DPP-4

BASEL, Switzerland I October 23, 2024 I AMYRA Biotech AG (“AMYRA”), a company developing novel, oral digestive enzyme therapeutics for gastrointestinal diseases announced the peer-reviewed publication of its clinical proof-of-principle study with its lead product AMYNOPEP in Frontiers in Immunology – Nutritional Immunology ( https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1425982/full ). AMYNOPEP is the first and only gluten-digesting enzyme combination that supports and enhances the activity of critical endogenous enzymes on the lining of the small intestine. AMYNOPEP is designed to break down hard-to-digest gluten peptides into harmless and absorbable single amino acids and dipeptides, thereby supporting individuals with gluten-related health disorders in avoiding exposure to inflammatory peptides. AMYRA’s first-in-human clinical study assessed gluten-digesting enzyme efficacy using high-resolution analytics and demonstrated in near-real-time that AMYNOPEP swiftly and significantly enhanced the digestion of proteolytically-resistant, immunogenic gluten peptides in healthy volunteers. A team of researchers from AMYRA and the University of Greifswald (Germany) evaluated AMYNOPEP’s digestive efficacy on the degradation of a long, proteolytically resistant gluten peptide known as the 33-mer, which has been associated with an adverse immune response in celiac disease. The digestion efficacy of AMYNOPEP on the 33-mer was first assessed in vitro , demonstrating end-to-end degradation of the gluten immunogenic peptide into single amino acids and dipeptides. These in vitro results were then validated in a crossover study of 14 healthy volunteers who received stable isotope-labelled 33-mer with and without AMYNOPEP. The study clearly showed that AMYNOPEP enhanced 33-mer digestion kinetics within minutes, significantly increasing levels of stable isotope-labelled amino acids detected in blood. Strikingly, AMYNOPEP improved 33-mer digestion even under “stress-test” conditions that included competing food substrates such as hydrolyzed whey protein and wheat gluten, revealing up to 3 times higher maximum concentrations of labelled amino acids in blood with AMYNOPEP compared to control. “The positive results of this proof-of-principle study pave the way for a new therapeutic enzyme paradigm leveraging specific exopeptidase combinations that support, enhance, or even replace the activity of critical endogenous enzymes lining the small intestine,” said Dr. Sulay Mourabit, CSO of AMYRA and co-lead author on the study. In the human gastrointestinal tract, most exopeptidases are found at the intestinal brush border membrane, which is sensitive to inflammatory damage. These exopeptidases are essential for completing protein digestion by cleaving peptides from end-to-end, generating absorbable amino acids. He added: “As single agents, exopeptidases are inefficient as they have limited substrate range, and we see this with DPP-IV supplements currently on the market. AMYRA specializes in developing unique combinations of exopeptidases with complementary and enhanced activity, designed to thoroughly break down proteolytically resistant food peptides. Ultimately, complex digestive diseases such as celiac may require a combination of treatment approaches. Given the critical role of the exopeptidase machinery in the human GI tract, and the vulnerability of the intestinal brush border membrane to chronic inflammatory damage, we’re excited to see the role that AMYNOPEP will play in digestive disease therapeutics.” “This is an encouraging and far-reaching proof-of-principle study demonstrating the validity and therapeutic relevance of our approach,” said Dr. Werner Tschollar, CEO and founder of AMYRA and senior author of the study. “As a next step, AMYRA is planning further clinical studies to investigate AMYNOPEP’s enzyme efficacy, immune response suppression, and symptom relief in patients with celiac disease. We strongly believe that supplementing the body with specific exopeptidases will prove to be a valuable adjunct therapy to the gluten-free diet, which alone represents a suboptimal solution.” About AMYRA Biotech AG AMYRA Biotech AG is a privately held biotech company developing novel therapeutic solutions for patients suffering from dietary peptide-driven disorders including celiac disease, gluten sensitivity, and other gastrointestinal disorders. The Company’s proprietary enzyme combinations have the unique capability of rapidly and systematically digesting proteolytically resistant gluten peptides from one end to the other, generating harmless and absorbable degradation products in the small intestine.  AMYRA is based in Basel, Switzerland. For further information, please visit www.amyra.com. About AMYNOPEP Several digestive enzyme supplements on the market and therapeutics under development seek to help the body break down hard-to-digest gluten peptides, which are known to trigger adverse reactions in individuals with gluten-related health disorders. The vast majority of these are endopeptidases that target gluten digestion in the stomach and generate smaller protein fragments (peptides) that may retain the ability to trigger an inflammatory response. In contrast, AMYNOPEP is a novel therapeutic enzyme principle based on specific combinations of exopeptidases that thoroughly degrade gluten peptides from end-to-end in the small intestine, generating individual, easily absorbable, and harmless amino acids and dipeptides that are incapable of triggering an immune response. AMYRA’s lead exopeptidase combination, AMYNOPEP, is capable of digesting proline-rich, hard-to-digest peptides found in foods such as gluten, which is notoriously linked to gastrointestinal distress. SOURCE: AMYRA Biotech

iStock, hapabapa A retrospective cohort study of more than 33,000 patients with type 2 diabetes showed that Novo Nordisk’s GLP-1 may lower the risk of opioid overdose by 42% to up to 68%. Novo Nordisk ’s blockbuster diabetes drug Ozempic (semaglutide) appears to lower the risk of opioid overdose in patients with type 2 diabetes, according to a study published Wednesday in JAMA Network Open . Leveraging the federated health research network TriNetX Analytics Platform, the cohort study looked at the electronic health records of more than 33,000 patients with comorbid type 2 diabetes and opioid use disorder. Just over 3,000 patients were given semaglutide, while the remaining 30,000 were taking other anti-diabetic agents such as insulin, metformin and liraglutide. After propensity-score matching—in which study participants were balanced according to age, sex, ethnicity and comorbidities—patients on semaglutide demonstrated a significantly lower risk of opioid overdose versus other treatment groups. Compared with insulin, semaglutide suppressed the risk of overdoses by 58% while the GLP-1 receptor agonist held a 54% advantage over metformin. Semaglutide’s benefits were strongest against thiazolidinediones and dipeptidyl peptidase-4 inhibitors, resulting in a 68% and 63% reduction in the risk of overdoses, respectively. Semaglutide also performed significantly better when compared against other GLP-1 therapies. Relative to liraglutide, semaglutide resulted in a statistically significant 55% reduction in overdoses. The only other anti-diabetic medication that semaglutide was not significantly better against was Eli Lilly’s Trulicity (dulaglutide). Despite these promising data, however, the study’s authors acknowledged that their findings have several methodological limitations, such as potentially unmeasured and uncontrolled confounders and other biases inherent in observational studies. “Results need validation from other data resources and study populations,” the researchers said, noting that further studies are needed to “investigate the underlying mechanisms” of semaglutide’s effects on opioid use. Clinical trials are also necessary to better confirm the clinical benefits of semaglutide in this patient population. Despite these uncertainties, Wednesday’s study adds to the growing list of potential therapeutic benefits of semaglutide and GLP-1 treatments. Last week, a paper published in JAMA Internal Medicine showed that these incretin therapies could potentially help patients with metabolic dysfunction-associated steatotic liver disease reduce their risk of progressing to cirrhosis and its related complications. In July 2024, a separate study in the Annals of Internal Medicine showed that semaglutide may lower tobacco use disorder in diabetes patients . Meanwhile, a Phase II study suggested that GLP-1 therapies could also have cognitive benefits in neurodegenerative disorders, with Alzheimer’s disease patients on liraglutide showing slower cognitive decline versus placebo.

Three scientists whose work paved the way to the multibillion-dollar obesity drug boom have won the Lasker Award for “the discovery and development of GLP-1-based drugs that have revolutionized the treatment of obesity,” the Lasker Foundation announced Thursday. Joel Habener from Massachusetts General Hospital and Svetlana Mojsov from The Rockefeller University were honored for unraveling the molecular mysteries of the natural version of GLP-1 made by the body. And Lotte Bjerre Knudsen from Novo Nordisk was honored for figuring out how to turn the short-lived natural molecule into a longer-lasting drug. The trio will split the $250,000 that comes with the 2024 Lasker-DeBakey Clinical Medical Research Award, which is sometimes viewed as a stepping stone to a Nobel Prize. But while the Nobel committee at times seems to pride itself on honoring esoteric discoveries that, while foundational to science, are rarely known to the general public, several recent Lasker Awards have gone to researchers whose fields of work are currently in the limelight. For example, in 2021, the Lasker Foundation honored Katalin Karikó and Drew Weissman for their foundational work on mRNA vaccines that paved the way to Covid-19 shots. And last year the Foundation awarded Google scientists Demis Hassabis and John Jumper for their creation of AlphaFold, the AI-based software for predicting protein structures that quickly swept through biotech labs. Although 2024 might be remembered as the year GLP-1 drugs exploded on the market, the science behind them dates back more than four decades to the early days of genetic engineering, when scientists were just learning how to clone and manipulate genes for the first time. Habener, while studying the biology of diabetes, discovered what would later be called GLP-1 by looking at glucagon genes from anglerfish. The animal was chosen for its unusual organ that makes copious quantities of the blood sugar-stimulating hormone, and because it skirted early rules restricting work on human genes. In 1982, Habener found that the fish genes contained code not only for glucagon, but a similar gene that looked like glucagon but with six extra amino acids on one end. A year later, glucagon biochemist Mojsov moved from New York to Boston and helped disentangle how that molecular endcap on GLP-1 gets cleaved to release an active molecule. Habener, Mojsov, and other collaborators in Boston soon went on to show that the cleaved hormone potently stimulates insulin secretion and lowers blood glucose levels. By the early 90s, it was clear that an artificial version of GLP-1 could become the basis of a powerful diabetes drug, and companies including Eli Lilly and Novo Nordisk soon began working on the idea. Of course, making a good drug often turns out to be a lot harder than expected. Simply injecting synthetic versions of GLP-1 into the blood didn’t work well because much of the molecule got chewed up by an enzyme called DPP-4, and the rest got sucked out of circulation by the kidneys. But Knudsen, a Danish scientist in charge of GLP-1 work at Novo Nordisk, figured out a way around that problem. By attaching fatty acids to the drug, she helped it hitch a ride on a common blood protein called albumin, keeping it moving throughout the body longer. The work led to Novo’s drug liraglutide, and subsequent chemical modifications helmed by other scientists at the company led to the successor semaglutide, now sold as Ozempic for diabetes and Wegovy for weight loss. The franchise is now a blockbuster, and Wall Street analysts have projected that the category could be one of the biggest in industry history.