Trends and Commonalities of Approved and Late Clinical-Phase RNA Therapeutics
Abstract
1. Introduction
2. Antisense Oligonucleotides and siRNA
2.1. Tissue Targeting and Drug Delivery Systems
2.1.1. Approved Products
2.1.2. Late Clinical-Phase Products
2.2. Structure-Based Approach to Delivery
2.2.1. Approved Products
2.2.2. Late Clinical-Phase Products
2.3. Case Study: Non-RNase H-Dependent ASOs
2.4. Conclusion and Perspective on Antisense Oligonucleotide and siRNAs Delivery
3. mRNA
3.1. Challenges Compared to Other Nucleic Acids
3.2. mRNA Delivery
3.3. Conclusion and Perspective on mRNA Delivery
4. Aptamers
4.1. Structure-Based Approach to Delivery
4.2. Delivery of Aptamers
4.3. Conclusion and Perspective on Aptamer Delivery
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
MDPI | Multidisciplinary Digital Publishing Institute |
DOAJ | Directory of open access journals |
ASO | Antisense oligonucleotide |
ASGPR | Asialoglycoprotein receptor |
circRNA | Circular RNA |
CRISPR | Clustered regularly interspaced short palindromic repeats |
DDS | Drug delivery system |
DMD | Duchenne muscular dystrophy |
DNA | Deoxyribonucleic acid |
EMA | European Medicines Agency |
EV | Extracellular vesicle |
FDA | Food and Drug Administration |
GalNac | N-acetylgalactosamine |
LNP | Lipid nanoparticle |
RNA | Ribonucleic acid |
mRNA | Messenger RNA |
miRNA | Micro-RNA |
ORF | Open Reading Frame |
PMO | Phosphorodiamidate morpholino-oligomer |
PS | Phosphorothioate |
RISC | RNA-induced silencing complex |
saRNA | Self-amplifying RNA |
siRNA | Small interfering RNA |
sgRNA | Single guide RNA |
UTR | Untranslated region |
2′-F | 2′-Fluororibonucleotides |
2′-OMe | 2′-O-methyl-ribonucleotides |
2′-O-MOE | 2‘-O-(2-Methoxyethyl)-ribonucleotides |
Appendix A
Modality | Drug Names | Clinical Trial Status | Deliv. Route | Nucleic Acid Modifications | Target Site (Target) | Deliv. System | Disease Indication |
---|---|---|---|---|---|---|---|
Oligonucleotide | Lefitolimod/GS-1703/MGN1703 [207,208] | Ongoing | SC | Fully natural | Undisclosed (TLR9 agonist) | Undisclosed | Acquired immunodeficiency syndrome (AIDS); advanced solid tumors; extensive-stage (ES) small cell lung cancer (SCLC); HIV infection; melanoma; metastatic colorectal cancer; metastatic solid tumors; neuroendocrine tumors of pancreatic origin; peritoneal cancer; small cell lung cancer (SCLC) |
Cobitolimod [209] | Ongoing | Rectal | PS | Undisclosed (TLR9 agonist) | Undisclosed | Severe ulcerative colitis; ulcerative colitis | |
Imetelstat/GRN163L/Imetelstat sodium [210] | Ongoing | IV | Thiophosphoramidate (NPS), lipid conjugate (for permeability) | Undisclosed (telomerase inhibitor) | Undisclosed | Acute myeloid leukemia; adenocarcinoma of the breast; adult giant cell glioblastoma; advanced non-small cell lung cancer (NSCLC); anaplastic astrocytoma; anaplastic ependymoma; anaplastic oligodendroglioma; astrocytoma; bone marrow metastatic disease; brain cancer; brain tumor; brainstem glioma; brainstem tumor; breast adenocarcinoma; breast neoplasm; central nervous system tumors; cytopenia; diffuse intrinsic pontine glioma; ependymoma; essential thrombocythemia; Ewing’s sarcoma; glioblastoma multiforme; gliosarcoma; hepatoblastoma; HER2-positive breast cancer; high-grade glioma; liver cancer; lymphoma; lymphoproliferative disease; malignant solid tumor; metastatic breast cancer; metastatic non-small cell lung cancer; myelodysplastic syndrome; myelofibrosis; myeloid malignancies; myeloma/multiple myeloma/Kahler’s disease/myelomatosis; myeloproliferative neoplasm and myelodysplastic syndrome; neuroblastoma; non-secretory myeloma; non-small cell lung cancer (NSCLC); oligodendroglioma; osteosarcoma; peripheral primitive neuroectodermal tumor; polycythemia vera; post-essential thrombocythemia (Post-ET) myelofibrosis; post-polycythemia vera myelofibrosis; post-transplant lymphoproliferative disorders (PTLD); primary myelofibrosis; rhabdomyosarcoma; cecondary myelofibrosis; secretory multiple myeloma; small intestine lymphoma; solid tumors | |
gRNA | Exa-cel/CTX001/Exagamglogene autotemcel [211] | Ongoing | IV | Undisclosed | Hematopietic stem cells (BCL11A) | Ex vivo—electroporation | Anemia; beta thalassemia; genetic-related diseases; hematological disease; hemoglobinopathy; sickle cell anemia; sickle cell diseases; thalassemia; transfusion-dependent β-thalassemia |
LBP-EC01/crPhageTM [212,213] | Ongoing | Intraurethral/IV | Undisclosed | Vesical E. coli | In vivo—bacteriophage | Urinary tract infection | |
saRNA | ARCT-154 | Ongoing | IM | Undisclosed | Undisclosed | Undisclosed | SARS-CoV-2 (COVID-19) infection |
GRANITE-001/GRT-C901 (Prime)/GRT-R902 (Boost) [214,215] | Ongoing | IM | Undisclosed | Undisclosed (neoantigen) | ChAd68 LNP; Replicon RNA (samRNA) (adenovirus) | Colorectal cancer; colorectal neoplasms; gastroesophageal adenocarcinoma; metastatic cancer; metastatic colorectal cancer; metastatic gastroesophageal adenocarcinoma; metastatic microsatellite-stable colorectal cancer; metastatic non-small cell lung cancer; metastatic urothelial carcinoma; microsatellite-stable colorectal cancer; non-small cell lung cancer (NSCLC); solid tumors; urothelial cancer | |
shRNA | Vigil/FANG Immunotherapy/Gemogenovatucel-T/VigilTM Vaccine [216] | Clinically active | ID | Undisclosed | Undisclosed (neoantigen) | Undisclosed | Advanced breast cancer; advanced cervical cancer; advanced endometrial cancer; advanced fallopian tube cancer; advanced gynecologic cancer; advanced melanoma; advanced non-small cell lung cancer (NSCLC); advanced ovarian cancer; advanced peritoneal cancer; advanced solid tumors; advanced uterine cancer; bone tissue neoplasm; breast cancer; cervical cancer; clear cell epithelial ovarian cancer; colorectal carcinoma; connective tissue neoplasm; endometrial cancer; endometrioid epithelial ovarian cancer; endometrioid ovarian cancer; Ewing’s sarcoma; Ewing’s tumor; fallopian tube cancer; high-grade serous ovarian cancer; large bowel (colon) cancer; liver cancer; lung cancer; melanoma; metastatic breast cancer; metastatic cervical cancer; metastatic endometrial cancer; metastatic Ewing sarcoma; metastatic Ewing’s tumor; metastatic fallopian tube cancer; metastatic melanoma; metastatic non-small cell lung cancer; metastatic ovarian cancer; metastatic peritoneal cancer; metastatic solid tumor; metastatic uterine cancer; neoplasms; non-small cell lung cancer (NSCLC); ovarian cancer; ovarian clear cell carcinoma; ovarian neoplasm; papillary ovarian cancer; peritoneal cancer; peritoneal neoplasms; primary peritoneal carcinoma; rare tumors; sarcoma; serous epithelial ovarian cancer; serous ovarian cancer; soft tissue neoplasms; solid tumors; uterine cancer; uterine papillary serous carcinoma |
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INN Name | Approval(s) | Target Site (Target) | Disease | Posology | Delivery Route | Delivery System | Conjugation/Termination |
---|---|---|---|---|---|---|---|
Casimersen (Amondys 45) | FDA 2021 | Muscle fibers (DMD exon 45) | Duchenne muscular dystrophy (DMD) | 30 mg/kg q.w. | Intravenous (IV) | Naked in PBS | Short PEG tail |
Eteplirsen (Exondys 51) | FDA 2016 | Muscle fibers (DMD exon 51) | Duchenne muscular dystrophy | 30 mg/kg q.w. | IV | Naked in ~PBS | Short PEG tail |
Golodirsen (Vyondys 53) | FDA 2019 | Muscle fibers (DMD exon 53) | Duchenne muscular dystrophy | 30 mg/kg q.w. | IV | Naked in PBS | Short PEG tail |
Milasen117 | FDA 2017 | SNC (CLN7) | Batten’s disease (patient-customized) | 42 mg quarterly after induction phase | Intrathecal (ITh) | Undisclosed | NA |
Nusinersen (Spinraza) | FDA 2016 EMA 2017 | SNC (SMN2 pre-mRNA) | Spinal muscular atrophy | 12 mg every four months after induction phase | ITh | Naked in ~PBS | NA |
Viltolarsen118 (Viltepso) | FDA 2020 | Muscle fibers (DMD exon 53) | Duchenne muscular dystrophy | 80 mg/kg q.w. | IV | Naked in pH-adjusted saline | NA |
Fomivirsen (Vitravene) | FDA 1998 EMA 1999 | Eye (CMV mRNA) | Cytomegalovirus retinitis | 0.165/0.330 mg/eye q.2w after induction phase | Intravitreal (IVt) | Naked in bicarbonate buffer, NaCl | NA |
Inotersen (Tegsedi) | FDA 2018 EMA 2018 | Liver (TTR mRNA) | Hereditary transthyretin mediated amyloidosis | 285 mg q.w. | Sub- cutaneous (SC) | Naked in pH-adjusted water | NA |
Mipomersen (Kynamro) | FDA 2013 | Liver/Intestine (apo-B-100 mRNA) | Familial hypercholesterolemia | 200 mg q.w. | SC | Naked in pH-adjusted water | NA |
Volanesorsen (Waylivra) | EMA 2019 | Liver/Intestine (apoC-III mRNA) | Familial chylomicronemia | 285 mg q.2w after induction phase | SC | Naked in pH-adjusted water | NA |
INN Name | Approval(s) | Target Site (Target) | Disease | Posology | Delivery Route | Delivery System | Conjugation/Termination |
---|---|---|---|---|---|---|---|
Givosiran (Givlaari) [35] | FDA 2019 EMA 2020 | Liver/hepato-cytes (ALS1 mRNA) | Acute hepatic porphyria | 2.5 mg/kg q.m. | SC | Naked in pH-adjusted water | GalNAc-conjugate |
Inclisiran (Leqvio) [32,36] | EMA 2020 | Liver/hepatocytes (PCSK9 mRNA) | Primary hypercholesterolemia | 284 mg every six months after induction phase | SC | Naked in pH-adjusted water | GalNAc-conjugate |
Lumasiran (Oxlumo) [37] | FDA 2020 EMA 2020 | Liver/hepatocytes (HAO1 mRNA) | Primary hyperoxaluria | 3 to 6 mg/kg quarterly after induction phase | SC | Naked in pH-adjusted water | GalNAc-conjugate |
Vutrisiran (Amvuttra) [38,39,40] | FDA 2022 EMA 2022 | Liver/hepato-cytes (TTR mRNA) | hATTR amyloidosis | 25 mg quarterly | SC | Naked in phosphate buffer + NaCl | GalNAc-conjugate |
Patisiran (Onpattro) | FDA 2018 EMA 2018 | Liver (TTR mRNA) | hATTR amyloidosis | 0.3 mg/kg every three weeks | IV | Lipid nanoparticles (LNPs) | NA |
Drug Names | Clinical Trial Status | Target Site (Target) | Disease Indication | Deliv. Route | Deliv. System | Conjugation/Termination |
---|---|---|---|---|---|---|
Tofersen */BIIB067/IONIS-SOD1Rx/ISIS 333611/BIIB067/IONIS-SOD1Rx/ISIS 333611 [52] | Ongoing | CNS (SOD1 mRNA) | Amyotrophic lateral sclerosis (ALS); superoxide dismutase 1-amyotropic lateral sclerosis (SOD1-ALS) | ITh | Naked RNA | NA |
Tominersen/IONIS-HTTRx/ISIS 443139/RG6042/RO7234292 [52,53] | Ongoing | CNS (HTT mRNA) | Huntington’s disease | ITh | Naked RNA | NA |
Zilganersen/ION-1166998/ION373 [54] | Ongoing | CNS (GFAP mRNA) | Alexander disease | ITh | Undisclosed | NA |
Sepofarsen/ QR-110 [55] | Ongoing | Eye (CEP290 mRNA) | Blindness; congenital eye disorders; eye disorders; Leber congenital amaurosis (LCA); Leber congenital amaurosis 10 (LCA10); neurological disorders; retinal degeneration; retinal disease; retinal dystrophy; sensation disorders; vision disorders | Intraocular (IO) | Naked RNA | NA |
OT-101/AP 12009/AP-12009/ATB-301/TASO-001/TGF-β2 targeting anti-sense oligonucleotide/Trabedersen [56] | Ongoing | Tumor (TGF-B2 mRNA) | Advanced malignant pleural mesothelioma; advanced solid tumors; cancer indications; colorectal cancer; diffuse intrinsic pontine glioma; glioma; melanoma; metastatic solid tumors; pancreatic cancer; pleural malignant mesothelioma; progressive myopia; SARS-CoV-2 (COVID-19) infection; solid tumors | Intratumoral (IT) | Undisclosed | NA |
Drisapersen/GSK2402968/Kyndrisa/PRO051 [57,58] | Stopped | Muscles (DMD exon 51) | Duchenne muscular dystrophy (DMD); muscular dystrophies | SC | Undisclosed | NA |
Ultevursen/QR-421a [59,60] | Ongoing | Eye (USH2A exon 13) | Blindness; congenital eye disorders; deafness; eye disorders; hereditary conditions; retinal disease; retinitis pigmentosa; Usher syndrome type 2; Usher syndrome type 2a; vision disorders | IO | Undisclosed | NA |
Bepirovirsen/GSK3228836/IONIS-HBVRx/ISIS 505358/ISIS-GSK3Rx/ISIS-HBVRx [61] | Ongoing | Liver (HBsAg mRNA) | Hepatic impairment; hepatitis B; liver cirrhosis; liver disorders | SC | Undisclosed | NA |
Mongersen/GED-0301 [62] | Ongoing | GI epithelium (SMAD7 mRNA) | Crohn’s disease; ulcerative colitis | Oral | Delayed release tablet | NA |
IONIS-PKK-LRx/Donidalorsen/ISIS 721744 [63,64] | Ongoing | Liver (KLKB1 mRNA) | Cardiovascular diseases; hereditary angioedema; SARS-CoV-2 (COVID-19) infection | SC | Undisclosed | Ligand-conjugated antisense (LICA) (GalNac) |
Eplontersen */AKCEA-TTR-LRx/ION-682884/IONIS-TTR-LRx/ISIS-TTR(Rx) [65,66] | Ongoing | Liver (TTR mRNA) | Amyloidosis; familial amyloid polyneuropathy (hereditary transthyretin-mediated amyloid polyneuropathy); transthyretin amyloid cardiomyopathy | SC | Undisclosed | Ligand-conjugated antisense (LICA) (GalNac) |
ION363/Jacifusen [67] | Ongoing | CNS (FUS mRNA) | Amyotrophic lateral sclerosis (ALS) | ITh | AAV (Adeno Associated Virus) | NA |
Custirsen/OGX-011/TV-1011 [68,69] | Not active (clinical) | Tumor (sCLU mRNA) | Adenocarcinoma of the prostate; advanced non-small cell lung cancer (NSCLC); cancer indications; cardiac conduction and repolarization; castrate prostate cancer; metastatic castrate prostate cancer; metastatic non-small cell lung cancer; prostate cancer; solid tumors | IV | Undisclosed | NA |
Pelacarsen/AKCEA-APO(a)-LRx/ASO 144367/IONIS-APO(a)-LRx/ISIS 681257/TQJ230 [70] | Ongoing | Liver (LPA mRNA) | Acute coronary syndrome; cardiovascular diseases; coronary artery disease (coronary heart disease); elevated serum lipoprotein(a); genetic polymorphisms; hepatic impairment; hyperlipoproteinemia (hyperlipidemia, lipoproteinemia); inflammation; ischemic stroke; liver cirrhosis; myocardial infarction; peripheral arterial disease (PAD); renal impairment; stenosis | SC | Undisclosed | Ligand-Conjugated Antisense (LICA) (GalNac) |
Suvodirsen/WVE-210201 [71] | Stopped | Muscles (DMD mRNA) | Duchenne muscular dystrophy (DMD) | IV | Undisclosed | NA |
Aganirsen/GS-101 [72,73] | Ongoing | Eye (IRS1 mRNA) | Ischemic central retinal vein occlusion; neovascular glaucoma | Eye, Topical | Naked RNA | NA |
Alicaforsen/ISIS-2302 [74] | Ongoing | Colon (undisclosed) | Inflammatory bowel disease; pouchitis; ulcerative colitis | Rectal | Naked RNA | NA |
Olezarsen */AKCEA-APOCIII-LRx/IONIS APOCIII-LRx/ISIS 678354 [75,76,77] | Ongoing | Liver (APOC3 mRNA) | Atherosclerosis; atherosclerotic cardiovascular disease (ASCVD); cardiovascular diseases; coronary artery disease (coronary heart disease); elevated triglycerides; familial chylomicronemia syndrome (FCS); familial lipoprotein lipase deficiency (hyperlipoproteinemia type I); hypertriglyceridemia; ischemic stroke; pancreatitis; peripheral arterial disease (PAD) | SC | Undisclosed | Ligand-conjugated antisense (LICA) (GalNac) |
Drug Names | Clinical Trial Status | Target Site (Target) | Disease Indication | Deliv. Route | Deliv. System | Conjugation/Termination |
---|---|---|---|---|---|---|
Revusiran/ALN-TTRsc/SAR438714/siTTRsc [78] | Stopped | Liver (TTR mRNA) | Amyloidosis; cardiac amyloidosis; familial amyloid polyneuropathy (hereditary transthyretin-mediated amyloid polyneuropathy); hereditary ATTR amyloidosis | SC | Undisclosed | GalNAc |
Teprasiran/I5NP/QPI-1002 [79] | Ongoing | Kidney (p53 mRNA) | Acute kidney injury (AKI); renal failure | IV | Undisclosed | NA |
Tivanisiran/SYL1001 [80] | Ongoing | Eye (TRPV1 mRNA) | Dry eye disease; ocular Pain; Sjögren’s syndrome | Eye, topical | Naked RNA | NA |
Nedosiran */DCR-PHXC [81] | Ongoing | Liver (LDHA mRNA) | Genetic-related diseases; kidney disorders; primary hyperoxaluria; primary hyperoxaluria type 1; primary hyperoxaluria type 2; primary hyperoxaluria type 3; renal disease | SC | Undisclosed | GalNAc |
Olpasiran/AMG 890/ARO-LPA [82,83] | Ongoing | Liver (LPA mRNA) | Atherosclerotic cardiovascular disease (ASCVD); cardiovascular diseases; elevated serum lipoprotein(a); hepatic impairment; myocardial infarction; renal impairment | SC | Undisclosed | Targeted RNAi Molecule (TRiMTM) platform (GalNac) |
ARO-APOC3 [32] | Ongoing | Liver (APOC3 mRNA) | Dyslipidemia; familial chylomicronemia syndrome (FCS); hypertriglyceridemia | SC | Undisclosed | Targeted RNAi Molecule (TRiMTM) platform |
Fazirsiran/ADS-001/ARO-AAT/TAK-999 [32,82] | Ongoing | Liver (SERPINA1 mRNA) | Alpha-1 antitrypsin deficiency; liver fibrosis; PiZZ alpha-1 antitrypsin deficiency (ZZ type alpha-1 antitrypsin deficiency) | SC | Undisclosed | Targeted RNAi Molecule (TRiMTM) platform (GalNac) |
Cemdisiran/ALN-CC5 [84,85,86] | Ongoing | Liver (C5 mRNA) | Anemia; atypical hemolytic uremic syndrome (aHUS); immunoglobulin A nephropathy (Berger disease); myasthenia gravis; paroxysmal nocturnal hemoglobinuria (PNH); renal impairment; thrombocytopenia; tuberculous meningitis | SC | Undisclosed | GalNAc |
QPI-1007 [32,87] | Ongoing | Eye (CASP2 mRNA) | Glaucoma; non-arteritic anterior ischemic optic neuropathy (NAION) | IVt | Naked RNA | NA |
Fitusiran */ALN-AT3SC/SAR439774 [87,88] | Ongoing | Liver (antithrombin III mRNA) | Hemophilia; hemophilia A; hemophilia B | SC | Undisclosed | GalNAc |
INN Name | Approv. | Target Site (Target) | Disease | Posology | Deliv. Route | Backbone Mod. | 2′ Mod. | 5′/3′ Mod. |
---|---|---|---|---|---|---|---|---|
Casimersen (Amondys 45) | FDA 2021 | Muscle fibers (DMD Exon 45) | Duchenne muscular dystrophy | 30 mg/kg q.w. | IV | PMO | NA | Short PEG tail |
Eteplirsen (Exondys 51) | FDA 2016 | Muscle fibers (DMD Exon 51) | Duchenne muscular dystrophy | 30 mg/kg q.w. | IV | PMO | NA | Short PEG tail |
Golodirsen (Vyondys 53) | FDA 2019 | Muscle fibers (DMD Exon 53) | Duchenne muscular dystrophy | 30 mg/kg q.w. | IV | PMO | NA | Short PEG tail |
Milasen [104] | FDA 2017 | SNC (CLN7) | Batten’s disease (patient-customized) | 42 mg quarterly after induction phase | ITh | PS | 2′-O-MOE | NA |
Nusinersen (Spinraza) | FDA 2016 EMA 2017 | SNC (SMN2 pre-mRNA) | Spinal muscular atrophy | 12 mg every four months after an induction phase | ITh | PS | 2′-O-MOE | NA |
Viltolarsen (Viltepso) [105] | FDA 2020 | Muscle fibers (DMD Exon 53) | Duchenne muscular dystrophy | 80 mg/kg q.w. | IV | PMO | NA | NA |
Fomivirsen (Vitravene) | FDA 1998 EMA 1999 | Eye (CMV mRNA) | Cytomegalovirus retinitis | 0.165/0.330 mg/eye q.2w after induction phase | IVt | PS | NA | NA |
Inotersen (Tegsedi) | FDA 2018 EMA 2018 | Liver (TTR mRNA) | Hereditary transthyretin-mediated amyloidosis | 285 mg q.w. | SC | PS | 2′-O-MOE | NA |
Mipomersen (Kynamro) | FDA 2013 | Liver/intestine (apo-B-100 mRNA) | Familial hypercholesterolemia | 200 mg q.w. | SC | PS | 2′-O-MOE | NA |
Volanesorsen (Waylivra) | EMA 2019 | Liver/intestine (apoC-III mRNA) | Familial chylomicronemia | 285 mg q.2w after induction phase | SC | PS | 2′-O-MOE | NA |
INN Name | Approv. | Target Site (Target) | Disease | Posology | Deliv. Route | Backbone Mod. | 2′ MOD. | 5′/3′ Mod. |
---|---|---|---|---|---|---|---|---|
Givosiran (Givlaari) [35] | FDA 2019 EMA 2020 | Liver/hepatocytes (ALS1 mRNA) | Acute hepatic porphyria | 2.5 mg/kg q.m. | SC | PS | 2′-F, 2′-Ome | NA |
Inclisiran (Leqvio) [32,36] | EMA 2020 | Liver/hepatocytes (PCSK9 mRNA) | Primary hypercholesterolemia | 284 mg every six months after induction phase | SC | PS | 2′-F, 2′-Ome | NA |
Lumasiran (Oxlumo) [37] | FDA 2020 EMA 2020 | Liver/hepatocytes (HAO1 mRNA) | Primary hyperoxaluria | 3 to 6 mg/kg quarterly after induction phase | SC | PS | 2′-F, 2′-Ome | NA |
Vutrisiran (Amvuttra) [38,39,40] | FDA 2022 EMA 2022 | Liver/hepatocytes (TTR mRNA) | hATTR amyloidosis | 25 mg quarterly | SC | PS | 2′-F, 2′-Ome | NA |
Patisiran (Onpattro) | FDA 2018 EMA 2018 | Liver (TTR mRNA) | hATTR amyloidosis | 0.3 mg/kg every three weeks | IV | NA | 2′-Ome | NA |
INN Name | Clinical Trial Status | Target Site (Target) | Disease | Deliv. Route | Backbone Mod. | 2′ Mod. | 5′/3′ Mod. |
---|---|---|---|---|---|---|---|
Tofersen */BIIB067/IONIS-SOD1Rx/ISIS 333611/BIIB067/IONIS-SOD1Rx/ISIS 333611 [52] | Ongoing | CNS (SOD1) | Amyotrophic lateral sclerosis (ALS); superoxide dismutase 1-amyotropic lateral sclerosis (SOD1-ALS) | ITh | PS | 2′-O-MOE | NA |
Tominersen/IONIS-HTTRx/ISIS 443139/RG6042/RO7234292 [52,53] | Ongoing | CNS (HTT) | Huntington’s disease | ITh | PS | 2′-O-MOE | NA |
Zilganersen/ION-1166998/ION373 [54] | Ongoing | CNS (GFAP) | Alexander disease | ITh | PS | 2′-O-MOE | NA |
Sepofarsen/QR-110 [55] | Ongoing | Eye (CEP290) | Blindness; congenital eye disorders; eye disorders; Leber congenital amaurosis (LCA); Leber congenital amaurosis 10 (LCA10); neurological disorders; retinal degeneration; retinal disease; retinal dystrophy; sensation disorders; vision disorders | IO | PS | 2′-O-Me | NA |
OT-101/AP 12009/AP-12009/ATB-301/TASO-001/TGF-β2 targeting anti-sense oligonucleotide/Trabedersen [56] | Ongoing | Tumor (TGF-B2) | Advanced malignant pleural mesothelioma; advanced solid tumors; cancer indications; colorectal cancer; diffuse intrinsic pontine glioma; glioma; melanoma; metastatic solid tumors; pancreatic cancer; pleural malignant mesothelioma; progressive myopia; SARS-CoV-2 (COVID-19) infection; solid tumors | IT | PS | NA | NA |
Drisapersen/GSK2402968/Kyndrisa/PRO051 [57,58] | Stopped | Muscles (DMD exon 51) | Duchenne muscular dystrophy (DMD); muscular dystrophies | SC | PS | 2′-O-MOE | NA |
Ultevursen/QR-421a [59,60] | Ongoing | Eye (USH2A exon 13) | Blindness; congenital eye disorders; deafness; eye disorders; hereditary conditions; retinal disease; retinitis pigmentosa; Usher syndrome type 2; Usher syndrome type 2a; vision disorders | IO | PS | 2′-O-MOE | NA |
Bepirovirsen/GSK3228836/IONIS-HBVRx/ISIS 505358/ISIS-GSK3Rx/ISIS-HBVRx [61] | Ongoing | Liver (HBsAg) | Hepatic impairment; hepatitis B; liver cirrhosis; liver disorders | SC | PS | 2′-O-MOE | NA |
Mongersen/GED-0301 [62] | Ongoing | GI epithelial cells (SMAD7) | Crohn’s disease; ulcerative colitis | Oral | PS | NA | NA |
IONIS-PKK-LRx/Donidalorsen/ISIS 721744 [63,64] | Ongoing | Liver (KLKB1) | Cardiovascular diseases; hereditary angioedema; SARS-CoV-2 (COVID-19) infection | SC | PS | 2′-O-MOE | NA |
Eplontersen */AKCEA-TTR-LRx/ION-682884/IONIS-TTR-LRx/ISIS-TTR(Rx) [65,66] | Ongoing | Liver (TTR mRNA) | Amyloidosis; familial amyloid polyneuropathy (hereditary transthyretin-mediated amyloid polyneuropathy); transthyretin amyloid cardiomyopathy | SC | PS | 2′-O-MOE | NA |
ION363/Jacifusen [67] | Ongoing | CNS (FUS) | Amyotrophic lateral sclerosis (ALS) | ITh | PS | 2′-O-MOE | NA |
Custirsen/OGX-011/TV-1011 [68,69] | Stopped | Tumor (sCLU) | Adenocarcinoma of the prostate; advanced non-small cell lung cancer (NSCLC); cancer indications; cardiac conduction and repolarization; castrate prostate cancer; metastatic castrate prostate cancer; metastatic non-small cell lung cancer; prostate cancer; solid tumors | IV | PS | 2′-O-MOE | NA |
Pelacarsen/AKCEA-APO(a)-LRx/ASO 144367/IONIS-APO(a)-LRx/ISIS 681257/TQJ230 [70] | Ongoing | Liver (LPA) | Acute coronary syndrome; cardiovascular diseases; coronary artery disease (coronary heart disease); elevated serum lipoprotein(a); genetic polymorphisms; hepatic impairment; hyperlipoproteinemia (hyperlipidemia, lipoproteinemia); inflammation; ischemic stroke; liver cirrhosis; myocardial infarction; peripheral arterial disease (PAD); renal impairment; stenosis | SC | PS | 2′-O-MOE | NA |
Suvodirsen/WVE-210201 [71] | Stopped | Muscles (DMD) | Duchenne muscular dystrophy | IV | PS | 2′-O-Me, 2′-F | NA |
Aganirsen/GS-101 [72,73] | Ongoing | Eye (IRS1) | Ischemic central retinal vein occlusion; neovascular glaucoma | Eye, topical | PS | NA | NA |
Alicaforsen/ISIS-2302 [74] | Ongoing | Colon (undisclosed) | Inflammatory bowel disease; pouchitis; ulcerative colitis | Rectal | PS | NA | NA |
Olezarsen */AKCEA-APOCIII-LRx/IONIS APOCIII-LRx/ISIS 678354 [75,76,77] | Ongoing | Liver (APOC3) | Atherosclerosis; atherosclerotic cardiovascular disease (ASCVD); cardiovascular diseases; coronary artery disease (coronary heart disease); elevated triglycerides; familial chylomicronemia syndrome (FCS); familial lipoprotein lipase deficiency (hyperlipoproteinemia type I); hypertriglyceridemia; ischemic stroke; pancreatitis; peripheral arterial disease (PAD) | SC | PS | 2′-O-MOE | NA |
INN Name | Clinical Trial Status | Target Site (Target) | Disease | Deliv. Route | Backbone Mod. | 2′ Mod. | 5′/3′ Mod. |
---|---|---|---|---|---|---|---|
Tivanisiran/SYL1001 [80] | Ongoing | Eye (TRPV1 mRNA) | Dry eye disease; ocular pain; Sjögren’s syndrome | Eye, topical | NA | NA | NA |
Nedosiran */DCR-PHXC [81] | Ongoing | Hepatocytes (Liver) (LDHA mRNA) | Genetic-related diseases; kidney disorders; primary hyperoxaluria; primary hyperoxaluria type 1; primary hyperoxaluria type 2; primary hyperoxaluria type 3; renal disease | SC | PS | 2′-O-Me, 2′-F | NA |
Olpasiran/AMG 890/ARO-LPA [82,83] | Ongoing | Hepatocytes (Liver) (LPA mRNA) | Atherosclerotic cardiovascular disease (ASCVD); cardiovascular diseases; elevated serum lipoprotein(a); hepatic impairment; myocardial infarction; renal Impairment | SC | PS | 2′-F, 2′-O-Me | NA |
ARO-APOC3 [32] | Ongoing | Liver (APOC3 mRNA) | Dyslipidemia; familial chylomicronemia syndrome (FCS); hypertriglyceridemia | SC | PS | PS, 2′-OMe, 2′-F | Inverted base |
Fazirsiran/ADS-001/ARO-AAT/TAK-999 [32,82] | Ongoing | Liver (SERPINA1 mRNA) | Alpha-1 antitrypsin deficiency; liver fibrosis; PiZZ alpha-1 antitrypsin deficiency (ZZ type alpha-1 antitrypsin deficiency) | SC | PS | PS, 2′-OMe, 2′-F, inverted base | Inverted base |
Cemdisiran/ALN-CC5 [84,85,86] | Ongoing | Liver (C5 mRNA) | Anemia; atypical hemolytic uremic syndrome (aHUS); immunoglobulin A nephropathy (Berger disease); myasthenia gravis; paroxysmal nocturnal hemoglobinuria (PNH); renal impairment; thrombocytopenia; tuberculous meningitis | SC | PS | 2′-O-Me, 2′-F, PS | NA |
QPI-1007 [32,87] | Ongoing | Eye (CASP2 mRNA) | Glaucoma; non-arteritic anterior ischemic optic neuropathy (NAION) | IVt | NA | 2′-O-Me, | 5′ inverted deoxybasic sense |
Fitusiran */ALN-AT3SC/SAR439774 [87,88] | Ongoing | Liver (AT III mRNA)) | Hemophilia; hemophilia A; hemophilia B | SC | PS | 2′-O-Me, 2′-F | NA |
INN Name | Approv. | Target Site | Indication | Posology | Deliv. Route | Deliv. System | 2′/Backbone Mod. | 5′/3′ Mod. | Base Mod. |
---|---|---|---|---|---|---|---|---|---|
Elasomeran (Spikevax) [140] | FDA 2020 EMA 2020 | Undisclosed | COVID-19 vaccine | 0./0.2 mg two doses 28 days apart | IM | LNP | Undisclosed | 5′-cap, Poly A tail | N1-methylpseudouridine |
Tozinameran (Comirnaty) [141] | FDA 2020 EMA 2020 | Undisclosed | COVID-19 vaccine | 0.03 mg 2 doses at least 21 days apart | IM | LNP | Undisclosed | 5′-cap2, Poly A tail | N1-methylpseudouridine |
INN Name | Clinical Trial Status | Target Site | Indication | Deliv. Route | Deliv. System | 2′/Backbone Mod. | 5′/3′ Mod. | Base Mod. |
---|---|---|---|---|---|---|---|---|
BNT162b1 [142] | Ongoing | Undisclosed | Respiratory disease; SARS-CoV-2 (COVID-19) infection; viral diseases | IM | LNP | Undisclosed | Undisclosed | N1-Methylpseudouridine |
mRNA-1273.213 [143,144,145] | Ongoing | Undisclosed | SARS-CoV-2 (COVID-19) infection | IM | LNP | Undisclosed | Undisclosed | N1-Methylpseudouridine |
RQ3013 [146] | Ongoing | Undisclosed | SARS-CoV-2 (COVID-19) infection | IM | LNP | Undisclosed | Undisclosed | N1-Methylpseudouridine |
LVRNA009 [147,148,149] | Ongoing | Undisclosed | SARS-CoV-2 (COVID-19) infection | IM | Undisclosed | Undisclosed | Undisclosed | LNP |
Pfizer BioNtech Omicron BA.1-adapted bivalent COVID-19 vaccine | Approved; ongoing | Undisclosed | SARS-CoV-2 (COVID-19) infection | Undisclosed | Undisclosed | Undisclosed | Undisclosed | LNP |
Oslo University Hospital tumor (glioblastoma) stem cells/hTERT/Survivin mRNA transfected autologous DCs [150] | Ongoing | Ex vivo cell therapy | Glioblastoma multiforme | ID | Undisclosed | Undisclosed | Undisclosed | LNP |
Elasomeran/Imelasomeran/Imelasomeran/mRNA-1273.529/Spikevax Bivalent Original/Omicron BA.1 | Ongoing | Undisclosed | SARS-CoV-2 (COVID-19) infection | Undisclosed | Undisclosed | Undisclosed | N1-Methylpseudouridine | LNP |
DS-5670/Daiichi Sankyo COVID-19 mRNA vaccine [151] | Ongoing | Undisclosed | SARS-CoV-2 (COVID-19) infection | IM | Undisclosed | Undisclosed | Uridine-modified | LNP |
ABO1020 [152] | Ongoing | Undisclosed | SARS-CoV-2 (COVID-19) infection | IM | Undisclosed | Undisclosed | Undisclosed | LNP |
Rocapuldencel-T/AGS-003/AGS-003-LNG/CoImmune CMN-001 [153] | Ongoing | Ex vivo cell therapy | Advanced renal cell carcinoma; clear cell renal cell carcinoma; infiltrating bladder urothelial carcinoma; kidney cancer; metastatic kidney cancer; metastatic renal cell carcinoma; muscle-invasive bladder cancer; non-small cell lung cancer (NSCLC); renal cancer; renal cell carcinoma (RCC); urothelial carcinoma of the bladder; urothelial cell carcinoma | SC | Undis-closed | Undisclosed | Undisclosed | Electroporation; naked RNA |
mRNA-1273.211 [143] | Ongoing | Undisclosed | SARS-CoV-2 (COVID-19) infection | IM | Undis-closed | Undisclosed | N1-Methylpseudouridine | LNP |
Pfizer Quadrivalent Influenza modRNA Vaccine [154] | Ongoing | Undisclosed | Influenza; SARS-CoV-2 (COVID-19) Infection | IM | Undisclosed | Undisclosed | modRNA | Undisclosed |
BNT161 [155,156,157] | Ongoing | Undisclosed | Influenza; SARS-CoV-2 (COVID-19) infection | IM | Undis-closed | Undisclosed | modRNA | LNP |
mRNA-1010 | Ongoing | Undisclosed | Cytomegalovirus disease (CMV disease); influenza; respiratory syncytial virus (RSV) infection; SARS-CoV-2 (COVID-19) infection | IM | Undis-closed | Undisclosed | Undisclosed | LNP |
mRNA-1647 | Ongoing | Undisclosed | Cytomegalovirus disease (CMV disease); cytomegalovirus infections; influenza; respiratory syncytial virus (RSV) infection | IM | Undis-closed | Undisclosed | Undisclosed | LNP |
mRNA-1273.617.2 [143,158] | Ongoing | Undisclosed | SARS-CoV-2 (COVID-19) infection | IM | Undisclosed | Undisclosed | N1-Methylpseudouridine | LNP |
Imelasomeran/elasomeran/mRNA-1273.214 [143,159] | Approved; ongoing | Undisclosed | Asthma; cystic fibrosis (CF); diabetes mellitus; HIV infection; influenza; Middle East respiratory syndrome (MERS, MERS-CoV); respiratory syncytial virus (RSV) infection; SARS-CoV-2 (COVID-19) infection | IM | Undis-closed | Undisclosed | N1-Methylpseudouridine | LNP |
Walvax COVID-19 Vaccine/ARCoV/ARCoV mRNA vaccine/AWcorna [22,160] | Approved; ongoing | Undisclosed | Pneumonia; SARS-CoV-2 (COVID-19) infection; viral pneumonia | IM | NA | NA | NA | LNP |
mRNA-1345 [161] | Ongoing | Undisclosed | Chronic obstructive pulmonary disease; congestive heart failure (CHF); cytomegalovirus disease (CMV disease); influenza; respiratory syncytial virus (RSV) infection; SARS-CoV-2 (COVID-19) infection | IM | Undis-closed | Undisclosed | Nucleoside-modified | LNP |
PTX-COVID19-B [162] | Ongoing | Undisclosed | SARS-CoV-2 (COVID-19) infection | IM | Undis-closed | Undisclosed | Undisclosed | LNP |
SW-BIC-213 mRNA vaccine [163,164,165,166] | Ongoing | Undisclosed | SARS-CoV-2 (COVID-19) infection | IM | Undisclosed | Undisclosed | Undisclosed | Lipopolyplex |
CVnCoV/CureVac COVID-19 mRNA vaccine/CV07050101 [167] | Discontinued (clinical) | Undisclosed | Respiratory disease; SARS-CoV-2 (COVID-19) infection | IM | NA | NA | NA | LNP |
SYS6006 [168,169] | Ongoing | Undisclosed | SARS-CoV-2 (COVID-19) infection | IM | Undisclosed | Undisclosed | Undisclosed | LNP |
INN Name | Approv. | Target Site (Target) | Disease | Posology | Delivery Route | Backbone Mod. | 2′ Mod. | 5′/3′ Mod. |
---|---|---|---|---|---|---|---|---|
Defibrotide (Defitelio) [192] | FDA 2016 EMA 2013 | Liver endothelium/blood (adenosine A1/A2 receptor) | Sinusoidal obstruction syndrome | 25 mg/kg daily, up to 6 week | IV | Undisclosed | Undisclosed | Undisclosed |
Pegaptanib (Macugen) | FDA 2004 | Eye (heparin-binding domain of VEGF-165) | Age-related macular degeneration | 0.3 mg every six months | IVt | NA | 2′-O-Me, 2′-F, | 3′-inverted nucleotide; PEG conjugate |
INN Name | Clinical Trial Status | Target Site | Disease | Deliv. Route | Backbone Mod. | 2′ Mod. | 5′/3′ Mod. |
---|---|---|---|---|---|---|---|
Pegnivacogin/REG1 (RB006) [193,194] | Ongoing | Blood (factor IXA) | Angina (angina pectoris); coronary artery disease (coronary heart disease) | IV | NA | 2′-F, 2′-O-Me | 3′ inverted deoxythymidine; PEG conjugate |
Fovista®/E10030, Pegpleranib [195] | Ongoing | Eye (PDGF) | Choroidal neovascularization; dry age-related macular degeneration (atrophic macular degeneration); neovascular age-related macular degeneration (wet age-related macular degeneration) | IO | PEG loops | 2′-F, 2′-O-Me | 3′ inverted deoxythymidine; PEG conjugate |
Zimura/Avacincaptad pegol [116,196] | Ongoing | Eye (C5 inhibitor) | Age-related macular degeneration (AMD); cancer indications; choroidal neovascularization; dry age-related macular degeneration (atrophic macular degeneration); hereditary ATTR amyloidosis; idiopathic polypoidal choroidal vasculopathy; macular degeneration; neovascular age-related macular degeneration (wet age-related macular degeneration); Stargardt macular dystrophy (Stargardt disease, fundus flavimaculatus) | IVt | NA | 2′-O-Me | 3′ inverted deoxythymidine; PEG conjugate |
INN Name | Approval(s) | Target Site (Target) | Disease | Posology | Deliv. Route | Deliv. System | Conjugation/Termination |
---|---|---|---|---|---|---|---|
Defibrotide (Defitelio) | FDA 2016 EMA 2013 | Liver endothelium/blood (Adenosine A1/A2 receptor) | Sinusoidal obstruction syndrome | 25 mg/kg daily, up to 6 week | IV | Naked in citrate buffer | NA |
Pegaptanib (Macugen) | FDA 2004 | Eye (Heparin-binding domain of VEGF-165) | Age-related macular degeneration | 0.3 mg every six months | IVt | Naked in NaCl phosphate buffer | NA |
INN Name | Clinical Trial Status | Target Site (Target) | Disease | Deliv. Route | Deliv. System | Conjugation/Termination |
---|---|---|---|---|---|---|
Pegnivacogin/REG1 (RB006) [193,194] | Ongoing | Blood (Factor IXA) | Angina (angina pectoris); coronary artery disease (coronary heart disease) | IV | Undisclosed | NA |
Fovista®/E10030, Pegpleranib [195] | Ongoing | Eye (PDGF) | Choroidal neovascularization; dry age-related macular degeneration (atrophic macular degeneration); neovascular age-related macular degeneration (wet age-related macular degeneration) | IO | Undisclosed | NA |
Zimura/Avacincaptad pegol [116,196] | Ongoing | Eye (C5 inhibitor) | Age-related macular degeneration (AMD); cancer indications; choroidal neovascularization; dry age-related macular degeneration (atrophic macular degeneration); hereditary ATTR amyloidosis; idiopathic polypoidal choroidal vasculopathy; macular degeneration; neovascular age-related macular degeneration (wet age-related macular degeneration); Stargardt macular dystrophy (Stargardt disease, fundus flavimaculatus) | IVt | Undisclosed | NA |
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Tufeu, M.; Herkenne, C.; Kalia, Y.N. Trends and Commonalities of Approved and Late Clinical-Phase RNA Therapeutics. Pharmaceutics 2025, 17, 903. https://doi.org/10.3390/pharmaceutics17070903
Tufeu M, Herkenne C, Kalia YN. Trends and Commonalities of Approved and Late Clinical-Phase RNA Therapeutics. Pharmaceutics. 2025; 17(7):903. https://doi.org/10.3390/pharmaceutics17070903
Chicago/Turabian StyleTufeu, Maxime, Christophe Herkenne, and Yogeshvar N. Kalia. 2025. "Trends and Commonalities of Approved and Late Clinical-Phase RNA Therapeutics" Pharmaceutics 17, no. 7: 903. https://doi.org/10.3390/pharmaceutics17070903
APA StyleTufeu, M., Herkenne, C., & Kalia, Y. N. (2025). Trends and Commonalities of Approved and Late Clinical-Phase RNA Therapeutics. Pharmaceutics, 17(7), 903. https://doi.org/10.3390/pharmaceutics17070903