Two siRNA IND Packages Delivered in 14 Months
The FDA approval of the first siRNA drug in 2018 marked a key milestone for RNAi therapeutics, confirming the potential of gene-silencing oligonucleotides (1). Small interfering RNAs (siRNAs) selectively silence disease-related genes, enabling targeted treatments for genetic and metabolic diseases.
Among current delivery strategies, conjugation with N-acetylgalactosamine (GalNAc) has shown strong clinical potential for targeted delivery to hepatocytes via subcutaneous administration. However, the synthesis of GalNAc-siRNA conjugates involves complex chemistries and stringent quality requirements, making process development and manufacturing particularly challenging.
WuXi TIDES recently supported a US-based biotech company in advancing two GalNAc-siRNA candidates to IND submission within 14 months through integrated Chemistry, Manufacturing, and Controls (CMC) services and internal supply of GalNAc.
Mastering Complexity
A client approached WuXi TIDES with a complex siRNA therapeutic candidate. The initial synthesis route yielded a crude purity of only 18% and a final yield of 13%, with additional challenges including a complex GalNAc moiety and unstable intermediates. The client’s objective was to accelerate the development of this challenging molecule to IND filing as soon as possible.
Through process optimization with innovative conjugation chemistry, the crude purity was significantly improved to 75% (vs. originally 18%) and final yield increased to 62% (vs. originally 13%), while getting the project ready for IND filing in 11 months without sacrificing quality.
Precise Solutions
An integrated CMC development strategy effectively managed the complexities of GalNAc supply, oligonucleotide synthesis, formulation development and manufacturing, as well as analytical support for both drug substance and drug product.
This collaborative effort, coupled with a tailored and optimized process workflow, resulted in the delivery of two siRNA-GalNAc conjugate drug candidates ready for IND submission within 14 months.
Integrate, Innovate
GalNAc Process Development and Manufacturing
The specialized GalNAc team improved the synthesis route for the GalNAc fragment and established an internal kilogram-scale supply in under 4 months. High-quality GalNAc (>98% purity and <0.5% critical impurity) was achieved by employing recrystallization and flow chemistry, which minimized impurities and maximized the purity and yield. Securing a high-quality internal GalNAc supply ensured a reliable and consistent source, enabling efficient downstream conjugation.
GalNAc-siRNA Conjugate Process Development and Manufacturing
The team developed specific on-resin click reaction conditions to simplify downstream processing. This method allowed conjugates to be cleaved from the solid support in a single step, resulting in higher purity products with enhanced crude stability.
By streamlining synthesis and purification, the development timeline for the siRNA-GalNAc conjugate drug candidate was significantly accelerated. The optimized process improved conjugation efficiency and yield, producing products with the purity and stability required for clinical trials. The on-resin click chemistry strategy also allowed effective impurity control, reducing purification steps from three rounds to one and achieving an endotoxin level below 0.1 EU/mg.
Formulation Development and Manufacturing
Drug Product (DP) team started formulation development at month 4 using 25 g of API from a DS demo batch, followed by DP formulation and process development activities with 500 g GLP API delivered at month 6 to support toxicity studies.
Clinical trial material (CTM) batch manufacturing started immediately after the release of 500 g of GMP API at month 13, allowing DP GMP batch release for clinical use and IND filing at month 14. This synchronized effort across multiple teams rapidly advanced the siRNA-GalNAc conjugate project, ultimately accelerating the IND submission process.
Leveraging our advanced sterile fill-finish line and carefully designed process, we achieved a batch yield of >99%, significantly minimizing the overall loss of costly API. Additionally, the optimal study design during development streamlined the scale-up process, resulting in fewer trials and more efficient production runs.
Analytical Development
Our integrated platform and quality system enabled seamless analytical method transfer from API to Drug Product, with shared analytical methods between the Drug Substance and Drug Product teams. Our multidisciplinary approach, combining expertise in GalNAc chemistry, oligonucleotide synthesis, formulation development, and analytical validation, allowed us to overcome the development and manufacturing challenges of this complex modality to deliver clinical trial materials for first-in-human (FIH) dosing with an accelerated timeline.
References and notes
1. U.S. Food and Drug Administration. (2018, August 10). FDA approves first-of-its-kind targeted RNA-based therapy to treat a rare disease. https://www.fda.gov/news-events/press-announcements/fda-approves-first-its-kind-targeted-rna-based-therapy-treat-rare-disease
Your Complex Challenges, Our Precise Solutions
At WuXi TIDES, complexity doesn’t slow us down, it drives us forward.
We understand the unique needs of your oligonucleotide and peptide programs.
We’ve built a comprehensive, integrated enabling platform that delivers specialized expertise
and reliable execution at every stage from discovery through commercialization.
Purpose-Built for Complex Molecules
Expertise in developing and manufacturing all synthetic oligonucleotides, peptides, and their complex conjugates, including peptide phosphorodiamidate morpholino oligomers (PPMO), GalNAc conjugated oligonucleotides, and radionuclide drug conjugates.
Vertical Supply Chain
In-house production of key starting materials and intermediates, including unnatural amino acids, amidites, and other building blocks, ensures consistent quality, accelerated timelines, and reduced supply risk.
Integrated CMC Services
End-to-end support across API, drug product, analytical development, and CMC dossier preparation powered by comprehensive technologies and world-class manufacturing facilities to accelerate development and ensure quality from preclinical to commercial.
About WuXi TIDES
WuXi TIDES, part of WuXi AppTec, is a unique Contract Research, Development and Manufacturing platform. WuXi TIDES offers our partners efficient, flexible, and high-quality solutions from discovery through the commercial supply of oligonucleotides, peptides and related synthetic conjugates (“TIDES” drugs).
Website
www.tides.wuxiapptec.com/
