Musk, who once personally stood by Smegglutide, may not have imagined that one day the R&D company of Smegglutide, Novo Nordisk, would surpass its own Tesla in market value.
On Thursday of this week, Novo Nordisk announced that its new oral GLP-1 weight-loss drug, amycretin, with a dual action mechanism to treat obesity, can cause an average weight loss of 13% in participants over a 12 week course of early testing. As a result, Novo Nordisk's stock price surged during trading, with a closing market value of $606.561 billion, successfully surpassing Tesla.
Musk once mentioned on his social media account that his secret to slimming down is light fasting and smeglutide. With Smegglutide becoming a well-known drug among the global weight loss population, Novo Nordisk's sales revenue and market value have also risen again and again.
In 2023, Wegovy, the weight loss preparation of Smegglutide, achieved a total annual revenue of 31.343 billion Danish kroner (approximately 4.557 billion US dollars), a year-on-year increase of 407%; The total sales of Smeglutide last year exceeded 20 billion US dollars by superimposing the injection and oral tablets with indications for type 2 diabetes. Some institutions predict that Smegglutide is only one step away from the global "king of medicine".
At present, the battle for "besieging" Smegglutide has begun. In November last year, Lilly's weight-loss indication for telposide was approved by the US Food and Drug Administration (FDA), and it sold nearly $200 million in its first month on the market, making its strength not to be underestimated.
At present, the competition between Smegglutide and Telposide is still ongoing, from the expansion of indications in the laboratory, the comparison of head to head weight loss effectiveness to market share harvesting, and a big battle has just sounded the horn.
The Battle for Efficacy: The Most Critical Weight Loss "Competition" Data Has Not Been Released yet
In the field of weight loss pills, Lilly is regarded as Novo Nordisk's number one rival.
In November 2023, the weight loss indication of Lilliputide was approved by the FDA under the trade name Zepbound. According to financial data released by Lilly, Zepbound sold nearly $200 million in its first month of listing.
And Novo Nordisk's Smegglutide still holds a scale advantage. In 2023, Wegovy, a weight loss formulation of Smegglutide, achieved a total revenue of 31.343 billion Danish kroner (approximately 4.557 billion US dollars), a year-on-year increase of 407%.
Weight loss enthusiasts may not be concerned about the extent to which the two drugs have sparked a wave in the pharmaceutical market. They are more concerned about who has the better weight loss effect between Smegglutide and Telposide.
According to publicly available clinical trial data, the weight loss effect of tirposide seems to be slightly better than that of smeglutide.
Liu Lihe, Managing Director of CIC Zhuoshi Consulting, stated in an interview with the Daily Economic News that currently available clinical trial data on non head to head Simeglutide STEP 1 and Telposide SURMOUNT-3 show that the weight loss effect of Simeglutide is indeed slightly inferior to that of Telposide. In a clinical trial with a weekly dose duration of 68 weeks, users of 2.4mg semaglutide lost an average of 14.9% weight, while in a clinical trial with a weekly dose duration of 72 weeks, users of 10mg/15mg tirposide lost an average of 21.1% weight.
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But when comparing key indicators such as drug efficacy, head to head clinical trials are the gold standard.
Liu Lihe also mentioned that "in this regard, it is worth noting that Lilly and Novo Nordisk registered head to head clinical trials of tirposide compared to semaglutide or its combination therapy CagriSema on April 21 and November 14, 2023, respectively. These trials will provide more accurate data to further understand the differences in weight loss effects between the two drugs.".
For the crucial weight loss effect, Novo Nordisk also has something to say. The company stated in a written interview with a reporter from the Daily Economic News that there is currently no head to head clinical trial data available to provide a conclusion on the efficacy of comparing telposide with the weekly injection of sitagliptin 2.4mg (foreign trade name Wegovy) used for long-term weight management. The comparison between the two needs to be done with caution.
Novo Nordisk also stated that "we welcome any new data to enhance our understanding and clinical application of these next-generation treatment methods.".
That is to say, currently, the results announced by Tilposide and Smegglutide are on their respective tracks, and the results of their matches on the same arena have not yet been released.
However, it is worth noting that Zepbound is no longer able to meet the ambition of Lilly and Novo Nordisk to compete in the market. In February this year, Lilly also launched a head to head clinical trial of the three target (GLP-1R/GIPR/GCGR) agonist Retatrutide and Smeglutide, aiming to evaluate the efficacy and safety of this drug in adult patients with type 2 diabetes. This drug is an agonist targeted at glucose dependent insulin stimulating polypeptide, glucagon like peptide 1 and glucagon receptor in Lilly's research. It has been developed to treat patients with type 2 diabetes and obesity, and is also Lilly's blockbuster in the field of weight loss.
According to relevant clinical trial search websites, the research on Retarutide being promoted by Lilly includes four key registered trials, evaluating the safety and efficacy of Retarutide for chronic weight management, obstructive sleep apnea (OSA), and knee osteoarthritis (OA) in obese and overweight patients.
Liu Lihe believes that the dual target Mazdutide and triple target Restarutide developed by Lilly should be the most competitive potential competitors of Smegglutide.
Mechanism differentiation: The advantages of multi target drugs require more clinical data support
Although the final outcome is uncertain, it is worth examining the difference between telposide and smeglutide in terms of their mechanism of action.
Firstly, Smegglutide is an analogue of long-acting glucagon like peptide-1 (GLP-1). Tilposide is a novel dual receptor agonist of glucagon like peptide-1 receptor (GLP-1) and glucose dependent insulinotropic peptide (GIP). GLP-1 and GIP both belong to enterotropin.
Does this difference mean that telposide has an additional site of action than smeglutide to achieve better weight loss effects?
Liu Lihe explained that single target GLP-1 drugs refer to drugs that only act on GLP-1 receptors and exert their effects by simulating or enhancing the biological properties of GLP-1; Multi target GLP-1 refers to drugs or treatment strategies that simultaneously act on GLP-1 receptor and other diabetes related receptors. The fundamental difference between the two lies in the number of interacting receptors.
"Compared to GLP-1 single target drugs, it can be reasonably inferred that multi target drugs have certain advantages in weight loss. From a pharmacological perspective, dual or triple agonists can simultaneously activate multiple receptors, usually producing more significant synergistic effects than single receptor agonists and better performance in expanding indications. However, more clinical data is still needed to support this," Liu Lihe added.
Screenshot of the official website of Novo Nordisk for GLP-1 tablets
Liang Guibai, co-founder and chief scientist of Kaiyi Pharmaceutical and author of "The Story of New Drugs", also explained to a reporter from the Daily Economic News that single target GLP-1 receptor agonists only activate the GLP-1 receptor, while the commonly referred to "multi target GLP-1 receptor agonists" refer to other receptors that can act in addition to activating the GLP-1 receptor, commonly including Glucagon receptors and GIP receptors. The development of drugs targeting GLP-1 receptor agonists as the main target is currently a hot field, and whether it is a multi target or a single target, it will have a place, which is determined by the diversity and different needs of patients.
In addition, some industry insiders are concerned that long-term use of GLP-1 receptor agonists may lead to drug desensitization issues. If this issue exists, would it be helpful to switch to multi target drugs?
Regarding this, Liang Guibai said, "Drug desensitization is a common problem with agonist drugs. For example, long-term use of insulin may cause a decrease in the sensitivity of insulin receptors. However, I have not yet read any research literature or data on 'reduced sensitivity of GLP-1 receptors'.". In addition, the currently observed therapeutic effects, such as lowering blood sugar, losing weight, and improving heart and kidney function, mainly come from the regulatory circuit of GLP-1 receptors, while other targets are auxiliary effects
"If there is desensitization of the GLP-1 receptor, switching to dual or even triple target drugs may be helpful, but it is unlikely to be significant. This is because single drugs targeting other targets have not shown sufficient efficacy and have not been marketed separately," he added.
Formulation Controversy: Smegglutide Oral Formulation was the first to be launched, but it has not yet broken through the indications for weight loss
In addition to weight loss effects, Novo Nordisk and Lilly have fully opened up their products in terms of price, dosage form, indications, and production capacity.
The first thing to "roll" is the dosage form. Novo Nordisk's oral Smegglutide tablets are currently the world's first and only oral glucagon like peptide-1 receptor agonist (GLP-1RA). In January this year, the tablet was approved for marketing in China for the treatment of type 2 diabetes.
But this medication has not yet been approved for weight loss indications. The drug clinical trial registration and information disclosure platform shows that in China, the indications for "weight management" of Smegglutide tablets are still in phase III clinical stage. In May last year, the official website of Novo Nordisk released Phase I clinical trial data for oral administration of smeglutide for weight loss. At 68 weeks, obese and overweight patients took 50mg of smeglutide orally, achieving 15.1% weight loss.
Screenshot of Novo Nordisk official website
Lilly is also racing on weight loss indications for oral preparations. Last July, the medical journal NEJM published phase II clinical research data on the new oral GLP-1 agonist Orforglipron from Lilly.
The research results showed that at week 26, the average change in body weight relative to baseline in the Orforglipron dose group was -8.6% to -12.6%, while in the placebo group it was -2.0%. At week 36, the average range of change for the Orforglipron dose group was -9.4% to -14.7%, while for the placebo group it was -2.3%.
One of the important reasons why pharmaceutical companies such as Pfizer and AstraZeneca have abandoned the research and development of oral formulations is the difficulty in bioavailability of oral GLP-1 drugs. Liu Lihe explained that GLP-1 is a peptide that is easily degraded in acidic environments with stomach acid. Therefore, the main issue when making GLP-1 drugs into oral formulations is to address their stability in the stomach to ensure that the drug maintains integrity before reaching the intestine, allowing it to be absorbed by the intestine and exert therapeutic effects. In addition, it is necessary to ensure that the GLP-1 drug absorbed by the intestine has sufficient bioavailability, that is, it can enter the circulatory system to achieve therapeutic effects.
Liu Lihe said, "AstraZeneca can be said to be one of the pioneers of GLP-1 drugs. The world's first GLP-1 drug to be launched was AstraZeneca's exenatide. However, in the oral field, AstraZeneca still chose to introduce ECC5004 from Chengyi Biotechnology, which is enough to demonstrate the great difficulty of developing oral GLP-1 drugs."
Regarding the issue of bioavailability, Novo Nordisk also told reporters that the absorption of peptide drugs through the gastrointestinal tract and oral administration has always been a challenge in the drug development process. This is because peptides have extremely low intercellular permeability in the epithelial layer of the gastrointestinal tract, making it difficult to be absorbed through the intercellular pathway; Meanwhile, peptides have a large molecular weight and are difficult to penetrate through tight intercellular connections. In addition, the complex pH environment of the gastrointestinal tract can lead to changes in peptide structure, denaturation, and inactivation, as well as degradation by enzymes in the digestive tract.
The oral administration of Smegglutide tablets relies on the absorption enhancer SNAC, whose absorption promoting effect can increase the molecular bioavailability of Smegglutide through oral administration by about 100 times.
At present, Smegglutide tablets have been the first to be launched, does Lilly still have a chance? Liu Lihe believes that Smegglutide tablets are traditional peptide oral preparations, while Lilly's oral preparations are small molecule drugs. Due to the production process constraints, traditional peptide oral formulations are at a disadvantage in terms of cost and production capacity. Molecular drugs are at a disadvantage, while Novo Nordisk's Smegglutide faces both high prices and insufficient production capacity. Therefore, peptide drugs need to strive to reduce costs and expand production capacity by improving production processes. However, small molecule drugs are not as mature as peptide oral preparations and require efforts in both efficacy and safety.
He also mentioned that clarifying the oral dosage for weight loss indications will be an important challenge for Smegglutide oral formulations to break through weight loss indications.
The dilemma of production capacity: The market is constantly calling, but will the two be in short supply for a long time?
But currently, the common problem that troubles these weight loss "twin stars" is production capacity limitations. Novo Nordisk previously stated that there will be a long-term supply shortage of smeglutide. Many countries have strictly tightened the issuance and use of smeglutide for type 2 diabetes preparations, and the over indication drugs for people with weight loss in China have affected the normal needs of diabetes patients for a period of time.
After its launch, there have also been intermittent discontinuities of some formulations of telposide. On Wednesday of this week, Anat Ashkenazi, Chief Financial Officer of Lilly, stated at TD Cowen's annual healthcare conference that although Lilly is embarking on the most significant expansion plan in company history, increasing production capacity will take time. Ashkenazi added that even by 2025, Lilly may not be able to meet the market demand for Zepbound and Mounjaro.
On February 5th this year, Novo Nordisk just announced plans to acquire three filling production bases of global CDMO (Contract Development and Production Services) leader Catalent for $11 billion. Last year, Lilly announced that it would invest an additional 450 million dollars in the diabetes drug factory in North Carolina, and also planned to increase the investment of 1.6 billion dollars in the new production base located in LEAP Innovation Park in Boone County, Indiana, USA.
According to media reports, on March 7th local time, Novo Nordisk held the Capital Markets Day (CMD) event. At the event, Novo Nordisk revealed that it is expected that Wegovy will be approved for launch in China this year, and this product will initially focus on self funded patients with a quantity limit.
In addition to vigorously increasing investment and expanding the market, what the outside world is concerned about is whether the different preparation methods of the two drugs will widen the gap in production capacity between the two in the future, thereby affecting their competitive situation? Public information shows that simagliptin is prepared through fermentation and solid-phase synthesis, while telposide is synthesized through solid-phase and liquid-phase chemical synthesis.
Liu Lihe believes that from the perspective of increasing production capacity in the future, the fermentation+solid-phase synthesis method has a higher technical threshold and production cost compared to the liquid-phase synthesis method, because the fermentation process usually requires longer time and more complex equipment. However, once a stable production process is established, this method can achieve large-scale production and help meet market demand. From the perspective of manufacturing cost, liquid phase synthesis is more economical for individual products because its production process is relatively simple and easy to expand. However, compared with solid-phase synthesis, liquid-phase synthesis has the disadvantage of having a small synthesis range, generally focusing on peptide synthesis within 10 amino acids. In addition, purification of intermediates is required during synthesis, which takes a long time and requires a large amount of work.
Liang Guibai told reporters that the two preparation methods cannot be compared in general terms, but can only be said to have their own characteristics. He explained, "Generally speaking, liquid-phase synthesis has a wide range of applications, the greatest flexibility, and is suitable for large-scale production; in contrast, solid-phase synthesis has a high degree of automation, but is not very suitable for large-scale production; fermentation and enzyme engineering are also suitable for large-scale production, but the scope of application is limited."
According to Liang Guibai's analysis, "this field has developed rapidly in recent years, with rapidly changing technology and blurred boundaries. This has made the production process of peptide drugs no longer limited to a single mode, but a flexible combination of multiple different methods to obtain the optimal process. In addition, with the continuous intervention of AI, this field is expected to achieve breakthroughs in multiple different directions.".
At present, Smegglutide has a larger market share due to its first mover advantage, but Telposide is also gaining momentum. The competition between weight loss effects, increased production capacity, and medication delivery methods has begun in all aspects. But who can share more cake in the weight loss market is not yet the final answer.
