Table 1.
Overview of Clinical Trials of Various RNA Therapeutics Discussed in This Reviewa
| Candidate | Type of RNA | Vehicle | Route of administration | Biological target | Condition or disease | Clinical stage | Year (first posted) | Clinical trial number |
|---|---|---|---|---|---|---|---|---|
| Antisense oligonucleotides | ||||||||
| QR-010 | ASO | NA | Inhalation | Cystic fibrosis transmembrane conductance regulator (ΔF508 mutation) | Cystic fibrosis | Phase Ib | 2015 | NCT02532764 |
| QR-421a | ASO | NA | Intravitreal injection | Usherin (exon 13 of USH2A) | Retinitis pigmentosa | Phase I/II | 2018 | NCT03780257 |
| QR-110 | ASO | NA | Intravitreal injection | Centrosomal protein 290 (p.Cys998X mutation) | Leber’s Congenital amaurosis | Phase II/III | 2019 | NCT03913143 |
| QR-1123 | ASO | NA | Intravitreal injection | Mutant P23H of the rhodopsin gene | Retinitis pigmentosa | Phase I/II | 2019 | NCT04123626 |
| Candidate | Type of RNA | Vehicle | Route of administration | Biological target | Condition or disease | Clinical stage | Year (first posted) | CT identifier |
|---|---|---|---|---|---|---|---|---|
| siRNA and miRNA | ||||||||
| TD101 | siRNA | NA | Intralesional injection | Keratin 6A | Pachyonychia congenita | Phase I | 2008 | NCT00716014 |
| PF-04523655 | siRNA | NA | Intravitreal injection | RTP801 | Age-related macular degeneration | Phase II | 2008 | NCT00713518 |
| Choroidal neovascularization Diabetic retinopathy Diabetic macular edema |
Phase II | 2011 | NCT01445899 | |||||
| ALN-RSV01 | siRNA | NA | Inhalation of nebulized solution | Nucleocapsid protein of respiratory syncytial virus | Lung transplant patients infected with respiratory syncytial virus | Phase IIb | 2010 | NCT01065935 |
| ALN-VSP02 | siRNA | siRNA-LNPb (2 siRNAs) | i.v. infusion | Kinesin spindle protein and vascular endothelial growth factor | Solid tumor | Phase I | 2009/2010 |
NCT01158079 NCT00882180 |
| TKM-080301 | siRNA | Stable nucleic acid–lipid particles (SNALPs) | i.v. infusion | Polo-like kinase 1 | Neuroendocrine tumors Adrenocortical carcinoma |
Phase I/II | 2010 | NCT01262235 |
| Primary or secondary liver cancer | Phase I | 2011 | NCT01437007 | |||||
| Advanced hepatocellular carcinoma | Phase I/II | 2014 | NCT02191878 | |||||
| QPI-1007 | siRNA | NA | Intravitreal injection | Caspase 2 | Nonarteritic anterior ischemic optic neuropathy | Phase II/III | 2015 | NCT02341560 |
| Acute primary angle closure glaucoma | Phase II | 2013 | NCT01965106 | |||||
| ALN-PCS02 | siRNA | siRNA–LNP | i.v. infusion | Proprotein convertase subtilisin/kexin type 9 | Elevated LDL-cholesterol | Phase I | 2011 | NCT01437059 |
| siG12D-LODER | siRNA | Miniature biodegradable polymeric matrix | Intratumoral using endoscopic ultrasound biopsy needle | KRAS | Pancreatic cancer | Phase II | 2012 | NCT01676259 |
| DOPC-encapsulated siRNA | siRNA | Neutral liposome | i.v. infusion | EphA2 | Advanced malignant solid neoplasm | Phase I | 2012 | NCT01591356 |
| Atu027 | siRNA | Liposomal siRNA | i.v. infusion | Protein kinase N3 | Pancreatic cancer | Phase Ib/IIa | 2013 | NCT01808638 |
| SYL040012 | siRNA | NA | Ophthalmic administration | β2-Adrenergic receptor | Open angle glaucoma Ocular hypertension |
Phase II | 2014 | NCT02250612 |
| ND-L02-s0201 | siRNA | LNP | i.v. infusion | Heat shock protein 47 | Hepatic fibrosis | Phase I | 2014 | NCT02227459 |
| Idiopathic pulmonary fibrosis | Phase II | 2018 | NCT03538301 | |||||
| QPI-1002 | siRNA | NA | i.v. injection | P53 | Delayed graft function | Phase III | 2015 | NCT02610296 |
| Risk for AKI following cardiac surgery | Phase III | 2018 | NCT03510897 | |||||
| ALN-PCSSC (Inclisiran) | siRNA | GalNAc-siRNA | s.c. injection | Proprotein convertase subtilisin/kexin type 9 | Elevated LDL-cholesterol | Phase I | 2014 | NCT02314442 |
| Atherosclerotic cardiovascular disease (or risk equivalents) | Phase II | 2015 | NCT02597127 | |||||
| Renal impairment | Phase I | 2017 | NCT03159416 | |||||
| High cardiovascular risk and elevated LDL-cholesterol | Phase II | 2017 | NCT03060577 | |||||
| Atherosclerotic cardiovascular disease Elevated LDL-cholesterol |
Phase III | 2018 |
NCT03399370 NCT03400800 |
|||||
| Homozygous Familial Hypercholesterolemia | Phase III | 2019 | NCT03851705 | |||||
| Atherosclerotic cardiovascular disease (or risk equivalents) Hypercholesterolemia Elevated LDL cholesterol |
Phase III | 2019 | NCT03814187 | |||||
| SYL1001 | siRNA | NA | Ophthalmic administration | Transient receptor potential cation channel subfamily V Member 1 | Dry eye disease | Phase III | 2017 | NCT03108664 |
| ALN-GO1 (Lumasiran) | siRNA | GalNAc-siRNA | s.c. injection | hydroxyacid oxidase 1 | Primary hyperoxaluria type 1 | Phase III | 2018 |
NCT04152200 NCT03905694 NCT03681184 |
| ALN-AT3 (Fitusiran) | siRNA | GalNAc-siRNA | s.c. injection | Antithrombin | Hemophilia | Phase IIIα | 2018 |
NCT03549871 NCT03974113 NCT03754790 NCT03417102 NCT03417245 |
| ALN-AAT02 | siRNA | GalNAc-siRNA | s.c. injection | Mutant of α-1 antitrypsin | ZZ Type α-1 Antitrypsin deficiency liver disease | Phase I/II | 2018 | NCT03767829 |
| Patisiran (label expansion studies) | siRNA | LNP | i.v. infusion | transthyretin | hATTR with cardiomyopathy hATTR progression post liver transplant Polyneuropathy |
Phase III | 2019 |
NCT03997383 NCT03862807 NCT02510261 NCT04201418 (Phase IV) |
| ALN-CC5 (Cemdisiran) | siRNA | GalNAc-siRNA | s.c. injection | Complement component C5 | IgA nephropathy Berger disease |
Phase II | 2019 | NCT03841448 |
| ALN-AGT01 | siRNA | GalNAc-siRNA | s.c. injection | Angiotensinogen | Hypertension | Phase I | 2019 | NCT03934307 |
| ALN-TTRsc02 (Vutrisiran) | siRNA | GalNAc-siRNA | s.c. injection | Transthyretin | Amyloidosis, hereditary transthyretin amyloidosis | Phase III | 2018 | NCT03759379 |
| Transthyretin amyloidosis (ATTR) with cardiomyopathy | Phase III | 2019 | NCT04153149 | |||||
| ARO-APOC3 | siRNA | TRiM™ formulation | s.c. injection | Apolipoprotein C3 | Hypertriglyceridemia Familial chylomicronemia |
Phase I | 2018 | NCT03783377 |
| ARO-ANG3 | siRNA | TRiM™ formulation | s.c. injection | Angiopoietin like protein 3 | Dyslipidemia | Phase I | 2018 | NCT03747224 |
| RG6346 (DCR-HBVS) | siRNA | GalNAc-siRNA | s.c. injection | Hepatitis B surface antigen | Chronic hepatitis B viral infection | Phase I | 2018 | NCT03772249 |
| KrasG12D siRNA (iExosomes) | siRNA | Mesenchymal Stromal cell derived Exosomes |
i.v. infusion | KRAS | Pancreatic cancer patients with KrasG12D mutation | Phase I | 2018 | NCT03608631 |
| OLX10010 | siRNA | cp-asiRNA | i.d./s.c. injection | Connective tissue growth factor | Hypertrophic scar | Phase I | 2018 | NCT03569267 |
| ARO-AAT | siRNA | TRiM™ formulation | s.c. injection | Mutant of α1-antitrypsin (Z-AAT) | α1-Antitrypsin deficiency | Phase II | 2019 | NCT03946449 |
| ARO-HSD | siRNA | TRiM™ formulation | s.c. injection | Hydroxysteroid 17β-dehydrogenase 13 | Nonalcoholic steatohepatitis | Phase I | 2019 | NCT04202354 |
| ARO-HIF2 | siRNA | TRiM™ formulation | i.v. infusion | Hypoxia-inducible factor 2α | Clear cell renal cell carcinoma | Phase I | 2019 | NCT04169711 |
| DCR-PHXC | siRNA | GalXC-siRNA | s.c. injection | Lactate dehydrogenase A | Primary hyperoxaluria type 1 and type 2 | Phase II | 2019 |
NCT03847909 NCT04042402 (Phase 3) |
| JNJ-3989 | siRNA | TRiM™ formulation | s.c. injection | Hepatitis B surface antigen | Chronic hepatitis B viral infection | Phase I | 2019 | NCT04208386 |
| Phase II | 2020 | NCT04439539 | ||||||
| BMT101 | siRNA | cp-asiRNA | i.d. injection | Connective tissue growth factor | Hypertrophic scar | Phase II | 2019 | NCT04012099 |
| DCR-A1AT | siRNA | GalXC-siRNA | s.c. injection | α1- Antitrypsin | α1-Antitrypsin deficiency | Phase I/II | 2019 | NCT04174118 |
| ARO-ENaC | siRNA | NA | Inhalation of nebulized solution | Epithelial sodium channel α subunit | Cystic fibrosis | Phase I/IIa | 2020 | NCT04375514 |
| AMG 890 | siRNA | GalNAc-siRNA | s.c. injection | Lipoprotein(a) | Elevated plasma lipoprotein(a) | Phase II | 2020 | NCT04270760 |
| STP705 | siRNA | Histidine–lysine copolymer peptide | Intralesional injection | TGF-β, Cox-2 | Cutaneous squamous cell carcinoma in situ | Phase I/II | 2020 | NCT04293679 |
| Miravirsen | LNA-modified anti-miR | NA | s.c. injection | miR-122 | Hepatitis C | Phase II | 2010/2015 |
NCT01200420 NCT02508090 NCT02452814 |
| TargomiRs | miR-mimic | EDV (nonliving bacterial minicells) | i.v. infusion | miR-16 | Malignant pleural mesothelioma Non-small cell lung cancer |
Phase I | 2015 | NCT02369198 |
| RG-125 (AZD4076) |
Anti-miR | GalNac | s.c. injection | miR-103/107 | Nonalcoholic steatohepatitis | Phase I | 2015 | NCT02612662 |
| SAR339375 | Anti-miR | NA | s.c. injection | miR-21 | Alport’s syndrome | Phase II | 2016 | NCT02855268 |
| MRG-106 (Cobomarsen) | LNA-modified anti-miR | NA | i.v. infusion | miR-155 | Cutaneous T cell lymphoma Mycosis fungoides |
Phase II | 2018 | NCT03713320 |
| s.c. and intratumoral injection i.v. infusion |
miR-155 | Lymphoma/leukemia | Phase I | 2015 | NCT02580552 | |||
| MRG-110 | Anti-miR | NA | i.d. injection | miR-92a | Wound healing | Phase I | 2018 | NCT03603431 |
| MRG-201 | miR-mimic | Cholesterol | i.d. injection | miR-29 | Keloid | Phase II | 2018 | NCT03601052 |
| mRNA | ||||||||
| Melanoma mRNA vaccine | mRNA | NA | i.d. injection | Melan-A Mage-A1 Mage-A3 Survivin GP100 Tyrosinase |
Melanoma | Phase I/II | 2005 | NCT00204516 |
| Melanoma mRNA vaccine | mRNA | Protamine-complexed mRNA | i.d. injection | Melan-A Mage-A1 Mage-A3 Survivin GP100 Tyrosinase |
Melanoma | Phase I/II | 2005 | NCT00204607 |
| CV9201 | mRNA | RNActive® technology | i.d. injection | Tumor-associated antigens | Non-small cell lung cancer | Phase I/II | 2009 | NCT00923312 |
| RBL001/RBL002 | mRNA | NA | i.nod. injection | Melanoma antigens | Melanoma | Phase I | 2012 | NCT01684241 |
| BNT114 | mRNA | Proprietary size- and charge-based RNA-LPX | i.v. infusion | Shared TAA for TNBC and neoantigens identified by NGS | TNBC | Phase I | 2014 | NCT02316457 |
| CV7201 | mRNA | RNActive® technology | i.m. injection i.d. injection |
Rabies virus glycoprotein | Rabies | Phase I | 2014 | NCT02241135 |
| Lipo-MERIT | mRNA | Liposome-complexed mRNA | i.v. infusion | RBL001.1 RBL002.2 RBL003.1 RBL004.1 |
Melanoma | Phase I | 2015 | NCT02410733 |
| mRNA-4157 | mRNA | Lipid encapsulated mRNA | i.m. injection | Tumor-associated antigens (personalized) | Solid tumors | Phase I | 2017 | NCT03313778 |
| Melanoma | Phase II | 2019 | NCT03897881 | |||||
| BI 1361849 | mRNA | RNActive® technology | i.d. injection | Tumor-associated antigens | Non-small cell lung cancer | Phase I/II | 2017 | NCT03164772 |
| mRNA-1647 mRNA-1443 |
mRNA | Undisclosed | i.m. injection | Viral antigens | Cytomegalovirus infection | Phase I | 2017 | NCT03382405 |
| mRNA1325 | mRNA | LNP | i.d. injection | Viral antigen | Zika virus infection | Phase I | 2017 | NCT03014089 |
| VAL506440 | mRNA | LNP | i.d. injection | H10N8 antigen influenza | Influenza | Phase I | 2017 | NCT03076385 |
| VAL339851 | mRNA | LNP | i.d. injection | H7N9 Antigen influenza | Influenza | Phase I | 2017 | NCT03345043 |
| mRNA-2416 | mRNA | LNP | Intratumoral injection | OX40 ligand | Advanced malignancies | Phase I/II | 2017 | NCT03323398 |
| CV9202 (BI 1361849) | mRNA | RNActive® technology | i.d. injection | Six non-small cell lung cancer antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1) | Non-small cell lung cancer | Phase I/II | 2017 | NCT03164772 |
| Neo-antigen mRNA |
mRNA | NA | s.c. injection | Tumor antigen | Digestive tract adenocarcinomas | NA | 2018 | NCT03468244 |
| CV7202 | mRNA | LNP | i.m. injection | Rabies virus glycoprotein | Rabies | Phase I | 2018 | NCT03713086 |
| mRNA1653 | mRNA | LNP | i.d. injection | Viral antigen | Human metapneumovirus and human parainfluenza infection | Phase I | 2018 | NCT03392389 |
| mRNA-2752 | mRNA | LNP | Intratumoral injection | OX40L IL-23 IL-36γ |
Advanced malignancies | Phase I | 2018 | NCT03739931 |
| mRNA-1944 | mRNA | LNP | i.v. infusion | Anti-Chikungunya virus mAb | Chikungunya virus infection | Phase I | 2019 | NCT03829384 |
| BNT131 (SAR441000) | mRNA | Proprietary size- and charge-based RNA-LPX | Intratumoral injection | IL-12sc IL-15sushi IFNα GM-CSF |
Metastatic neoplasm | Phase I | 2019 | NCT03871348 |
| mRNA-1893 | mRNA | LNP | i.m. injection | Undisclosed | Zika virus | Phase I | 2019 | NCT04064905 |
| mRNA-3704 | mRNA | LNP | i.v. infusion | Methylmalonyl-coenzyme A mutase | Methylmalonic acidemia | Phase I/II | 2019 | NCT03810690 |
| mRNA-1273 | mRNA | LNP | i.m. injection | SARS-CoV-2 glycoproteins | COVID-19 | Phase III | 2020 | NCT04470427 |
| BNT162 | mRNA | LNP | i.m. injection | Undisclosed SARS-CoV-2 proteins | COVID-19 | Phase I/II Phase II/III |
2020 |
NCT04380701 NCT04368728 |
| BNT122 (RO7198457) | mRNA | Proprietary size- and charge-based RNA-LPX | i.v. infusion | Tumor-associated antigens | Colorectal cancer stage II/III Advanced melanoma |
Phase II | 2020 |
NCT04486378 NCT03815058 |
| Locally advanced or metastatic solid tumors | Phase I | 2017 | NCT03289962 | |||||
| CVnCoV | mRNA | LNP | i.m. injection | SARS-CoV-2 spike protein | COVID-19 | Phase I | 2020 | NCT04449276 |
| RNA Aptamers | ||||||||
| NOX-E36 | Aptamer | L-RNA, PEGylated |
i.v. injection s.c. injection |
Chemokine (cysteine–cysteine motif) ligand 2 |
Chronic inflammatory diseases Type 2 diabetes mellitus Systemic lupus erythematosus |
Phase I | 2009 | NCT00976729 |
| Renal impairment | Phase I | 2011 | NCT01372124 | |||||
| Type 2 diabetes mellitus albuminuria | Phase II | 2012 | NCT01547897 | |||||
| NOX-A12 | Aptamer | L-RNA, PEGylated |
i.v. injection | Chemokine (C-X-C motif) ligand 12 Stromal-derived factor 1 |
Autologous stem cell transplantation | Phase I | 2009 | NCT00976378 |
| Chronic lymphocytic leukemia | Phase II | 2011 | NCT01486797 | |||||
| Multiple myeloma | Phase II | 2012 | NCT01521533 | |||||
| Colorectal cancer Pancreatic cancer |
Phase I/II | 2017 | NCT03168139 | |||||
| Glioblastoma | Phase I/II | 2019 | NCT04121455 | |||||
| NOX-H94 | Aptamer | L-RNA, PEGylated |
Undisclosed | Hepcidin | Anemia of chronic disease | Phase II | 2012 | NCT01691040 |
| Anemia End-stage renal disease |
Phase I/II | 2014 | NCT02079896 | |||||
| Zimura (ARC1905) |
Aptamer | NA | Intravitreal injection | Complement component 5 | Age-related macular degeneration | Phase II | 2017 | NCT03362190 |
| Stargardt disease 1 | Phase II | 2017 | NCT03364153 | |||||
| saRNA | ||||||||
| MTL-CEBPA | saRNA | SMARTICLES® liposomal nanoparticle | i.v. infusion | CCAAT enhancer binding protein | Hepatocellular carcinoma Liver cancer |
Phase I | 2016 | NCT02716012 |
| Other | ||||||||
| CV8102 | Noncoding ssRNA | NA | Intratumoral injection | Activation of TLR7/8/RIG-1 | Melanoma Squamous cell carcinoma of the skin or head/neck Adenoid cystic carcinoma |
Phase I | 2017 | NCT03291002 |
a
Only the most advanced clinical stage for each RNA candidate is mentioned. Table was compiled using data from i–ix, [25], and [81].
b
Abbreviations: AKI, acute kidney injury; cp-asiRNA, proprietary cell-penetrating asymmetric interfering RNA by OliX Pharmaceuticals; GalXCL, proprietary siRNA formulation by Dicerna Pharmaceuticals; GM-CSF, granulocyte-macrophage colony-stimulating factor; i.d., intradermal; IFN, interferon; Il, interleukin; i.m., intramuscular; i.nod., intranodal; i.v., intravenous; LNA, locked nucleic acid; LNP, lipid nanoparticle; NA, not applicable; NGS, next-generation sequencing; s.c., subcutaneous; TRiM™, targeted RNAi molecule, platform for ligand-mediated targeted RNA delivery by Arrowhead Pharmaceuticals; TAA, tumor-associated antigen; TNBC, triple-negative breast cancer.