RecentlyPeriod, NationwideBallMorePeptideAnd fewNucleusGlycosideAcid (TIDES）LeadFieldWelcomeComeSeriesAdvanceExpandThe Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has adopted a positive opinion, recommending the approval of the lipid-lowering small interfering RNA (siRNA) drug plozasiran.UpCity. Bepirovirsen, an investigational antisense oligonucleotide (ASO) therapy for the treatment of chronic hepatitis B (CHB), has been granted Priority Review by the U.S. FDA. Boehringer Ingelheim announced positive results from a Phase 3 clinical trial of its glucagon/GLP-1 receptor dual agonist, survodutide, which enabled patients with obesity or overweight to achieve an average sustained weight loss of 16.6%. This article will provide a brief introduction to some of these significant advancements for readers' reference.

Plozasiran: Receives Positive Opinion from the European Medicines Agency's Committee for Human Medicinal Products

Arrowhead Pharmaceuticals announced that the Committee for Medicinal Products for Human Use of the European Medicines Agency has adopted a positive opinion, recommending the approval of Redemplo (plozasiran) for marketing authorization.This drug is an siRNA medication intended as an adjunct to dietary control for reducing triglyceride levels in adult patients with familial chylomicronemia syndrome (FCS).Redemplo aims to silence the mRNA encoding apolipoprotein C-III (apoC-III).ApoC-III is a key regulator of triglyceride metabolism, which can inhibit the breakdown and clearance of triglycerides, leading to elevated triglyceride levels. CarriersAPOC3Individuals with loss-of-function genetic variants typically have significantly lower triglyceride levels and a reduced risk of atherosclerotic cardiovascular disease.

The positive opinion of the CHMP is based on clinical data from the Phase 3 PALISADE study. This study was a randomized, double-blind, placebo-controlled trial conducted in adult patients clinically diagnosed or genetically confirmed with FCS. The PALISADE study met its primary endpoint and all key secondary endpoints adjusted for multiplicity, including significant reductions in triglyceride and apoC-III levels in the pooled dose group, as well as a decrease in the incidence of acute pancreatitis.In the PALISADE study, the 25 mg dose of Redemplo reduced triglyceride levels by a median of 80% from baseline, compared to a 17% reduction in the placebo group; additionally, the number of acute pancreatitis cases in the Redemplo group was significantly lower than in the placebo group.

Bepirovirsen: Granted Priority Review by the U.S. FDA

Ionis Pharmaceuticals and its partner GSK announced,The U.S. FDA has accepted the New Drug Application (NDA) for the investigational ASO therapy bepirovirsen, intended for the treatment of adult patients with chronic hepatitis B, and has granted it Priority Review. The PDUFA date for this application is set for October 26, 2026.At the same time, this therapy has also received Breakthrough Therapy Designation from the FDA. Currently, bepirovirsen is under review by multiple regulatory agencies, including the European Medicines Agency (EMA), Japan's Ministry of Health, Labour and Welfare (MHLW), and China's National Medical Products Administration (NMPA).

This regulatory submission and Breakthrough Therapy Designation are primarily based on the positive results of the Phase 3 B-Well 1 and B-Well 2 clinical trials. The studies showed,Compared with standard treatment alone, bepirovirsen combined with standard treatment achieved statistically significant and clinically meaningful improvements in functional cure rates across all ranked endpoints., especially in patients with lower baseline levels of hepatitis B surface antigen (HBsAg), the efficacy is even more significant. Meanwhile, the therapy has shown good performance in safety and tolerability, consistent with previous study results.

Bepirovirsen is a potential "first-in-class" ASO therapy with a triple mechanism of action., aiming to identify and target the genetic components (i.e., RNA) of the hepatitis B virus, potentially enabling the patient's immune system to regain control over the viral infection. Bepirovirsen can inhibit viral replication in the body, reduce HBsAg levels in the blood, and activate the immune system, thereby increasing the chances of achieving a sustained response. GSK acquired the rights to bepirovirsen from Ionis Pharmaceuticals in 2019 and has since collaborated with them to advance the drug’s development.

Survodutide (BI 456906): Phase 3 Clinical Trial Data Released

Boehringer IngelheimGSK AnnouncesPositive Topline Results Announced from Phase 3 SYNCHRONIZE-1 Clinical Trial. In the trial, the therapy survodutide achieved both co-primary endpoints using two methods: the efficacy estimand and the treatment policy estimand. When evaluated using the efficacy estimand,In a 76-week treatment of adults with obesity or overweight but without type 2 diabetes, survodutideThe group achieved an average sustained weight loss of up to 16.6%, which was statistically significantly different (p<0.0001) from the 3.2% in the placebo group.The trial also met another co-primary endpoint: using efficacy estimands, after 76 weeks of treatment with survodutide,Up to 85.1% of treated adults achieved a ≥5% weight reduction, compared to 38.8% in the placebo group (p<0.0001). Preliminary analysis indicates,survodutideThe weight loss mainly comes from the reduction of fat tissue, while the decrease in lean body mass accounts for only a small part of the total weight loss.This level of weight loss effect demonstrates survodutideAs a potential treatment option with clinical value for obese or overweight populations.

Survodutide is a dual agonist of glucagon/GLP-1 receptors, capable of simultaneously activating both glucagon receptors and GLP-1 receptors.These two receptors play an important role in regulating the body's metabolic functions. Currently, survodutide is undergoing a systematic and comprehensive Phase 3 clinical development program for evaluation, including the SYNCHRONIZE series of studies targeting overweight or obese populations, as well as the LIVERAGE series of studies for individuals with metabolically associated steatohepatitis (MASH) and liver fibrosis. SurvodutideHas the potential for treating MASH in adult patients with moderate or severe (stage 2 or 3) liver fibrosis, and has been granted Fast Track designation and Breakthrough Therapy designation by the U.S. FDA. SurvodutideLicensed by Zealand Pharma to Boehringer Ingelheim, which is exclusively responsible for its global R&D and commercialization.

Integrated Platform Empowers Oligonucleotide Drug Development

As an enabler of pharmaceutical innovation, WuXi TIDES, a platform under WuXi AppTec's chemistry business, has established a one-stop service platform for compound synthesis, process development, and production around oligonucleotide therapies such as siRNA and ASO. Covering the entire lifecycle from drug discovery, CMC development to commercial production, it accelerates the transformation of partners' innovative ideas into reality, benefiting patients worldwide. The following case study will demonstrate how WuXi TIDES’ integrated platform expedites the development process of partners’ ASO drugs.

For example, a biotechnology company collaborated with WuXi TIDES on early screening research for ASO drugs. WuXi TIDES' medicinal chemistry team provided more than 400 ASO compounds carrying backbone chemical modifications to help identify the most promising molecules. However, early research revealed that innovative backbone modifications led to new impurities in the candidate compounds. During the initial synthesis process, these impurities accounted for up to 25%, not only reducing yield and purification efficiency but also potentially introducing toxicity, posing challenges for subsequent clinical development.

In response to this challenge, the WuXi TIDES medicinal chemistry team and process development team worked closely together, tackling the problem from two directions. On one hand, the medicinal chemistry team collaborated with partners to explore the potential causes of impurity formation, designing customized amidites and molecular building blocks to circumvent key synthetic mechanisms responsible for impurity generation. They rapidly produced these new molecular building blocks, assisting the process development team in accelerating the validation of process design strategies to effectively control impurities. Additionally, the process development team systematically reduced impurity formation by optimizing process parameters. Ultimately, through continuous process optimization, the impurity level was successfully reduced from 25% to 5%, while the final yield increased from an initial 0.5 g/mol to 3.4 g/mol.

In this project, the various teams of WuXi TIDES collaborated efficiently, not only completing the optimization of lead compounds, process development, and GMP production within 12 months, but also assisting partners in making rapid data-driven decisions to select ASO candidate compounds with excellent overall potency, stability, and development potential, laying a solid foundation for subsequent clinical research. As more and more ASOs and other oligonucleotide drugs enter clinical development, this industry collaboration model will become an important driving force in accelerating the pace of research and development.

WuXi AppTec's Drug Metabolism and Pharmacokinetics (DMPK) Department has developed an integrated solution centered on high-sensitivity bioanalysis and mechanism-driven interpretation to address the key challenges of complex in vivo metabolism of oligonucleotide drugs and the difficulty in distinguishing and quantifying active metabolites. Unlike traditional small molecules, oligonucleotides are mainly degraded by endonucleases and exonucleases in vivo, easily producing active metabolites such as N-1 and N-2. These metabolites are highly similar in structure and physicochemical properties to the parent drug, significantly increasing the difficulty of separation and quantification. To tackle this challenge, WuXi AppTec DMPK has established a highly selective analytical platform based on liquid chromatography-tandem mass spectrometry (LC-MS/MS), incorporating various separation strategies such as ion-pair reversed-phase liquid chromatography (IP-RPLC), hydrophilic interaction liquid chromatography (HILIC), and ion-exchange chromatography (IEC) to achieve high-resolution separation and precise quantification of oligonucleotides and their multiple active metabolites.

At the same time, WuXi AppTec DMPK effectively addresses analytical challenges such as the high polarity, multiple charge states, and matrix interference of oligonucleotides by systematically optimizing sample pretreatment, chromatographic conditions, and mass spectrometry parameters. It also enables the simultaneous detection and spectrum analysis of parent drugs and metabolites in complex biological matrices. Building on this, WuXi AppTec DMPK further integrates metabolite identification (MetID), exposure quantification, and cross-species comparative studies to support a comprehensive characterization of the in vivo metabolic pathways and activity contributions of oligonucleotide drugs. With this integrated capability of "high-sensitivity analysis + multi-strategy separation + metabolic mechanism elucidation," WuXi AppTec DMPK can help customers enhance the accuracy and interpretability of pharmacokinetic studies for oligonucleotide drugs, accelerating the efficient translation of innovative nucleic acid therapies from early research to clinical development.

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