AG019 is a pill containing an engineered micro-organism (Lactococcus lactis, often shortened to "L. lactis") which generates Proinsulin and Interleukin-10 (IL-10). People in the study will take 2-6 pills once a day. So there is a lot to consider:
First, there is Lactococcus lactis. This is the microorganism that turns milk to cheese. It is also involved in making beer, buttermilk, pickled veggies, kefir, etc. The L. lactis used here has been modified to generate proinsulin and IL-10. The idea is that as the L. lactis passes through the intestine it will dose the patient with proinsulin and IL-10. The effect should be similar to injecting small amounts of Proinsulin and IL-10 many times per day, but much less hassle and no needles. The L. lactis does not colonize the person's digestive system; it just passes through.
Second, what will the Proinsulin do? Proinsulin is a molecule closely related to insulin. It is naturally created by the body as part of the process of creating insulin. To make insulin, first beta cells make Proinsulin, and then at the last step, they break up the Proinsulin in order to create insulin. The goal behind giving Proinsulin is that it will help the immune system learn not to attack insulin, which is one of the things that lead to T1D.
Third, what will the IL-10 do? In mice, IL-10 can prevent or delay the onset of type-1, although this is dependent on when and where the IL-10 is given. The mechanism involves stimulating more regulatory T cells, and fewer "killer" T cells. An on-going issue with directly dosing IL-10 is that it does not last for very long in the body, so it would require many small injections around the clock. That is why these researchers (and others) are using a microorganism to continually secrete it.
Proinsulin and IL-10 generated by L. lactis has cured mice, which you can read about here:
Everyone involved in this trial will be honeymooners (within 150 days of diagnosis). The trial is complex and will have two separate parts.
The first part is open label (so everyone will get the treatment, and the researchers will know who got which doses). This part will be AG019 only (no Teplizumab). There will be 4 groups of six people each. The first two groups will be adults. The first will be tested at a low dose and the second group at a high dose. The next two groups will be teenagers, and again, the first will get a low dose, the second a high dose.
The second part has two groups, adults and teenagers. Each group will be 12 people, but the first 2 people will be "open label" (meaning the researchers will know they got the treatment). The next 10 people will be blinded and randomly assigned to get the treatment or get a placebo at a ratio of 4:1. This means that for the blinded/randomized group, 10 people will get the treatment and 2 will not.
This study is mostly measuring safety and pharmacodynamics of the treatment. C-peptides are being measured as a secondary endpoint (although not listed in the clinical trial record). Pharmacodynamics refers to how much of the treatment is actually getting into the patient. Since this trial is testing a two step process (give the person a microorganism, and then the microorganism makes the treatment, there is a real question of how much treatment the patient will end up with, and how consistent it will be. So measuring pharmacodynamics is important. C-peptide measures how much insulin a person is producing, so increases in C-peptide shows progress towards a cure.
This study started in Oct-2018 (sorry I'm so late in reporting it) and is expected to finish in June-2020. However, since they are still recruiting new participants, and will gather data for a year for each participant, I don't see how they can finish in less than a year from now (Oct-2020).
This clinical trial is funded by ActoBio Therapeutics which is a subsidiary of Intrexon. The animal research that led to this trial was funded by JDRF and a large collection of European charity and research funds.
Press Release: https://investors.dna.com/2018-10-29-ActoBio-Therapeutics-TM-Doses-First-Patient-in-Phase-Ib-IIa-Clinical-Study-of-AG019-for-the-Treatment-of-Type-1-Diabetes
US Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT03751007
EU Clinical Trial Registry: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-002871-24/BE
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All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.