Beyond GLP-1s: is there a new wave of metabolic disease treatments? 

The likes of Ozempic and Mounjaro stirred a media frenzy over two years ago, which has stuck around, as off-label GLP1 agonists have taken over online market spaces. But many people who have metabolic diseases like diabetes and obesity can’t access these medicines, simply because they don’t work for them. A new wave of drugs is emerging to address these unmet needs of people with metabolic diseases. 

Aphaia Pharma’s glucose formulation: activating the brain to release hormones 

The mechanism of GLP-1 agonists is straightforward. They mimic the effects of the naturally occurring hormone, GLP-1, which regulates blood sugar and appetite in the body. While they are highly targeted as they are tuned to specific receptors, they also come with a host of side effects including nausea, vomiting, diarrhea, and constipation.  

“When you look at the hormone replacement therapies like Mounjaro (tirzapetide) which is dual agonist imitating GLP1 and GIP, what they try to emulate is part of this endocrine response. They do this by injecting hormones that are stabilized. And they take this in very high concentrations. The idea is to not only activate their specific receptors, but have a widespread effect, as we know, that produces a lot of side effects. Beside all the benefits, it produces a lot of side effects, which is seen as the primary problem these days,” said Steffen-Sebastian Bolz, chief scientific officer (CSO) of Aphaia Pharma. 

So, what if instead of mimicking hormones like GLP-1, you could just turn on already existing pathways in the body to regulate blood sugar and appetite? Seems like a challenge, but Aphaia Pharma is rising to it.  

The Swiss company has figured out a way to activate parts of the brain to signal fullness and activate key metabolic pathways with the help of glucose that switches on cells in the lower part of the small intestine. 

“The (lower part of the) small intestine is optimized to sense nutrients. Those cells do not absorb anymore, but they are able to sense nutrients, which actually means that these cells in the epithelium that can sense the quality of foods; whether it’s glucose, a complex carbohydrate, proteins, lipids, or flavonoids, they can actually sense exactly what it is, which is remarkable,” said Bolz. 

But unfortunately, most often, food does not reach this part of the small intestine as it is absorbed fairly quickly by the upper small intestine. 

“The main reason for this is that we eat food in quantities that are beyond what we should eat but also in a composition that we should not eat. We eat far too many proteins and lipids, and actually, not enough complex carbohydrates and fibers,” said Bolz. “This is the problem, and this slows down the passage of the food bolus.” 

If these nutrient-sensing cells in the lower part of the small intestine were to come into contact with nutrients, Bolz explained that this instantly triggers a broad repertoire of signaling mechanisms that regulate various functions like appetite and metabolic activity. This includes the release of a whole spectrum of hormones, like GLP-1 and others, as well as direct signaling of neuronal pathways to the brain via vagal afferents. These are sensory neurons that carry information from organs to the brain and are sensitive to signals from the gastrointestinal (GI) tract, including the uptake of food. 

Metabolic disease drugs: can Aphaia’s glucose bead prevent diabetes? 

Aphaia’s technology is essentially an oral glucose formulation in the form of many beads and a powder that forms a hydrogel when it comes in contact with water. The beads are designed to travel to the lower part of the small intestine bypassing the food bolus – the ball-like mixture of food and saliva that forms in the mouth upon chewing – where it is released to interact with the cells there. 

“Why we formulated glucose is so that it is not held up by the pyloric sphincter (the muscular ring at the lower end of the stomach). Because it behaves like a fluid, our formulation travels alongside the walls of the small intestine. It doesn’t matter whether there’s a food bolus or not, if we take this formulation, after two and a half hours, it will actually trigger those cells,” said Bolz. “It was actually a very conscious decision to use glucose.” 

For people who are pre-diabetic, this could be major in preventing diabetes. So far, the formulation has been tested in two phase 2 trials in patients with pre-diabetes as well as people with obesity who have type 2 diabetes and/or metabolic dysfunction-associated steatohepatitis (MASH) – a serious form of liver disease where fat buildup causes inflammation and damage – among other comorbidities. It has been found to improve glucose tolerance in the clinic. 

In both trials, the glucose formulation, also known as APHD-012, achieved targeted release in the distal small intestine, and managed to release a range of hormones such as GLP-1, GLP-2, peptide tyrosine-tyrosine, glicentin, oxyntomodulin, and glucose-dependent insulinotropic peptide (GIP), all of which are involved in metabolic activity. 

“By virtue of the design of the beads, our response lasts longer, so the total amount of released hormones is larger than after a meal; that’s a desired effect. We don’t see side effects because our responses never go higher than following a normal meal, which the system is adapted to,” said Bolz. 

New ways of regulating metabolism in diabetes and obesity 

Moreover, it released insulin, a key indicator of metabolic health.  

“What we do is very targeted. We target those cells, and we use what’s already there. We use, if I may put it this way, what mother nature provides. Those cells have these hormones pre-stored in vesicles, and all we do is trigger those responses to actually let those hormones out and let them do their job.” 

In pre-diabetic patients, the therapy improved glucose levels for six weeks, according to an oral glucose tolerance test (OGTT) while placebo had no significant effect on patients.

“The vagal nerve projects down there. It is the main target that we need to use to change satiety in a physiological way. This is where we need to trigger those cells to use the infrastructure that’s already there. It’s like lighting the Christmas tree,” said Bolz. “You put in one plug, and then the whole thing lights up because you have put all the lights where they should be before. But it’s inevitable, they all light up. That’s exactly what we’ve done there.”   

Besides, as the twice-daily medicine is an oral formulation that can just be washed down with water or even yogurt, it is more convenient to take compared to GLP-1 agonists, which are given as injections.  

Cortisol: a key driver of metabolic disorders  

As Aphaia’s candidate aims to go beyond the scope of GLP-1s, at the crux of it, is finding ways to address unmet medical needs. This is also what researchers at American biotech Sparrow Pharma want to do by targeting cortisol. 

Currently a buzzword doing its rounds in the wellness space on social media, cortisol is a hormone released by the adrenal glands, and excessively at times of stress.  

For people with endogenous Cushing syndrome, cortisol is overproduced often due to a tumor in the brain – usually, not cancerous – which can lead to other metabolic conditions like type 2 diabetes, obesity, and severe heart problems.  

Sparrow thinks that targeting cortisol is the way to go. Its lead candidate clofutriben blocks an enzyme called 11β-Hydroxysteroid dehydrogenase type 1 (HSD1), which regulates cortisol levels inside the cells.  

Cortisol actually gets converted into its inactive form, cortisone, which circulates around the body and acts like a reservoir of inactive steroids. But what HSD1 does is that it converts cortisone back to cortisol inside cells. So, in people with metabolic conditions where the underlying cause is excess cortisol, the best bet is to put a plug on the enzyme responsible for this, which is HSD1.  

Metabolic disease drugs: Sparrow Pharma’s clofutriben takes on cortisol imbalance  

However, unlike Aphaia’s approach to treating metabolic conditions where the goal is for patients to turn to its glucose formulation instead of GLP-1s, Sparrow’s chief executive officer (CEO) Robert Jacks explained that clofutriben is specifically for people whose metabolic conditions are caused by abnormal cortisol levels, and these patients will most likely already be on GLP-1 agonist treatments. 

“I think that a lot of patients out there are very frustrated; they’re looking around and everyone else seems to be doing really well on these GLP-1s. I think that’s a very difficult place to be,” said Jacks. “Patients are often blamed by providers who say ‘Oh, they must not be compliant, or they must have a poor diet, or not be exercising enough.’ But unfortunately, for a lot of these patients, there’s another underlying driver of their disease that they’re not aware of.” 

Jacks compared this feeling to swimming upstream against an invisible current.  

“They don’t know it, and they don’t realize that there’s something that’s making it very difficult for them to control their disease,” said Jacks. “So, I think offering those patients an answer to say, ‘we can test you and identify why you’re having difficulty treating your disease, and that we have a targeted agent to specifically address the underlying driver of your resistance;’ I think that is a very exciting breakthrough.” 

Sparrow was granted orphan drug designation from the U.S. Food and Drug Administration (FDA) last year, and its recent $95 million series B funding round will back a phase 2 study of clofutriben in patients with type 2 diabetes linked to elevated cortisol. As nearly half the patients with diabetes that is difficult to manage have high levels of cortisol, this study holds promise. 

“Pretty much most diabetes patients are going to be on GLP-1 agonists soon. Despite that, diabetes prevalence is growing faster than the rate of population. Half of patients are still not well-controlled; cardiovascular disease, often caused by metabolic syndromes, remain the leading cause of death in the U.S. So, there’s a huge amount of unmet medical needs remaining,” said Jacks. “I think one thing that the GLP-1 craze has done is turned a lot of eyes back to this space.” 

While the GLP-1 receptor agonist market hit $53.46 billion last year and is projected to reach $156.71 billion by 2030, according to a report by Grand View Research, hormone therapies, particularly GLP-1s aren’t going anywhere anytime soon. Although this class of drugs dominate the metabolic disease space at the moment, there are many people who could benefit from a wider range of therapeutic options. That’s what Aphaia and Sparrow’s technologies could do, and how well they succeed in late-stage studies might be worth watching out for.