Episode 11: Could a Drug Cure Celiac Disease? 

Vanessa:

Welcome to Raising Celiac, a podcast dedicated to raising the standard of education, awareness, and research on celiac disease and related autoimmune conditions. I’m Vanessa Weisbrod, the education director of the Celiac program at Boston Children’s Hospital. At each month on the podcast, we will invite leading experts to dive into a condition related to celiac and look at how it impacts a patient family, the latest research, and offer suggestions for health providers to manage these complex cases. Every episode of the Raising Celiac podcast is accredited by the Boston Children’s Hospital Continuing Education Department for 0.5 AMA PRA Category 1 credits for physicians. 0.5 contact hours for nurses, 0.5 CE continuing education credits for social workers, and 0.5 CEUs for registered dieticians. To claim your credits for listening to today’s episode, please visit dme.childrenshospital.org/raisingceliac. Let’s get started with this month’s raising celiac patient story.

Janis:

Amelia was born into a family where celiac disease was a common occurrence. Her mom was diagnosed with celiac disease while in college, and her grandmother was diagnosed in her mid ’40s after a battle with fertility issues. She had four first cousins all diagnosed with celiac after experiencing very different symptoms. One cousin suffered from extreme fatigue, and another had debilitating rheumatoid arthritis. Another cousin had a severe case of alopecia and her little brother had eczema all over his body. Over the course of 12 years, they all got an accurate diagnosis that changed their lives, so it wasn’t much of a surprise when just after her 17th birthday, Amelia started getting stomach aches and diarrhea after almost every meal. She’d noticed the stomach aches for several months. They’d started while she had COVID, but they had gotten progressively worse.

Vanessa:

Celiac disease is an autoimmune disease for which the genetic susceptibility is known, meaning that it is passed through families. Even though it’s passed down from parent to child, the symptoms could be entirely different from individual to individual. One person may experience diarrhea and abdominal pain while another may have skin rashes, headaches, or depression. Some people show signs of celiac disease early in life while others remain symptom free well into adulthood. In certain cases, some people with celiac disease experienced no notable symptoms at all.

Janis:

Amelia’s more severe stomach aches went on for about two weeks before her mom took her to the doctor and asked them to run a celiac blood test. Four days later, they got the positive tissue transglutaminase antibody test and four weeks later they were in to see a gastroenterologist for the small bowel biopsy. Amelia really didn’t want to have the biopsy given her strong family history of celiac disease and positive blood results with such a high likelihood that she had celiac disease. She just wanted to start on a gluten-free diet like so many others in her family.

Amelia’s mom insisted on the biopsy. She wanted confirmation that this was in fact celiac disease and not anything else. When she was diagnosed herself, they had found she also had H. pylori at the time of her biopsy. So, she felt it was important that Amelia verify that celiac was the only thing causing her stomach troubles. In addition to her mom’s persistence that she had the biopsy, Amelia’s gastroenterologist had another reason. He mentioned that many drugs for celiac disease were entering clinical trials and that most trials required confirmation of diagnosis via a small bowel biopsy. A quick and easy procedure today would allow her to be part of research in the future.

Vanessa:

An endoscopy is an outpatient procedure that allows your gastroenterologist to see what is going on inside a patient’s small intestine. A small scope is inserted through the mouth and down the esophagus, stomach, and small intestine, giving the physician a clear view to take samples of the tissue. Samples of the lining of the small intestine are studied under a microscope to look for damage and inflammation caused by celiac disease. It is recommended that at least four to six duodenal samples are taken from the second part of the duodenum and the duodenal bulb in order to obtain an accurate celiac diagnosis.

Janis:

Amelia begrudgingly agreed to the endoscopy procedure not because of her mom’s nagging, but because she was intrigued about being able to participate in research. If a drug was developed for celiac disease, maybe there was hope that one day she could eat some semblance of a normal gluten-containing diet. Three days after the procedure, Amelia had a positive biopsy result and immediately started on a gluten-free diet. About six weeks after starting on a gluten-free diet, Amelia noticed a substantial improvement in how she felt after meals, but it wasn’t perfect. She saw her gastroenterologist for a two-month follow-up visit, and the physician reassured her that healing from celiac disease can take time and not to fret that she wasn’t feeling completely recovered.

Vanessa:

The time to feel better after starting a gluten-free diet varies for each person with celiac, some people feel completely better after a few days on the gluten-free diet, and for others it takes a bit longer. A small number of people with celiac disease don’t see improvement on a gluten-free diet. This could be because they are not adhering to the gluten-free diet. There is another condition that is affecting the intestine, or in extremely rare cases, the disease isn’t responding to diet alone and medications such as steroids or immunosuppressants are needed.

Janis:

Amelia persisted with a strict gluten-free diet, but still one and a half years after her biopsy, she still wasn’t feeling back to her normal self. She was now in college. Sure, she did normal college kid things like go to parties, stay up too late and occasionally drink alcohol, but she never ever ate gluten. During her winter break from school, Amelia returned to her gastroenterologist in hopes of finding a solution to her ongoing bloating, cramping, and loose stools. It wasn’t horrible and she could function in school, but she didn’t like the way she felt and hoped for improvement in her symptoms. Her gastroenterologist recommended meeting with their dietician to take a close look at her diet and see if she may be intolerant to other foods. Amelia met with the dietician and decided to try eliminating lactose from her diet.

Vanessa:

Some patients with celiac disease may have trouble digesting lactose because their small intestine is damaged. However, unlike gluten exposure in people with celiac disease, lactose is not causing damage to the small intestine. Some patients need to avoid lactose altogether while their gut is healing. While others do well on a low lactose diet, it’s important to talk with a doctor and dietician before experimenting with additional food eliminations.

Janis:

Just as she was vigilant about eliminating gluten from her diet, Amelia was strict about not eating dairy. She wanted to feel good. She met with her university food services manager and worked out a system to have gluten and dairy free meals in the dining hall. They weren’t the most exciting meals, but they served the purpose. Three months later, Amelia was feeling better. She was significantly less bloated and often had normal bowel movements. She didn’t feel perfect, but she felt good enough. She met with her gastroenterologist virtually and they agreed that sticking to the gluten and dairy-free diet was the right way to proceed. For now, they would reevaluate. In six months’ time, Amelia hung up from the video visit with her doctor, unsure if she was happy or sad. Inside, she knew she didn’t feel normal yet and longed to feel completely healthy. In the back of her mind, she thought about what her doctor said more than two years ago about drugs and clinical trials. Perhaps one of those drugs would be the answer to her issues.

Vanessa:

There are a number of drugs in clinical trial for celiac disease. Some of them are designed to help patients with ongoing symptoms of celiac disease. Others will protect against small amounts of gluten cross contact. But how far away are these drugs from being approved by the FDA? Will they be available to all patients with celiac disease? Will you need biopsy confirmed celiac to take the drugs? How can patients like Amelia join these clinical trials to help researchers learn about how well their drugs might work? We’ll discuss this and more on today’s episode of Raising Celiac.

Today we talk about drug development for celiac disease with Dr. Jocelyn Silvester from Boston Children’s Hospital. Dr. Silvester completed her PhD in biology at the University of Cambridge, England. Prior to studying medicine at Dalhousie University in Halifax, Nova Scotia. She completed her residency at the University of Manitoba in Winnipeg, Canada and her fellowship in gastroenterology, hepatology, and nutrition at Boston Children’s Hospital. Dr. Silvester is the director, director of research for the Celiac Disease Program at Boston Children’s and truly leading the way to finding a way to treat celiac disease beyond the gluten-free diet. Welcome Dr. Silvester to raising celiac.

Dr. Jocelyn Silvester:

Thank you, Vanessa. It’s great to have the opportunity to join you.

Vanessa:

So, I really don’t want to bury the lead too much. We know that there are drugs in development. How many are there and how soon might they be used in the celiac community?

Dr. Jocelyn Silvester:

That’s a great question and one that comes up a lot. We have about a dozen right now, and that number changes around the edges as new compounds enter the pipeline and compounds exit. And that’s one of the really important things about drug development is that most drugs don’t actually make it through the development process to be something that’s actually available to patients. So, how long it takes? Usually, the drugs have to go through three phases. Phase one is first-in-human to make sure they’re safe. Phase two is to get some idea about how it’s going to work, and then phase three is a larger trial that would be to try and get an indication to get the FDA to approve it. So, this whole process could take five to 10 years or longer. And we do have some drugs that are now in phase two, which is exciting because you have to pass phase one to get to phase two and ultimately through phase two to phase three before you get the drug.

Vanessa:

Can you tell our listeners about some of the drug candidates and how they might work? For example, would they allow you to eat a gluten containing croissant?

Dr. Jocelyn Silvester:

So that’s the hope. I think that a lot of my patients tell me they want to eat a normal diet and that includes gluten. And so, the way the medications are currently being conceptualized, there’s definitely some that are thought of as not a way to mitigate the effects of gluten entirely, but potentially help if there’s cross contact at a restaurant or the small amounts of gluten that we know everybody has in their diet from time to time, but not intentional gluten exposure. And then there’s other medications that actually work more to change how the immune system recognizes to and reacts to gluten. And the hope, which really, we have to do the studies to figure out if this is true or not, is that these would be something that would potentially be an alternative to gluten-free diet.

Vanessa:

Wow. So, there is hope for that gluten containing croissant down the line.

Dr. Jocelyn Silvester:

There is, and then I think there’s also folks who, it’s not really a drug, but there’s active efforts to try and modify wheat so that it has the gluten parts of gluten that make gluten do all the things that make things behave like bread products without having the gluten bits that affect people with celiac disease. And that’s a really interesting thing because that’s a food that’s been modified for medical purpose, but it’s not actually a drug. And so, it’s not really clear how we would get to figuring out if that’s something that is safe for patients.

Vanessa:

So interesting. So, are the drugs that you’re thinking about, would you take these in a pill form or would they be an infusion?

Dr. Jocelyn Silvester:

That’s a good question and I think one of the things that definitely changes as drugs evolve, but currently there’s both infusion-based medications and pill-based medications and there was a subcutaneous injection, the Nexvax2, but that one didn’t pass phase two.

Vanessa:

How often would you need to take these? Is this something you would take every day, like a lactate pill or something that you would get once, and it would work forever?

Dr. Jocelyn Silvester:

I think it really depends on the compound and the purpose. So, some of the medications really are sort of lactate for gluten. So, lactate is an enzyme. Lactate contains the enzyme lactase, which breaks down lactose. And so, people who have lactose intolerance they don’t have lactase themselves in order to break it down. So, by replacing the enzyme, they then can tolerate the lactose again. And so, the idea behind the glutenase enzymes is that if you could break gluten down, then people wouldn’t recognize it because one of the things that’s special about gluten is that it has a lot of prolene in it, and those are something that our enzymes that we have in our digestive tract aren’t very good at breaking down. So, if people eat gluten, that’s why we can find gluten intact in their poop. Whereas most foods that we eat, we’re able to break them down into the amino acids, which are like the building blocks of the protein, and then you don’t find them in the poop.

So, even though it’s not that people with celiac disease have an enzyme deficiency like people with lactase deficiency, if you could give them a glutenase to chop up all the glutens, then potentially that would be helpful. And so, of course, if you’re trying to chop up the gluten, then you would have to have this whenever you eat gluten and this needs to be in the stomach, and so these are things that are pills.

Vanessa:

And how about the infusions? Is it a one in a done or is it repeated over time?

Dr. Jocelyn Silvester:

There’s really not the data to know, and I think that’s one of the questions is what are the long-term effects? What’s really exciting about some of the medications that are being tested is that they’re really a first in class medication. And so, when we think about other autoimmune diseases that we don’t understand as well as celiac disease. Really, we don’t have a target like gluten, and so we’re just trying to suppress the immune system and stop it from being active. Now of course, this has lots of bad side effects because your immune system does lots of really important things like fight infections and watch out for cancer. And so, these drugs that we’re doing for celiac disease are actually exquisitely focused on actually the immune response specifically to gluten. And so, it’s a different way of manipulating the immune system. And celiac disease is really being used as sort of the test case, keeping in mind that this is something that would also be applicable to potentially type I diabetes where we know some of the antigens or multiple sclerosis where we know some of antigens.

So, if we know the protein antigen that’s involved, then we can potentially use these technologies. And celiac disease is the first. So, we don’t know whether infusions need to be ongoing or not. And I suspect in the process of doing this, we’re going to learn a little bit about what celiac disease is and what turns celiac disease on and what turns it off.

Vanessa:

Absolutely. So, you mentioned the Nexvax2 trial, and I know that at the time we were talking about it as a vaccine. Would any of the candidates that are now being looked at prevent development of celiac disease or would you already have to have celiac to take these?

Dr. Jocelyn Silvester:

So that’s a great question and let’s take a step back first and talk about Nexvax2, which was called a vaccine. It was a peptide mixture that was subcutaneously injected. And the idea here was again, if you can manipulate how you present gluten to the immune system, then you can change how the immune system responds to the gluten. And so, although it was called a vaccine, it wasn’t a vaccine in the sense we traditionally think about where you’re thinking about something where you want to activate the immune system towards it. And so, the Nexvax2 was a subcutaneous injection, but it wasn’t like a COVID vaccine or a flu vaccine. The injections that we’re doing now aren’t necessarily considered to be quote vaccines because again, for vaccines you’re trying to generate immune response to what you’re vaccinating against, whereas here we’re trying to reduce the immune response to what we’re doing.

Vanessa:

That’s a really interesting way of thinking about it. So now that you have everyone excited about the different types of drugs that are being tested, let’s dive into what needs to happen for these drugs to actually come to market. How does a drug go from an idea that a scientist has to clinical trial and then eventually to our pharmacy shelves?

Dr. Jocelyn Silvester:

So, I think that’s partly some of the process that we started to talk about a little bit earlier. And one of the things that often gets missed out on this, it’s super important is the so-called preclinical phase. So, there’s a lot of work that happens before somebody could even go to the FDA or Health Canada or the European Medicines Agency and ask for permission to test a drug in humans. And so, this is where the idea happens. And then usually for most diseases we have animal models or tissue culture-based models. Celiac disease is interesting in that we don’t really have as developed animal models as we do perhaps in other diseases. And so, we have celiac diseases interesting in that we don’t have as developed animal models as we do in other diseases, but we’re able to get data with animals to support the idea that it’s worth trying in humans.

And so, then the first process in the United States, it’s similar in other countries, but for this conversation we’ll really focus on the United States because it’s Boston Children’s Hospital, so is to apply for a so-called IND or an Investigational New Drug Application. And this involves taking all of the preclinical data and also outlining a plan of how to show that this drug is safe and effective and what it’s effective for.

And so, the first step is to look at that data and part of the preclinical studies is always toxicity studies in rats and look well below the dose that was toxic in rats and start giving that to humans and see what’s happens to people. This is a so-called phase one or first-in-human phase, and this is usually starting at a very low dose with three or five people and then reviewing the toxicity and if it appears safe, then going up to a next dose and sort of going up to what the target dose range is to see what that relationship between dose and toxicity is. And then that information from the phase one trial is used to inform the dosing for the phase two trial.

And then the phase two trial is more about looking at, all right, what’s this drug actually doing to people? Is it actually affecting the response to gluten? Is it making any difference in their celiac disease? And then the phase three trial is saying, “Okay. We want to use this drug particularly for symptoms and people who are already on a gluten-free diet.” For instance, if it’s a gluten aids, that might be an indication. And then once that is sorted out, then the FDA can review it and approve it and then you have a drug. Now something that’s really interesting is that, as we were saying earlier, a lot of the drugs for celiac disease are really unique because they’re actually affecting the immune system. And while they’re so-called tolerogenic in that we’re trying to make the immune system tolerate gluten as opposed to get activated when it sees gluten, they’re very targeted to celiac disease.

And so, it’s less clear that safety needs to be tested in people who don’t have celiac disease. And so, for some of these medications, the first-in-human, the phase one studies are actually being done in people with celiac disease because they’re more likely to have adverse effects if you’re giving them gluten peptides than people who don’t have celiac disease. So, there’s many ways in which celiac disease is a little bit different and a little bit special. And that’s definitely one of the challenges because celiac disease has a treatment which is a gluten-free diet. And so, how do you manage people if you’re putting a treatment on top of a treatment or you take them off their gluten-free diet or you keep them on a gluten-free diet and then put gluten on top of that, that’s where it starts to get complicated.

Vanessa:

So, okay, in phase one you said this is the early stages where they’re looking at the safety in just a small number of people, right?

Dr. Jocelyn Silvester:

Right.

Vanessa:

In those trials, are people with celiac disease eating gluten or are they looking just at taking that particular drug to see how it works in a person?

Dr. Jocelyn Silvester:

So those are really just looking how it works in a person and they want as healthy as possible. So, they’re looking for healthy treated people with celiac disease if they’re tested in celiac patients.

Vanessa:

And then they don’t actually get into the eating gluten until phase two.

Dr. Jocelyn Silvester:

Correct. And not all trials involve eating gluten.

Vanessa:

Correct. So, we know that patients don’t love the idea of eating gluten for clinical trials. Can you tell our listeners why it’s important for people with celiac to eat gluten for research?

Dr. Jocelyn Silvester:

Yeah. I think this is something that we struggle with as a community because we spent a lot of time telling people, “You have celiac disease, you shouldn’t eat gluten, you shouldn’t touch gluten, you should avoid gluten.” And now we’re saying, “Well, wait a minute, maybe we have a treatment for celiac disease. Can you eat some gluten and see if you can help us figure out if this is going to work or not?” And I think that’s sort of the key thing here is that we’re very selective about who can participate in clinical trials. So, anybody who has an anaphylactic reaction to gluten or wheat is automatically excluded. And anybody who has severe reactions to gluten is excluded from many trials because fortunately one of the things that’s unique about celiac disease is that there’s many people who have no symptoms at all. And we can learn about the immune response even if people aren’t having overt symptoms, which is interesting.

And so, I think the reason we need to have people eat gluten is because the disease happens when people are eating gluten. And so, if we want to treat active disease, we have to study active disease. And the way to activate the disease is to give people gluten.

Vanessa:

If people eat gluten for these clinical trials, are they going to have lifetime damage occur to them? Or are they going to heal and be okay?

Dr. Jocelyn Silvester:

That’s a great question. And based on what we know, this is something that we are going to transiently see damage, but people will get better. We actually did this study here at Boston Children’s Hospital with our colleagues at Mass General where we did a gluten challenge study with adults, and we had two different doses of gluten. And in addition to doing the endoscopies like we do when we diagnose people. We also did video capsule endoscopies, which are when you swallow a pill that has a camera in it. And so, we were able to get a look at the villi that way and we could see that yes, if you give people gluten, their villi don’t look very good afterwards. But if we looked a month after we stopped giving them gluten, their villi for the most part looked much better and like they did at the beginning of the study.

And that’s very reassuring and genuinely corresponds with what we see clinically because we know that most people, although they try really hard to avoid gluten, gluten finds them, and they still look healed if we’re to do an endoscopy because intestine has a tremendous healing capacity. One of the things that we spend a lot of time thinking about in designing trials is, okay, first of all, do we need gluten at all to test the hypothesis we’re testing? Second of all, how much gluten do we actually need? And that’s not just how many times does the person actually eat gluten, but how much gluten do they eat each time? And so, we’re actually currently planning a trial at Children’s to look specifically at looking at the doses of gluten that we’re giving adults to look at immune responses. Can we give children lower doses and still see the responses because we really want to minimize the amount of gluten so that we can get the most available information with the least inconvenience to the participants.

Vanessa:

So, you know how much I love to bring social media dilemmas to you and help find the right answer. So, I’m hoping you can give some words of wisdom to other clinicians listening to this interview. So, there’s a recent debate on Facebook about is it really a terrible thing if I eat gluten once a month? Or if my friends are all out and I just don’t feel like being different. If they say it’s okay to eat gluten for science, is it okay if I do it once a month? How do you help people through that discussion and advising patients on what the best way is to proceed forward?

Dr. Jocelyn Silvester:

I think this is where it becomes difficult because as human beings, we really like black and white, which is why the idea that I have celiac disease, I can never touch gluten and I’m never having gluten is very appealing because the idea that actually I have celiac disease and I’m living in a world where I’m surrounded by gluten and I’m going to try my hardest to avoid gluten, but there’s going to be times when gluten is going to find me, particularly because eating really relies on a whole lot of other people and a lot other systems that are outside of your control. And so, I think how I conceptualize it with my patients is we want you to have the healthiest villi possible. And we know that giving you gluten is not good for your villi. So, any intentional gluten exposure that’s on purpose is something that we want to avoid.

Now, is there some threshold that’s safe for exposure? That study’s never really been done either in terms of is there a minute amount that people could eat every day or how long does it take the villi to recover and is once a month too much is once every six months too much? We don’t really know, but we do know that a lot of people are getting ongoing gluten exposure in amounts that are measurable, but that won’t necessarily cause symptoms. And so, symptoms aren’t a great guide to exposure, which is why it’s best to avoid exposure wherever possible.

And part of the reason why, if we’re doing a study and we’re asking people to eat gluten for the study, a big part of being able to do this study is there’s an ethical review for the study. And one of the questions in any ethical review is, does the risk to the participant outweigh the scientific benefit? Because if you’re giving lots of people large doses of gluten to show that gluten causes villous atrophy, well we already know that, and so we’re not actually getting useful information. If we’re giving people large doses of gluten to see if this drug prevents villous atrophy, that’s actually moving the field forward. And so, in order to get approved for a study, we have to demonstrate that actually by doing it, we’re going to add something to what we already know.

Vanessa:

So, let’s talk about placebos. Why are there placebos in drug trials and why can’t everyone get the active drug?

Dr. Jocelyn Silvester:

That’s a great question. And the reason we have placebo is because we know that symptoms fluctuate, conditions fluctuate. And especially when we’re looking at something like symptoms, which for the most part are somewhat subjective, we know that there’s a propensity for us to our mind can control our body and if we believe something is going to help, then that can potentially help even if it’s placebo. And we don’t really understand that process very well, but we know that it’s a thing. And so, particularly for conditions which are not infectious because the placebo response to infection is very low, because if you have the bacterial infection, the bacteria is there whether you think it’s there or not. But for things where you’re looking at things like nausea or vomiting or diarrhea, which are a little bit more subjective, we know that there’s a placebo response. And we also know that there’s a nocebo response, which is really interesting.

Actually. There was an interesting study recently where they took patients with non-celiac gluten sensitivity, and they gave them either gluten or placebo.

And half of the people who got gluten, they told them they got gluten. And half of the people who got gluten, they told them they got placebo. And half of the people who got placebo, they told them they got gluten. And half of the people who got placebo, they told them they got placebo. So, in each group you had people who were told that they got what they got and people who were told that they got something different than what they actually got. And yes, there was a very stringent ethical review for this because we’re very careful in conducting research studies to be honest with participants. And so, it was actually subsequently disclosed to the participants after the data had been collected that this was what they were actually trying to test. But they couldn’t tell people that in advance otherwise they couldn’t do the study.

And so, what we found was that the people who had the most symptoms were the people who got gluten who were told they got gluten. And the people who got gluten who were told they got placebo had less symptoms than the people who got placebo who were told they got gluten. And so, thinking that they got gluten, the so-called nocebo effect was very powerful. And that’s super important for clinical trials because the FDA wants us to use clinical endpoints and symptoms. And so, if whether or not people know they’re getting gluten effects, they’re reporting that’s super important. And so, the reason to use placebo is both to use placebo gluten and to use placebo medication. And so, just as you can have expectations, what will happen to you if you have gluten, you can have expectations what will happen to you if you have the drug.

And some people their symptoms may just get better for some reason independent of being in the trial. And so, it’s important to have that comparison so that if everybody gets better you know that it wasn’t actually the drug. And this is super important in celiac disease and what we learned from some of the early trials, because when they looked at the people who got the drug, their villi got taller, but when they looked at the people who got placebo, their villi got taller too. And what that tells us is that everybody tries really hard to follow a gluten-free diet. And when they go into a trial, they try really hard to follow a gluten-free diet and they probably do a little bit better, which means that their villi grow better, which is part of the reason why it’s so important to incorporate gluten into study designs because then we have some idea of how much gluten people are actually getting.

Vanessa:

So, can someone choose if they get the placebo or the drug?

Dr. Jocelyn Silvester:

So that’s a great question. And generally, no. And so, part of the principles of clinical trials is you have screening criteria because you want to get people who are similar and that they all have celiac disease, either they’re all healed or they’re all not healed. And so, that you are starting with people who are similar, but there’s still going to be some differences. And so, the people who choose to have placebo, there might be something that’s systematically different from them than the people who choose to have drug. And so, when you hear about clinical trials, they often talk about randomized double-blind placebo-controlled trials. And what randomization is that when it gets time to treat a patient and assign them to the treatment, you essentially slip a coin to decide if they get placebo or the drug. And the reason for this is that if you do it randomly, then all of the random things that are different should be equal between the two groups. And so, if you see a difference between the two groups, it’s more likely to be related to the intervention.

Now, exceptions to that are that there’s some trials where they’re designing that after a certain point, if it looks like the intervention is promising, then they will allow adolescents into the trial and those trials are not giving adolescents placebo.

Vanessa:

Got it. So, as you heard, our patient Amelia wasn’t thrilled with the idea of a biopsy. Why are biopsies for clinical trials important?

Dr. Jocelyn Silvester:

So, I think clinical trials for the most part want people to have a biopsy confirmed diagnosis of celiac disease just because that’s how we define the disease. And often part of the sort of screening process to enter a trial is to do a repeat biopsy because it’s important to know are the people who are starting the trial healed or not healed? Because not everybody who’s on a gluten-free diet is healed. And so, having had initially when one’s diagnosed a biopsy means we have something that we can go back to that we can reference and confirm, “Yes. This person actually did have celiac disease.’ And it’s actually interesting how often when you go back and look, you see that people may not have quite met criteria for celiac disease but have been treated and told they have celiac.

Vanessa:

What do you do with them then?

Dr. Jocelyn Silvester:

So those people usually are ineligible for the trial. And I think this is one of the things that is worthy of another discussion is this whole idea of how do we know what celiac disease is and how do we define celiac disease and what you do when not all the signs point the same way. So, if you have a biopsy that looks like you have celiac disease, you have symptoms of celiac disease and your serology looks like you have celiac disease, that’s really easy. But what if you only have two out of the three? That’s where it gets more complicated. And this is part of the reason why people may have had serologies and symptoms, but the biopsy may not quite have been severe enough, or potentially the reason the biopsy wasn’t severe enough is because they had decreased gluten already while they were waiting for their biopsy.

So there’s lots of different things that can happen, but generally if you can document that somebody had a biopsy consistent with celiac disease at the time of diagnosis, this is a way of confirming that the people in your trial are actually people who have celiac disease because we don’t really know the mechanism of non-celiac gluten sensitivity, but the immune-based drugs for celiac disease probably wouldn’t work for somebody with non-celiac gluten sensitivity. So, we need to make sure that the people in the trial are people we want in the trial.

Vanessa:

So, for people who were diagnosed with celiac disease during COVID, or for kids who were diagnosed using the ESPGHAN criteria. They’re obviously going to get older and be adults or eligible to participate in trials. What do you do if they just never had a biopsy as part of their diagnosis?

Dr. Jocelyn Silvester:

And that depends on the trial, and it depends on the design of the trial. And so, some trials, if you have a biopsy when you enter the trial that shows you have celiac disease, then that can be taken as a diagnostic biopsy. Some will look at serology only diagnoses, but for the most part, people who are investing the money to test their drug want that additional confirmation of a biopsy to be sure they’re testing the drug in the right people.

Vanessa:

Makes sense. So, what do you think are the biggest barriers researchers are facing today with drug development?

Dr. Jocelyn Silvester:

I think the main barriers that we always face are money and time. And also, I think this isn’t really about researchers. This is about patients with celiac disease and it’s a partnership. And so, we can’t develop drugs in a laboratory because we’re not developing drugs for rats or any other animal. We’re developing drugs for humans, which means we need to do clinical trials, which means we need volunteers for clinical trials. And so, I think we really need to remember as a celiac disease community that it’s our collective responsibility if we want a treatment other than a gluten-free diet to help work toward having a treatment other than a gluten-free diet. And there’s lots of ways to do this that may not necessarily involve being in a clinical trial where you consume gluten because there’s a lot we don’t know about celiac disease and some gaps we need to fill in order to be able to test the drugs.

For instance, things like how many symptoms does somebody with celiac disease actually have? And what is more symptomatic or less symptomatic? It’s really interesting in celiac disease you sort of have celiac disease or you don’t. And most conditions where there’s drugs, the drug is for mild to moderate Crohn’s disease or severe Crohn’s disease. Well, nobody really talks about severe celiac disease or mild celiac disease. And so, there’s certain things that we need to do and figure out that are totally independent of actually testing the medications.

Vanessa:

For sure. So, are the current clinical trials just for adults or are there ones that kids or teenagers can participate in?

Dr. Jocelyn Silvester:

So, right now, the trials that are enrolling are predominantly for adults. And there may be some looking at non-drug, so a drug is a compound, it’s not a organism. So probiotic trials, I know there have been some done in children, I’m not sure if any are actively recruiting right now, but those aren’t considered drugs. So, it may be that those are open, but for the most part, the idea has been to start with adults and then work towards children. But I think that’s a really important question because arguably children have the most to gain from a drug for celiac disease because children are still growing, and time is important, and nutrition is important to growing. And so, if we could accelerate recovery from celiac disease and treatment of celiac disease, and if we could change the burden of gluten-free diet, I think children have a tremendous amount of benefit.

Vanessa:

For sure. So, do most drugs make it to market or do they fail along the way?

Dr. Jocelyn Silvester:

Most drugs fail, fail to come to market. And I think this is one of the things that is really interesting that I didn’t really appreciate until I became more involved in drug development that a good clinical trial is actually about a lot more than whether the drug works or not. And this is part of the reason why if you participate in a clinical trial, there’s lots of questionnaires, there’s blood draws, you may be having capsule endoscopies with the camera plus actual endoscopies. And part of the reason for this is that we can learn more about the disease and markers of the disease even if the drug doesn’t work.

And so, a great example of this is we mentioned the Nexvax2 earlier, and this was a subcutaneous injection of peptides that people with celiac disease recognized from gluten. And one of the early findings was if somebody vomited when they ate gluten, you could inject the peptide under their skin. And that made them vomit too, which was something that was unexpected and really made us sort of reconsider how we were thinking about celiac disease. They also were looking for markers, and so they found that when somebody has celiac disease, there’s certain chemical mediators and cytokines that are released and you can measure these. And so that has also been something that’s changed how we think about celiac disease.

So, Nexvax2 isn’t going to be a drug that’s going to be available for people with celiac disease, but did the people who participated in those trials contribute something really useful to understanding celiac disease and have those trials really being foundational to future trials for celiac disease? Absolutely. And so, I think when we think about failure here, we need to really think about the context because a successful trial will have enough so-called ancillary studies that will help move the field along even if the drug “fails”.

Vanessa:

This is so fascinating. What about all of that other data that’s collected in these failed trials? What happens to it?

Dr. Jocelyn Silvester:

That’s a great question, and it depends a little bit on who’s running the trial. So, in general, there’s two types of trials. There are those that are sponsored by industry where there’s a company that owns a license or owns a compound and they want to test the compound. And so, they may approach somebody like myself and say, “We’re interested in running this trial, would you like to be a site principal investigator and help us recruit participants to this trial?” And then we would have a negotiation process, a contract process, and ethics review process. And then in running the trial, we would be helping with recruiting patients, enrolling them, conducting the trial. But all of these samples go back to the company, and then it’s the company that owns the samples and the company that has access to the data. The other type of trials are investigator initiated trials. Sometimes these are funded by companies, but more often they’re funded by foundations or by the National Institutes of Health or governments.

And so, in this case, it’s the investigators that own the data or the institutions that have the grants that own the data. And so, there’s potentially more opportunities to publish. However, I think it’s important that even if the data doesn’t get published immediately, it’s still there and it can still influence what happens later on.

Vanessa:

For sure. So, how are you feeling about the future of drugs for celiac? Are you optimistic that there will be a treatment for patients like Amelia?

Dr. Jocelyn Silvester:

I’d say I’m cautiously optimistic, and the reason for my optimism is as you’ve alluded to many times, most drugs that we trust in people never become drugs that we can prescribe to people. And so, what you need in order to have a drug is lots of shots on target. And right now, there’s not only lots of shots on target, but there are different mechanisms to get to the target. And that’s really what we need because it means if for instance, you do subcutaneous peptides didn’t work, but that doesn’t have any impact on whether a gluten is would work.

And so, the fact that we have multiple products that have different mechanisms and also that the companies that are starting to get involved in this field are mainstream pharmaceutical companies, and there’s an interest on a large scale, and it’s not small startup companies that are necessarily pushing this work in the most responsible for the work also makes me feel more optimistic because as we mentioned earlier, the limitations are money and time. And often the folks who already have some drugs that they’re selling have deeper pockets than those who are just trying their first celiac drug for the first time.

Vanessa:

So, in comparing this to something that’s really common, like migraine and headaches and there’s dozens of different drugs and different classes of medicine that you can take for them, could it be hopeful that someday there would be different drugs for different people with celiac disease?

Dr. Jocelyn Silvester:

Definitely, right now there’s different drugs with different mechanisms that are being tested, and it’s possible that multiple of those will be successful.

Vanessa:

Fingers crossed. So, before I let you go, can you tell our listeners how they can find out more about participating in clinical trials both for physicians who may be interested in becoming a trial site and for patients wanting to enroll?

Dr. Jocelyn Silvester:

Absolutely, and I think that’s a really great question because one of the hardest things is to connect the volunteers with the people who are conducting the research. And so, the best thing to do is, number one, ask your doctor if they’re involved in anything. Number two, you can look at clinicaltrials.gov, which is a registry of clinical trials. There’s analogous registries in Europe and in Australia and other parts of the world. You also can join a research registry. So, here at Boston Children’s Hospital, we have a research registry, and that’s the first place we go to recruit people when we’re doing a study. And you don’t have to be a child to register, and you don’t have to be a patient at Children’s Hospital to register. So, if you’re interested, you can look in the show notes and we’ll have a link.

As for investigators, I think that’s a little bit more complicated, but the important thing to do is get involved, get engaged, attend meetings. Most of the celiac meetings and the large GI meetings, there is a presence from the folks who are developing drugs for celiac disease, and they are interested in developing investigators because it’s very unique to be trying to do clinical trials in a field where you don’t have medications and people haven’t been doing clinical trials before. And so, I think if you’re interested in getting into clinical trials, it’s a great opportunity, and I think it’s worth volunteering and finding out.

Vanessa:

So, if a patient wants to go to clinicaltrials.gov and they find a trial that’s interesting to them, but their doctor isn’t listed as a site, can they reach out to other sites on their own? Or do they have to have an affiliation with that medical center?

Dr. Jocelyn Silvester:

Oh, good question. Absolutely. So, on clinicaltrials.gov, it will list information about the trial and then it will list participating sites. And so, you’ll have contact information for those sites, and you can reach out to them. The other way to find out about trials is a lot of the companies are partnering with patient organizations to help with recruiting. So, often patient organizations will know about what trials are happening, so their websites are also another place to get some information. But certainly, I think if you’re interested, the first thing to do is to reach out and we certainly do get inquiries from clinicaltrials.gov and we do respond to them. So, definitely if you’re interested and you see something that’s interesting, don’t be afraid to click the button to find out more.

Vanessa:

Great advice. So, thank you so much Dr. Silvester, for all of this wonderful information. We’re going to take a quick break and when we come back, we’ll have a patient here to tell us about their experience participating in a clinical trial for celiac disease.

We’re going to take a quick break to hear from our podcast sponsor, the Global Autoimmune Institute.

Speaker 5: The Global Autoimmune Institute:

The Global Autoimmune Institute works to empower solutions in the diagnosis and treatment of autoimmune diseases, through research, education, and awareness while supporting multidisciplinary approaches to health. We are thrilled to support the production of this educational podcast.

Vanessa:

Welcome back and welcome Prachi to the podcast. First of all, thank you so much for participating in research. As you heard from Dr. Silvester, the only way to advance the celiac world is for people to participate in trials. So, truly thank you for joining one and contributing to the future of our celiac community. So, can you tell our listeners which trial you participated in and how you learned about it?

Prachi:

Yeah. So, I’m actually one of the editors on the Celiac Kids Connection Newsletter. So, as I was editing one of the additions, I just saw this ad for a trial, and it was looking for people who have celiac but don’t have a very strong reaction when they consume gluten. And I thought that was perfect for me because that’s exactly what happened to me. So, we just contacted the people who run the trial and I got in and basically, they were just looking for what the immediate changes in blood are after consuming gluten. So, it was very interesting.

Vanessa:

Can you tell our listeners how old are you?

Prachi:

I’m 15.

Vanessa:

Awesome. And how did your parents feel about you participating in the trial?

Prachi:

They were all for it. They were as excited as me, I think ’cause none of us have ever participated in a hospital trial like that. So, we were all really interested to see what it entailed and how it would go.

Vanessa:

Were you nervous to participate?

Prachi:

Not really. I was actually very excited ’cause I’m interested in science and about how the body works, so it was very interesting for me to learn about how my blood and my contribution to the trial would help in manufacturing a potential drug in the future.

Vanessa:

So, what was it like being in the trial? Can you tell us about the experience?

Prachi:

Yeah. So, when we got there, the researchers were actually super nice. They really put me at ease. They almost made it seem like a fun experience going. So, they just had us fill out some forms and it was really fun, and my mom and I went, we actually kind of made a day out of it. We went to Boston, went to a Museum of Fine Arts in our free time between the trials. So, it was really fun participating in the trial, and I think I would definitely do it again.

Vanessa:

So, did you eat gluten for science?

Prachi:

I did. I went in thinking I would get a cookie. Unfortunately, that did not happen. But yeah, I did eat a gluten powder mixed since just an apple juice.

Vanessa:

How did it taste?

Prachi:

I think the powder itself was pretty bland, but so basically just apple juice.

Vanessa:

So, there were no croissants or cookies involved in this situation?

Prachi:

No. Unfortunately.

Vanessa:

How did you feel about having to eat gluten?

Prachi:

I was excited because I thought I would get some cake, but yeah.

Vanessa:

So, going forward, you obviously ate gluten for science once. Do you worry that eating gluten for science once you’ll ever want to eat gluten again, not for science?

Prachi:

Yeah. Probably. But just got to keep the diet.

Vanessa:

Absolutely. It’s so important to remember that we have to stick to that gluten-free diet outside of these limited times we’re participating in research. So, do you have any other words of wisdom that you might want to share with our listeners about participating in future trials?

Prachi:

Yeah. Just go in excited and interested and know that you’re contributing to science and really plan to make the day more fun than just sitting in a hospital because you will have time in between the blood draws and the tests and things. So, just kind of maybe go out into the city, make a day out of it, and just make it a fun experience for yourself.

Vanessa:

That sounds like a really, really good plan. So, thank you so much Prachi and to Dr. Silvester for all of the wisdom that you shared today. Now, let’s find out where our patient Amelia is today.

Janis:

Things haven’t changed much for Amelia in the past year. She’s still gluten and lactose free and still wishes she felt like her old normal self. She has thought about clinical trials for celiac disease but hasn’t committed to joining one because of the requirements to eat gluten. In her own words, ‘I do want to join a clinical trial, and hopefully I will find the right time between constantly thinking about what I eat to feel good attending classes and trying to have as normal a college experience as I can. I haven’t found the time to potentially be sick for meeting gluten, but I’m very thankful for everyone who has found the time and are working to make life better for everyone with celiac disease.”

Vanessa:

Thanks for listening to this episode of Raising Celiac. A special thanks to the generous contribution from the Global Autoimmune Institute to make this podcast possible. A reminder to all physicians, nurses, social workers, dieticians, and psychologists to claim your continuing education credits. For listening to today’s episode, please visit dme.childrenshospital.org/raisingceliac and complete the short survey attached to this episode. If you like what you heard, be sure to write a review, like, and subscribe wherever you get your podcasts. For more information, check us out on social at @bostonchildrensceliac on TikTok, @childrensceliac on Twitter, or @celiackidsconnection on Instagram. Have a great month.