Pemvidutide Demonstrates Triple Benefits in Phase 2 Trial: Significant Weight Loss, Lipid Lowering, and Blood Pressure Improvement

01

On December 1, 2023, the NMPA official website showed that the marketing application for the liraglutide injection submitted by Tonghua Dongbao Pharmaceutical has been approved.

Among them, liraglutide is a human glucagon-like peptide-1 (GLP-1) analog that can activate the human GLP-1 receptor and promote insulin secretion by the pancreas. This product was developed by Novo Nordisk and entered the Chinese market in 2011, being approved for blood sugar control in adult patients with type 2 diabetes. Additionally, liraglutide has a significant weight-loss effect, and its obesity indication product (Saxenda) was launched in the United States in December 2014.

01

On November 30, 2023, Altimmune announced preliminary results from the Phase II MOMENTUM study of its investigational glucagon-like peptide-1 receptor (GLP-1R)/glucagon receptor (GCGR) dual agonist for obesity, which lasted 48 weeks. The results showed that patients receiving 2.4 mg of pemvidutide had an average weight loss of 15.6%, along with a significant decrease in blood lipids and improved blood pressure.

Analysis showed that, at week 48, patients receiving pemvidutide treatment achieved average weight loss of 10.3%, 11.2%, 15.6%, and 2.2% in the 1.2 mg, 1.8 mg, and 2.4 mg dose groups and the placebo group, respectively. A near-linear trajectory of continued weight loss was observed in the 2.4 mg dose group at the end of treatment. Additionally, among patients receiving the 2.4 mg dose, more than 50% lost at least 15% of their body weight, and more than 30% lost at least 20% of their body weight.

As in previous clinical trials, pemvidutide significantly reduced blood lipids and improved blood pressure without causing cardiac events, arrhythmias, or clinically meaningful increases in heart rate compared to placebo. Glycemic homeostasis was maintained, with no significant changes in fasting glucose or glycated hemoglobin (HbA1c). A greater proportion of patients receiving pemvidutide remained in the trial compared to those on placebo, with 74.1% of pemvidutide-treated subjects completing the trial versus 61.9% in the placebo group. Nausea and vomiting accounted for the majority of adverse events (AEs), primarily mild to moderate in severity. Only one patient (1.0%) experienced a drug-related serious adverse event (SAE).

Among them, Pemvidutide is a novel, investigational, peptide-based dual agonist of glucagon-like peptide-1 (GLP-1) and glucagon. It is being developed for the treatment of obesity and metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH). Pemvidutide utilizes Altimmune's proprietary EuPortTM domain, a technology that extends the drug’s serum half-life, facilitating once-weekly dosing while potentially slowing the entry of pemvidutide into the bloodstream, thereby enhancing its tolerability.

02

On December 1, 2023, Pfizer announced the data from the Phase IIb clinical trial (NCT04707313) of Danuglipron (PF-06882961), an oral small-molecule glucagon-like peptide-1 receptor agonist (GLP-1RA), for adult obesity (non-type 2 diabetes) patients. The study met its primary endpoint, with a statistically significant change in body weight from baseline. However, Pfizer stated that it does not plan to advance this twice-daily oral medication into Phase III clinical trials.

03

Recently, Ganlee Pharmaceutical Shandong Co., Ltd. submitted GZR18 tablets, a Class 1 innovative therapeutic biologic product, and has received the "Drug Clinical Trial Approval Notice" issued by the National Medical Products Administration (NMPA) (acceptance numbers: CXSL2300633, CXSL2300634, CXSL2300635; approval notice numbers: 2023LP02424, 2023LP02425, 2023LP02426). The approved indication is for Type 2 diabetes.

Among them, the GZR18 injection is intended for the treatment of type 2 diabetes (T2DM) in adult patients and weight management in obese/overweight patients. It is currently in Phase II clinical trials. Compared with traditional injectable formulations that require subcutaneous injection, the GZR18 tablet is expected to effectively address issues such as low oral bioavailability and suboptimal efficacy of peptide-based GLP-1 RAs while ensuring safety and efficacy. Additionally, it aims to improve patient compliance and provide a wider range of treatment options for patients.

04

On November 27, 2023, Protagonist Therapeutics announced two additional Phase III studies, ICONIC-ADVANCE 1 and ICONIC-ADVANCE 2, to evaluate JNJ-2113 (formerly known as PN-235) in a head-to-head comparison with deucravacitinib (an oral TYK2 inhibitor) in patients with moderate to severe psoriasis.

Among them, JNJ-2113 is a potential first-in-class oral IL-23 receptor antagonist targeting drug. IL-23 is a cytokine involved in the inflammatory process and is considered to be associated with many chronic immune-mediated diseases, including psoriasis. JNJ-2113 is an oral IL-23R antagonistic peptide that can block the IL-23 signaling pathway for the treatment of plaque psoriasis. JNJ-2113 was co-developed under a nearly $100 million collaboration agreement reached between Janssen Biotech and Protagonist Therapeutics in 2017.

05

2023-11-29, Entera Bio Ltd. announced interim data from the ongoing Phase I study, which aims to evaluate and compare the pharmacokinetics (PK) and early pharmacodynamics (PD) profiles of its oral peptide platform (NCT05965167) for current and several next-generation formulations.

Phase Ⅰ Study First Compared the PK Profile of Entera’s Phase Ⅲ Candidate Drug, an Oral Once-Daily PTH(1-34) Mini-Tablet (EB613, also Known as EBP05 Formulation), with Subcutaneous (SC) Injection of PTH(1-34) 20 µg (Forteo®). Consistent with Previously Reported PK and Bioavailability Data, EBP05 Induced a Rapid and Dose-Proportional Increase in Plasma PTH(1-34) Concentrations at All Tested Doses. The Target Bioavailability of PTH(1-34) for EB613 at Doses of 1.5 mg and 2.5 mg Reached the Planned Dose Range for Use in Phase Ⅲ. Additionally, EB613 Showed Consistent and Statistically Significant (p<0.05) Effects on All Early PD Markers, Including Endogenous PTH(1-84) in Plasma, Serum Calcium, Phosphorus, and 1,25-Dihydroxyvitamin D Levels.

01

Recently, Chengdu Taihe Weiye Biotechnology Co., Ltd. (hereinafter referred to as "Taihe Weiye") announced the completion of a nearly 300 million yuan A+ round of financing. This round of financing was led by CITIC Securities Investment Co., Ltd. and Maotai Jinshi Fund under Goldstone Investment, with participation from Qiming Venture Partners, Highlight Capital, and Jiayuan Capital. Existing shareholders GL Ventures (under Hillhouse Capital), CCID Capital's CCID Qichen Fund, and GF Xinde continued their investment.

According to reports, the funds obtained from this round of financing will be mainly used to accelerate the production of the company's 240-mu Phase II factory and the construction of a 500-mu Phase III factory. It is planned to achieve the production of 1,000-mu Phase I, II, and III factories by 2025, further meeting the growing global demand for Fmoc amino acids.

02

On December 1, 2023, Perpetual Medicines announced the completion of an $8 million seed funding round to advance its highly integrated computational design-automated synthesis peptide drug discovery platform. This round was led by Chengwei Capital.

The company also announced the latest appointments to its core leadership team, including Co-founder, Chairman and Chief Executive Officer Kerry L. Blanchard (Kori Bo), Ph.D., Chief Technology Officer Ved Srivastava, Ph.D., and Chief Scientific Officer Ye Xiangsheng, Ph.D.

Dr. Blanchard stated, "Dongpeptide Pharmaceuticals is fully leveraging the latest advancements in computational models based on artificial intelligence, deep learning, and machine learning to open the door for the first time to drug discovery targeting the vast, unexplored chemical space of peptides." The company has built an integrated platform capable of virtually iterating millions of peptide sequences using physics-based computational methods to predict their binding affinity and other drug-like properties. Combined with experimental data, this approach facilitates the discovery and optimization of drug candidates. This method is expected to accelerate the speed of peptide drug discovery, reduce R&D costs, and improve the quality of candidate drugs. Through this round of financing, the company will advance its leading projects into clinical stages and continue to expand its preclinical pipeline in the fields of oncology, autoimmune diseases, and metabolic disorders.

Dr. Blanchard also pointed out that polypeptide therapy has become the fastest-growing field in the pharmaceuticals industry, with annual sales expected to exceed US$1.4 trillion by 2030. He said, "Polypeptide drugs fill the gap between small molecule drugs and therapeutic antibodies. They have a relatively large structural space and sufficient selectivity, making them suitable for blocking protein-protein interactions inside and outside cells. These characteristics, combined with the vast chemical space that polypeptides can generate, enable their applications to expand into various targets and pathologies once considered undruggable."

03

According to an official communication from Novo Nordisk and the European Medicines Agency, Novo Nordisk is temporarily reducing the supply of its diabetes treatment drug Victoza (liraglutide) to increase the production of its next-generation type 2 diabetes medication Ozempic (semaglutide).

The announcement stated that healthcare providers should anticipate "intermittent shortages" of Ozempic, which will continue until 2024. Meanwhile, the supply of Victoza will be interrupted at least until Q2 2024.

04

On December 1, 2023, according to foreign media Endpoints reports, the Pharmacovigilance Risk Assessment Committee (PRAC) of the EMA raised new concerns about the risk of suicide and self-harm associated with GLP-1 receptor agonists. PRAC stated that it would discuss this issue again in April next year.

The review was initiated in July this year, following several reports received by the Icelandic Medicines Agency from users of liraglutide (Saxenda) and semaglutide (Ozempic and Wegovy) experiencing suicidal thoughts and self-harming behaviors.

As of 2023-11-7, the PRAC has collected approximately 150 reports of suicidal and self-harm events associated with GLP-1 receptor agonists. The review scope has expanded from Ozempic (semaglutide), Wegovy (semaglutide), and Saxenda (liraglutide) to other GLP-1 class drugs, involving manufacturers including Novo Nordisk, Lilly, AstraZeneca (AZ), and Sanofi.

05

Recently, Novo Nordisk announced that it will launch its popular weight-loss drug Wegovy in Japan on 2024-2-22. This will be Novo Nordisk's first launch of Wegovy in the Asian market. Amid a supply shortage of Wegovy, Novo Nordisk has chosen Japan as the sixth country to introduce the drug. So far, Novo Nordisk has only launched Wegovy in the United States, the United Kingdom, Germany, Norway, and its home market, Denmark.

01

Professor Dongmin Lee from the School of Medicine at Korea University published an article titled “A single-component, light-assisted uncaging switch for endoproteolytic release” in Nature Chemical Biology.

The article points out that proteases have been widely identified in a diverse range of organisms. They rely on post-translational modifications as signaling cues and initiate a broad spectrum of biological events through cleavage. Therefore, in synthetic biology, efforts have been made to utilize proteases as molecular switches to regulate intracellular events. Evolutionarily distant plant virus proteases are excellent candidates for proteolytic switches since they lack natural substrates in the human proteome and exhibit strict sequence specificity; the authors chose the tobacco etch virus protease (TEVp). Traditionally, control of this enzyme has been achieved through chemically or light-induced dimerization to unleash its activity. However, the complementary strategy involving two separate polypeptides often results in a low signal-to-noise ratio, with complex components unsuitable for integrated use.

In the article, the author proposed a single-component optogenetic enzyme cleavage decaging method for this issue, named LAUNCHER. It includes a subcellular localization component, such as the TM component for membrane localization; the C-terminal and N-terminal subunits of Tev enzyme connected by a flexible linker; the blue light-activated optogenetic element iLID; the Tev enzyme cleavage sequence; and the substrate protein, such as tTA for transcriptional activation. Upon blue light excitation, the conformational change of the optogenetic element iLID induces proximity between TevC and TevN, leading to the cleavage and release of the substrate protein from its caged state. After completing the conceptual design, the author mainly optimized the linkers of LAUNCHER, selecting appropriate lengths for two segments of linkers to achieve efficient release of protease activity and substrate accessibility. Additionally, a higher signal-to-noise ratio was achieved by using two optogenetic elements. The author believes that this tool has excellent spatial resolution, capable of achieving substrate protein decaging only in the illuminated area, thereby displaying the word "LAUNCHER." Moreover, it exhibits good orthogonality; introducing three systems using different plant virus proteases into a single cell allows for non-interfering substrate release. It also has faster release kinetics compared to traditional tools, enables localization in different subcellular regions, and is compatible with various cell types. These advantages make it an excellent plug-and-play integrable chemical biology tool.

02

Professor Xuefeng Jiang from East China Normal University published an article titled "Disulfide click reaction for stapling of S-terminal peptides" in Angew. Chem. Int. Ed.

The article points out that polypeptides can mimic the sequence structure of protein-protein interactions (PPIs), bind to functional protein active sites in a targeted manner, and act as inhibitors, making them a very important class of drugs. However, linear polypeptides cannot maintain their α-helix structure as found in native proteins, presenting variable conformations. Researchers have used chemical stapling to covalently link two or more sites within linear polypeptides, which restricts the conformation of the polypeptide, allowing it to revert to an α-helix, while also enhancing its transmembrane capability and preventing enzymatic degradation.

The article describes the efficient preparation of novel linkers using diynyl or triynyl compounds and phthalimide sulfonyl chloride, which can react with 2 or 3 thiol groups for stapling peptides or proteins. This stapling reaction is reversible, and the stapled peptides can be reduced to their original linear form by TCEP.