Emerging Role of Dual GLP-1 Receptor Agonists

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Emerging Role of Dual GLP-1 Receptor Agonists

The management of diabetes has changed
dramatically during the past hundred years. Biguanides, insulins,
sulfonylureas, glycosidase inhibitors, thiazolidinediones, glinides, DPP-IV
inhibitors, and SGLT-2 inhibitors are all competing in this field.
Today, Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are one of the
most attractive option for the treatment diabetes because they effectively lower
A1C and weight while having a low risk of hypoglycemia. To date, GLP-1RAs
have accounted for 12% of the glucose-lowering drug market and are
maintaining a high growth trend.

Development of GLP-1RA

Since the first GLP-1RA, exenatide, was approved in 2005, more than 10
products (by active ingredient/combination) have been marketed
worldwide. At present, there are three blockbuster products, liraglutide,
dulaglutide and semaglutide (with annual sales of USD 5 billion).

Figure 1. Listed GLP-1RA drugs
Liraglutide, approved by the FDA in 2010 under the brand name Victoza®,
has surpassed exenatide in sales in the first two years of marketing due to its

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excellent efficacy and lower adverse effects. Liraglutide has occupied the top
spot in the market of GLP-1 RAs for nearly a decade, with sales peaking at $5
billion in the 10th year after launch (2019).

Dulaglutide was launched by Eli Lilly in 2014 and proved non-inferior to
liraglutide in a type 2 diabetes head-to-head trial. Thanks to the reduced
frequency of dosing (once a week), dulaglutide sales climbed rapidly, topping
$5 billion in the sixth year after launch (2020). But the good times did not last
long, as semaglutide sales surpassed dulaglutide in the first half of 2022.

Semaglutide was launched in 2017 and beat dulaglutide in a phase 3
head-to-head superiority trial, demonstrating excellent clinical
glucose-lowering effects. After the approval of the injectable Ozempi, the oral
tablet Rybelsus and the weight reduction drug Wegovy have been launched
successively. Semaglutide has exceeded USD 5 billion in only 3 years of
market launch and will sprint for USD 10 billion in 2022, and the future market
ceiling will be higher than the first two drugs.

Figure 2. 2012 to 2022H1 sales of three blockbuster GLP-1RA drugs

GLP-1RA has continued to iterate on the demand for improved adherence,
with essentially every new generation of GLP-1 drugs achieving a
comprehensive overtake of the previous generation. The first marketed
GLP-1RA drug, exenatide, began to decline in sales in the second year of
liraglutide's launch, with peak sales ending at $797 million in 2009. The same
was true for the first long-acting weekly formulation, exenatide microspheres,
with sales peaking at $580 million three years after launch. The market
performance was even more average for lixisenatide launched by Sanofi (2013)
and albiglutide launched by GSK (2014, withdrawn from the market in 2018).

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The above products are not as effective in lowering glucose as earlier products
or have greater side effects, so even though they had a lead at the time of
commercialization, they were eventually replaced by later-marketed drugs with
better efficacy.

Emerging Dual GLP-1 Receptor Agonists

In the face of fierce competition from single-target drugs, Novo Nordisk and Eli
Lilly introduced GLP-1/GIP receptor dual agonists to the clinic in 2014 and
2016, respectively. And in May 2022, Eli Lilly received FDA approval for
its dual GLP-1R/GIPR agonist Tirzepatide (Mounjaro), becoming another
blockbuster drug in the glucose-lowering field.

Figure 3. Dual GLP-1 RAs under investigation

GLP-1R/GIPR

Tirzepatide has achieved rapid sales growth since its launch. According to Eli
Lilly's third-quarter financial report, Mounjaro generated $187 million in
revenue in the third quarter and $200 million in cumulative revenue since its
launch. Mounjaro is expected to be Eli Lilly's new ace in the hole against Novo
Nordisk's semaglutide. Mounjaro sales are expected to reach $4.7 billion in
2026, according to an analysis of data from research firm Refinitiv.

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Tirzepatide not only showed better results in glucose lowering and weight loss
than semaglutide in a phase 3 head-to-head study in type 2 diabetes
(SURPASS-2), but also achieved an average weight loss of 22.4% in clinical
phase 3 (SURMOUNT-1), making it the first drug to achieve an average weight
loss of more than 20% in clinical phase 3 (the average weight loss of
semaglutide in the clinic was around 15%). Eli Lilly has planned to file a
marketing application for tirzepatide for weight loss in the fourth quarter of
2022.

Figure 4. Comparison of glucose-lowering and weight-loss effects of
Tirzepatide and semaglutide in the SURPASS-2 head-to-head trial (Source:

Reference 4)

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GLP-1R/GCGR

As the competition for type 2 diabetes drugs is too fierce, nonalcoholic
steatohepatitis (NASH) has become a priority choice for late-stage clinical dual
GLP-1/GCG receptor agonists, such as the development programs of
AstraZeneca, Merck Sharp & Dohme (Efinopegdutide), and Boehringer
Ingelheim.

In the Phase IIb clinical results published in 2021, AstraZeneca's Cotadutide
was compared with liraglutide and had similar glucose-lowering and
weight-loss effects in the clinical setting (except for the 500ug weight-loss
effect). Such data is disappointing when dual agonists are compared to older
drugs marketed 10 years ago, not to mention benchmarking against a host of
newer drugs, such as simeglutide.

Figure 5. Comparison of glucose-lowering and weight-loss effects of
Cotadutide and liraglutide (Source: Reference 5)

Thankfully, patients showed significant improvement in liver parameters
AST and ALT levels and liver fibrosis after Cotadutide treatment and
contrasted differently with liraglutide. As a result, AstraZeneca also
initiated a phase III clinical study of Cotadutide for NASH in May 2022. It
should be noted that in this study there was a significant increase in TRAEs
(46%-61% vs. 22.7%) and discontinuation rates (13%-21% vs. 1.8%) after
Cotadutide treatment compared to liraglutide.

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Figure 6. Clinical improvement of liver indices with Cotadutide versus
liraglutide (Source: Reference 5)

Conclusion

The long-acting and oral administration of GLP-1 drugs are the two major
achievements in the field of glucose lowering, and Professor Daniel Drucker,
one of the founders and outstanding leaders in the field of GLP-1 research,
has optimistically predicted that in the near future, GLP-1 drugs will replace
insulin as the main line of diabetes treatment. In the weight loss market, GLP-1
drugs, which can be used to lose weight with a single injection, have even
more room for imagination.

Huateng Pharma is known worldwide for a variety of pharmaceutical
intermediates used in research and development. We can provide antidiabetic
drug intermediates such as Canagliflozin intermediates, Dapagliflozin
intermediates and Empagliflozin intermediates for commercial scale
production. We can also supply Alogliptin intermediates, Linagliptin
intermediates, Liraglutide intermediates, Semaglutide intermediates and
Sitagliptin intermediates which are on R&D stage.

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References:
1. Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and
GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From
discovery to clinical proof of concept. Mol Metab. 2018;18:3-14.
doi:10.1016/j.molmet.2018.09.009
2. Frias JP, Bastyr EJ 3rd, Vignati L, et al. The Sustained Effects of a Dual
GIP/GLP-1 Receptor Agonist, NNC0090-2746, in Patients with Type 2
Diabetes. Cell Metab. 2017;26(2):343-352.e2. doi:10.1016/j.cmet.2017.07.011
3. Campbell JE. Targeting the GIPR for obesity: To agonize or antagonize?
Potential mechanisms. Mol Metab. 2021;46:101139.
doi:10.1016/j.molmet.2020.101139
4. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide
Once Weekly in Patients with Type 2 Diabetes. N Engl J Med.
2021;385(6):503-515. doi:10.1056/NEJMoa2107519
5. Nahra R, Wang T, Gadde KM, et al. Effects of Cotadutide on Metabolic and
Hepatic Parameters in Adults With Overweight or Obesity and Type 2 Diabetes:
A 54-Week Randomized Phase 2b Study [published correction appears in
Diabetes Care. 2022 Oct 03;:]. Diabetes Care. 2021;44(6):1433-1442.
doi:10.2337/dc20-2151

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