With over 750 million individuals worldwide classified as obese, according to the World Health Organization, the urgency to combat this global health crisis has reached unprecedented levels. Obesity is associated with several health complications, including an increased risk of co-morbidities, including type 2 diabetes, cardiovascular disease, chronic kidney disease (CKD) and metabolic dysfunction-associated steatohepatitis (MASH).
Recent FDA Approvals and Advances in Anti-obesity Drugs
Breakthrough Treatments: Semaglutide and Tirzepatide
The long-acting glucagon–like peptide-1 (GLP-1) receptor agonist Semaglutide (Wegovy®; Novo Nordisk) has emerged as an effective peptide-based drug for weight management. Wegovy was Food and Drug Administration (FDA) approved for chronic weight management in June 2021. Subsequently, the dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist peptide tirzepatide (Zepbound®) received an FDA-approval for the treatment of obesity in November 2023. Both drugs are injectable and were initially developed for the treatment of type 2 diabetes (Ozempic®, Mounjaro®).
Comparative Efficacy: Semaglutide vs. Tirzepatide
While head-to-head clinical obesity trials for semaglutide vs. tirzepatide remain to be reported, an open-label 40-week study in type 2 diabetes patients (SURPASS-2) and recent meta-analyses have suggested greater weight loss (up to 22%) achieved with tirzepatide as compared to semaglutide (15-18%). The major anti-obesity mode of action of semaglutide and tirzepatide is increasing satiety by regulating the activity of appetite-sensing neurocircuits at the level of the brain stem and hypothalamus. Given their overlapping molecular modes of action, common side effects – mostly gastrointestinal (notably nausea) – are also largely similar between tirzepatide and semaglutide.
Next-generation Weight Loss Drug Therapies
Obesity pharmacotherapy is a rapidly moving field. The recent FDA-approval of semaglutide and tirzepatide for weight management has spurred intense research within obesity drug and target discovery. As result, the preclinical and clinical pipeline of innovative weight loss drugs is expanding as pharmaceutical companies are rushing to develop first- or best-in-class weight loss drugs.
Innovative Monotherapies and Combination Therapies
It is therefore anticipated that the landscape of obesity medications will diversify to offer both novel monotherapies, drug combination concepts and dual/triple hormone receptor agonists. As such, next–generation anti-obesity drugs will continue to be based on long-acting enteroendocrine cell-derived hormone analogues with complementary actions which hold promise for enhancing weight loss efficacy while also improving tolerability. In support, early clinical data suggests that targeting more than one peptide receptor may promote greater weight loss and cardiovascular benefits than achieved by semaglutide and tirzepatide monotherapy. There is also an increasing appreciation that future weight loss drug combination therapies must aim to mitigate nausea and emesis frequently observed with GLP-1 receptor agonists, which can be dose-limiting and reduce patient compliance.
Emerging Injectable Obesity Pharmacotherapies
Looking to the current pipeline of obesity pharmacotherapies, pharmaceutical companies seek to differentiate from currently approved weight loss medications. For example, long-acting amylin analogues are in various stages of clinical development (Cagrilintide, Novo Nordisk; AZD6234, AstraZeneca; Petrelintide (ZP8396), Zealand Pharma; GUBamy, Gubra). Cagrilintide is now being developed in combination with semaglutide (CagriSema, Novo Nordisk). Several injectable dual GLP-1 receptor and glucagon receptor (GCG) agonists are in phase-2/3 clinical trials (Survodutide, Boehringer-Ingelheim/Zealand Pharma; Mazdutide, Innovent Biologics/Eli Lilly; Pemvidutide, Altimmune). Also, a once-monthly, injectable GIP antibody conjugated to two GLP-1 receptor agonist peptides (AMG 133/MariTide, Amgen) has been progressed into clinical development. Furthermore, a triple GLP-1/GIP/GCG receptor agonist (Retatrutide, Eli Lilly) is currently in phase-3 clinical development for obesity. Several of the compounds targeted for obesity are also in various stages of clinical development for type 2 diabetes, CKD and MASH.
Advancements in Oral Drug Formulations
Development of oral medications will undoubtedly change the landscape of obesity treatment by providing patients with alternative treatment options. An oral semaglutide formulation (Rybelsus®) has been approved for treating type 2 diabetes patients and is now in late-stage clinical development for the treatment of obesity. Accordingly, the once-daily (50 mg) oral formulation of semaglutide has in a recent phase-3 trial for obesity demonstrated equivalent placebo-corrected weight loss efficacy (OASIS1 trial) as previously reported for injectable semaglutide (2.4 mg, STEP1 phase-3 trial). In addition, non-peptide once-daily oral GLP-1 receptor agonists (Orforglipron, Eli Lilly; Danuglipron, Pfizer; CT-996, Carmot Therapeutics) are in current clinical development for obesity.
Sarcopenia and Its Impact on Anti-obesity Drug Development
Sarcopenic obesity, a condition defined by the co-existence of obesity and sarcopenia (loss of muscle mass and function) has emerged as a public health concern, particularly in the aging population. Rapid weight loss afforded by obesity therapeutics can also concomitantly decrease muscle mass in obese individuals. Hence, the health benefits of weight loss pharmacotherapies may to some degree be compromised by concomitant loss of muscle mass and strength. The pharmaceutical industry is therefore increasingly focusing on developing drugs that can promote a sustainable and healthy weight loss. Because maintained muscle mass is important for healthy metabolism, it is important to identify medications that can prevent or reverse muscle mass loss in obese individuals. While drug development for sarcopenia is in its infancy, an activin type II receptor antibody (Bimagrumab, Versanis/Eli Lilly), has recently been progressed into a phase-2 clinical trial (BELIEVE trial) in obese individuals with the aim to assess the safety and efficacy as monotherapy and in combination with semaglutide.
Benchmarking and Preclinical Evaluation of Drug Candidates
Preclinical drug and target discovery for obesity is a highly competitive area. Numerous candidates with different molecular targets and mechanisms of action are being characterized in obesity models with the aim to demonstrate in vivo preclinical proof-of-concept. A benchmarking study typically aims to profile the drug candidate as monotherapy compared to semaglutide or tirzepatide. Upon confirmation of weight loss efficacy, the drug candidate may be further characterized as combination therapy with semaglutide or tirzepatide for detecting potential additive/synergistic effects on weight loss. At this stage, it may be advantageous to obtain information on the mode-of-action of the drug candidate.
Key Endpoints in Translational Diet-induced Obese Rodent Models
Diet-induced obese (DIO) mice and rats represent the standard translational obesity models in preclinical drug discovery, where excessive caloric intake and the drive for weight regain plays a major role in the etiology, pathology and progression of the disease.
As in clinical studies, major outcomes in DIO model studies are main metabolic parameters such as body weight and adiposity. Adiposity can be monitored at baseline and during the study by non-invasive whole-body composition analysis using echo-magnetic resonance imaging (Echo-MRI) to assess fat and lean (muscle) mass. Upon study termination, changes in fat depots can also be measured by weighing abdominal fat compartments. We have conducted multiple DIO mouse studies characterizing the efficacy of various weight loss drugs, including semaglutide and tirzepatide, on body weight and adiposity.
Preclinical mode-of-action (MoA) studies
While all anti-obesity medications improve body weight and metabolic parameters, they have different MoA and can for example be distinguished by their ability to e.g. suppress appetite and increase energy expenditure.
Food intake is an important endpoint which serves as a proxy for potential anti-obesity efficacy and can inform about anti-obesity mode of action. Computerized platforms have been developed for continuous monitoring of food intake in lean and DIO mice and rats. At Gubra, we use state-of-the-art systems enabling real-time assessment of individual food and water intake in group-housed animals. The systems can also assess locomotor activity.
Because changes in basal metabolic rate play an important role in body weight homeostasis, energy expenditure (measured by indirect calorimetry) and physical activity (measured by locomotor activity) represent important parameters for gaining further mechanistic insight into anti-obesity drug effects.
Distinct metabolic effects of semaglutide and resmetirom at thermoneutrality in diet-induced obese mice
MoA of weight-lowering drugs may also involve increased preference for e.g. protein-dense or less caloric-rich diets, which can be addressed in food-preference studies in DIO rodents. Additionally, analysis of the rate of gastric emptying can be instrumental to assess for satiety-promoting drug effects at the level of the gut.
Potential weight loss drug-induced aversive stimuli can be evaluated preclinically using the conditioned taste aversion (CTA) test, which can provide important information on contributory appetite-suppressive mechanisms and inform about potential CNS-mediated gastrointestinal adverse effects.
3D imaging modalities are often applied to determine biodistribution and effects of preclinical drug candidates. Light sheet fluorescence microscopy (LSFM) has emerged as a powerful tool in preclinical obesity target and drug discovery, as LSFM allows for ex vivo whole-organ labelling and quantitative 3D imaging in the intact organ, including the brain, at cellular resolution. For example, we routinely apply c-Fos as a proxy for neuronal activation in mouse whole-brain LSFM imaging studies, which have proven instrumental for mapping distinct CNS activity profiles of compounds with anti-obesity potential. Depending on the scope of the study, whole-brain c-Fos labelling can be performed using immunohistochemical (IHC) or in situ mRNA hybridization (ISH) protocols.
3D mapping and quantification of semaglutide-induced neuronal activation: a study of mRNA and protein signatures in whole mouse brains using light sheet fluorescence microscopy
Gubra’s Expertise: Profiling and Developing Anti-Obesity Drugs
Being a multi-faceted player, Gubra stands at the forefront of preclinical research, as a leading Contract Research Organization (CRO) specializing in obesity pharmacology as well as working as a full-service peptide drug and target discovery partner.
Through in vivo studies and biomarker analysis services, Gubra offers invaluable insights into the molecular mechanisms underlying obesity. The expertise comes from successfully profiling numerous anti-obesity drug candidates with experience in anti-obesity drug development stretching for over more than 16 years.
As a significant development, Gubra has announced the signing of a new research and license agreement with Boehringer Ingelheim to discover novel peptides for the treatment of obesity. This collaboration builds on the successfully progressing joint research projects between the companies, aiming to identify, validate, and develop innovative treatments to improve health outcomes for individuals living with obesity.
Not stopping there, Gubra’s latest breakthrough with the initiation of its Phase 1 clinical trial for GUBamy, a long-acting amylin agonist analogue, marks a significant milestone in obesity therapeutics. With promising preclinical data showing significant weight loss effects, GUBamy holds tremendous potential as a novel treatment option for obesity, both as a monotherapy and in combination with other anti-obesity drugs.
Conclusion: A Beacon of Hope
In the face of the obesity epidemic, the emergence of novel weight loss medications offers a beacon of hope for millions worldwide.
By embracing novel approaches, forging strategic partnerships, and prioritizing patient well-being, we could witness a transformation of the lives of millions affected by obesity and pave the way for a healthier future.
If you are interested in delving into Gubra’s collection of Diet-Induced Obesity (DIO) models with proven clinical relevance and understanding why leading companies have selected us as their preferred preclinical partner, feel free to reach out to us.
