In the 20 years since FDA approved the first antisense oligonucleotide (ASO), eight RNA interference products have cleared the agency. Only six are still on the market.

Novartis Ophthalmics and Isis’ Vitravene (fomvirsen), the first ASO, was approved in 1998 to treat cytomegalovirus retinitis, an eye infection found in AIDS patients – a market that, thanks to the advent of highly active antiretroviral therapy (HAART) for HIV infection, has substantially declined. Vitravene is now discontinued.

Another ophthalmic antisense approval followed in 2004, when FDA approved Eyetech’s RNA aptamer Macugen (pegatinib) for ‘wet’ age-related macular degeneration. Macugen has struggled to get a foothold in the market and has bounced between sponsors. Pfizer partnered on the product before Eyetech was acquired by OSI in 2005; Eyetech later spun out from OSI and was acquired by Valeant (now Bausch) in 2010.

Almost 10 years passed before FDA approved another ASO – Isis and Genzyme’s ill-fated Kynamro (mipomersen) for HoFH. Kastle briefly licensed Kynamro in 2017 before discontinuing the product after FDA intensified the Risk Evaluation and Mitigation Strategy (REMS).

Antisense approvals picked up in 2016. FDA controversially approved Sarepta’s exon-skipping ASO Exondys 51 (eteplirsen) for certain Duchenne muscular dystrophy patients. The approval of Biogen and Ionis’s Spinraza (nusinersen) followed, with less controversy, to treat spinal muscular atrophy.

FDA also approved Jazz Pharmaceuticals’ Defitelio (defibrotide) in 2016 for severe hepatic vaso-occlusive disease after high-dose chemotherapy or bone marrow transplant. Defitelio is one of the rare products where FDA did not include the therapeutic class in the indication, but the drug is a complex mixture including oligonucleotides.

Dynavax’ hepatitis B vaccine Heplisav, approved in 2017, includes an adjuvant that is based on an immunostimulatory oligonucleotide.

On Aug. 10, 2018, Alnylam’s Onpattro became the first small interfering RNA approved. Onpattro treats hATTR amyloidosis.

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