Ionis Pharmaceuticals, Inc. / Akcea Therapeutics, Inc.

Hereditary transthyretin amyloidosis (hATTR) and familial chylomicronemia syndrome (FCS) — antisense oligonucleotide franchise

50K US cases/yr · $4.5B Global TTR amyloidosis drug market 2020 (USD MM, including Onpattro, Tegsedi, Vyndaqel) · 64000000 US adults with elevated Lp(a) >50 mg/dL (pelacarsen TAM)

Disease Overview

Hereditary transthyretin amyloidosis (hATTR) is a rare autosomal-dominant disease caused by mutations in the TTR gene leading to misfolded transthyretin tetramers depositing in peripheral nerves (polyneuropathy phenotype, hATTR-PN) and cardiac tissue (cardiomyopathy phenotype, hATTR-CM). Approximately 50,000 patients worldwide carry hATTR-PN with another 200,000-300,000 estimated for hATTR-CM (often misdiagnosed as HFpEF). Untreated, hATTR-PN is fatal within 5-15 years from symptom onset; hATTR-CM median survival without therapy is ~2-3 years post-diagnosis. The therapeutic landscape was transformed in 2018 with FDA approvals of Alnylam's Onpattro (patisiran, RNAi) and Akcea's Tegsedi (inotersen, ASO) for hATTR-PN, followed by Pfizer's Vyndaqel/Vyndamax (tafamidis, TTR stabilizer) for hATTR-CM. Familial chylomicronemia syndrome (FCS) is an ultra-rare LPL-deficient disorder (~3,000-5,000 patients globally) with severe hypertriglyceridemia and recurrent pancreatitis — Akcea/Ionis's Waylivra (volanesorsen) gained EMA approval in 2019 but received an FDA Complete Response Letter in 2018 due to thrombocytopenia/safety concerns. Pelacarsen (TQJ230) targets elevated lipoprotein(a), a genetically-defined CV risk factor affecting ~64M Americans with Lp(a) >50 mg/dL, in partnership with Novartis.

Competitive Landscape

The antisense oligonucleotide and RNAi space surrounding the Akcea franchise is intensely competitive. In hATTR, Alnylam (Onpattro patisiran, RNAi-LNP, FDA-approved 2018; vutrisiran follow-on Phase 3 HELIOS-A 2020) competes head-to-head with Ionis/Akcea (Tegsedi inotersen, GalNAc-conjugated ASO; eplontersen/AKCEA-TTR-LRx next-gen partnered with AstraZeneca 2018). Pfizer's Vyndaqel/Vyndamax (tafamidis, TTR stabilizer) holds hATTR-CM since FDA approval May 2019, generating $1.3B in 2020. BridgeBio Pharma (acoramidis, AG10, TTR stabilizer Phase 3 ATTRibute-CM ongoing) and Eidos Therapeutics (acquired by BridgeBio 2020) are emergent threats. In Lp(a), pelacarsen (Novartis/Ionis) competes with Amgen's olpasiran (RNAi, Phase 2 OCEAN study), Silence Therapeutics (SLN360, Phase 1 2020) and Arrowhead's ARO-LPA. In FCS, vupanorsen (ANGPTL3 ASO licensed to Pfizer 2019, $250M upfront) and Regeneron's evinacumab (Evkeeza, anti-ANGPTL3 mAb, FDA-approved Feb 2021) emerged as competitive ANGPTL3 mechanisms. Broader ASO/RNAi platform competitors include Alnylam, Arrowhead, Dicerna, Wave Life Sciences, Sarepta, and Stoke Therapeutics.