Capsules or Colonoscopies? today’s Reality and Tomorrow’s Potential
Tom Lendvay, co-founder and Chief Medical Officer at Tend, is a surgeon, entrepreneur, and Professor in the Department of Urology at the University of Washington.
In this latest installment of our Q&A series on the gut microbiome and FMT (Fecal Microbiota Transplant), Tom answers questions about how FMT’s are administered today to patients with recurrent Clostridium difficile—and how that could change tomorrow to expand access and understanding of this life-saving treatment.
If I’m a patient with Clostridium Difficile (C. diff) and I get prescribed a FMT or fecal microbiota transplant, how am I going to receive that transplant today?
In the United States, the majority of FMTs are administered through colonoscopy, which is a somewhat invasive procedure where a big camera scope is placed through the anus, into the rectum and into the colon. And then a solution of a donor's stool sample is squished into the colon. The next most common is by an enema, whereby a little bottle of the solution pushes the stool material into the colon via your rectum.
A less common, also pretty invasive, method is transplant via nasogastric tube where a tube goes from the nose to the stomach or even into the intestines to deliver the solution
And then there are orally ingested capsules that have been frozen prior to use. So those are the primary routes of administration, but in the United States, most likely your GI provider will be administering it through colonoscopy.
Is the prep for that primary route of colonoscopy similar or different to what you do for a typical colonoscopy screening?
It’s similar to the screening for cancer colonoscopy that we all go through once we hit 45 where a lot of providers require that their patients do a bowel prep. I call it a colon blow (from the 80s SNL skit), but basically pushing everything out of your gut. And that's because when you do scoping into the intestines, you have to be able to see. You can't actually see where you're going if the person is full of stool.
In the case of colonoscopy for FMT, sometimes they actually give patients antibiotics beforehand, ironically, to try to reduce the existing bacteria and to replace it. Although it's unclear whether that's necessary. But the bottom line is that you come into a procedure room, you get sedated or put to sleep, and then you have a 20-30 minute procedure to instill the solution.
You mentioned “in the US”, do modes of administration for FMT vary in different parts of the world?
It can be country specific. But in general, some route from below so to speak (colonoscopy or enema) is more common than a route from above (nasogastric tube, capsules) and that's across the board globally.
Why are those routes “from below” like colonoscopy more common than routes “from above” like capsules?
I think it’s because of ease of preparing the transplant material with today’s methods. As it stands today, it's easier to prepare a slurry or a solution of poop material for colonoscopy or enema. And sometimes the patients are really frail and might not be able to take stuff from above.
Conversely, right now there is no standard way to prepare capsules which is an extremely laborious undertaking. So even though in the United States people are used to taking capsules for treating diseases, popping pills basically, there’s no standard and simple way to prepare capsules for this less invasive mode of administering a transplant. Instead, clinicians are basically taking that solution that you've created for colonoscopy and enema, and then doing more processing to get it into a capsule. It’s just a lot of work, and messy. Which makes it not something that clinicians have the kind of resources or time to do.
What about efficacy? Are some of these routes more effective than the others?
Originally studies showed that the best routes were the routes from below, colonoscopy and enema. But the more that capsules have been used, the efficacy has been shown to be fairly equivalent between a route from below and a route from above. Also, the amount of stool material that has to be brought into the body is less with the from-above method. People aren’t really sure why that is, but the amount you get in capsules is not quite as much as you get rectally.
The bottom line is that clinicians are starting to realize that the capsule route is actually just as good. And certainly when clinicians have spoken to us about it, they say that their patients would prefer to have an oral capsule version if it existed than an invasive colonoscopy or enema. Those aren't very pleasant, as you can imagine.
So capsules are easier for the patients, for sure. But in the current state of preparation, it's harder for the clinicians to do capsules.
If the efficacy is the same with capsules, and they are less invasive for patients than a colonoscopy, what keeps capsules from being more common?
It’s really because there isn't an easy way to make capsules from donor stool material. Right now, clinicians are in the lab processing capsules in a way that you'd run a chemistry experiment. There hasn't been innovation to engineer a simpler capsule-making or encapsulating process until Tend has come up with a device that can do all the steps – mix, filter, homogenize and encapsulate.
How does the device you’re building at Tend potentially make capsule-making easier?
We’re addressing the user experience problems. I.e. trying to help the clinicians, doctors, and practitioners who provide microbiome transplants have a whole lot easier time doing it, and potentially add standardization to this whole process. So they can collect a stool sample from a donor, filter it to make sure that there aren't any kind of particulates, mix and homogenize it so that it's uniform, and transfer it into capsules. All with our device, in minutes. Those capsules can then be stored in their freezer for later use.
Now contrast that with today’s method for preparing capsules which take hours and may result in degrading the sample. Here’s what that method looks like and where some of that sample alteration may happen.
It starts with a clinician or their staff taking a stool sample, mixing it with saline, and putting it in a blender. The blender piece potentially disturbs the balance of bacteria in the microbiome of that sample because half of the bacteria in the sample don't like oxygen. When you put it in a blender, you're really kind of jacking up the amount of air that is mixed in. And that may not be good for some of the bacteria that are very important for doing the clinical work of a microbiome transplant. Our device minimally processes the material, meaning it’s disturbed less en-route to capsules. That potential difference needs to be tested but clinicians who’ve used the device tell us there may be an upside there.
Then that sample from the blender is filtered through a series of filters and often spun in a centrifuge to basically isolate the microorganisms. This is another spot where questions emerge. We don't know if it's the microorganisms alone or all the stuff around those bacteria and fungi and viruses that make up the secret sauce of the microbiome transplant. So, it's possible you're actually removing good parts to the microbiome material.
After filtering, the sample is remixed again with a material called glycerol that helps preserve the sample in a freezer when it's frozen. And then clinicians use pipettes, which are these little pumps that allow people to take a known quantity of the material and drip it into capsules, one at a time. And then each capsule is closed. That whole process takes multiple hours and it's quite laborious.
What are you hearing from clinicians and researchers who have made capsules the current way and are now doing so with your device?
It's way faster and way easier. The Massachusetts General trial site has already given us feedback that what would take them basically a day of work with preparation and set up and clean up has been reduced to an hour or two of work. And that time is including everything they have to do, like the administration of logging the samples and getting them into the freezer. So, the device itself has stripped down the preparation time to tens of minutes from what used to be a day long process.
And they’ve also said it's a lot less messy. If messy at all, when they're doing this work. There's almost no cleanup. And that's in part because our device, we call it a CAP device for collection and processing, has disposable food grade plastics for any part that comes in contact with the sample and then a reusable component. So, we're minimizing the environmental footprint of this process while making it faster.
Currently when anybody does any microbiome transplant processing, they have to basically clean all the material that they're using, the blender, the filter and all that stuff. And I can tell you that any doctor or technician who has done this process describes that cleanup as just being horrible.
What led you to a hand-powered design versus something electronic?
We had envisioned that we would be creating some electronic mechanized device. And when we started doing some of the foundational engineering for the guts, if you will, the insides of the device, we identified that the parts are actually quite small and could potentially be very modular. I.e., with a few components put together in the right way you have the essential functionality of the device.
So with user experience and increasing access to microbiome transplants on our mind, we started realizing, hey, wait a second… this actually could get into many more hands than if it's some big capital purchase that a hospital has to make to put in their microbiology lab setting tens for thousands of dollars a machine. As opposed to a device that's hundreds of dollars instead of thousands, that can basically do all that work with a little bit of manual work from the human, as opposed to some mechanized process.
Plus, from a regulatory perspective, it actually is a lower hurdle to get a manual device through the FDA compared to an electronic digital mechanized device. It reduces the points of failure for a user to have a device like this. And again, it's lower impact on the environment, can scale more easily, is less expensive and easier to use. So, all those things we thought made this really interesting that we kind of just fell upon during the engineering process.
You mentioned standardization as a challenge with today’s processing methods for FMT, and as a potential benefit of your device, what's important about that?
When studies are done with microbiome transplants today, every study is done differently. The processing is done completely differently from one site to the next to the next. The question becomes, can you really compare the results of one microbiome transplant study to another. We believe that this device, if it gets into the hands of more of these trial sites that publish on the efficacy of microbiome transplant for whatever they’re studying -- recurrent Clostridium, difficile, inflammatory bowel diseases, irritable bowel syndrome, even the mental health disorders that are being now tested with microbiome transplants -- allows people to eliminate the variables of how that sample was processed. What can then be adjusted by the clinician is how many capsules does the clinician want to give over what kind of period of time, and what's the regimen. But the actual way that the capsules are made is going to be uniform across studies. And I think that as people start publishing with our device, they'll be able to say, well, we use the CAP device and then others will see that and say, oh, this sounds like we should use that because then we can tell how our patients did relative to this other study. And so we think that that's going to be highly valuable to accelerate the learning of the value of microbiome transplants across many diseases.
What about the ick factor, have there been barriers to capsules as an administration method for FMT based on hesitation to ingest poop?
That question is really the X factor question. What clinicians who use capsules tell us, though, is that for the populations of patients with the diseases for which microbiome transplants are relevant, patients do not balk or resist taking capsules. These are patients that are seriously ill and have often tried everything. Not just over a few days of treatments, we’re often talking months and years of constant discomfort, pain and symptoms. And so, they are on board with and haven’t had any issues with ingesting multiple capsules over a few days or even a regimen that's over a few weeks. In fact, we’ve talked to gastroenterologists who are the ones on the front line doing colonoscopies, which are part of their livelihood, and they tell us that frankly, their patients would rather do something easy, like take some capsules, then have to undergo colonoscopy. We are definitely hearing that there is a growing interest to have capsules, even from the patient side of things.
You note that these are double capsules, how does that factor into transplant via this method and the potential hesitation of ingesting poop capsules?
What we tried to do when we engineered the device is to parallel what happens in capsule processing already and that is the use of double enteric coated capsules. Essentially, these are capsules within a capsule, a bit like a Russian nesting doll. Clinicians do this in part so that the sample doesn't release in the stomach where the stomach acids could kill some of the bacteria that may be helpful in a microbiome transplant. So the idea is to get the sample into the intestines before the capsules break down.
We’re engineering towards a device that does that - creates capsule shells that are acid resistant and double layered. Our tests show that the capsules, even in a very strong acid solution that replicates stomach acid levels, don't break down for over an hour, which is well longer than the time it takes for a capsule to get in and out of the stomach, into the intestines.
If we move to capsules as a primary administration method for FMT, what improves? Why are we better off?
Greater access to treatment and more research. We think in multiple ways…
First in the treatment of Clostridium difficile. We know already there’s a large body of evidence that microbiome transplants are the most effective management for recurrent Clostridium difficile infections, which affects 200,000 - 300,000 people a year. But the average clinician cannot have access to this. So you have patients who are still getting 1, 2, 3, 4 rounds of antibiotics to try to eradicate their disease without success.
Next is clinicians or trial sites that can start testing microbiome transplants for efficacy with other diseases. There is mounting evidence that a lot of the diseases we experience are a consequence of our gut microbiome being disturbed or altered in some way. Not just because the imbalance of bacteria prevents normal digestion of food. More that bacteria can influence our immune system, and a substantial number of the immune cells in our body line the intestines. So there is a really unique interplay between the microbes in our gut and how our immune system is basically trained or taught to act. There's a slew of diseases in the immune space that can be tested with microbiome transplants and altering the gut microbiome. In addition, mental health disorders may be linked to alterations of the gut microbiome. There is growing evidence that the gut microbiome influences our mental health, whether it's depression or whether it's autism or bipolar disorder.
Yet now there's a relatively limited number of trial sites that are actually testing in this area in part because they have no standard way of processing donor samples. And so we think that our device will allow trial sites to start expanding how they could test other areas for potential impact and see if transplant is effective. And once that happens, if there's strong enough evidence to support the use of microbiome transplants in other diseases, that's when the FDA in the United States determines the regulation around this.
And at that stage when more conditions are cleared for treatment with transplant, you can get to a third access expansion area which is the average clinician being able to treat Clostridium difficile and these other diseases with a microbiome transplant. That requires a processing method that’s inexpensive, easy to move around and simple to use with disposable and reusable components. Because the average clinician doesn't have a lab setting in their offices. They may have a bathroom or may have a back office, but we want to make sure that this device, ultimately, could be used at the point of care, in office environments which is the more common environment for clinicians. If we do that, we can help improve the access to this sometimes lifesaving superpower of our gut microbiome.
Do you see a world where that expanded access comes to include individuals using their own microbiome for healing?
We think one of the most valuable long-term propositions for our device is ultimately being able to preserve your own microbiome before some known insult or disruption, such as taking an antibiotic or taking chemotherapy, both of which are atomic bombs to healthy microbiome balance. A number of people get ill after they've had antibiotics or chemotherapy, because those bacteria are now changed in their intestines and the balance they had before may not return. If there was a way to bank or preserve your microbiome in advance, that would be transformational, we believe.
And there's a much larger number of applications for that… for changes in your diet, stress levels changes, etc. These all have to be studied. But under the guidance of a clinician, there are going to be reasons why it'll be helpful for someone to bank their own microbiome and potentially they could be the ones actually doing the processing of capsules with their own material. Our device needs to go through a lot of validation to get to that point. But it is entirely possible that our device could be made into something that anyone could use at home to bank their own microbiome.
So if we put on our future glasses and look ahead five years, how will patients be getting FMT treatment?
I think orally ingested capsules will be the mainstream and demanded by patients. Once more patients know that this is a possibility as opposed to colonoscopy or an enema.
I also think in five years we will have more diseases that the FDA and regulatory bodies have recognized as potential places where microbiome transplants can be utilized to help people heal.
And then lastly, the autologous or the self-derived banking of your own microbiome, I believe is going to be more, if not mainstream, certainly more asked for by patients from their providers when they're about to go on broad spectrum antibiotics or some type of chemotherapy as a way to know they can replenish their microbiome after it takes the hit we know these treatments deliver. And that sort of “poop insurance” could alleviate a lot of suffering people go through today.