Novo Nordisk's Oral Semaglutide (Rybelsus) Approved by FDA for Type 2 Diabetes

On September 20, the FDA officially approved Novo Nordisk’s marketing application for Rybelsus (oral semaglutide, once daily) to improve glycemic control in patients with type 2 diabetes, in conjunction with diet and exercise.

Novo Nordisk submitted the New Drug Application (NDA) for oral semaglutide on March 20, 2019. As a Priority Review Voucher was utilized, this NDA was approved within six months under the FDA’s Priority Review program. On the same day, Novo Nordisk also submitted an NDA for oral semaglutide to reduce the risk of cardiovascular events in adults with type 2 diabetes, as well as a Supplemental New Drug Application (sNDA) for a new indication of Ozempic (subcutaneous semaglutide injection) to reduce the risk of cardiovascular events in adults with type 2 diabetes. Since these two applications did not utilize a Priority Review Voucher, they were subject to the FDA’s Standard Review process, with approval expected by January 20, 2020. On April 26, 2019, Novo Nordisk submitted a marketing authorization application to the European Medicines Agency (EMA) for oral semaglutide for the treatment of type 2 diabetes. In July 2019, Novo Nordisk submitted a marketing authorization application for oral semaglutide to the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan.

The application for market approval and the subsequent approval of oral semaglutide were based on the results of 10 PIONEER clinical trials, which involved a total of 9,543 patients with type 2 diabetes. A series of head-to-head clinical trials within the PIONEER program confirmed that oral semaglutide demonstrated significant advantages over sitagliptin, empagliflozin, and liraglutide in reducing HbA1c levels and body weight (as shown in the figure below). Furthermore, oral semaglutide exhibited a safety and tolerability profile consistent with other GLP-1 receptor agonists, with nausea being the most common adverse event.

Note:

· PIONEER 6 is a cardiovascular safety study, and PIONEER 9 and PIONEER 10 are studies conducted in Japan.

· PIONEER 1: Oral Semaglutide (3, 7, and 14 mg) vs Placebo in Adults with Type 2 Diabetes Managed with Diet and Exercise Alone

·PIONEER 2: Adults with T2D, Oral Semaglutide 14 mg vs Empagliflozin 25 mg

· PIONEER 3, adult patients with T2D, oral semaglutide (3, 7, 14 mg) vs sitagliptin 100 mg

·PIONEER 4: Adults with Type 2 Diabetes, Oral Semaglutide 14 mg vs. Liraglutide 1.8 mg vs. Placebo

· PIONEER 5: Oral Semaglutide 14 mg vs. Placebo in Adults with Type 2 Diabetes and Moderate Renal Impairment

·PIONEER 7: Dose-adjusted oral semaglutide vs. sitagliptin 100 mg in adults with type 2 diabetes

· PIONEER 8: Oral Semaglutide (3, 7, 14 mg) vs. Placebo in Patients with Type 2 Diabetes on Long-term Insulin Therapy

Semaglutide belongs to the class of glucagon-like peptide-1 (GLP-1) receptor agonists. GLP-1 is a hormone that induces insulin secretion and exerts beneficial effects on multiple vital organs, including the pancreas, heart, and liver. The advantages of GLP-1 receptor agonists include effective glycemic control, a significant reduction in the incidence of hypoglycemic events, as well as notable benefits in weight reduction and lowering the risk of cardiovascular events.

One limitation of GLP-1 medications is that their specific peptide structure leads to degradation by gastric acid upon oral administration, necessitating subcutaneous injection. However, the pharmaceutical industry has been striving to extend the in vivo half-life of GLP-1 drugs to reduce dosing frequency, while also exploring formulation technologies that can enhance oral bioavailability. Currently, there are eight GLP-1 receptor agonists approved for marketing worldwide, five of which are long-acting formulations administered via once-weekly injections. The most predominant GLP-1 medications on the market include Victoza (liraglutide, once-daily injection), Trulicity (dulaglutide, once-weekly injection), Ozempic (semaglutide, once-weekly injection), and Bydureon (exenatide extended-release microspheres, once-weekly injection).

Given the multiple benefits of GLP-1 receptor agonists for patients with diabetes and the significant convenience offered by once-weekly long-acting formulations in glycemic management, the global market size for GLP-1 drugs has expanded rapidly, driven by Trulicity. As the successor to liraglutide developed by Novo Nordisk, semaglutide’s once-weekly subcutaneous injection, Ozempic, received initial FDA approval in late 2017. Its global sales reached $563 million in the first half of 2019, with annual revenues expected to surpass $1 billion, thereby achieving blockbuster status.

The launch of oral semaglutide will help Novo Nordisk defend its leading position in the GLP-1 drug market. First, liraglutide is currently the only GLP-1 drug with a label indication for “reducing the risk of major adverse cardiovascular events in patients with type 2 diabetes,” ensuring a solid foundation for Novo Nordisk in the GLP-1 sector. Second, Ozempic, the once-weekly subcutaneous injection formulation of semaglutide, has demonstrated strong growth since its launch. Its new indication for reducing cardiovascular event risk in patients with type 2 diabetes is expected to receive FDA approval as early as next January, positioning it for direct competition with Trulicity. In the SUSTAIN 7 trial, semaglutide at doses of 1 mg and 0.5 mg demonstrated superior efficacy in glycemic control and weight reduction compared to dulaglutide at doses of 1.5 mg and 0.75 mg (see figure below). Finally, oral semaglutide represents Novo Nordisk’s flagship product. Administered once daily by mouth, it eliminates the inconvenience and psychological burden associated with injections. Meanwhile, it offers superior glycemic control and weight loss effects compared to mainstream therapies such as liraglutide (once-weekly injection), empagliflozin (an SGLT-2 inhibitor), and sitagliptin (a DPP-4 inhibitor), making it highly attractive to both patients and physicians.

Oral Semaglutide Reshapes the Global Diabetes Drug Market Landscape

According to statistics, the global number of people with diabetes reached 425 million in 2017. Due to the incurable nature of the disease and the accelerating aging of the population, the global diabetic population is projected to reach 629 million by 2045. Consequently, diabetes represents one of the largest pharmaceutical markets worldwide. In 2018, the global annual market size for original branded glucose-lowering drugs reached $42 billion, with injectables (insulin and GLP-1 receptor agonists) accounting for $29 billion (69%) and oral formulations (DPP-4 inhibitors and SGLT-2 inhibitors) accounting for $13 billion (31%).

If further subdivided by mechanism of action, insulin, as the mandatory treatment for patients with type 1 diabetes and the last-line therapy for those with type 2 diabetes, accounts for 50% of the entire diabetes drug market. However, due to the expiration of original patents, the availability of generics, and pricing pressures, insulin’s global market share has ceased to grow and is even showing a declining trend. The same situation applies to DPP-4 inhibitors.

GLP-1 and SGLT-2 inhibitors are currently the most prominent classes of glucose-lowering medications, with their market size and share steadily expanding. GLP-1 agonists offer well-established benefits in glycemic control, weight reduction, and cardiovascular outcomes. SGLT-2 inhibitors, which promote urinary glucose excretion through an insulin-independent mechanism, also have robust evidence supporting cardiovascular benefits. Consequently, many patients who achieve suboptimal glycemic control with conventional oral antidiabetic drugs are switching to subcutaneous GLP-1 agonists or oral SGLT-2 inhibitors. However, given the increased risk of genital infections associated with SGLT-2 inhibitors, the approval and launch of oral semaglutide is likely to provide a more ideal therapeutic option for this patient population.

According to EvaluatePharma’s forecasts, GLP-1 and SGLT-2 inhibitors will account for half of the global top 10 antidiabetic drugs in 2024. The title of the world’s best-selling antidiabetic drug will no longer belong to insulin, and none of the top three antidiabetic drugs will be insulin products. Global sales of subcutaneous semaglutide are projected to reach $5.28 billion by 2024, while oral semaglutide is expected to achieve $3.23 billion in sales.

In summary, GLP-1 drugs are feasible for development into oral formulations due to their glucose-lowering efficacy comparable to insulin and a relatively wide safety window. Currently, oral semaglutide utilizes an excipient (absorption enhancer) called sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC) to improve bioavailability, thereby enabling oral administration and achieving market approval—a milestone achievement. Meanwhile, the subcutaneous formulation of semaglutide is also under development for the treatment of obesity and non-alcoholic steatohepatitis (NASH). Semaglutide is projected to become a super blockbuster drug with annual sales exceeding $10 billion; its market performance remains to be seen.