Antisense oligonucleotides (ASOs) are short synthetic single-stranded nucleic-acid molecules designed to bind complementary messenger RNA and either block translation, alter splicing, or trigger degradation of the target transcript. As a modality, ASOs sit adjacent to peptides in the therapeutic taxonomy: both are synthetic biomolecules that operate below the antibody size threshold, share manufacturing infrastructure with peptide synthesis, and increasingly ride the same delivery platforms (Denali's Oligonucleotide TransportVehicle shuttles ASOs across the blood-brain barrier through the same TfR1 mechanism used for peptide-conjugate CNS delivery).
The 2026 ASO landscape spans several therapeutic areas. Biogen's diranersen (BIIB080) is an intrathecally administered anti-MAPT ASO for Alzheimer's disease; the Phase 2 CELIA study presented at AAIC 2026 on Tuesday July 14 missed its primary endpoint on CDR-SB dose response but showed strong tau pathology reduction and cognitive benefit particularly at the lowest 60 mg q24w dose. AstraZeneca and Ionis' Wainua (eplontersen) missed the primary composite endpoint in the CARDIO-TTRansform Phase 3 study in transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) announced July 9, though the drug remains FDA-approved for hereditary ATTR polyneuropathy. Ionis' Tryngolza (olezarsen) received FDA approval June 24 for severe hypertriglyceridemia.
Stories here cover ASO trial readouts, delivery platform advances, and the modality's positioning relative to peptides. See #tau, #alzheimers-disease, and #blood-brain-barrier for adjacent threads.
Ionis Pharmaceuticals (NASDAQ: IONS) CEO Brett Monia participated in a fireside chat Thursday September 10, 2026 at the Wells Fargo 21st Annual Healthcare Conference in Boston, disclosing TRYNGALZA (olezarsen, an antisense oligonucleotide that reduces apolipoprotein C-III production and lowers triglycerides) H1 2026 U.S. net product sales of $32 million (Q2 alone was $5 million) with full-year 2026 guidance of $100-110 million. The severe hypertriglyceridemia (sHTG) launch followed June 2026 FDA approval and represents the first indication expansion from the initial familial chylomicronemia syndrome (FCS) indication. Ionis raised peak sales guidance in the sHTG indication from $1 billion-plus to $2 billion-plus. The sHTG marketing application is under review in the European Union with potential launch in 2027. Ionis is also commercializing the September 3, 2026 FDA-approved ZANVASTRO (zilganersen, an antisense oligonucleotide) for Alexander disease, a first-in-class disease-modifying therapy for a rare progressive neurodegenerative disorder with no other approved therapies. The company acknowledged parallel setbacks in cardiovascular studies including the Novartis pelacarsen Phase 3 Lp(a)HORIZON miss reported September 4.
Novartis (NYSE: NVS) announced Friday September 4, 2026 that the pelacarsen Phase 3 Lp(a)HORIZON trial did not meet its primary endpoint of reducing major adverse cardiovascular events (a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularization requiring hospitalization) versus placebo in patients with elevated lipoprotein(a) plus established cardiovascular disease on guideline-directed background therapy including lipid-lowering and antihypertensive medications. Pelacarsen (an antisense oligonucleotide targeting hepatic APO(a) production, licensed from Ionis Pharmaceuticals in 2019) did achieve substantial lower Lp(a) levels versus placebo. The trial enrolled roughly 8,000 patients globally over 6 years and represents the largest and most consequential test to date of the Lp(a)-as-causal-cardiovascular-risk-factor hypothesis. The miss substantially raises the bar for Amgen's olpasiran (RNAi, Phase 3 OCEAN(a) ongoing), Silence Therapeutics's zerlasiran (RNAi), and Lilly's lepodisiran (RNAi) — all of which are testing similar Lp(a)-lowering-plus-cardiovascular-outcome frameworks. Ionis and Royalty Pharma both hold economic interests in pelacarsen.
Ionis Pharmaceuticals (NASDAQ: IONS) announced Thursday September 3, 2026 FDA approval of Zanvastro (zilganersen, an intrathecally-administered antisense oligonucleotide designed to reduce glial fibrillary acidic protein / GFAP production) for the treatment of Alexander disease in pediatric and adult patients. The approval is the first-ever disease-modifying therapy for Alexander disease, an ultra-rare autosomal dominant neurodegenerative disorder caused by GFAP gene mutations that presents in infancy through adulthood with progressive motor and cognitive decline. Approval landed 19 days ahead of the September 22, 2026 PDUFA target action date. In the registrational trial, walking speed stayed stable in Zanvastro-treated patients while control patients saw a 33% decline. FDA granted Ionis a Rare Pediatric Disease Priority Review Voucher (PRV) alongside the approval; PRVs have historically sold for $150-350 million on secondary markets. Zanvastro follows Ionis's Wainua (eplontersen) commercial franchise for hereditary transthyretin amyloid polyneuropathy and lands after the August 28 CARDIO-TTRansform ATTR-CM Phase 3 primary endpoint miss for the same molecule.
Ultragenyx Pharmaceutical (NASDAQ: RARE) announced Wednesday September 2, 2026 that the Phase 3 Aspire study of apazunersen (GTX-102, an intrathecally-administered antisense oligonucleotide designed to reduce production of the paternal UBE3A antisense transcript in Angelman syndrome) did not meet its primary endpoint of change from Baseline in Bayley-4 cognitive raw score, nor its key secondary endpoint of Multidomain Responder Index (MDRI) net response. The 129-patient trial enrolled ages 4 to 17 with genetically confirmed full maternal UBE3A gene deletion. Safety was consistent with the Phase 1/2 program. The result is the first Phase 3 miss for an antisense drug in Angelman syndrome and closes off the primary regulatory path for GTX-102 in the enrolled population. Ultragenyx will discuss next steps with regulators and continues the Aurora study evaluating GTX-102 in additional Angelman syndrome genotypes and age groups. RARE shares fell substantially in premarket trading. The failure joins Roche/Ionis's tominersen Huntington's disease miss (GENERATION HD1, 2022) and Sage-Biogen's zuranolone MDD approval-with-restrictions as instances where CNS antisense programs failed to translate promising Phase 1/2 signals into Phase 3 wins.
Ionis Pharmaceuticals (NASDAQ: IONS) awaits its September 22, 2026 PDUFA target action date for zilganersen (an intrathecally-administered antisense oligonucleotide designed to reduce production of glial fibrillary acidic protein / GFAP) for the treatment of Alexander disease, a rare autosomal dominant neurodegenerative disease caused by GFAP gene mutations. If approved, zilganersen would become the first FDA-approved therapy for Alexander disease and Ionis's next commercial launch following Wainua (eplontersen) for hereditary transthyretin amyloid polyneuropathy (with the CARDIO-TTransform ATTR-CM primary endpoint miss now behind the company). Zilganersen was granted FDA Fast Track designation and Orphan Drug designation. Alexander disease presents in infancy through adulthood with progressive motor and cognitive decline; no disease-modifying therapies are currently approved. Not a peptide, but the antisense oligonucleotide class continues to complement peptide-based rare-disease therapies (Rein Therapeutics LTI-03 Caveolin-1 peptide for IPF among others) as the RNA modality expands into ultra-orphan indications.
AstraZeneca (NASDAQ: AZN) and Ionis Pharmaceuticals (NASDAQ: IONS) presented Sunday August 30, 2026 at ESC Congress 2026 Munich the detailed subgroup analyses from the Phase 3 CARDIO-TTRansform trial of Wainua (eplontersen, an antisense oligonucleotide targeting transthyretin) in adults with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM). CARDIO-TTRansform did not meet its primary composite endpoint (cardiovascular mortality plus recurrent CV events through 140 weeks) versus placebo. In the prespecified subgroup analysis, patients receiving eplontersen monotherapy achieved a nominally significant hazard ratio of 0.71 versus placebo, while patients on background TTR stabilizer therapy (tafamidis, Vyndaqel/Vyndamax) at baseline showed no treatment effect. The read-out complicates the silencer-plus-stabilizer commercial approach in ATTR-CM that Alnylam's HELIOS-B trial of vutrisiran validated with 28.2% mortality reduction and 32.8% CV event reduction on background tafamidis. AstraZeneca and Ionis will analyze the full dataset to inform next steps in the CARDIO-TTRansform program.
Biogen (NASDAQ: BIIB) presented full Phase 2 CELIA study data for diranersen (BIIB080), an investigational tau-targeting antisense oligonucleotide (ASO) delivered intrathecally, at AAIC 2026 in London on Tuesday July 14, 2026 during the Developing Topics in Phase 2 Clinical Trials Session (2:00-3:30 PM BST). The 76-week placebo-controlled study evaluated three doses (60 mg every 24 weeks, 115 mg every 24 weeks, and 115 mg every 12 weeks) and did not meet its primary endpoint of dose response on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at Week 76. Strong reductions in tau pathology occurred across all studied doses, generally consistent with the Phase 1b study. Prespecified analyses of cognitive endpoints demonstrated slowing of clinical decline across all doses, with the effect particularly pronounced at the lowest 60 mg q24w dose. Biogen framed the results as the first randomized Phase 2 evidence of a tau-directed therapy showing both biomarker impact and cognitive benefit, and plans to advance diranersen to registrational Phase 3 development.
Biogen (NASDAQ: BIIB) will present Phase 2 CELIA study data for diranersen (BIIB080), an investigational tau-targeting antisense oligonucleotide (ASO), at AAIC 2026 in London during the Developing Topics in Phase 2 Clinical Trials session on Tuesday July 14, 2:00–3:30 PM BST. The 18-month CELIA study evaluated diranersen in patients with early Alzheimer's disease and is the first study to show reduction in tau pathology and cognitive benefit for a tau-targeted therapy. Biogen will present clinical, biomarker, and safety data that build on the May 2026 topline announcement and further characterize the molecule as the program advances toward Phase 3 development. Diranersen targets MAPT RNA to reduce tau production at its source, a differentiated approach to addressing abnormal tau both inside and outside neurons. The CELIA readout is a peptide-adjacent nucleic-acid biologic milestone that shifts the tau treatment conversation from 'reducing pathology' to 'reducing pathology and moving cognition.'
AstraZeneca and Ionis Pharmaceuticals announced Thursday July 9, 2026 that the Phase 3 CARDIO-TTRansform trial of Wainua (eplontersen) did not meet its primary efficacy endpoint in adults with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM). The trial enrolled over 1,400 patients and was the largest Phase 3 study conducted in the ATTR-CM population to date; the primary endpoint was a composite of cardiovascular mortality and recurrent CV clinical events through 140 weeks compared with placebo. Prespecified subgroup analyses showed nominally significant reductions in composite events with eplontersen monotherapy versus placebo, while patients also receiving a baseline TTR stabilizer showed no incremental effect. Eplontersen is an antisense oligonucleotide (a nucleic-acid therapeutic modality distinct from peptides but adjacent in the metabolic-and-cardiovascular therapeutic territory this site tracks); the drug is already FDA-approved as Wainua for hereditary transthyretin amyloidosis polyneuropathy. Full CARDIO-TTRansform results will be presented at the European Society of Cardiology (ESC) Congress in August 2026. AstraZeneca and Ionis shares fell on the readout.
Aligos Therapeutics presented additional EASL 2026 data on its chronic hepatitis B (HBV) combination strategy. An analog of ALG-170675, a potential best-in-class antisense oligonucleotide (ASO), demonstrated additive-to-synergistic effects when combined with ALG-001075 (the active parent moiety of pevifoscorvir sodium, a capsid assembly modulator). Separately, 40% of HBeAg-positive chronic HBV patients treated with pevifoscorvir sodium for 48 weeks reached HBsAg reductions low enough to potentially qualify for ASO treatment — supporting a sequencing strategy toward functional HBV cure where the capsid modulator lowers viral antigen load before the ASO finishes the job. The data complements the ALG-055009 THR-β MASH results (46.2% liver-fat reduction) Aligos presented earlier in the week. The combination-and-sequencing approach mirrors the broader trend in liver disease toward layered mechanisms rather than single-agent therapy, and positions Aligos across the HBV, HDV, and MASH liver-disease franchises.