September_New Drugs｜Nucleic Acids: A New Blue Ocean: New Drug Development Opportunities in the Spotlight

Published On: 2023/09/22|Categories: 大健康(Healthcare)|

Nucleic acid therapy has unlimited potential and has become the focus of technology, capital and market pursuit

Nucleic acid therapy is a series of nucleotides composed of drugs, for the treatment of human genetic diseases, rare diseases, tumors, chronic diseases, and infectious diseases to provide new treatment options, is expected to succeed the small molecule chemical drugs and protein antagonists as a new class (modality) of mainstream drugs. Proteins (Remarks: Proteins are gene products) are important components of life activities and diseases, and their mechanism of action is closely related to diseases and is also the core of drug development. According to the analysis of Nature Reviews journal, due to the structural characteristics of proteins, there are about 85% target disease-causing proteins or disease-associated proteins that cannot be acted upon by small molecule chemicals or protein antiseptics, and therefore cannot be made into drugs. The core value of nucleic acid drugs is that they can break through the difficulties in protein structure design and selectively inhibit the disease-causing proteins associated with the undruggable protein targets at the molecular level by inhibiting gene expression, targeting non-coding RNAs involved in transcriptional and epigenetic regulation, changing mRNA splicing, up-regulating the target genes and editing genes, etc., so as to carry out the treatment of the relevant diseases, which theoretically can be directed against a wide range of disease-causing proteins. Theoretically, it can inhibit a wide range of disease-causing proteins, and therefore new nucleic acid drugs are attracting attention in the market.

核酸新藥依據作用機制可簡單區分為反義寡核苷酸(antisense oligonucleotide, ASO)、RNA干擾(RNAi)、信使RNA(mRNA)及核酸適配體(RNA aptamer)等四大類，截止目前美國FDA已經批准約10個ASO、5個siRNA、2個mRNA及1個aptamer，其中正在進行臨床試驗的核酸藥物約有上百項，適應症涵蓋人類遺傳病、罕病、腫瘤、傳染病、慢性病到尚無治療藥物的疾病。根據Mordor intelligence估計2023年全球核酸藥物市場規模約48.95億美元(不含新冠mRNA疫苗)，預估2028年可成長1.95倍達到95.45億美元，年複合成長率為14.29%，從實際核酸新藥銷售額來看，目前核酸藥物的銷售冠軍是Biogen/Ionis開發用於治療脊髓性肌肉萎縮症的Spinraza^®(nusinersen)，在2022年的銷售額達17.94億美元，其次是Alnylam開發用於治療甲狀腺素運載蛋白澱粉樣變性的siRNA藥物Onpattro^® (patisiran)，在2022年的銷售額約5.58億美元，USFDA核准核酸藥物中已有7項核酸藥物的銷售額已超1億美元，隨著核酸新藥治療商機明確、審批速度加快，以及近年國際市場交易熱度增高如ReNAgade、ADARx和Alltrna等皆在今年成功募資破億元美元，核酸療法新藥開發潛力引起關注，已成為技術、資金和市場的追逐焦點。

核酸藥物新機遇，吸引新興生技公司和國際大藥廠押注

核酸新藥核心技術涵蓋藥物標的序列、修飾與傳遞載體技術，以及藥物量產等，由於核酸藥物極其脆弱，容易在血液中被代謝破壞，且必須經體內適當位置被正確細胞吸收才能發揮效用，如何將核酸藥物傳遞至靶向細胞(或特定組織)就是關鍵的挑戰，因此以保護核酸結構、增強靶向能力、減少遞送藥量和減少毒副作用的核酸藥物修飾和傳遞載體技術，就成為保證核酸藥物安全性和療效的關鍵，也是藥廠核心技術的兵家必爭之地，隨著核酸GalNAc conjugates修飾和脂質奈米顆粒(LNPs, Liposomes and lipid-based nanoparticles)傳遞載體系統的發展，雖然脂質奈米顆粒(LNP)是最常見的藥物傳遞系統約佔總數的81%，但創新的病毒載體系統、外泌體(exosomes)遞送系統，或直接用於患者的基因編輯技術等仍有可為。

核酸新藥主要開發商多為新興生技公司如Alnylam、Ionis 、Sarepta和Nippon Shinyaku等，隨著清晰且有潛力的新藥開發商機，國際大藥廠除Pfizer合作BioNTech外，GSK收購Wave Life Sciences、Novo Nordisk收購Dicerna、Novartis收購Medicines Company(技術源於Alnylam)、Regeneron投資Alnylam和Bayer 擴大Acuitas合作等，都標誌著核酸療法對國際大藥廠戰略重要性的日益增加，適應症開發領域也從罕病單基因突變疾病，朝向代謝相關慢性疾病領域發展，似乎期待核酸新藥應用未來有望成為替代傳統小分子化學藥在代謝疾病的治療方案。

台灣核酸新藥多路進擊，以核酸傳遞系統為基礎搶攻國際合作商機

縱觀輝瑞和BioNTech的新冠 mRNA疫苗Comirnaty^®，以及Alnylam 的siRNA罕病藥物Onpattro^®的核酸藥物傳遞系統，都出自於Acuitas公司的關鍵脂質奈米顆粒(LNP)核酸傳遞系統，台廠亦可借鏡其成功發展模式，台廠核酸新藥開發廠商如法信諾生醫、醣基、聖安生醫、予宇生技和智新生技，雖多屬早期開發階段，關鍵製程技術仍在持續發展，且各具技術發展利基，透過結盟組隊或合作授權，從核酸新藥、修飾載體及核酸新藥製造代工(CDMO)三大路徑分別切入，持續朝向專業分工，創造與國際市場接軌合作機會。

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