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Welcome to BIOTECH NATION !!! With understandable interviews requiring no background in science, BTN attracts a wide global audience. From everyday people looking for hope in treatments in development, to bioentrepreneurs interested in the experience of their fellow travelers, to venture capitalists looking for possibilities in cutting-edge breakthroughs, to scientists simply interested in the work of others, BioTech Nation is the voice of human endeavor, driving science to new realities for everyone. These interviews are drawn directly from the public radio program, "Tech Nation", which also can be heard in numerous global radio and podcasting venues.
The world we know is changing. I'm Moira Gunn and welcome to Biotech Nation. There's no doubt that Ozempic and Wegovy and similar drugs are at the forefront of today's popular approach to weight loss with many also intended to treat type 2 diabetes. Common to their success and key is releasing the hormone known as GLP 1. But GLP 1 is only one of a whole complement of hormones involved.
Dr. Moira Gunn:What about bringing all of the relevant hormones back into play and without an injection? Doctor Steffen Sebastian Bolz is the chief scientific officer of Aphaia Pharma in Zurich, Switzerland. Doctor Bolz, welcome to the program.
Dr. Steffen-Sebastian Bolz:Thanks for having me.
Dr. Moira Gunn:I've never started a biotech interview in this particular way, and it's because of something you told me in our pre interview. And what you told me was about eating refined food versus, we'll say, whole foods. And the role of or problem with our small intestines when we eat those foods. Now now paint that picture for us.
Dr. Steffen-Sebastian Bolz:I'm happy to. So let's go back 130 years. 130 years ago, the Swiss surgeon, Cedric Roux, who is actually who stands for the r in RYGP surgery, which is the surgery that's applied to morbidly obese patients to reduce the size of their stomach. So, essentially, who did this this operation and taught us many things. Among those things was the fact that the small intestine can be separated into 2 parts.
Dr. Steffen-Sebastian Bolz:One upper part that is equipped to absorb food and one lower part that is equipped to sense food. And that's actually an ingenious construction because whenever you eat food, some of the food makes it way down to the second part of the small intestine where its presence can be sensed. And that actually generates a signal that ramps up digestive processes. And that's exactly what you need when you have have food intake. You wanna use the food.
Dr. Steffen-Sebastian Bolz:You would wanna utilize it, and you wanna digest it first, and then you wanna take it up and distribute it in the body. And that's orchestrated by the lower part of the small intestine. And what's important is what's implied here is that food gets down there. The problem we have with a highly refined food is that less and less food actually reaches this distal part of the small intestine. The reason for this is that it's not only the fact that the food is refined.
Dr. Steffen-Sebastian Bolz:It's also the quantity and the whole composition of food. Now we eat far too much fat and far too much proteins, which slows down the passage passage to the upper part of the small intestine, and that's a problem because what is now lacking is the stimulation of the slow lower part of the small intestine, which is essential to regulate the process.
Dr. Moira Gunn:Now when we get a portion of the food down to the lower part of the lower intestine and the the cells down there, the food sensing cells are down there, What happens from there in our body?
Dr. Steffen-Sebastian Bolz:This is actually very, very fascinating. It was noted that these cells were responsible for higher insulin output to digest glucose. What we know now is much more they do much, much more. They have they have direct nerve links to the brain. They can regulate brain functions like hunger, satiety, energy expenditure, and and at the end of the day, food intake.
Dr. Steffen-Sebastian Bolz:And that's a property that that comes more and more into the focus of everything we do and try to try to, affect with our with our therapeutic approaches. The reason why these cells can do this is that they produce hormones, as I said before, and these hormones can stimulate nerve endings that directly project into the brain. And some of these cells even form synapses with the nerves in the brain. So they actually directly connect to the brain. This is how you can actually look at this.
Dr. Steffen-Sebastian Bolz:And this is, this gives the brain a very clear picture, and you just said it, Maura, not only that food is there, but even what quality food is on there. So it's a very it's a very fine tuned mechanism. And so we have 3 different signaling mod modalities. 1 is endocrine, which are the hormones, then neuroendocrine, where the hormones stimulate nerve cells, and then a direct connection to the nerve cells, which is a neuronal pathway. And these three things together incredibly powerful to regulate our behavior and our energy expenditure.
Dr. Steffen-Sebastian Bolz:So when we treat those cells, when we stimulate these cells, we actually directly tickle the brain. And that's something that kind of surfaced as an idea only a few years ago.
Dr. Moira Gunn:Now I feel hungry is in our brain. I feel full is in our brain, not in our stomachs.
Dr. Steffen-Sebastian Bolz:Well, there is you feel full, and this is why pretty much every language has has this term, I feel full. Right? And and, so because he can feel it. And this is the distention of the stomach. And this gives the first signal to, hey.
Dr. Steffen-Sebastian Bolz:You better stop now. But but this isn't this can adapt. So some people can eat enormous amounts of food as we know. But what what you feel later on so when you feel hunger, when when hunger ceases, that's an effect of those pathways we talked about before. Hunger goes away, and that's important because then your whole behavior changes.
Dr. Steffen-Sebastian Bolz:Food cravings stops. Even craving for certain specific special foods like chocolate stops. And this is this is a central effect. It's not that feeling full. It comes later.
Dr. Steffen-Sebastian Bolz:It's an effect that comes to the back door and regulates your behavior. That's your brain. That's not the stomach.
Dr. Moira Gunn:Now we've all heard so much about Ozempic, the weight loss drug, and something called GLP 1. Paint that picture for us. And how does that relate to what you've told us?
Dr. Steffen-Sebastian Bolz:Well, it actually it's very closely related. Because when when this when these mechanisms were discovered that these hormones can sensitize the pancreas to to produce more insulin, and GLP 1 was then after it was cloned and made available and accessible, was used and designed to treat type 2 diabetes. Based on this idea that it exerts metabolic control mostly on glucose. And it was approved for for type 2 to treat type 2 diabetes in 2,005. Only much later, and that was in 2021, it was approved to induce weight loss or to treat people with obesity in order to allow them to lose weight.
Dr. Steffen-Sebastian Bolz:This is what Vicovea and Ozempic do. The point here is the fact that that they these these that, you know, if you want to induce weight loss was was a serendipitous finding during the trials. It was never meant or designed to to induce weight loss. It it came second. It's a very, very well defined effect.
Dr. Steffen-Sebastian Bolz:It's a very it's a f an effect that's very beneficial to the patients without any question. The point is GLP 1 is just one of many hormones that are being released from from those cells. And these cells release many more, many other hormones, GLP 2, which which has very prominent roles locally around those cells. Then, oxymptomodulin, placentin, PYY, just to name a few. It's a whole portfolio of formers that interact very precisely to regulate all the different functions that are necessary when you eat something.
Dr. Steffen-Sebastian Bolz:You can see there are many functions that that need to be that need to be orchestrated, need to be achieved by very different hormones. And gmp one is just one of those. That's that's the point. And it was a it's it was a very good choice to to to type to treat type 2 diabetes and also now weight loss. But there's much more to come.
Dr. Steffen-Sebastian Bolz:It's if you wanna if you wanna look at it as a treasure chest down there, it it certainly is one because there are many, many more, many other hormones that we could exploit.
Dr. Moira Gunn:Now this whole area that Afaya is working in, what are you doing?
Dr. Steffen-Sebastian Bolz:Well, we act we came together, and we we looked at what's known. We we looked at what's known, and and we first we were first fascinated by how well the system is orchestrated. And then we we thought this should be something that we could use potentially. And the idea was a combination of what the two things we've talked about before. So it was very well known that GLP 1 is a very potent hormone, has very has a lot of beneficial effects, and that GLP 1 is normally produced by those cells.
Dr. Steffen-Sebastian Bolz:The fact that it is it is not produced anymore is due to the fact that these cells are deprived from contract to food. So food that normally gets down there in a and when you eat eat healthy and when you're when you're healthy yourself, does not appear anymore down there in patients with metabolic diseases, most importantly, obesity, but also lots of other diseases. It also it's it's affected by our quality of food as we discussed before. If you eat highly refined food and and and and inadequate compositions, you have a lack of exposure of these cells to to food. So the very simple the the frighteningly simple idea we had is to just reexpose these cells to food.
Dr. Steffen-Sebastian Bolz:So we develop beads, or a better word word might might be granules. And these granules behave like fluids. And because they behave like fluids, they are able to bypass the food that blocks the the upper part of the small intestine. And this is why they will get down to this to the lower part of the small intestine no matter what happens or blocks the the upper part of the small intestine. That's exactly what we wanted to achieve.
Dr. Steffen-Sebastian Bolz:And once we were sure that we got our beats down there, completely independent of who who took them, how much that people had eaten before, and so on, we have to decide what to put into the beats because it's it's not about the beats. It's about getting them down there, but they they have to release something to stimulate the cells. And what we found to be most effective to stimulate these cells as a food component is glucose. Just simple glucose because the cells are equipped very well equipped to sense glucose. And the signal they generate after having seen glucose, after having sensed glucose is a massive signal that then leads to the release of all the hormones we we talked about before.
Dr. Steffen-Sebastian Bolz:And these hormones then as a receptor.
Dr. Moira Gunn:All the hormones, not g l just GLP 1? All the hormones?
Dr. Steffen-Sebastian Bolz:All the all the hormones, not not just GLP ones. The entire portfolio. And that's that's an important fact. And these hormones will then do what they need to do locally. They will they will get into the bloodstream, get distributed throughout the body.
Dr. Steffen-Sebastian Bolz:They will they will excite the nerve endings and so on. And this is all preformed. We use what's already there. The only thing that might be our claim to fame is we wake up a system that fell dormant because these cells haven't seen fruit components in quite a while. So this is why we why we what we do here is really kind of waking the cells up and exploiting a a complete mechanism that's already there, formed in 1000000 of years and optimized in 1000000 of years.
Dr. Moira Gunn:Are these cells sort of dormant, in these conditions like obesity?
Dr. Steffen-Sebastian Bolz:What we think and and and what what the literature thinks is is, that these cells, yeah, you could call it dormant. So because of the lack of exposure to food, they even down regulate the the different proteins that are there to sense food. So they they become less ready, less equipped to sense food. So there could be even such effect as waking them up and then getting them back to full speed over time. We don't know this yet.
Dr. Steffen-Sebastian Bolz:But it's very well accepted that a common denominator of all these metabolic diseases is the lack of exposure to food, which has this impact on those cells. Yes. As I said, more dormant is a good is a good description. I mean, we've we've described at other places just Sleeping Beauty. And in this case, we would be the prince.
Dr. Moira Gunn:There you go. Very good. Now let me also ask you. You you keep saying glucose. How different is that from just sugar?
Dr. Steffen-Sebastian Bolz:It is actually just sugar. So they're they are different. That's not quite accurate from a from a chemical biochemical standpoint. But when we talk about sugar, we actually refer to glucose. That's I think that's an accurate accurate definition.
Dr. Moira Gunn:Yeah. It's pretty much the same thing. Pretty much the same thing.
Dr. Steffen-Sebastian Bolz:Yes.
Dr. Moira Gunn:Now APHAIA, and for those people who want to know, that's aphaia. APHAIA, You're well into phase 2 in the US, in Germany, and in the nation of Georgia. And you're fully enrolled, and that's great. But I wanna start with phase 1, that time when you were first putting this drug into humans, the granules into humans. What did you do in phase 1, and and what did you learn?
Dr. Steffen-Sebastian Bolz:Well, we did a few things, and we learned a lot. So what what phase 1 typically is, and it was the same in our case, it's a phase of concept it's a proof of concept trial. So we had to prove our concept. And what we did is we chose we chose 20 obese and otherwise healthy people. This trial was conducted in Romania, and those 20 patients took our formulation in the morning.
Dr. Steffen-Sebastian Bolz:And then we did a pharmacodynamic, And that's a monstrous word, but it what it means is that we that we gave the formulation to the to the people and to the volunteers, and we took blood every 30 minutes afterwards. And in all those samples that we drew from them over the over 10 hours, we measured the hormones. We measured GLP 1. We measured oxenzyme albumin, GLP 2, PYY, and so on. And what we hope to find is that our treatment would increase the level levels of these hormones because that is the prediction after everything we we had discussed and we kind of fantasized about.
Dr. Steffen-Sebastian Bolz:And so what we saw was exactly that. Our treatment did release all those hormones. It released all those hormones in 20 patients, pretty much more or less at the same time point. So all the patient with the hormone profiles reached the peak within 1 hour. It was highly reproducible, which actually means that the idea to bypass the food bottles and also design a treatment that's independent of motility or or or length of the of the small intestine or whatever worked.
Dr. Steffen-Sebastian Bolz:And we we learned that that this that these hormones that we release were not just GLP 1, as I said before, but the entire portfolio.
Dr. Moira Gunn:Now you just don't say, here, take this packet of granules. What's the size of the of the of the packet or the amount of of granules? And how do you adjust it?
Dr. Steffen-Sebastian Bolz:So when you when you think about the dose, these very tiny beats kind of fill 1 teaspoon. And when you mix it with water, because we mix it with a powder that creates a Jell O, you have approximately 1 tablespoon of Jell O, which you then can ingest and wash down with water. And that is how you take it. So we try to make it easy to to take, and we try to make it palatable. And we also the gel can be can be flavored.
Dr. Steffen-Sebastian Bolz:So the the current flavor is orange, but you can you're free to choose any other flavor. The idea behind this is to make it as easy as possible because the ingestion should not be harmful, which is definitely isn't, and it should be easy to take because we want the patients to take this on a daily basis.
Dr. Moira Gunn:You've gone through this now with a number of participants in phase 1, many more in phase 2. They've gotta mix the the granules with water, come up with a tablespoon or 2 of of Jell O and then get it down. Has this been a problem? Have you lost participants because of this formulation?
Dr. Steffen-Sebastian Bolz:No. We didn't lose any patients because of the mode of intake. So patients were were happy with with the way they had to take the formulation and complied very well.
Dr. Moira Gunn:Now you say once a day. Does it matter when you take this?
Dr. Steffen-Sebastian Bolz:Well, what we did as as a start, and, again, this phase 2 trial that we that we designed is is a trial where we try to deliver the proof that our formulation, which worked well in the phase one, also works in a deceased population. So that was is our main goal. This is why we allowed the patients to take it or advise the patients to take the formulation 2 hours at minimum 30 minutes before their main meal, which means that the patient, he or she, had to decide whether it's gonna be the break before breakfast, whether it's gonna be before lunch or before dinner. And we did this on purpose because, again, we wanted to do this, make it as easy as possible for the patients, and we wanted to do it under real world conditions. That was our main goal.
Dr. Steffen-Sebastian Bolz:So we trusted our formulation quite a bit and did not try to put too many boundary conditions in. We we let them go very free with whatever they felt was necessary to do. They just had to take it regularly. And that's that's what they did. That's that's what they complied for.
Dr. Steffen-Sebastian Bolz:In further approaches, we might think about varying this this regime a bit because we know, and this links back to what what you what we discussed before, there are circadian effects when it comes to to food intake. So it's not only important when what you eat, but also when you eat food. And this is when you think about time restricted feeding, interval fasting, and all these kind of things. This is those are those ideas. And they could easily be combined with what we have in our hands right now.
Dr. Steffen-Sebastian Bolz:Because what we do, and that is what's clearly shown by our phase one data, we emulate the hormonal response of an entire meal with 8 to 12 gram of glucose that has not even been absorbed. And that's that's what we what we're gonna build on now.
Dr. Moira Gunn:Well, right now, you have about a 150 patients in in phase 2 studies across 3 countries. How long will it be before we get some results from that phase 2?
Dr. Steffen-Sebastian Bolz:Well, we we know pretty well when this when this will when we will get the first results because we have all patients enrolled and we know the treatment durations, so we can very well extrapolate. And we're gonna get the first headline results in June next year, so on June 24.
Dr. Moira Gunn:Pretty quick. Pretty quick for that. That'll be very interesting. You said another thing in our pre interview that I wanna bring up. You said that 70% of prediabetics convert to diabetics within a year.
Dr. Moira Gunn:And you're trying to intervene here as well with this same drug. Tell us what you're trying to do here.
Dr. Steffen-Sebastian Bolz:Yeah. So I think that's that's that's the the second phase 2 trial that would that is ongoing and that we are fully enrolled. And the idea behind this is is, again, relatively simple. As you said, depending on the age and the the comorbidities, you the prediabetics progress towards becoming diabetics pretty quickly within a year or at at latest within 5 years. So this is this is a point where one should intervene, where one should to start to treat patients to prevent this from happening.
Dr. Steffen-Sebastian Bolz:And that's exactly the idea of prevention that's that's being discussed everywhere is something where we thought we could do this because we have we have a simple drug a simple formulation. We have it is benign. It has a very it has a very benign side effect profile or adverse effect profile. So it could be something to really prevent something from happening. And this is why we tried whether it would be working.
Dr. Steffen-Sebastian Bolz:So the trial design is is, well, again, a short trial. We do not wait for them to convert or not to convert because that would take too much time. We look at their oral glucose tolerance. And the the oral glucose tolerance is affected in prediabetics. They have a reduced oral glucose tolerance, which means that the glucose that the blood glucose goes higher and needs more time to come back down again than in a healthy population.
Dr. Steffen-Sebastian Bolz:This can obviously be measured. And what we did is we designed the trial in a way that we treat those those prediabetic patients with our substance, and the surrogate parameter for improvement is our our glucose tolerance test. And what we hope to see is that after 6 weeks of treatment with our formulation, the our glucose tolerance will improve in those prediabetics, which would be an indicator that the prediabetic situation itself also improves, which would could mean that the progression towards diabetes gets delayed. And that would be prevention right there.
Dr. Moira Gunn:Now one last question. Diet sodas, everyone's drinking them. Sugar substitutes, you find them in every sugar bowl in a restaurant. You have regular sugar and right next to it, a number of sugar substitutes. What does that do in this small intestine equation?
Dr. Moira Gunn:Is it related there at all?
Dr. Steffen-Sebastian Bolz:Yeah. So this is a question that's that's a tricky one because, I mean, people and and we know this from many friends of ours are quasi religious about the fact that they eat this theory or whatever, and I try not to to mention the brands here, but everyone knows them. So what really happens after ingestion of those those, those drinks is only a part and not completely understood and controversially discussed. It's very clear that the sweetness that is maintained in those drinks and which is the primary stimulus, stimulates a digestive reaction in the body. And one of the ideas behind behind the fact why those drinks could be less effective than you would wish for is that this triggers an insulin response.
Dr. Steffen-Sebastian Bolz:And once insulin is up, you need to get glucose. You you get you become hungry, and you need to eat something. So what you could act what you could achieve with those with those strings is actually an opposite effect, that you eat more afterwards. But I would be I would be I try to to be very, very careful here because this is truly controversial. What it does in the in the distal small intestine as intestine that we're we're involved with and that we're interested in, there are absolutely no data.
Dr. Steffen-Sebastian Bolz:So I I I can answer you the your question, what's happening there. I can only tell you that that the facts are are diverse, and, many many people, that is why I said it's cross religious, benefit from those strings, and others see opposite effects. And what what's left to us, the scientists, is we try to explain what's happening, and that's all I can I can say to that?
Dr. Moira Gunn:The jury is out. The jury is out on that.
Dr. Steffen-Sebastian Bolz:That's true. Okay.
Dr. Moira Gunn:Well, doctor Bolt, very exciting. I hope you'll come back and see us again.
Dr. Steffen-Sebastian Bolz:Oh, I would love to. Thank you very much.
Dr. Moira Gunn:Doctor Steffen Sebastian Bolz is the chief scientific officer of Aphaia Pharma in Zurich, Switzerland. More information is available at Aphaia, that's aphaia, AphaiaPharma dotcom. Listen to more biotech podcasts atbiotechnation.com or subscribe on your favorite podcast provider. Bio Tech Nation is a regular feature of the weekly public radio program, Tech Nation. Listen to the full show via podcast or on your local public radio station.
Dr. Moira Gunn:For Bio Tech Nation, I'm Moira Gunn.