TECHNOLOGY EXPLAINER
Oligonucleotide Therapeutics
— Behind a 20-base sequence lie 500,000 possible molecules
Nucleic acid drugsChemically synthesizes short chains of DNA and RNA (oligonucleotide)Comment The target is determined by a base sequence, and the behavior in the body isChemical QualificationAnd just by changing the oxygen of the skeleton to 'of', 20 base chains.219The mixture of street heterogeneous bodies
- What is Nucleic Acid Drugs?
- 4 types - antis , siRNA, aptamer
- Chemical Qualification – 2′ place of skeletal and sugar
- The calculation in this paper: What ways do phosphoate produce?
- Material Technician Perspective 1: 'Managed mixture' rather than 'single compound'.
- GalNAc - Deliver to the liver with 3 sugars
- Off-Target Effect – 7-base coincidence
- Solid Phase Syn and Refining - Repeating 4-stage reaction by 1 base
- Material Technician Perspective 2: Raw Material 4 t to 1 kg
- Example of approval (reco zed by the regulatory official publication)
- Glossary/Reference Materials/Reference Table
Facts= Contents described in the publication material (with source link)
The calculation of this paper= The value calculated based on the specified premise
Undetermined / Future= Items that have not been confirmed as a plan and goal
In addition to this, it is possible to organize structures and read materials and process designs."Description"is distinguished.
About this articleExplanation of chemical, material and manufacturing technologyHome not to evaluate the effects and safety of the treatment, No medical advice. It is not recommended for certain medicines or treatments or to discuss the superiority of drugs. FDA, PMDA, Ministry of Health, Labour and Welfare
1. What is Nucleic Acid Medicine?
- What's done:Roberts"Polymer of Nucleic Acid"The antis of a single chain isApprox. 4-10 kDasiRNA, bi-strandabout 14 kDaHome"Large hydrophilic polyanion"That's why"Do not pass cell membrane easily"FactsHome Low ) drugs (about 150 kDa) and antibodiesMiddle sizeHome
- What's Features:Khvorova andtsts have the key benefits of nucleic acid drugs'The nature of delivery and delivery is mainly determined from the chemical structure of oligonucleotide, while the target is defined by the base sequence.'It isFacts。You can design "where it works" and "where it arrives" separatelyThat is
- What’s hard:Roberts"To achieve efficient delivery to non-liver tissues"is still a bigFactsHome Nucleic acid is because it is difficult to pass through the membrane, it is dissolved outside the cell and discharged from the kidney
Nucleic acid drugs can only be found in half if they see only "array". the same array,How to change skeletal oxygen to , what to do in 2′ place of sugar, what to do at the endHome The difficulty of manufacturing and quality control will change even if it is decomposed. Khvorova and Watts have the characteristics of tissues that determine tissue distribution and,「Dianophore」Name Nucleic acid drugs"Chemical modification of sugar, base and phosphate skeleton, structure of single chain or double chain, presence of targeted ligand"Accepted to be largely prescribed byFacts。
2. 4 types - antis , siRNA, aptamer
Nucleic acid drugs approved are divided into four major ways of working. First 3Correlation of base sequencesthe target RNA and theStructureBind to protein.
| Type | Article description (Roberts et al 2020) |
|---|---|
| Gapmer type Antis | DNA-based internal gaps and RNA-like wings modulated in 2′-OMe and LNA are combined with high affinity to targeted transcription products.The RNA-DNA double chain is the base of RNASEH1 and the target is decom d. |
| Disability type Antis | Targeting the splicing signal of the mRNA precursor, depending on the type of signal targetedSkip to main content |
| siRNA | Classical19+2, i.e. 19 bases have two pro sions at the end of 3′21 RNA 2 double chainsHome Guide chain is part ofCSCAGO2to target and completely complementary10-11 times of guide chainthe target is cut |
| Aptamer | GenerallyApprox. 20-100 basefolded into a fixed secondary structure,ligands interacting with target proteins through a three-dimensional structure and adaptive fitWorking as not ration designSELEXThe method of evolution of the test tube |
AllFacts(Roberts et al 2020 [Reference 1]). This paper is mainly used by the marker.Targets outside cells (receptors, etc.)forIt becomes simple even if the problem of delivery is somewhatFacts。
3. Chemical Qualification – 2′ place of skeletal and sugar
Natural DNA and RNA are immediately dissolved in the body. Khvorova andtsts“All antis、s require chemical modification to have sufficient activity in the organism”I wroteFactsHome where to qualify is large2′ of skeletal (phosphate) and sugar
(1) Skeleton – Phospho (PS)
Roberts'The introduction of phosphoate (PS) bonds that replace one of the non-crosslinked oxygen ofs between nucleotides is widely used in the chemical oligonucleotides.'Facts。
Khvorova andtstsThe chemical modification applied to anti-s、 technology is still the most widely used. "It is a phosphatioate skeleton"HOME “It was originally introduced to give nuclaase stability, but the influence of phosphatioate modifier has appeared in the body of oligonucleotide and intake.”and organizeFacts。
PS has a clear two-sided property. Roberts:Facts。
- Advantage:"Nucrease resistance, as well as binding to protein in plasma and in cells"has a double effect. Binding with albumin, etc.Increase circulation time and reduce renal excretion.
- Advantage:The interaction with intracellular proteins (such as nucleoline) is not possible,Accumulation in nuclearIt is believed to be useful. Nucleus is an action site of antis that changes splicing
- Point:"Lower binding affinity to target"Home This complements different types of modifications
- siRNA is different:"The siRNA that PS-qualifies all bindings is less active than the equivalent phosphodiester (PO) siRNA."For PSCloseExample
(2) 2′ place of sugar
Roberts2′-O-Methyl(2′-OMe), 2′-O-Metoxyethyl(2′-MOE), 2′-fluoro(2′-F)2′ subst tion, "Replacement of the 2′ hydrochloric acid group of unmodified RNA with a nucleus 2′ hydrochloric acid group increases nuclease resistance, stability in plasma, half-life in tissue, and lasting efficacy."Facts。
More“These modifiers also increase the binding affinity to complementary RNA by adding the revos’ 3′-end packer (RNA).”FactsHome However,“These 2′-Revos modifiers are not compatible with RNase H activity”so, it is used for three-dimensional obstacle type or gapmerDouble WingsSet toFacts。
On how much affinity goes up, Khvorova and Watts are double chain melting temperatures per qualified 1 base (T)mshows the rise width ofFacts。
| ΔT per 1 basem | Paper Description | |
|---|---|---|
| 2′-MOE | 0.9〜1.7℃ | Dozens of 2′-O-alkyll subst tions"It floated as one of the most useful analogs"Home Increases nuclease resistance. approved mipomelsen and drugs in many clinical trials have this modifier |
| 2′-F | Approx. 2.5°C | RNA 2′-Fluoro-modification also increases affinity |
| LNA | 4〜8℃ | Revos2′ Oxygen and 4′ Carbon BridgeHOME RNA binding"The affinity of unprecedented"Methylation analogscEt（constrained ethyl）called |
| tcDNA | Approx. 2°C | Another lig。 fixed type based on the tricyclic skeleton. The affinity is smaller than LNA, but is promising in applications that change splicing |
AllFacts(Khvorova and Watts 2017).Koshkin et al (1998) and 2′-O,4′-C-Methylene cross-linked type (Kobiga, 1998) are quoted in the paper.Facts。
RobertsPMOHome "The nucleic acid chemistry of nucleic acids in charge"ExplainFactsHome It is designed to make both sugar and skeleton.
Bill Thorsen approved in Japan (Biltepsotomy 250 mg) in the PMDA review report "Synthetic oligonucleotide with Morpholino skeleton"Original medicine"It is a phosphorothioate (PS) oligonucleotide consisting of 21 residual nucleotides, white powder, and original medicine is amorphous."Facts。
4. The ulation of this paper: How many PS bonds are produced
It may be the most surprising thing for engineers of materials. When a PS bond is made, the phosphorothioate (PS) center becomes uncentered.
Roberts"Sulfur atoms are added to PS bonds, which causes the uncentered PS center to each qualified atom.p And Rp The shape of the two three-dimensional heterogeneous bodies called "HOME "So the skeleton is completely PSized 20 oligonucleotides are actually 219 It is a semi-mixture of the sequence of the street (i.e., a different molecule of more than 500,000).Facts。
More"The physical chemical properties of each three-dimensional center differ in terms of hydrophobic/ionic, nuclease resistance, target affinity, and RNase H activity."Facts。
It is counted according to the description of the paper and calculated even if the chain length is changedThe calculation of this paper。
- Premise:There are (n-1) nucleotide interconnects in the chain of the base.
- Premise:Each PS binding is Sp And Rp the two streets are independent of each position
- 20 base (all PS):219 ＝ 524,288 streets(Cons) with more than 500,000 papers)
- 18 base (all PS):217 ＝ 131,072 streets
- 21 base (all PS):220 ＝ 1,048,576 views。Adding one base will double the number of isomers
- (General design in siRNA):6 PS locations 26 ＝ 64 streets
Premises and Limits:This isNumber of combinationsIt does not indicate that each isomer can be equal. MoreThe number of heterogenes does not mean quality or safety problems. This number is used to understand the situation that "not managed as a single compound" seen in the next chapter.
Origonucleotide stretches one base. If the coupling is not perfect,Short Chainsleft. Change the yield per stage to measure the ratio of up to 20 basesThe calculation of this paper。
- Premise:20 Couplings to get base19 times
- Premise:The yield of each stage is equal, and the failed chain does not stretch afterward (actually the failure end is capped)
- Each step 98%：0.9819 ＝ about 68%
- Each step 99%：0.9919 ＝ about 83%
- Each step 99.5%：0.99519 ＝ about 91%
- For 40 bases:0.9939 ＝ about 68%。Even the same yield, double the chain, the purity of the coarse product falls to 98% of the 20 base
Andrews"Coarse purity exceeding 80% is not unusual"It saysFactsHome This is equivalent to 99% of each stage. Contrast to this article). Premises and Limits:This calculation is based on the simplicity of equal yield, and does not indicate the actual impurity profile.
5. Material Technician Perspective 1: 'Managed mixtures' rather than 'single compound'.
The number of 500,000 streets in the previous chapter is"Isolation and」ntification"It means. Notice of the Ministry of Health, Labour and Welfare "Matters to Consider in the Security and Evaluation of Nucleic Acid Drugs" is handled from the front.
If it is technically difficult to evaluate the distribution of three-dimensional heterogeneities of active ingredients in oligonucleotides (if non-cross-linked oxygen groups are substituted by functional groups) or morpholino-nucleic acids, the production process and parameters that affect the three-dimensional chemistry of the molecules should be clearly defined, and the normality of the three-dimensional heterogeneous distribution of the active ingredient should be explained.Facts
Changes that occur here are familiar to material engineers(This article) If you cannot guarantee the standard by analysis of the final product, we will guarantee it in terms of the process.Dutch It is a way of thinking that has been done for a long time with polymers with weight distribution and granularity distribution.
The notice is the same posture for impurities. “It is often difficult to develop an analysis method that shows similar physical chemical properties and separates all oligonucleotides.”When appropriate"One group of oligonucleotides can be managed as a group of oligonucleotides."Contact UsFacts。
More“In with the characteristics of oligonucleotides, the significance of applying ICH guidelines M7 for oligonucleotides is considered to be a lack.”、 "It is not practical to apply thresholds of reports, structural decisions and safety confirmations shown in Q3A (R2) to oligonucleotides."Facts。 The framework of impurities management made for low-、 drugs is not effective as it isIt is.
The PMDA review report is about the original drug of Birtralsen The original drug is a unique stereo compound with an asymmetric center on carbon atoms and 20-lyne atoms on the Morpholin ring.Facts。
This is a description of the applicant for the treatment of affinity substances. Origonucleotides have chemical properties that are similar to each other, so it is difficult to separate and analyze them individually. That's why I think it's appropriate to manage impurities detected in HPLC analysis using purity testing because the impurities profile between lots is consistent.Facts。
Original medicine standardContainment, sexual test (UV/VIS, IR, MS), pH, purity test (solute, affinous substance (HPLC), residual solvent (GC), moisture, endotoxin, microbial limit, quantitative method (HPLC)set Multiple processes of and purification are specified as an important processFacts(Specific process names and parameters are private part of the review report)
There is another sentence to read from the procurement side in the same notification.
Since the impurities included in the starting substance that are into the original drug are considered high risk, it is necessary to consider the impurities profile of the starting substance. The management of the starting substance is limited to purification opportunities in the production of oligonucleotides compared to low- chemical 、 drugs, and in the final product there is a limit to the separation and detection of oligonucleotides, and it is necessary to be positioned properly in the management strategy of impurities.Facts
"Refining opportunities are limited"This is the essence of this field. In the。 of low。s, the purity can be raised by crystallization and extraction for each intermediate. But Oligonucleotide isAfter stretching to the end on the carrier, apply only one chromatographyIt is basic. In other wordsI can't make quality on the wayHome SoThe impurities of raw materials (such as phosphate) are reflected in the impurities profile of the product.。
If you look from the side that defines the material, this"Monomer's purity specification directly connects to the final product standard"It is a composition. It is a position similar to high purity chemicals for polymer polymerization monomers and semiconductors (in this article).
6. GalNAc - Deliver to the liver with 3 sugars
The most clear and successful delivery of nucleic acid drugsLiverComment The main roleGalNAc (N-acetyl Galactosamine)This is the modification of sugar.
Roberts"GalNAc is a high affinity (K) to the athyrogen protein receptor 1 (ASGR1) that expresses high in the liverd = 2.5 2.5M) is the sugar part that binds antisense and siRNA into hepatocellular cells by endocytosis.ExplainFacts。
The nature of the receptor is also essential.“ASGR1 is very high in the liver and is ideal for effective delivery targeting the liver because it is quickly recycled to the cell membrane.”Facts。
It is designed to be outward."The interaction between GalNAc and ASGR1 is pH-sensitive, and during the acidification of endosomes, the receptor isoform and oligonucleotide complex dissociate. Then the GalNAc part is enzymatically degraded and the oligonucleotide is free."Facts。
This paper explains why GalNAc binding is now a major strategy "High liver silence, smallness with nanoparticle complexes, clear chemical composition, low cost"Facts。
A number is shown for the improvement width of the spindle. "GalNAc binding increased antis。 secretion by about seven times in the mouse, which was specific to the liver. 30 times in human patientsFactsHome More"GalNAc binding antisense is given priority to liver cells in the organism, while unbound antisense is mainly detected with non-liver cells in the liver."Contact UsFacts。
One of the original works of GalNAc binding, Nair et al. 2014 paperJACS) There is a definitive statement from the material and process side.
"The ligand from GalNAc is linked with the conditions of solid phase oligonucleotide and deprotection, and the yield is equivalent to the standard oligonucleotide."Facts
"In other words, this ligand can use existing devices and processes as it is""Sorry, this entry is only available in Japanese. When in、 new functional groups"it fits into existing line protection base strategy and de-protection conditionsThis is similar to the composition that only monomers on existing polymerization processes are practically used.
The same paper obtained RNAi activity of the liver by subcutaneous administration and optimized chemical modification "In vivo achieves 5 times greater improvement in parent design and 50% effective after single dose (ED)50) was 1 mg/kgComment More“This makes it possible to subcutaneously administer the、eutic meaningful dose with a dose of less than 1 mL”ReportFacts （Pre ical data in rodents. Dosage or effects in humans）。
1 mL or less"It is important that the condition is expressed (This article explains). The capacity that can be put once in subcutaneous injections has a upper limit." Raising blood pressure is also a problem of “whether it can be an injectable formulation”"Dutch When viewed from the side of the preparation, the improvement of the surface is also a means of solving the dissolution and capacity."
7. Off-target effect – 7-base coincidence
Although it is the strength of nucleic acid drugs that can be targeted by arrays, Act even with short matchingIt is a weak point and back. This was shown in the analysis of gene expression profiles in 2003.
“RNA、 has been considered to require almost identical arrays between siRNA and its tribe mRNA.”——The result is differentFacts。
“The profile of the transcription product was not a targeted signature, but a specific signature to the siRNA and included a direct silence of non-targeted genes with only 11 consecutive matches of siRNA.”Facts
Con"siRNA indicates cross-reacting with a limited array similarity and not targeted"It wasFacts。
After that, I narrowed down which part of the match is effective. Janas et al 2018 papers (Nature CommunicationsHome Off-target effect by RNAi"The seed area of the antisense chain (second to eight nucleotides) should be combined into the complementary part of the 3′UTR"Driven by organizeFacts。
This paper is a summary of liver toxicity seen in RNAs in GalNAc binding siRNA.
"Hepatotoxicity in rodents observed with excessive exposure is not chemical modulation or RNAi pathway disruption, but can be attributed to off-target effects through RNAi as a main element."Facts
and measuresChemical QualificationComment "These off-target effects can be mitigated by regulating seed conflicts using thermally unstable chemical modifiers, which significantly improves the safety profile of GalNAc-siRNA in dots."FactsHome"7 of anti-nucleic acid (GNA), anti-sense chain"Methods are shownFacts。
We check how much "7-base match" and "11-base match" were found.The calculation of this paper。
- Premise:Consider random arrays with four different bases (actual arrays are not random)
- 7 Probability that the base coincides:1 ÷ 47 ＝ 1 ÷ 16,384。1 time per 16,000 basesIt becomes a calculation that appears
- If you examine the array of 100,000 bases:100,000 ÷ 16,384 ＝ Approx. 6 locations
- 11 Probability that the base coincides:1 ÷ 411 ＝ 1 ÷ About 419 million
- 19 Probability of all bases coincidence:1 ÷ 419 ＝ 1 ÷ Approx. 2,750 billion。No coincidence occurs first
This contrast shows the nature of the off-target problem(This article) The design of "align with the entire length of the array" is unique enough, but it is actually a short part matchingHome So the specificity is not guaranteed in length.
Premises and Limits:Because the base of the actual genome or transfer product is not randomly aligned, this calculation isulation to grab the sense of the digitComment It does not indicate that something actually matches a specific array, and it does not evaluate toxicity.
The Guidelines for Non-Clinical Safety Assessment of Nucleic Acid Drugs on March 30, 2020 are divided into two off-target toxicities.Facts。
- Off-target toxicity due to hybridization:"Toxic by Hybridizing on Similar Base Arrays other than Targets"
- Off-target toxicity not caused by hybridization:"Toxic that is attracted by the structure and physical and chemical properties of nucleic acid drugs without using hybridization"
and how to evaluate it. About Us "It is recommended to use in silico analysis using human genome DNA and RNA information, or in vitro gene expression analysis using human cells, because humans and animals have different genome sequences."FactsHome About the latter"It is thought that the non-clinical safety evaluation of chemical products is helpful because it is attracted by the physical properties of nucleic acid drugs (chemical modification, etc.)"Facts。
This section changes the order of development (in this article). The toxicity derived from the array is different from the genome if the species is different. SoTest in silico and human cellsis positioned as a normal evaluation method.
HomeThe toxicity derived from chemical modifications evaluates the same as chemical productsContact UsFactsHome The safety evaluation of nucleic acid drugs Going forward in another way by separating the story of the array and the story of the materialStructure
The relationship between material engineers is clearly the latter side (in this article). Types of skeletal modification, terminal ligand, salt shape, impurities — Array is independent, rated as chemicalwill be in charge area. This guideline includes animal species"It should be used with rodents and non-dentures as well as facts."Facts。
8. Solid-phase and purification – repeating the reaction of four-stage by one base
For the manufacture of nucleic acid drugsNo cell culture or fermentationHome Repeat chemical reaction in the device. Andrews et al (co-reported by chemical process representatives of multiple pharmaceutical companies) organizes this figure.
"The manufacture of oligonucleotides for the treatment of a single chain typically consists of four main elements: (1) oligonucleotide synthesis on solid-phase carriers, (2) removal of protective bases, (3) purification by detachable chromatography, (4) drying by freeze drying."Facts
"Oligonucleotide is synthesized by the phosphoramidite method using solid-phase carriers that have been the mainstream of oligonucleotide synthesis for about 40 years."FactsHome Substance"Hosperamidite monomers in the form from protected Nucleoside"HomeFacts。
is used, "Synthetic is fully automated with computer control, and reagents are se」tially flown into columns"It is writtenFacts。
| Writer (Andrews et al 2021) | |
|---|---|
| 1 Detritilization | "5′ Dimethoxytritil (DMT) protection base on the hydrochloric acid base is removed with a solution of organic acid, dichloroacetic acid (DCA) in the toluene, typically" |
| 2 Coupling | "The next nucleoside phosphate amidite in the array is activated with acidic activator, and the coupling with the oligonucleotide in the extension 5′ water acid base" |
| 3 Oxidation/Sulfurization | "Add oxygen or to the groups with iodine or sulfide and give either a phosphate diester or a phosphate diacetate group."。This step determines whether to put PS binding |
| 4 Capping | "Cap unresponsive 5′ hydrochloric acid base with anhydrous acid, reduces further expansion of the coupling failure chain, minimizing N-1 impurities." |
| End of | "Clean with amine solution to remove cyanoethyl protector from phosphate diester/phosphoacetioate skeleton" |
| Cut out and de-protection | "Protect long-generated objects are cut out from solid carriers, and unstable protective bases are typically removed by heating the ammonia surface."Home RNA2′-O-Si protection group removal requires fluoride treatment |
| Refining | Reverse and Anion Exchange chromatographyis most common.“The last 5′-DMT protective base is often attached to it because it can use its hydrophobicity to separate chromatography.” |
| Freeze drying.Energy-intensive operation (over 2 kJ/kg)Home"One of the main process bottlenecks"Made |
AllFacts(Andrews et al 2021 [Reference 3]). The entire process"If you think about the size and complexity of the nucleic acids and the number of chemical conversions involved (about 80), it is a remarkable achievement that can be synthesized, refined, and isolated with excellent yield (about 50%) and purity (about 90%)."ratedFacts。
This paper describes the efficiency of raw materials. "The efficiency of the starting substance is low (e.g., average 36% in four deoxyribonucleoside phosphate). Because the protective base is widely used, as a result, most of the raw materials of these nucleic acid precursors are not taken into the final drug and are discarded as waste. "Facts
About DMT“DMT groups are equivalent to approximately one third of the mass of deoxy phosphate.”and Smaller weight alternative protectionContact Us However,“In order to use it as a purification handle, it will still be useful to use DMT protected phosphate in the final cycle.”Facts。
9. Material Technician Perspective 2: Raw Material 4t to 1 kg
Andrews’ reports are very valuable.5 companies have published their actual material incomeComment IndicesPMI (Engineering Mass Intensity)—— "A measure of the amount of raw materials needed to produce one kilogram of isolated original medicine"HomeFacts。
Contact Us8 processes including antis and siRNA(MOE, LNA, cEt, etc.)Facts。
"PMI is included in the range from 3,035 to 7,023, and the average was 4,299. These values are among the values of PMI calculated for low、s (center value 168-308) and biopharmaceu、s (about 8,300).Facts
The value divided by the chain length is also shown."PMI per nucleotide ranges from 199 to 251, the average is 199."Facts。
| Breakdown | Writer (Andrews et al 2021) |
|---|---|
| Material Type | Almost equal amount of organic materials and water.half of organic materialsWater ratio is oligonucleotide process51%Low process28%——“The result of using water purification technology” |
| View at the Step | Synthetic phase and purification phasecontributes to PMI. Composite stage of materialApprox. half |
| View in the stage of | The biggest contribution to detritilizationHomeAlmost half of the materials used in the phaseContact Us |
| Washing solvent | half of organic materials,Total PMI 25%Contact Us |
| Relationship with development stage | "Normally seen in low doses"The trend of PMI falls over time。“The production of oligonucleotides is a platform-based approach, and the opportunity to lower PMI in the development process, as the best practice conditions of previous projects apply to new compounds.”Seeking |
AllFacts(Andrews et al 2021 [Reference 3]).Materials used to synthesize the phosphate itself, and ligands such as GalNAc intermediates are not included in this ag、ationFacts。
Converts the average PMI and the amount of approved productsThe calculation of this paper。
- Premise:PMI4,299(Average of 8 items)Facts
- Premise:Gyburari1 vial 1 mg during mLIncludeFacts
- Premise:LEXI1 syringe 1.5 mL 284 mgIncludeFacts
- Original medicine per kg:4,299 kg ＝ Approx. 4.3 tonss
- 189 mg (equivalent to 1 vial):0.189 g × 4,299 ＝ Approx. 813 g。Over 800 g of raw materials for the amount of original medicine on the fingertipContact Us
- 284 mg (1 syringe equivalent):0.284 g × 4,299 ＝ Approx. 1.2 kg
- Water Content:If 51% of PMI is water, the original drug per kg Approx. 2.2 tonswater
- Washing solvent packaging:If 25% of total PMI, the original drug per kg Approx. 1.1 tons
Premises and Limits:The average value of PMI is calculated by the individual product.This is not the actual PMI of these products. Andrews8 items under developmentThe product name has not been published. It does not contain the phosphate and ligand content.
Sorry, this entry is only available in Japanese. This article explains. The itself is fast.Andrews“All reactions during the cycle are fast”I wroteFactsHome However, when the substance is consumed, 25% of total PMI, half of organic materials Nearly half of the material in the stage with the step of detritileizationUseFacts。
It is better to consider solid-phase engineering as a 'cleaning process' rather than a 'reaction process' is true.(This article) After each stage, it is always washed and it is repeated 19 times. The improvement plan of the paper is concentrated thereFacts。
- Re cleaning:like after coupling or after sulfideMinimizes critical cleaning
- Ex the reagent with nitrogen pressure:Do not use solvents to remove reagents from columns
- Reuse of cleaning fluid:Clean solvents at the end of the washing are used at the entrance of the same cleaning.
- column space:Use dynamic axis compression column to change column height according to the progress of ,Reduces cleaning amount of detritilization by eliminating head space
- Optional capping steps:"It has recently been shown that the sub-product of the sulfide reaction can be used as a capping agent for the coupling failure chain, removing the capping stage and resulting in a 14% reduction in PMI."
This is a typical notice of process design(This article) Half of material efficiency can not be improved only by looking at yield and reaction speed. "Use sub-products as reagents and processes"The last example is It can be said that application is effective as it is to improve the material process.
In addition to solvent selection, the paper is reflected in the CheM21 Guide. Dichloromethyl (DCM) has been used as a solvent for detritilization, but in large-scale production, it is replaced by toluene.Comment pyridine and triethylamine work as a base for oxidation, sulfide, capping, and skeletal detachment protection, but it is classified as "toxic" as low as the occupational exposure limitthat encourages alternative reviewFacts。
10. Examples of approval (reco tions made by regulatory authorities)
The following:FDA’s Drugs@FDA has the date of initial approval (ORIG-1) and has confirmed chemical composition with attachment or review theoryonly. Do not handle efficacy, effects, clinical results, and usage.Only the chemical composition and approval date.
| Product name | First Approval (FDA) | Remarks | |
|---|---|---|---|
| VITRAVENE (Fomyvillesen) | All 21 base PS DNA(First-generation antis)) / Injection in the glass body | August 26, 1998 （NDA 020961） | Roberts"The first approved nucleic acid drug"HOME"It is no longer used by a decrease in clinical needs."Contact Us |
| MACUGEN (Pegaptanib sodium) | 27 bases 2′-F/2′-OMe modifier, PEG aptamer/Injection in glass | 2004 （NDA 021756） | Roberts"First approved marketer"Contact Us Drugs@FDADisco)edContact Us |
| EXONDYS 51 (Eteprilsen) | 30 PMOs3D anti-s) | September 19, 2016 （NDA 206488） | type by Roberts |
| SPINRAZA (Nucinersen) | Attachment"2′ hydrochloric acid group is replaced by 2′-O-2-methoxyethyl group, and the amine acid bond was replaced by a phosphodiester bond."Contact Usweight 7,501.0/Intrathenal administration | December 23, 2016 （NDA 209531） | It is described that it is not frozen and light-proofed at 2 to 8 °C |
| ONPATTRO (Patisilane) | siRNA lipid nanoparticle preparationContact Us | August 10, 2018 （NDA 210922） | Roberts“The first approved RNAi drug”Contact Us LNP treats with this series "lipid nanoparticles" and "mRNA" |
| GIVLAARI (Gybosilane) | siRNA that shares the third GalNAc ligand(2′-F/2′-OMe) / subcutaneous injection.weight 17,245.56(s) salt), 16,300.34 in iso) acid | November 20, 2019 （NDA 212194） | 1 vial 1 mL189 mg。2〜25℃Save and write |
| VILTEPSO (Birtralsen) | 21 Subunit PMOReplace the five-member ribonosyl ring in the home with the six-member morpholino ring.Concatenate without charge。weight 6,924.82Contact Us | August 12, 2020 (NDA 212154, Quick approval) | In JapanMarch 25, 2020approved (approved number 30200AMX00428000).Applicable to conditional early approval system |
| LEQVIO (INC) | 3' GalNAc binding siRNA。2′-F or 2′-OMeHome6' shodiester skeletons at the end。weight 17,284.72Subcutaneous injection | December 22, 2021 （NDA 214012） | 1 syringe to 1.5 mL284 mg。Room temperature from 20 to 25°CSave and write |
| AMVUTTRA English | 3' GalNAc binding siRNA/ subcutaneous injection.weight 17,290(s) salt), 16,345 with free acid | June 13, 2022 （NDA 215515） | to 0.5 mL25 mg |
| IZERVAY (Avasin Captade Pegor) | 43 43 kDa RNA PEG to RNA aptamerHOMEWeight Approx. 56 kDa/Glass | August 4, 2023 （NDA 217225） | 0.1 mL to2 mg(Origonucleotide equivalent) Stored at 2 to 8 °C, not frozen or shaken |
The date of approval is FDA Drugs@FDA [Reference Material 8], chemical composition and storage conditions are attached to each product [Reference Material 7], EXONDYS 51, ONPATTRO, VITRAVENE, MACUGEN type is based on Roberts et al (2020) [Reference Material 1]FactsHome Bill Tracen’s approval in Japan depends on the administrative contact of the Ministry of Health, Labour and Welfare [Reference Material 12] and the PMDA review report [Reference Material 11]Facts。The date of action of ORIG-1 by the Drugs@FDA is as of September 17, 2004, while the approval notice PDF of the application has an electronic signature as of December 17, 2004, and the table of Roberts is "December 2004". Since the date does not match, this table only describes "2004".
- Dosage routes are biased to local or liver.From the skin and veins to the liver - Roberts“Transmission to non-liver tissue still has a great goal.”the status of the approved product is displayed as it isFacts
- siRNA approved products have si weight.Gibosilane 17,245.56, Inclusive 17,284.72, Butrysilane 17,290—All3' GalNAc binding siRNAthe mass is almost the sameFacts。Another array is placed on the same skeletonal values Commentary by this article
- Antis is separated by the chemical system.2′-MOE, All PS type (Nucinelsen) and PMO type without charge (Eteprilsen, Bill Tralsen)Facts
- The storage conditions are completely different from the product.2 to 8°C, 2 to 25°C, 20 to 25°CFacts。Low temperature transport is not required for nucleic acid drugs(This article)
- Aptamer is two examples.In Pegaptanib and Abasin Captade Pegor,Both are PEG-based and locally administered to the eyeHomeFacts
- Nucleic acid drugs determine the target in an array and determine how to reach it with chemical modification.Khvorova et al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al al alFacts
- All-PSified 20 base chains become a mixture of 524,288 street heterogeneous bodiesThe calculation of this paperHome Notification of the Ministry of Health, Labour and Welfare is difficult to evaluate distributionProcess parameters should be used to describe the permanentityFacts
- GalNAc delivers three sugars to liver cells.KdIt is a design that combines with = 2.52.5M and is removed by acidification of endsomeFacts
- Off-targets occur in short partial matching.7 The match of the base is calculated by about 16,000 basesThe calculation of this paper
- Production is a repeat of four reactions per base.19 cycles, 76 reactions, 14 hours in timeThe calculation of this paper
- The speed of material efficiency is cleaning.Raw material of about 4.3 tons per 1 kg of original medicineThe calculation of this paper25% of total PMIFacts
11. Glossary
- Origonucleotide
- short nucleic acid chain. There are many treatments around 20 bases.
- Antis (ASO)
- Nucleic acid of a single chain that complements the target RNA. Decomposition type and three-dimensional obstacle type.
- Gapmar
- RNA-type anti-s with DNA and double wings. RNase H
- RNase H
- RNA‐DNA double chain RNA side. Gapmer worker.
- siRNA
- 2 double chains of 21 base. Returns target mRNA onCSC including AGO2.
- RISC／AGO2
- RNA derivative silence complex and its core cutting .
- Guide Chain/Passenger Chain
- 2 siRNAs. A guide chain with a complementary side.
- Seed area
- The second to eighth of the guide chain. This partial match generates off target.
- Aptamer
- One-strand nucleic acid that binds to protein with a three-dimensional structure. SELEX
- SELEX
- How to repeat the selection and identification in the test tube and select the desired martamer.
- Phos) (PS)
- A skeletal modifier that replaces one non-crosslinked oxygen of phosphate with .
- 2′-MOE
- Qualification of 2-methoxyethyl base in 2′ place of sugar. Increases resistance and affinity.
- LNA／cEt
- Nucleic acid that crosses 2′ and 4′ of sugar to fix the lig . Increased affinity.
- PMO
- Morpholinonucleic acid. Consists of a skeleton that does not have a charge.
- GalNAc
- N-acetyl galactosamine. Sugar that binds to ASGR1 of liver cells.
- ASGR1
- Acyanol sugar protein receptor 1. Highly expressed in the liver and quickly recycled.
- HosHor Amidaito Method
- A 40-year method that extends the chain by one base on solid-phase carriers.
- DMT Group
- 5′ water acid base protection base. Remove by acid at the beginning of each cycle. Used for purification marks.
- Capping
- Operation to block unresponsive 5′ water acid base and prevent failure chains to stretch further.
- N-1 Impurities
- Sub-products that are shorter than the purpose. caused by coupling failure.
- PMI
- Process weight strength. The mass of raw materials required to obtain 1 kg of original medicine.
- Off Target
- action to unintended targets. There is a chemical origin of an array.
12. Reference materials (primary information)
- Roberts, T.C., Langer, R., Wood, M.J.A.「Advances in oligonucleotide drug delivery」Nature Reviews Drug Discovery 19(10), 673–694 (2020). doi:10.1038/s41573-020-0075-7 — pmc.ncbi.nlm.nih.gov
- Khvorova, A., Watts, J.K.「The chemical evolution of oligonucleotide therapies of clinical utility」Nature Biotechnology 35(3), 238–248 (2017). doi:10.1038/nbt.3765 — pmc.ncbi.nlm.nih.gov
- Andrews, B.I. (ACS GCI Pharmaceutical Roundtable)「Sustainability Challenges and Opportunities in Oligonucleotide Manufacturing」The Journal of Organic Chemistry 86(1), 49–61 (2021). doi:10.1021/acs.joc.0c02291 — pmc.ncbi.nlm.nih.gov
- Nair, J.K.「Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing」Journal of the American Chemical Society 136(49), 16958–16961 (2014). doi:10.1021/ja505986a — pubmed.ncbi.nlm.nih.gov
- Jackson「Expression profiling reveals off-target gene regulation by RNAi」Nature Biotechnology 21(6), 635–637 (2003). doi:10.1038/nbt831 — pubmed.ncbi.nlm.nih.gov
- Janas, M.M.「Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity」Nature Communications 9, 723 (2018). doi:10.1038/s41467-018-02989-4 — pmc.ncbi.nlm.nih.gov
- DailyMed（U.S. National Library of Medicine）FDA approved documentation (GIVLAARI/LEQVIO/SPINRAZA/IZE)」AY/AMVUTTRA/VILTEPSO) — dailymed.nlm.nih.gov
- FDADrugs@FDA: FDA-Approved Drugs — accessdata.fda.gov
- Ministry of Health, Labour and Welfare, Department of Pharmaceutical Affairs and Health"Things to Consider in the Security and Evaluation of Nucleic Acid Drugs" clinical drug trial No. 0927 No. 3, September 27, 2018 (PDF) — pmda.go.jp
- Ministry of Health, Labour and Welfare, Department of Pharmaceutical Affairs and Health"Guide) for Non-clinical Safety Assessment of Nucleic Acid Drugs" Pharmaceutical Trial No.0330, March 30, 2020 (PDF) — pmda.go.jp
- Pharmaceutical Medical Devices (PMDA)"Biltepsotomy 250 mg trial results report and review report" (2020) (PDF) — pmda.go.jp
- Ministry of Health, Labour and Welfare, Department of Pharmaceutical Affairs and Health"About the drug approved as a new drug" March 25, 2020 Office contact — mhlw.go.jp
13. Response Table of Claim and Source (Audit)
| Content | Home | |
|---|---|---|
| oligonucleotide is a polymer of nucleic acid, one-strand antisense is about 4-10 kDa, two-strand siRNA does not pass the cell membrane easily with a large hydrophilic polyanion of about 14 kDa. Organ delivery to non-liver tissue is still a major challenge. Gapmer, 3D, siRNA, and martamer mechanisms (resolved by RNASEH1, acting on splicing signals, 19+2 structures and AGO2, CSC, cutting at guide chains 10-11, tamers are obtained by SELEX, and cellular tamers are mainly applied to extracellular targets). Phosphoate (PS) replaces one non-crosslinked oxygen with, giving nuclease resistance and protein bonding, albumin bonding reduces circulating time, interaction with nucleolin, etc. is considered to be a nuclear accumulation, lowering the target affinity, and all-binding PssiRNA is less active than comparable PO siRNA. 2′-OMe・2′-MOE・2′-F is a OM2′ substitution, which replaces the nucleic 2′ hydrophilic group to improve resistance, plasma stability, tissue half-life, efficacy and promotes 3′-end packers to enhance affinity, but does not match RNase H activity. PMO is a chemical that is charged neutral and the five-member revose is replaced. All PS 20 bases are two 19-way semi compounds (more than 500,000 different molecules), which differ in terms of hydrophobic, ionic, nuclease resistance, target affinity, and RNase H activity. GalNAc joins ASGR1 with Kd=2.5 GalM, ASGR1 is rapidly recycled to the liver, the interaction is pH sensitivity and isolated by endosomic acidity, GalNAc is enzymatically dissolved and oligonucleotide is free, the triple GalNAc is typical, and GalNAc binding gives about 7 times more than a human patient with a mouse, the uncombined antisense is detected by non-real cells, the reason that GalNAc is low liver chemistry. | Roberts et (2020)[Reference 1]https://pmc.ncbi.nlm.nih.gov/articles/PMC7419031/ | Facts |
| The key advantage of nucleic acid drugs is that the delivery and delivery are mainly from chemical structures in the base sequence. The characteristics of tissue distribution and metabolism are called "Dyanofor", which is largely prescribed in chemical modification of sugar, base and phosphate skeleton, single chain or double chain, or presence of targeted ligand. All antisense molecules need chemical modification because they are active in the body. The first applied modifier was a phosphate skeleton, initially because of nuclease stability, but the main influence appeared in the body and intake. ΔTm per base is 2′-MOE, 0.9~1.7°C, 2′-F, about 2.5°C, 4~8°C in LNA, 2°C in tcDNA, 2′-MOE is one of the most useful analogues in dozens of candidates, including mipomersen, LNA crossed 2′ oxygen and 4′ carbon, and methylation analogue called cEt". | Khvorova and Watts (2017)[Reference 2]https://pmc.ncbi.nlm.nih.gov/articles/PMC5517098/ | Facts |
| The production of oligonucleotides for single-chain treatment consists of four main elements (solid phase, cutout and de-protection, purification with separating chromatography, and lyophilization). The mainstream of the phosphorus amidite method using solid-phase carriers is about 40 years old, starting with a protective nucleotide-derived phosphorus amidite, transferred from CPG to Polyethylene with UnyLinker, and the reagents are fully automated and the reagents are sequentially flown. A 3′ to 5′ directional 4-stage cycle (detritiation: toluene dichloroacetic acid, coupling: acidic activator, oxidation/furization: iodine or sulfide, capping: minimizing N-1 impurities due to anhydrous acid), cleaning after each stage, completing about 45 minutes, 20 salts within 24 hours, and finally minimizing the cyanoethyl protective base with an amine solution. Cutout and de-protection by ammonia water heating, fluorocarbon processing in case of RNA content, and no rough purity exceeding 80% are uncommon. Reverse phase and anion exchange chromatography are commonly used to separate 5′-DMT. This is one of the bottlenecks due to energy-intensive operation at 2 k /kg. The conversion efficiency of about 80% yield, 50%, purity of 90%. The efficiency of four deoxyribonucleoside phosphate amidites is average 36%, and the DMT group is equivalent to one third of the mass of the deoxyribonucleoside, and the DMT protector is important in the final cycle. PMI definition and 8 items (3,035 to 7,023, average 4,299, 168 to 251 per nucleotide, average 199), the median value of low 168 to 308 and the ratio of about 8,300 of biopharmaceuticals, water 51% (low 28, cleaning solvents 25% of organic materials, stages about half of material, detritiation is almost half of material in stages, and PMI tends to fall in the development phase, according to the platform approach that phosphoride and PMI materials are aggregated. Improvement plan (reduction of cleaning, ex of reagent by nitrogen pressure, reuse of cleaning liquid, omission of capping stage by dynamic axis compression column, sulfide sub-product and PMI 14% reduction). DCM has been replaced by toluene, pyridine and triethylamine are classified as hazardous from low occupational exposure limits. | Andrews et al(2021)[Reference 3]https://pmc.ncbi.nlm.nih.gov/articles/PMC8154579/ | Facts |
| GalNAc-derived ligands are equivalent to standard oligonucleotides under the conditions of solid phase oligonucleotide synthesis and deprotection. RNAi gene silencing in the liver was achieved through subcutaneous administration. Chemical modifications resulted in a fivefold increase in the parent design's efficacy in vivo, with an ED50 of 1 mg/kg after a single dose, allowing for subcutaneous administration of less than 1 mL (including preclinical reports on rodents). | Nair et al )[Reference 4]https://pubmed.ncbi.nlm.nih.gov/25434769/ | Facts |
| RNA profiles have been considered to require almost identical arrays, and the transcription product profile indicates a siRNA-specific signature rather than a target-specific signature, including the silencing of non-targeted genes with only 11 consecutive bases, and siRNA intersects with limited array similarity and no targets. | Jackson et al (2003)[Reference 5]https://pubmed.ncbi.nlm.nih.gov/12754523/ | Facts |
| The off-target effects of RNAi are mainly driven by the combination of antisense chain seed area (2nd to 8th) and 3′ UTR complementary parts. The liver toxicity observed in rodents during overexposure to GalNAc-siRNA can be attributed to off-target effects, primarily through RNAi, rather than chemical modifications or disruption of the RNAi route. Thermally unstable chemical modifiers reduce off-target effects by adjusting seed conflicts and significantly improve safety profiles. | May 2018[Reference Material 6]https://pmc.ncbi.nlm.nih.gov/articles/PMC5818625/ | Facts |
| The chemical composition, weight, content, and storage conditions of each product described in Chapter 10 (Nucinersen's 2′-O-2-Methoxyethyl and Phosphoate bonding, weight 7,501.0, 2–8°C, non-freezable and light; GalNAc-binding siRNA and 2′-F/2′-OMe, weight 17,245.56 / free acid 16,300.34, 1 mL to 189 mg, 2-25 °C; Bosutinib Pegol is a RNA aptamer that combines RNA PEG of about 43 kDa, about 56 kDa, 2 mg to 0.1 mL, 2 to 8°C, cannot be saved and frozen; Biallerans' 21 sub-unit PMO contains a weight of 6,924.82, and a 250 mg to 1 vial of 5 mL and a fast approval based on approval). | DailyMed FDA Approved documents[Reference Material 7]https://dailymed.nlm.nih.gov/dailymed/ | Facts |
| Chapter 10 FDA approval date (VITRAVENE August 26, 1998 / NDA 020961, MACUGEN NDA 021756, EXONDYS 51 September 19, 2016 / NDA 206488, SPINRAZA December 23, 2016 / NDA 209531, ONPATTRO August 10, 2018 / NDA 210922, GIVLAARI November 20, 2019 / NDA 212194, VILTEPSO August 12, 2020 / NDA 2154, DA 2212, DA1222, DA221222, DA1222, DA22, 202522, 2025, 2025, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 2022, 20 Please note that MACUGEN will be disco。ed. MACUGEN’s ORIG-1 action date is as of September 17, 2004, but the electronic signature of the approval notification PDF was as of December 17, 2004. | FDA Drugs@FDA[Reference 8]https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm | Facts |
| If the distribution of a three-dimensional heterogeneous body is difficult to technically, it is necessary to describe the permanentity of a three-dimensional heterogeneous distribution by specifying the manufacturing process and parameters that measure the three-dimensional chemistry of the resin. It is often difficult to develop an analysis method that separates all oligonucleotides and can be managed as an analogue group in the appropriate case. ICH M7 is considered to be less meaningful, and the threshold of ICH Q3A (R2) is not practical. It is necessary to position it in management strategy based on the risk of impurities included in the departing substance, limited purification opportunities and limitations in separation and detection | Ministry of Health, Labour and Welfare “Matters to Consider in the Security and Evaluation of Nucleic Acid Drugs”[Reference 9]https://www.pmda.go.jp/files/000228569.pdf | Facts |
| Off-target toxicity is divided into “that is caused by hybridization” and “that is not caused”. Since the genome sequence differs between humans and animals, it is recommended to evaluate in silico analysis and in vitro gene expression analysis using human cells. The non-clinical safety evaluation of chemical products for the latter is considered reference. To be used with rodents and non-stick teeth as animal species | [Ministry of Health, Labour and Welfare “Guide for Non-clinical Safety Assessment of Nucleic Acid Drugs”][Reference Materials 10]https://www.pmda.go.jp/files/000234603.pdf | Facts |
| Biltralsen is an oligonucleotide with a morpholino backbone, the original drug is an amorphous white powder consisting of 21 residual nucleotides, and is a stereoisomer with an asymmetric center on the morpholine ring and 20 atomic centers. It was difficult to separate and analyze oligonucleotides into individual components, and the applicant explained that it was appropriate to manage them as an impurities group, and the impurities profile between lots was consistent. A water-based injector containing 250 mg in 1 vial of 5 mL and the additives are sodium, hydrochloric acid, sodium hydroxide, and water for injection. Applicants of the conditional early approval system, rare and predetermined pharmaceuticals, and pre-examination designated medicines, deliberation results were reported on March 6, 2020, and the examination report must be submitted by February 19, 2020. [Calculation in this article. It is assumed that the yield of each stage is equal, that the base is randomly equal, and the average value of PMI is applied to individual products. The numbering of combinations and probability does not indicate the actual impurity ratio or toxicity, but is not the meaningful interpretation] | PMDA Biltepsotomy 250 mg Trial Results Report / Review Report[Reference Materials 11]https://www.pmda.go.jp/drugs/2020/P20200408002/530263000_30200AMX00428_A100_1.pdf | Facts |
| “Biltepsotomy 250mg” (Japan New Drug Co., Ltd., approval number 30200AMX00428000) was approved as a new drug on March 25, 2020 | Office contact by Ministry of Health, Labour and Welfare (March 25, 2020)[Reference Material 12]https://www.mhlw.go.jp/web/t_doc?dataId=00tc4855&dataType=1&pageNo=1 | Facts |
| As of May 24,288, 131,072, 1,048,576, and 64 in 6 PS. approx. 68%, approx. 83%, approx. 91%, and approx. 68%, respectively. The 7-basin coincidence was about 6 expected values per 1/16,384,100,000 bases, 1/11 bases per 1/about 419, 19 bases per 1/about 27.5 billion. 19 cycles: 76 times, 45 minutes x 19 = 14 hours. About 4.3 tons per kg of original drug from PMI 4,299, about 813 g of 189 mg, about 1.2 kg of 284 mg, about 2.2 tons of solvent, about 1.1 tons of cleaning solvent | The 20-basin array has 500,000 ways behind it. | The calculation of this paper |
| Production cost, production scale, actual PMI, hosmidite price and supply system | The scope of this article has not been stated because the primary information published cannot be confirmed. | |
| Efficacy and effect of each product, clinical results, safety evaluation, usage and dosage, superiority of the product | This article is an explanation of chemical, material and manufacturing technology, and does not evaluate the effects and safety of the treatment. For approved products, only chemical composition, approval date and storage conditions listed in the regulators’ publication. The description of the ED50 and Chapter 7 of Chapter 6 relating to hepatotoxicity is that the contents of the animal test reported by the paper are quoted as it is | |
| Which technology will be solved by delivery to non-liver tissues, and the mainstream of the controlled oligonucleotide | At the time of the investigation of this article (September 2026), the primary information indicating the arrival and trend could not be confirmed | Undetermined / Future |
| The management of the three-dimensional heterogeneous body is organized by the process rather than the analysis of the final product. Monomers for polymerization and high purity liquids are used to determine the composition that the purity of the starting substance remains in the final product. Calculation in solid phase as "cleaning process" instead of "reaction process". Read that the specificity is not guaranteed in the length. Evaluation methods are divided by toxicity array from array and toxicity. from chemical. Read that GalNAc ligand was adopted by fitting existing conditions. It was positioned as a means to solve the dosage capacity. I read the use of the same skeleton because the weight of the approved product is increasing. Read from the table | and commentary of this article based on the publication content. It is not the opinion of authors and regulatory authorities of each paper | |
| Fig. 1 - Fig. 4, Fig. 6, Fig. 7 must be a drawing for explanation, not actual structure, device, and measurement image. Hero image and figure 5 are AI generation images | Notes by this article |
Last Updated: September 26, 2026/Source is limited to primary information (Reference paper, FDA approval attachment and Drugs@FDA, Notification Guidelines for the Ministry of Health, Labour and Welfare, and PMDA review report). They are distinguished from the facts cited as "explanation" because they contain chemical design and process design readings. We do not describe the cost of production, the size of production, the actual PMI per product, and the price and supply system of raw materials because we can not confirm with the primary information published. PMI data from Andrews et al (2021)The name of the product is not published. This article is an explanation of chemical, material and manufacturing technology.It does not evaluate the effectiveness and safety of the treatment, but it is not medical advice. All diagrams are illustrations for explanation. Figure 1 - Figure 4 · Figure 6 · Figure 7 is a vector drawing, is an image and figure 5 is an AI generation image.We do not show actual s, devices, and products.