Memorandum
The Helmsley Charitable Trust recently announced five grants totaling $52 million to support the Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) and its first trial, the Primary Oral Insulin Trial (POInT). This phase 2b study will investigate high-dose oral insulin in infants with high genetic risk for type 1 diabetes, with an aim to prevent or delay onset of autoimmunity. The funding, part of Helmsley’s Type 1 Diabetes Prevention Initiative, will support recruitment of infants across the GPPAD network already established in Germany, as well as new sites in Sweden, the UK, Belgium, and Poland (investigators anticipate screening >300,000 newborns to fully enroll POInT). The grants have been awarded to Helmholtz Zentrum München and its partners, including the University of Oxford, Lund University, and Katholieke Universiteit Leuven. While oral insulin prevention studies have given few promising results thus far (including the TrialNet Oral Insulin study presented at ADA), the POInT trial will be intervening in children who have genetic risk for T1D prior to the development of autoimmunity – this is “primary prevention.” In contrast, TrialNet enrolled people who already have autoimmunity. Research indicates that once a person has multiple auto-antibodies, it’s a question of “when” rather than “if” they will develop type 1 diabetes. Helmsley noted that GPPAD will also serve as a platform for other intervention and mechanistic trials, not just in type 1 diabetes, but possibly also in other childhood diseases.
Helmsley has invested extensively in very ambitious projects aimed at better treating and possibly preventing type 1 diabetes, recently committing $5 million to the JDRF T1D Fund, and we can’t thank them enough for their dedication to their Type 1 Diabetes Program. Below, you'll find an interview with leaders from the Helmsley Charitable on this important and truly inspired, inspiring initiative that we believe will serve as a remarkable model for prevention of diseases of all kinds.
Interview with Dr. Gina Agiostratidou and Dr. Anne Koralova
Q: Could you tell us a bit about your vision for HCT’s prevention initiative?
Dr. Agiostratidou: About 3 years ago, David [Panzirer] said, “Gina, we have prevented some infectious diseases like polio, but we have never really prevented chronic diseases. From a logic perspective, you’d think that it may be easier to prevent something than reverse it.” So we said, alright, let’s see what a prevention initiative would look like. We hired a firm to study the landscape and gaps in primary prevention [of type 1 diabetes], what the main players in prevention are, and what strategy we can develop to try to prevent type 1 diabetes. A year later, we developed a strategy and a vision. The vision is to develop a platform to focus on the general population and try to develop clinical trials with the goal of preventing type 1 diabetes. As we do that, we would also like to learn about how type 1 diabetes is developed. We want to produce bio-samples that we can develop into biomarkers to learn about how type 1 diabetes is developed. But the ultimate goal is to think beyond type 1 diabetes in the general population, so in the future we can think about other diseases to be screened through our platform. We started talking to scientists in Germany, and after two years we decided to give this $54 million grant to create this platform among Germany (where the coordination center is), Belgium, Sweden, Poland, and the UK. In these 5 countries, we will screen 300,000 children with the goal to identify newborns who have genetic risks associated with type 1 diabetes, and they can choose to be enrolled in a clinical trial – in this case, it will be oral insulin. We’re already thinking about what is after oral insulin. After the screening for the oral insulin trial is complete, we would like to start screening for another trial. We would like the platform to be available in the future for other diseases associated with a genetic risk and we also hope that screening for type 1 diabetes, if it’s successful, can become something that many other countries can use.
Q: If down the line it turns out that primary intervention with oral insulin can be successful in preventing type 1, where do you think you would go from there? Have you thought in any way about the logistics of building an infrastructure for widespread screening or targeting specific populations?
Dr. Koralova: I think the whole concept of personalized medicine is moving forward on a lot of different fronts, not specific to type 1 diabetes or even autoimmune diseases. I don’t think that type of infrastructure is something that one stakeholder alone can build; it’s really going to have to be something that can be integrated into the various health systems around the word. But what we can contribute at Helmsley is helping to pilot some of those efforts and show they would work, but not necessarily building the massive amount of infrastructure to do that on a global scale.
Q: How well do you even think genetic risk has been characterized in type 1 – do you think there are important variants that haven’t yet been uncovered?
Dr. Agiostratidou: For GPPAD, it’s going beyond HLA to include another 40 SNPs, so it’s far more specific. And we know the problem is that we’re going to screen 300,000 kids in order to get 1,000 to do a clinical trial. Even with the specific genetic risk, it’s only a 10% risk of developing type 1 diabetes; it’s a higher incidence than the HLA genetic screen, but it’s still extremely low. To be honest, if we had all the money in the world, we would really try to identify a better tool for telling who is going to develop type 1 diabetes. Then the trial wouldn’t be $54 million, it would be much lower. As we think about type 1 diabetes, genetics plays a role but there are so many other environmental reasons to develop type 1 diabetes. I’m not sure how much we can improve the genetic risk. We’re doing the best we can do, but type 1 diabetes develops for far more reasons than genetics.
Q: How is screening going to be logistically carried out? I know that for Trialnet’s type 1 prevention trials, they’re now doing at-home screening.
Dr. Koralova: It’s complicated because it depends on the country that you’re in. For example, in the US, newborn screening is done in the hospital while you’re still there. In different countries like in the UK, they actually do the newborn screening for metabolic diseases after the child’s release from the hospital – there’s a midwife who goes to their home. The screening for GPPAD is going to be done in compliance with however newborn screening is done in that country. In Germany, I think they do it at the same time as their normal newborn screening, but it’s in the hospital. In Sweden they’re going to do cord blood at the time of birth. And then in Poland they have a national newborn screening where they get a drop of blood from all the babies and it’s processed centrally.
Q: It sounds like there already is a lot of infrastructure set up for infant screening. Is type 1 diabetes just not typically included in that?
Dr. Koralova: Newborn screening right now is regulated differently per country. Even in the US, the diseases that you screen for are actually recommended on a state-by-state level. But they tend to be diseases that you basically have a 100% chance of getting based on genetic risk. As Gina mentioned, even though we have a very high, relatively speaking, test for genetic risk, it’s still 10% genetic risk – so we’re not talking about something that you’ll definitely get. Whereas, for example, cystic fibrosis is monogenic, and there are a host of enzyme deficiency diseases where the problem is absolute. They can’t necessarily treat all of them, but they know that for sure you have the disease.
Q: Could you elaborate on your comment that we haven’t successfully reversed many chronic diseases but we’ve prevented them through vaccines? How is the GPPAD program like or not like a vaccine? And are there any other models like this in immune conditions that we can learn from?
Dr. Agiostratidou: The only diseases we’ve prevented are those caused by viruses. The reality is that we have diseases like HIV that we’ve turned into chronic diseases but haven’t reversed any disease. So, we hope oral insulin will be successful and able to prevent type 1 diabetes. The hope is that one day we’ll find a compound, a drug, or whatever you want it to be, that can really be like a vaccine and every child can take it and be vaccinated.
Dr. Koralova: If you think about the vaccines we give kids now, in terms of preventing various diseases, the whole point of it is to educate your immune system. In the case of viral or bacterial vaccines that you get in childhood, it’s to tell your immune system how to fight off bad infections. Oral insulin would act, if it’s successful, as the opposite type of vaccine. So, it’s also meant to educate your immune system, but to educate your immune system on what not to do. You proactively tell your immune system how to act, which is the same thing as proactively telling it how to react when you get an infection of some sort.
Q: So the underlying idea is that autoimmunity arises when the immune system turns to attack endogenous insulin and its source. We’re wondering what work Helmsley has funded to look at disease etiology and what you think of data suggesting an environmental cause, for example on the Ivory Coast? And then what are your thoughts on how heterogeneity in type 1 presentation plays into primary prevention?
Dr. Koralova: GPPAD actually also has the possibility of providing observational data. We don’t expect everybody who screens as high risk for developing autoimmunity to be in the interventional trial, but we can do some sort of observational trial. I think the key part here is that there’s still a lot to learn about how type 1 develops, and as you mentioned there’s a lot of heterogeneity and we need to do a lot of work with a lot of people to tease that apart. But in addition to that, we support a natural history study in Australia called ENDIA, which actually looks at environmental factors starting before birth and how it affects islet autoantibodies. There’s a lot of work in many diseases suggesting that your prenatal environment also affects your health during your life.
Dr. Agiostratidou: And if we think about the Ivory Coast, I think it’s not first time that we hear about a country entering the industrialized era sees not only an increase in type 1 diabetes but also in other autoimmune diseases. In industrialization, we all agree that different foods and different lifestyles emerge, and something encourages autoimmune diseases. The problem has really been that we cannot single out one factor.
Q: Do you think it would be possible to design a trial to enroll the highest risk patients? Are there any helpful biomarkers that could possibly contribute to a shorter trial design and maybe a greater chance of seeing success?
Dr. Koralova: I do think the lack of biomarkers is one of the big gaps – biomarkers beyond genetic risk and autoantibodies. Ideally, you’d want to have something between the genetic risk and the autoantibodies before you actually develop the autoantibodies. But that’s an area of pretty active research that still requires a lot to be put into it – so that’s maybe something for the future. In terms of shortening trials, using islet autoantibodies as an endpoint is already shortening it quite a bit. It’s still long, but it has already allowed for, instead of a 10-15 year trial, to a 6-7 year trial.
Q: Could you tell us a little bit more about Helmsley’s philosophy on funding? What factors do you consider when choosing what to fund, and is your approach more to fund as many different things as possible or to concentrate the investment in one area that you view as really, really promising?
Dr. Agiostratidou: Within Helmsley’s type 1 diabetes program, we actually have four main priorities. We believe that to be focused is really important because all these problems are so big and so difficult that I don’t think we can shoulder them alone – we need to work with other partners like JDRF and NIDDK. But all our priorities and all the grants that we decide to do are based on the following criteria: (i) to be impactful for people who have type 1 diabetes, (ii) to have a clear pathway to become available to people, (iii) to be feasible, and (iv) to have a funding gap. We have an opportunity and an obligation to support projects that others won’t support – not because they’re not good projects but because they’re too risky or too long-term. We want our projects to be able to change the systems. For example, when we think about prevention and about GPPAD, we would like to create the data so genetic screening becomes universal – a global screening for every child for type 1 diabetes. How do we create the data – the financial data and the benefit data – that we need so that it can become something used by everyone? I think it’s very important to collaborate with all the different partners – it’s extremely important. GPPAD is actually based on collaboration and is based on sharing; it includes data sharing and biosample sharing and is actually the first project where Helmsley has introduced data sharing terms into our grant agreement. We believe we want to extend this in all our programs. It’s really great that the grantees in all the GPPAD institutions have accepted and they’re very engaged in sharing.
-- by Ann Carracher, Payal Marathe, and Kelly Close