The GBD study published by NEJM in 2017 stated that as of 2015, 107.7 million children and 603.7 million adults were obese. Numerous studies have confirmed that obesity and overweight are risk factors for developing cardiovascular disease, type 2 diabetes, chronic kidney disease, and malignancies, and that individuals with a BMI in the range of 30-34.9 kg/m2 have a more than 40% increased risk of total mortality compared to individuals of normal weight, while individuals with a BMI above 40 kg/m2 have an increased relative mortality rate of 100%.

Obesity is a chronic metabolic disease that results in increased body mass due to excessive accumulation and/or abnormal distribution of body fat as a result of a combination of genetic and environmental factors, lack of exercise, and poor diet.

Due to the limited efficacy of lifestyle and behavioral interventions, obesity treatment strategies need to be enhanced by adding pharmacological and/or surgical interventions. Bariatric surgery is the most effective method for weight loss, but surgical interventions do not meet the medical needs on a global scale.

1. Development History of Anti-Obesity Medications

The development of anti-obesity medications (AOMs) has been a major challenge due to technical and social factors. In retrospect, the introduction of AOMs to the market has raised many safety concerns. Most of them are associated with cardiovascular adverse effects (sibutramine,fenfluramine, dexfenfluramine, rainbow pills), increased risk of suicide (rimonabant) or increased drug dependence and abuse (methamphetamine).

Currently, orlistat, a lipase inhibitor developed by Roche, is the only drug approved by the FDA and EMA for chronic weight management. It was approved for prescription sale in 1999 and for over-the-counter sale in 2007, and is the only FDA-approved over-the-counter weight loss drug.

Orlistat is a selective and potent gastrointestinal lipase inhibitor that slows down the hydrolysis process of food fats in the gastrointestinal tract, thereby reducing the hydrolysis and absorption of dietary fats by 25-30%. Its common adverse effect is steatorrhea, and cases of hepatotoxicity and acute nephrotoxicity have been subsequently reported during use. 

With the improvement of human living conditions, obesity has become a global public health problem. In the face of the increasing number of overweight and obese people, the demand for clinical medication is obviously not being met.

Table 1: History of drug development for AOMs , source: Nature Reviews Drug Discovery

2. Novel & Emerging Anti-Obesity Medications

Despite numerous disappointments, several prominent therapeutic targets have captured the attention of the scientific community.

2.1 Incretin-based therapy

2.1.1 GLP-1-related drug candidates

Over the past few decades, developments in incretin biology and the success of DPP4 inhibitors have given rise to a series of GLP-1R agonists. Glucagon-like peptide-1 (GLP-1) is an incretin, a human endogenous peptide that slows gastric emptying, controls appetite, and reduces body weight. However, natural GLP-1 has a short half-life and loses its activity in vivo within 1-2 minutes after being degraded by dipeptidyl peptidase 4 (DPP4).

GLP-1 receptor agonists (GLP-1RAs) are structural modifications of GLP-1 ( e.g. changing the amino acid sequence and adding long chains of fatty acids), which can not only exert the effects of GLP-1, but also prolong the duration of action. In addition to acting on central and gastrointestinal GLP-1 receptors (GLP-1R) to suppress appetite and slow down gastric emptying, thereby reducing body weight by reducing food intake and absorption, GLP-1ARs can also act on adipose tissue by promoting the conversion of white adipocytes into brown adipocytes, resulting in increased lipolysis and thermogenesis of brown adipocytes.

Figure 1. Regulation of body weight and glucose metabolism by GLP1R agonists, source: Nature Reviews Drug Discovery.

In late 2014, liraglutide became the first GLP-1R agonist approved for the treatment of obesity at a dose approximately twice the maximum therapeutic dose for type 2 diabetes (T2D). After 1 year of dosing, patients in the liraglutide group reported an average weight loss of 8%, compared with an average weight loss of 2.6% for patients in the control group. Approximately 2/3 of patients in the liraglutide group lost more than 5% and 1/3 lost more than 10% of their body weight, while only 27% and 11% of patients in the control group lost 5% and 10% of their body weight.

In June 2021, semaglutide was approved for chronic weight management in adults who are obese or overweight. In a 1-year Phase II clinical study, daily subcutaneous injections of semaglutide 0.2 mg and above resulted in a mean weight loss of 11.2%-13.8% in subjects at week 52 and 7.8% in the liraglutide group (3.0 mg). Half of the subjects in the study lost 15% of their body weight on daily dosing and 1/3 of the subjects lost 20% of their body weight. In a recent phase III clinical trial in non-diabetic overweight patients, once-weekly injections of semaglutide (2.4 mg) resulted in a 14.9% weight loss after 68 weeks of treatment, significantly better than the placebo group (2.4%).

Several other peptides and small molecule GLP-1RAs are currently in clinical development, including studies of oral formulations. GLPR-NPA, an oral GLP-1R agonist, is currently in Phase III clinical trials by Eli Lilly.

In clinical practice, the most common adverse reactions to GLP-1ARs are gastrointestinal adverse reactions, manifested as nausea, vomiting, diarrhea, and abdominal distention, which generally diminish or are tolerated with the duration of treatment.
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2.1.2 Incretin-based poly-agonists

Pharmacological studies have demonstrated that mammals regulate energy homeostasis through far more than one hormone. Meanwhile, the discovery of poly-agonists targeting GLP-1, GIP and/or glucagon receptors has made breakthroughs in this direction, and several drug candidates have entered clinical development, among which the phase II clinical results of some long-acting GIPR/GLP-1R co-agonists have been disclosed. In a 12-week phase II clinical study in patients with T2D, subcutaneous administration of NN9709 reduced blood glucose, body weight and total cholesterol compared to placebo. However, there was no statistical difference in the improvement in body weight with NN9709 compared to liraglutide with dose titration (which is the adjustment of the dose administered during treatment based on the patient's response, such as adding from 0.2 mg to 0.5 mg). Given the efficacy of semaglutide in Phase III clinical trials, development of NN9709 was terminated in 2020.

Tirzepatide is a once-weekly glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 receptor dual agonist developed by Eli Lilly. In a phase III clinical study in patients with T2D, patients in the tirzepatide treatment group showed significant reductions in glycated hemoglobin and body weight from baseline after 26 weeks compared to injections of a specific single GLP-1R agonist. The use of the highest dose had an unusually strong glycemic control effect on patients, with nearly one-third of subjects losing more than 10% of their body weight.

A recent phase III clinical trial in overweight patients with T2D showed good results with Tirzepatide compared to semaglutide (1 mg) at all doses tested: after 40 weeks of treatment, 29-51% of patients in the Tirzepatide group (semaglutide group: 20%) had a reduction in glycated hemoglobin to less than 5.7%, and 15-40% of patients (semaglutide group: 9%) lost more than 15% of their body weight.

Figure 2. Effect of tirzepatide and semaglutide on body weight in overweight patients with T2D, source: The New England Journal of Medicine

Dual GLP-1R and glucagon receptor (GcgR) agonists are designed to control body weight and minimize the risk of hyperglycemia through multiple mechanisms including appetite suppression, increased thermogenesis, and lipolysis.

GLP-1R and glucagon receptor (GcgR) dual agonists are designed to control weight and minimize the risk of hyperglycemia through multiple mechanisms such as appetite suppression, increased thermogenesis and lipolysis. Cotadutide, a palmitoylated GLP-1R/GcgR dual agonist developed by AstraZeneca, reduced body weight and liver fat content and improved glucose tolerance compared to the placebo group in a 54-week Phase IIb clinical study enrolling overweight and obese patients with T2D. Patients lost an average of approximately 5% of their body weight, and 15.5% lost more than 10% of their body weight.

LY3437943, a GIP/GcG/GLP-1 triple agonist, was administered once weekly in a phase I clinical study in patients with T2D and showed that after 12 weeks of treatment, weight loss was more pronounced in the LY3437943 group compared to tirzepatide.

2.2 Leptin, leptin sensitizers and MCR4 agonists

In 1994, the discovery of leptin deepened the understanding of how peripheral hormones send signals to the brain to regulate energy balance. Leptin deficiency can lead to severe metabolic disorders such as binge eating, lipodystrophy and hypothalamic amenorrhea.

Approved by the FDA in 2014 and by the EMA in 2018 for the treatment of adipodystrophy, metreleptin's active ingredient is a recombinant human leptin analogue. Leptin supplementation is intended to normalize metabolic and neuroendocrine alterations in patients with congenital leptin deficiency and anorexia nervosa. However, although leptin supplementation is effective in individuals with congenital leptin deficiency, it has little effect on weight loss in patients with polygenic obesity.

Leptin regulates energy metabolism by activating POMC neurons in the arcuate nucleus (ARC) and inhibits AgRP neurons in the same region.POMC neurons project to the paraventricular nucleus (PVN), where they induce satiety by activating the brain's MC4R.

Although MC4R is a recognized therapeutic target for obesity, developing selective and safe MC4R agonists is challenging. MC4R agonists readily cross-stimulate structurally related MC1, MC3 and MC5 receptors that play important roles in a variety of neuroendocrine processes, including hair and skin pigmentation, energy homeostasis and erythrocyte differentiation.

In addition, activation of MC4R can increase blood pressure and heart rate in men by activating the sympathetic nervous system, causing sexual arousal. Over the past 30 years, various MC4R agonists, such as Lilly's LY2112688, Novo Nordisk's MC4-NN-0453, Merck's MK-0493 and AstraZeneca's AZD2820 have been tested in clinical trials, but all were discontinued due to insufficient weight loss or the aforementioned adverse effects.

It is worth mentioning that setmelanotide, an MC4R agonist developed by Rhythm Pharmaceuticals, does not affect human heart rate and blood pressure, and the drug showed good tolerability in patients with congenital lack of POMC or LEPR in phase III clinical studies, with significant weight loss and no serious adverse effects; in November 2020 , the FDA approved it for the treatment of obesity conditions in patients with POMC, PCSK1 or LEPR deficiency.

2.3 Amylin

Amylin (also known as IAPP) is a peptide that is co-secreted with insulin, and its anorexigenic potential has given rise to pramlintide. Pramlintide has been approved by the FDA for use in T1D and T2D patients, and importantly, pramlintide's role in reducing food intake and lowering body weight is not limited to patients with impaired glucose metabolism. Therefore, other amylin analogues with improved pharmacokinetics of relevance are also classified as AOMs.

2.4 Ghrelin

Ghrelin is a peptide hormone secreted by gastric fundic x/a-like cells that acts on the hypothalamic feeding center to stimulate food intake. A therapeutic peptide vaccine to reduce acyl-ghrelin, CYT009-GhrQb, developed by Cyto Biotechnology, is in early clinical studies, but it has no effect on body weight or ingestion. Amgen tested a specific anti-ghrelin monoclonal antibody in DIO mice, but did not find a long-term beneficial effect on body weight and feeding.

2.5 Targeted mitochondrial uncouplers

Mitochondria are one of the most important organelles of human cells and are the main sites of intracellular oxidative phosphorylation and ATP formation. Uncoupling agents are an inhibitor of oxidative phosphorylation that targets the mitochondrial membrane potential, stimulating mitochondrial oxygen consumption and promoting the consumption of sugars, fats, and proteins.

In 2006, Spiegelaman proposed that uncouplers could be used at safe doses for the treatment of obesity-related metabolic syndrome. 2, 4-dinitrophenol (DNP) was the most talked about weak acid proton uncoupler and was the first to target mitochondria for the treatment of obesity. The effective dose of DNP is very close to the toxic dose, making it susceptible to serious side effects from overdose.

BAM15 is an orally administered mitochondrial proton carrier uncoupler that increases nutrient oxidation and reduces body fat mass without altering food intake, muscle mass, or physiologically relevant markers, with potent anti-obesity and insulin sensitizing effects.

Table 2: Advances in AOMs research (Source: Nature Reviews Drug Discovery)

3. Conclusion

Obesity drug development has had a challenging journey, and few drugs have actually reached the clinical stage with significant efficacy to date. Obstacles to new drug development are the complexity of the pathways involved in obesity and the limitations of translating preclinical data into human studies. As the number of people who are overweight and obese increases, there is a growing awareness of the dangers of obesity and related diseases.

Huateng Pharma, founded in 2013, is a one-stop contract development and manufacturing organization (CDMO) to supply researchers and companies with PEG derivatives and products used across the pharmaceutical value chain including intermediates, excipients, APIs, and reagents.

References:
1. Muller, T. D.et al. Anti-obesity drug discovery: advances and challenges. Nature Reviews Drug Discovery. 21, 201-223 (2022).
2. Frias, J. P. et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N. Engl. J. Med. 385, 503–515 (2021).
3. O’Neil, P. M. et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet 392, 637–649 (2018).
4. Gilbert W. K. et al. New advances in models and strategies for developing anti-obesity drugs. Expert Opin Drug Discov. 2013, 8(6): 655–671.

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