An Orally Delivered Alternative Approach To Obesity With Aphaia's Steffen-Sebastian Bolz

Offering an alternative to injectable peptides, Chief Scientific Officer Steffen-Sebastian Bolz from Aphaia Pharma describes for videocast host Tom von Gunden an obesity treatment that leverages the body’s natural mechanisms for processing food and engaging the brain’s intake-management functions. The approach loads glucose into orally consumed beads that travel to the lower intestine and trigger combinations of brain-signaling hormones, including GLP-1s.

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Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader

Welcome to another episode of Sit and Deliver. My name is Tom von Gunden, Chief Editor at Drug Delivery Leader and, as always, your host for the episode. Today, I'm pleased to be joined by Steffen-Sebastian Bolz, who is Chief Scientific Officer at Aphaia Pharma, a Phase 2 biotech company.

Welcome, Steffen.

Steffen-Sebastian Bolz, Chief Scientific Officer, Aphaia Pharma

Thank you very much for having me, Tom.

Well, it's my pleasure to have you. So, let's go ahead and dive in.

First, I want to frame this up for our audience in terms of the context in which what we'll talk about today fits — and that is, the space of delivering treatments for metabolic conditions, such as obesity and diabetes.

As we all know, it's quite the popular focus now, both in terms of the industry's work and also the patient population out there. And I think you'd have to almost be asleep not to be aware of all the excitement around the GLP-1s, for example, and treating those conditions typically by injection and some trending lately in interest and demand for, if possible, getting those into oral formulations and administration.

So, I know that, at Aphaia, you folks are also working on oral delivery, targeting metabolic conditions, but with a quite different approach, actually — one that, as I understand it, leverages the body's own physiology to take in the payload and get it where it needs to go.

So, tell us about that — the different way that you're approaching these kinds of conditions, leveraging the body itself.

First of all, I mean, you're absolutely right: obesity is everywhere. It's in the news, it's in all discussions, and it has become the major condition that we're trying to treat right now. And we do this because, after decades of being unsuccessful with treating obesity and reducing weight, we have something in our hands that actually does reduce weight. And those are the GLP-1 agonists, or anchor to an agonist, because tirzepatide is the combination of two increments.

So, there has been this massive progress. And all of a sudden, we all know you can do it; It's possible. And that's a major paradigm shift.

We have also seen that, despite all those benefits — the weight loss we see and the cardiovascular benefits — we also see side effects from those treatments. And that's kind of the dark side of a very bright side.

So, I think it's important; there's historical merit of these substances that are guiding the way for all of us.

But now it's the time to really think about what could we do better? So, how could we increase tolerability? How could we reduce side effects? And how could we really focus on the patient outcomes?

Because one of the problems for the side effects with these agonists is that they produce high dropout rates. And those patients who drop out of the treatment and never come back will never harness the cardiovascular benefits.

And that's what it's all about. I think that's an important point. It's not primarily about losing weight; it's about actually getting a cardiovascular benefit out of this. And so, if you don't stay long enough on this treatment, it won't work.

The other thing that's very important and that has also changed our entire perspective from this — again, because of the increase in agonists — we understand that obesity is a chronic disease. It's not a lack of will; it’s not any kind of weakness. It’s a disease. And it's a chronic disease that needs a chronic treatment.

And this is where we started, where we started our thought process, and thought, well, if you want to achieve the similar weight losses, if you want to reduce side effects, if you want to increase tolerability, if you want to build something that can be used chronically and that should actually be accessible to everyone, we need to go back to the drawing board and really think about how could we do this differently.

I'm a physiologist by training, so I try to understand functions of life, and also the structures of life, of course. And here it's a mix of structure and function. When you eat something, you obviously put it into your mouth, you chew it, you swallow it through your esophagus, through your stomach, and then it enters a part of the GI tract that's called the small intestine. And then this is where the absorption actually happens. And afterwards, it goes into the colon, and then it's excreted.

But let's focus on the small intestine. The small intestine has two parts, an upper part and a lower part, that you can actually kind of separate functionally. The upper part absorbs the food. It's everything there, the epithelium, the cells that line the lumen there; they are made to absorb — highly efficiently absorb — nutrients. And that stops, more or less halfway.

And then we enter a territory where there's no absorption anymore, but where there are cells that can actually sense food. And when you think about this construction, this structure, it makes sense. Because if we were to eat too much, it would trickle down —and that's a simplified version of the whole thing — but it would trickle down. And these cells down in the distal part of the small intestine would sense that and actually send signals to the brain and to other organs to change their metabolism — to increase energy expenditure, reduce hunger, increase satiety.

So, all in all, what happens is that the small intestine regulates metabolism and behavior. And this only works because we have cells down there — and this is what we home in on, the so-called L-cells, primarily — that can not only sense food but that also release hormones. And those hormones are actually the agents who travel to those organs in the periphery to change their metabolism — liver, pancreas, and so on, to just name a few —but which are also hardwired to the brain.

So, there's a neural connection between these cells and the brain. Within milliseconds, the brain knows what's happening down there and gets commands to change behavior. And that's an incredibly fascinating aspect. And what actually made it for us is the understanding that this system is dysfunctional in obesity.

Well, that all sounds very interesting. Thanks for enlightening me about that. I wasn't familiar with how that all works. Sounds like a very complex system.

So, when it works, it's great. Tell us a little bit more about what happens when it doesn't.

That's, again, very complex because when you think about eating and the complex behavior behind it, it really matters not only what we eat, but also when we eat it, for example, right? So, it's very important, and you heard this from your moms or your grandmothers who said, well, you should eat a lot for breakfast, less at noon, and not so much in the evening.

And now science tells us exactly the same thing. If you listen to Satchidananda Panda from the Salk Institute: he says late eating is a bad thing, and that's true. So, we now have the biochemical evidence for what our grandmothers and mothers have told us. Mostly those are the … it's the female lineage that actually tells us that and for good reason.

And so, this is what we've completely forgotten about. We live in an environment where there is far too much food. We have billboards showing food. We have ads on the TV showing food. We have smells everywhere we go. We have those triggers for food intake everywhere. And we eat too much.

And we also eat food in a composition that the system I just talked about, in all its complexity, was never optimized for. The system was optimized for an environment where food was scarce because our ancestors walked in the savannah. And they had to eat whatever: some fruit, occasionally, but mostly grass and corn, and every once in a while, maybe some meat. But that was it.

Today, it's exactly the other way around. We eat far too much fat, far too much protein, and not enough carbohydrates, or highly complex carbohydrates, I should say. And that's a problem. And we're not only eating the wrong quality of food, but we also eat in a very refined manner. So, we actually break down food to its very essential parts and then mix it again to produce some whatever.

And when we eat this, what happens is, it slows down the passage in the small intestine. So, this food that we're eating travels far, far slower than it should. And at the same time, it has highly refined components, which are easily accessible to the absorption process. So, we pretty much absorb everything.

And I exaggerate this a little bit because it links back to the image I tried to develop earlier, where the cells down there wait for food to be excited. It’s not coming in this scenario, and that's the problem. So, because we have too much food that travels not fast enough, a food bolus sits there and literally obstructs passage. And that's the problem.

So, when we went back to this, we thought, well, we should overcome this. We should actually do something differently. And what we did then is we thought about ways to actually deliver food to this area. So, we tried to think about a method to get the food, or whatever particles, from ingestion through the esophagus, through the stomach, through the upper part of the small intestine without being absorbed.

And then we wanted to develop something that then drops the cargo on those cells right there down in the distal part of the small intestine to excite those cells. And that's exactly what we did.

Gotcha, gotcha. So, thanks for walking us back through what I probably learned something about in fourth grade or something like that. But anyway, it's interesting to be reminded about how the body actually naturally processes things.

So, I understand that, in some way, the therapeutic payload that you're talking about is also one that most of us have known and heard about for years, and that's the simple concept of glucose. So, tell us about how that enters the picture and why that's so significant.

Thank you. Yes, that's the other great question — the question of the cargo. So, once we solved the problem of how to get down there — and I might want to quickly describe this: We started with tablets, but tablets are far too slow, and they get stuck in this bolus there, right? They get stuck in this mud that's in the upper part of the small intestine. And please excuse me being very graphic here, but this is the problem.

We use beads — beads smaller than 1 millimeter because they behave like fluids. They travel just alongside this bolus and get down there. And then we developed a coating, a polymer coating, that opens up exactly what we needed.

And, after we had optimized this, the question really was, Tom, as you just asked: What is it? And we decided on glucose. From a pharmacologic perspective, from a pharma perspective, glucose is pretty much the worst choice you can make, right? Because it's a naturally occurring substance: it's not an API, it's not a drug. And we've heard this many times. We don't hear this anymore because it works so well.

But we chose glucose because we had a closer look at the cells — this is where the molecular part comes into play. We looked at those cells; we looked at the sensors. And those sensors on top of those cells are proteins, of course. And they are optimized, and Mother Nature did a fantastic job. They are optimized in a way that the brain really knows not only when something appears, but also what. It actually decodes the quality, or it codes the quality for the brain. It's a fascinating system.

And this is highly skewed, or highly optimized, towards glucose. Why? Because, I mean, I have a window in front of me and see all those trees and stuff. That has glucose. Glucose is the most abundant biomolecule on the planet. Because everything, every biomolecule that we are made of starts with glucose and the photosynthesis. This is where the carbon atoms come together that then form the backbone for lipids, for proteins, and so on.

So, this is the number one substance. So, it makes perfect sense that it was highly abundant in the environment where these systems were built and optimized. And so, this is why it gives you, and again, excuse my language, the biggest bang for the buck. It is the strongest signal for those cells. This is why we chose glucose.

And when this dawned on us — I mean, we thought about this and said, “Oh my god, let’s keep this under the radar; let's stay in stealth mode until we have built a patent portfolio protecting what we do.” Because in pharma development, as everybody knows, this is one of the key things.

We did that. And once we felt safe enough, and once we had built everything that we needed to be able to protect this, we went public. And we did two Phase 1 trials, which we published. We did one Phase II trial. The two Phase 1 trials showed that glucose indeed releases all those hormones.

Now the interesting part: It releases all those hormones, GLP-1 being one of those.

And that's the fun part.

So, what we do is we bring the glucose down there. It triggers the cells. The cells send the endocrines to the hormonal signals and the nervous signals to the brain. And when they do this — when these cells are being activated by glucose — we actually see the normalization of the metabolism. We see normalization of behavior.

And that's actually something that we could show. We could show that we'd have this large portfolio of hormones, not only GLP-1, but also a whole plethora of hormones, which interact together with GLP-1.

And what is important, and what I tried to say before, is that we have hormone levels. And the hormones are released by the cells. You can measure this in the serum. And then they come back to normal.

And when you look at those profiles, they're identical to what you would see after intake of a normal meal. So, when you eat, it's exactly the same profile. We prolong this a little bit, but this is a little bit of a trick of the formulation.

The most important part is the amplitude. It's so low that it would never produce any side effects. But because all of these hormones work together, we get a substantial effect. And we see this in our Phase 1 study in pre-diabetic patients, where we increased or improved glucose handling. And we also see this now in our obesity trials, where we induce weight loss.

And the idea behind this is to not only use one hormone in astronomically high concentrations, but also to combine many hormones and let them act together, like an orchestra. Rather than just having one violin, you have the entire orchestra doing the job and filling the room in sounds, so to speak.

Gotcha, gotcha. Very interesting.

So, coming back to a couple of things you mentioned: obviously, the cargo or payload, and then the dosage form being beads. So, tell us about how you envision a typical patient’s regimen. It might seem obvious, but how are folks going to consume these beads? What format and how often? And what are the expectations for the patient's part in getting these to the place you would like them to go in those patients' bodies?

The beads contain glucose. Every bead has the same amount of glucose. The number of beads define the dose. So, we can actually stagger the dose.

The beads, per se, come together with a powder that turns into a hydrogel when it gets in contact with water. The idea is to increase palatability, so you can spoon it up and scoop it up. You could also use this with yogurt.

But for a clinical trial, it was absolutely pivotal to have something reproducible and standardized, so we developed this gel, which also has a protective effect for the beads, for the passage through the mouth, through the stomach, and also during shelf time that they might have when they're dissolved in water and forgotten to be taken.

In order to really reduce hunger effectively, we understood that we have to give it twice per day. So, what we have now done is emulate the circadian cycle. We actually place the two application times on the circadian cycle that we know about feeding behavior and also GLP-1 release data and everything.

So, we placed it at 8 o'clock in the morning and at 4 o'clock in the afternoon. And that produces two hormone increases, or two hormone release waves, that superimpose. So, we actually cover the patient for the day and keep hunger under control and increase satiety and increase energy expenditure. And that's pretty effective.

So, again, the whole idea here to be as physiologic as possible led us to a regimen where we give it twice per day. And the patients actually take these — you asked how we actually apply it: It comes as a sachet. So, then you can put it into a glass, mix it with water, and then you scoop it up. You can do this pretty much everywhere where we have access to water.

And patients — we were very curious to see how  well patients would accept this and how well they would do this, what the compliance would be. And patients actually like this. Patients tell us routinely that this is not a burden; they don't see this as a burden. Sometimes we hear it's nice to be part of this, or whatever that means, to do something for themselves in this case. It works. That was my concern. I was trained as a physician, so my concern was more the compliance side of all this.

I can see that those patients, those obese patients, are very different from what the stereotype is. And again, the old stereotype, and lots of the publications, lots of the arguments about only once per month or once per week, one injection because it needs to be this way; otherwise, compliance will be a problem. We don't see this.

Gotcha, gotcha. Well, as I'm listening, I'm thinking that glucose delivered in beads strikes me as potentially in the category of nutraceutical. So, I'll ask whether it's initially or eventually a prescription pharmaceutical, an over-the-counter nutraceutical, one or the other or both. What are the thoughts there?

The nice thing, from a regulatory perspective, is everything is open; everything is on the table because it's GRAS, Generally Regarded as Safe. This is a completely safe product; all our data supports this. What you would think about glucose — that it does no harm,  and it doesn't. We've shown this many times now in more than 300 patients. So, all of the above routes would be open.

We decided to go the pharmaceutical route because I think, again from a physician background and how I think about the management of the problem, it’s good to have your diabetologist or your cardiologist or whomever would be responsible for you following this regimen at your side to really reinforce your behavior and help you with going through this.

We also see this with our PRs in our studies, that they do not have to intervene. But it's always good to reinforce behavior and say, this is good, and you see you’re losing weight, and isn't this a good thing, and so on. I really believe in this close relationship between a doctor and a patient, a physician and a patient. This is why we did it that way. We wanted to have the maximum outcome.

Of course, this could be immediately switched to OTC, right? There's no reason it shouldn't. But then we would lose the management opportunity that you would have in the other contexts.

To be totally fair, the margins are much higher when you have it as a pharmacological substance. I mean, that's an open secret. But, in all honesty, that was not the primary driver here.

Nutraceutical? I can reveal that companies that approached us, that we have discussed this with are not necessarily all pharma companies. There are companies which are also in the food business and do earn their money there. And they're trying to join the bandwagon with all these  how to lose weight.

And as you might know, the big food companies — and I'm not bringing up any names here — now have specially tailored groups of food and combinations of food for people on the path, right? So, that kind of thing is happening. They try to be part of this, and this is why they approached us, too.

I'm going to ask you about two horizons, one near and one far. And the near horizon I'm describing or thinking about is the one right in front of you and the other folks at Aphaia. Let's start with the formulation science or the delivery methods:

Are there any additional problems to solve or questions to answer or challenges to overcome that you and the folks have right in front of you that you're trying to move the dial on when it comes to the actual science and technology?

What we built, these beads, are something that has never been done before. No one has ever achieved this. It was tried before by an Australian group, for example, but it has never been achieved. And now, what opens up is a massive playground.

So, I've told you about the distal small intestine. When you talk about the distal small intestine and the nerval efferents, the nerves that actually go from those cells or from the mucosa there to the brain. The further you go down in the small intestine, the higher the brain center that is targeted. So, there's a hierarchy in all this.

What we're going to do now, together with our friends and colleagues in Toronto, is map this. We're going to build our formulation, modify our formulation — that's

a dream becoming a plan right now: We're going to map the surface and see what actually projects where, what this function projects where? Because you can actually map this with an MRI. And then we would know where to target.

As you know, GLP-1s have been massively discussed in the context of addiction and addictive behaviors. I mean, we could do the same. Very distally, there's a cell population that directly connects to the reward cycles in the brain. Getting our payload down there and getting a full burst release on those cells, rather than further upstream — just concentrating all our load down there could be very effective. This is one thing.

The other thing, with a formulation change or with an adaptation of the formulation, the idea [to] target the cells that project into the substantia nigra. The substantia nigra is the place in the brain where the cells degenerate in the context of Parkinson's. And there's a high correlation between Parkinson's disease and obesity. So, there could be a connection, could very well be that the lack of trigger from those cells leads to degeneration up there [the brain].

So, this is all speculation at this point. And I think we're allowed to speculate. As scientists, we need to speculate to understand what we now need to prove. But we have the tool in our hands to really try all this. And this would be something we could do.

So, having the Aphaia formulation right now that promises to be very effective in obesity is not the end. What really comes now is to home in on really different regions in the small intestine to have very focused stimulation and see what happens to that. I cannot promise what the result would be, but if you really think about this from a physiological and pathophysiologic perspective, it's quite promising.

Gotcha, gotcha. And so, I'm going to ask you this final question, one farther out — you can define how far you think the far horizon might be. Maybe you'll say it's not far at all.

Looking at any of these aspects of product development, whether it's making your way through regulatory pathways, whether it's getting buy-in from medical practitioners and prescribers, whether it's managing the payer landscape, and then certainly patient adoption:  Looking a little bit further out, what do you see in any of those avenues that needs to be traversed, so to speak?

And then, if you can look with your hopes and dreams lens on: Should these solutions and products and approaches land in the market at some degree of scale, how do you think the therapeutic landscape and the lives and health patients will look?

So, starting with the regulatory landscape, which obviously, from here to approval are the next steps, which are quite important. I mentioned before that it's GRAS. We had IND discussions, and we have an IND on the substance with the FDA. We talked about this with the FDA.

I can say that I have never had more amicable interaction of the FDA than this one. Because it's GRAS, it's uncomplicated, and it comes with a lot of promise. This was a very good experience.

We  built our trials, our Phase 2 trials, in a way that we said, “You take this at 8 o'clock and you take this at 4pm, plus or minus 30 minutes.” But that's it: no calorie restriction, no need to exercise, no lifestyle changes, nothing. We didn't mandate any of those, which actually means that it's massively de-risked in its progression to Phase 3.

So, this is one of the strong points. People thought we were crazy when we hadn’t confined everything, or had so little ring-fenced it, you could say. But we thought, no, we want to be in a real-world scenario. We want to know whether it works in a real-world scenario or not. And this has always been the spirit behind this.

I think that regulatory should be relatively straightforward.

Patient adoption is something I really look forward to learning about in our trials. I can say that in our trials it was surprisingly well adopted. Surprisingly, because I thought, well, twice per day and stuff, right? Is this really going to land for the people? Are they going to adopt it? Is this seen as a burden? No, as I told you, they say, it's great that I can be part of this.

So, it's going to be about education. And that's the key point, I guess. We need — and this is why I'm very grateful that you have us here and have me here. We have to tell the story again and again and again because it's so different from what's out there. It’s such a different idea behind this. It's this idea to restore balance in the body by using the body's own resources.

[We] need to tell this. So, I'm going to conferences, I'm sitting on panels, I'm giving talks there, trying to advocate for this. And it works. It works.

And what I really think what's also important is, when you think about how this would change the life of patients, I really think that it has the potential to massively improve outcomes.

If the data as we see them now — it’s still blinded, I can't wait to see this unblinded in a few months: If this development is really what it is, then there will be a massively positive effect on patients. We will keep them on the treatment … we have the chance to keep them on there chronically for long term, maybe forever. And this would actually allow us, if we're effective enough, to actually get them to the cardiovascular benefits. So, it would necessarily better patient outcomes.

Maybe as the last thought: With sugar being one of the things we have more than enough of on this planet, in every corner of this planet, we could really build something, together with our partners — and we have already modeled this — that will be very accessible to patients in need, which is not the case for GLP-1 agonists. It’s still not, despite all the massive investments and efforts from the respective pharma companies, which is absolutely laudable as an effort, right? But it's a far more complicated thing that they have in their hands.

So, that's the dream: to really build something that could be rolled out globally. As I said, we modeled this. It could really better the life of many patients. And I'm really convinced, if we get the data in as they look and as we hope for them, then it's going to work. Then we're going to do this.

Great, great. Well, it all sounds very promising. Steffen. I want to thank you for joining me to give some visibility into the work there to our Drug Delivery Leader audience and share your perspectives on the need for it. And to that audience, I want to thank you for joining for another episode of Sit and Deliver. And we'll see you next time.