This article is from the WeChat public account: Yiyao (ID: yiyao-jinduan006), author: Lin Yaoshi, original title: "Small Nucleic Acid Drugs: Second Evolution", title from: Visual China
Following ADCs, small nucleic acid drugs have become a new gold mine mined by MNC.
First, on January 3, Ribo Biosciences announced that it had reached a cooperation with Boehringer Ingelheim (BI) of Germany to grant each other innovative small nucleic acid therapies for steatohepatitis (NASH), with a total transaction amount of more than 2 billion US dollars, and then on January 7, Novartis purchased a number of small nucleic acid drugs for cardiovascular diseases from Bowang Pharmaceutical, with an initial payment of up to 185 million US dollars and a total transaction value of 4.165 billion US dollars.
Figure: List of main license-outs in the first week of 2024, source: Brocade Research Institute
Compared with the previous ADC going overseas, the total turnover of small nucleic acid drugs has been significantly higher recently, and the pharmaceutical companies favored by MNC are also younger. After a series of successive license-out transactions, Chinese innovative pharmaceutical companies have stood at the forefront of global drug research and development.
Small nucleic acid drugs are not new, they were the core direction of MNC's layout long before the epidemic, but they were later interrupted by the epidemic. 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 no longer dare to play a supporting role.
1. Innovative Drugs 3.0
If chemical small molecule drugs have laid the foundation of modern medicine, then Genentech has created a new era of biotechnology, and chemical small molecule drugs and biological antibody drugs constitute the main framework of modern medical therapy.
While this framework is capable of treating a wide range of diseases, it falls far short of meeting the needs of human medicine. Whether it is a chemical small molecule drug or a biological antibody drug, they mostly target proteins, such as kinases, receptors, antigens, etc. Unfortunately, more than 80% of disease-causing proteins are still difficult to target, and they are also known as undruggable targets.
Figure: Overview of drug targets, source: Guojin Securities
However, protein synthesis must go through two major processes: transcription and translation, and nucleic acid substances such as DNA, mRNA, and tRNA are required. Theoretically, as long as the gene coding sequence of the pathogenic protein is mastered, the corresponding RNA chain can be designed, and by silencing this RNA sequence, it is expected to prevent the formation of the disease-causing protein, thereby solving many incurable 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 small nucleic acid drug development to move from the surface protein level to the deeper nucleic acid level, trying to bypass the protein and directly solve the more essential underlying coding problem. Because it solves the problem from the bottom code, people have more expectations for small nucleic acid drugs, and many people even think that small nucleic acid drugs can subvert the entire pharmaceutical industry.
Throughout the development process of small nucleic acid drugs, it can be roughly divided into three main stages: the exploration period (1978-1998), the confusion period (1998-2013), and the growth period (2013-present).
Figure: Development history of nucleic acid drugs, source: Guojin Securities
During the exploration period, small nucleic acid drugs were still in the theoretical stage, and people still did not know whether they could be successfully formulated through nucleic acids. This leads to the slow development of small nucleic acid drugs in this stage, and the milestones are mainly academic, and the industry exploration is cautious. It took 20 years from theory and practice to the approval of the first drug, and it was not until 1998 that Fomivirsen, a nucleic acid drug from Ionis, was approved by the FDA.
After the first drug was approved, the field of small nucleic acid drugs quickly attracted a large number of giant companies to enter the game, such as Roche, Merck, Pfizer, Sanofi, and Abbott all made heavy bets, but no one expected that the small nucleic acid drugs at that time were not mature. First, the first drug, Fomivirsen, was forced to be delisted in 2003 due to low sales, and then three blockbuster drugs and small nucleic acid drug pipelines failed clinically, which led to the rapid decline in the popularity of this emerging field to freezing point, and a lot of funds were also cut off during this period.
Despite the thorns ahead, Ionis, a pioneer of small nucleic acid drugs, chose to persevere, and finally made another breakthrough in 2013 when its second product, mipomersen, was approved for the treatment of pure joint venture familial hypercholesterolemia, thus once again proving the value of small nucleic acid drugs.
It is precisely because of the dedication to innovation of companies such as Ionis, Sarepta and Alnylam that small nucleic acid drugs have sprung up in the following years, not only giving birth to the explosive drug nusicersen with annual sales of more than 2 billion US dollars, but also more than 10 approved indications, and most of them are in the orphan drug market with high difficulty in research and development.
2. Three years interrupted by the epidemic
This is the epitome of the development of small nucleic acid drugs.
After regaining industrial recognition, small nucleic acid drugs have once again become the focus of a large number of MNC layouts, and if all goes well, it should become the third major 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 smoothest, the epidemic suddenly broke out.
In addition to bringing the economy to a standstill, the most important impact of the pandemic is that it has tempted companies to pay too much attention to another emerging nucleic acid drug platform, mRNA.
mRNA and small nucleic acid drugs together constitute a large classification of nucleic acid drugs, but unlike small nucleic acid drugs, which have undergone many years of industrial iteration, mRNA is a sudden outbreak during the epidemic. Under the golden sign of the new crown vaccine, a large number of MNCs have frantically poured in, stealing the light that should belong to small nucleic acid drugs, which is why the volume of small nucleic acid drugs has declined in the past two years.
Figure: Classification of nucleic acid drugs, source: CITIC Securities
As we have previously argued, the COVID vaccine has amplified the technology expectations of mRNA, and it is highly likely to be the largest medical investment bubble in the 21st century. Although mRNA is still a hot technology, it is far less popular than the previous investment, and MNC has gradually begun to return its attention to the small nucleic acid drugs that were previously neglected.
Throughout the history of small nucleic acid drug licensing transactions, from 2018 to 2020, there were frequent transactions in this field, such as Biogen, Eli Lilly, GSK, Pfizer, Roche, Novartis, and many MNCs have staged pipeline rush wars, just like they snapped up ADC pipelines last year. However, after the epidemic, the popularity of small nucleic acid drug M&A transactions plummeted, and it was only recently that it re-emerged as the core target of MNC's layout.
Figure: List of small nucleic acid drug licensing transactions, source: CICC
If there is no sudden epidemic, it is very likely that small nucleic acid drugs will become a popular technology platform with a higher priority than ADC. However, there is no if in this world, in the period of rapid development, small nucleic acid drugs were tragically blocked by the epidemic, so that ADC took away the light that should belong to it.
3. The next gold mine to be mined
Small nucleic acid drugs have elevated human drug development to a whole new dimension - the nucleotide coding level.
With the help of RNA coding, many undruggable 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 original genome of patients, so they are safer. At the same time, the RNA coding sequence has a certain regularity, and small nucleic acid drugs are expected to make greater progress in iterations after iterations.
Prior to this, the reason why small nucleic acid drugs entered the confused period was mainly because of the poor stability of the nucleotide molecular chain, the short half-life, and the easy degradation, and the poor targeting, which may lead to mop problems. In response to these problems, the industry has proposed two major solutions, one is the chemical modification of RNA, and the other is the delivery system of RNA.
Through the chemical modification of RNA, the stability of the nucleotide molecular chain has been greatly improved, and the half-life has been greatly extended, such as phosphate backbone, ribose five-membered ring modification, nucleotide chain end modification and other methods. On the other hand, the emergence of delivery systems has greatly improved the endocytosis efficiency of small nucleic acid drugs, thereby helping them reach the specific location where they want to play a role, and the common delivery systems are cyclodextrin nanopolymers, lipid nanoparticles, conjugate delivery systems, etc.
With the two major 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 main categories of drugs: ASO drugs (antisense oligonucleotides) and siRNA drugs (small interfering RNA).
Figure: List of listed small nucleic acid drugs, source: Guojin Securities
ASO is a single-stranded oligonucleotide molecule, usually containing 15-25 nucleotides, after ASO enters the cell, under the action of ribonuclease, it locks the target RNA through the principle of base complementary pairing, and then cuts the target RNA through RNase H to make the protein unable to be expressed.
An siRNA is a 21-23 bp long double-stranded RNA that is transcribed in the nucleus and then cleaved by RNase III nucleases to form single-stranded siRNAs. The resulting single-stranded siRNA binds to proteins such as Ago for recognition of complementary mRNAs and serves as a template for cleavage, resulting in protein complexes called silencing effect complexes (RISCs).
The core mechanism of both small nucleic acid drugs is to limit the expression of target RNA, ASO can play a role in the cytosol and nucleus, but the toxicity is usually greater, and siRNA only acts in the cytosol, but the safety is usually higher.
In addition to these two therapies, there is also an Aptamer therapy that targets proteins and regulates protein activity, but at present, only one drug has been approved for marketing on this route, and more follow-up research and development iterations are still needed.
For the promising small nucleic acid drug market, leading pharmaceutical companies such as Junshi Biosciences, Innovent Biologics, and Hengrui Pharmaceutical have taken the lead in layout. In April last year, Junshi Biosciences started a clinical trial of ANGPTL3 siRNA drugs, becoming the first innovative pharmaceutical company to explore small nucleic acid drugs. Coincidentally, Hengrui Pharmaceutical also launched a clinical trial of the siRNA drug HRS-5635 in 2023. Also interested in small and medium-sized nucleic acid drugs are Huadong Medicine and Innovent Biologics, both of which have reached cooperation with Shengyin Biologics to enter the field of small nucleic acid drug research and development.
In addition to these leading pharmaceutical companies, Sirnaomics has its own delivery system, peptide nanoparticles, and the company has also entered the clinical trial of a number of siRNA drugs, while Brii Biosciences, Ribo Biosciences and Bowang Pharma have also accumulated deep experience in the field of small nucleic acid drugs.
Starting from the logic of the pharmaceutical industry, small nucleic acid drugs that penetrate the surface of proteins are undoubtedly a technological leap, and if this technology is mature, it is very likely to break through the limits of human medical treatment at this stage. There is a high probability that small nucleic acid drugs will be the next gold mine to be mined, or a blockbuster product of the king of drugs will be born.
This article is from the WeChat public account: Yiyao (ID: yiyao-jinduan006), author: Lin Yaoshi
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