Frost & Sullivan releases 'Research Report on the Current Industry Situation and Future Development of the Nucleic Acid Drug Market'

In the historical process of combating diseases, traditional drugs have used 'proteins' as drug targets. However, many 'pathogenic proteins' in the human body are unattainable drug targets, resulting in a lack of effective treatment methods for many diseases. To solve this problem, people have developed nucleic acid drugs along the central dogma, utilizing the translation or regulatory functions of nucleic acid molecules to address the unmet clinical needs brought about by 'undruggable' targets, which is expected to become the third major class of drugs following small molecule and antibody drugs. In recent years, several blockbuster nucleic acid drugs have been introduced, demonstrating unprecedented application value in treating metabolic diseases and preventing infectious diseases. The Report provides an in-depth analysis of two types of nucleic acid drugs, mRNA and small nucleic acids, exploring the opportunities and challenges faced by nucleic acid drugs.

According to the use and type of the drug,mRNA drugs mainly have three major application directions, including infectious disease vaccines (preventive vaccines), tumor treatment (therapeutic vaccines), and protein replacement therapy (therapeutic drugs).

Currently, mRNA technology is particularly prominent in the application of preventive vaccines. It develops rapidly and has a clear advantage in dealing with sudden epidemiological crises. At the same time, its production capacity climbs extremely fast, with batch output reaching hundreds of millions of doses. Compared to traditional vaccines, mRNA vaccines possess excellent immune activation capabilities. By endogenously expressing antigen proteins, they can induce a broader and more effective cellular and humoral immune response, resulting in higher protection rates. The vaccination of hundreds of millions of doses of mRNA COVID-19 vaccines has verified the safety and efficacy of mRNA technology.The advantages of mRNA technology are evident and it will become an important choice for the development of new vaccines.

Due to the large molecular weight, strong immunogenicity, and easy degradation of mRNA molecules, there are many obstacles in the development of mRNA drugs. To solve these problems, optimization can be made in three aspects: mRNA structure, delivery system, and production technology.

The main delivery vector technologies for mRNA drugs include liposomal nanoparticles, protamine carriers, polymer carriers, etc.Currently, liposomal nanoparticles are the most widely used delivery system.The latest generation of ionizable lipid nanoparticles carry a positive charge in an environment with low pH values, forming complexes with mRNA to improve its stability. At physiological pH, they are neutral, which reduces their interaction with the cell membranes of cells in the blood and lowers lipid toxicity. After being ingested by cells, the acidic environment of the endosome recharges them with a positive charge, which may help break down the stability of the endosomal cell membrane and promote the release of mRNA from the endosome.

LNP also carries other lipid molecules, including phospholipids, cholesterol, and polyethylene glycol (PEG). These lipid molecules help improve important characteristics of LNP such as stability, delivery efficiency, tolerance, and biodistribution. The defect of ionizable LNP is that it still leads to the release of inflammatory cytokines, lacks targeting ability, and has poor liposome stability.Continuously improving the security and stability of LNP is a key research focus in the future.

mRNA vaccines are a general-purpose platform technology that provides a flexible, rapid, large-scale, and cost-effective production process. They have clear advantages in the face of the threat of the COVID-19 pandemic. At the same time,According to phase III clinical results, the mRNA COVID-19 vaccine demonstrated superior protective efficacy against other COVID-19 vaccines and its ability to activate the immune system.

2020 was a breakthrough year for mRNA vaccines, with two mRNA COVID-19 vaccines developed by Pfizer/BioNTech and Moderna, respectively, receiving emergency use authorization. In 2021,The global sales revenue of the two mRNA COVID-19 vaccines reached as high as $58.7 billion, far exceeding the sales of other COVID-19 vaccines.

In the short term, the main contributor to the future market of mRNA products will still be COVID-19 vaccines.In addition to COVID-19, the main market opportunity in the field of preventive vaccines lies in unmet immunization needs, such as the development of vaccines against Zika, HIV, EBV, RSV, and other viruses.

In the field of tumor treatment, mRNA design and production are rapid, offering certain advantages in personalized tumor vaccines. BioNTech and Moderna have both entered clinical trials with corresponding pipelines, but the application of tumor vaccines is currently still in the concept validation phase; in the field of protein replacement therapy, there are still key technical bottlenecks that need to be overcome in the future, including two major obstacles: poor targeting and unstable expression.

Small nucleic acid drugs, also known as oligonucleotide drugs, are short-chain nucleic acids composed of ten to dozens of nucleotides linked together. They act on pre-mRNA or mRNA and achieve disease treatment by interfering with the expression of target genes. Currently, small nucleic acid drugs mainly include siRNA drugs and ASO drugs.

Currently, a total of 14 small nucleic acid drugs have been approved for marketing globally (3 early-stage drugs have been withdrawn from the market), including 9 antisense oligonucleotides (ASOs), 4 small interfering RNAs (siRNAs), and 1 nucleic acid aptamer.After years of development, blockbuster products have emerged for small nucleic acid drugs.Among them, Nusinersen developed by and Ionis is the world's first drug for the treatment of spinal muscular atrophy, with global sales reaching $1.951 billion in 2021, making it the currently highest-selling small nucleic acid drug; Inclisiran developed by Novartis and Alnylam is a long-acting lipid-lowering drug that requires only two injections a year, opening a new chapter in the application of small nucleic acid drugs for common chronic diseases.

The emergence of small nucleic acid drugs has made it possible to actively design drug sequences for targeted silencing of disease genes, offering multiple advantages compared to traditional drugs.

• Rich candidate targets and a wide range of indications

Theoretically, any disease caused by overexpression of specific genes can be treated with small nucleic acid drugs, which provides a rich array of candidate targets for the development of such drugs, including many targets that are currently untreatable with traditional medications.

• Drug design is simple, and the R&D cycle is short.

Small nucleic acid (SNNA) drugs represent the most significant area of benefit from the development of genomics and functional genomics to date. The design of SNNA drugs enables direct digital design targeting disease gene (mRNA) sequences, thus eliminating the large-scale screening cycles of traditional drugs. This allows for proactive drug design and a relatively higher success rate in research and development.

• Strong targeting specificity

Small nucleic acid drugs achieve gene expression regulation at the post-transcriptional level, specifically targeting the mRNA transcribed from pathogenic genes. They can regulate the expression of pathogenic genes upstream of the disease and can achieve sequence specificity at the single base level, featuring 'targeted' and 'both symptomatic and root cause' treatment. In addition, the delivery systems for nucleic acid drugs are constantly innovating, enabling effective delivery of nucleic acid drugs to target organs and truly realizing targeted drug administration.

• Long-acting drug effect

The target of small nucleic acid (SNNA) drugs is mRNA. Taking siRNA drugs as an example, when the target mRNA is degraded, RNA-induced silencing complexes can work in a cyclic manner, participating in the next round of target mRNA degradation. Therefore, SNNA drugs can achieve long-term action within cells. In addition, the chemical modification technology of nucleic acid drugs is constantly innovating, including phosphate backbone modification, glycosylation modification, and base modification, etc., which can improve the stability and half-life of nucleic acid drugs, make the drug action more sustained, and greatly improve patients' compliance with treatment.

Small nucleic acid drugs face challenges such as how to efficiently enter target cells, release into the cytoplasm, and exert their effects efficiently and sustainably over a long period.Different issues in the research and development process of small nucleic acid drugs require corresponding technologies to solve. According to the sequence of the small nucleic acid drug R&D process, core technologies are divided into design, chemical modification, delivery, synthesis, and formulation technologies.The most critical core technology is nucleic acid drug delivery technology. Drug delivery plays an important role in protecting RNA structure, enhancing targeting ability, reducing dosages, and minimizing toxic side effects.

Small nucleic acid delivery systems can be divided into naked RNA-modified delivery systems, liposomal nanodelivery systems, conjugated linker delivery systems (small molecule ligands, antibodies, and other molecules), and other delivery systems (polymer matrices, exosomes, viral transfection, etc.).

Among the 14 marketed small nucleic acid (SNAs) drugs, 10 do not use delivery systems. One is a nucleic acid aptamer, and the remaining nine are ASO drugs. This is mainly due to the low molecular weight of ASO drugs, which gives them strong ability to enter cells. Especially when ASO drugs are administered via intrathecal injection, they can enter the central nervous system without the need for delivery systems. Therefore, many ASO drugs targeting central nervous system diseases are currently under development. The other four siRNA drugs all use delivery systems, one using lipid nanoparticle delivery systems, three using GalNAc conjugated linker delivery systems.

The implementation of the GalNAc conjugate delivery system represents a major breakthrough in the development of small nucleic acid drugs. This technology has addressed three major pain points in the development of small nucleic acid drugs: poor targeting, severe off-target effects, and poor stability, bringing about significant advancements in the field of liver targeting.GalNAc connects to siRNAs and is administered by subcutaneous injection. It binds to the liver cell surface receptor ASGP receptor, targeting the liver with a greatly improved delivery efficiency, and its action lasts for several months. Due to its excellent targeting performance in the liver, multiple small nucleic acid drugs for liver diseases are under development. In addition, GalNAc also has affinity for targets such as TTR in the cardiovascular system, and it also has broad application prospects in the field of cardiovascular system diseases.

The three earliest listed small nucleic acid drugs have now been delisted. With the launch of two ASO drugs in 2016, it broke the long-standing silence in the pharmaceutical market.The global market size of small nucleic acid drugs has grown from $0.1 billion in 2016 to $3.25 billion in 2021, with an annual compound growth rate as high as 217.8%. In the future, with the continuous launch of clinical-stage small nucleic acid drugs, especially for indications targeting larger patient populations, such as potential curative drugs for hepatitis B, the market will further drive rapid development.

Currently, all marketed small nucleic acid (SNP) drugs are ASO and siRNA drugs. ASO drugs were launched earlier and have a more mature commercial development phase, accounting for nearly 80% of the overall SNP market share. In terms of indications, spinal muscular atrophy is currently the most commercially successful indication. In 2021, there was only one drug for this indication, yet it contributed nearly $2 billion in sales. Other indications include Duchenne muscular dystrophy, etc. Overall,Currently, the listed products are mainly in the field of rare disease indications. While achieving commercial success, they also fulfill their original intention of addressing clinical needs and pain points. However, this has also revealed from the side that there is a current shortage of indications with a larger patient population in the small nucleic acid drug market.

It is worth noting that, due to the unique mechanism of action of small nucleic acids, they have greater development potential and clinical value in a variety of indications. There are no lack of clinical trials targeting major diseases such as cancer, diabetes, and hepatitis B in the clinical research pipeline, which will greatly compensate for the current weakness of commercial blockbuster drugs and support the future development of the small nucleic acid drug market.

The Report has sorted out domestic and international companies focusing on the nucleic acid drug field, highlighting their differentiated technological competitive advantages. The following is an introduction to some nucleic acid drug companies:

SirnaomicsFounded in 2007, headquartered in Bethesda, Maryland, USA, the company currently has a R&D center in Suzhou, China, and has established a production base in Guangzhou. It is a leading enterprise that promotes the clinical research of small nucleic acid new drugs in both China and the United States, and also the first biotechnology company listed on the Hong Kong stock market focused on developing new drugs using RNA technology. The company possesses a globally unique peptide nanoparticle (PNP) delivery platform and uses it to develop innovative biopharmaceutical drugs for various disease indications, including oncology, fibrotic diseases and conditions, viral infections, and metabolic diseases. Currently, the core product STP705 is the first candidate drug to achieve positive Phase IIa clinical results in the field of oncology.

Aibo Biotech:Founded in 2019, it is an innovative biopharmaceutical company dedicated to the research and development of messenger ribonucleic acid (mRNA) drugs. The company possesses industry-leading mRNA platform technologies with independent intellectual property rights, including nanolipid particle delivery technology for efficient mRNA drug delivery, mRNA design, synthesis, and modification techniques that ensure the stability, safety, and effectiveness of mRNA molecules, as well as dynamic and precise mixing technology for industrial production of delivery systems. Currently, the company's pipeline covers areas such as infectious disease prevention and control and tumor immunology. Among them, the mRNA vaccine developed against COVID-19 has entered phase III clinical studies in multiple international centers and obtained a drug production license.

Agnera BiotechnologyEstablished in 2020, it is an RNA innovation pharmaceutical company co-founded by RNAi discoverers, Nobel laureates in 2006, and senior returnees from overseas. The company boasts an experienced RNA drug R&D team, advanced RNA drug R&D platforms, and large-scale mRNA vaccine production lines, holding more than 20 invention patents in the RNA field. The company owns the GalPET liver-targeted RNAi and lipid nanoparticle (LNP) delivery core platform technology with independent intellectual property rights. In March 2022, the COVID-19 mRNA vaccine developed by Agnova Biotech and Ribo Biotech commenced Phase II clinical trials.

Ruibio Biology:Established in 2004, it is a high-tech enterprise integrating R&D, production, sales, and scientific research services with nucleic acid technology as its core and nucleic acid drug production services and nucleic acid scientific research products as its leading areas. The company provides nucleic acid drug product production and CMC pharmaceutical services through oligonucleotide production, process development, and analysis method research. Currently, the company owns multiple platforms including oligonucleotide drug production, analysis and testing, high-throughput sequencing, and new nucleic acid drug R&D, offering nearly a hundred kinds of products and services. The company not only has the production capacity for various chemically modified oligonucleotide drugs and large-scale production bases but also can provide full industrial chain production and development services from plasmid manufacturing, raw materials and excipients, enzyme production, to mRNA production, LNP preparation, and packaging of mRNA vaccines.

Ribo BiotechnologyFounded in 2007, the company is dedicated to innovative research and development of small nucleic acid drugs and is a major pioneer in China's small nucleic acid technology and pharmaceutical industry. The company has established an integrated small nucleic acid innovation technology system covering the entire life cycle of small nucleic acid drugs from early discovery to industrialization, centered around the characteristics of these drugs. Based on the company's independently developed GalNAc delivery technology pipeline, which has advanced to clinical trials, four products are currently in clinical research. In response to unmet clinical needs, the company has formed an ongoing product pipeline focusing on multiple disease areas such as liver diseases, cardiovascular diseases, metabolism, ophthalmology, and rare diseases. The company established an European R&D center in 2022, initiating internationalization efforts.

In 2020, mRNA vaccines received widespread attention from the public, leading to rapid development of nucleic acid drugs. Nucleic acid drugs have gradually become a focus of biomedical investment and a hot topic in R&D for pharmaceutical companies.Dr. Wang Xin, Global Partner at Frost & Sullivan and President of the Greater China Region, said,"The vaccination of hundreds of millions of doses of mRNA COVID-19 vaccines has validated their efficacy, and it has also reignited the enthusiasm for nucleic acid drug research and development. Nucleic acid drugs have a rich variety of targets and strong specificity, enabling them to intervene at the source of diseases. Currently, dozens of nucleic acid drugs have been launched globally and have received positive market feedback, indicating that the development of the nucleic acid drug industry is in full swing."