After ADC, small nucleic acid drugs have become a new gold mine for MNC mining.

First, on January 3, Yunbio announced that it had reached a cooperation with Boehringer Ingelheim (BI), Germany, to grant each other a small nucleic acid innovative therapy for steatohepatitis (NASH), with a total amount of more than $2 billion. Then on January 7, Novartis purchased a number of small nucleic acid drugs for cardiovascular diseases from Huiwang Pharmaceutical, with an initial payment of $185 million and a total transaction value of $4.165 billion.

Compared with the previous ADC tide, the recent total transaction amount of small nucleic acid drugs is significantly higher, and the drug companies that are favored by MNC are also younger. After a series of consecutive license-out deals, China’s innovative pharmaceutical companies have been at the forefront of global drug research and development.

Small nucleic acid drugs are not new things. They were the core direction of MNC layout as early as before the epidemic, but were interrupted by the epidemic later. Now with the landing of two blockbuster mergers and acquisitions, small nucleic acid drugs are returning to the core battlefield of innovative drugs, and Chinese pharmaceutical companies are no longer willing to play a supporting role.

New Medicine 3.0

If chemical small molecule drugs have laid the foundation of modern medicine, Yunbio has ushered in a new era of biotechnology. Chemical small molecule drugs and biological antibody drugs form the main framework of modern medical therapy.

This framework, while capable of treating a wide variety of diseases, falls far short of the needs of human medicine. Whether it is chemical small molecule drugs or biological antibody drugs, most of them use proteins as targets, such as kinases, receptors, antigens, etc. Unfortunately, more than 80% of pathogenic proteins are always difficult to find targets, which are also called undrugeable targets.

However, protein synthesis must go through two major processes of transcription and translation, which require DNA,mRNA,tRNA and other nucleic acid substances. In theory, as long as we master the gene coding sequence of the pathogenic protein, we can design the corresponding RNA chain. By silencing this RNA sequence, it is expected to prevent the formation of the pathogenic protein, so as to solve many difficult and complicated diseases.

Based on this, the concept of small nucleic acid drugs came into being, which is also regarded as an innovative drug 3.0 after chemical small molecule drugs and biological antibody drugs.

It is the core logic of the research and development of small nucleic acid drugs to move from the superficial protein level to the deeper nucleic acid level, trying to bypass the protein and directly solve the more essential underlying coding problem. Because the problem is solved from the bottom level of coding, people have given more expectations for small nucleic acid drugs, and many people even believe that small nucleic acid drugs can subvert the entire pharmaceutical industry.

Throughout the development of small nucleic acid drugs, it can be roughly divided into three main stages: the exploration stage (1978-1998), the confusion stage (1998-2013), and the growth stage (2013-present).

In the exploration period, small nucleic acid drugs are still in the theoretical stage, and people still do not know whether they can be successfully developed through nucleic acid. As a result, in this stage, the development of small nucleic acid drugs is relatively slow, and the milestones are mainly academic, and the industrial exploration is cautious. It took 20 years from theory and practice to the approval of the first drug. It was not until 1998 that fomivirsen, a nucleic acid drug from Ionis, was approved by FDA.

After the approval of the first drug, the field of small nucleic acid drugs quickly attracted a large number of giant enterprises into the business, such as Roche, Merck, Pfizer, Sanofi, and Abbott all placed big bets, but no one thought that the small nucleic acid drugs at that time were not mature. First, fomivirsen was forced to withdraw from the market in 2003 due to low sales, and then there were three heavy drugs and small nucleic acid drug pipeline clinical failure, which led to the heat of this emerging field quickly dropped to freezing point, and a lot of funds also left the market during this period.

Despite the difficulties ahead, Ionis, the pioneer of small nucleic acid drugs, persisted and finally achieved another breakthrough in 2013, when its second product, mipomersen, was approved for the treatment of pure familial hypercholesterolemia, thus proving the value of small nucleic acid drugs.

It is due to the persistent innovation of Ionis, Sarepta, Alnylam and other companies that have mushroused small nucleic acid drugs in the following years. Not only has the explosive drug nusicersen with annual sales of more than 2 billion US dollars, but also has been approved for more than 10 indications, and most of them are orphan drug markets with high research and development difficulties.

Three years interrupted by the pandemic

This is the development of small nucleic acid drugs in miniature.

After regaining industry recognition, small nucleic acid drugs have once again become the focus of a large number of MNCS, and if all goes well, it should become the third class of drugs alongside chemical small molecule drugs and biological antibody drugs. Unexpected things happened again, when the development of small nucleic acid drugs was the most smooth, the epidemic suddenly broke out.

In addition to shutting down the economy, the most important effect of the pandemic has been to lure companies into focusing too much on another emerging nucleic acid drug platform, mRNA.

mRNA and small nucleic acid drugs together constitute a major category of nucleic acid drugs, but unlike small nucleic acid drugs, which have undergone many years of industry iteration, mRNA epidemic is a sudden outbreak. Under the golden signboard of COVID-19 vaccine, a large number of MNCS have flooded into the country, taking away the light that should belong to small nucleic acid drugs, which is also the reason why the sound volume of small nucleic acid drugs has decreased in the past two years.

As we have argued before, the COVID-19 vaccine overinflated technical expectations of mRNA, which is likely to be the biggest healthcare investment bubble of the 21st century. Nowadays, although mRNA is still a hot technology, it is far from the previous investment heat, and MNC has gradually begun to return to the attention of small nucleic acid drugs that were neglected before.

Looking at the history of small nucleic acid drug licensing transactions, from 2018 to 2020, there were frequent transactions in this field. Biogen, Eli Lilly, GSK, Pfizer, Roche, Novartis, and a number of MNCS staged pipeline purchase wars, much like their purchase of ADC pipelines last year. However, after the epidemic, the popularity of small nucleic acid drug mergers and acquisitions plunged, and it has only recently become the core target of MNC layout again.

If there is no sudden epidemic, small nucleic acid drugs are likely to become a popular technology platform with higher priority than ADC. However, there is no way in the world if, in the period of rapid development, small nucleic acid drugs are tragicly blocked by the epidemic, so that ADC takes away its light that should belong to it.

The next gold mine to be mined

Small nucleic acid drugs have promoted human drug development to a new dimension – the level of nucleotide coding.

With the help of RNA coding, many undrugable proteins are expected to find new nucleic acid targets, which also greatly increases the range of small nucleic acid drug targets. Compared with gene therapy, small nucleic acid drugs focus on the RNA level and do not change the patient’s original genome, so they are safer. At the same time, RNA coding sequences have certain regularity, and small nucleic acid drugs are expected to make greater progress in iteration after iteration.

Before that, the reason why small nucleic acid drugs entered the confusion period was mainly because of the poor stability of the nucleotide molecular chain, short half-life, and easy degradation. At the same time, the target is poor, and off-target problems may occur. To solve these problems, the industry has proposed two major solutions, one is RNA chemical modification and the other is RNA delivery system.

Through chemical modification of RNA, the stability of nucleotide molecular chain has been greatly improved, and the half-life has been greatly prolonged, such as phosphate skeleton, ribose five-membered ring modification, and nucleotide scouring end modification. On the other hand, the emergence of delivery systems has greatly improved the endocytosis efficiency of small nucleic acid drugs, so as to help them reach the desired location. Common delivery systems include cyclodextrin nanopolymers, lipid nanoparticles, and conjugate delivery systems.

With the two weapons of chemical modification and delivery system, small nucleic acid drugs have developed rapidly, and 13 drugs have been marketed so far. At present, small nucleic acid drugs mainly include two types of drugs: ASO drugs (antisense oligonucleotide) and siRNA drugs (small interfering RNA).

ASO is a kind of single-stranded oligonucleotide molecule, usually containing 15 to 25 nucleotides. After entering the cell, the ASO locks the target RNA by the principle of base complementary pairing under the action of ribonuclease, and then severs the target RNA by RNase H, so that the protein cannot be expressed.

siRNA is a 21-23 base-pair, double-stranded RNA. After transcription in the nucleus, the double-stranded siRNA and the associated protein cross the nuclear pore, where it is cleaved by RNase III to form a single-stranded siRNA. The single-stranded siRNA thus formed binds to proteins such as Ago for the recognition of complementary mRNA and serves as a template for cleavage. The protein complexes formed are called silencing effector complexes (RISC).

The core mechanism of the two small nucleic acid drugs is to restrict the expression of the target RNA. ASO can act in the cytoplasm and nucleus, but the toxicity is usually high. siRNA acts only in the cytoplasm but is generally safer.

In addition to these two therapies, small nucleic acid drugs also have a Aptamer therapy that targets proteins and regulates protein activity. However, at present, only one drug, Pegaptanib, has been approved for marketing, and more subsequent research and development iterations are needed.

For the small nucleic acid drug market with great prospects, Junshi Biological, Xinda Biological, Henrui Pharmaceutical and other head pharmaceutical companies have premedly laid out. In April last year, Junshi Biological opened a clinical trial of ANGPTL3 siRNA drugs, becoming the first innovative pharmaceutical company to explore small nucleic acid drugs. Similarly, Hengrui Pharma also launched a clinical trial of a siRNA drug HRS-5635 in 2023. Also looking at small and medium-sized nucleic acid drugs are Huadong Medicine and Xinda Biology, which have reached cooperation with Shengin Biology to enter the research and development field of small nucleic acid drugs.

In addition to these leading pharmaceutical companies, Sannuo Pharmaceutical has its own self-developed delivery system – polypeptide nanoparticles, and the company also has a number of siRNA drugs into the clinic; Tengshengbo Pharmaceutical, Ribobio, and Huibo Pharmaceutical also have deep accumulation in the field of small nucleic acid drugs.

Starting from the logic of the pharmaceutical industry, the small nucleic acid drugs that penetrate the appearance of proteins are undoubtedly a technological leap, and if the technology is mature, it is very likely to break through the limits of human medical treatment at this stage. Small nucleic acid drugs are likely to be the next gold mine to be mined, or a blockbuster product of the king of drugs will be born.