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RNA therapeutics are an execution race in the liver and a delivery race beyond it
RNA drugs aimed at the liver now compete on clinical outcomes, safety, dosing and cost rather than on whether they work, while beyond the liver the race is still about delivery. Sleuth’s September 2026 analysis counts about 3,150 therapeutic oligonucleotide programs, about 684 of them in clinical development, and 26 approved oligonucleotides, the only approved RNA therapeutic class outside vaccines. GalNAc conjugation made delivery to the liver repeatable. Liver programs now routinely reach more than 90% knockdown and six-month dosing, many converge on the same targets, and GalNAc conjugate patents begin expiring in 2028.
Beyond the liver, only about 12% of all clinical programs clearly try to reach a distant tissue through the bloodstream. Novartis paid about $12 billion for Avidity, a price for a muscle delivery platform, and in September 2026 Avidity’s del-desiran missed its Phase 3 functional endpoint in myotonic dystrophy. Sponsors now have two paths: take proven liver targets into larger chronic indications and compete on outcomes, or unlock the next tissue. On the second path, the value lies in a genuine platform, where the second and third drugs use the same route into the tissue.
684 clinical programs, 26 approvals and a field concentrated on a few targets
siRNA leads the pipeline while ASO holds the most approvals
Of the roughly 684 clinical programs, about 300 are at IND or Phase 1, 110 in Phase 1/2, 190 in Phase 2 and 60 in Phase 3 or filed. By chemistry, siRNA leads with 285 clinical programs, followed by antisense oligonucleotides (ASO) with 223, splice-switching oligos with 26 and antibody-oligonucleotide conjugates (AOC) with 11. ASOs hold 11 of the 26 approvals and siRNA 8, and every approval sits in a chronic or rare disease, where a durable oligonucleotide pays off most. US companies originate about 370 clinical programs, Chinese companies about 165 and the rest of the world about 150.
China has become a core contributor to the pipeline, but Western companies originated every approval, 21 of them from the US.
A few proven targets draw most of the clinical programs
Hepatitis B leads with 29 clinical programs, followed by dystrophin (21), AGT for hypertension (17), PCSK9 (15), INHBE for obesity (13), and ANGPTL3, APOC3 and HTT (11 each). TTR has 9, and factor XI, CFB and C3 have 8 each. Because only a handful of targets are proven, most new programs compete on delivery and dosing rather than biology.
Deal value stays high, and M&A has moved to extrahepatic delivery
Disclosed oligonucleotide deal value peaked at $36.6 billion across 47 deals in 2024, a jump driven by larger deals rather than more of them. 2025 brought $18.3 billion across 50 deals, and 2026 reached $15.0 billion across 45 deals through September, a run rate of about $20 billion. Deals cluster on cardiovascular targets such as AGT, PCSK9, ANGPTL3 and APOC3. M&A has concentrated with one buyer: Novartis bought three extrahepatic delivery platforms, Avidity for muscle ($12 billion, 2025), Regulus for kidney ($1.7 billion, 2025) and DTx Pharma for neuro ($1.0 billion, 2023). Astellas’s $5.9 billion acquisition of Iveric in 2023 bought an eye aptamer.
Buyers are paying for delivery platforms before those platforms reach clinical validation, and Sarepta’s rights to Arrowhead’s extrahepatic delivery point the same way.
Cardiovascular is the proven liver franchise, and outcomes now decide it
siRNA crowds nine cardiometabolic targets
Sleuth mapped 84 active programs from 48 companies against nine cardiometabolic pathways, and 77 of the 84 are siRNA. Seven of the nine pathways already have a program in Phase 3 or later, as Sleuth’s cardiometabolic RNA competitive map shows. Novartis’s Leqvio (inclisiran), dosed twice a year, reached $1.2 billion in 2025 revenue, and twice-yearly dosing has become the entry ticket for new programs.
Three targets have outcomes proof, and Lp(a) is the open question
PCSK9, APOC3 and TTR have proven clinical outcomes. PCSK9 lowering has proven cardiovascular benefit at the class level, though inclisiran’s own ORION-4 outcomes trial is due to read out in the second quarter of 2027. Arrowhead’s plozasiran and Ionis’s olezarsen are approved in familial chylomicronemia syndrome, with broader cardiovascular outcomes still to come. Four TTR drugs are approved, and Alnylam’s vutrisiran showed a positive cardiovascular outcome in ATTR cardiomyopathy in HELIOS-B. ANGPTL3 (Arrowhead’s zodasiran) lowers triglycerides but has no outcomes data yet. Lp(a) is unresolved: Novartis’s pelacarsen lowered Lp(a) sharply but missed its cardiovascular endpoint in Lp(a)HORIZON, so the class now depends on Amgen’s olpasiran readout, expected in the second half of 2027.
In cardiometabolic disease, knockdown is no longer the differentiator. The next winners will be the programs that pair twice-yearly or longer dosing with outcomes data on a validated target.
Five closely watched programs missed clinical endpoints in 2026
In 2026, five programs hit their molecular target but missed the clinical endpoint. Pelacarsen lowered Lp(a) but missed on major cardiovascular events. Del-desiran moved splicing biomarkers but missed the video hand opening time (vHOT) functional endpoint in HARBOR. Ultragenyx’s GTX-102 showed clean target engagement but missed the Bayley-4 cognitive endpoint in Angelman syndrome in Aspire. AstraZeneca and Ionis’s eplontersen lowered TTR but missed its overall cardiovascular primary in CARDIO-TTRansform, with only a monotherapy subgroup nominally positive. Roche’s tominersen lowered mutant HTT but showed no clinical benefit at 16 months in the Phase 2 GENERATION HD2 study, and Roche discontinued the program.
Genetic causality is established for all of these targets, but lowering them has not always changed outcomes. Where a rival oligo already works, as in TTR, a miss reprices the asset, a shift Sleuth traced in why lowering TTR no longer wins on its own. In Lp(a) and HTT, the whole class still needs outcomes validation, and in Angelman syndrome and myotonic dystrophy the biology is causal but clinical function has not yet followed.
Durability and chemistry sort the field by tissue
siRNA takes over as dosing gets less frequent
Across 282 siRNA and ASO programs with a disclosed dosing interval, siRNA makes up 27% of weekly or daily programs, 46% of monthly, 63% of quarterly and 88% of twice-yearly programs. Most oligonucleotides are taken chronically, so a longer interval pays off when patients stay on therapy.
Durability is a trade-off. siRNA buys adherence on chronic, well-validated liver targets, while ASO still leads where a drug needs to reach the central nervous system or muscle. The chemistry should match whether the indication rewards convenience or demands access.
Each tissue has its chemistry and its leading delivery technology
siRNA dominates the liver, with 183 of its 254 tissue-classified programs there. ASO has a significant pipeline in the central nervous system (63 programs) and tumors (40), splice-switching oligos focus on muscle (20 of 23), and conjugates are emerging in muscle. By access route, about 235 clinical programs target the liver, led by GalNAc (about 175). About 200 are delivered locally or regionally by intrathecal, inhaled or eye routes, mostly with unconjugated chemistry, and nusinersen is the most advanced. About 80 use systemic redirection to reach a distant tissue through the bloodstream, led by antibody and other conjugates (about 40), with Avidity’s del-zota the most advanced after its BLA filing.
Tissue access is a chemistry decision. Local and regional delivery is an execution race with approved assets, while systemic redirection is earlier and its winning technology has yet to be clinically validated.
Beyond the liver, CNS and muscle carry different risks
Approved CNS oligonucleotides are all intrathecal rare-disease drugs
Sleuth counted 64 intrathecal ASO programs, from preclinical through approval, including nine in Phase 3. The three approved, Biogen’s nusinersen (spinal muscular atrophy) and tofersen (SOD1 ALS) and Ionis’s zilganersen (Alexander disease), all use intrathecal delivery in single-gene disease. The hardest targets, including HTT, tau and Angelman syndrome, keep missing on clinical function, and only four programs attempt systemic delivery to the brain.
CNS has split into two risk classes: proven with intrathecal delivery in monogenic disease, and unproven at the frontier of neurodegeneration and systemic reach.
Muscle conjugates have solved delivery, but function is the harder test
The muscle-conjugate field has more than 30 programs. Two antibody-oligonucleotide conjugates for Duchenne muscular dystrophy are filed: Avidity’s del-zota, whose BLA was accepted for priority review in September 2026, and Dyne’s z-rostudirsen, which restored 5.46% dystrophin in DELIVER and has a January 2027 FDA decision date. In myotonic dystrophy, del-desiran missed in HARBOR, while Dyne’s z-basivarsen has a registrational readout expected in 2027. Avidity’s del-brax hit its DUX4 biomarker in FSHD, with functional data still to come. The four approved exon-skipping drugs for Duchenne were cleared on dystrophin production, and the ESSENCE confirmatory study of casimersen and golodirsen missed its functional endpoint.
The bottleneck for muscle conjugates has moved from delivery to clinical function. Del-zota validated the delivery, del-desiran showed function is not guaranteed, and Novartis’s Avidity deal shows that the delivery platform is what holds the value.
What the RNA findings mean for developers and buyers
These implications are Sleuth’s interpretation of the data above.
For developers, pick the path before the target. In the liver, a new program needs a reason to exist beyond knockdown: outcomes data, a larger chronic indication, a longer interval or lower cost, with GalNAc patent expiries starting in 2028 lowering the barrier for followers. Beyond the liver, the chemistry has to fit the tissue, and a single asset matters less than proof that the route works for the next drug.
For buyers, separate the asset from the platform. Del-desiran’s miss says less about whether muscle conjugates work than about one drug in one disease. Diligence should ask whether a platform’s second and third programs use the same route into the tissue, and whether the target’s biology has been shown to change clinical outcomes, not just biomarkers.
What Sleuth expects in RNA therapeutics
These predictions are Sleuth’s analytical interpretation, looking beyond what the data shows today.
- The first antibody-oligonucleotide conjugate approval will land in 2027 and reset the field. With del-zota filed and z-rostudirsen facing a January 2027 decision, a conjugate that carries an oligo through the bloodstream into muscle will reach the market, shifting deal and pipeline focus to the next tissue.
- At least one more delivery-platform acquisition or major licensing deal in the $2 billion to $3 billion range will close before pivotal proof, as buyers keep pricing the platform ahead of the readout, as Novartis did with Avidity, Regulus and DTx.
- The Lp(a) class still needs the target validated. After pelacarsen’s miss, Amgen’s olpasiran and Lilly’s lepodisiran are testing whether lowering Lp(a) helps at all. If they miss, a multibillion-dollar thesis collapses across the class; if they hit, durable siRNAs will likely take the market over ASOs.
How Sleuth built this analysis
Pipeline scope
The analysis covers therapeutic oligonucleotides only, about 3,150 programs of all statuses and about 684 in clinical development as of September 2026. Prophylactic vaccines are excluded. Originator region is based on company headquarters.
Targets and cardiometabolic map
Target counts are clinical programs per target, split by most-advanced stage. The cardiometabolic map covers 84 active programs across nine pathways.
Deals
Deal values are headline totals as disclosed, with upfronts shown separately, for oligonucleotide deals from 2021 to September 2026. The 2026 run rate annualizes deals through September.
Dosing, chemistry and access
Dosing intervals cover the 282 siRNA and ASO programs that disclose one; about a quarter of programs do not. Tissue and access classifications cover clinical programs, and about 25% of programs could not be classified by access route. Systemic redirection means reaching a target beyond the liver or a proven local region.
Trial outcomes
Outcomes and readouts are compared across trials, not head to head.
Interpretation
The implications and predictions are Sleuth’s analytical interpretation rather than direct findings from the data.
Pipeline, deal and clinical figures are as of September 2026 unless otherwise noted. Regulatory timing is current as of late September 2026.
Frequently asked questions about RNA therapeutics
How many RNA therapeutics are in development?
Sleuth tracked about 3,150 therapeutic oligonucleotide programs as of September 2026, about 684 of them in clinical development and 26 approved. siRNA leads the clinical pipeline with 285 programs, followed by ASOs with 223.
What is the difference between siRNA and ASO drugs?
Both are short synthetic strands that bind a target RNA to silence a gene or change how it is spliced. siRNA has taken over infrequent dosing on liver targets, making up 88% of twice-yearly programs, while ASOs hold the most approvals (11 of 26) and lead where drugs must reach the central nervous system or muscle.
Why is liver delivery easier for RNA drugs?
GalNAc conjugation targets a receptor on liver cells, which made liver delivery repeatable. About 175 clinical programs use GalNAc, and liver programs now routinely reach more than 90% knockdown with dosing as infrequent as twice a year.
What are antibody-oligonucleotide conjugates?
Antibody-oligonucleotide conjugates (AOCs) attach an oligonucleotide to an antibody that carries it into a specific tissue, such as muscle. Avidity’s del-zota and Dyne’s z-rostudirsen for Duchenne muscular dystrophy are filed with the FDA, and z-rostudirsen has a January 2027 decision date.
Which RNA drugs missed their endpoints in 2026?
Pelacarsen (Lp(a)), del-desiran (myotonic dystrophy), GTX-102 (Angelman syndrome), eplontersen (TTR cardiomyopathy) and tominersen (Huntington’s disease) all hit their molecular target in 2026 but missed their clinical endpoints.
How big are RNA therapeutics deals?
Oligonucleotide deal value peaked at $36.6 billion in 2024 and reached $15.0 billion across 45 deals in 2026 through September. The largest acquisition was Novartis’s roughly $12 billion purchase of Avidity for its muscle delivery platform.
What are the key RNA catalysts through 2027?
Key events include an FDA decision on GSK’s bepirovirsen for hepatitis B (goal date October 26, 2026), the z-rostudirsen decision in January 2027, del-zota’s review, inclisiran’s ORION-4 outcomes readout in the second quarter of 2027 and Amgen’s olpasiran Lp(a) outcomes readout in the second half of 2027.
