Obesity has become a global public health problem. There are much needs for the development of anti-obesity medications. Let's review the history and development of anti-obesity drugs.

1. Huateng Pharma https://us.huatengsci.com
Anti-Obesity Drugs: History And
Development
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. (We can
provide orlistat key intermediates CAS NO.:104801-96-9 form lab to
commercial scale. )
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.

2. Huateng Pharma https://us.huatengsci.com
Table 1: History of drug development for AOMs , source: Nature Reviews Drug
Discovery

3. Huateng Pharma https://us.huatengsci.com
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.

4. Huateng Pharma https://us.huatengsci.com
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.
（Note: We can provide semaglutide and Liraglutide key intermediates to
meet your need.）
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:

5. Huateng Pharma https://us.huatengsci.com
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.

6. Huateng Pharma https://us.huatengsci.com
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

7. Huateng Pharma https://us.huatengsci.com
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)

8. Huateng Pharma https://us.huatengsci.com
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

9. Huateng Pharma https://us.huatengsci.com
number of people who are overweight and obese increases, there is a growing
awareness of the dangers of obesity and related diseases.
Hunan Huateng, founded in 2013, is a one-stop a 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.