Table 1.
FDA-approved oligonucleotide therapeutics
| Name (market name), company | Target (indication) | Organ (ROA) | Chemistry (modality) | FDA approval | Comments |
|---|---|---|---|---|---|
|
Fomivirsen (Vitravene), Ionis Pharma Novartis |
CMV UL123 (cytomegalovirus retinitis) | Eye (IVI) | 21mer PS DNA (first-generation ASO) | August 1998 |
First approved nucleic acid drug Local delivery Withdrawn from use owing to reduced clinical need |
|
Pegaptanib (Macugen), NeXstar Pharma Eyetech Pharma |
VEGF-165 (neovascular age-related macular degeneration) | Eye (IVI) | 27mer 2ʹ-F/2ʹ-OMe pegylated (aptamer) | December 2004 |
First approved aptamer drug Local delivery Limited commercial success due to competition |
|
Mipomersen (Kynamro), Ionis Pharma Genzyme Kastle Tx |
APOB (homozygous familial hypercholesterolaemia) | Liver (SQ) | 20mer PS 2ʹ-MOE (gapmer ASO) | January 2013 |
Rejected by EMA owing to safety Limited commercial success due to competition |
|
Defibrotide (Defitelio), Jazz Pharma |
NA (hepatic veno-occlusive disease) | Liver (IV) | Mixture of PO ssDNA and dsDNA | March 2016 | Unique sequence-independent mechanism of action |
|
Eteplirsen (Exondys 51), Sarepta Tx |
DMD exon 51 (Duchenne muscular dystrophy) | Skeletal muscle (IV) | 30mer PMO (steric block ASO) | September 2016 |
Systemic delivery to non-hepatic tissue Low efficacy |
|
Nusinersen (Spinraza), Ionis Pharma Biogen |
SMN2 exon 7 (spinal muscular atrophy) | Spinal cord (IT) | 18mer PS 2ʹ-MOE (steric block ASO) | December 2016 | Local delivery |
|
Patisiran (Onpattro), Alnylam Pharma |
TTR (hereditary transthyretin amyloidosis, polyneuropathy) |
Liver (IV) | 19 + 2mer 2ʹ-OMe modified (siRNA LNP formulation) | August 2018 |
First approved RNAi drug Nanoparticle delivery system Requires co-treatment with steroids and antihistamines |
|
Inotersen (Tegsedi), Ionis Pharma Akcea Pharam |
TTR (hereditary transthyretin amyloidosis, polyneuropathy) |
Liver (SQ) | 20mer PS 2ʹ-MOE (gapmer ASO) | October 2018 | Same gapmer ASO platform as mipomersen |
|
Givosiran (Givlaari), Alnylam Pharma |
ALAS1 (acute hepatic porphyria) | Liver (SQ) | 21/23mer Dicer substrate siRNA (GalNAc conjugate) | November 2019 |
Enhanced stability chemistry Hepatocyte-targeting bio-conjugate |
|
Golodirsen (Vyondys 53), Sarepta Tx |
DMD exon 53 (Duchenne muscular dystrophy) | Skeletal muscle (IV) | 25mer PMO (steric block ASO) | December 2019 | Same PMO chemistry platform as eteplirsen |
ASO, antisense oligonucleotide; dsDNA, double-stranded DNA; 2ʹ-F, 2ʹ-fluoro; GalNac, N-acetylgalactosamine; IT, intrathecal; IV, intravenous; IVI, intravitreal injection; LNP, lipid nanoparticle; 2ʹ-MOE, 2ʹ-O-methoxyethyl; 2ʹ-OMe, 2ʹ-O-methyl; NA, not applicable; PMO, phosphorodiamidate morpholino oligonucleotide; PO, phosphodiester; PS, phosphorothioate; ROA, route of administration; siRNA, small interfering RNA; SQ, subcutaneous; ssDNA, single-stranded DNA.