On January 26, the official website of the State Food and Drug Administration showed that Novo Nordisk Megglutide Tablets had been approved by the State Food and Drug Administration (NMPA) for marketing to treat type 2 diabetes. This is the first domestically approved oral GLP-1 (glucagon like peptide-1) receptor agonist.
Rybelsus, also known as Smegglutide Tablets, is an oral dosage form of Smegglutide, composed of Smegglutide and absorption enhancer SNAC. SNAC can locally increase pH to protect smectide from protease degradation, and on the other hand, it can promote cross cellular transport of smectide to enhance gastric absorption.
According to the magic prescription of medicine, the hypoglycemic effect of oral smeglutide was confirmed in 10 PIONEER clinical trials, involving 9543 patients with type 2 diabetes. A series of "head to head" clinical trials of the PIONEER project have confirmed that oral simagliptin has significant advantages in reducing HbA1c and weight compared to sitagliptin, empagliflozin, and liraglutide. Additionally, oral simagliptin has the same safety and tolerability as other GLP-1 drugs, with nausea being the most common adverse event.
Moreover, the experimental results showed that the larger the dosage taken, the better the hypoglycemic effect. In the PIONEER PLUS phase III trial published by Novo Nordisk, in patients with type 2 diabetes who need intensive treatment, 25 mg and 50 mg of oral smeglutide were added to 14 mg of oral antidiabetic drugs at 1 to 3 stable doses to compare the efficacy and safety. This experiment achieved its main endpoint, which demonstrated a better HbA1c reduction (glycated hemoglobin) in the oral administration of 25mg and 50mg of smeglutide at 52 weeks compared to the 14mg treatment group.
However, it is worth noting that gastrointestinal events are most significant during the dose escalation phase, and are more common in oral administration of 25mg and 50mg of smeglutide compared to oral administration of 14mg. That is to say, the larger the dosage taken, the more obvious the adverse reactions.
After Smeglutide's diabetes indication was approved for marketing, the market paid more attention to when its weight loss indication could be launched. According to the drug clinical trial registration and information disclosure platform, the weight loss indications of the oral dosage form of Smegglutide are still in the third phase of clinical trials.
The Novo Nordisk trial data shows that oral administration of 50mg of smeglutide has a good weight loss effect. According to the official website of Novo Nordisk, in May 2023, Novo Nordisk announced that in the OASIS1 trial, oral administration of 50mg of smeglutide achieved 15.1% weight loss in obese and overweight patients.
OASIS1 is a 68 week efficacy and safety trial comparing the daily administration of 50mg of oral smeglutide with placebo for weight management in 667 adult obese or overweight patients with at least one comorbidity. Both treatment groups were combined with lifestyle interventions. The trial reached its main endpoint, and at week 68, oral administration of 50mg of smeglutide showed a statistically significant and superior weight loss compared to placebo.
However, similar to the pattern of adverse reactions observed in the above experiments, the most common adverse event observed in this study was gastrointestinal events, with the majority being mild to moderate, which gradually decreased with prolonged treatment. Gastrointestinal events mainly occur during the dose escalation phase.
Previously, in February 2021, Smegglutide Injection was approved for marketing in China. At present, the domestic formulations of Smegglutide can be divided into two types: Smegglutide Injection and Smegglutide Tablets. The specifications of Smegglutide Injection are 2mg/1.5 mL (1.34mg/mL) and 4mg/3 mL (1.34mg/mL), injected once a week; The specifications of Smegglutide tablets are 3mg, 7mg, and 14mg, taken orally once a day.
At present, in China, although Smegglutide Injection has not been approved for weight loss indications, it has become common for many people to purchase it for weight loss. After the oral version is launched, it is almost certain that similar situations will occur again.
However, in addition to the risk point of not having an approved indication for weight loss, there is another major challenge when using oral Smegglutide for weight loss.
Just looking at the specifications of the injection and oral dosage forms of Smegglutide, it can be found that the dosage of the oral dosage form is larger than that of the injection form. This is because in order for oral dosage forms to achieve the blood drug concentration of injection forms, a larger dosage is required. SUSTAIN and PIONEER series studies have found that 7mg and 14mg oral smeglutide tablets have similar blood drug concentrations to 0.5mg and 1.0mg subcutaneous injection of smeglutide, respectively.
However, in order to achieve the same effect as the injection form, the oral dosage of Smegglutide cannot be achieved simply by increasing the dosage. This is determined by the molecular structure of Smegglutide. Smegglutide is a peptide molecule, and this molecular drug is easily degraded by enzymes, has low permeability, and is severely affected by the gastrointestinal environment during oral administration, resulting in low oral bioavailability.
Previously, consumers who purchased overseas oral Smegglutide tablets on their own revealed to Interface News reporters that oral administration not only has a high dosage, but also has average effects.
The oral dosage form of Smegglutide adopts an oral delivery technology. As mentioned at the beginning, Smegglutide tablets add an absorption enhancer SNAC to the peptide chain of the original Smegglutide molecule, thereby protecting the Smegglutide molecule entering the stomach from being degraded by gastric protease and increasing the bioavailability of the oral administration pathway.
In addition, Smegglutide tablets are also the first oral peptide drug in China, which means that similar oral peptide drugs are more likely to be approved in the future. At present, there are also several pharmaceutical companies in China that are developing oral peptide GLP-1 drugs, including East China Pharmaceutical, Xianweida, and Wentai Pharmaceutical.