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What are the challenges of anti-obesity drug development?
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What are the challenges of anti-obesity drug development?
What is the most troublesome problem for contemporary people, “obesity” must be one of them.
According to Nature reports, since 1975, the obesity rate of the world population has doubled. In the United States, two-thirds of the population are overweight, and more than one-third of adults and children are obese. “Losing weight” has become the “main theme” of contemporary people’s daily lives.
With the deepening of scientific research, scientists have discovered that obesity not only affects the appearance, but is also closely related to our physical health. Overweight people are at increased risk of many serious diseases.
For example, obese people are more likely to suffer from diseases such as type 2 diabetes (T2D), cardiovascular disease, colorectal cancer, liver cancer, and gallbladder cancer, and the death rate is higher than that of normal-weight people.
During the COVID-19 pandemic, researchers also found that the mortality rate after illness increases with the increase in body mass index (BMI). In this way, “weight loss” is indeed urgent.
Metabolic and psychological diseases closely related to obesity (Source: Nature Reviews Drug Discovery)
There are many reasons for obesity. The popularity of high-calorie foods, reduced exercise, lack of sleep, mental stress, and the use of anti-epileptic or psychotropic drugs can all cause obesity.
At the same time, the influence of genetic factors on body weight cannot be ignored. We often associate “fat” with “self-discipline”, but at present, the scientific community generally classifies obesity as a chronic degenerative disease.
This requires more investment in basic and clinical research fields related to obesity, and encourages pharmaceutical companies to formulate weight management strategies and conduct scientific interventions on weight from a medical perspective.
Limited by technical and social factors, it is still difficult to find the way to anti-obesity drugs (AOM).
For a long time, our understanding of the molecular mechanisms of appetite control has been very limited, and it has not been until the past 20 years that it has developed to the extent that drug discovery can be carried out.
Not only that, AOM is often accompanied by cardiovascular (such as sibutramine, fenfluramine, dexfenfluramine), increased risk of suicide (such as rimonabant), drug dependence and abuse and other side effects, which severely limits AOM Applications.
The molecular mechanism of appetite control (Source: Nature Reviews Drug Discovery)
Until recently, glucagon-like peptide 1 receptor (GLP1R) agonist drug candidates have performed well in clinical trials, giving us more confidence in the feasibility of drug-based obesity management.
On June 4 this year, the FDA approved the Wegovy (simeglutide) injection developed by Novo Nordisk for use in overweight adults or obese patients with at least one weight-related disease (hypertension or T2D, etc.) .
This is the second GLP1R agonist approved by the FDA for weight management. In 2014, liraglutide was approved for the treatment of adult obesity.
However, compared with surgical weight loss, the currently approved weight management drugs are still much inferior.
The ideal AOM should be able to reduce the risk of cardiovascular disease or other complications, while reducing weight on a large scale and sustainably.
Comparison of the effects of AOM and surgical fertilization (Source: Nature Reviews Drug Discovery)
The review article published on Nature Reviews Drug Discovery on November 23 reviewed the development of drug therapy for weight loss, and discussed the current challenges and the latest developments in the development of AOM.
History of Anti-obesity drugs
The development of weight-loss drugs is long and tortuous, and many drugs eventually withdraw from the market due to safety issues.
In the last century, drugs such as amphetamines, thyroid hormones, and dinitrophenol were withdrawn from the market shortly after obtaining approval from the regulatory authorities due to serious adverse reactions.
Some sympathomimetic drugs that act on the central nervous system, such as phentermine and bupropion, can only be used as short-acting Anti-obesity drugs.
Researchers try to develop weight-loss drugs through a variety of mechanisms, such as mitochondrial uncoupling agents, sympathomimetic drugs, serotonergic agonists, lipase inhibitors, etc.
However, researchers have found that when administered in tolerable doses for a long period of time, the goal of an average weight loss exceeding 10% of the original body weight is often not achieved, and what is more serious is that with the continuous weight loss, many serious acute and chronic ills The reaction also followed.
AOM mainly acts through peripheral or central pathways that control energy balance, but few drugs can act on both pathways at the same time.
For example, orlistat only acts on the gastrointestinal tract and has no effect on the central nervous system. It can be used as a lipase inhibitor to reduce the absorption of dietary fat in the gastrointestinal tract.
AOM, which acts on the central nervous system to enhance satiety, usually exerts a weight loss effect by regulating serotonergic, noradrenergic, or dopaminergic effects.
In the United States and Europe, orlistat, naltrexone/bupropion, liraglutide 3 mg, and the recently approved smeglutide 2.4 mg have been approved and widely used as obesity treatment drugs.
Bupropion is a reuptake inhibitor of dopamine and norepinephrine.
Although the opioid antagonist naltrexone does not cause weight loss in monotherapy, it blocks the inhibitory effect of β-endorphin-activated opioid receptors released by the hypothalamus, which can be reduced when combined with bupropion Food intake.
In 2014, liraglutide 3 mg became the first GLP1 AOM drug approved by the FDA for the treatment of adult obesity, and in 2020 it was approved for weight management in obese adolescents 12 years and older.
Prior to this, liraglutide was actually a subcutaneous injection of T2D therapy, with a daily dose of 1.8 mg, and showed a low incidence of cardiovascular adverse reactions.
The latest FDA-approved GLP1R agonist smeglutide has a surprisingly good weight loss effect.
Phase III clinical trial results showed that compared with a 2.4% weight loss in the placebo group, after 68 weeks of treatment with smegaglutide, individuals who were obese or overweight but did not suffer from diabetes lost 14.9% of their weight.
Although typical GLP1 adverse reactions (mainly nausea, diarrhea, vomiting, and constipation) are still common, the drug is generally well tolerated.
Emerging weight loss strategies
Although AOM still faces the problems of poor tolerance and safety, with the improvement of drug development technology, multiple important targets are still attracting attention in the research and development of weight-loss drugs.
Anti-obesity drugs currently in the clinical stage (Source: Nature Reviews Drug Discovery)
1. Incretin therapy
Incretin (incretin) is a type of polypeptide hormone produced in the intestine that has the effect of promoting insulin secretion. Incretin in the human body mainly includes glucagon-like peptide 1 (GLP1) and glucose-dependent insulin-promoting polypeptide (GIP). ).
DPP4 inhibitors can indirectly increase the circulating concentrations of GLP1 and GIP to improve blood sugar control without the risk of hypoglycemia.
GLP1 related drug candidates
In the past few decades, advances in incretin-related research and the success of DPP4 inhibitors have prompted the approval of a series of GLP1R agonist drugs.
After the body eats, GLP-1 can promote the secretion of insulin and the growth of insulin β cells, which can delay gastric emptying and maintain a sense of fullness, thereby producing weight loss.
GLP1R agonists have direct and indirect effects on the energy and glucose metabolism of key peripheral organs in the body and the brain.
GLP1’s effects on peripheral organs and brain (Source: Nature Reviews Drug Discovery)
In December 2014, Liraglutide 3mg became the first GLP1R agonist approved by the FDA for the treatment of obesity, and the dose used was about twice that of the treatment of T2D.
After 1 year of treatment with liraglutide, the average weight of the subjects dropped by 8%, and the weight of the control group dropped by 2.6%.
About 1/3 of the patients in the liraglutide treatment group lost more than 5% of their weight, and 1/3 of the patients lost more than 10% of their weight; in contrast, 27% and 11% of the subjects in the control group achieved The above effect.
The results of clinical trials prove that GLP1R agonists can be used to improve the metabolism of obese patients and reduce weight moderately, while reducing cardiovascular risk.
Smeglutide 2.4 mg was approved in June this year for the chronic weight management of obese or overweight adults, and the dose used is much higher than the approved dose for the treatment of T2D.
In a one-year phase II clinical study, the daily dose was approximately 10% of the high-dose liraglutide, and the weight loss was approximately doubled. Half of the subjects lost more than 15% of their body weight, and 1/3 of the subjects lost more than 20% of their body weight.
In a phase III clinical trial of smeglutide, after 68 weeks of treatment with once a week, obese patients without diabetes lost 14.9% of their body weight (the control group lost 2.4%); those with diabetes The weight of obese patients lost 9.6% (-3.4% in the control group).
The effect of smeglutide in reducing weight in obese patients, especially obese patients with diabetes, can be described as transformative, and it has established a new standard of treatment for AOM drugs.
There are still other peptide drugs and small molecule GLP1R agonists in clinical development. Eli Lilly’s oral GLP1R agonist GLPR-NPA is currently in phase II clinical trials.
GIP-related drug candidates
GIP, also called gastric inhibitory peptide, is produced by K cells in the small intestinal mucosa, and belongs to the incretin family with GLP1.
GIP is an important metabolic hormone in the body, which plays a variety of physiological roles, such as inhibiting gastric acid secretion, stimulating insulin release, inhibiting gastric peristalsis and emptying, and promoting the secretion of small intestinal fluid.
Whether GIP agonists can be used to treat obesity and T2D is still unclear. Studies have shown that the insulin-promoting effect of GIP is weakened in T2D patients.
However, a large amount of preclinical evidence shows that human GIP antagonists can improve energy and glucose metabolism throughout the body, possibly by improving the sensitivity of the central nervous system to leptin. In general, long-acting GIPR agonists can reduce body weight and improve glucose uptake.
Currently, Novo Nordisk’s long-acting GIPR agonist is undergoing phase I clinical trials for the treatment of T2D and obesity.
2. Multiple agonists based on incretin
In addition to the structural optimization of selective GLP1R and GIP single agonists, considering that there is far more than one hormone that regulates energy balance in mammals, there are currently multiple multi-agonists that simultaneously target GLP1R, GIP and/or glucagon The drug enters the clinical phase of research.
The Phase II clinical results of two GIPR/GLP1R dual agonists have been reported. Novo Nordisk’s NN9709, in collaboration with Roche, reduced blood sugar, body weight and total cholesterol in a 12-week T2D phase II clinical study, but there was no statistical difference in weight loss compared with liraglutide.
Taking into account the excellent performance of smeglutide 2.4 mg in phase III clinical trials, Novo Nordisk suspended the clinical development of NN9709 in 2020.
Eli Lilly’s tirzepatide is a macromolecular peptide drug and a GIPR/GLP1R dual-acting agonist with both hypoglycemic and weight loss effects.
In the clinical trial SURPASS-4, the HbA1c level of patients who used 15 mg of tirzepatide was reduced by 2.58%, compared with the control group who received insulin glargine therapy, only 1.44%; in terms of body weight, the weight of the experimental group was reduced on average within 52 weeks 11.7 kg.
According to the Q3 financial report released by Eli Lilly, Eli Lilly has submitted a new drug application for tirzepatide to the FDA and is expected to enter the market in 2022.
3. Leptin, leptin sensitizer and MC4 agonist
The discovery of leptin in 1994 deepened the scientific community’s understanding of how peripheral hormones send signals to the brain to regulate energy balance. Leptin deficiency can cause severe metabolic disorders, including extreme eating, lipodystrophy, and hypothalamic amenorrhea. Metriptine (metreleptin) was approved by the FDA in 2014 for the treatment of lipodystrophy.
Leptin supplements have greatly improved the metabolic and neuroendocrine status of patients with congenital leptin deficiency. The effect of single leptin in reducing weight is not obvious, but the combination with pramlintide has a certain weight loss effect.
In addition, preclinical experiments have confirmed that some plant-derived small molecules such as celastrol and withaferin A can reduce weight by improving the body’s sensitivity to leptin.
Leptin regulates energy metabolism by activating POMC neurons in ARC, and further activates MC4 receptors to induce satiety in the brain.
The scientific community has high hopes for the development of weight-loss drugs targeting the MC4 receptor.
However, the currently developed MC4 receptor agonists often cross-stimulate the structurally related MC1, MC3 and MC5 receptors, which play an important role in the neuroendocrine process. , Such as pigmentation of hair and skin, energy homeostasis and red blood cell differentiation.
At present, many MC4 receptor agonists have suspended clinical trials due to poor weight loss and adverse reactions, such as Eli Lilly’s LY2112688, Novo Nordisk’s MC4-NN-0453, Merck’s MK-0493 and AstraZeneca’s AZD2820 and so on.
Islet amyloid peptide (IAPP) is produced by pancreatic β cells and is a peptide substance secreted together with insulin.
IAPP can reduce the production of glucose and slow down the emptying speed of food in the stomach, and reduce food intake by centrally controlling the feeling of fullness.
Novo Nordisk’s long-acting IAPP analog, cagrilintide (AM833), previously announced a phase II trial of monotherapy and a phase I trial in combination with smeglutide 2.4 mg.
The single-agent trial showed that after 26 weeks of treatment, the weight of the AM8334.5 mg group lost 10.8%, while the placebo group lost only 3%, which reached the main clinical endpoint of the study and showed good safety and tolerability; and The smeglutide combination trial showed that after 20 weeks of treatment, the average weight of the patients receiving the highest dose of treatment decreased by 17.1% from the baseline of 95.1 kg.
Ghrelin is a peptide hormone mainly secreted by P/D1 cells in the stomach, which acts on the hypothalamus to stimulate food intake. Ghrelin can inhibit the secretion of insulin, have the effect of raising blood sugar, and can cause weight gain.
However, whether ghrelin can be used as a target for the treatment of obesity is still controversial. According to reports, the circulating concentration of acyl-ghrelin increases in lighter-weight people and patients with anorexia, while the concentration is lower in some obese people.
So far, no clinically proven AOM drugs have been found in drug discovery targeting ghrelin, but ghrelin is still the only known cyclic signal that can increase hunger and effectively activate the hypothalamic AGRP neurons that drive appetite.
In addition to the above new strategies for the development of AOM drugs, methods such as mitochondrial uncoupling agents, GDF15 and tyrosine peptides have gradually received widespread attention and are considered as potential treatments for obesity.
The development of AOM is limited by factors such as the limited translation value of animal models for predicting cardiovascular safety and considerable patient heterogeneity.
Currently, there are still many difficulties. Obese patients are usually high-risk groups of cardiovascular disease, and often suffer from complications that complicate drug safety evaluation.
The recent successes of smeglutide and tirzepatide have regained confidence in the development of AOM. Both drugs reported an average weight loss far exceeding 10%.
Whether there is an AOM better than meglutide and tirzepatide that can achieve the same effect as bariatric surgery, it is worth looking forward to.
 Timo D. Müller et al. Anti-obesity drug discovery:advances and challenges. Nature Reviews Drug Discovery. 2021.
 Lilly Reports Robust Third-Quarter 2021 FinancialResults as Pipeline Success Strengthens Future Growth Potential.（
 Novo Nordisk successfully completes AM833 phase 2trial and phase 1 combination trial with AM833 and semaglutide in obesity.
What are the challenges of anti-obesity drug development?
(source:internet, reference only)