Targeting nutrient signaling in the gut to tackle metabolic disease

Obesity affects more than 800 million people worldwide and drives conditions such as type 2 diabetes and cardiovascular disease (1). In recent years, the treatment landscape for metabolic disease, particularly type 2 diabetes, has burgeoned. Synthetic drugs designed to target key signaling pathways in the gut effectively reduce blood glucose levels and restore insulin signaling. However, researchers at the global biopharmaceutical company Aphaia Pharma take a different, more natural approach to improve metabolic health. Their approach may well pay off as preliminary findings from a Phase I clinical trial suggest that their novel drug may be a viable alternative to more invasive procedures such as gastric bypass surgery. 

Moving down the tract

While relaxing after a tasty meal, the human gut is hard at work. As food and liquids travel from the stomach through the upper and lower parts of the small intestine they leave valuable nutrients in their wake. Gut function varies along this path, with upper regions driving nutrient absorption and passing along leftover food particles to lower regions where they orchestrate nutrient sensing. 

The gut reduces that slice of pizza to the basic building blocks of nutrition. Carbohydrates become simple sugars; proteins break down to amino acids; and fats transform into fatty acids and glycerol. These nutrients trigger the release of gut hormones that rapidly communicate information with other organs, including the pancreas, liver, and brain to regulate insulin release, blood glucose levels, and feelings of satiety. 

Dampened nutrient signaling contributes to the disrupted metabolic functioning seen in people with obesity and metabolic diseases such as type 2 diabetes (2). While deficits in blood glucose regulation and satiety are present in these patient populations, the exact causes remain unknown. Some studies suggest that a majority of food nutrients get absorbed in the upper small intestine, depriving the lower small intestine of the nutrients it needs to trigger release of gut hormones.  Alternatively, a variety of factors including a high fat diet, genetics, and environmental exposures may fundamentally change how cells in the gut respond to available nutrients. Either way, a common denominator across theories of metabolic imbalance is that hormone signaling is disrupted.

Following their release, gut hormones receive marching orders to infiltrate different downstream signaling pathways. Two hormones in particular, glucagon-like peptide-1 (GLP-1) and glucose-independent insulinotropic polypeptide (GIP), help lower blood glucose by stimulating insulin release and inhibiting glucagon release (3).  Over the last decade, drugs targeting these gut hormones, specifically GLP-1 receptor agonists, have gained popularity for treating type 2 diabetes. Some GLP-1 receptor agonists also lead to more than 20% weight loss, making them an attractive candidate for treating obesity and comorbid type 2 diabetes (4). 

In addition to behavioral and lifestyle interventions, gastric bypass surgery is an effective treatment for some individuals with obesity. Shrinking and rewiring the stomach to connect it directly to lower regions of the small intestine not only helps reduce food intake, but also dumps nutrients on top of the nutrient sensing cells that may otherwise be deprived of these signals. In line with this theory, gastric bypass almost immediately increases levels of key hormones like GLP-1 and GIP (3). 

Despite the promise of these treatments, side effects including nausea, gastrointestinal discomfort, and elevated heart rate often lead to treatment discontinuation, raising concerns about their long-term use (5). 

A simple approach to a complex system

In experiments conducted in the 1960s, scientists observed that oral administration of glucose better increases plasma insulin levels compared to intravenous administration, highlighting the strong connection between the gut and the insulin-producing pancreas (6). Glucose delivered directly to lower parts of the small intestine also better stimulates insulin release and secretion of the gut hormones GLP-1 and GIP compared to glucose delivered higher up the tract (7).  

This literature inspired scientists at the global biopharmaceutical company Aphaia Pharma in their quest to find a natural approach for the treatment of metabolic disease. The research team developed APH-012, an oral bead formulation designed to transport glucose to precise regions of the small intestine. Although the nuts and bolts of the technology remain proprietary, Aphaia Pharma scientists designed tiny coated beads that release natural substances specifically to the lower parts of the small intestine. “We can bypass everything that's happening in the upper small intestine that prevents nutrient sensing cells from exposure to food with a formulation that drops food on top of those cells,” said Steffen-Sebastian Bolz, the chief scientific officer of Aphaia Pharma. 

We can bypass everything that's happening in the upper small intestine that prevents nutrient sensing cells from exposure to food with a formulation that drops food on top of those cells. 
- Steffen-Sebastian Bolz, Aphaia Pharma

In contrast to most GLP-1 receptor agonists, which target just one hormone, the team at Aphaia Pharma hoped that exposing the nutrient sensing cells of the lower small intestine to glucose would result in a broader shift in metabolic response. “It's a good approach,” said Frank Duca, a gastrointestinal biologist who is not involved with the research but studies gut hormones and gut-brain signaling at the University of Arizona Cancer Center. “It's a more natural, endogenous approach to increase GLP-1 levels versus GLP-1 receptor agonists, which is going to be more physiological.” 

Aphaia Pharma recently completed a Phase I trial of APH-012 in 20 individuals with obesity. Following a single dose of the drug, the researchers observed a broad-spectrum increase in serum levels of important gut hormones, including GLP-1. In 90 percent of patients, they observed these effects within one hour of administration, evidence of low variability in this technology’s pharmacokinetic profile. Additionally, patients receiving APH-012 did not report any adverse side effects. The research team is currently preparing the complete findings from the Phase I trial for publication, which they hope will occur sometime this year. 

Bolz described the nutrient sensing cells of the lower intestine as Sleeping Beauty, awaiting her prince, APH-012, to reactive dormant physiological mechanisms and restore metabolic balance. The Phase I findings are promising and suggest that APH-012 pharmacologically mimics aspects of gastric bypass while avoiding the invasive surgical procedure.  Furthermore, designing a drug that combines multiple agonists to target the sundry gut hormones activated following a meal poses a challenge that oral glucose appears to meet. 

The proof is in the Phase II trials

Aphaia Pharma is in the process of recruiting 150 adult patients with obesity for a Phase II proof-of-concept study. The single dose used in the Phase I trial was too brief to measure any meaningful clinical endpoints. In contrast, the Phase II trial will follow patients taking a daily dose of APH-012 for either six months or a year. The researchers hope to see significant changes across a wide variety of measures of metabolic health, including weight, insulin resistance, fasting plasma glucose, cholesterol, and fatty liver disease. 

Aphaia Pharma has big plans for their small drug. A second Phase II trial is currently in the pipeline to determine APH-012’s impact on glucose tolerance in patients categorized as prediabetic.  Nearly a third of American adults have blood sugar levels hovering just below the threshold required to be considered type 2 diabetes. The good news is that prediabetes can be reversed and Aphaia Pharma is optimistic that APH-012 can step in and give a gut punch to blood glucose and delay or prevent the emergence of type 2 diabetes following detection of early warning signs.

This is why we think that APH-012 can be disruptive, and it can really change the treatment landscape. 
– Steffen-Sebastian Bolz, Aphaia Pharma

These studies are critical to determine APH-012’s potential in the clinic. GLP-1 receptor agonists are quickly hitting the market as an effective means of controlling insulin and reducing weight. In part, these drugs are so effective because they deliver synthetic GLP-1, which has a significantly longer half-life than endogenous GLP-1.  “A lot of the effects attributed to GLP-1 receptor agonists for weight loss are likely due to central mechanisms in the brain,” said Duca. “It's unlikely that increasing endogenous GLP-1 is going to be able to reach the brain to have the same effects on weight loss that the agonists will.” 

Researchers at Aphaia Pharma hope that the enhanced safety profile of their natural approach will give them an edge in an increasingly competitive market. With a lower risk of adverse events, APH-012 should have higher treatment compliance and reach a wider patient population. For this reason, the researchers think the oral bead formula could be particularly effective for treating younger populations. Childhood obesity is pervasive and scientists predict that it will increase by 60% over the next decade, reaching 250 million by 2030 (1). 

“This is why we think that APH-012 can be disruptive, and it can really change the treatment landscape,” said Bolz. 

References

1. The Lancet Diabetes Endocrinology. Metabolic health: a priority for the post-pandemic era. Lancet Diabetes Endocrinol  9, 189 (2021). 
2. Duca, F.A., Waise, T.M.Z., Peppler, W.T., & Lam, T.K.T. The metabolic impact of small intestinal nutrient sensing. Nat Commun 12, 903 (2021). 
3. Drucker, D.J. The role of gut hormones in glucose homeostasis. J Clin Invest  117, 24–32 (2007). 
4. Jastreboff A.M. et al. Tirzepatide once weekly for the treatment of obesity. NEJM  387, 205-216 (2022).
5. Drucker, D.J. Advances in oral peptide therapeutics. Nat Rev Drug Discov 19, 277-289 (2020). 
6. Elrick H., Stimmler L., Hlad C.J. Jr., & Aria Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab  24:1076-82 (1964).
7. Wu, T. et al. Comparative effect of intraduodenal and intrajejunal glucose infusion on the gut–incretin axis response in healthy males. Nutr & Diabetes  5, e156 (2015).