Since Novo Nordisk's development of Wegovy (semaglutide) was proven to be safe and effective in weight control, and was approved by the US FDA for the treatment of obese patients in 2021, the weight loss drug market has gradually become a hot spot for industry investment. Following semaglutide, Eli Lilly and Company's Mounjaro (tirzepatide) is also expected to be approved for the treatment of obese patients by the end of this year. In addition to large pharmaceutical companies, many biotechnology companies are also focusing on the development of weight loss drugs, with many companies focusing on therapies based on non glucagon like peptide-1 (GLP-1). Combining industry media STAT's reports with other publicly available materials, introduce to readers how these emerging biotechnology companies have innovative strategies to establish themselves in the weight loss market.
Not only weight loss, but also muscle building
Although currently approved weight loss drugs can help obese patients lose weight, they also cause muscle loss in patients. According to clinical trial results, about 40% of the weight loss in obese patients is fat free. Some doctors are concerned that elderly people taking this medication may become weak and more prone to accidents.
The investigational therapy bimagrumab developed by Versanis Bio is expected to break this problem. Bimagrumab is a potential "first in class" monoclonal antibody that targets the Activin 2 receptor (ActRII). ActRII is an activator receptor expressed in both fat and muscle cells. The activation of ActRII receptor signaling can lead to muscle atrophy and accumulation of fat in adipose tissue. Therefore, targeting this pathway is expected to increase the muscle composition of patients while driving fat loss. In a 48 week phase II clinical trial, compared with placebo, bimagumab can cause about 22% fat mass loss and 4.5% fat free weight increase in overweight or obese patients with type 2 diabetes. In addition, unlike many incretin based therapies, no weight gain was observed in patients within 12 weeks of discontinuing treatment. So far, the safety data of bimagrumab shows that its side effects include muscle spasms and diarrhea, which occur in the early stages of treatment and are mostly mild.
In addition to Versanis, Italian startup Resalis Therapeutics has also set its sights on adipocytes. The lead project RES-010 of Resalis is an antisense oligonucleotide (ASO) therapy that inhibits miR-22 microRNA. MiR-22 plays a crucial role in regulating fat metabolism and energy expenditure. In many proof of concept experiments on rodents and non-human primates, RES-010 has demonstrated good tolerability and sustained efficacy. According to industry media STAT's report, senior executives of Resalis company pointed out that in preclinical studies, drugs only cause the loss of fat storage, while muscle mass is not affected. Resalis expects to launch human clinical trials of RES-010 in early 2024.
Natural weight loss to avoid side effects
According to STAT statistics, over half of the 80 weight loss therapies currently under development are based on therapies targeting GLP-1 receptors. The activation of GLP-1 receptors can stimulate insulin production and inhibit glucagon secretion, reducing appetite and food intake, thereby achieving weight loss. However, such therapies often lead to side effects such as nausea and vomiting, which are unbearable for some patients. In a large-scale clinical trial, 5% of participants had to discontinue medication due to side effects.
Swiss startup Aphaia Pharma aims to change this situation by developing a "natural" way to lose weight. Dr. Steffen Sebastian Bolz, Chief Scientific Officer of Aphaia, pointed out that when cells in the lower small intestine are stimulated by nutrients in food, they release a series of hormones that send satiety signals to the brain and produce other metabolic effects simultaneously. However, in obese patients, nutrients do not reach this area but are absorbed at higher levels in the intestine, which also leads to high blood sugar levels in patients. The lead project APH-012 developed by Aphaia is an oral microsphere that can release glucose in the lower small intestine to stimulate nutrient sensing cells to release hormones (including GLP-1, etc.) to control various homeostasis and metabolic functions, such as appetite, hunger, satiety, glucose metabolism, energy consumption, etc. Through the design of microspheres, the glucose released by APH-012 will not be absorbed in the upper part of the small intestine, nor will it enter the systemic circulation, which is a key safety design for patients with diabetes. Compared to other therapies based on synthetic GLP-1 receptor agonists, this type of therapy is expected to produce fewer side effects by promoting the secretion of natural hormones.
Kalliope company also adopts a principle similar to Aphaia therapy. Kallyope focuses on identifying and developing weight loss metabolic therapies targeting the gut brain signaling axis, and has partnered with Aardvark Therapeutics. The latter is a startup company developing targeted therapies for bitter receptors in the gut, which they have discovered can trigger the release of hormones such as GLP-1. Dr. Brett Lauring, Chief Medical Officer of Aphaia, stated in an interview that this type of therapy has similar effects as weight loss surgery that alters an individual's digestive system. "One of the outcomes of the surgery is an increase in levels of various hormones that regulate appetite and glucose, such as GLP-1, PYY, and CCK," he said
What innovative weight loss therapies need to face is
Having a differentiated and innovative drug pipeline is the key to the success of new therapies, but biotech companies still face many challenges when entering the field of weight loss therapy. For example, unlike the development of cancer therapies, regulatory agencies have stricter safety standards for weight loss drugs. Therefore, when developing weight loss therapies, the industry often needs to conduct larger clinical trials to prove the safety and efficacy of the investigational therapies, which is a significant burden for many biotech companies. In addition, existing approved therapies have shown impressive weight loss effects. Therefore, Dr. Randy Seeley, director of the Michigan Nutrition Obesity Research Center, stated that the new therapy needs to demonstrate at least about 20% weight loss and also demonstrate benefits for heart health in order to highlight its advantages.
In addition to examining the monotherapy efficacy of new therapies, many biotechnology companies are also examining the effectiveness of their investigational products when used in combination with existing approved drugs. For example, Versanis is conducting a clinical 2b trial to examine the efficacy of its lead drug bimarumab and smeglutide combined therapy in obese or overweight patients without diabetes. In addition, some studies suggest that patients taking GLP-1 drugs alone may have an increase in another gut hormone, ghrelin (commonly known as hunger hormone), which may be one of the reasons for weight recovery after discontinuing treatment. In the Phase 2a clinical trial of Aardvark's lead project ARD-101, there are indications that drug treatment can reduce levels of hunger hormones.
Dr. Tien Lee, CEO of Aardvark, said, "Like treating other diseases, we ultimately need a drug combination to achieve the best weight loss effect. Nowadays, many people are focused on developing the next generation of GLP-1 drugs, but in fact, they can also promote the treatment effect of obesity in many other aspects
According to incomplete statistics from WuXi AppTec last year, there are at least 31 therapies in the weight loss field that are in clinical phase 2, phase 3, pre registration, and already on the market. The types of therapeutic targets in the Phase 2 clinical development stage are more diverse and the mechanisms are more novel, including controllable metabolic accelerators and neuropeptide YY5 receptors, IKKε/TBK1， Activin type II receptor, etc. These data demonstrate from another perspective that the industry is exploring weight loss therapies beyond the GLP-1 signaling pathway.
