Memorandum

TrialNet provides update on type 1 diabetes prevention studies – November 23, 2015

Executive Highlights

  • TrialNet’s updated messaging on type 1 diabetes progression uses JDRF and ADA’s new staging system for type 1 diabetes.
  • TrialNet Chair Dr. Carla Greenbaum provided an overview of TrialNet’s ongoing trials, future plans, and exciting new initiatives to increase participant accessibility.

TrialNet provided an update on its current type 1 diabetes prevention trials and a peek at its future goals in a webinar last week led by TrialNet Chair Dr. Carla Greenbaum. Dr. Greenbaum particularly emphasized TrialNet’s updated messaging surrounding the progression of type 1 diabetes. The messaging adopts JDRF and ADA’s new staging system for type 1 diabetes, which begins long before clinical diagnosis and is divided into three stages: (i) multiple islet autoantibodies with normoglycemia and no symptoms; (ii) multiple islet autoantibodies with dysglycemia (glucose intolerance) and no symptoms; and (iii) symptomatic type 1 diabetes. Within that framework, TrialNet hopes to identify ways to prevent type 1 diabetes and stop the disease progression by preserving insulin secretion. Their Pathway to Prevention program screens for antibodies in first- and second-degree relatives of patients with type 1 diabetes and either monitors them or enrolls them in clinical trials. Dr. Greenbaum highlighted that only 3% of those screened through Pathway to Prevention presented with DKA at the time of diagnosis, compared to 30% of the overall newly-diagnosed population with type 1 diabetes. Dr. Greenbaum also provided an overview of TrialNet’s ongoing trials, its future plans, and exciting new initiatives to increase participant accessibility. See below for more highlights from this enlightening webinar, followed by Q&A.

  • Enrollment in TrialNet’s oral insulin trial is nearly complete, with results expected in 2017. The oral insulin trial aims to enroll those who are at “stage 1” of type 1 diabetes, where at least two antibodies are present but blood glucose is normal. The original DPT-1 trial found that oral insulin was ineffective in preventing type 1 diabetes in the overall population but delayed diabetes progression by four years in individuals with a specific mlAA antibody. In this trial, TrialNet plans to investigate the use of oral insulin in maintaining beta cells and delaying the conversion to dysglycemia. Enrollment for the trial is expected to complete in December 2015.
    • A new dosing study with oral insulin will begin enrollment next month. The study will test responses to both different dose sizes (higher and lower than the 7.5 mg dose currently under investigation) and different dose schedules (once-daily to once-weekly). Insights into the best dosing schedule for oral insulin in this population should be useful as pharmaceutical companies including Novo Nordisk, Biocon, and Oramed enter the oral insulin arena in the mid-term future.
  • Abatacept, an on-the-market rheumatoid arthritis drug, is also being investigated for individuals with stage 1 type 1 diabetes. Previous studies have shown that abatacept is effective in delaying beta cell destruction in newly-diagnosed type 1 diabetes, delaying C-peptide decline by 9.5 months. The trial is currently enrolling.
  • TrialNet is investigating the anti-CD3 therapy teplizumab for individuals with stage 2 type 1 diabetes. These individuals have abnormal blood glucose but do not meet the threshold for a clinical diagnosis of type 1 diabetes. The trial is currently enrolling. Teplizumab was developed by Macrogenics and Lilly and failed to meet its primary endpoint in phase 3 trials in 2010. GSK and Tolerex’s phase 3 study for their anti-CD3 therapy otelixizumab also had disappointing results. That said, the class seems to be experiencing a revival of sorts based on analyses suggesting that there are sub-groups of responders who could benefit from anti-CD3 therapy. At EASD 2015, Dr. Bart Keymeulen (University Hospital Brussels, Belgium) suggested that individuals who had not yet progressed to a clinical diagnosis of type 1 diabetes could particularly benefit from anti-CD3 therapy due to their higher baseline beta cell mass. GSK has revived its clinical development program for otelixizumab with a phase 1/2a trial expected to complete in January 2021. During Q&A, Dr. Greenbaum shared her enthusiasm for the class and expressed optimism that it will show a benefit for the right patients.
  • ATG/GCSF is under investigation for its potential to preserve beta cell function in those with newly-diagnosed type 1 diabetes. Dr. Greenbaum emphasized that previous studies have shown that, even after clinical diagnosis, patients who still have some beta cell function and a degree of endogenous insulin production do better than other patients. A pilot study showed that ATG/GCSF had a benefit on preserving beta cell function, which sparked this randomized trial. The trial is currently enrolling and randomizing patients diagnosed within the past 100 days. Dr. Greenbaum also highlighted the fact that this is a combination therapy, which she (and many others) believe is the future of new therapies for type 1 diabetes.
  • Dr. Greenbaum noted that many ancillary studies use data and samples collected by TrialNet. She emphasized that TrialNet’s trials are designed to be built on and that investigators around the world are using the tens of thousands of blood samples TrialNet has collected. Dr. Greenbaum believes that in the near future, type 1 diabetes prevention trials will have very specific enrollment criteria involving new biomarkers to better identify which people respond best to which treatments. Dr. Greenbaum also suggested that future trials will have a greater focus on enrolling children, as disease progression in children is much more rapid than in adults and children tend to benefit more from beta cell preservation. Several organizations including TrialNet hosted an informative consensus conference in January on the differences between pediatric and adult type 1 diabetes and the need for a new paradigm for research in children.
  • TrialNet aims to make patient engagement with the program more convenient and accessible. To that end, it has created a new website with the updated messaging to help families understand the progression of type 1 diabetes. Trial participants will also be able to provide consent online. As we learned previously, TrialNet is also piloting a mail-in, at-home fingerstick kit for the initial antibody screen. Dr. Greenbaum noted that TrialNet will be piloting the program through 2016 and that “the preliminary results look terrific.” She highlighted that the program provides convenience for participants but also allows TrialNet to screen individuals who live too far to access one of its clinical sites.

Questions and Answers

Q: A reaction we hear a lot on Glu is that people say ‘I don’t want to get involved because I don’t want to know and I don’t want life affected by this black cloud hanging over me’. Do you have a specific response that we in the online community can use for that type of concern?

A: Obviously it’s a concern we hear often. We tend to think that knowledge is power. People feel empowered instead of just being a victim of the disease. People who participate in studies feel like they’re doing something to change the future. It really gets them in a whole different space. It doesn’t mean I’m dismissing the emotional component of having to wrestle with the idea of knowing someone else is going to get the disease in your family, but pretending it’s not going to happen doesn’t mean it’s not going to happen. Many people say ‘I already have a child with diabetes, so I’m clearly going to know if my other child is going to get diabetes.’ We know that’s not true. Many people feel like they will recognize the symptoms and they will check people’s blood glucose periodically, and it’s just not a very effective way of finding out who’s at risk. We know that if one child has diabetes, the other child is worrying about it all the time. You now have the opportunity to have the conversation and explain what is going on. We certainly don’t expect that everyone who hears about TrialNet is going to do this. If people don’t want to participate that’s their decision. The other answer is that people want diabetes to be cured, we all do, and we have to have people participate. We already know that we can affect the progression of disease. If we can prevent it that’s a huge impactful activity for people to participate in.

Q: Can you talk a little bit about why there’s this large division between people with one autoantibody and people with two autoantibodies?
A: That is evolving data. Obviously since people go from one to two antibodies there is a certain percentage of people with one that will develop two antibodies. We don’t have enough information today to say which people with one antibody will develop two, and which will not. It’s very rare for people with two or more antibodies to not progress to the disease. We do have evidence showing that the younger you are, the more likely you are to progress to having two antibodies if you already have one antibody. For reasons we don’t yet understand, people who are older and have one antibody don’t have quite the same risk of progression. Now we have accumulated several decades of information to support that. I would anticipate in the next several years, TrialNet will also have studies where we will take that proportion of people who are most at risk to progress from one to two antibodies and do therapies to see if we can stop the disease at that point as well.

Q: How many antibodies is TrialNet testing for?

A: There are five different antibodies. When the initial blood sample comes in, we test for several of the antibodies, and if any of the initial ones are positive we then test for all five. TrialNet and the samples from TrialNet are used as a platform for new developments. For example, there’s been some publications suggesting there’s a modification of one of the methods to measure antibodies, and TrialNet is currently testing that and seeing how valid it is. We are constantly evolving to be more precise in our measures.

Q: Can you explain the yogurt as prevention clinical trial?

A: The TEDDY study is studying babies who are at risk of developing diabetes from birth. They measure everything they can on genetically at-risk babies and following them until they get antibodies and potentially diabetes. A paper just came out a month or so ago suggesting that babies who receive probiotics during the first month of life seem to have fewer antibodies. Unlike a clinical trial, those kinds of studies don’t prove anything, but it is certainly of great interest. TEDDY is studying this now.

Q: Can you give us any updates on the anti-CD3 trials? What is your level of optimism with the anti-CD3 trial given the disappointments in the past?

A: TrialNet’s anti-CD3 trial is still ongoing, and we won’t have results for a while longer. There’s currently a study ongoing in Europe to evaluate a different type of dosing of anti-CD3. What’s my level of optimism? This gets to an interesting subtlety about designing clinical trials. As many of you know, the anti-CD3 therapies have been tested in many different studies. Most of them have shown quite a dramatic impact of the therapy on preserving beta cell function, but the large phase 3 study was unable to demonstrate that convincingly. There were a lot of concerns that they enrolled a wide variety of different types of people in different places of the world that may have different types of type 1 diabetes management. It’s hard to interpret that in the face of all these other studies that had a dramatic effect. We’ve been conducting anti-CD3 studies here for quite a bit, and participants do quite well. Pharmaceutical companies haven’t given up on the drug either, so we’re quite optimistic that this drug – whether alone or in combination with others – will have a big impact on the disease.

Q: What are the biggest challenges in getting people enrolled in trials and conducting the trials?

A: The biggest challenge is getting people to enroll. Despite our best efforts, most people who have type 1 diabetes have no idea that their family members are at risk of getting the disease, or that there’s an opportunity to participate in trials. Most healthcare providers don’t even know it. We have a huge problem with communication and explaining this disease progression so I look to you guys to explain why to participate and what the advantages are for people. That is by far the biggest problem we have. There’s too much misinformation, and people don’t hear our message.

Q: What are you doing to make it easier for people to participate in these trials? Can you give us an update on how the mail-in fingerstick blood sample collection pilot is going?

A: We have a mail-in fingerstick pilot, and the preliminary results look terrific. We will continue to roll it out in 2016.

Q: What do you see as the “future” of clinical trials?

A: You are going to see a lot more combination therapies, and a lot more targeted therapies.

Q: What sort of collaboration is going on between TrialNet and other organizations work in the type 1 cure research space (such as Helmsley Charitable Trust’s type 1 prevention initiative, the NIH RFA for the type 1 diabetes genetic research, and J&J’s Disease Interception Accelerator program)?

A: As you all know, it’s a pretty incestuous world of type 1 diabetes research. It’s often many of the same people sitting in the same spaces have similar conversations. With Helmsley Charitable Trust, they’re coming out to our office in Seattle to spend time with our team to understand this in more depth. The coordinating center for TrialNet is the same for TEDDY, and I think we’re very closely tied into their initiatives. With the NIH RFA, RFA is just asking people to apply to do research in diabetes. It’s not just genetic research – they also have proposals for ancillary studies. A huge number of NIH-funded investigators are using TrialNet samples to study the disease, so we are very closely related there.

Mr. Levy: When you talk about targeting patients, you talked about number of autoantibodies and you talked about adults vs. children. Do you see other forms of targeting in addition to those?

A: Yes. We are only doing it a little bit now. We now have more sophisticated measures. For example, one of the ancillary studies was looking at signatures in the blood that suggest a period of inflammation in the blood as they are progressing through to diabetes. We hope to look into targeting that group of people in the future. We would probably start by doing mechanistic trials using targeted therapies. Doing it that way will teach us something to build on for the larger trial. All of these prevention trials take a lot of people and lot of years. We are trying to accelerate our ability to do a lot of people and a lot of trials. Particularly that’s going to be the case for combination therapies.

 

-- by Helen Gao, Ava Runge, Emily Regier, and Kelly Close