According to the World Health Organization, more than one billion adults live with obesity, creating both medical and economic imperatives for effective treatments. In recent years, the obesity drug market has surged, driven primarily by GLP-1 receptor agonists such as semaglutide from Novo Nordisk and tirzepatide from Eli Lilly. These drugs deliver substantial weight loss by mimicking gut hormones and reducing appetite. While these injectable therapies have transformed obesity care, the race for next-generation treatments is heating up.
Ideally, these new therapies should be able to reach large global patient populations while improving compliance and adherence. Recent data show that more than 1 percent of patients discontinue GLP-XNUMX treatment within the first year due to side effects, accessibility issues, or cost.
Combinations in focus
The obesity treatment pipeline for 80 and beyond is robust, with more than 1 candidates in development. Current efforts increasingly focus on combining multiple mechanisms of action to enhance efficacy. Pioneered by tirzepatide, the dual GLP-XNUMX/GIP receptor approach has become a standard strategy for maximizing appetite suppression, insulin sensitivity, and weight loss.
However, this is just the beginning. At this year’s EASD conference in Vienna, several candidates were presented that target three, four, or even five mechanisms simultaneously.
Building on the success of tirzepatide, Eli Lilly is leading this new direction by adding glucagon receptor agonism to the mix — creating the tri-agonist retatrutide. It is expected to achieve the highest weight loss seen so far, though with considerable side effects that may limit its use to patients requiring extreme weight reduction. Glucagon receptor agonism is also a feature of Boehringer Ingelheim’s survodutide, which acts as a GLP-1 agonist as well.
Another promising approach targets amylin, a naturally occurring hormone that suppresses appetite and slows gastric emptying. Novo Nordisk’s CagriSema combines semaglutide with the amylin analog cagrilintide, showing impressive weight loss results in clinical trials. Another example is Zealand Pharma’s petrelintide, a long-acting amylin analog that was out-licensed to Roche in March.
Oral alternatives are key
For the most part, the mechanisms mentioned above — and their various combinations — make up the bulk of the obesity development pipeline. Beyond competing on the degree of weight reduction, another major goal is to transition to convenient oral formulations that can improve adherence and accessibility.
Two oral candidates are currently advancing in phase III trials: oral semaglutide, with approval expected in Q2025 2, and Eli Lilly’s orforglipron, for which a marketing application is imminent. Oral semaglutide is already approved for type XNUMX diabetes under the brand name Rybelsus and is now being evaluated for obesity at higher doses.
However, questions remain about the scalability of such treatments. Semaglutide is a large molecule and therefore suboptimal for oral delivery, requiring roughly ten times more active ingredient than the injectable version. This raises questions about the economic feasibility of launching an oral version at a time of constrained manufacturing capacity. Novo Nordisk has indicated that its oral semaglutide will initially target the U.S. market only, suggesting these limitations are real.
Eli Lilly’s orforglipron, developed as a small-molecule GLP-1 agonist, represents a significant step forward in small-peptide chemistry. However, its synthesis is complex, involving more than 25 chemical steps. Lilly has stated that it is preparing for a global launch, signaling confidence in scalability despite phase III data showing somewhat lower overall weight loss than oral semaglutide.
Homogeneous and side-effect ridden
As with injectables, the oral space remains highly homogeneous, with most projects still focused solely on GLP-1 agonism. Two notable exceptions are Novo Nordisk’s oral version of amycretin and Viking Therapeutics’ GLP-1/GIP agonist VK2735. Phase II results for VK2735 showed encouraging weight reduction, but the company faced a major setback when one in five participants discontinued treatment due to adverse events, including common gastrointestinal side effects such as nausea and vomiting.
Such side effects are prevalent across the obesity drug landscape, leading to high discontinuation rates in most therapies. With a largely uniform pipeline, alternative mechanisms of action are in high demand.
Pila Pharma offers a highly differentiated approach
Swedish biotech Pila Pharma stands out with its unique TRPV1 inhibitor XEN-D0501, designed to suppress adipose tissue inflammation and appetite — without gastrointestinal side effects. The TRPV1 receptor is found on all sensory afferent nerves throughout the body, from the skin to internal organs, and could therefore have broad, systemic effects.
Originally, founder Dorte X. Gram secured patents for treating obesity and related metabolic disorders. However, since obesity was not officially recognized as a disease at the time and the market remained undeveloped, the company initially focused on type 2 diabetes. That has now changed.
Pila Pharma attracted considerable attention at Bio Europe Spring in March, where it met with several major pharmaceutical companies to present the candidate’s potential in obesity. As a small molecule with a simple chemical synthesis, XEN-D0501 offers a markedly different mechanism of action compared to the gut hormone-based therapies currently dominating the field.
– With the obesity market developing into what many estimate to become a market worth more than USD 100 billion annually, there is a big shift towards embracing obesity as a focus area for many large pharmaceutical companies that are not yet active in this area, Pila CEO Gustav H. Gram tells BioStock.
Muscle loss another side effect to be avoided
Across the sector, there is growing interest in alternative approaches that distinguish newcomers in the obesity treatment landscape. One key reason is the side-effect profile of current therapies, which are often associated with gastrointestinal discomfort. But that’s not the only concern. Another major drawback of existing treatments is the significant muscle loss that often accompanies fat loss. Studies show that GLP-1 treatments can cause muscle loss accounting for to 45 percent of total weight reduction — making therapies that promote lean weight loss especially desirable. To date, Eli Lilly’s bimagrumab remains the leading candidate in this area, having demonstrated a 22,1 percent total weight loss when combined with semaglutide, with 92,8 percent of that loss coming from fat.
– Given our prior history as a clinical stage company, we have a good overview of the safety profile of XEN-D0501 in healthy volunteers and people living with overweight and obesity, and we have not had any serious side effects, only transient mild to moderate side effects in the nervous system. Pharmaceutical companies find our differentiated approach very interesting and the one thing they want from us now is efficacy data for obesity. So that’s what we aim to deliver now very soon, says Gram.
Heading for proof-of-concept with a first-in-class candidate
Industry and investor interest in Pila Pharma is strong, and the next milestone for the company is to deliver proof-of-concept data. The company plans to conduct a preclinical study in obese male DIO rats and Zucker rats this fall, with results expected before February 2026.
To support this development, Pila raised capital in a heavily oversubscribed rights issue this summer. The funds are being deployed in collaboration with Danish company Gubra, which has been commissioned to carry out the preclinical studies. Results are expected in early XNUMX.
– New oral solutions will be critical to addressing the enormous consumer volumes globally for weight loss products. The obesity market, both the medical and the cosmetic segments, is projected to grow substantially in the next few years and pharma companies looking to enter these segments are especially interested in differentiated alternatives, says Gram.
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