After Setbacks in Immuno-Oncology, Merck Bets Big on Oral GLP-1 with $2B Deal for HS-10535
Hansoh Pharma
Pharmaceutical Research, Production, and Sales
On December 16, Merck announced on its official website the formal termination of the development of its anti-TIGIT antibody Vibostolimab and anti-LAG-3 antibody Favezelimab. This adjustment marks the loss of years of efforts by Merck in the field of immune checkpoint inhibitors. Two days later, Merck announced its next target. On December 18, Merck announced a collaboration with China's Hansoh Pharma. Merck will obtain the global exclusive license rights to the latter’s investigational oral small-molecule GLP-1 receptor agonist (GLP-1RA) HS-10535, while Hansoh Pharma will temporarily retain control over HS-10535 in China. The total amount of the collaboration could reach up to 2 billion US dollars.
Behind the frequent business adjustments is MSD's K drug (Pembrolizumab) is about to face the anxiety of a patent cliff. The next competitive focus that Merck is betting on also provides inspiration for innovative pharmaceutical companies.
TIGIT, LAG-3 Targets Fail, Years of Effort Down the Drain
One of the products discontinued by Merck this time, Vibostolimab, is an anti-TIGIT antibody. TIGIT is an inhibitory receptor expressed on T cells and NK cells and belongs to the immunoglobulin superfamily. It can bind to ligands such as CD155 and CD112, thereby inhibiting the killing effect of NK cells and T cells on tumor cells. Therefore, antibodies or other drugs targeting TIGIT can be used to block the TIGIT signaling pathway, thereby enhancing the body's immune response to tumor cells and increasing anti-tumor activity.
Based on the mechanism of action of TIGIT, the TIGIT target is regarded as the next breakthrough, attracting competition from multiple pharmaceutical companies, but no company has succeeded so far.In the TIGIT track, Merck and Roche are the most active developers. Both pharmaceutical companies have persisted in development for eight to nine years, competing against each other for many years, but neither has yet succeeded. Merck's Vibostolimab has experienced multiple failures.
In December 2023, Merck terminated the KeyVibe-002 trial, which aimed to evaluate the use of K drug + Vibostolimab combination therapy compared to standard treatment with docetaxel in patients with metastatic NSCLC.The efficacy. The results showed that, compared with patients treated with docetaxel alone, the Vibostolimab+K drug group did not improve median PFS or median OS.
In May 2024, Merck announced the termination of the ongoing study comparing Keytruda + Vibostolimab versus Keytruda monotherapy as adjuvant treatment for patients with high-risk stage IIB-IV melanoma after surgical resection.
Ultimately, based on all data from the existing KeyVibe series of studies, Merck decided to terminate the development plan for Vibostolimab.
Another drug whose study was terminated is the anti-LAG-3 antibody Favezelimab, a self-developed antibody drug by Merck targeting Lymphocyte Activation Gene 3 (LAG-3). It aims to restore T-cell effector function by blocking the binding of LAG-3 to its major ligand, the Major Histocompatibility Complex (MHC) class II molecule.
For Favezelimab, Merck conducted the Phase III KEYFORM-007 study investigating the combination of Favezelimab and Keytruda (K drug) for the treatment of PD-L1 positive microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) patients, but it failed to meet the primary endpoint in the final pre-specified analysis.
In addition to the KEYFORM-007 study, Merck also conducted two Phase III studies to evaluate the therapeutic potential of Favezelimab + K drug combination. However, based on all existing clinical data, Merck decided to terminate the clinical development program of Favezelimab.
In fact, in the original development plan, both Vibostolimab and Favezelimab were being developed in combination with Keytruda. Now that their development has been abandoned, where is Merck placing its next R&D focus?
Is Oral GLP-1 the Next Blockbuster?
On December 18, Merck announced a cooperation agreement with China's Hansoh Pharma regarding HS-10535, an investigational oral small-molecule GLP-1 receptor agonist, with a total cooperation value of up to 2 billion US dollars. Currently, Hansoh Pharma has not disclosed the R&D progress or specific indications of HS-10535. Based on Merck’s expectations for HS-10535, its indications may be related to weight loss and cardiometabolic diseases.
GLP-1-related products, as weight-loss drugs, hold significant appeal for pharmaceutical companies. Novo Nordisk and Eli Lilly have generated substantial profits with their GLP-1 products, semaglutide and tirzepatide. In the first three quarters of this year, sales of semaglutide reached $20.6 billion, while tirzepatide achieved $11 billion, with growth continuing.
Therefore, it is essential for Merck to lay out the GLP-1 field in its search for the next "Keytruda." In fact, Merck started its GLP-1 project as early as 2010, but has yet to successfully bring a product to market. This shift toward the oral small molecule space may present an opportunity to overtake competitors.
Currently, the oral semaglutide tablet (Rybelsus) remains the only marketed oral GLP-1 drug. Rybelsus utilizes SNAC technology, which, with the addition of 300mg of SNAC molecules, temporarily increases gastric pH and promotes transcellular absorption in the gastric mucosa at specific concentrations. Since its launch in 2019, Rybelsus has seen consistently strong sales.
Currently, in the field of oral GLP-1R agonists, Eli Lilly's Orforglipron is the most advanced. Orforglipron was initially developed by Chugai Pharmaceutical, and in 2018, Eli Lilly acquired global development and commercialization rights for the drug with an upfront payment of $50 million. In Phase II clinical trials, Orforglipron demonstrated significant efficacy in weight management for patients who are obese or overweight.
HRS-7535, developed by China's Hengrui Medicine, is also an orally administered small-molecule GLP-1 receptor agonist, primarily targeting type 2 diabetes and weight loss. It is currently in Phase II clinical trials. Notably, even with a lower baseline body weight (67.6 kg), subjects treated with HRS-7535 for four consecutive weeks showed a significant weight loss of 4.38 kg (vs. 0.8 kg in the placebo group). In February this year, HRS-7535 received NMPA approval to initiate Phase II clinical research for weight loss indications.
VCT220, an oral small molecule GLP-1RA developed by Ontix Pharma, has entered Phase III clinical trials in China targeting obesity and overweight patients. According to previous Phase II clinical trial results, CX11 demonstrated more competitive weight loss effects compared to current similar drugs, while showing good safety and tolerability.
Currently, with only about three years left until the expiration of Keytruda's (K药) patent (in 2028), Merck & Co. is anxiously searching for its next blockbuster drug but has yet to achieve satisfactory results. Particularly, the setbacks in the development of highly anticipated targets such as TIGIT, LAG3, and GLP-1 have made Merck even more anxious. This time, betting on an oral GLP-1 small molecule could be Merck’s chance to overtake competitors.
Reference Source:
1.Merck provides update on KeyVibe and Keyform Clinical development programs evaluating investigational vibostolimab and favezelimab fixed dose combinations with Pembrolizumab.
2.Safety, pharmacokinetics and pharmacodynamics of HRS-7535, a novel oral small molecule glucagon-like peptide-1 receptor agonist, in healthy participants: A phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, and food effect trial.
3.https://www.empr.com/home/news/mycapssa-octreotide-approved-capsules-acromegaly-patients-chiasma/.
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