Emerging new therapy classes (e.g. CAR-T and gene therapies) with potential curative benefits across severe and rare diseases are likely candidates for expedited regulatory approval but their high prices will incur strong payer scrutiny. Previous innovative therapy classes can provide valuable insights in this regard. Oligonucleotide therapies (antisense oligonucleotides (ASOs), morpholinos, aptamers, and siRNAs) can target and modify transcripts of specific disease-causing genes. This research evaluates their regulatory, reimbursement and commercial success. Food and Drug Administration (FDA) and European Commission (EC)-approved oligonucleotide therapies were identified alongside their reimbursement status in US, EU5, Nordic countries, Australia and Canada from relevant websites plus a targeted review of company press releases for sales data (to 05/31/2018). Six oligonucleotide therapies have FDA-approvals (Spinraza®, Exondys 51®, Macugen®, Vitravene®, Kynamro® and Defitelio®), four also with EC-approvals. For Macugen®, Vitravene®, and Kynamro®, sales have significantly diminished since launch through competitor product launches (anti-VEGFs, HAART, and Repatha/Praluent, respectively). ASOs targeting RNA splicing modification in lethal pediatric diseases: Spinal Muscular Atrophy (SMA), Spinraza®, and Duchenne Muscular Dystrophy (DMD), Exondys 51®, were US-launched in 2016 with first-year drug costs of $750,000 and $300,000, respectively. Some US insurers initially restricted/denied coverage but subsequently mostly relaxed these restrictions. Spinraza® also faced ex-US reimbursement challenges: many payers restricted access based on age and severity (SMC, HAS, PBAC, TLV, NT, CADTH), few granted broad access (G-BA, DGFPS, PBS), and DMC and NoMA initially rejected reimbursement. Lack of long-term data was a frequent critique. Oligonucleotide therapies have struggled to translate expedited regulatory approval into rapid and broad reimbursement, which is key for commercial success in these highly competitive indications. Strategies to bridge the payer evidentiary gap, including making clinical trials more payer-relevant, early payer advice, RWE strategies, and innovative contracting/reimbursement models need to be considered for the commercial success of innovative transformational therapies.