Small nucleic acid drugs moving from the laboratory to clinical application still need to "climb over hurdles" to achieve industrialization.

Ask AI · What are the key challenges in impurity control for the industrialization of small nucleic acid drugs?

“Science and Innovation Board Daily” March 17 News (Reporter Shi Shiyun) “In 2025, the news that Eli Lilly’s tirzepatide (sales performance of 36.5 billion USD) has become the world’s ‘king of drugs’ is well known. When the wheel of fortune turns, it can also turn to our small nucleic acid drugs,” a pharmaceutical industry insider recently joked to reporters from the “Science and Innovation Board Daily.”

Currently, the best-selling small nucleic acid drugs worldwide have only managed to enter the ‘2 billion USD club,’ and to reach a scale of over 10 billion USD, there is still a long road ahead.

Looking back at the development history of small nucleic acid drugs, their journey has never been smooth from the start. Since researchers first proposed the concept of antisense nucleic acids in the 1970s, it took 20 years for the world’s first antisense oligonucleotide (ASO) drug to be approved for market. It seemed poised to benefit from the Nobel Prize (two scientists awarded for first revealing the mechanism of RNA interference in nematodes), but around 2010, due to delivery and stability challenges, the development stalled. It was not until the 2014 breakthrough in GalNAc (N-acetylgalactosamine) delivery technology that the path to commercialization was reignited.

“After so many years of industry accumulation, and with the current development, what is the maximum batch production capacity of small nucleic acid drugs? After multi-step purification, what level of purity can be stably maintained at over 90%? Based on current industry trends, what price range is expected for small nucleic acid drugs in the next 3-5 years?” When Zhang Peizhuo, Chairman and Chief Scientist of Jima Gene, posed these questions at the recent BIOCHINA2026 (11th) Yimai Bio Industry Conference, the venue was packed, but responses were few.

Zhang Peizhuo understands well that it’s not that everyone is unwilling to answer, but that the development and industrialization of small nucleic acid drugs today face numerous complex challenges that cannot be summarized in a single sentence.

▌Where is the way to break the deadlock?

Data shows that small nucleic acid drugs, also known as oligonucleotide drugs, are short-chain nucleic acids composed of a chain of a dozen to several dozen nucleotides. Their mechanism involves: a specific nucleotide sequence acting on mRNA to silence gene expression, thereby achieving therapeutic effects.

In a narrow sense, small nucleic acid drugs refer to RNA interference drugs (siRNA). Broadly, they also include antisense oligonucleotides (ASO), microRNA (miRNA), small activating RNA (saRNA), mRNA, RNA aptamers, and others. Currently, the main types are siRNA and ASO.

Compared to small-molecule and antibody drugs, small nucleic acid drugs feature high specificity and efficacy, shorter R&D cycles, strong druggability, low resistance development, and long-lasting effects. These advantages position small nucleic acid drugs as the potential third major drug class after small molecules and antibodies.

So far, small nucleic acid drugs have shown preliminary ability to replace existing therapies and address unmet medical needs. Globally, over 20 such drugs have been approved, mainly led by giants like Alnylam, Ionis, and Sarepta. Approved indications primarily target genetic rare diseases, but also include ophthalmic and cardiovascular conditions. However, to date, no domestically developed small nucleic acid drug has received approval for market.

“Within China, many are working with determination—including RuiBo Bio (06938.HK), Bo Wang Pharmaceutical, Yuekang Pharmaceutical, SanonMed (02257.HK), and TenGen BioPharma (02137.HK)—and they are very ‘bold,’** directly entering major disease tracks such as cardiovascular diseases and hepatitis B, whereas the existing approved giants initially started with rare diseases,” said an industry insider during recent field research for the “Science and Innovation Board Daily.”

“However, achieving a ‘leapfrog’ advantage is not overnight. For example, in the industrialization of small nucleic acid drugs, impurity control during process scale-up is a major challenge. Specifically, as synthesis steps increase, impurities accumulate, and because these impurities are structurally very similar to the target product, they are difficult to separate using conventional methods. This not only impacts product purity but may also pose potential safety risks,” the insider further explained.

Compared to small-molecule drugs, small nucleic acid drugs have more complex structures, a wider variety of impurities, and limited purification and analytical detection methods. Their synthesis typically uses solid-phase phosphoramidite chemistry, which involves complex steps, many cycles, and requires precise control of temperature, pH, and reagent ratios at each stage.

Dong Huifang, Head of R&D and Manufacturing at Boteng Co., Ltd., believes that the most significant challenge in moving small nucleic acid drugs from laboratory research to industrial production lies in the process scale-up stage, mainly in establishing a comprehensive quality control system, developing and validating analytical methods, and managing new impurities.

Dong also pointed out that chemical modifications are necessary to enhance resistance to nuclease degradation, but introducing multiple modifications significantly increases synthesis complexity and difficulty, and generates more related impurities, bringing greater challenges to process development and quality control in early R&D.

In February, the NMPA Center for Drug Evaluation issued the “Guiding Principles for Pharmaceutical Research on Chemically Synthesized Oligonucleotide Drugs (Innovative Drugs) (Trial),” which clearly states that the acceptable impurity reporting limit for oligonucleotides is 0.2%, much higher than the typical limits for small-molecule drugs.

Wan Jinqiao, Chairman of InnoDerivatives, noted that this guideline provides, for the first time, clear technical guidance and requirements for small nucleic acid drug R&D, helping to bridge the “last mile” from laboratory to clinical application, and companies should study it carefully.

“Beyond meeting quality and registration standards, companies also need to focus on R&D efficiency and cost control—especially process optimization—because these factors directly influence clinical development timelines and final drug costs. Planning ahead is essential. A full process optimization often takes one to three years or longer; delaying until later stages will significantly increase difficulty,” Wan emphasized.

Additionally, Huang Yi, General Manager of GuoWei Pharma’s Innovation Business Unit, reminded that small nucleic acid drugs require tailored CMC (Chemistry, Manufacturing, and Controls) strategies based on different indications, and the route of administration will also impact CMC design. For example, inhalation delivery must consider excipient irritability and compatibility, while subcutaneous and intravenous injections must balance drug stability and bioavailability. Moreover, specific populations such as patients with high blood sugar, lipids, or hypertension are more sensitive to side effects, requiring targeted quality controls in CMC work.

Zhou Sheng, Deputy General Manager of Lifor Technology, envisioned a more “exciting” future for industrialization, believing that the key breakthrough lies in building a standardized industrial platform. Entire production processes should rely on standardized industrial software to achieve “one-click production,” rather than dependence on a single vendor or specific equipment, thereby reducing risks and turning industrialization into a systematic project.

(Science and Innovation Board Daily reporter Shi Shiyun)