siRNA dominates the cardiometabolic RNA field We mapped ~85 active programs from 48 companies targeting 9 popular cardiometabolic pathways (about ~40% of the total active pipeline). ~92% of programs are siRNA, versus just 8% ASO. That concentration is mostly due to delivery. GalNAc has made liver delivery efficient / repeatable, and every target on this map is largely produced there. Once this core delivery platform is in place, a company can swap the RNA sequence fairly easily. So clinical validation leads to fast followers: for 7/9 of these pathways, programs have already reached Ph3 or beyond. That crowding is making durability, convenience (2x / year is increasingly the entry ticket) and outcomes data much more important to differentiate. And just showing activity ≠ a meaningful clinical benefit waits on the other side: • Most recently, Novartis' Pelacarsen lowered Lp(a) but did not reduce CV events in an 8K+ patient Ph3 • AZ / Ionis' Eplontersen reduced TTR but missed overall Ph3 primary endpoint in ATTR-CM • Ionis' Olezarsen reduced TG by 64% and remnant cholesterol by 72%, but did not change non-calcified coronary plaque at 12 months All of these are ASO readouts, which mostly highlights that it's a more mature modality that reached outcomes-stage testing earlier. siRNA programs will face the same question: does deep, durable knockdown actually produce a benefit on top of modern standard of care? Looking ahead, the next battleground is 'extrahepatic' delivery (reaching the heart, muscle, CNS and other tissues beyond the liver), just one topic we'll cover in far more depth tomorrow when we drop a 15+ slide report on the RNA space. In the meantime, comment below if you'd like a hi-res PDF of this map!