•Laikai Pharmaceutical has fully deployed the ActRII channel and established a new drug research and development platform

• Selective Actriia monoclonal antibody LAE102, may further improve fat loss and muscle building effects and safe tolerability

• LAE102 and subsequent ones are more likely to be an ideal solution for public health management

On May 13, Laikai Pharmaceutical announced that its ActriIA monoclonal antibody LAE102 was approved for weight loss clinical trials in China. This will be the world's second ActRII monoclonal antibody to enter the clinical phase of weight loss.

At the 4th DJ Seedin Innovation Cooperation Summit (“DJSeedIn”) last Thursday, Zou Guoqiang, chief financial officer of Laikai Pharmaceutical, first announced the company's comprehensive layout in the field of muscle gain and fat loss: through the team's efforts, the company has established a new drug development platform with the ActRII channel. Following LAE102, the company is also further developing the ActRIIB selective antibody LAE103 and the ActRIIA/IIb dual-target inhibitor LAE123.

Previously, the world's first ActRII monoclonal antibody Bimagrumab to enter clinical research had initially verified its effects on muscle gain and fat loss in phase 2 trials. bimagrumab was first developed by Novartis and later licensed to Versanis Bio. In July 2023, Eli Lilly, which already owns weight loss products with various mechanisms such as tiverpotide, spent about 1.95 billion US dollars to acquire Versanis, thereby taking bimagrumab into its pocket.

According to Zou Guoqiang, the GLP-1 market, led by Enoch & Nordisk and Eli Lilly, has successfully completed market education work in the early stages. Joint use of ActRII monoclonal antibodies on this basis means a healthy and high-quality weight loss plan, and the market potential is huge.

Why ActRIA

According to statistics, the current weight loss drug market is dominated by GLP-1 therapies. The results are 20% to 25% weight loss within a year, and the weight loss ceiling is still being refreshed.

But at the same time, is there still room for improvement in terms of the quality of weight loss and the sustainability of curative effects? Zou Guoqiang asked this question on DJ SeedIn. In fact, this is a proposition that will sooner or later be faced on the weight loss drug development circuit. It represents the voices of many current doctors, the public, and new drug developers.

For example, up to 40% weight loss in patients using GLP-1 therapy is considered muscle loss, and muscle loss increases the risk of cardiovascular disease, osteoporosis, etc.

Further reading

GLP-1 is constantly in turmoil, how will it go next?

However, drugs related to the ActRII channel are thought to be expected to break through the shortcomings of existing targets. ActRII is an activin (Activin) receptor expressed in both adipose and muscle cells, and includes two members, ActRIIb and ActRIIb. Activation of this signaling pathway causes fat accumulation and muscle atrophy. Therefore, inhibitors targeting this pathway can be expected to increase the body's muscle composition while driving fat loss. Judging from this mechanism, ActRII therapy can be hoped for the next generation of “seed players.”

In January 2023, Versanis announced the results of a phase 2 trial of bimagrumab on overweight or obese patients with type 2 diabetes: patients lost about 22% fat while gaining 4.5% fat-free body weight, and patients did not observe weight gain within 12 weeks of stopping treatment. This also means that bimagrumab also has many of the key features of a new generation of weight loss treatments, such as weight loss, muscle gain, and no rebound.

Bimagrumab is an ActRIIA/IIb dual inhibitor. Its activity against ActRIIb is much higher than ActriIa, and is a “strong B weak A.” If you compare ActRIa and ActRib to a person's right and left fist, then bimagrumab's “left fist” is more powerful than the “right fist.”

However, some preclinical research data shows that “right fist” ActRIa may play a more critical role in muscle regeneration and lipid metabolism.

Analysis of previous data from companies such as Novartis and Versanis shows that bimagrumab has not obtained satisfactory clinical data on various indications, including body myositis and muscle atrophy. According to the latest data published by Versanis, bimagrumab has also observed some potential side effects in obesity indications, including diarrhea and muscle cramps. Most of these side effects are mild and occur in the early stages of treatment, but gastrointestinal reactions are also common side effects of existing GLP-1 products. Once these two products are used together, is there a risk of overlapping side effects?

Based on this, Laikai Pharmaceutical began exploring stronger and safer “right fist attacks” — antibodies that selectively inhibit ActRIA, or LAE102.

Picture source | Laikai Pharmaceutical's official website

According to Laikai Pharmaceutical's introduction on DJSeedin, LAE102 has shown the effect of increasing muscle and reducing fat in pre-clinical studies. When used in combination with the GLP-1 receptor agonist simeglutide, it not only co-reduces fat loss, but also significantly reduces muscle loss caused by the latter, and has the potential to become a potential drug candidate for better body fat composition and high-quality weight loss.

Recently, LAE102 has been clinically approved in the US and China. Currently, the trial is about to begin recruiting subjects for obesity. After completing early clinical exploration, Lai Kai will carry out corresponding post-clinical research work according to the different populations and needs of China and the US.

Development difficulties of ActRII therapy in weight loss

In fact, the first breakthrough in ActRII therapy was not obesity.

As early as November 2019, another biomedical company, Acceleron, developed and authorized the new Actriib fusion protein Reblozyl under BMS to treat symptoms of anemia in patients with transfusion-dependent beta-thalassemia, was approved by the FDA. In March 2024, the ActriIA fusion protein WinRevair, obtained through MSD's $11.5 billion acquisition, was approved for listing in the US to treat pulmonary hypertension.

Due to the complex relationship between ActRII receptors and ligands, ActRII fusion proteins block all the various ligands that can bind ActRII in a ligand trap, which may affect other signaling pathways, leading to potential side effects such as mucocutaneous hemorrhage. For “extreme diseases” such as pulmonary hypertension and thalassemia, clinically, in order to achieve therapeutic purposes, these side effects are relatively well tolerated.

However, the indications for weight loss, which are chronic diseases, are completely different. It is impossible for the public and doctors to put themselves at risk in order to look good, and any side effect could kill a potential new drug halfway.

Therefore, on the basis of efficacy, how to raise the safety threshold is the key to the efficacy of the Activin-ActRII pathway in the field of obesity. This is also a question Dr. Lu Xiangyang, founder of Laikai Pharmaceutical, has been thinking about.

As early as 2001, Lu Xiangyang began studying the Activin-ActRII signal channel, and later initiated and led the development of the bimagrumab project at Novartis. After Lai Kai founded it, he also set out to develop the next generation of safer ActRII receptor blocking drugs. Based on its scientific team's many years of experience and heritage in this pathway, Laikai Pharmaceutical is targeting ActRII's monoclonal antibodies.

Compared with fusion proteins and antagonists, ActRII monoclonal antibodies can accurately block signal transduction in this pathway. Not only is it safer, but it is also more advantageous in terms of efficacy.

However, the development of monoclonal antibodies is by no means easy, especially monoclonal antibodies with high selectivity for ActRIIA or ActRIIB. LAE102 is also a phased breakthrough in Lai Kai's long-term continuous research. At present, the company has trained a research team composed of young scientists and established a new ActRII drug development platform, which can develop single-target or dual-target inhibitors for different receptor types to meet different treatment needs.

Dr. Zhang Ruipeng, a young scientist from Laikai who participated in early research on ActRII targets Picture source｜Laikai Pharmaceutical Official Website

How to play various arrangement combo punches

Research over the past 20 years has shown that the Activin-ActRII pathway may be therapeutic in obesity, muscle atrophy (age-related muscle weakness), pulmonary hypertension, liver disease, and oncology. To maximize the value of targeting ActRII receptors, Laikai Pharmaceutical is developing more drug candidates. Among them, LAE102, which mainly focuses on obesity, is a priority project promoted by Laikai Pharmaceutical at this stage.

Judging from Kai's annual report, the other two products under development for fat loss and muscle gain — ActRIIB selective antibody LAE103 and ActRIIA/IIb dual-target inhibitor LAE123, both focus on “muscle-related indications.” Among them, age-related sarcopenia (Sacopenia) has not had any solutions so far, and it is also a problem that needs to be solved in the future. Perhaps it is another blue ocean.

If LAE102 and LAE103 had a single right or left fist, what about “open the bow left and right”? I can't help but think of the “old urchin” Zhou Botong's unique study in Jin Yong's novel — “the art of fighting left and right,” where the left and right fist work at the same time, “tantamount to using the power of one person to exert the power of two.” This is also the reason why Lai Kai also developed LAE123.

Currently, LAE103 has reached the IND preparation stage, and LAE123 is in the pre-clinical development stage.

Zou Guoqiang said, “Based on the accumulation of early research, Lai Kai's team has mastered the 'martial arts cheat' targeting ActRII, the so-called 'martial arts cheat'. We know how to play a variety of 'combo punches' to suit different indications.”

Laikai Pharmaceutical also announced for the first time that it is seeking more strategic partners to cover a wider range of potential ActRII related drug indications and more diverse medical solutions to address major unmet needs in the fields of metabolism, cardiovascular, and cancer.

In the future, LAE102 and beyond are likely to be an ideal solution for public health management.

Currently, looking at the industry, Novo Nordisk's market capitalization has surpassed that of LV's parent company, and Lilly's market capitalization has soared to $70+ billion. The latter, along with technology stocks such as Microsoft and Nvidia, is in the top ten of the US stock market capitalization list, surpassing Tesla, which is at the end of the “Big Seven.” A weight loss track propelled two pharmaceutical companies to reach 500 billion+ market capitalization, breaking through the “market capitalization bottleneck” of pharmaceutical companies up to 200 billion US dollars in the past. This may mean that when a pharmaceutical company and its innovative drugs serve the broader meaning of public health management, its value and room for growth are immeasurable. Let's wait and see how LAE102 and its successors will join the “Huashan Sword” to lose weight.

Source: R&D customer