In the global obesity drug market dominated by glucagon-like peptide-1 (GLP-1) injectables such as "Wegovy (semaglutide)" and "Mounjaro (tirzepatide)," small-molecule oral (pill) drugs are emerging as new contenders. That is because they can be taken conveniently as pills instead of injections, have lower production costs, and cause fewer side effects. With the development race expected to heat up starting next year with Eli Lilly's launch of an oral obesity drug, Ildong Pharmaceutical in Korea has secured the most advanced clinical trial data, drawing market attention to the possibility of the first out-licensing deal.
According to the industry on the 4th, global drugmakers are accelerating development of small-molecule obesity pills as a next-generation growth engine. Among them, Unovia, a new drug development subsidiary of Ildong Pharmaceutical, recently demonstrated superior efficacy to competing substances in a phase 1 trial. The company is developing a once-daily oral GLP-1 candidate (ID110521156).
In a phase 1 trial involving 36 Korean adults, the high-dose (200 mg) group recorded an average weight loss rate of 9.9% (8.8 kg) after four weeks, higher than Eli Lilly's oral obesity drug Orforglipron (6.4%) or the candidate from Switzerland's Roche (7.3%). In particular, Ildong Pharmaceutical said, "Liver function indicators actually improved, and all adverse events after dosing were mild, so there were no concerns about hepatotoxicity."
The obesity drug market now demands next-generation treatments that overcome the limitations of Wegovy and Mounjaro, including gastrointestinal side effects, weight regain after stopping treatment, and muscle loss. Competition for mergers and acquisitions (M&A) among global drugmakers is intensifying over corporations with such technologies. More than 15 candidates are under development worldwide by companies including Roche, AstraZeneca, and Merck (MSD) in the United States, and in Korea, Hanmi Pharmaceutical and Ildong Pharmaceutical have also entered development.
Unlike peptide drugs such as Wegovy and Mounjaro, the candidate under development by Ildong Pharmaceutical is a small-molecule compound made through chemical synthesis. Because complex biotechnological processes are not required, mass production is easier and manufacturing costs are lower. With a long half-life and ease of developing an oral formulation, it offers both convenience and cost-effectiveness.
Peptides are fragments that make up proteins. While peptide-based drugs are mostly broken down during digestion in the body and are difficult to formulate as pills, small-molecule compounds, which have much lower molecular weight, do not have this limitation. In fact, a significant share of the drugs recently approved by the U.S. Food and Drug Administration (FDA) are small-molecule compounds.
However, GLP-1 drugs have complex molecular structures and are difficult to synthesize, leading to poor development outcomes so far. U.S. companies Pfizer and Terns (TERNS) halted development, and Roche and AstraZeneca also failed to deliver improved results over existing drugs. The main reason for failure was difficulty in increasing doses due to side effects such as abnormal liver function.
Lilly's Orforglipron cleared this technological barrier. Orforglipron, a next-generation obesity drug based on a small-molecule compound that will follow the once-weekly injectable Mounjaro, was brought in through a technology introduction from Japan's Chugai in 2018 and developed. It is currently under review for approval by the U.S. Food and Drug Administration (FDA).
Aside from Orforglipron, which succeeded in phase 3, Pfizer's danuglipron had been the most advanced candidate, but development was halted in March due to side effects, putting new drugs in phase 1, including those from Ildong Pharmaceutical, in the lead group.
SK Securities said in a report the previous day, "Currently, aside from Lilly's Orforglipron, there is almost no supply of oral small-molecule obesity drugs," and analyzed, "Ildong Pharmaceutical is highly likely to clinch the first big pharma technology transfer deal." It projected the deal size at between 1.5 trillion and 4 trillion won, exceeding the scale of rival contracts.
Choi Hyeong-jin, a professor in the anatomy department at Seoul National University College of Medicine, said, "Peptide drugs can be improved based on existing receptor binding structures, but small-molecule drugs are much more difficult because you have to newly design substances that bind well to the receptor from the start," and added, "Animal model experiments are demanding, and the risk of side effects such as hepatotoxicity was also high, which limited development."
Even so, Choi noted, "The convenience of an oral form, low production costs and simple distribution and storage, and the potential for fixed-dose combinations using new mechanisms of action are major advantages for drugmakers," and analyzed, "Expectations are high for combination development with other drugs based on new mechanisms of action."
Choi is a physician-scientist who, together with researchers at the University of Texas Southwestern Medical Center, first identified that GLP-1 analogs enhance satiety through neurons in the middle and dorsal regions of the hypothalamus, and released the findings in Science last year.