Small nucleic acid drugs are an area of great attention to new drug research and development in recent years, and with their unique technical characteristics, they provide an important research direction to meet the unmet clinical needs, especially for the field of rare diseases
RNA interference (RNAi) refers to a biological process
Small nucleic acid drugs in the narrow sense refer to small interfering RNA drugs (SiRNA); The broad sense is that in addition to SiRNA, it also mainly includes antisense oligonucleotides (ASOs) and targeted microRNAs (microRNAs, miRNA) and so on
As mentioned above, the relatively mature areas of small nucleic acid drug development are SiRNA and ASO, and so far, more than 13 varieties have been approved for marketing in these two fields, of which the number of ASO varieties is about twice the
In terms of indications, since such drugs are from a genetic point of view, more focus is on the treatment of rare diseases, such as Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA) and so on
In terms of development companies, 2 companies have been approved relatively many varieties, namely Ionis and Alynlam
From the perspective of material basis, small nucleic acid drugs are more between small molecule chemical drugs and biological drugs, slightly biased towards small molecule drugs, to a certain extent, similar to polypeptide drugs, and mostly injections
However, different from the characteristics of small molecule chemical drugs, small nucleic acid drugs are easily degraded by blood nucleases in the human circulatory system, and the stability is poor, so how to modify, how to administer drugs, and how to deliver specific targets is a technical difficulty
? Structural decorations
Resistance to the degradation of blood nucleases by incorporating unnatural nucleic acid molecules, increasing their blood stability and prolonging the in vivo half-life
? Conveyor carrier
In vivo delivery vectors are mainly divided into viral vectors and non-viral vectors
Drug development, from pharmacological, non-clinical, clinical explanation
? Pharmacological aspects
Due to the preparation of small nucleic acid drugs, usually using solid-phase synthesis technology, there are certain barriers to process development, process amplification and quality control, and there are higher requirements for technology, equipment and environment, accompanied by high costs, and there is still a lot of room
? Non-clinical aspects
Domestic studies have summarized
Clinical aspects
Most of the clinical development of small nucleic acid drugs, most of them have experienced more than 10 years, and the number of clinical trials completed in the true sense is not very large
The above briefly describes the global development background and technical characteristics of small nucleic acid drugs, and further summarizes them as follows: 1) Global drug development is growing, the domestic market space is huge, and no self-developed varieties have been approved for listing; 2) The unique mechanism of action has spawned special technical characteristics, and basic research still needs to be accumulated; 3) Preclinical development will become a short-term bottleneck, and the domestic market space is huge; 4) Work on the basis of peptide drug development, theoretically there will be a qualitative growth rate, which is a good product line expansion method; 5) The investment cost of R&D will be relatively high, so whether to enter this field must be comprehensively considered
Small nucleic acid drugs are an area of great attention to new drug research and development in recent years, and with their unique technical characteristics, they provide an important research direction to meet the unmet clinical needs, especially for the field of rare diseases
RNA interference (RNAi) refers to a biological process
by which small RNA (sRNA) molecules silence the expression of target genes at the time of transcription or after transcription by inhibiting chromatin modifications that target mRNA or reducing their stability or potential for translation.
Small nucleic acid drugs in the narrow sense refer to small interfering RNA drugs (SiRNA); The broad sense is that in addition to SiRNA, it also mainly includes antisense oligonucleotides (ASOs) and targeted microRNAs (microRNAs, miRNA) and so on
.
The global drug development focus is primarily SiRNA and ASO
.
As mentioned above, the relatively mature areas of small nucleic acid drug development are SiRNA and ASO, and so far, more than 13 varieties have been approved for marketing in these two fields, of which the number of ASO varieties is about twice the
number of SiRNAs.
In terms of indications, since such drugs are from a genetic point of view, more focus is on the treatment of rare diseases, such as Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA) and so on
.
In terms of development companies, 2 companies have been approved relatively many varieties, namely Ionis and Alynlam
.
Specific information about some of the drugs is shown in the table below
.
From the perspective of material basis, small nucleic acid drugs are more between small molecule chemical drugs and biological drugs, slightly biased towards small molecule drugs, to a certain extent, similar to polypeptide drugs, and mostly injections
.
In the "Technical Guidelines for The Application of Phase I Clinical Trials of New Drugs" issued by cde, the pharmaceutical research - preparation process section has mentioned that "for the use of fermentation process, extraction process preparation, peptide, small molecule nucleic acid drugs, etc.
, more preparation process information
is needed.
" ”
However, different from the characteristics of small molecule chemical drugs, small nucleic acid drugs are easily degraded by blood nucleases in the human circulatory system, and the stability is poor, so how to modify, how to administer drugs, and how to deliver specific targets is a technical difficulty
.
Based on this, we can mainly start
from the following aspects.
? Structural decorations
? Structural decorations
Resistance to the degradation of blood nucleases by incorporating unnatural nucleic acid molecules, increasing their blood stability and prolonging the in vivo half-life
of the drug.
However, the non-natural nucleic acid molecule itself is significantly cytotoxic may also cause toxic side effects
.
This is very similar
to the development of peptide drugs.
? Conveyor carrier
? Conveyor carrier
In vivo delivery vectors are mainly divided into viral vectors and non-viral vectors
.
Although the viral vector has high delivery efficiency, it is limited by its own insurmountable defects for nucleic acid drug delivery systems; Non-viral vectors have the advantages of connecting two different environments inside and outside the target cell, without affecting normal tissue cells, and can be targeted to find and reach the lesion and release drugs in time
.
Drug development, from pharmacological, non-clinical, clinical explanation
.
? Pharmacological aspects
? Pharmacological aspects
Due to the preparation of small nucleic acid drugs, usually using solid-phase synthesis technology, there are certain barriers to process development, process amplification and quality control, and there are higher requirements for technology, equipment and environment, accompanied by high costs, and there is still a lot of room
for development in China for hardware conditions in this area.
Early registration declaration, if the work is carried out in accordance with the "Technical Guidelines for The Application of Phase I Clinical Trials of New Drugs", the APIs and preparations need to be carried out
in accordance with the following contents.
? Non-clinical aspects
? Non-clinical aspects
Domestic studies have summarized
the non-clinically relevant content of some small nucleic acid drugs that have been listed.
In terms of pharmacodynamics, in vitro and in vivo two directions, but the number of efficacy tests is significantly less than the number of small molecule drugs
.
In terms of pharmacokinetics, specific absorption, distribution, metabolism, and excretion were carried out, and some trials were listed, but the number of trials was relatively small
.
In terms of toxicology, single, multiple, safe pharmacology, genetic toxicity, reproductive toxicity, carcinogenicity, and some special toxicity tests
have been carried out.
Examples are given below
.
Clinical aspects
Clinical aspects
Most of the clinical development of small nucleic acid drugs, most of them have experienced more than 10 years, and the number of clinical trials completed in the true sense is not very large
compared with the traditional drug development.
Take the example of a clinical trial that Leqvio has completed, as follows
.
The above briefly describes the global development background and technical characteristics of small nucleic acid drugs, and further summarizes them as follows: 1) Global drug development is growing, the domestic market space is huge, and no self-developed varieties have been approved for listing; 2) The unique mechanism of action has spawned special technical characteristics, and basic research still needs to be accumulated; 3) Preclinical development will become a short-term bottleneck, and the domestic market space is huge; 4) Work on the basis of peptide drug development, theoretically there will be a qualitative growth rate, which is a good product line expansion method; 5) The investment cost of R&D will be relatively high, so whether to enter this field must be comprehensively considered
based on capital management.
