Table 8.

Other Anti-Obesity Drug Monotherapies in Development. This table lists illustrative anti-obesity drugs in development, mechanisms of action, and applicable notes.

Therapeutic agent	Mechanism	Notes
Ghrelin-O-acyltransferase (GOAT) inhibitors	GOAT activates ghrelin. Ghrelin increases hunger. GOAT inhibitors may reduce hunger and reduce body weight.	GOAT inhibitors may be the basis of future treatments for diabetes and obesity. [171]
Fibroblast growth factor 21 analogues and receptor/binding protein agonists	Promotes lipid catabolism, lipolysis, fatty acid oxidation, mitochondrial oxidative activity, and thermogenic energy dissipation; may promote browning of adipocytes (beige) [172]	FGF 21 agonists may reduce fat mass, reduce hyperglycaemia, reduce insulin resistance, improve dyslipidaemia, and reduce cardiovascular disorders and non-alcoholic steatohepatitis (NASH) [173,174].
Macrophage inhibitory cytokine 1 (MIC-1)/Growth differentiation factor 15 (GDF15) agonists	Reduces food intake	Transforming growth factor super family cytokine that binds to the brain glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) receptor [175]
Dopamine, serotonin, and noradrenaline reuptake inhibitor (phenyltropane family)	Increases satiety/reduces hunger	Tesofensine is a triple monoamine reuptake inhibitor [176]
Fatty acid desaturase 1 (FADS1) inhibitors	FADS1 helps regulate fatty acid metabolism, eicosanoid production, and inflammation	Fatty acid desaturase 1 knockout mice are lean, with improved glycemia and decreased atherogenesis
Therapeutics that increase energy expenditure via enhanced thermogenesis [[177], [178], [179]]	Within the mitochondria, food- derived molecules are metabolized via oxidative phosphorylation to form stored energy [adenosine triphosphate (ATP)] via the citric acid cycle or utilized to generate heat via the “futile cycle” [3]. This thermogenic process is regulated by mitochondrial uncoupling protein 1, mostly found in brown adipose tissue (BAT). Thermogenesis in BAT and other organ occurs through sympathetic, β-adrenergic receptors.	Challenges in development of agents to increase energy expenditure include how to safely limit ATP formation and activate thermogenesis, without hyperthermia and adverse cardiovascular side effects.
Agents that act upon factors related to brown and beige fat [(e.g., amino acid derivatives, PPAR gamma agonists, JAK inhibition, irisin, musclin, and transcription factor A mitochondrial (TFAM)] [180,181]	Increases energy expenditure. White adipocytes have a unilocular fat droplet and few mitochondria. Brown adipocytes have multilocular fat droplets, high content of mitochondria, and high levels of uncoupling protein-1. Beige adipocytes have an origin like white adipocytes but function more like brown adipocytes.	Targeting of brown adipose tissue and browning white adipose tissue (inducing white adipocytes to become beige adipocytes) may increase thermogenesis, lead to negative energy balance, and decrease glucose and triglyceride levels [181].
11beta-hydroxsteroid dehydrogenase type 1 inhibitors [182]	11beta-HSD1 in adipose tissue converts cortisone to more active cortisol.	May reduce multiple components of the metabolic syndrome and help correct “local Cushing's syndrome”
Asprosin antagonists	Protein produced by adipose tissue that is orexigenic and promotes hepatic glucose production	Neonatal Progeroid Syndrome (NPS) or Marfan Lipodystrophy Syndrome have gene mutations resulting in asprosin deficiency and extreme leanness. Anti-asprosin monoclonal antibodies reduce blood glucose, appetite, and body weight [183].
Phosphodiesterase-4 inhibitors	May reduce appetite, increase satiety via increased GLP-1 secretion and may also increase energy expenditure	Roflumilast is approved for treatment of chronic obstructive pulmonary disease and may reduce body weight and increase insulin sensitivity [184].
Human monoclonal antibody to the myostatin/activin type II receptor (ActR II)	ActR II receptor mediates muscle loss. Loss of ActR II function mutations result in increased muscle mass of animals and humans.	Bimagrumab is a monoclonal antibody to the ActR II receptor that increases lean mass and reduces fat mass [185].
G-protein coupled receptor 75 (GPR75) inhibitors	GPR75 is found in the brain and was discovered by gene sequencing [186]. Individuals with at least one inactive copy of GPR75 gene have lower body mass index and about 50% lower risk of obesity [186].	Therapeutic inhibition of GPR75 is a potential treatment target for obesity, dyslipidemia, diabetes, cardiovascular disease, and cerebrovascular disease [187].
Anti-obesity vaccines (adipose tissue antigens, somatostatin, ghrelin, glucose-dependent insulinotropic polypeptide, adenovirus36)	Utilize immunotherapy to inhibit proteins and other factors involved in energy homeostasis	Among the immunotherapy approaches towards the orexigenic ghrelin include passive and active immunization with or without virus-like particles [188,189]
Self-expanding polymer that when swallowed and delivered to stomach, creates a pH-sensitive super absorbent gel structure.	The encapsulated device may promote satiety via activation of the gut–brain axis thereby leading to weight loss [190].	Study ongoing: The Effect of Epitomee Capsule on Body Weight in Patients With Overweight and Obesity With and Without Prediabetes (https://clinicaltrials.gov/ct2/show/NCT04222322)