bets, you hope one is blockbuster, three to four don’t lose money, and the rest are dead. Is this different because the mission is focused?
Dr. Behr: That description of returns is based on the assumption that you’re swinging for the fences. In the risky business we’re invested in, we expect to have failures. That’s not because they’re bad investments, but because science is risky. We’ll invest in early-stage companies closer to clinic, as well as others. We’ll balance risk, ensure we have staged a series of investments. We expect some losses, and are hoping that a few in portfolio will be blockbusters with respect to impact on patients.
Q: Are you getting involved with IP?
Dr. Behr: One consideration for fund is not putting provisions in place that’ll keep them from getting capital. Don’t put roadblocks in place, if we structure in a counterproductive way, we’re not servicing our mission. We have to be really sophisticated when we think through how we structure these with the mission in mind.
Mr. Doherty: Closing thought – it is our fervent wish to capture intellectual capital of this group. We’d like to continue that process, because we’re all affected by type 1 diabetes and our goal is to pull something together to best affect our mission. We encourage input, we need it.
Understanding the Biology of T1d: Leads for Prevention
Translating a Trillion Points of Data into Therapies and New Insights in Health and Disease
Atul Butte, MD, PhD (University of California, San Francisco, San Francisco, CA)
The always-insightful Dr. Atul Butte delivered an engaging talk on the cheap and incredibly effective tactic of utilizing the enormous amount of public data in free, online databases such as PubChem and other National Center for Biotechnology Information (NCBI) resources to conduct scientific research. To date, humans have generated more data than researchers can possibly process – 2 million samples of gene data, 1300 relevant to human type 1 diabetes – and these stores are growing exponentially. “It’s like a bank where everyone knows how to deposit, but no one knows how to withdraw the money,” Dr. Butte explained, urging people to start scientific projects using public data. “PubChem beats pharma and biotech databases. No password needed, free and just sitting there. I’ve been using it, with JDRF grants.” To demonstrate the potential of data aggregation, Dr. Butte told the story of his lab’s recent discovery of vitamin D binding protein (VDBP) as a possible autoantibody in type 1 diabetes. This project started entirely from analyzing public data, 118 gene expression samples from 17 published experiments, and finding commonalities in gene expression (Diabetes 2016). VDBP was a hit in 16 of the 17 experiments, so Dr. Butte’s lab investigated further – it turned out that the protein sits in alpha cells, induces T-cell proliferation, and is elevated in type 1 diabetes patients. “And this started with public data! Just because someone wrote a paper, that’s the beginning of a data set, not the end,” he exclaimed. Other public data studies have found alternate uses for drugs, such as using the antidepressant Imipramine against small cell lung cancer – and the total cost of the phase 2 trial was just $50,000. The advantages to using this data – other than availability – are that it’s much cheaper and faster than performing full-scale benchtop work. Dr. Butte suggested that more people, especially students, be trained to look at public data and learn to ask questions and make predictions. The amount of potential in the “data deluge” was not surprising, but we are surprised that we don’t hear more people talking about it (we imagine there are a number of private companies exploring the possibilities in stealth mode). We love hearing Dr. Butte’s talks on the promise of big data, and hope they spur other bright minds to go out and mine public resources!
- Dr. Butte suggested in Q&A that VDBP, which resembles a virus, could play a role in environmentally triggering type 1 diabetes. Although he called it “pure speculation,” the idea that something inherent to our bodies, like VDBP, could not only predict but also factor into the development of diabetes is fascinating. As Dr. Butte acknowledged, more studies need to be done in these “early days.”
- There was no shortage in the talk of examples of the sheer magnitude of data we are generating today:
- The human species generates two Zettabytes (1021) of data each year.
- NASA will soon generate Exabytes (1018) of data each day! NASA admits that they take so many pictures of the sky that there are not enough astronomers in the world to look at them.
- Microarrays started as one gene chip, moved to 96-well plates, and now commonly come in 384-well format. This is a perfect illustaration of exponential growth in the biomedical field, and now RNAseq has been added to scientists’ arsenals.
- Dr. Butte always puts a different spin on his healthy obsession with big data when he speaks: At Partnering for Cures 2016, he made a direct call-to-action, asking that funders require and help investigators to release data to the public, noting that “your one dollar will go that much further if more eyes are on the data you just funded.” He added that he would like to see all of the raw data – what dose? What failed? Why? – not just summary data. He believes in a total liberation of data – and we find his logic difficult to argue with. At JPM 2017 last month, he remarked: “Data is frozen knowledge. It’s up to us to bring the heat to melt it.”
Questions and Answers
Q: Is there value in collecting routine blood tests from type 1 diabetes patients?
Dr. Butte: Yes, even differences in complete blood counts. Precision medicine. The cancer world thinks of not just one, but five subtypes. They get it. But in type 1 diabetes, we’re still not really there yet. We could use blood tests and other molecular markers. We have almost a billion lab test results in the Ucal system. You better believe we’re going to use that.
Q: How will AI help here?
Dr. Butte: AI, deep learning, is an old technique we’re all using again. Everything I showed you is some form of AI. As data gets more digitized we can use those tools – no reason not to partner.
Q: How would diabetes being reportable enhance your work?
Dr. Butte: There is a great swath of the disease in CA, but many others places as well. It’s surprising we don’t have a count of how many Americans has which diseases.
Q: My son has type 1 diabetes but no autoantibodies. Any research for patients like him?
Dr. Butte: Levels can decrease over time, so it’s possible he had them at some point. Or different subset of disease, type 1 diabetes is not just a single disease, but a clinical manifestation of many different sub-conditions. There’s not a large amount of research in low-AA subjects, mostly because it’s hard to identify them. There’s a large interest in trying to get to disease mechanisms and heterogeneity based on tools and data already out there.
From Disease Care to Health Care in Type 1 Diabetes
Joseph Hedrick, PhD (Venture Leader, Disease Interception Accelerator at Janssen Research & Development)
Using Juvenile Idiopathic Arthritis (JIA) as comparator, Dr. Joseph Hedrick explained that we need a shift in how diabetes is defined – not by symptoms, but rather by the underlying pathology. In 1972, Dr. Hedrick was a six-year-old boy diagnosed with JIA, he was told he would eventually end up in a wheelchair, and his treatment at the time consisted of 16 adult aspirins per day. Today, there are many advanced therapies for JIA that can cause remission. Compare that narrative with type 1 diabetes: In 1922, a boy named Edwin was one of the first people in the world to receive insulin. 90+ years later, Edwin’s great granddaughter, Amelia, is taking, more or less, the same drug. Granted, different diseases have varying degrees of complexity, but Dr. Hedrick conveyed a sense of urgency, furthering the comparison with JIA: We currently define diabetes on the basis of symptoms, not the underlying pathology. In JIA, the pathology is obvious – painful and swollen joints indicate a disease state, and physicians don’t wait until the joints are destroyed to make a diagnosis. Dr. Hedrick advocated for making the early part of type 1 diabetes visible by identifying biomarkers. The Janssen Disease Interception Accelerator (DIA) and JDRF have been collaborating in type 1 diabetes research (one of the DIA’s first interception ventures) to better understand this “interception window” before a patient is symptomatic. Objectives include identifying immune biomarkers of type 1 diabetes, gathering more information about the earliest phases of type 1 diabetes before biomarkers appear, and working to “rebalance the immune system” in order to protect beta cell function. This requires collaboration, not just between JDRF and Janssen but also academics, advocacy groups, government, and corporations. To us, one of the most remarkable aspects of the DIA, in terms of fostering collaboration, is that all of the information derived from the JDRF collaboration is available to anyone who wants it – wow! Overall, we appreciated Mr. Hedrick’s optimism about making the same strides in type 1 diabetes as have been made in JIA, a disease which Mr. Hedrick himself is managing successfully, and agree that the paradigm of care needs to shift from “disease care” (going to the doctor because you need treatment) to “health care” (going to the doctor because you’re healthy and want to stay healthy).
- Dr. Hedrick made the fascinating point that the only way to incentivize early type 1 diabetes screening is to develop therapies, and the only way to incentivize the development of therapies is to start screening. Both processes must move in parallel. Payers, providers, and the general population would find it difficult to rationalize widespread screening if there is no treatment, and on the flipside, pharmaceutical companies would not be able to conduct robust clinical trials unless they had a large population of individuals known to have an elevated risk of developing type 1 diabetes.
- Dr. Hedrick concluded his presentation with a thought-provoking quote from DIA founder Dr. William Hait: “A 100 years from now, someone’s going to look back on us and say ‘can you believe they waited until you got a disease and then did something’?”
Questions and Answers
Q: Is the endgame to develop tools to test for antibodies?
Dr. Hedrick: We can actually do the test today. It’s time to move from academic efforts to broad-based screening and identification of individuals. It’s a challenge, we have to make economic arguments – with payers, particularly in the US, it can be a challenging discussion. It’s on us to demonstrate feasible, affordable, and returns value from the people and payer perspectives.
Q: Are we talking about something, screening, that would start at birth?
Dr. Hedrick: It could, we all know about HLA risk alleles. They do test in Finland, and then follow individuals for the development of autoantibodies. Part of what we have to figure out is what makes sense, and that’ll change. We’re not far from having the entire genome sequenced at birth.
Dr. Jessica Dunne (Director of Discovery Research, JDRF, New York, NY): We would need better predictive genetics – currently, can identify at best 65% of individuals who will develop it.
Q: Once antibodies are identified, what is the treatment protocol?
Dr. Hedrick: That depends where you are. Unfortunately, the prospective benefit is really two things: You can avoid someone coming in to a clinic with DKA, which has consequences – in some places, there is no formal guidance as to when you start insulin. Depending on that conversation, in some places they do start earlier. There’s no guidance, those are the things that you can do. In the past, pharma said no one is screening, so we won’t develop drugs for early stage disease so we don’t screen, and people looking for screening say there is no solution, so why do it. We need to move the two together in parallel. I don’t want to read another newspaper story about another kid showing up in the ER with blood glucose of 600 when that’s totally avoidable.
Dr. Dunne: We had conversation with parents on whether they screened their kids. The rates of DKA are much decreased if the child was screened. In general, 30% present with DKA at diagnosis, and that number is as low as 6% when they got screened before.
JDRF supported studies to use gene expression to identify biomarkers of risk and progression in t1d and to identify novel drugs to block disease progression
Gary Fathman, MD (Stanford University, Palo Alto, CA)
Dr. Gary Fathman discussed two ongoing projects in his lab that address genetic biomarker detection and intervention of type 1 diabetes respectively. Dr. Fathman opened with an overview of his team’s work toward identifying biomarkers in peripheral blood cells that predict risk of developing type 1 diabetes. They lab analyzes the gene expression of first-degree relatives of people with type 1 diabetes from TrialNet, and tracks them over time to see if they are autoantibody-negative (AA-), autoantibody-positive (AA+) non-progressors, or AA+ progressors. The lab has already identified a number of candidate genes upregulated in those who eventually progress to type 1 diabetes, and currently has experiments in progress to confirm the prodromal gene expression signature on the way to a point-of-care. Given that only 15% of patients with type 1 diabetes have a family history and that 15% of patients with one autoantibody (currently to pancreatic antigens) develop hypoglycemia within 10 years, this research could significantly improve early detection and allow for early intervention. Accordingly, Dr. Fathman’s lab is also involved in early-stage prevention research. He presented his work on low-dose IL-2 (interleukin-2) therapy for type 1 diabetes and other autoimmune diseases. This approach stimulates the endogenous regulatory T cells (Tregs) of the immune system, which constitutively express the IL-2 receptor (IL-2R), to continue activating the IL-2R/pJAK1/SOCS3 signaling pathway and prevent Treg desensitization that would lead to beta cell destruction. Delivery of the drug uses a Trojan horse approach; a novel vault drug-delivery system of bioengineered nanoparticles tagged with IL-2 with high affinity to the IL-2R. Upon interaction between the vault and IL-2R, drugs would be released specifically to the IL-2R-expressing body. It’s great to see an accomplished researcher such as Dr. Fathman working on both the detection and intervention side of type 1 diabetes, and we look forward to following both aspects of his bench work as they progress.
- Dr. Fathman suggested that environmental factors such as hygiene or viruses could be responsible for triggering epigenetic alterations leading to type 1 diabetes, given its low genetic component. He specifically mentioned a “hygiene hypothesis,” which stems from a study performed in young children in Finland. The children had a much lower incidence of asthma than their peers after being exposed to dirt and other germs in pig farms for a number of months. “Getting the right infection at the right the right time” (namely, childhood) may prevent development of diseases, a common belief among immunologists.
Q: Can this strategy reverse established type 1 diabetes?
Dr. Fathman: When beta cells are already destroyed, it wouldn’t work. But this could prevent progression in AA+ normoglycemics.
Q: Why is type 1 diabetes not a reportable disease?
Ms. Cynthia Rice (Excecutive VP, JDRF, New York, NY): There is uncertainty about whether detection tests are 100% ready to be used. JDRF is playing a leading role, interested in looking to what other countries are doing, the pilots in Colorado and Germany. There is no national health system in the US, unlike in other countries. State by state, different states collecting different diseases. It is useful to prevent DKA, however.
Novel Designs Toward Glucose Responsive Insulins
Smart Insulin Delivery
Zhen Gu, PhD (University of North Carolina, Chapel Hill, NC)
The brilliant Dr. Zhen Gu shared a high-level view of the work going on in his iMedication laboratory, including that on glucose-responsive microgels, a glucose-responsive nano-network, and smart insulin and cell patches. As evidenced by this wide array of approaches, the iMedication lab combines biomaterial design, micro- and nano-fabrication, and biomolecular engineering to develop biochemical devices with two key elements – glucose-sensing capabilities and a material that can then be activated to release insulin. Dr. Gu received a grant from JDRF and Sanofi in February to further translate these findings (optimize the smart insulin patch with regard to stability, loading capacity, response speed, and biocompatibility, test on pigs with CGMs, exploit novel glucose-responsive formulations, and focus on the most promising formulation and bring it to clinical trials ASAP). We love the Gu Lab’s multi-pronged and creative approaches to solving a very non-trivial problem.
- Both the microgels and nano-network rely on the glucose oxidase enzyme, which converts glucose into gluconic acid to generate an acidic environment. Insulin is packaged inside either a microgel or a scaffold, which swell and degrade, respectively, to release their contents when pH drops. In a rodent type 1 diabetes model, the administration of the glucose-responsive nano-network keeps glucose in a normal range for 10 days.
- The smart insulin patch leverages a different facet of the glucose oxidase-catalyzed reaction. When glucose levels rise, the reaction consumes both the excess glucose and oxygen, resulting in a hypoxic environment. Thus, Dr. Gu zeroed in on a hypoxic sensor as another proxy for detecting elevated glucose levels. The lab incorporated this sensor into a smart insulin patch, which rests on the skin and delivers insulin through 500 um-800 um transcutaneous needles (not long enough to reach nerves, so essentially pain-free; see pictures here). In mice with streptozotocin-induced type 1 diabetes, the patch was shown to effectively respond to varying blood glucose concentrations, only administering insulin when glucose levels were between 200 mg/dl and 500 mg/dl. ACS Nano published a paper reporting this preliminary success just last month.
- To take things one step further, the Gu lab is developing a smart cell patch, which combines external beta cell capsules which rest on top of the microneedle patch (see pictures here). Because the cells are not inside the body, the immune response is not a concern, yet they would inherently display glucose-responsiveness and deliver insulin in a painless manner.
- Though very early stage, Dr. Gu is exploring the possibility of using red blood cells for smart insulin delivery – cool! A preliminary publication is in press. The basic principle, as we understand it, is that red blood cells are isolated from a donor and linked to a glucose-insulin complex. After being injected intravenously back into the donor, the glucose-insulin complex dissociates from the blood cell and binds GLUT receptors. In hyperglycemic environments, the insulin then leaves the bound glucose molecule to complex with circulating glucose, where it can then lower blood glucose on a systemic level. We look forward to seeing this full publication!
Alborz Mahdavi, PhD (Founder, Protomer Technologies, Pasadena, CA)
Dr. Alborz Mahdavi, a disciple of the great MIT scientist Dr. Bob Langer, explained Protomer Technologies’ mutate and iterate approach to glucose-responsive insulin. Unlike Dr. Gu’s Lab, Promoter is working from a strictly protein-based methodology, attempting to develop an insulin that only assumes its active, receptor-binding conformation upon binding glucose. Likewise, when glucose concentration is low, the insulin is less likely to bind glucose and adopts its inactive conformation. In Q&A, Dr. Mahdavi stated that version 1.0 will likely just serve as fast-acting insulin, whereas version 2.0 might cover basal as well. How is this perfectly-glucose-responsive insulin generated? Many stages of iteration. Bacteria produce insulin, the insulin is chemically modified and selected for high glucose affinity, and then the cycle repeats until the protein is only active in the desired range of glucose concentrations. Given that there are 64 million possible amino acid combinations in the sequence of insulin, Dr. Mahdavi remarked that “undergrads would be great,” but he settles for robots. The machines used in Protomer labs generate over one million sequences in a matter of days. Once a sequence has been deemed glucose-responsive, it is tested in a mouse model of diabetes. They are injected with the insulin, and then subjected to glucose challenges while blood glucose levels are monitored. The iterative approach holds promise, but Protomer, founded in 2014, is still very early stage – Dr. Mahdavi doesn’t expect to file an IND application with FDA until at least two years from now. In the meantime, the company will run toxicity studies (hypoglycemia is a major concern if the insulin doesn’t stay inactive when it is supposed to), determine preliminary dosing requirements, and figure out how frequently the insulin needs to be taken (the goal is once every two days). One thing is clear, Dr. Mahdavi is “not keen on running to FDA” until Protomer has a sound candidate.
- Dr. Mahdavi is a star in the glucose-responsive insulin field – he previously won both JDRF’s Glucose-Responsive Insulin Grand Challenge Prize and received significant funding from a collaboration between JDRF and Sanofi to advance glucose-responsive insulin.
Questions and Answers
Q: What is JDRF doing in terms of regulatory pathway – this is completely novel. Also, the impression I got is that blood glucose has to be quite high to trigger insulin release. Does that have implications for complications? Spikes are what is really dangerous.
Dr. Sanjoy Dutta (Assistant VP, JDRF, New York, NY): Our teams work closely – research and advocacy. For every project we do we have collaboration. Glucose-responsive insulins at the moment are still in early discovery research, we have plans to work with our team in DC to approach and educate FDA.
Ms. Cynthia Rice (Senior VP, JDRF, New York, NY): I agree with everything you said. The work JDRF is doing in collaboration with the Helmsley Trust and T1D Exchange for outcomes beyond A1c is very relevant for glucose-responsive insulin. FDA is currently focused on A1C. It’s important, but not the only one of importance. We have had and will continue to have public workshops, consensus meetings with the goal of having other ways to measure outcomes (time in range).
Dr. Mahdavi: It works in a gradient – we do a lot of work to tune sensitivity of glucose-responsive insulin. That’s one of the challenges of developing a good one.
Dr. Gu: In the meanwhile, we can adjust kinetics by altering enzyme amounts and insulin amounts to respond to certain range.
Q: For a blood glucose level that only requires a little insulin, how do you ensure that only a little gets activated?
Dr. Gu: We encapsulate a number of particles and we’ve adjusted degradability of particles so some quickly dissociate and some sit there waiting for other events. And once blood glucose becomes normal, dissociation is inhibited.
Mr. Bryan Mazlish (CTO, Bigfoot Biomedical, Milpitas, CA): What’s the tradeoff between quick response and risk of hypoglycemia? Will this just be a basal? Or take care of meals? What’s the orkng scenario?
Dr. Mahdavi: It’s a continuum. First, it will probably just cover the fast-acting space and have to take basal at the same time. It’d be nicer if you had a glucose-responsive insulin that covered both, but that might be version 2.0. You don’t have to hit a home run on the first try. The idea from our perspective is sub-cutaneuous injection every morning and you don’t have to worry about it, it’s already in your system.
Dr. Dutta: That’s an important area, developing target product profiles. There are many ideas on the table – start small, establish proof-of-concept and safety, but the goal is to cover entire insulin.
Q: You mentioned the Merck trial (MK-2640), do we expect that will inform your work?
Dr. Mahdavi: Absolutely. Anytime you get more information, it’s helpful to us. Merck spent a lot of time changing their concept. They found their gel sensor caused an immune response, so they had to change their system with similar idea but entirely changed molecularly.
Dr. Dutta: We’re anxious to know the results. Merck is not required to divulge the results. Regardless if positive or not, we will have learnings on how to do the study, whether basal or bolus, how to deliver, etc. But for timeline, your guess is as good as mine.
Exciting Advances in T1d Prevention and Beta Cell Biology
Generating and interrogating mature beta cells from Human Stem Cells
Matthias Hebrok, PhD (UCSF, San Francisco, CA)
According to Dr. Matthias Hebrok, the field is getting very, very close to replicating and regenerating insulin-producing beta cells. He described the roadmap to functional beta cells using an east coast to west coast United States road trip as a metaphor – New York is the stem cell, Chicago is the endoderm, Denver is the pancreas, San Francisco is the near-beta cell, and UCSF is the true beta cell. Two years ago, he said, researchers successfully generated the immature beta cell, placing the field at the Embarcadero on the analogous US map, just five miles from UCSF. Today, he set out to convince attendees that we are knocking on UCSF’s door, with essentially fully functional mature beta cells. Dr. Hebrok outlined five critical characteristics of beta cells – with each digit of UCSF’s 94143 area code corresponding to one – and showed data to suggest that the cells generated in his lab adhered to the criteria very closely.
9: The cells must generate insulin. In vitro, reaggregated beta cell clusters (eBCs; the artificially-induced beta-like cells) were genetically engineered to produce GFP (green fluorescent protein) when expressing insulin. Dr. Hebrok showed an image of these cells that was ripe with green, indicating insulin production.
4: Cells must specifically produce insulin (immature beta cells often also produce glucagon). eBCs have high expression of c-peptide (i.e. insulin production), and only 5%-6% of these cells also have glucagon.
1: Cells must express critical transcription factors: eBCs express PDX1 and NKX6.1, and don’t express SOX9 (a progenitor marker) or CK19 (a duct marker).
4: Cells must be glucose responsive: C-peptide spikes in response to high glucose levels and KCl in vitro. In addition, eBCs assume human islet morphology in vivo and convey resistance to severe STZ-induced diabetes.
3: Cells must be equivalent to human beta cells: The gene expression is 92% identical between human beta cells and eBCs.
This very convincing data suggests that, indeed, the field is very close to generating legitimate beta cells. The remaining debate is whether or not the 92% similarity between the expression profiles is sufficient. Dr. Hebrok argued that some pieces of the beta cell, those corresponding to “94143,” are more important than others – much like a car, in which the engine is required but niceties such as leather seats are superfluous. The sooner scientists know exactly which pieces are unnecessesary, the better; annually, there are only 1,562 pancreases recovered from donors in the US, and only a small fraction of those can be used in transplant procedures. An inexhaustible source of islets could help countless people each year.
- To illustrate how fast the beta cell generation field has moved, Dr. Hebrok compared its progression to that of insulin therapy. The first human embryonic stem cells were isolated in 1998. In the 18 years since then, researchers have molded glucose-responsive, insulin-producing cells in culture. Meanwhile, in the 90+ years since the first patient was treated with insulin in 1922, Dr. Hebrok argues that very little has happened comparatively – insulins are getting better and more precise (first short-acting insulin released in 1996, and first long-acting insulin released in 2001), but the rate of scientific innovation has, he believes, been much slower.
Targeting therapeutics to human islets with chimeric antigen receptor T cells
Seung Kim, MD, PhD (Stanford University, Palo Alto, CA)
Dr. Seung Kim presented his lab’s work modifying regulatory T cells (Tregs) to express chimeric antigen receptors on their surface, targeting them to islets to protect and/or proliferate beta cells. These modified Tregs, called CAR T cells, are commonly used in oncology, but their immunosuppressive and localizing properties could be leveraged in diabetes. Dr. Kim likened T cells to jedis, and CAR T cells to jedis with a compass, so you can tell them exactly where you want them to go. His lab has experimented extensively with graft experiments. Typically, islet cells allografted into a mouse host will be rejected. However, when mice in Dr. Kim’s lab received an islet graft in conjunction with CAR T cells targeted to the islets, the islets survived longer and had lower levels of cytotoxic CD8 T cells in the surrounding tissue. Similarly, when human islets are transplanted into a mouse kidney in vivo, the CAR T cells home to the graft, though researchers will be exploring whether or not the human islets are protected in the next year or so. The hope for CAR T administration is not only in immunomodulation, but also in the delivery of therapeutics – Dr. Kim’s lab is exploring the possibility of engineering CAR T cells to express beta cell mitogens (such as, possibly, GLP-1) as well as immunosuppressants (such as certain interleukins). This exciting preliminary work, supported in part by the Helmsley Trust, has the potential to stop the immune assault on beta cells in type 1 diabetes, and perhaps even induce regeneration. Dr. Kim hopes to head to clinical trials “ASAP,” and suggested that Helmsley is interested in funding such trials.
- Dr. Kim introduced the Stanford Diabetes Research Center, recently-established, 94-investigator-strong, group. Acclaimed researchers in the Center include Drs. Bruce Buckingham, David Maahs, Everett Meyer, Karl Deisseroth, and Dr. Kim himself. Each falls into a different “affinity group”: either pancreas and islet research, diabetes metabolism and signaling, diabetes immunology and transplantation, or diabetes bioengineering and behavioral science.
Questions and Answers
Q: How important is it to have an abundant supply of human-like beta cells to do research on?
Dr. Hebrok: So important. We still only get human islets once a month or once every six weeks. The heterogeneity of the islets we’re seeing is dramatic (age, gender), as is the quality of the islets. We can work with immunologists – as a research tool with a bend towards therapy, this can be unbelievably powerful. Human betas are different from mouse betas. They’re almost identical, but different because our cells are young. They are generated in 27 days for mice – 27 weeks for human embryo. Expression is different from what we see in the mice. We think we will learn a tremendous amount from human islets.
Q: If restrictions are put on ePSCs (embryonic pluripotent stem cells), are we talking a journey from Boston? Or from London, where there’s no way to drive to UCSF?
Dr. Hebrok: Good question. Canada, Florida, yes. A cell is very complicated. It’s difficult to generate a Porsche when you start with a tractor. It’s not impossible, a tremendous amount of effort will go into this, it’s just not 100% certain.
Dr. Kim: This organization [JDRF] understands disease politics better than anyone, they may have even created the field. If we think of a certain congresswoman from Tennessee and the use of fetal tissue, that has tremendously slowed research in terms of our understanding of how a human beta cell forms. The best way to figure that out, if you can’t study the real thing, is to study other surrogates, studying how you make a tractor. It’s already cast a pall on people because of leaks of names to press, there’s a lot of reluctance for people to enter a field if they think they might be subpoenaed by congress.
Ms. Cynthia Rice (Executive VP, JDRF, New York, NY): JDRF has been very vigilant with the new administration, working with allies. To date, we have no indication that the administration is planning on changing the executive order. Today is a major pro life march today, and Pence spoke, and that wasn’t brought up. We made it through the gauntlet of the first week – marchers could’ve focused on this, but they focused on other things like who they want for the next pick on the supreme court. Given that this disease is not getting a lot of public attention, the last thing we want to do is stir up the marchers for this.
Q: When you look at next steps, do you think use of CAR T cells in cancer will accelerate your timeline?
Dr. Kim: Dr. Everett Meyer and I want to move to clinical trials ASAP, and Helmsley is interested. Everett is experienced in clinical trials. We would like to move quickly to that. We have multiple steps in mind but we think we could move that forward more quickly if we could develop, for example, an islet transplant focused on something that is reimbursed now, autologous transplant, and there would be opportunities, because those grafts fail at about five years after, to do CAR T cell research after that. The venture Fund could be useful for that. We’re seeking partners for that in terms of IP, so that would be a concrete thing to discuss maybe later on.
Mr. Derek Rapp (President, JDRF, New York, NY): Once cells are inside the doors of UCSF, then what? They’re not usable yet – what are your thoughts on encapsulation? On applying gene editing techniques? Help us take it from that point to something that will be usable and safe.
Dr. Hebrok: Of course we’re thinking about this – we’re part of the encapsulation consortium. We’re working with bioengineers. Tons of stuff going on. Very futuristic things are to modify the immune system – the thymus instructs new T cells to come in, so they could recognize new B cells as self because recognized as okay. It’s like a cloak of invisibility.
Q: Is there work converting alpha to beta cells?
Dr. Kim: We’re still very interested in pursuing as many possible ways to replace beta cells, or in the case of T1d, it may also be important to quell or support under-enthusiastic alpha cells that are dysfunctional. Through support from JDRF and NIH, we’ve been able to genetically convert alpha to beta cells – I’d say they’re full beta cells, but that will be published soon. The idea that maybe we could use some system like CAR T cells to promote that conversion is intriguing.
Welcome & Mission Update
Mark Fischer-Colbrie (Chairman, International Board of Directors, JDRF, New York, NY) and Derek Rapp (President, JDRF, New York, NY)
Chairman Mr. Mark Fischer-Colbrie expressed that he is “very excited by the science” in which JDRF is participating, and illustrated how far research has come – in large part thanks to JDRF – since 2000. In 2000, there was one to two clinical trials underway relating to type 1 diabetes. Now, there are 67. So much else has changed since 2000, according to Mr. Fischer-Colbrie: The complexity of transfer from academic to clinical trials has increased, which is a good thing, as it has forced JDRF to partner with companies and collaborate with the likes of NIH and the Helmsley Trust. There are now over 400 ways of curing type 1 diabetes in animal models, which is “naturally frustrating.” But in 2000, those data sets were exciting because they pointed the way toward clinical trials. The Foundation now has four different programs with Sanofi for developing smart insulin, and the idea of stem cells producing insulin was just a pipe dream in 2000. Mr. Derek Rapp delivered the mission update later in the day, speaking to the overarching JDRF goal to do the greatest amount of good for the greatest number of people in the shortest amount of time. JDRF expects that half of its funding dollars will continue to go to glucose management, and the other half toward activities to prevent and cure the disease. Mr. Rapp is personally excited about the application of gene editing, understanding the staging of type 1 diabetes, and immunotherapy. “I feel quite optimistic that we will see science areas lead to potential projects, therapies, commercial availability, and implementation and to people being cured and prevented.” We certainly hope so! Mr. Rapp ended with a note on advocacy, a role in which JDRF has flourished over the past few years: “We are working to help FDA understand that while there are risks to commercializing therapies, there are also risks to doing nothing.”
- The 2017 Summit got off to a solemn start, as Mr. Mark Fischer-Colbrie led attendees in a moment of silence for the incomparable diabetes advocate Ms. Mary Tyler Moore, who tragically passed away a day earlier. As JDRF's great Chief Mission Officer Dr. Aaron Kowalski explained in a conversation at the Summit: “Mary Tyler Moore was an icon to so many for her incredible talent in entertainment and she was an icon to people with type 1 diabetes for her advocacy." He reminisced about how Mary was always at the JDRF Children’s Congress, on Capitol Hill, and on television speaking about the need for a cure, continuing, "Mary was an incredible T1D champion and will be tremendously missed.”
-- By Brian Levine, Hae-Lin Cho, Adam Brown, and Kelly Close