Spanning two disease areas with over 100 million patients, will it be the next PD-1?

There are 90 million obese people in China, but only one diet pill has been approved for marketing, and sales are mediocre.

For a long time, the traditional pharmaceutical market has formed a stereotype that the market for diet pills is limited and cannot be the main source of revenue.

In a global market of 200 million obese patients, a drug with annual sales of more than $1 billion has yet been born.

Until June 2021, the FDA approved the sixth long-term treatment drug for obesity, the GLP-1 receptor agonist (GLP-1RA), somaglutide.

Less than half a year after the listing, somaglutide rapidly increased, in the U.S. diet pill market, has shown great potential.

"It's out of stock in the U.S." An industry insider said.

In addition to the emerging field of obesity treatment, the main battlefield of GLP-1 receptor agonists is the field of diabetes treatment, taking Novo Nordisk's somaglutide as an example, its annual sales in the field of diabetes treatment exceed $4 billion, and its revenue is close to insulin drugs.

Spanning two disease areas with more than 100 million patients, GLP-1 agonists have become one of the hottest tracks in the pharmaceutical industry.

Image from Visual China

On PD-1, because of the price war, the 100 billion market has become 10 billion, and the Chinese innovative pharmaceutical companies that have suffered setbacks have been looking for the next super target. Now it seems that GLP-1, which has broadened from diabetes to obesity, meets their requirements.

At present, including Lilarute generic drugs, there are nearly 20 approved clinical GLP-1 products in China that target the indications for obesity, and the research and development stages range from the first to the third phase of the clinic, and independent research and development go hand in hand with imitation. Especially after 2019, domestic innovative pharmaceutical companies have increased their investment in research and development to seize the opportunity.

More than a month ago, the first edition of the CDE's Technical Guidelines for Clinical Trials of Weight Control Drugs added a new fire to this boom. The industry generally predicts that the new regulations will benefit GLP-1 R&D enterprises.

A new track has been paved. This time, in the treatment of obesity that is more flexible in payment and does not take the path of medical insurance reimbursement, what kind of differentiated competition road will China's innovative pharmaceutical companies embark on? Will they be able to escape the prisoner's woes of PD-1?

Game-changing "Medicine King"

In June 2021, Novo Nordisk's GLP-1 receptor agonist (GLP-1RA) somaglutide was approved by the FDA for the treatment of obesity. This is the sixth FDA-approved long-term treatment for obesity and the most promising drug to date to revitalize the diet pill market.

Taken once a week, somaglutide can achieve about 15% weight loss in 68 weeks. Compared with the data of about 5%-7% of the first GLP-1 agonist weight loss drug approved in 2014, the weight loss effect has doubled.

Previously, no obesity drug has ever achieved this effect. Even, no weight loss drug was able to break through the 10% data.

More than just efficacy, somaglutide is a game-changer in many ways. Since orlistat was launched in 1999, the traditional pharmaceutical market has formed a stereotype: the market for heavyweight drugs is not large, and it is easy to delist products after several years of marketing due to safety problems.

The fundamental reason is that for many years, the modern pharmaceutical industry has never produced a elixir to save fat people. There is no ideal drug that meets the needs of effectiveness, durability, good safety and non-addiction, but there are not a few drugs that are withdrawn from the market after listing: including sibutramine, phenylpropanolamine and many other drugs that have been delisted due to adverse reactions. Among them, liver damage, as well as the suicidal tendency to depression found in subsequent observations, are the most discouraging to patient confidence.

Somaglutide offers real hope for the long-stagnant field of obesity treatment.

According to Eight Points, less than half a year after the listing, somaglutide has been rapidly released, and in the US diet pill market, it has shown great potential.

This is extremely rare. Previously, although the theoretical market space for weight loss drugs was large, the market sales performance has been less than expected. Patients' distrust of the efficacy and safety of drugs and the low willingness of doctors to prescribe are the main reasons. Annual sales of liraglutide in the United States have been stable at around $800 million, failing to break the $1 billion "blockbuster" drug mark.

In 2021, somaglutide can be described as a booming and sunny year. In addition to the approval of obesity indications, it quickly occupied the market; subcutaneous preparations for the treatment of diabetes once a week sold as much as $3.805 billion in the first three quarters of 2021; oral preparations were also accepted by the market, and the rapid release of volume, with sales reaching $499 million in the first three quarters. Somaglutide's combined sales in the first three quarters were around $4.6 billion.

"To develop new drugs, we must keep up with the standard treatment in this field. Now, everyone is looking at whether somaglutide will become the standard treatment in the field of obesity. A senior industry insider analyzed eight points of health, "In addition, somaglutide is likely to become the gold standard for GLP-1 drugs." ”

PD-1 in the field of metabolic diseases

For years, the pharmaceutical industry has struggled to find the safest, most effective, and most profitable molecules in the world. But there are only a few molecules like GLP-1 that can open up the situation.

GLP-1 has the potential of "a new generation of miracle drugs". As a drug-ready mechanism that has been running for more than 20 years, proven, very mature, and born a target such as the "medicine king" such as somaglutide, it is attractive enough in many ways:

Since the first GLP-1 receptor agonist (GLP-1RA) exenatide was listed in 2005, there have been 8 GLP-1R agonists on the market worldwide; GLP-1 has become the world's best-selling hypoglycemic drug, giving birth to a number of "blockbuster" drugs; but it still has huge market space in multiple indications such as diabetic eye disease, diabetic nephropathy, obesity, non-alcoholic steatohepatitis and so on.

Secondly, from daily preparations to weekly preparations; from injection to oral; from polypeptides to small molecule chemical drugs; GLP-1 still has a lot of room for improvement in dosage forms.

After 2010, fierce competition between large pharmaceutical companies was launched, followed by GLP-1 drugs entering the clinic and being approved. The competition between Novo Nordisk and Eli Lilly is particularly fierce. From liraglutide, dulaglutide to somaglutide, the chair of the popular star is constantly replaced.

Somaglutide has just taken the top spot, and challengers have emerged, and Eli Lilly's Tirzepatide, a new weekly GLP-1R and GIPR dual agonist, will directly challenge Novo Nordisk. The industry predicts that once approved, Tirzepatide will become the next blockbuster product.

Differentiated competition mainly comes from three aspects, "one is the expansion of different indications, previously all of which were diabetes, future development of weight loss, non-alcoholic hepatitis, Alzheimer's disease and other different indications; the second focus is to change to oral dosage forms and improve medication compliance; the third is to pursue better safety and efficacy, the main progress is to do multi-target combination therapy." Pan Hai, chairman of the innovative pharmaceutical company, told Eight Point Jianwen.

It can be said that the old large pharmaceutical companies and innovative pharmaceutical companies, whether in the dosage form, safety and efficacy, or combination therapy, are making rapid progress and are facing the "Battle of Tianwangshan".

For domestic innovative drug companies, from the pile of anti-tumor drugs to the layout of metabolic diseases, GLP-1 agonists that can be broadened to multiple indications are becoming the next outlet.

Pan Hai believes that GLP-1 agonists, which can be broadened to multiple indications, are a cornerstone drug in metabolic diseases and can be combined with a variety of other drugs, which is equivalent to the significance of PD-1 for the development of tumor drugs.

Not only the broad spectrum of the therapeutic field, the signs of "overheating" that have appeared in the domestic GLP-1 track have also reminded the industry of the PD-1.

Including Lilalutai generic drugs, there are currently nearly 20 GLP-1 products in the clinical trial stage in China, and the research and development stages range from the first to the third phase of the clinic, and independent research and development go hand in hand with imitation.

Innovative pharmaceutical companies are seizing the opportunity. Especially after 2019, pharmaceutical companies, including Hengrui, have begun the research and development of drugs related to GLP-1 receptor targets. The development of several GLP-1 agonist products has entered the clinical research phase. In the next two years, more projects will be pushed to the clinic.

Can GLP-1 leverage the domestic diet pill market?

Compared with the United States, there are already 6 kinds of long-term treatment drugs for obesity approved, and liraglutide and somaglutide two GLP-1 receptor agonists have been approved for obesity indications, there is a huge gap in the domestic diet pill market, and for a long time, orlis is the only approved diet pill in mainland China.

Moreover, the Enthusiasm of Chinese people for health care products is far better than that of drugs. In the past 10 years, counterfeit drugs, banned drugs, and health care products have swept the domestic weight loss consumer market.

The delisted slimming drugs are mixed into traditional Chinese medicines; illegal ingredients such as sibutramine are added to health foods; thyroxine and even diuretics are added to slimming teas; and the media has repeatedly reported incidents of body damage and even death caused by buying weight loss products in abnormal ways.

Bad money drives out good money, and obese patients flow to health care institutions and nutrition institutions in society. Even though many hospitals have begun to set up weight reduction clinics in the past two years, there are still a few patients who actually come to the hospital to seek professional treatment and management.

On the other hand, although liraglutide and somaglutide are not approved for weight loss in China, they are both approved for the treatment of type 2 diabetes. "Many obese patients have heard that there are these two drugs, and the effect is good, and they have to prescribe themselves." A director of the endocrinology department of a top three hospital in China said.

Eight Point Healthwen understands that because patients have needs, clinicians use drugs for hyper-indications with informed consent is common. In addition, at their own expense, liraglutide and somaglutide are purchased through various channels, and there are not a few patients for weight loss purposes, who even adjust the dose themselves and inject themselves.

For many years, regulators have been very conservative about obesity as an indication. However, the increasing market demand, more and more GLP-1 R & D companies in the weight reduction related clinical trials, but also prompted december 8, 2021, CDE issued the first edition of the "Weight Control Drug Clinical Trial Technical Guidelines", drawing a track, pointing out the direction of approval, to the relevant enterprises to take a reassuring pill.

"CdE's guiding principles are critical to the clinical development of new drugs." Pan Hai said, "Because the Guiding Principles do not require as many clinical people as the FDA, and the cost of clinical development is relatively low, at this stage, in the field of metabolic diseases, our company will be relatively more focused on the research and development and development of obesity drugs." ”

At present, a number of pipelines have been laid out for Dabio, including GLP-1 week preparation injection, as well as its oral formulation; small molecule GLP-1 receptor agonists; and the combination of GLP-1 analogues and injectable GIP receptor agonists. Among them, the fastest progress is GLP-1 week preparation injection, the clinical enrollment of diabetes phase 2 has been completed, and the enrollment of obesity phase 2 has also progressed rapidly.

Qian Lei, executive director of the Special Disease Department of Innovent Biomedical Sciences, also believes that it is a better stage to develop weight loss drugs. "Because regardless of the maturity of the market's demand, or the recognition of this product by the academic community, and the guidance of the national regulatory agency to the demand, it has entered a more appropriate stage." Especially for innovative companies, we want the track to be an orderly track, not a mixed bag. ”

The ultimate goal, of course, is to bring formal products to market. Industry insiders generally believe that it is only a matter of time before the first GLP-1 weight loss drug is approved in China. A number of industry insiders interviewed by Eight Point Jianwen predicted that the new drug would be approved next year.

The probability of somaglutide being approved first is very high, and it has not only started a phase III clinical trial of obesity indications in China. There is also dual insurance by the FDA.

"In addition to somaglutide, I estimate that there should be several drugs on the market within 2 to 5 years." Pan Hai said.

Can the domestic GLP-1 avoid the prisoner's dilemma of PD-1?

From tinibs to PD-1 to CD19 targets for CAR-T therapies, the development and competitive landscapes of China's innovative pharmaceutical companies are always strikingly similar – capital piles, low-level duplication, and finally a sea of blood.

In the arms race for innovative drugs, can GLP-1 avoid Chinese-style inner rolls? This is one of the biggest concerns in the industry right now.

At present, in the domestic GLP-1 track, enterprises are still following (follow) and fast follow (fast follow).

Globally, the research and development of oral small molecules belongs to the most cutting-edge first-in-class, and the small molecule GLP-1 agonist developed by Pfizer has made the fastest progress and has entered the second phase of clinical development.

The oral series of small molecules of domestic innovative pharmaceutical company Regerale Pharmaceuticals has also entered phase II clinical practice in the United States, ranking first in the world's R&D echelon with Pfizer and Eli Lilly. Last December, Reger and Eli Lilly entered into a License out (licensing) cooperation agreement to jointly develop new therapies for metabolic diseases. In the preclinical License in/out project, the collaboration of more than $1.5 billion set a new record.

In addition, the fastest progress in China is Hengrui's oral preparation, the clinical declaration has been approved, and the phase I clinical trial has just begun. The oral peptide of Xianweida is also about to be clinically tested in Australia.

"For most domestic enterprises, it has not yet reached that stage, most of the companies in the market are still single targets, and single targets are still long-term than whether they are long-term." Industry insiders revealed. "Some companies are even doing biosimilars, including imitation lilalute injection. Such enterprises have made the fastest clinical progress in China, and most of them have entered phase III clinical practice. ”

"At present, in China, the relatively high-end competition is multi-target competition, not a special number." Qian Lei introduced that among them, Innovent Biology has made rapid progress in the research and development of multi-target and dual agonists. In August last year, Innovent Biologics' GLP-1R/GCGR dual agonist published the results of a Phase IB clinical study in Chinese overweight or obese subjects in the Lancet journal. At present, the second phase of the drug's diabetes and obesity enrollment has ended, and both studies have enrolled about 250 people.

It is worth mentioning that the pharmaceutical companies that took the lead in carrying out phase II clinical trials of diabetes and obesity at the same time in China found that in clinical trials, the recruitment of obese patients is much faster than diabetes.

In 2014, liraglutide became the first GLP-1 drug to break into the obesity market from the type 2 diabetes market. Previously, pharmaceutical companies generally paid more attention to the diabetes market, a major reason is that at the level of social consensus, did not think that obesity is a disease that seriously affects life, "if you do not give medical insurance reimbursement, many companies will feel that they have done this indication, drugs cannot be sold, they cannot be measured, from commercial considerations, they have not developed this indication." ”

Including liraglutide, a number of FDA approved obesity drugs have not been clinically tested in China, and an important reason is that there are not enough obese patients in China.

But companies that were reluctant to conduct clinical trials in China have also realized that China's weight loss consumer market has changed dramatically, both in terms of the size of obese people and their willingness to treat and pay.

Moreover, after the inclusion of PD-1 in medical insurance, the market of 100 billion yuan has shrunk to 10 billion yuan, and the attitude of domestic innovative pharmaceutical companies to medical insurance is also undergoing subtle changes.

At present, there is no precedent for the inclusion of weight loss drugs in medical insurance. This may be conducive to China's local innovative drug industry, in the future to avoid the PD-1 facing the prisoner's dilemma: because of the price war into medical insurance, in more than two years, the price of domestic PD-1 fell by about 70%, there is a patent cliff that will appear after 7-10 years for general patented drugs.

At present, respondents, including Cinda Biologics and Xianwei biology, are more optimistic about the commercial prospects of GLP-1 as a weight reduction drug.

"From a business evaluation perspective, diabetes has a broad patient population and medication needs, and at the same time, in the obese population, there is also unimaginable potential." Qian Lei said.

"The market just needs to be large, the requirements for the number of domestic clinical trials are not as high as those of the FDA, and the payment side is relatively flexible and relaxed." Pan Hai believes, "Relatively speaking, you can avoid some of the problems of inner volume, of course, provided that you are fast." ”

Zhu Xueqi 丨 wrote

Xu Zhuojun 丨 Responsible editor

This article was first published on the WeChat public account "Eight Points Health" (ID: HealthInsight)

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