Overview of weight loss drugs approved and in clinical trials, and future trends analysis. There are three trends of weight loss drug development.

1. Huateng Pharma https://us.huatengsci.com
Ongoing Investigation of Weight Loss
Therapies: 3 Positive Trends
How to lose weight? Whenever this topic comes up, exercise and dieting are
the preferred methods, while drugs always leave the impression of being
unsafe and ineffective.
Recently, some weight loss therapies have made quite positive progress. A
paper in a Nature sub-publication has identified a key gene mutation that
reduces abdominal fat that could eliminate love handles in the future with just
one injection a year. In the New England Journal of Medicine, Eli Lilly
announced the results of the phase 3 clinical trial of tirzepatide, in which
patients lost up to 22.5% of their body weight after 72 weeks of treatment,
setting a new benchmark for weight loss with the drug.
On the premise of safety and effectiveness, drug therapy is a shortcut
compared to exercise and dieting which require persistent efforts. Based on
the huge unfinished needs in the field of weight loss, we have compiled the
latest clinical pipeline of drugs under investigation for this indication (as of
August 2022) to present the current status and future trends of weight loss
drug development.
According to incomplete statistics, a total of 10 weight loss therapies
have been marketed, and 21 are in clinical phase 2 (17), phase 3 (2), and
pre-registration (2) status. There are three trends of weight loss drug
development.

2. Huateng Pharma https://us.huatengsci.com
Figure 1. Overview of weight loss drugs approved and in clinical trials

3. Huateng Pharma https://us.huatengsci.com
Targets: Dominated by GLP-1 receptors, followed by
multi-mechanism incretin
The largest number of therapies targeting the GLP-1 receptor have been used
in all phases of development from Phase 2 clinical to market. GLP-1
(glucagon-like peptide 1) belongs to a group of hormones called incretin, which
is produced by endocrine cells located in the gut and secreted into the
bloodstream within minutes after eating. Its physiological effects include
regulating the release of insulin after eating and acting on the body's
hypothalamus to regulate appetite. In addition to GLP-1, GIP
(glucose-dependent insulinotropic polypeptide) is also a common
incretin. Semaglutide and liraglutide, both approved by FDA in recent years,
are GLP-1 receptor agonists, and the safety and efficacy of this target has
been verified in studies.
Figure 2. Targets of Weight loss drugs in clinical trials
Specifically, GLP-1 receptor agonists account for 30% of marketed drugs, 50%
of pre-registered drugs, and 18% of phase 2 drugs. This shows that the
proportion of single GLP-1 receptor agonists in early clinical development
therapies is gradually decreasing, while dual and triple receptor agonists such
as GLP-1/GCG, GLP-1/GIP, and GLP-1/GCG/GIP are more distributed in
phase 2 and phase 3 clinical trials. The safety and efficacy of GLP-1 targeted
therapies on the market has led to research on incretin therapies targeting
multiple mechanisms, as the regulation of energy metabolism itself involves
multiple hormones, and drug targeting multiple signaling pathways may
produce synergistic effects, thus making the efficacy more significant.
Besides incretin, there is a trend of more diversified and novel
targets from marketed to phase 2 therapies. Five of the 10 marketed drugs

4. Huateng Pharma https://us.huatengsci.com
target non-incretin targets, sibutramine sulfate and sibutramine mesylate are
serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs), orlistat and
cetilistat target gastrointestinal lipase, and naltrexone and bupropion target
opiate receptors and adrenergic receptors, respectively.
Of the 2 pre-registered therapies, tesofensine remains an SNDRI, while of the
phase 3 therapies, tirzepatide is a dual GLP-1/GIP receptor agonist and
cagrilintide is a long-acting amylin analogue. Amylin, a peptide that is
co-secreted with insulin, reduces food intake through a signaling pathway that
regulates satiety.
Finally, among the 17 therapies undergoing phase 2 clinical trials, a total of 8
therapies adopted non-incretin mechanisms of action, namely controlled
metabolic accelerators (CMAs), neuropeptide YY5 receptors,
appetite-regulating hormones, IKKε/TBK1, an important regulator of metabolic
disease, SIRT1 protein, activin type II receptor, bitter taste receptor TAS2R,
amylase/glucosidases, which are relatively novel mechanisms. Bitter taste
receptors mediate the perception of bitter taste not only in the oral cavity but
are also expressed in other tissues of the body.
Aardvark's lead product, ARD-101 is a first-in-class oral composition targeting
extraoral bitter taste receptors (TAS2R). ARD-101 was largely restricted to the
gut while still inducing systemic effects, including increased expression of
endogenous gut peptide hormones. HU6 is a controlled metabolic accelerator
(CMA) that can activate proton leak and mitochondrial uncoupling, a natural
process in the body that regulates and dissipates energy. By ferrying protons
out of the mitochondrial intermembrane space, CMAs cue the increased
oxidation of sugars and fats, while maintaining the same baseline production of
adenosine triphosphate (ATP). Activating this process results in the reduction
of accumulated fat throughout the body.
Dosage form: Slightly more oral formulations than injectable
formulations, better development trend of oral formulations in
the future
Of the 31 drugs, 16 are oral drugs and 15 are injectable drugs. Currently, the
oral form accounts for 60% of the marketed weight loss drugs, while the
proportion of oral drugs decreases to 50% and 53% for drugs in the
pre-registration and phase 2, and the two drugs undergoing phase 3 clinical
trials are administered by injection. Among the drugs in the market and
pre-registration phase, the incretin therapies represented by GLP-1 receptor
agonists were all administered by injection. Of the seven incretin therapies in
Phase 2, only two were administered orally. This shows that incretin therapies
have a shorter half-life and are better absorbed by injection than by oral
administration. This explains the fluctuations in the proportion of oral therapies

5. Huateng Pharma https://us.huatengsci.com
at different stages of clinical trials. Among the drugs in the market,
pre-registration and phase 3, the proportion of oral drugs decreases as the
proportion of incretin therapy rises. For drugs in Phase 2, the percentage of
oral drugs rebounded with the diversification of target distribution and the
development of oral incretin therapy.
Figure 3. Rout of administration of weight loss drug
Looking ahead, oral weight loss therapies may be preferred over injections, as
compliance with oral dosing is significantly higher than that of injections. It is
assumed that the industry will invest more in developing oral formulations of
weight-loss drugs, as incretin, a drug that is difficult to make into oral dosage
forms, is being explored for oral use.
Weight lose results: newcomers prevail & the upper limit keeps
rising.
Figure 4. Body weight loss achieved through lifestyle changes, currently

6. Huateng Pharma https://us.huatengsci.com
approved anti-obesity medications (AOMs) and bariatric surgery (part a) and
correlation of drug-induced body weight loss in rodents and humans (part b).
Source: Reference [1]
The effectiveness of weight loss therapies is a topic of great interest, as shown
here in a review of weight loss therapies from Nature Reviews Drug Discovery.
Of the available weight loss methods, bariatric surgery is the most effective,
with an average weight loss of about 30%, but the conditions for performing
bariatric surgery are demanding, and the risks of surgery and postoperative
recovery are uncertainties that cannot be ignored. In contrast, weight loss
drugs greatly surpass surgery in terms of convenience and safety, but are less
effective than the former, with most weight loss drugs only reducing weight by
5%-10% and very few by 10%-15%. Historically, the development of weight
loss drugs has been fraught with ups and downs. According to the literature,
drugs were approved for weight loss as early as the 1930s, yet most were
withdrawn from the market because of serious toxic side effects.
Figure 5. Average percentage weight loss
The average percentage of weight loss for marketed, pre-registered, and
Phase 3 weight loss drugs is increasing sequentially, and the upper limit of the
drug's weight loss efficacy is increasing. For example, results from the STEP
Phase 3a clinical trial of semaglutide showed that obese patients treated with
the drug lost an average of 17-18% of their body weight and that the effect was
maintained for more than 68 weeks. On July 26, Eli Lilly published in the New
England Journal of Medicine the results of the clinical Phase 3 trial of
tirzepatide, SURMOUNT-1, in which patients lost up to 22.5% of their body
weight after 72 weeks of treatment, an effect comparable to bariatric surgery.

7. Huateng Pharma https://us.huatengsci.com
Although drugs are not currently the preferred method of weight loss in the
public perception, and most weight loss drugs are still in the early to mid-stage
of development, the three major trends of target diversification, increased
convenience of dosage forms, and improved weight loss effects reflect the
industry's concern and commitment to weight loss therapies. We expect more
effective, safe and convenient weight loss drugs to emerge as soon as
possible to alleviate the public health crisis of the expanding global obesity
population.
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.
Reference:
1. Müller et al., (2021). Anti-obesity drug discovery: advances and challenges. Nature
Reviews Drug Discovery, https://doi.org/10.1038/s41573-021-00337-82.
2. Lilly's tirzepatide delivered up to 22.5% weight loss in adults with obesity or overweight
in SURMOUNT-1. Retrieved August 25, 2022, from
https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-delivered-22
5-weight-loss-adults-obesity-or
Related Articles:
Anti-Obesity Drugs: History And Development
Overview of Diabetes Treatment Strategies