Efficacy plateaus, muscle loss and weight rebound are testing the limits of GLP-1 success, pushing companies toward new mechanisms and multitarget designs to close the gap. But progress depends on understanding disease biology and selecting the right drug candidates to derisk clinical trials.
The obesity therapeutic market shows no sign of slowing, with drugmakers pursuing alternative mechanisms and pathways to improve GLP-1s and deliver benefits beyond weight loss.
BioSpace spoke to Dr. Shuxin Xu, senior scientific director at GemPharmatech, on the unmet medical need in weight loss treatments despite the plethora of GLP-1s. Xu discussed the metabolic‑disease model platforms used to address emerging challenges in weight‑loss and metabolic drug development, along with her predictions for the next generation of obesity treatments.
Metabolic drug market has room for improvement
The pace of evolution for GLP1-s is unprecedented, Xu said, with an approximate growth of $5.5 billion in 2023 to more than $55 billion by 2033. GLP-1s are used to treat not only obesity but diabetes, with added cardiovascular benefits.
Even so, unmet medical needs persist. They include efficacy plateaus and muscle loss that can impair metabolic health and physical function. Gastrointestinal (GI) side effects such as diarrhea and vomiting that affect patient compliance are concerns, and weight rebound after drug discontinuation.
This gap is opening the door for next-generation obesity therapies, Xu said, with particular focus on increasing energy expenditure, promoting fat metabolism, preserving muscle mass and optimizing novel formulations. The field has advanced from single targets to double- and triple-target approaches, she added.
Value in the right animal model
As companies prepare to innovate beyond standard of care, they must first determine the proper metabolic‑disease model platforms for early development, Xu said. The first consideration is animal model selection, the cornerstone of pharmacodynamic evaluation.
Developers must consider, from the earliest stages, that failure rates in preclinical-to-clinical translation are a persistent pain point. Among the hurdles in translating results between animals and humans are differences in target sequence, expression distribution and metabolic pathways.
An incorrect mouse model can derail research and development by producing data with poor reliability and translation. GemPharmatech has established both induced and spontaneous mouse models to address this: induced models involve disease triggered intentionally by the researcher, while spontaneous models develop disease naturally through genetic engineering, without external induction.
The diet-induced obesity model is the most widely used obesity model in drug development because it can replicate clinical manifestations. The gene-edited obesity model is better suited to specific phenotypes and mechanistic studies.
Beyond mouse models, there are the rat obesity models, which consider not just the difference in body size but species-specific differences. For example, an amylin analog has an anti-obesity effect in rats but not in mice. The amylin analog activates NTS Prlh-expressing neurons and Prlh gene expression in rats but not in mice.
Another consideration for new therapeutics, designed to target the human gene sequence, are humanized mice and rat models, Xu said. “Since efficacy results in animals do not guarantee efficacy in humans, humanized models can make them more predictive for human responses,” she added.
Humanized models work particularly well for new obesity innovations using antibodies, peptides, nucleic acid-based therapies and small molecules. A difference in amino acid sequence between the mouse and the human target can mean an antibody recognizes the human protein but not its mouse counterpart.
For siRNA/gene therapy drugs, which function through Watson-Crick base pairing, sequence divergence between human and murine genes directly impacts knockdown efficiency. For small molecules, binding pockets of certain targets exhibit conformational differences between humans and mice, altering drug affinity.
GemPharmatech has established an extensive animal model library, including diet-induced and gene edited models such as the leptin deficient and Alms1 deletion models. It also has humanized mice models expressing GLP-1R, GIPR and GPCR, Xu said, moving beyond the single-target humanized mouse models to double- and triple-target models. Beyond the GPGR‑humanized mouse model, it has developed models for newer metabolic targets including ALK7, INHBA and GPR75.
More than body weight data
Body weight is a primary parameter for metabolic models, but body composition changes, as measured by quantitative nuclear magnetic resonance, are also key to therapeutic development success, Xu said.
Adipose and muscle tissue data should be collected, with the fat further divided into subcutaneous or visceral depots. Apart from tissue weighing, pathological analysis is valuable for understanding the mechanism behind tissue changes. Energy expenditure and food intake should also be measured, to distinguish whether weight loss stems from reduced caloric intake or increased energy expenditure.
Glucose levels and other blood chemistry parameters can be monitored as well. This systemic evaluation provides developers with a clear, multidimensional picture of how their therapeutic candidate compares to positive controls and is key to optimizing molecule design, Xu said.
The broader metabolic landscape
Obesity is not merely a body weight issue, but is linked with cardiovascular disease, diabetes and metabolic dysfunction-associated steatohepatitis, among other conditions, Xu said.
As a result, the industry aims to develop next-generation therapies that deliver holistic benefits addressing body weight alongside cardiac, liver and renal protection. GemPharmatech’s metabolic platform addresses these aspects, as well as sarcopenia and hyperuricemia, helping companies expand the value proposition for their therapies, Xu said.
What’s next for obesity treatments?
Companies will continue pursuing multitarget approaches, Xu predicted, with potential to advance quadruple or higher target designs. She also forecasted improvements in safety and tolerability to reduce GI side effects, along with therapies optimized to preserve muscle mass.
More convenient administration methods, such as oral and long-acting depot formulations, are increasingly on the horizon due to higher patient adherence. This translates to better commercial success, she added.
The final direction is personalized obesity therapy. As patients vary in their drug response, the future treatment paradigms will select optimal therapy based on each patient’s metabolic profile, Xu said.
This article was written in partnership with GemPharamtech.
