Sirnaomics Files for Hong Kong IPO, Poised to Become China's First RNA Therapeutics Listing

On November 17, the internationally renowned biotechnology newsletter *Genetic Engineering & Biotechnology News* (GEN) released its ranking of the top ten RNA biopharmaceutical companies worldwide, with Sirnaomics prominently featured among the top three in the privately held category.

This July, Sirnaomics filed its prospectus with the Hong Kong Stock Exchange. Amidst the recent surge in nucleic acid therapeutics and frequent news of large multinational pharmaceutical companies acquiring nucleic acid drug firms internationally, China is poised to see its first publicly listed company specializing in nucleic acid drugs and technologies. Prior to its IPO, Sirnaomics had already completed five rounds of financing in the primary market, attracting investors such as Xuan Shi Capital, China Resources Zhengda Life Science Fund, Walvax Biotechnology, Xiantong Capital, Sunshine Ronghui Capital, and Yuexiu Industrial Fund, with total capital raised exceeding USD 270 million. Just before submitting its prospectus, Sirnaomics completed its Series E financing round, achieving a post-money valuation of USD 657 million, equivalent to approximately RMB 4.2 billion.

From the Sirnaomics founders’ 25-plus years of steadfast dedication to nucleic acid drug delivery, and the company’s more than a decade of solid efforts in the global innovation of RNA interference therapeutics, to its emergence as a star enterprise in the capital markets, this journey reflects the long-term perseverance of a team of scientists and entrepreneurs, and serves as a microcosm of the history of global innovative drugs growing from the laboratory to clinical application.

In November 2017, the U.S. FDA designated patisiran, an RNAi therapy developed by Alnylam Pharmaceuticals, as a Breakthrough Therapy. More than nine months later, patisiran received FDA approval and was launched as a targeted treatment for hATTR amyloidosis with polyneuropathy, marking the advent of the first-ever RNAi drug in human history. This represents a groundbreaking milestone both for Alnylam, a leading nucleic acid therapeutics company, and for the numerous global teams still committed to innovating new nucleic acid-based drugs. It demonstrates that the drug delivery challenge, which had long constrained the development of small nucleic acid therapies and deterred multinational pharmaceutical companies, now has a viable solution: enabling the safe and effective delivery of next-generation nucleic acid drugs, which require lower doses and offer longer durations of action, into patient cells. Starting in 2018, multinational pharmaceutical giants such as Roche, Novartis, Eli Lilly, Amgen, and Regeneron have heavily reinvested in the burgeoning field of nucleic acid therapeutics.

To date, four siRNA drugs and eight ASO drugs have been approved for marketing worldwide. Among them, Spinraza, an ASO drug developed by Ionis, achieved sales of $2.097 billion in 2019, becoming the first “blockbuster” in the field of nucleic acid therapeutics. The true breakthrough of nucleic acid drugs into the mainstream occurred after the outbreak of the COVID-19 pandemic. Moderna and BioNTech developed mRNA-based COVID-19 vaccines within just a few months, generating billions of dollars in global revenue within only one quarter after launch. Moderna’s stock price surged, with its market capitalization briefly surpassing that of Merck & Co., a century-old pharmaceutical giant. Nucleic acid therapeutics, jokingly referred to as “a technology capable of saving the universe,” have once again taken center stage.

Meanwhile, the development and exploration of nucleic acid therapeutics in China are also gaining momentum. Although it started a few years later than star companies such as Alnylam and Ionis, China’s nucleic acid therapeutics sector has gathered many professional teams with years of deep expertise, including Sirnaomics, Ribo Life Science, Ribobio, Genepharma, and Staidson. As pharmaceutical supply chain companies such as WuXi AppTec, Asymchem, and Porton Bio increasingly invest in nucleic acid therapeutic manufacturing capacity, the industrial ecosystem for nucleic acid therapeutics in China is continuously maturing. Industry practitioners told VCBeat that even from a global perspective, China’s supply-side advantages in the field of nucleic acid therapeutics are quite evident: “Some nucleic acid therapeutic companies developing products in the United States have already begun to frequently collaborate with Chinese active pharmaceutical ingredient (API) manufacturers.”

Dr. Lu Yang, founder of Sirnaomics, has long been dedicated to the research and development of nucleic acid therapeutics. He pioneered the use of peptide nanoparticles (PNP) as a delivery platform for nucleic acid drugs, expanding the indications of RNAi therapeutics from hepatocyte-related diseases to oncology, and advancing clinical trials globally. Meanwhile, by recruiting international industry experts and promoting source innovation, he has leveraged optimized GalNAc drug delivery technology to further diversify Sirnaomics’ technological platform.

As early as 2000, Dr. Lu Yang co-founded a biotechnology company named Intradigm with colleagues also from Novartis, based on PNP delivery technology. Six years later, Intradigm was acquired by an investment consortium led by Genentech, and Dr. Lu gradually shifted his focus to China. As one of the few technologists who truly saw the dawn of success, Dr. Lu firmly believes that nucleic acid therapeutics, acting through mechanisms more upstream than those of antibody drugs, can play a greater role in the treatment of complex diseases and even change the rules of the game for traditional therapies.

Nucleic acid therapeutics, commonly referred to as such, primarily include antisense oligonucleotides (ASOs), small interfering RNA (siRNA) therapeutics, aptamer drugs, and messenger RNA (mRNA) therapeutics. These agents work by disrupting the mechanisms of the central dogma from DNA to protein, thereby blocking the formation of specific proteins to achieve therapeutic effects. Before Moderna rose to prominence with its COVID-19 mRNA vaccine, ASOs and siRNAs were the relatively mainstream types of nucleic acid therapeutics. Among these, siRNA is a common molecule involved in the RNA interference (RNAi) mechanism; bolstered by Nobel Prize recognition, RNAi has attracted significant attention from the industry. Consequently, many of the multinational pharmaceutical companies mentioned earlier that have made substantial investments in nucleic acid therapeutics have predominantly chosen siRNA as their focus.

In a sense, nucleic acid therapeutics may represent the most ideal class of drugs for humanity, offering the combined advantages of long-acting efficacy, low cost, and broad indications.

Specifically, nucleic acid drugs directly target mRNA and inhibit the production of disease-related proteins, thereby modulating the expression of various extracellular and intracellular proteins. This approach has the potential to expand the range of druggable targets. Such a mechanism of action leverages natural biological processes to achieve gene silencing. With technological advancements, the risks of cytotoxicity and immunogenicity have been significantly reduced.

Leqvio, Acquired by Novartis for a Hefty $9.7 Billion^®(Taking inclisiran, a PCSK9-targeting RNA interference therapeutic for cholesterol lowering, as an example), patients require only two injections per year to achieve efficacy comparable to that of monoclonal antibodies targeting the same mechanism with monthly dosing. Moreover, this long-acting characteristic is evident across RNA interference therapeutics targeting different pathways and indicated for various conditions.

Data show that zilebesiran, for which Alnylam is initiating Phase II clinical trials, enables subcutaneous administration once every six months for patients with hypertension. Meanwhile, Sirnaomics’ STP122G demonstrated target inhibition lasting more than 140 days in recently completed non-human primate studies. Furthermore, compared with conventional drugs, nucleic acid therapeutics require lower doses per administration and involve less hardware investment in manufacturing processes, thereby resulting in lower production costs.

Of course, nucleic acid therapeutics are still far from ideal at present. For instance, Biogen’s antisense oligonucleotide (ASO) drug nusinersen sodium injection, used to treat spinal muscular atrophy, once drew public attention due to its high price. However, as global demand for nucleic acid therapeutics continues to grow, it will stimulate sustained efforts on the supply side, ultimately reducing prices through a mature industrial ecosystem. According to an industry insider speaking to VCBeat, once nucleic acid therapeutics achieve large-scale production, treatment costs could drop to one-third of those for antibody drugs, with virtually no technical barriers remaining—only the accumulation of demand is needed. In this sense, the real challenge facing nucleic acid therapeutics is the expansion of indications. Addressing this challenge involves complex technical logic, which has been the focus of Dr. Lu Yang’s dedicated exploration over the past two decades.

To elaborate slightly, small interfering RNA (siRNA) is a synthetically produced double-stranded RNA molecule consisting of 19–25 nucleotides. By designing their sequences, researchers can create siRNAs that suppress specific pathogenic proteins by achieving complementarity with short regions of messenger RNA (mRNA) transcribed from genes encoding the target proteins. In other words, nucleic acid therapeutics operate upstream of antibody drugs or small-molecule drugs in terms of mechanism of action, functioning within cells. This implies that the effective delivery of engineered RNA molecules to their targets constitutes the most significant bottleneck in the development of nucleic acid therapeutics. Indeed, this has been the case; prior to Alnylam Pharmaceuticals mastering the technical nuances of GalNAc conjugation for RNA delivery, there was considerable debate over whether nucleic acid therapeutics could ultimately succeed in clinical applications.

In many scenarios, GalNAc defines the boundaries of nucleic acid therapeutics. However, Sirnaomics has chosen a different path, achieving what GalNAc cannot. Before founding Sirnaomics, Dr. Yang Lu worked at Novartis for over seven years, primarily participating in the early-stage development of gene therapy drugs for this multinational giant. He gained deep expertise in the mechanisms, advantages, and limitations of various delivery systems, including the peptide nanoparticle (PNP) technology that later became Sirnaomics’ key foundational platform. Composed of natural amino acids, PNP degrades into non-toxic byproducts while overcoming challenges related to drug targeting and stability. It demonstrates superior targeting capability and efficiency in cell types beyond hepatocytes compared to both GalNAc and earlier lipid nanoparticles (LNPs). Furthermore, because PNP can simultaneously carry multiple siRNAs with different targets, it enables synergistic gene silencing effects within the same target cells, thereby enhancing the therapeutic efficacy of RNA interference (RNAi) drugs.

Here is an interlude. When Dr. Lu Yang first founded Intradigm based on PNP technology, he had engaged with Alnylam’s angel investors. Although the collaboration did not ultimately materialize, this episode somewhat strengthened his resolve to persevere. Upon observing Alnylam’s continuous development of a series of nucleic acid therapeutics leveraging GalNAc technology, Dr. Lu became even more convinced that his initial choice was correct. After all, the development of nucleic acid drugs is a process of continuous trial and error and accumulation; starting earlier means being closer to the destination.

To date, nucleic acid drug delivery platforms have undergone at least two major iterations, along with countless minor innovations in between.

Initially, nucleic acid delivery relied primarily on viral vectors and non-viral polymeric materials such as dextran. The limitations of these carriers, including low efficiency and immunogenicity, significantly hindered the development of nucleic acid therapeutics. In the late 1980s, researchers discovered that lipid nanoparticles (LNPs) formed by positively charged lipid molecules could transfect DNA with high efficiency, achieving rates 5 to 100 times higher than those of dextran. This marked the inception of LNP carriers. However, the safety risks associated with cationic LNPs in vivo soon became apparent, leading to the concept of “ionizable” LNPs, which resolved the clinical application barriers for Patisiran, the first approved siRNA drug. Nevertheless, severe allergic reactions confined the use of nucleic acid therapeutics during this period to serious conditions such as rare diseases and cancer.

Subsequently, N-acetylgalactosamine (GalNAc) hepatocyte-targeting technology emerged. This targeting strategy essentially leverages triantennary N-acetylgalactosamine ligands to specifically bind to the asialoglycoprotein receptor (ASGPR) on the surface of hepatocytes, which rapidly recognizes galactose residues, thereby enabling targeted drug delivery to liver cells. This technology can deliver a wide variety of therapeutics into the liver, including small molecules, peptides, proteins, and nucleic acids.

Through a series of incremental innovations, N-acetylgalactosamine (GalNAc) delivery technology has demonstrated significant advantages as a liver-targeted carrier for RNA interference (RNAi) therapeutics, bringing many aspirations for nucleic acid drugs closer to reality. These advantages include low dosing requirements (2–5 mg/kg), subcutaneous administration, durable effects lasting more than six months after a single dose, and simple formulation with high stability. Currently, three approved RNAi therapeutics on the market and over 30 candidate RNAi drugs in clinical trials utilize this delivery technology.

However, GalNAc is not without its limitations. For instance, it is only applicable to diseases associated with hepatocytes, and its large-scale manufacturing process is complex. Therefore, Sirnaomics’ unique drug delivery technology bypasses both GalNAc and lipid nanoparticles (LNPs), employing histidine-lysine copolymer peptide nanoparticles for cellular entry. Specifically, the PNP delivery platform is based on a proprietary peptide that self-assembles into nanoparticles to encapsulate siRNA, thereby protecting the siRNA in the bloodstream and facilitating cellular uptake and delivery to target cells, with low immunotoxicity and high efficiency.

Because the PNP delivery platform requires fewer components and steps and is water-soluble, enabling efficient lyophilization, its manufacturing process is simpler and more controllable than that of LNP technology. Unlike the GalNAc platform, which delivers RNAi triggers exclusively to hepatocytes in the liver, the PNP delivery platform can be used for local delivery to the skin or tumors, as well as for systemic delivery via other parenteral routes, thereby targeting various cell types and tissue types in organs beyond the liver, including tumor cells, lung cells, and non-hepatic cells.

Furthermore, as Sirnaomics has deepened its understanding of the PNP delivery platform, it has implemented a series of improvements. For instance, multiple RNAi therapeutics are loaded into a single PNP to simultaneously target multiple genes, thereby achieving synergistic effects and enhancing therapeutic efficacy. Currently, Sirnaomics is leveraging microfluidics technology to independently develop manufacturing processes for its PNP delivery platform and establish GMP-compliant commercial-scale production capabilities.

For Sirnaomics, various visions for nucleic acid-based therapeutics are becoming a reality.

In mid-July 2021, Sirnaomics filed its prospectus with the Hong Kong Stock Exchange, aiming to become the first publicly listed company in China specializing in small nucleic acid therapeutics. The prospectus revealed that Sirnaomics, founded in 2007, has developed a pipeline of more than ten drug candidates covering therapeutic areas such as oncology, fibrosis, and antiviral diseases. Among these, STP705 and STP707, both designed for cancer treatment, are Sirnaomics’ flagship products and have entered clinical trials.

STP705’s indication for cutaneous squamous cell carcinoma has advanced to Phase IIb clinical trials in the United States, making STP705 an investigational drug in the global oncology RNAi therapeutics field that has achieved positive Phase IIa clinical results. It has also been designated as an “Orphan Drug” by the U.S. FDA for the treatment of hepatocellular carcinoma, primary sclerosing cholangitis, and cholangiocarcinoma. Meanwhile, Sirnaomics is exploring STP707 for the treatment of liver cancer, multiple solid tumors, hepatic fibrosis, lung cancer, and pulmonary fibrosis, and has already obtained FDA approval for clinical trials targeting multiple solid tumor indications.

Like many unprofitable biotechnology companies, Sirnaomics remains in a loss-making position as it currently has no commercialized products. The prospectus shows that in 2019, 2020, and the first five months of 2021, Sirnaomics reported net losses of $17.127 million, $46.428 million, and $23.339 million, respectively, with corresponding R&D expenses of $10.213 million, $14.894 million, and $9.766 million.

Over the past two decades of development, Dr. Lu Yang and Sirnaomics have faced near-fatal setbacks and seemingly insurmountable challenges. Yet today, as foundational technologies for nucleic acid therapeutics, clinical applications, and market awareness advance in tandem, they are reaping the rewards of their perseverance. Statistics show that the number of ongoing RNAi clinical trials worldwide increased from 14 in 2013 to 50 in 2020, representing a 257% growth. The RNAi clinical trial pipeline spans various stages of development and therapeutic indications. Although oncology-related trials remain in relatively early stages of development, the trend of nucleic acid therapeutics expanding beyond liver-related diseases into broader application scenarios has become increasingly evident.

Against this backdrop, Sirnaomics is refining its technology platform. For instance, it has developed nucleic acid therapeutics based on the GalNAc delivery system, establishing the GalAhead and PdoV-GalNAc platforms. By conjugating GalNAc moieties with unique RNA structures, the company aims to deliver nucleic acid drugs with relatively lower synthesis and manufacturing costs. Sirnaomics’ investigational drug, STP122G, is formulated using the GalAhead™ platform and features an RNA interference trigger sequence targeting Factor XI. This novel RNAi therapeutic is intended for various clinical applications in anticoagulation therapy, with plans to submit an Investigational New Drug (IND) application to the U.S. FDA in the first half of 2022.

Furthermore, Sirnaomics has initiated research on PLNP and PNP formulations for mRNA, with its subsidiary RNAimmune undertaking the development of mRNA therapeutics and vaccine applications. Among these, RIM730, an investigational vaccine candidate developed by RNAimmune, is a preventive mRNA vaccine designed to provide protection against the SARS-CoV-2 Delta variant as well as broader variants.

On the other hand, Sirnaomics is also adopting a diversified strategy to cover a broad range of therapeutic indications beyond its key products, including the treatment of influenza, hepatitis B, HPV and coronavirus infections, cardiometabolic diseases, pancreatic cancer, colorectal cancer, and other cancers. Public information indicates that Sirnaomics is seeking out-licensing partnerships with multinational corporations and Chinese pharmaceutical companies. For instance, in early 2021, Sirnaomics entered into a licensing agreement with Walvax Biotechnology for the exclusive rights in China to the siRNA candidate STP702 (which includes an siRNA targeting conserved gene sequences of the influenza virus). Several other RNAi therapeutic programs are currently under negotiation for potential licensing partnerships.

Indeed, for Sirnaomics, sprinting toward an IPO and becoming the first publicly listed small nucleic acid drug company in China is undoubtedly a significant corporate milestone. However, as one of the leading enterprises at the forefront of global nucleic acid drug development, its immense potential is what truly warrants anticipation.