FDA Approves Novo Nordisk's Oral Semaglutide, First GLP-1 in Pill Form on Sept. 20^th. As a long-acting GLP-1 analog, semaglutide has a mechanism of action similar to GLP-1. And GLP-1 is a peptide hormone secreted by intestinal L cells, which, after specifically binding to the receptor, mainly gives play to the secretion of blood glucose-dependent incretin via the cyclic AMP signaling pathway. According to research, semaglutide could not only largely improve blood glucose of patients with type 2 diabetes but also decrease appetite and reduce food intake and induce weight loss. Besides, it could significantly reduce the risks of MACE of patients with type 2 diabetes. Semaglutide subcutaneous injection was approved by the FDA in Dec. 2017 to treat type 2 diabetes, with the trade name of Ozempic and 2018 sales reaching USD284 million.

Semaglutide subcutaneous injection has the same main ingredient as semaglutide tablets, with the only difference being that semaglutide tablets uses sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) as the excipient and its safety and effectiveness have been proved in the PIONEER trials. Besides the difference in the administration method, those two dosage forms also have different administration frequencies, with the injection administered once weekly while tablets administered once daily. If semaglutide tablets is smoothly approved, it will have inestimable business prospects. The pharmaceutical market research institution EvaluatePharma predicts that semaglutide’s sales in 2024 will reach USD1.994 billion.

With the Approval of World’s First Oral GLP-1 Receptor Agonist, Novo Nordisk Maintains its Dominance in the Diabetes Area

"When brothers come together, there is nothing they cannot achieve."

Novo Nordisk, when the competitive edge of its pillar product—insulin became less obvious, has locked on the GLP-1 receptor agonist area and launched Victoza (liraglutide) in 2010. Since marketed, Victoza’s sales have grown fast year by year (as shown in the following table) and it has rapidly become a pillar of Novo Nordisk in the diabetes area.

However, with other GLP-1 receptor agonists approved for marketing, we can see from the above table that Victoza’s growth was clearly not as good as previous years and its proportion in the GLP-1 market declined year by year. With the advantage of Novo Nordisk in the GLP-1 area of diabetes drugs whittled away, semaglutide developed in 2017 is expected to win a round for it, because according to the head-to-head SUSTAIN clinical trial data, semaglutide was significantly better than dulaglutide, sitagliptin, insulin glargine, or exenatide extended-release in terms of reducing blood glucose and losing weight and semaglutide was proved to provide cardiovascular benefits. This study has established the dominance of semaglutide among GLP-1 receptor agonists. Novo Nordisk is predicted to rapidly seize the share in the diabetes drug market in the diabetes area with the marketing of semaglutide and the approval of the new dosage form.

The increasingly white-hot competition of GLP-1 receptor agonists

So far, there have been 7 GLP-1 receptor agonists approved by the FDA, separately, Novo Nordisk’s liraglutide and semaglutide, AstraZeneca’s exenatide and its extended-release, Eli Lilly’s dulaglutide, Sanofi’s lixisenatide, and GSK’s albiglutide (see the following table for details). Exenatide analogs and human GLP-1 analogs are currently the two major categories in GLP-1 receptor agonist R&D, wherein, exenatide is a GLP-1 analog separated from lizard saliva, bearing a 53% homology to human GLP-1 and having a longer half-life and stronger bioactivity because its second amino acid residue, alanine, in N-terminal region is replaced by glycine not decomposed by human dipeptidyl peptidase IV (DPP-1V). Lixisenatide and albiglutide are exenatide analogs, while liraglutide, dulaglutide, and semaglutide are human GLP-1 analogs of which the immunogenicity is lower than that of exenatide and its analogs because human GLP-1 has a higher homology.

The above 7 GLP-1 receptor agonists approved also have different action times and injection frequencies mainly because of their structures. Wherein, exenatide and lixisenatide are short-acting preparations, while the other 5 are long-acting with differences in the mechanisms for the long action: exenatide extended-release achieves the long action by being made into an extended-release microsphere preparation, liraglutide and semaglutide achieve the long action by fatty acid side chain modification, albiglutide achieves the long action by albumin fusion, while dulaglutide achieves the long action by Fc fragment fusion.

The above 7 drugs all achieved good sales (see the following table for details) in 2017, wherein, liraglutide, the second GLP-1 receptor agonist marketed, achieved global sales of USD3.5 billion in 2017, ranking top among sales of GLP-1 receptor agonists, and its dominance in the GLP-1 market was not shaken by the three drugs marketed subsequently; plus, the marketing of semaglutide subcutaneous injection and the approval of its new dosage form will enable Novo Nordisk to have competitiveness in the GLP-1 area to be reckoned with. The competition of the GLP-1 receptor agonists will become more intense.

According to information, the diabetes prevalence is 6.6% in the world, and the number of patients reached 366 million in 2011, growing by nearly 30% than in 2010. Wherein, 90% of diabetes patients had type 2 diabetes. The disease has become an epidemic disease in the world following cardiovascular diseases and tumors and is the main cause of death and disability in adult patients. Insulin is still the mainstream product in the area, however, insulin’s market share will be gradually dented with the marketing of more and more therapeutic drugs. Among the numerous non-insulin drugs approved, GLP-1 receptor agonists are very promising. According to the data and prediction of Evaluate Pharma, the proportion of GLP-1 receptor agonists is expected to largely increase from 17% in 2014 to 35% in 2022, with the sales to exceed USD14 billion. At last, I sincerely hope that Novo Nordisk’s semaglutide tablets can be approved soon, to reduce the pain of diabetes patients in receiving the subcutaneous injection.

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