Nucleic acid drugs, potential release, China has become the world's largest exporter of nucleotide raw materials

In recent years, nucleic acid drugs have become a key area
of global R&D and investment.
Compared with traditional drugs that intervene in diseases at the protein level, nucleic acid drugs can play a role in the source of genetic information transmission, so they have the advantages of strong specificity, rich gene targets, long-lasting efficacy, etc.
, and avoid the complex synthesis and purification process of traditional drugs, which can significantly reduce production costs
.

Since the discovery of the DNA double helix structure in 1953, nucleic acid drugs have a history of 70 years of development, including antisense nucleic acids (ASO), small interference RNA (siRNA), microRNA (miRNA), small activating RNA (saRNA), messenger RNA (mRNA), aptamer, ribozyme, antibody nucleic acid conjugated drugs (ARC) and so on
。 In addition to mRNA drugs, basically other nucleic acid drugs are composed of single or double strands of ribonucleotides or deoxyribonucleotides within 100, so they are also called oligonucleotides or small nucleic acid drugs
.

Unlike mRNA drugs that encode proteins, oligonucleotide drugs are mainly paired with DNA, mRNA or pre-mRNA through the principle of base complementary pairing, and regulate gene expression
through a series of mechanisms such as gene silencing, noncoding RNA inhibition, and gene activation.

Timeline of nucleic acid drug development Source: Guosen Securities

At present, there are 17 nucleic acid drugs listed worldwide, three of which have applied for listing, and 32, 115 and 113 clinical pipelines of Phase III, Phase II and Phase I are respectively
.
Among the 719 nucleic acid drugs in the world, ASO varieties are the most (253), and the rest are siRNA (229) and mRNA (72
).
The top 5 global investment in nucleic acid drugs are Ionis (91 models), Alnylam (34 models), simaomics (25 models), arrowhead (24 models), and AstraZeneca (18 models
).

17 nucleic acid drugs marketed worldwide Source: Insights Database

Since most of the proportion of nucleic acid drugs is oligonucleotides, oligonucleotides have become an important raw material for nucleic acid drugs, and oligonucleotides are formed by the series of dozens to dozens of nucleotides, so nucleoside monomers are also the key raw materials
of nucleic acid drugs.

According to QYR forecasts, the global nucleotide market (including oligonucleotides and monomers) will have sales of $510 million in 2021, and China is the world's largest nucleotide production market, accounting for about 55%.

At present, the domestic nucleic acid drug raw material market size is expected to be 280 million US dollars, in addition, the global nucleotide market demand is about 50,000 tons, and the annual output value of the domestic nucleotide market is about 27,500 tons
.
Most of them are exported to the outside world, and the internal digestive capacity for nucleic acid drug production in China is weak
.
This is not unrelated to the fact that there is still a big gap between China's nucleic acid drug production and foreign countries
.
Because in general, 90% of the world's nucleotides are used for nucleic acid drug production, and only about 10% are used in health food, agriculture and other fields
.

From the perspective of oligonucleotide raw material production process, the mainstream method of synthesizing oligonucleotides in the upstream process is the solid-phase phosphoramide triester method, in which the phosphine monomer and the solid-phase carrier are de-protected, coupled, oxidized, capped and other steps in the nucleic acid synthesis instrument to obtain the target base sequence, that is, the oligonucleotide coarse, and then remove the protective group from the crude product and cut it off from the solid phase support, after preliminary detection of the purity of the crude product by liquid chromatography, and then purify, ultrafilter, Lyophilization and other steps can be obtained oligonucleotide API intermediates
.

Taking DNA primer synthesis as an example, the figure below shows the solid-phase phosphoryl synthesis steps
.
In the purification process, there are mainly three methods of reverse phase chromatography (solid phase synthesis - reverse phase chromatography purification - detriphenylation - ethanol precipitation, etc.
- lyophilization), ion exchange chromatography (solid phase synthesis - ion exchange chromatography - concentration / deep filtration - lyophilization), hydrophobic chromatography combined with ion exchange chromatography (solid phase synthesis - hydrophobic chromatography - detriphenylation - ion exchange - UF / DF - API solution), but most of the nucleic acid drugs currently listed on the market are prepared
by the first two methods 。 In addition to the above chemical synthesis methods, other methods for preparing nucleotides include RNA enzymatic solution, microbial fermentation and biocatalysis
.

Fig.
Solid phase phosphoryl method synthesis primer Source: Network public information

Oligonucleotides and nucleoside monomers are key materials for nucleic acid APIs, and qualified suppliers that meet quality requirements are rare worldwide
.
This is mainly due to the use of solid phase synthesis technology in the production of nucleic acid APIs, which has high barriers in process development, process amplification and quality control, and the preliminary investment in solid phase synthesis equipment and clean environment of nucleic acid APIs is very large, and the production needs to meet international GMP requirements
.

The top 10 giants of established qualified suppliers in the world are Danaher Corporation (founded in 1969), Merck KGaA (founded in 1668), Eurofins Scientific SE (founded in 1987), Thermo Fisher Scientific Inc.
(founded in 2006), Agilent Technologies, Inc.
(founded in 1999), GE Healthcare (founded in 1994), Kaneka Eurogentec S.
A.
(founded in 1985), GeneDesign, Inc.
(founded in 2000), LGC Biosearch Technologies (founded in 1993), Bio-synthesis Inc.
(founded in 1984).

There are about 160 nucleotide API suppliers that can be queried in China, and the regional distribution is relatively scattered, including 43 enterprises in Shaanxi, 22 in Jiangsu, 21 in Hubei, 21 in Hubei, 20 in Shandong, 16 in Guangdong, 11 in Anhui, 6 in Zhejiang, 6 in Shanghai, 5 in Henan, 5 in Hunan, 3 in Tianjin, and 2 in
Shanxi.

The representatives of domestic oligonucleotide production enterprises are Guangzhou Ruibo, Hequan Pharmaceutical, Shanghai Zhaowei and so on
.

Guangzhou Ruibo

Guangzhou Ruibo is a well-known oligonucleic acid API CDMO company in China, which took the lead in establishing a large-scale oligonucleic acid cGMP manufacturing workshop in China in 2013, and obtained the oligonucleonucleic acid API production license issued by the CFDA in 2016, and is also the only local enterprise
to obtain the certificate so far 。 In 2018, the construction of oligonucleonucleic acid cGMP production base was completed, the base area exceeded 20,000 square meters, of which the production workshop was planned for 2,700 square meters, the aseptic filling and finished product workshop was 2,500 square meters, and in 2019, a single-batch 1.
8mol scale synthesis workshop was launched, with a purification capacity of 4,000L/h and a lyophilized workshop of 1kg to 40kg, which can meet the commercial production needs of oligonucleic acid APIs above the kilogram level, and also provide process verification, analysis methods, Quality assurance and risk management services and guarantees
.

Hequan Pharmaceutical

In 2020, Hequan Pharmaceutical announced the official operation of its oligonucleotide API kilogram production workshop, which covers an area of 2800 square meters, and its oligonucleotide platform can support various types of oligonucleotide products, such as deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and morpholine antisense oligonucleotide (PMO), and polypeptide conjugated morpholine antisense oligonucleotide (PPMO).

。 In July this year, Hequan Pharmaceutical's new oligonucleotide and peptide production building in Changzhou's API R&D and production base was also put into operation, including an oligonucleotide production workshop
with an area of 2,840 square meters.
After the production is put into operation, Hequan Pharmaceutical will have 4 kilogram-level large-scale oligonucleotide production lines, as well as more than 20 small-scale and medium-scale production lines, and the maximum total scale of single-time oligonucleotide synthesis will increase from 1.
9mol to 6.
0mol
.

Mega Dimension Creatures

Founded in 2001, Mega Bio is one of the earliest enterprises engaged in the research and development and production of nucleosides and modified nucleosides in China, and passed the ISO9000 quality management system certification
in 2008.
The company focuses on the field of nucleosides and nucleotide products, producing and selling modified nucleosides, nucleotides, phosphoramide gene monomers, targeted tracers and biological enzymes and other series of products
.
As the world's largest manufacturer of oligonucleotides and gene monomers, the mRNA used in nucleic acid vaccines can reach 7 billion doses, and the total output value will reach 1.
5 billion
in 2021.
In July 2022, Zhaowei Bio invested 2.
5 billion yuan in small nucleic acid drug research and development and production base in Shanghai Hangzhou Bay
.

From a global perspective, the overall supply of nucleotide raw materials is in short supply, and it is still a global shortage of products
.
With the gradual release of the clinical potential of nucleic acid drugs in the future, it is bound to drive the continuous growth of related raw materials in the future, and the future prospects are good
.
As a domestic enterprise, we should focus on solving the technology research and development of innovative nucleic acid drugs, increase the ability of self-production and self-marketing, and grow into a leading nucleic acid drug enterprise
comparable to international giants as soon as possible.

Reference source:

1.
Oligonucleotide purification, what should I do? Hanbang Technology official website 20220413

2.
Nucleotide production process and prospects

3、TOP 10 COMPANIES IN OLIGONUCLEOTIDE SYNTHESIS MARKET，METICULOUS RESEARCH，20220105

4.
Gene drug series (1) - small nucleic acid drugs, Zhongguancun Industrial Research Institute, 20220410