Table 1.
Clinical development activities of antisense medicines
| A - approved RNA targeted drugs | |||||
|---|---|---|---|---|---|
| Drug | Indication | Target RNA | Mechanism | Chemistry | Year approved |
| Fomivirsen | Cytomegalovirus retinitis | HCMV UL122 | RNase H1 | PS, DNA | 1998 |
| Mipomersen | Homozygous familial hypercholesterolemia | APOB | RNase H1 | PS, MOE | 2013 |
| Nusinersen | Spinal muscular atrophy | SMN2 | Splicing, intron 7 | PS, MOE | 2016 |
| Eteplirsen | Duchenne muscular dystrophy | DMD | Splicing, exon 51 | PMO | 2016 |
| Inotersen | Hereditary transthyretin- mediated amyloidosis | TTR | RNase H1 | PS, MOE | 2018 |
| Volanesorsen | Familial chylomicronemia syndrome | ApoC-III | RNase H1 | PS, MOE | 2019 |
| Patisiran | Hereditary transthyretin- mediated amyloidosis | TTR | Ago2 | PO-siRNA Cationic lipid formulation |
2018 |
| Golodirsen | Duchenne muscular dystrophy | DMD | Splicing, exon 53 | PMO | 2019 |
| Givosiran | Acute hepatic porphyria | ALAS1 | Ago2 | Ome/F- siRNA, GalNAc | 2019 |
| Viltolarsen | Duchenne muscular dystrophy | DMD | Splicing, exon 53 | PMO | 2020 |
| B. ASO drugs under development | ||||||
|---|---|---|---|---|---|---|
| Chemistrya | Drug | Target | Organ | Dose | Route | Indication | Key observations | References |
| Phase 3 | ||||||
| 2ʹ-MOE | Tofersen (BIIB067/ISIS 666853) | SOD1, CNS | ALS (Ionis/Biogen) | Phase 2 findings of dose-dependent reduction in SOD1 CSF concentration; slowing decline in clinical function, respiratory function, and muscle strength, versus placebo; well tolerated with multiple dose administrations at doses of 20–100 mg | NCT02623699 (185) | |
| 2ʹ-MOE | Tominersen (RG6042/ISIS 443139) | HTT, CNS | 10−120 mg once every 4 weeks, IT | Huntington’s Disease (Ionis/Roche) | Phase ½a findings of dose-dependent reduction of mutant huntingtin CSF concentration; well tolerated with multiple dose administrations at monthly doses of 10–120 mg | NCT03761849 NCT02519036 (186) |
| undisclosed | Sepofarsen (QR-110) | LCA10, p.Cys998X | ITV | Leber’s Congenital Amaurosis Type 10 (ProQR) | Phase ½ findings included improvement in visual acuity | NCT03913143 |
| 2ʹ-MOE, GalNAc | Pelacarsen (TQJ230/AKCEA- APO(a)-LRx) | Apo(a), Liver | 80 mg once monthly, SC | CVD (Ionis/Akcea/Novartis) | Phase 2 findings of dose-dependent reduction in serum lipoprotein (a) levels; no difference compared with placebo-treated patients in platelet counts, liver and renal function tests | NCT04023552 NCT03070782 (129) |
| 2ʹ-MOE, GalNAc | AKCEA- TTR-LRx (ION 682884) | TTR, Liver | 45 mg once monthly, SC | ATTR (Ionis/Akcea) | Phase 1 findings of dose-dependent reduction in plasma TTR; well tolerated with multiple dose administrations; no clinically relevant effect on platelet counts, or liver and renal function tests | NCT04136184 NCT04136171 NCT03728634 (187) |
| PMO | Casimersen (SRP-4045) | Dystrophin Exon 45, Muscle | 30 mg/kg once weekly, IV | DMD (Sarepta) | Statistically significant increase from baseline in dystrophin protein (versus placebo) at week 48 interim end point Study ongoing (double-blind, placebo- controlled to 96 weeks) | NCT02500381 (188) |
| 2ʹ-H | Alicaforsen | ICAM-1, Colon | 240 mg once daily, Enema | Chronic Pouchitis and Ulcerative Colitis (Ionis) | Phase 2 findings included reduction in Pouchitis Disease Activity Index and endoscopy subscore | NCT02525523 (171, 189) |
| Phase 2 | ||||||
| 2ʹ-MOE | BIIB080 (IONIS- MAPTRx) | TAU, CNS | Once monthly, IT | Alzheimer’s Disease, FTD (Ionis/Biogen) | NCT03186989 | |
| 2ʹ-MOE | IONIS-FXIRx/BAY 2306001 | Factor XI, Liver | 100–300 mg once weekly, SC | Clotting Disorders (Ionis/Bayer) | Phase 2 findings included reduction of Factor XI protein, and reduction of thrombotic events without increase in bleeding. | NCT02553889 NCT01713361 (190) |
| 2ʹ-MOE | IONIS- GCGRRx | GCGR, Liver | 50−200 mg once weekly, SC | T2D (Ionis/Suzhou-Ribo) | Phase 2 findings included attenuation of glucagon-induced increase in blood glucose levels, dose-dependent reduction of HbA1c, no cases of severe or symptomatic hypoglycemia, dose- dependent increase in liver transaminase levels consistent with pharmacology, and no increase in hepatic glycogen content | NCT01885260 NCT02583919 NCT02824003 (191) |
| 2ʹ-MOE | IONIS- DGAT2Rx | DGAT2, Liver | 250 mg once weekly, SC | NASH (Ionis) | Phase 2 findings included significant absolute reduction in liver fat, versus placebo, and 50% of patients treated had at least a 30% relative reduction in liver fat; no changes in liver or renal function, no cases of thrombocytopenia | NCT03334214 (192) |
| 2ʹ-MOE | Apatorsen | HSP27, Tumor Cells | 200−1000 mg once weekly, IV | Cancer (Ionis/OncoGenex) | Phase 1 findings included decrease in tumor markers and decline in CTCs | NCT01454089 (193) |
| 2ʹ-MOE | ATL1102 | CD49d, Immune Cells | DMD: 25 mg weekly, SC MS: 200 mg twice weekly, SC | DMD, MS (Ionis/ATL) | Phase 2 findings in nonambulatory DMD patients included positive effects on modulating CD49d+ T cells in blood Phase 2 findings in MS patients included reduction in new active lesions, and moderate thrombocytopenia | ACTRN1261800 0970246 (194) |
| 2ʹ-MOE | Atesidorsen/ATL1103 | GHR, Liver | 200 mg once or twice weekly, SC | Acromegaly (Ionis/ATL) | Phase 2 findings included significant reduction in IGF-1 in patients with acromegaly who received ATL1103 200 mg twice weekly, versus once weekly | ACTRN1261500 0289516 (195) |
| 2ʹ-MOE | IONIS- HBVRx | HBV surface Ag, Liver | 150–300 mg once weekly, SC | HBV, chronic atypical (Ionis/GSK) | Phase 2 findings included dose dependent reductions of HbsAg and HBV DNA, and an acceptable safety profile to proceed to longer treatment durations | NCT02981602 (196) |
| 2ʹ-Ome Stereo-pure PS |
WVE-120101 | mHTT (rs362307), CNS | IT | Huntington’s Disease (Wave) | In progress | NCT03225833 |
| 2ʹ-Ome Stereo-pure PS |
WVE-120102 | mHTT (rs362331), CNS | 2–32 mg, IT | Huntington’s Disease (Wave) | In progress | NCT03225846 |
| cEt | DYN101 | DNM2, MTM1 | 1.5–9.0 mg/kg, IM | Centronuclear Myopathy (Ionis/Dynacure) | In progress | NCT04033159 |
| cET | IONIS- ENAC-2.5Rx | ENAC, Lung | Inhaled/Nebulized | Cystic Fibrosis (Ionis) | In progress | NCT03647228 |
| cET | AZD9150/IONIS- STAT3-2.5Rx | STAT3, Cancer and Stromal Cells | 2−4 mg/kg once weekly, IV | Cancer (Ionis/Astrazeneca) | Phase 1b findings included (1) reduction of STAT3, (2) reduction in serum IL6, and (3) reduction in tumor burden. | NCT02549651 NCT01563302 (197, 198) |
| cET | AZD5312/IONIS-AR- 2.5Rx | AR, Cancer Cells | 150−1150 mg once weekly, IV | Prostate cancer (Ionis/Suzhou- Ribo) | Phase 1 findings included declines in PSA and circulating tumor cells in some patients. | NCT03300505 NCT02144051 (199) |
| LNA | Cobomarsen (MRG-106) | miR-155, Cancer Cells | 75−900 mg once weekly, ITM/SC/IV | Hematological malignancies (miRagen) | Phase 1 findings included improvements in cutaneous lesions, and transcriptional changes consistent with target activity | NCT03713320 NCT02580552 (200) |
| LNA | Civi 007 | PCSK9, Liver | SC | CVD (Civi) | In progress | NCT04164888 NCT03427710 |
| PO, 2ʹ-Ome, ENA | DS-5141b | Dystrophin Exon 45, Muscle | 0.1−6.0 mg/kg once weekly, SC | DMD (Daiichi) | In progress | NCT02667483 |
| PMO Peptide | SRP-5051 | Dystrophin Exon 51, Muscle | Multiple ascending dose, IV | DMD (Sarepta) | In progress | NCT04004065 NCT03375255 |
| 2ʹ-MOE, GalNAc | Vupanorsen (AKCEA- ANGPTL3-LRx/ION 702803) | ANGPTL3, Liver | 40–80 mg total monthly dose, SC | Dyslipidemias (Ionis/Akcea/Pfizer) | Phase 2 findings in patients with HTG, T2D and NAFLD included dose-dependent reductions in ANGPTL3, TGs, ApoC-III, VLDL and non-HDL cholesterol, and total cholesterol with no reductions in liver fat or HbA1c; favorable safety and tolerability profile | NCT03371355 NCT02709850 (97, 201) |
| 2ʹ-MOE, GalNAc | AKCEA- APOCIII-LRx | ApoC-III, Liver | 10–50 mg total monthly dose, SC | CVD (Ionis/Akcea) | Phase 2 findings in patients with HTG and CVD, or high-risk of CVD, included >90% patients at 50 mg monthly dose achieved TG ≤ 150 mg/dl compared to 5% placebo, significant reduction in multiple risk factors, and no safety signals, including those related to platelet counts, liver or renal function | NCT03385239 NCT02900027 (98, 202) |
| 2ʹ-MOE, GalNAc | IONIS-AGT-LRx | AGT, Liver | Once weekly, SC | Treatment-resistant Hypertension (Ionis) | In progress | NCT04083222 NCT03714776 NCT03101878 |
| 2ʹ-MOE, GalNAc | GSK3389404/IONIS- HBV-LRx | HBV surface Ag, Liver | 30−120 mg single dose/once weekly, SC | Chronic HBV (Ionis/GSK) | In progress | NCT03020745 (203) |
| 2ʹ-MOE, GalNAc | IONIS-FB-LRx | Factor B, Liver | 10−40 mg once every 2 weeks, SC | Primary IgA Nephropathy Ocular Disease (Ionis/Roche) | Phase 1 findings included (1) dose- dependent reduction in factor B levels accompanied by similar reduction in factor B function and complement split factor Bb, and (2) no drug-related adverse events | NCT04014335 NCT03815825 ACTRN1261600 0335493 (204) |
| 2ʹ-MOE, GalNAc | IONIS-PKK-LRx | Kallikrein B1, Liver | 20–80 mg, once monthly, SC | HAE (Ionis) | Phase 1 findings included dose- dependent reduction of plasma prekallikrein levels with target reduction maintained during dosing intervals as predicted by PK properties | NCT04307381 NCT03263507 (177, 205) |
| 2ʹ-MOE, GalNAc | IONIS-GHR-LRx | GHR, Liver | Monthly, SC | Acromegaly (Ionis) | In progress | NCT03548415 |
| 2ʹ-MOE, GalNAc | IONIS-FXI-LRx | FXI, Liver | Monthly, SC | Clotting Disorders (Ionis/Bayer) | In progress | NCT03582462 |
| PO, 2ʹ-H Liposome | Prexigebersen | GRB2, Tumor cells | Twice weekly, IV | AML, CML, solid tumors (Bio-Path) | In progress | NCT04196257 NCT02923986 NCT02781883 |
| Undisclosed | QR-1123 (ION357) | RHO, P23H mutation, Eye | ITV | Autosomal Dominant Retinitis Pigmentosa (Ionis/ProQR) | In progress | NCT04123626 |
| Undisclosed | QR-421a | USH2A, exon 13 mutation, Eye | 50–200 μg, ITV | Retinitis pigmentosa (ProQR) | In progress | NCT03780257 |
| Undisclosed | QR-313 | COL7A1, exon 73 mutation, Skin | Once daily, topical cream | Recessive dystrophic epidermolysis bullosa (ProQR/Wings) | In progress | NCT03605069 |
| Undisclosed | RG-012 | miR-21, Kidney | 110−220 mg once weekly, SC | Alport Syndrome (Regulus/Genzyme) | In progress | NCT02855268 |
| Phase 1 | ||||||
| 2ʹ-MOE | BIIB078 (IONIS- C9Rx) | C9orf72, CNS | Multiple ascending doses, IT | ALS (Ionis/Biogen) | In progress | NCT04288856 NCT03626012 |
| 2ʹ-MOE | BIIB094 (ION859) | LRRK2, CNS | Single and multiple ascending doses, IT | Parkinson’s Disease (Ionis/Biogen) | In progress | NCT03976349 |
| 2ʹ-MOE | BIIB101 (ION464) | SNCA, CNS | IT | Multiple System Atrophy (Ionis/Biogen) | NCT04165486 | |
| LNA | RG6127 | Host target | SC | HBV (Roche) | NCT03762681 | |
| LNA | ISTH0036 | TGF-β2, Eye | 6.75−225 μg single dose, IVT | Glaucoma (Isarna) | Phase 1 findings included (1) dose–response trend observed in postoperative introcular pressure, and (2) no adverse events | NCT02406833 (206) |
| SNA Lipid nanoparticle | XCUR17 | IL17RA, Skin | Daily, Topical gel | Psoriasis (Exicure) | Phase 1 finding included decrease in the levels of psoriasis and inflammation markers downstream of target, with a significant reduction in keratin 16 expression and clinical improvement in epidermal thickness | (207) |
| Undisclosed | JNJ- 64991524 | Undisclosed | Oral | Undisclosed (Janssen) | NCT03346122 | |
| Nonactive | ||||||
| 2ʹ-MOE | IONIS- PTP1BRx | PTP1B, Liver | 200 mg once weekly, SC | T2D (Ionis) | Phase 2 findings included (1) reduction of HbA1c, (2) improved leptin and adiponectin levels, and (3) decreased body weight. | NCT00455598 (208) |
| 2ʹ-MOE | IONIS- GCCRRx | GCCR, Liver | 60−420 mg once weekly, SC | T2D (Ionis) | Phase 1 findings included (1) improvement in lipid profile, and (2) attenuation of dexamethasone-induced hepatic insulin resistance. | NCT01968265 (209) |
| 2ʹ-MOE | IONIS- FGFR4Rx | FGFR4, Liver | 100−200 mg once weekly, SC | Obesity (Ionis) | NCT02463240 | |
| LNA | Miravirsen | miR-122, Liver | 3−7 mg/kg once weekly, SC | HCV (Santaris/Roche) | Phase 2 findings included inhibition of miR-122 function | NCT01200420 (90, 91) |
| Discontinued | ||||||
| Stereo-pure PS 2ʹ-F, 2ʹ-Ome | Suvodirsen | Dystrophin Exon 51, Muscle | 3.5–5.0 mg/kg weekly, IV infusion | DMD (Wave) | Failure to demonstrate efficacy in multidose phase 1 open-label extension | NCT03907072 NCT03508947 |
| 2ʹ-MOE | IONIS- PKKRx | Kallikrein B1, Liver | 200 mg once weekly, SC | HAE Chronic Migraine (Ionis) |
Replaced with GalNAc conjugate | NCT03108469 (205, 210) |
| 2ʹ-H | Mongersen | SMAD7, Intestine | 160 mg once daily, Oral | Crohn’s Disease (Nogra Pharma/Celgene) | Phase 3 failed to demonstrate benefit in patients with active Crohn’s Disease with clinical remission (CD Activity Index score <150) attained in 22.8% of patients on GED-0301 versus 25% on placebo (p = 0.6210). Adverse events | NCT02596893 NCT02601300 (211, 212) |
| 2ʹ-Ome | Drisapersen | Dystrophin Exon 51, Muscle | 6 mg/kg once weekly, SC | DMD (Prosensa/BioMarin) | Rejected by FDA | (213, 214, 215) |
| 2ʹ-MOE | Custirsen | CLU, Tumor Cells | 640 mg once weekly, IV | Prostate Cancer and NSCLC (Ionis/OncoGenex) | Failure to meet primary endpoints in phase 3 trials | NCT01578655 NCT01630733 (216, 217) |
| 2ʹ-MOE | IONIS- APO(a)Rx | Apo(a), Liver | 300 mg once weekly, SC | CVD (Ionis) | Replaced with GalNAc conjugate | (218) |
| 2ʹ-MOE | ISIS 388626 | SGLT2, Kidney | 50−200 mg once weekly, SC | T2D (Ionis) | Availability of small-molecule inhibitors of SGLT2 | (63) |
| 2ʹ-MOE | ISIS 333611 | SOD1, CNS | 0.15−3.0 mg single dose, IT | Familial ALS (Ionis) | Replaced by more potent compound | (219) |
| 2ʹ-MOE | ISIS 104838 | TNFα, Immune Cells | 0.1−6 mg/kg IV, 200 mg once weekly, SC | Inflammatory Disease (Ionis) | Inadequate activity | (220) |
| 2ʹ-MOE | ISIS 113715 | PTP1B, Liver | 100−600 mg once weekly, SC | T2D (Ionis) | Replaced by more potent compound | |
| cET, 2ʹ-MOE | IONIS- DMPK2.5Rx | DMPK, Muscle | 100−600 mg once weekly, SC | MD type 1 (Ionis) | Inadequate activity | NCT02312011 (221) |
| LNA | EZN-4176 | AR, Cancer Cells | 0.5−10 mg/kg once weekly, IV | Prostate Cancer | ALT elevations | NCT01337518 (222) |
| Undisclosed, GalNAc | AZD4076/RG-125 | miR-103/107, Liver | SC | Diabetic NASH (Regulus/Astra Zeneca) | Failed in development | NCT02826525 |
| Undisclosed, GalNAc | RG-101 | miR-122, Liver | SC | HCV (Regulus) | Cases of hyperbilirubinemia | EudraCT 2016–002069–77 (223) |
All drugs are modified with PS linkages, except for the PMOs. All 2’-MOE chemistries include 2’-deoxy sugar residues to support Rnase H1 activity, unless specified as fully modified. Abbreviations are provided by column heading. Chemistry: 2’-H, 2’-deoxy; 2’-F, 2’-fluoro; 2’-Ome, 2’-methoxy; 2’- MOE, 2’-O-methoxy ethyl; cET, (S)-constrained ethyl; ENA, 2’-O,4’-C-ethylene-bridged nucleic acid; GalNAc, triantennary N-acetylgalactosamine; LNA, locked nucleic acid; PMO, phosphorodiamidate morpholino oligomer; PO, phosphodiester linkage; PS, phosphorothioate linkage; SNA, spherical nucleic acid nanoparticle. Drugs: 2.5, generation 2.5 ASO drugs containing cEt modification; L, ligand conjugate. Target/Organ: AGT, angiotensinogen; ANGPTL3, angiopoietin like 3; Apo(a), apolipoprotein A1; ApoB-100, apolipoprotein B-100; ApoC-III, apolipoprotein C-III; AR, androgen receptor; C9orf72, chromosome 9 open reading frame 72; CD49d, integrin subunit alpha 4; CEP290, centrosomal protein 290; CLU, clusterin; CMV IE2, cytomegalovirus immediate early gene 2; COL7A1, collagen type VII alpha 1 chain; DGAT2, diacylglycerol O-acyltransferase 2; DMD, dystrophin; DMPK, DM1 protein kinase; FGFR4, fibroblast growth factor receptor 4; GCCR, glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1); GCGR, glucagon receptor; GHR, growth hormone receptor; GRB2, growth factor receptor bound protein 2; HBV, hepatitis B virus; HCV, hepatitis C virus; HSP27, heat shock protein 27; HTT, huntingtin; ICAM1, intercellular adhesion molecule 1; IL17RA, interleukin 17 receptor alpha; KLKB1, kallikrein B1; LRRK2, leucine rich repeat kinase 2; MAPT (TAU), microtubule-associated protein tau; mHTT, mutant huntingtin; miR, microRNA; PCSK9, proprotein convertase subtilisin/kexin type 9; PTP1B, protein tyrosine phosphatase, nonreceptor type 1; RHO, Rhodopsin; SCNN1A (EnaC), sodium channel epithelial 1 alpha subunit; SGLT2, sodium/glucose cotransporter 2 (solute carrier family 5 member 2); SMAD7, SMAD family member 7; SMN2, survival of motor neuron 2; SNCA, alpha-synuclein; SOD1, superoxide dismutase 1; STAT3, signal transducer and activator of transcription 3; TGF-β2, transforming growth factor beta 2; TNFα, tumor necrosis factor alpha; TTR, transthyretin; USH2A, usherin. Dose/Route: IM, intramuscular; IT, intrathecal; ITM, intratumoral; IV, intravenous; IVT, intravitreal; SC, subcutaneous. Indication: ALS, amyotrophic lateral sclerosis; AML, acute myeloid leukemia; ATTR, transthyretin amyloidosis; CML, chronic myelogenous leukemia; CMV, cytomegalovirus; CVD, cardiovascular disease; DMD, Duchenne muscular dystrophy; FCS, familial chylomicronemia syndrome; HAE, hereditary angioedema; HBV, hepatitis B virus; HCV, hepatitis C virus; HoFH, homozygous familial hypercholesterolemia; MD, myotonic dystrophy; MS, multiple sclerosis; NASH, nonalcoholic steatohepatitis; NSCLC, non-small-cell lung cancer; SMA, spinal muscular atrophy; T2D, type 2 diabetes. Key Observations: AIDS, acquired immune deficiency syndrome; ALT, alanine aminotransferase; CTC, circulating tumor cells; FDA, Food and Drug Administration; HbA1c, hemoglobin A1c; IL6, interleukin 6; LDL, low-density lipoprotein; Lp(a), lipoprotein (a); PSA, prostate antigen. References: NCT, national clinical trial (registry, clinicaltrials.gov).