Long-Acting Oligonucleotide Development: Dosing, Yield and Stability Questions

• Longer-lasting activity is a defining feature of the next generation of oligonucleotide medicines, with chemical modifications, conjugation, and tissue-targeting strategies helping extend pharmacological activity from days toward months.
• Engineering longer-lasting oligonucleotides often requires more complex conjugate architectures, which in turn add complexity to synthesis, purification, analytical characterization, and scalable manufacturing.
• Long-acting design raises the development bar, requiring chemistry, DMPK, bioanalysis, analytical control, formulation, and manufacturing strategies to be aligned early.

San Diego, CA, Sept. 10, 2026 (GLOBE NEWSWIRE) -- Longer-acting oligonucleotide medicines are attractive to drug developers because they can reduce dosing burden, improve treatment convenience, and potentially support better adherence in chronic diseases. The clinical impact is visible. Vutrisiran is administered once every three months, while inclisiran uses a twice-yearly maintenance schedule after initial dosing. Investigational cardiovascular siRNAs are pushing duration further: in a Phase 2 study, a single 400-mg dose of lepodisiran produced substantial Lp(a) lowering that remained evident at 18 months.

Achieving that durability, however, requires more than simply extending circulation time. Chemical modifications, conjugation, and tissue-targeting strategies can prolong pharmacological activity by improving stability, uptake, and intracellular persistence, but they also change how the molecule behaves throughout development. Therefore, a drug that remains active for months raises new questions for developers.

WuXi AppTec, a contract research, development, and manufacturing organization (CRDMO) that works as an enabling partner to biotech and pharmaceutical innovators across 30+ countries, supports such programs through its TIDES CRDMO platform. As longer-lasting activity is engineered into these complex molecules, early choices around sequence, chemical modification, and delivery can directly influence purification, analytical methods, formulation, and manufacturing strategy downstream. For long-acting oligonucleotides, the challenge is therefore not only to make the medicine last longer, but to ensure that its duration, quality, safety, and manufacturability remain predictable as the program advances.

Question: How are long dosing intervals designed into an oligonucleotide?

Answer: Long-acting oligonucleotide development starts with the coordinated design of sequence, chemistry, delivery, and tissue exposure. Backbone and sugar modifications can improve nuclease resistance, target affinity, and intracellular persistence, while targeting ligands such as GalNAc can increase uptake into specific tissues and help sustain pharmacological activity. 

Because oligonucleotide pharmacological activity can persist in tissues after plasma concentrations have fallen, dose and dosing interval cannot be selected from plasma pharmacokinetics alone. Developers need pharmacodynamic and bioanalytical methods that connect tissue exposure with target engagement, magnitude and duration of effect, and reversibility. Those data, together with safety and dose-response information, ultimately determine how infrequently a long-acting oligonucleotide can be given.

Question: What drives conjugation yield in oligonucleotide synthesis?

Answer: Conjugation yield depends on both reaction design and the ability to separate the desired product from related species. Factors such as coupling equivalents, reaction temperature and time, solvent composition, oligonucleotide length and structure, and whether conjugation is performed on solid support or in solution can all influence conversion and the resulting impurity profile. WuXi AppTec addresses these variables through oligonucleotide API process development, optimizing the conjugation step together with downstream purification and analytical requirements so the process can remain robust as it scales.

Question: What determines oligonucleotide purification yield?

Answer: Purification yield depends largely on how effectively the desired oligonucleotide can be separated from closely related process- and sequence-related impurities. Solid-phase synthesis can generate shortmers from incomplete coupling, along with other chemically related species, and separation can become more challenging as sequence length, modification pattern, and molecular complexity increase. 

For conjugated oligonucleotides, additional species such as unconjugated oligonucleotide, incompletely conjugated products, linker- or ligand-related impurities, and other conjugation variants can further complicate the impurity profile. Reversed-phase and anion-exchange chromatography are widely used preparative approaches, with the purification strategy selected and optimized according to the physicochemical properties of the molecule and its specific impurity profile. 

"The next chapter of oligonucleotide therapeutics will not be defined by one chemistry, one delivery technology or one mechanism of action. It will be shaped by how effectively the industry connects sequence design with delivery, pharmacology, analytics, safety and manufacturing," said Yu Lu, Senior Vice President, WuXi TIDES, part of WuXi AppTec. "As these medicines become more durable, more tissue-selective and more functionally diverse, development infrastructure is no longer simply supporting innovation but helping determine which innovations can become viable medicines."

Question: What causes stability problems in oligonucleotide formulations?

Answer: Oligonucleotide stability depends on sequence, backbone chemistry, sugar modifications, and formulation conditions. Depending on the molecule, degradation can include backbone cleavage, oxidation, depurination, or modification-specific pathways such as oxidative changes at phosphorothioate linkages. Formulation variables including pH, buffer composition, excipients, temperature, and ionic conditions can influence both the rate and type of degradation. Forced-degradation studies help identify these pathways and establish stability-indicating analytical methods. By connecting drug-substance manufacturing, analytical development, and formulation, an integrated platform can also help determine whether observed impurities originate from the manufacturing process, formulation, or storage and guide the appropriate process or formulation changes.

Question: How does WuXi TIDES support the development of long-acting oligonucleotide therapies?

Answer: WuXi AppTec’s TIDES CRDMO platform can support long-acting oligonucleotide programs by connecting the design choices that drive durability with the development capabilities needed to translate them into scalable medicines. Its capabilities span modified oligonucleotide synthesis, monomers, linkers and ligands, conjugation, analytical development, formulation, process development, and drug substance and drug product manufacturing. This integration is particularly important for long-acting programs because chemical modifications and targeting conjugates that extend tissue exposure or intracellular activity can also change impurity profiles, purification requirements, analytical methods, formulation strategy, and manufacturing complexity. By considering these factors together from early development through scale-up, WuXi TIDES can help developers optimize not only how long an oligonucleotide acts, but also whether that durability can be characterized, controlled, manufactured reproducibly, and supported as the program advances toward clinical and commercial stages.

About WuXi AppTec

WuXi AppTec is a trusted partner and contributor to the pharmaceutical and life sciences industries, providing R&D and manufacturing services that help advance healthcare innovation. With operations across Asia, Europe, and North America, we offer integrated, end-to-end services through our unique CRDMO (Contract Research, Development, and Manufacturing Organization) platform. We are privileged to work alongside partners across 30+ countries, supporting their efforts to bring breakthrough treatments to patients. Guided by our vision that every drug can be made, and every disease can be treated, we are committed to advancing breakthroughs for patients—one collaboration at a time. Learn more at https://www.wuxiapptec.com.