The birth of the blockbuster GLP-1 drug

In recent years, glucagon-like peptide-1 (GLP-1) receptor agonists have received widespread attention from the industry. In addition to treating diabetes, researchers have found that it also has broad application prospects in the field of weight loss. However, 30 years ago, the development of GLP-1 receptor agonists was completely different. The bottleneck in the development of long-acting GLP-1 receptor agonists left scientists at a loss for several years, and its potential "side effects" "It also caused him to be relegated to the cold palace for a time.

In this process, the enthusiasm and belief of a female scientist eventually led to the birth of long-acting GLP-1 receptor agonists and spawned a new round of research and development in related fields. In today’s article, WuXi AppTec’s content team will analyze the relationship between Novo Nordisk’s two blockbuster GLP-1 receptor agonists liraglutide based on industry media STAT and related public reports. ) and semaglutide (semaglutide), and learn about the birth stories of these two drugs.

Forced to take over R&D projects that have made no progress for many years

Ms. Lotte Bjerre Knudsen is the current chief scientific advisor of Novo Nordisk. Thirty years ago, she was just a junior researcher in Novo Nordisk's R&D department. At that time, Novo Nordisk's main business was the production of insulin, which had the side effect of making people gain weight. Against the backdrop of the increasing incidence of diabetes and obesity year by year, it became a priority to develop new treatments targeting metabolic pathways to expand new treatment pipelines. important strategic goals of the company. As a result, Knudsen's R&D department, under the guidance of the company, began to search for new treatments for type 2 diabetes, and GLP-1 was their main target.

In the 1980s, some scientists discovered through experiments on animal organs and cells that GLP-1, a hormone mainly produced in the intestines, can stimulate large amounts of insulin secretion. Therefore, GLP-1 is regarded as a powerful potential treatment for diabetes. Although GLP-1 was later confirmed to increase insulin secretion in humans, the results of early human trials were not ideal because the half-life of natural GLP-1 in the blood is very short and will degrade in less than 2 minutes. Using it to treat diabetes requires large doses to achieve and maintain the effect. And when larger doses of GLP-1 are given, it can cause nausea and vomiting in patients. Therefore, if clinically available GLP-1 therapies are to be developed, the first problem to be solved is to extend the half-life of GLP-1.

▲The role and regulatory mechanism of GLP-1

However, since the launch of the GLP-1 development project in 1990, Novo Nordisk's research team has made many attempts without success. Their strategy mainly focuses on three directions, including eliminating the enzyme DPP-4 in the human body that degrades GLP-1, finding something to mask GLP-1 from being discovered and degraded by DPP-4, and increasing GLP-1 stability.

In 1994, when Knudsen returned to work after just taking maternity leave, it was at the bottleneck moment of the GLP-1 development project. She was asked to take over the GLP-1 project. This pair of Knudsen, who did not have a doctoral degree and had not led drug development at the time, was It's quite a challenge. However, she did not retreat because of this. Instead, she chose to move forward into the wind.

Re-examine the failure experience and finally find a way to break the situation

In the first few months after taking over the GLP-1 project, Knudsen spent a lot of time reviewing strategies that had failed before, trying to find a breakthrough.

In previous studies, researchers have tried to "catch" albumin, which is abundant in the blood, by adding a long fatty acid chain to GLP-1. In this way, the GLP-1 molecules under the cover of albumin cannot It will be discovered and broken down by DPP-4 enzyme, thus extending its half-life in the human body. However, GLP-1 with the added fatty acid chains was "viscous" and difficult to separate from the chromatography columns used to purify the therapeutic candidates, which led to the failure of this strategy.

After careful consideration, Knudsen concluded that the strategy was just that the properties of the drug candidates were less than ideal and there was room for improvement. So she hired a pair of talented chemists from other departments to help her improve the design of GLP-1 candidate molecules. The two scientists made the redesigned molecule not only more soluble in water by adding a spacer between the fatty acid chain and the GLP-1 analogue - so that it doesn't stick to separation equipment and make purification difficult, but also make it easier to purify. Proteins also have higher affinity. This molecule later became known as liraglutide.

Regarding which indication liraglutide should be developed first, although Knudsen has repeatedly stated based on the information he has available that the target indications can be diabetes and obesity, company executives do not believe that this drug molecule can contain multiple biological mechanism. Therefore, in 1997, Novo Nordisk advanced liraglutide into clinical trials only as a candidate treatment for diabetes.

Clinical trials had twists and turns, and after more than ten years, it was finally launched on the market

The clinical development process of liraglutide was full of twists and turns, but after making up her mind to take over the project, Knudsen never wavered in her belief and had enough patience. Regarding the various problems that occurred in clinical trials, she chose to block them with soldiers and cover them with soil.

The first problem in the clinical trials of liraglutide arose during Phase 2 clinical trials. The selected study dose was too low, resulting in unsatisfactory clinical results and the need for another identical trial. At that time, Novo Nordisk was full of insulin orders and had no spare production capacity to manufacture liraglutide for clinical research. This caused the progress of clinical trials to be repeatedly delayed.

Not only that, but bigger troubles followed - in toxicology tests on rats, some rats treated with liraglutide developed thyroid tumors. This test result made Novo Nordisk want to give up the continued development of liraglutide, because if a drug cannot even guarantee the most critical safety, let alone subsequent effectiveness studies. But Knudsen did not give up. Instead, he spent three years conducting in-depth exploration of this key issue. Finally, he found that the proportion of cancerous cells in rodents in the human thyroid is very small, while the proportion of cells that become cancerous in rodents is very small. Laglutide does not activate this particular cell in humans. Knudsen came to the rescue again with liraglutide.

During this period, the world's first GLP-1 receptor agonist took the lead. In 2005, exenatide, a synthetic natural GLP-1 analog found in lizard venom, was approved by the US FDA for the treatment of diabetes. However, the restriction of two daily injections of this drug makes patient compliance poor, and clinical demand for longer-acting, easy-to-use GLP-1 receptor agonists still exists. There is still a chance for liraglutide, which only needs to be injected once a day.

In 2006, liraglutide entered a pivotal clinical trial involving 3,800 patients across 42 countries. It is gratifying that there were no surprises in this trial, and the results were in line with expectations - liraglutide can bring clinical benefits to patients with diabetes and has a low risk of cancer. In 2010, the FDA approved liraglutide after weighing its possible benefits and risks for patients with diabetes. So far, liraglutide has become the second GLP-1 receptor agonist approved for marketing in the world.

Non-stop work to remove "obesity" indications

As the scientist who led the development of liraglutide, Knudsen knew that liraglutide had potential beyond just treating diabetes. The FDA approval review report for liraglutide also pointed out that in addition to lowering blood sugar, liraglutide also has the potential benefit of helping to reduce weight. Therefore, after liraglutide was approved for diabetes, Knudsen immediately began to promote clinical trials to evaluate liraglutide for weight loss, and at the same time led the research on the mechanism of liraglutide weight loss.

Previously, there were two main reasons why Novo Nordisk executives were reluctant to promote the use of liraglutide in the treatment of obesity. One was because the public’s concept of obesity at that time was that it was just a matter of aesthetics and personal willpower. A social problem, not a disease. Since it is not a disease, why does it need treatment? The second reason is that previous studies have shown that the targets of weight loss drugs are on neural circuits in the brain related to satiety and appetite. However, GLP-1 is a macromolecular hormone produced in the intestines. According to common sense, GLP-1 is a macromolecular hormone produced in the intestines. It is impossible for it to penetrate the blood-brain barrier and then act on these neural circuits.

However, over the years, some scientists have discovered GLP-1 receptors on the vagus nerve and many different brain regions, which opened the door for GLP-1 receptor agonists like liraglutide to act as neuromodulators for weight loss. hypothesis provides a physiological basis. The research team led by Knudsen subsequently found in mouse experiments that although liraglutide did not cross the blood-brain barrier, a small amount of the drug could directly enter the brainstem, septal nuclei and hypothalamus, and communicate with the brain through these periventricular organs. interact to modulate food intake preferences and intake in mice and induce weight loss without reducing energy expenditure.

In the process of exploring the weight loss mechanism of liraglutide, this therapy proved to be a powerful tool in the treatment of obesity and was approved by the FDA for the treatment of obesity in 2014. Not only that, in order to further extend the half-life of the drug, Novo Nordisk improved on liraglutide and developed semaglutide that can ensure efficacy with only one injection per week. Knudsen continues to take the lead in studying the biological effects of this new long-acting GLP-1 agonist on metabolism, cardiovascular and renal health, and the brain.

Surprisingly, the effect of semaglutide on weight loss is even more amazing. Compared with most of the weight loss drugs previously marketed that can only reduce body weight by 5% to 10%, semaglutide can reduce weight loss by 5% to 10% in clinical trials. Obese patients lost an average of 15% of their body weight and were safe. After being approved for diabetes indications in 2017, semaglutide also successfully received the indications in 2021. So far, Novo Nordisk's weight loss therapy kingdom has been born.

▲Molecular structural formula of semaglutide (Image source: Edgar181, Public domain, via Wikimedia Commons)

Outlook

In addition to diabetes and obesity, GLP-1 receptor agonists such as liraglutide and semaglutide are blooming in many areas. Taking semaglutide as an example, its indications that have entered Phase 3 clinical stage include type 2 diabetes combined with chronic kidney disease, cardiovascular disease, non-alcoholic steatohepatitis, Alzheimer's disease and other diseases. Among them, Knudsen pointed out that Alzheimer's disease may be one of the most promising applications of this type of drug in targeting brain diseases.

Novo Nordisk has launched two large phase 3 trials to evaluate whether semaglutide can relieve symptoms in patients with early Alzheimer's disease since 2021, with preliminary trial results expected in 2025. Separately, a number of smaller companies, including U.S.-based Neuraly Inc. and Denmark's Kariya Pharmaceuticals Inc., said they were evaluating their experimental GLP-1 drugs for Parkinson's disease and were considering futures following the results of Novo Nordisk's trial. Expanding the field of research into Alzheimer's disease.

Nowadays, the success of liraglutide and semaglutide has given rise to a new wave of enthusiasm in the field of GLP-1 agonist development. The scene of the past that was empty no longer exists. Looking back at the road to the launch of these two therapies, we can see how difficult it is to transform scientific discoveries into usable drugs. It requires thousands of key decisions and a firm belief to persevere to the end in order to finally make a drug. Potential therapeutic candidates are successfully launched. In the process of developing new drugs, there are countless adherents like Ms. Knudsen. It is precisely because of their unremitting efforts that candidate treatments have entered the clinic, and patients have more treatment options. Let us pay high respect to these new drug developers!