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siRNA dominates cardiometabolic RNA drugs, and outcomes data now decides the race
In cardiometabolic RNA drugs, lowering the target is no longer an edge: seven of nine targets already have a program in Phase 3 or later, so outcomes trials will decide the race. Sleuth’s September 2026 map counts 84 active programs from 48 companies against those nine targets, and 77 of the 84 are siRNA; the other seven are antisense oligonucleotides (ASOs).
The siRNA lead is mostly about delivery. GalNAc conjugation made liver delivery efficient and repeatable, and every target on the map is made mainly in the liver. Once a company has that platform, it can swap the RNA sequence fairly easily, so clinical validation of a target quickly brings fast followers.
Seven of nine targets have reached Phase 3 or approval
In the September 2026 map, AGT for hypertension draws the broadest field, with Roche in Phase 3 and dense Phase 1 and Phase 2 groups that include Novartis, Ionis, Hengrui and CSPC. PCSK9 has Novartis at approval with inclisiran (Leqvio), and CSPC and Qilu in Phase 3. ApoC3 has approved drugs from Ionis and Arrowhead, while ANGPTL3 (Arrowhead), Lp(a) (Amgen) and TMPRSS6, an iron-regulation target (Ionis), each have a Phase 3 program. TTR is the most mature row, with approved siRNA and ASO drugs from Alnylam, Ionis and AstraZeneca, although only Alnylam’s vutrisiran among them is approved in cardiomyopathy, as Sleuth traced in its ATTR cardiomyopathy asset map.
INHBE, an obesity target, and factor XI, an anticoagulation target, are the only rows without a Phase 3 program; both top out in Phase 2, with Wave Life Sciences and Basecure leading INHBE. Chinese companies appear in every row of the map and reach Phase 3 in PCSK9.
With most targets at Phase 3 or beyond, a new entrant needs more than target activity. Twice-yearly dosing is increasingly the entry ticket, and durability and outcomes data are what separate programs.
Lowering the target has not guaranteed a clinical benefit
Three ASO readouts show the gap between knockdown and outcomes. Novartis’s pelacarsen lowered Lp(a) but did not reduce cardiovascular events in Lp(a)HORIZON, a Phase 3 trial of more than 8,000 patients, according to topline results in September 2026. AstraZeneca and Ionis’s eplontersen (Wainua) lowered TTR but missed the overall primary endpoint of the Phase 3 CARDIO-TTRansform trial in ATTR cardiomyopathy in July 2026. Ionis’s olezarsen cut triglycerides by 64% and remnant cholesterol by 72% but did not change noncalcified coronary plaque at 12 months in the Essence-TIMI 73b imaging study, presented in April 2026.
All three are ASOs mainly because ASO is the older chemistry and reached outcomes-stage testing first. Alnylam’s vutrisiran, an siRNA, has already shown a cardiovascular outcome benefit in ATTR cardiomyopathy in the HELIOS-B trial. On the other targets, siRNA programs face the same question the ASOs did: whether deep, durable knockdown adds a benefit on top of modern standard of care. In Lp(a), that question now passes to siRNA outcomes trials such as Amgen’s olpasiran.
Sleuth expects extrahepatic delivery to be the next battleground
The cardiometabolic RNA field is liver-bound by design, and reaching the heart, muscle, central nervous system and other tissues beyond the liver will define the next generation of programs. Sleuth’s RNA Intelligence Report, Q3 2026 follows that delivery race across the wider oligonucleotide pipeline.
Programs, companies and stages are as of September 2026. The map counts each company once per target, at its most advanced stage, and is not exhaustive. Trial results are as reported through September 2026.
Frequently asked questions about cardiometabolic RNA drugs
How many cardiometabolic RNA programs are in development?
As of September 2026, Sleuth mapped 84 active programs from 48 companies across nine targets: AGT, INHBE, PCSK9, ApoC3, ANGPTL3, Lp(a), factor XI, TTR and TMPRSS6. Of the 84, 77 are siRNA and seven are ASOs.
Why are most cardiometabolic RNA drugs siRNA?
GalNAc conjugation made delivery to the liver, where all nine mapped targets are mainly made, efficient and repeatable. With that platform in place, developers can swap the sequence to follow a validated target.
Which cardiometabolic RNA targets have approved drugs?
In Sleuth’s September 2026 map, PCSK9 (Novartis’s inclisiran), ApoC3 (Ionis and Arrowhead) and TTR (Alnylam, Ionis and AstraZeneca) have approved RNA drugs. AGT, ANGPTL3, Lp(a) and TMPRSS6 have programs in Phase 3.
