Stand on the shoulders of giants.

The combined sales volume of GLP-1 double simeglutide and tirpotide will exceed 40 billion US dollars in 2024, and the market demand for muscle building drugs spawned by this is also huge.

Eli Lilly held the next-generation drug king tirpotide, and CDMO and Biotech collaborated with them all won. LY.US (LLY.US) is eagerly looking for a partner drug for tiverpotide, and the ActRII antibody is one of the best options.

A Chinese biotech stands on Eli Lilly's shoulders.

Eli Lilly will be responsible for carrying out a phase I clinical study and covering related expenses for LAE102, an ActrII muscle building and fat loss drug in the US, while Laikai Pharmaceuticals retains the global rights of LAE102. There's so much information here that it's hard to relax for a moment.

Why does Eli Lilly value ActRii muscle gain and fat loss drugs so much? After investing heavily in the acquisition of Bimagrumab (ActRIIA/b monoclonal antibody), which is the most advanced in the world, they also spent money to do phase I clinical trials for LAE102 (ActRIIa monoclonal antibody), which is the second most advanced in the world. Isn't the ActRIIA/b dual target as good as the ActriIa single target?

The fate of LAE102 is due to phase I clinical data. If it meets expectations, how much money will Laikai Pharmaceutical (02105) reap in BD transactions?

Key drugs in the ActRII pathway According to wisdom buds

01 The secret to a super figure

ActRii is not good, let's take a look at the Belgian Blue Bull first.

The secret of Belgian blue cows being super tall stems from a mutation failure in the gene that produces muscle growth inhibin (GDF-8), which produces more muscle fibers. ActRII is the main receptor for GDF-8, and inhibiting ActRII is expected to achieve similar or better muscle building effects than simply inhibiting GDF-8.

ActRII is found in fat and muscle cells, and signals sent through ActRII receptors cause fat accumulation and muscle atrophy. In adipose tissue, activin signaling through ActRII receptors directly promotes lipid storage, which is a key driver of visceral fat accumulation and obesity, thus blocking ActRII signaling in adipocytes and can promote fat metabolism; in muscle tissue, signals sent through ActRii receptors inhibit muscle growth and promote muscle atrophy, so blocking activin signaling in skeletal muscle can promote muscle regeneration. Overall, blocking ActRII signals is expected to promote muscle gain while reducing fat accumulation.

ActRII antibodies are a perfect match for tirpopeptides. While increasing weight loss effects, they can also patch the shortcomings of GLP-1RA drugs that cause muscle loss. The results of several clinical studies and review studies show that nearly 20-40% of the weight lost by GLP-1RA drug subjects was lean body weight (also known as lean mass, lean mass), which is mainly composed of muscle mass, and muscle loss increases the risk of cardiovascular disease and osteoporosis.

In July 2023, Eli Lilly acquired Versanis Bio for $1.925 billion to acquire the Actrii muscle-building and fat-loss drug bimagrumab. In October of this year, Eli Lilly officially launched a phase II clinical trial of Bimagrumab combined with titerpotide to gain muscle and lose fat.

Prior to the acquisition by Eli Lilly, data from the 48th week of Bimagrumab's phase IIA clinical trial showed that it was possible to reduce the subjects' fat mass by 20.5% (the weight loss effect was similar to terpopeptides), reduce waist circumference by 9.0 cm, increase lean body weight by 3.6%, and patients did not observe a weight rebound within 12 weeks of stopping treatment.

Dr. Lu Xiangyang, founder of Laikai Pharmaceutical, is the co-inventor of Bimagrumab.

02 Yakuou is in a hurry to find a partner

Lu Xiangyang has accumulated more than 20 years of experience in ActRII target research and is an authoritative global expert. According to the characteristics of iterative drug development, compared to Bimagrumab, Laikai Pharmaceutical LAE102 should be improved in terms of safety and drug mechanism, which may also attract Eli Lilly to bet on both sides.

improved version

Although targeting ActRII receptors can completely block skeletal muscle growth inhibition signals, they also cause broad-spectrum inhibition of various ligands, which may present potential safety hazards.

Bimagrumab clinical phase II safety data

Side effects of Bimagrumab include muscle cramps and diarrhea, which occurred early in treatment. In the phase IIa clinical trial, 5 patients (14%) were terminated due to adverse events. Bimagrumab is a dual target inhibitor of ActRIIA and ActRIIB. Which target is causing these adverse reactions? I believe Eli Lilly is also very interested in further verification, so I intend to make further comparisons through clinical trials.

Based on the differences in activity of the two ActRIIA/ActRIIb type II receptors for the four ligands (ActivinA, ActivInB, GDF8, GDF11) and the effects of the entire pathway in different diseases, Laikai Pharmaceutical has laid out a total of 3 ActRIII-targeted drugs. LAE102 (ActRIIb monoclonal antibody) focuses on muscle gain and fat loss, LAE103 (ActRIIb monoclonal antibody), and LAE123 (ActRIIb monoclonal antibody) indications mainly for muscle atrophy and other diseases.

According to the DIO model published by Laikai Pharmaceutical, LAE102 and LAE103 both have the effect of increasing lean body weight, while LAE102 is more significant, and LAE102 and simeglutide can work together to reduce fat.

LAE102 selects single-targeted ActriIa. Compared with Bimagrumab, this differentiated design is likely to achieve better safety and the effect of simultaneously gaining muscle and losing fat.

hypodermic

ActRII antibodies should also be injected subcutaneously as GLP-1RA companion drugs.

Lai Kai Pharmaceutical launched the subcutaneous injection (SC) portion of the LAE102 single dose escalation study in October of this year. The goal is to complete the single dose escalation study by the end of 2024.

Compared with intravenous administration, subcutaneous administration is more advantageous for patients with chronic diseases for long-term use, and is also easier to use in combination with GLP-GLP-1RA drugs, making it more attractive to large pharmaceutical companies with GLP-1RA drugs.

BD amount

2024H1, 25 biotechs around the world were acquired, including 6 mergers and acquisitions exceeding 2 billion US dollars and 15 mergers and acquisitions exceeding 1 billion US dollars. The goal of acquiring Biotech is of course to acquire the other party's core pipeline assets.

In the field of innovative treatments for weight loss, MNC is taking action harder and earlier. Last year, Bimagrumab was acquired by Eli Lilly at the stage of phase IIa clinical completion and phase IIb clinical enrollment; in October of this year, Eli Lilly deployed a dual-target weight loss therapy for 1.4 billion dollars, and launched before Phase I of KeyBioscience's Dacra (pancreant/calcitonin receptor dual agonist) molecule was completed or phase II started.

The clinical phase of BD is getting more advanced, and domestic innovative drug projects going overseas also reflect this trend. According to Guosheng Securities statistics, in 2023, China's innovative drug license-out accounted for 34% of pre-clinical projects, 26% for phase I clinical projects, 23% for post-marketing projects, and less than 10% for phase II/III clinical and application for marketing.

According to Wisdom Bud data, only Bimagrumab and LAE102 are the only weight loss drugs targeting the ActRII pathway that have entered the clinical phase. Scarce resources have led Lilai to take the lead.

In the post-GLP-1 era, the huge demand for muscle building is unquestionable. The muscle-building effect of ActRII antibodies has been verified by BimaGrumab. The suspense is that safety has yet to be verified with more clinical data.

The reading of LAE102's phase I clinical data is critical, and I'm looking forward to a super BD.

Lai Kai Pharmaceutical is exploring a new model for going overseas. MNC orders food first, then looks at data to pay for the bill, and Biotech's high-potential pipeline assets are also eligible to be sold at a price after receiving data endorsement.

The GLP-1 track is getting bigger and bigger. What Lai Kai Pharmaceuticals is demonstrating is a proper way to participate in popular racetracks. Building muscle and fat will be the focus of the differentiation of the GLP-1 track and the competitiveness of next-generation products.

This article was transferred from the WeChat account “Archimedes Biotech”, Zhitong Finance Editor: Li Cheng