WuXi AppTec outlines long-acting oligonucleotide manufacturing hurdles
Long-acting oligonucleotide medicines are reshaping expectations around dosing convenience, with approved products such as inclisiran already operating on a twice-yearly maintenance schedule and investigational candidates pushing durability further. A single 400-mg dose of lepodisiran, an siRNA targeting lipoprotein(a), produced Lp(a) lowering that remained measurable at 18 months in a Phase 2 study, illustrating how far the field has moved from the weekly or monthly dosing that characterised earlier RNA-based drugs. WuXi AppTec has used a new editorial-style technical release to outline the development trade-offs that accompany that ambition, speaking through its TIDES contract research, development, and manufacturing (CRDMO) platform.
The document, published on 10 September 2026, addresses the interdependence of sequence design, chemical modification, conjugation, purification, and manufacturing scale. WuXi AppTec's position is that choices made at the molecular design stage, including backbone and sugar chemistry, the use of targeting ligands such as GalNAc, and solid-phase versus solution-phase conjugation, propagate directly into downstream development complexity. Greater tissue persistence, for instance, means that plasma pharmacokinetics alone cannot reliably anchor dose-selection decisions; developers must generate pharmacodynamic and bioanalytical datasets that connect tissue exposure with target engagement over time.
Manufacturing and purification complexity
Purification yield is a central concern for conjugated oligonucleotides. Solid-phase synthesis generates shortmers from incomplete coupling reactions, and those sequence-related impurities become harder to separate as molecular length and modification density increase. Conjugated molecules introduce an additional tier of complexity: unconjugated oligonucleotide, partially conjugated species, and linker- or ligand-related impurities all add to the separation challenge. WuXi AppTec notes that reversed-phase and anion-exchange chromatography are the principal preparative tools, with strategy selection driven by the physicochemical properties of the specific molecule.
Stability is a parallel concern. Degradation pathways vary by molecule: backbone cleavage, oxidation, depurination, and modification-specific changes at phosphorothioate linkages are all possible, and formulation conditions, including pH, buffer, excipients, and ionic strength, modulate which pathways dominate. Forced-degradation studies are described as essential for establishing stability-indicating analytical methods and for distinguishing impurities that originate in manufacturing from those introduced during formulation or storage.
Yu Lu, Senior Vice President at WuXi TIDES, argued that the sector's next phase will be shaped less by individual chemistry or delivery innovations and more by how effectively the industry connects those elements with analytics, safety, and manufacturing. "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," he said.
Competitive landscape and context
The oligonucleotide CRDMO market has consolidated around a small number of large-scale providers capable of handling the complex chemistries involved. WuXi AppTec competes with organisations such as Lonza, Bachem, and Agilent's contract services arm, as well as specialist oligonucleotide manufacturers, for programmes requiring GalNAc conjugation, modified backbone synthesis, and integrated analytical support. The competitive pressure on CRDMOs to offer end-to-end platforms, rather than point services, has intensified as sponsors seek to reduce handoff risk between discovery, development, and manufacturing partners.
Broader sector demand for long-acting oligonucleotides is likely to grow. Regulatory precedent for six-monthly dosing is now established through inclisiran's approval, and several cardiovascular, neurological, and rare-disease programmes are investigating whether similar durability can be achieved in other tissue compartments. For CRDMOs, that pipeline translates into sustained demand for the complex conjugation and purification capabilities WuXi AppTec is positioning in this release.