As Eli Lilly and Novo Nordisk gain multiple approvals for their blockbuster weight loss drugs, a new model for developing drugs for metabolic disorders may be emerging in the pharmaceutical sector.
In July, the European Medicines Agency’s (EMA) Committee for Medicinal Human Products (CHMP) recommended a label expansion for Novo Nordisk’s semaglutide to include its use as a drug for reducing cardiovascular risk. Apart from its popular use as a treatment for obesity and type 2 diabetes, the drug, which is marketed as Ozempic and Wegovy, is also being developed for several different metabolic disorders including metabolic dysfunction-associated steatohepatitis (MASH), peripheral arterial disease, kidney disease, and more.
According to GlobalData, there are currently 202 ongoing clinical trials investigating semaglutide for its different uses.
GlobalData is the parent company of Pharmaceutical Technology.
Similarly, the FDA first approved Eli Lilly’s weight loss and diabetes drug tirzepatide in May 2022 for the treatment of type 2 diabetes, which helped the pharmaceutical giant earn $9.35 billion in overall 2023 revenues. Now, Eli Lilly is also investigating tirzepatide, which is marketed as Mounjaro and Zepbound, for multiple indications including MASH, obstructive sleep apnoea, and more.
Both Eli Lilly and Novo Nordisk’s therapies are glucagon-like peptide-1 receptor agonists (GLP-1RAs), which have risen in prominence over the last few years. This class of drugs shows major potential for several metabolic disease areas, says Dr. Paul Brennan, a clinical lecturer at the University of Dundee, Scotland. The success of the GLP-1 receptor agonists has opened a wider discussion about the possibilities of therapeutic development for several metabolic disorders, says Brennan.
In addition to the pharmaceutical giants’ plans for their approved drugs, other pharmaceutical companies are also choosing to expand their strategic plans from the outset, funneling money towards several different metabolic conditions from the beginning of the drug development cycle. Amgen, AstraZeneca, and smaller biotechs like NeuroBo Pharmaceuticals are a few of the companies developing therapies for sleep apnoea, heart failure with preserved ejection fraction, and more indications.
“We do not always know the downstream effects of any new agent until we have it in the clinic and watch people,” says Dr. Margaret Morris, the head of pharmacology at the University of New South Wales’s School of Medical Sciences, Sydney. As such, the possible uses of several pipeline weight loss drugs could extend much further than initially expected, she says.
The metabolic drug label
“There are people who are obese, [but] who do not have type 1 or type 2 diabetes…they have what's called metabolic syndrome,” says Dr. Morley Hollenberg, a professor in the Department of Physiology and Pharmacology at the University of Calgary, Calgary, Canada.
The US National Institutes of Health (NIH) describes metabolic syndrome as a “group of conditions that together raise your risk of coronary heart disease, diabetes, stroke, and other serious health problems. Metabolic syndrome is also called insulin resistance syndrome.” Markers of this include low high-density lipid (HDL) cholesterol, high triglycerides, high blood glucose levels, and more. Thus, metabolic syndrome encompasses symptoms and risk factors that can lead to several metabolic conditions.
It may not be “outlandish” to see a regulatory label for drugs to treat metabolic disorders overall in the future, says Hollenberg.
Several investigational metabolic disorder therapies act to reduce factors such as oxidative stress, steatosis, and fibrosis, which are common symptoms or risk factors for several diseases such as heart failure, says Brennan. For example, Madrigal Pharmaceuticals’ recently FDA-approved therapy, Rezdiffra (resmetirom) for non-alcoholic steatohepatitis, which is now called MASH, has been shown to have an unintended benefit of reducing low-density lipoprotein (LDL) levels and cardiovascular disease. “[Among patients with] metabolic dysfunction-associated liver disease, 5% of patients will get end-stage liver disease, and the other 90–95% will develop cardiovascular disease and cancer, including hepatocellular carcinoma,” he adds. Thus, regulators already view these disorders and their impacts in tandem with each other, says Brennan.
Currently, there is a push for clinicians to look at metabolic markers initially if patients experience any metabolic syndrome symptoms, says Hollenberg. Sometimes, this also translates to clinical trials, he says.
If an agent is effective in one metabolic disorder, it is likely that it will be “very useful” in other metabolic conditions, says Hollenberg.
Hollenberg’s lab is currently investigating the type 2 diabetes drug metformin’s general use for metabolic syndrome. Metformin is an adenosine monophosphate (AMP) protein kinase inhibitor that is commonly prescribed in type 2 diabetes and acts by modulating glucose pathways. “Metformin protects the endothelium from high glucose damage, even without affecting the blood glucose levels,” explains Hollenberg. He says that this can reduce vascular diseases such as peripheral vascular disease, carotid artery disease, and pulmonary embolisms.
Designing drug development for metabolic disorders
Some companies are extending the remit of what biomarkers in earlier trials are expected to show so they can identify other potential metabolic disorders for a drug’s label.
The triglyceride, beta cell function, and blood pressure-related endpoints measured in Amgen’s Phase II MASH trial (NCT05669599) for MariTide (maridebart cafriglutide) could give the company an idea of the drug’s future potential for other metabolic conditions, explains Dr. Dimitris Papamargaritis, a National Institute for Health and Care Research (NIHR) clinical lecturer in diabetes and endocrinology at the University of Leicester, UK. MariTide is a gastric inhibitory polypeptide receptor (GIPR)/glucagon-like peptide-1 receptor (GLP-1R) bispecific molecule in development for the treatment of weight loss, type 2 diabetes, and MASH.
GLP-1 receptor agonists are not the only drugs being investigated in this manner. Dr. Fiona Murray, a senior lecturer at the University of Aberdeen, is currently investigating the potential of a target, GPR75, for therapeutic development for metabolic syndrome. “GPR75 seems to encompass a lot of the health problems that people are at risk of in metabolic disease. This includes things like heart disease, high blood pressure, NASH, and diabetes,” says Murray.
Murray’s lab discovered the target while observing that patients with pulmonary arterial hypertension had an increased expression of GPR75. Murray and her colleagues are investigating an endogenous ligand for the receptor such that the target could be modulated using antibody therapies, clustered regularly interspaced short palindromic repeats (CRISPR), or an antagonist. “We’ve already had a lot of interest from industry,” says Murray, adding that the lab is partnering with a few undisclosed biotechs.
Once a potential GPR75-targeting drug is in human trials, Murray predicts a global approach where it is investigated for several metabolic disorder-related diseases. She says that the attention surrounding metabolic diseases as a whole has jumped significantly during her time working in the space, going past larger disease sections like diabetes and hypertension, and getting closer to how areas like cancer and Alzheimer’s disease are studied. “If you’re able to limit the progression of metabolic disease, you’ll probably be able to blunt the progression of other diseases,” she adds.
According to Murray, public funding from places like The British Heart Foundation and the UK Research and Innovations’ Medical Research Council has also increased due to the “drive to deal with the umbrella of metabolic diseases going forward”.
“Finding a target that is able to tap into all of these risk factors at the same time would be something really exciting, ” adds Brennan. US regulators have also stepped up their metabolic disease focus, with the FDA launching the Committee for the Evaluation of Genetic Metabolic Disease Treatments in December 2023, while the National Cancer Institute is offering funding opportunities for obesity policy evaluation ahead of January 2025.
