Small nucleic acid drugs transitioning from the laboratory to clinical use still require overcoming numerous challenges for industrialization.

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

“Science and Technology Innovation Board Daily” March 17 (Reporter: Shi Shiyun) “By 2025, Eli Lilly’s Teriparatide (sales performance of $36.5 billion) will become the world’s ‘King of Drugs.’ Everyone knows this. When the wind and water turn, it could also blow toward our small nucleic acid drugs.” A pharmaceutical industry insider recently joked to the Science and Technology Innovation Board Daily reporter.

Currently, the best-selling small nucleic acid drugs worldwide have only entered the “$2 billion club,” and there is still a long way to go to reach the hundred-billion-dollar scale.

Looking back at the development history of small nucleic acid drugs, the journey has not been smooth. Since the concept of antisense nucleic acids was first proposed by researchers in the 1970s, it took 20 years for the world’s first ASO drug to be approved for market. It seemed poised to benefit from the Nobel Prize (two scientists won for revealing the mechanism of RNA interference in nematodes), but around 2010, due to delivery and stability issues, the development plateaued. It wasn’t until 2014, with the breakthrough in GalNAc (N-acetylgalactosamine) delivery technology, that the commercial development was reignited.

“After so many years of industry accumulation, today, what is the maximum batch production scale of small nucleic acid drugs? After multi-step purification processes, what level of product purity can be stably maintained at over 90%? Considering 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) Yi Mao Biotechnology Industry Conference, the venue was full, but few responded.

Zhang Peizhuo is well aware that it is not that everyone is unwilling to answer, but that the development and industrialization of small nucleic acid drugs currently face many complex challenges that cannot be summarized in a single statement.

▌ Where is the way out?

Data shows that small nucleic acid drugs, or oligonucleotide drugs, are short-chain nucleic acids composed of a dozen to dozens of nucleotides linked together. Their mechanism involves: specific nucleotide sequences acting on mRNA to silence genes and inhibit target protein expression, thereby treating diseases.

Narrowly defined, small nucleic acid drugs refer to RNA interference drugs (siRNA). Broadly, they also include antisense oligonucleotides (ASO), microRNAs (miRNA), small activating RNAs (saRNA), mRNA, RNA aptamers, etc. Currently, the main types are siRNA and ASO.

Compared to small molecule and antibody drugs, small nucleic acid drugs feature high specificity and efficiency, short development cycles, strong drugability, low resistance, and long-lasting effects. With these advantages, they are expected to become the third major drug class after small molecules and antibodies.

So far, small nucleic acid drugs have shown preliminary ability to replace existing therapies and fill unmet indications. Globally, over 20 such drugs have been approved, mainly dominated by giants like Alnylam, Ionis, and Sarepta. Approved indications mainly include rare genetic diseases, as well as ophthalmic and cardiovascular diseases. To date, no domestically produced small nucleic acid drugs have been approved for market.

“In China, everyone is working hard, including Rebo Bio (06938.HK), Bo Wang Pharmaceuticals, Yuekang Pharma, Shengnuo Medicine (02257.HK), Tengsheng Boyao (02137.HK), and others. They are all very ‘bold,’ directly entering major disease tracks like cardiovascular and hepatitis B, whereas the existing approved giants initially started with rare diseases,” said an industry insider during recent on-site research for Science and Technology Innovation Board Daily.

“But aiming to surpass others quickly is not achieved overnight. For example, in the industrialization of small nucleic acid drugs, impurity control during process scale-up is a major challenge. Specifically, impurities increase with each synthesis step, and they are structurally very similar to the target product, making separation difficult with conventional methods. This not only affects product purity but also poses potential safety risks,” the insider added.

Compared to small molecule drugs, small nucleic acid drugs have more complex structures, numerous impurity types, and limited purification and analytical methods. Their synthesis process is also specialized. Currently, most use solid-phase phosphoramidite synthesis, which involves complex steps, many cycles, and requires precise control of temperature, pH, and reagent ratios at each step.

Dong Huifang, head of the Large Molecule New Drug R&D and Production Center at Boteng Co., believes that during the transition from laboratory research to industrialization, the biggest challenge lies in process scale-up, mainly in establishing a comprehensive quality control system, developing and validating analytical methods, and managing new impurities.

Dong also stated that small nucleic acid drugs need chemical modifications to enhance resistance to nucleases, but multiple modifications significantly increase process complexity and difficulty, and generate more related impurities, bringing tougher challenges in early-stage development and quality research.

In February this year, the National Medical Products Administration (NMPA) issued the Guidelines for Pharmaceutical Research of Chemically Synthesized Oligonucleotide Drugs (Innovative Drugs) (Trial), which clearly states that impurities related to oligonucleotides can be reported up to 0.2%, much higher than the typical limits for small molecules.

Wan Jinqiao, chairman of Xian Derivatives, pointed out that this guideline provides clearer technical guidance and requirements for small nucleic acid drug development, effectively bridging the “last mile” from laboratory to clinical trials, and companies should study it carefully.

“On the basis of meeting quality compliance and registration requirements, companies also need to focus on R&D efficiency and cost control, especially in process optimization, which directly impacts clinical development timelines and final drug costs. Proper early planning is essential. Complete process optimization often takes one to three years or more. Delaying until later stages makes it much more difficult,” Wan said.

Additionally, Huang Yi, General Manager of Guowei Medical Innovation Division, pointed out that besides tailoring CMC (Chemistry, Manufacturing, and Controls) strategies according to different indications, the route of administration also directly influences CMC design. For example, inhalation requires careful consideration of excipients’ airway irritation and compatibility, while subcutaneous and intravenous injections must consider drug stability and bioavailability. Moreover, for specific populations like high-risk patients, who are more sensitive to side effects, companies need to strengthen targeted quality control in CMC work.

Zhou Sheng, Vice General Manager of Lisu Technology, expressed a more “exciting” vision for the future industrialization of small nucleic acid drugs. He believes that the key breakthrough in industrialization lies in building standardized, automated production platforms, where the entire process is supported by standardized industrial software, aiming for “one-click production” rather than relying on single vendors or specific equipment, thereby reducing risks and making industrialization a systematic project.

*(Reported by Shi Shiyun, Science and Technology Innovation Board Daily)