8 Months to IND: How WuXi AppTec Leveraged Integrated Expertise to Resolve Divalent siRNA–GalNAc Conjugate Development Challenges

WuXi AppTec helped a client reach a key development milestone by applying integrated expertise to advance a dual-targeting, divalent siRNA–GalNAc conjugate from the preclinical candidate compound (PCC) to investigational new drug (IND) submission within 8 months. Rapid IND readiness was achieved not just by solving synthesis and analytical challenges, but by running process development, analytical development, and manufacturing in parallel rather than sequentially. That is the value of its platform—combining drug substance, drug product, analytical, and manufacturing to deliver an IND-ready CMC package on an accelerated timeline.

WuXi AppTec Overcomes CMC Challenges for Complex Oligonucleotide Conjugate Drug

The client developing the complex divalent dual-targeting siRNA–GalNAc conjugate approached WuXi TIDES, WuXi AppTec’s integrated CRDMO platform supporting drug discovery, development, and manufacturing for oligonucleotides, peptides, and related conjugated medicines. 

This was a more complex modality than a standard single-target siRNA. The molecule contained three strands, including a sense strand of more than 40 nucleotides (which anneal with two antisense strands), roughly twice the length of a typical siRNA strand which increased the number of solid-phase coupling steps and substantially reduced yield, and posed significant challenges for synthesis, annealing, and analytical control.

This project reflects a common industry challenge: new therapeutic modalities offer greater potential, but their increasingly complex structures require more from synthesis and delivery, which adds to the difficulties in development and manufacturing. 

The WuXi TIDES team quickly identified the factors constraining process development efficiency and product quality and resolved several CMC challenges in parallel.

During synthesis process development, the team optimized the GalNAc‑loaded solid support (the synthesis resin), screened different resin sources, and refined the synthesis conditions to overcome low crude purity and yield. As a result, crude purity improved from 40% to 75% and final yield nearly doubled.

Meanwhile, the team developed a controlled annealing strategy and optimized strand stoichiometry to address the challenges posed by the three-strand structure, improving assembly robustness and reducing unwanted intermediates.

Because the strand sequences were highly similar, impurity separation was difficult under both denaturing and non-denaturing conditions. In parallel, the analytical team established orthogonal denaturing and native analytical methods that provided the resolution needed to support IND filing.

Through parallel multi‑dimensional process development efforts, the team advanced this complex siRNA–GalNAc conjugate to the IND stage within just 8 months, a milestone that unequivocally demonstrates the platform’s robust capabilities in process development and execution for complex oligonucleotide conjugates.

Seamless Coordination Enables Complex Oligonucleotide Conjugate Development

Delivering the project within 8 months required more than resolving molecule-level technical problems; it also required combining drug substance, drug product, analytical, and manufacturing to deliver an IND-ready CMC package. WuXi AppTec's integrated, end-to-end TIDES CRDMO platform was key to this effort. 

Another key factor was seamless coordination between drug substance and drug product teams. Because active pharmaceutical ingredient (API), formulation, and analytical activities were closely aligned, the team was able to move efficiently from process optimization into good laboratory practice (GLP) and good manufacturing practice (GMP) manufacturing, and then into drug product engineering (ENG) and clinical trial material (CTM) production. Specifically, the process development and manufacturing of the GalNAc‑loaded solid support were carried out simultaneously with drug substance process development, producing a demo batch within 2 months. The drug substance team then continued process optimization and seamlessly initiated the GLP batch. Meanwhile, the drug product team advanced preformulation and formulation development concurrently using only minimal amounts of API, shortening the time for the drug product ENG batch. Thereafter, the drug product ENG batch and the drug substance GMP batch proceeded in parallel, freeing up time for the drug product CTM batch.

Method development, validation, and ongoing analytical support were carried out throughout the project lifecycle, leveraging the integrated CMC platform to support the delivery of the IND package.

The value of the integrated platform model was reflected in this collaboration. Rather than simply working in parallel, teams maintained coordination throughout the project, anticipated and addressed potential bottlenecks early, and upheld quality standards while driving efficiency. This approach increases success rates, minimizes deviations and repetitive re-validation during method transfers, and strengthens data integrity—supporting CMC consistency and regulatory acceptance. In short, cross-stage, cross-team, and cross-site frictions and risks are substantially reduced, enabling faster, more reliable project progression. 

This is not an isolated example. The number of molecules in the WuXi TIDES pipeline using both API and drug product services has grown steadily and even has more than doubled between 2023 and 2025. That trend reflects growing demand for integrated development support, especially for more complex modalities.

Complex oligonucleotide conjugate technologies and precision delivery approaches continue to expand the possibilities of precision medicine. WuXi AppTec supports partners in advancing novel therapies through efficient, flexible, and high-quality solutions for oligonucleotide conjugates, ultimately making new treatments available to patients.

Key Takeaways:

1. WuXi TIDES, WuXi AppTec’s integrated CRDMO platform supporting drug discovery, development, and manufacturing for oligonucleotides, peptides, and related synthetic conjugates, advanced a complex dual‑targeting, divalent siRNA–GalNAc conjugate from PCC to IND in eight months through its integrated platform.
2. WuXi TIDES addressed CMC challenges across synthesis, annealing, and analytical control in parallel, enabling timely IND readiness for a complex dual‑targeting, divalent siRNA–GalNAc conjugate.
3. WuXi TIDES’s integrated platform enabled parallel execution across drug substance, drug product, analytical, and manufacturing functions, with cross‑functional coordination that shortened the overall timeline.
4. WuXi TIDES supports partners in advancing novel therapies through efficient, flexible, and high quality solutions for oligonucleotide conjugates, ultimately making new treatments available to patients.

Reference:

[1] Jadhav V, Vaishnaw A, Fitzgerald K, et al. RNA interference in the era of nucleic acid therapeutics[J]. Nat Biotechnol, 2024(42):394–405. DOI:https://doi.org/10.1038/s41587-023-02105-y