Semaglutide Expands Beyond Weight Loss to Chronic Kidney Disease: Is the 'Blockbuster Drug' Crown Within Reach?

On October 10 local time, Novo Nordisk announced the early termination of the Phase III clinical trial FLOW, which was investigating the effect of semaglutide on the progression of kidney damage in patients with type 2 diabetes and chronic kidney disease.

This decision was made based on the recommendation of the independent Data Monitoring Committee (DMC). The committee concluded that the interim analysis results met certain pre-specified criteria, justifying the early termination of the trial to enhance efficacy.

To protect the integrity of the trial, Novo Nordisk will remain blinded to the results until the trial is completed. The FLOW trial is expected to read out results in the first half of 2024.

This is the 4th clinical progress report on semaglutide released by Novo Nordisk in 2023. From being endorsed by Musk as the "miracle weight-loss drug" to achieving superior results in trials for dual and triple indication therapies, Novo Nordisk has pushed GLP-1 drugs to new heights.

Semaglutide (also known as Ozempic, Semaglutide) is a glucagon-like peptide-1 (GLP-1) receptor agonist. Glucagon-like peptide-1 (GLP-1) is an "incretin" naturally secreted by the mucosa of the human gastrointestinal tract. After binding to its receptor GLP-1R, it stimulates insulin secretion, suppresses glucagon release, thereby promoting glucose metabolism and reducing blood sugar levels.

In patients with type 2 diabetes, the significant decline in GLP-1 secretion largely leads to uncontrolled blood glucose. It can also delay gastric emptying, reduce food intake through central appetite suppression, slow gastric emptying, increase satiety, and thereby lower blood glucose.

In 2017, Novo Nordisk improved upon liraglutide to develop semaglutide, which was later renamed as Ozempic. In head-to-head studies on blood sugar reduction and weight loss, Ozempic significantly outperformed dulaglutide, earning the title of "the best diabetes drug in history." By the first half of 2019, Ozempic's revenue had reached $562 million. In April 2021, the Ozempic injection was approved in China for the treatment of type 2 diabetes.

In June 2021, the FDA approved Wegovy for marketing, intended for chronic weight management in individuals with obesity (BMI≥30kg/m²) and at least one weight-related comorbidity.²) or overweight (BMI≥27kg/m²) and related complications in adults, with a once-weekly subcutaneous injection of 2.4mg. From this point on, semaglutide gained immense popularity due to its obesity indication, achieving sales of $10.882 billion in 2022. It has now been approved for marketing in over 50 countries and regions, including the United States, Europe, Canada, and Japan.

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HFpEF (Heart Failure with Preserved Ejection Fraction) accounts for half of heart failure cases, imposing a burden of fatigue, shortness of breath, and limited physical capacity on patients. The majority of HFpEF patients (80%) are overweight or obese, which exacerbates symptoms and reduces quality of life.

In the disclosure this August, the Phase III SELECT trial met its primary endpoint, showing that 2.4 mg of semaglutide per week effectively alleviated heart failure symptoms in obese adults with HFpEF, improved exercise function, and promoted weight loss. It reduced the risk of major adverse cardiovascular events in overweight or obese adults by 20%. The trial recruited 17,604 adults aged 45 years or older who were overweight or obese, had cardiovascular disease, and no history of diabetes, with follow-up lasting up to five years.

In terms of weight, the semaglutide group decreased by 13.3%, while the placebo group decreased by 2.6%. Compared with the start of the study, patients in the Wegovy group were able to walk an additional 21 meters within 6 minutes, compared to 1.2 meters for the placebo group. During the study, one patient in the Wegovy group was hospitalized or had an emergency visit due to heart failure, and scores on a questionnaire assessing heart failure symptoms improved; in the placebo group, this number was 12.

Based on this result, Novo Nordisk is expected to submit a regulatory approval application for the label indication expansion of 2.4 mg semaglutide (Wegovy) in the United States and the European Union within the year. This will significantly increase the potential patient population for semaglutide.

FLOW is a randomized, double-blind, parallel-group, placebo-controlled superiority trial that was initiated in 2019. The trial compares semaglutide 1.0mg with placebo as an adjunct to standard care in preventing the progression of renal impairment and the risk of renal and cardiovascular mortality in patients with type 2 diabetes and chronic kidney disease.

The FLOW trial enrolled a total of 3,534 patients across more than 400 research sites in 28 countries. The composite primary endpoint included a sustained reduction in eGFR by more than 50%, and a sustained eGFR of less than 15 ml/min/1.73m².²Time, time to dialysis or kidney transplantation, mortality due to kidney disease or cardiovascular disease.

GLP-1, in addition to being an incretin hormone that regulates blood sugar, is also a confirmed neurotransmitter. Its receptors are expressed in many regions of the brain, leading to discoveries in alleviating neurodegenerative diseases.

An animal study showed that administration of the GLP-1 receptor agonist liraglutide improved memory and learning abilities, increased the number of neurons, reduced β-amyloid (Aβ), and prevented tau accumulation. Modulation of GLP-1 activity also increased dopamine levels in a mouse model of Parkinson's disease.

Novo Nordisk launched two large Phase III trials in 2021 to examine whether semaglutide can alleviate symptoms in patients with early-stage Alzheimer's disease. Each trial is expected to recruit 1,840 patients, randomly assigned to receive either once-daily oral semaglutide (with the dose gradually increased to 14 mg) or a placebo over 173 weeks. Preliminary results are anticipated by September 2025.

Studies show that the increase in NASH prevalence is related to population aging and the rising incidence of metabolic syndrome, which is associated with the growing prevalence of obesity and type 2 diabetes.

Semaglutide has been granted Breakthrough Therapy Designation by the FDA for NASH indication and included in the breakthrough treatment category in China, currently in Phase III clinical trials. In July 2021, Novo Nordisk initiated a Phase III international multicenter clinical trial of semaglutide for non-cirrhotic NASH in China.

In Phase II clinical trials, semaglutide has yielded positive results. Compared with placebo, semaglutide monotherapy significantly eliminated NASH histological symptoms in patients without exacerbating liver fibrosis.

In patients receiving the highest dose of semaglutide, 66.7% experienced resolution of NASH symptoms. Semaglutide also showed a trend toward providing clinical benefits in improving liver fibrosis in patients, with fewer NASH patients showing progression of liver fibrosis compared to placebo. In patients receiving the highest dose of semaglutide, 5.8% showed progression of liver fibrosis.

In this small trial involving 20 obese patients, the number of NK cells and the levels of cytokines mediating cytotoxic effects (such as interferon IFN-γ) were significantly lower in obese patients compared to the non-obese control group.

However, after obese patients received treatment with semaglutide once a week for up to six months, in addition to the expected positive effects such as weight loss and blood sugar control, the metabolic function of NK cells in the patients was restored. The levels of IFN-γ and granzyme B (which can induce tumor cell apoptosis) produced by these cells also significantly increased. This change in level was not significantly correlated with the proportion of the patients' weight loss. The ability of NK cells isolated from the patients to fight cancer cells doubled compared to before the treatment.

In March this year, the Phase III clinical trial PINOEER PLUS data for oral semaglutide in the treatment of type 2 diabetes reached the primary endpoint. At week 52 of treatment, the 25mg and 50mg doses of oral semaglutide showed significantly better efficacy in reducing glycated hemoglobin (HbA1c) compared to the previously approved 14mg dose, with weight loss effects also significantly superior to the 14mg dose.

In May, Novo Nordisk announced the primary results of the Phase III clinical trial OASIS 1 for oral 50mg semaglutide. Among 667 obese or overweight adults with one or more comorbidities, combined with lifestyle intervention, patients taking once-daily oral 50mg Wegovy lost 15.1% of their body weight, while those in the placebo group lost 2.4%. Novo Nordisk assessed the treatment effect, stating that if all participants adhered to the treatment, the weight loss could reach 17.4%.

Novo Nordisk is expected to apply for regulatory approval of 25mg and 50mg oral semaglutide tablets in the United States and the European Union in 2023. To date, the oral formulation of semaglutide has not been approved for weight loss indications in any country or region.

In terms of blood sugar control indications, oral semaglutide (Rybelsus) was approved by the FDA for marketing as early as 2019, becoming the world's first oral GLP-1RA.

The oral formulation consists of semaglutide combined with the small molecule absorption enhancer SNAC, allowing semaglutide to be absorbed in the stomach. Additionally, the dissolution of SNAC in the stomach locally increases the pH level, enhancing the solubility of semaglutide and protecting it from degradation by peptidases in the stomach.

In March, the European Medicines Agency (EMA) officially announced that Novo Nordisk's semaglutide injection Ozempic, used for lowering blood sugar, will face a prolonged supply shortage, expected to last throughout the entire year. Although the supply of semaglutide will continue to increase, it remains uncertain when market demand will be met. The EMA further requested that healthcare institutions should prioritize the allocation of Ozempic for diabetic patients over those using it for obesity.

At this time, although the weight-loss injection Wegovy has not yet been widely launched in Europe, given the strong demand in the U.S. market and the potential for it to squeeze European supplies, Ozempic is also expected to face a severe shortage in Europe. The popularity of semaglutide has even driven up sales of Novo Nordisk's earlier weight-loss drug liraglutide (Saxenda), which is now in short supply.

In July, the semaglutide weight-loss injection Wegovy launched in Germany, the largest pharmaceutical market in Europe, and officially launched in the UK in September. The popularity of Wegovy prompted Novo Nordisk to emphasize in their announcement title that the UK launch was "controlled and limited." Simple, an online pharmacy in the UK, revealed that over 50,000 people had made online reservations for Wegovy.

"The Craze of 'Weight Loss Wonder Drugs' Reaches US Stocks: On August 8, an announcement regarding the prevention and treatment of heart failure with semaglutide caused a stir again, driving Novo Nordisk's stock price up by 17%, with intraday gains surpassing 19%. On September 1, Novo Nordisk (Novo Nordisk) closed with a market value surpassing that of French luxury giant LVMH, becoming the highest-valued listed company in Europe at one stroke."

Novo Nordisk's financial report for the first half of 2023 shows that sales in the diabetes and obesity care fields reached DKK 99 billion (approximately RMB 103 billion), increasing by 36% year-on-year, with growth in the obesity care field reaching 158%.

On September 22, the FDA updated the drug label information on its official website, stating that semaglutide (Ozempic) may have a new potential side effect – intestinal obstruction.

On October 5, the Journal of the American Medical Association (JAMA) published a study indicating that GLP-1 drugs such as semaglutide may increase the risk of users developing serious gastrointestinal diseases. This study, conducted by the University of British Columbia, analyzed a diagnostic and prescription database containing information from 16 million patients and ultimately selected over 5,400 valid records.

The study results indicate that, compared to the serious side effect rate of another weight-loss drug, bupropion/naltrexone, the use of GLP-1-based weight-loss medications increases the risk of gastroparesis nearly fourfold, the risk of pancreatitis ninefold, and the risk of intestinal obstruction fourfold. Specifically, nearly 10 out of every 1,000 patients experience gastroparesis when taking semaglutide, and about 5 out of every 1,000 patients develop pancreatitis.

At the same time, discussions about the lack of appetite and efficacy comparisons after taking semaglutide have become an enduring social topic in 2023, symbolizing the weight-loss storm stirred up by semaglutide. Positive reviews suggest that the explosion of the global weight-loss drug market has updated the perception worldwide that "obesity is a condition requiring long-term management." On the other hand, negative reviews argue that the rapid increase in semaglutide sales has brought risks such as drug abuse and side effects.

However, the "miracle drug" has arrived, and the trend of GLP-1 drug pipeline competition has swept the globe.

In 2023, can Semaglutide become the new "blockbuster drug"? Where will the next "miracle drug" come from?