AstraZeneca PLC / Ionis Pharmaceuticals, Inc.

Hereditary transthyretin-mediated amyloid polyneuropathy (hATTR-PN) and ATTR cardiomyopathy (ATTR-CM)

150K US cases/yr · $3.3B Pfizer Vyndaqel/Vyndamax 2022 global sales (USD MM, 10-K) · 50000 Global hATTR-PN prevalence (NORD)

Disease Overview

Transthyretin amyloidosis (ATTR) is a progressive, fatal disease caused by misfolded TTR protein depositing as amyloid fibrils in nerves and the heart. Two clinical phenotypes: hATTR polyneuropathy (hATTR-PN, autosomal dominant from TTR gene mutations, peripheral and autonomic neuropathy, untreated median survival 5-15 years post-symptom onset) and ATTR cardiomyopathy (ATTR-CM, both wild-type and hereditary, restrictive cardiomyopathy and heart failure, median survival 2-3.5 years untreated). NORD estimates 50,000 hATTR-PN patients globally; ATTR-CM is dramatically larger and underdiagnosed, with US prevalence estimated at 100,000-150,000 (Maurer et al. JACC 2017; AHA 2020 review) and total addressable diagnosed-prevalent population projected to reach 200,000+ in the US alone as cardiac imaging awareness grows. Pfizer's tafamidis (Vyndaqel/Vyndamax) achieved $3.3B in 2022 sales as the first ATTR-CM therapy, validating multi-billion-dollar commercial potential. Eplontersen is a GalNAc3-conjugated antisense oligonucleotide that knocks down hepatic TTR mRNA expression, with monthly self-administered subcutaneous dosing — a meaningful convenience advantage over Alnylam's Onpattro (q3-week IV infusion) and similar patisiran-class agents.

Competitive Landscape

ATTR therapeutic landscape continues to densify. Approved/late-stage TTR-lowering and stabilizer agents: Alnylam patisiran (Onpattro, IV RNAi, hATTR-PN 2018) and vutrisiran (Amvuttra, sc RNAi, hATTR-PN 2022; HELIOS-B ATTR-CM win Jun 2024); Ionis inotersen (Tegsedi, sc ASO, hATTR-PN 2018, US-withdrawn 2022); Pfizer tafamidis (Vyndaqel/Vyndamax, oral stabilizer, ATTR-CM 2019, $3.3B 2022 sales); BridgeBio acoramidis (Attruby, oral stabilizer, ATTR-CM Nov 2024). Eplontersen (next-gen GalNAc/LICA ASO; monthly sc, improved platelet/renal profile vs Tegsedi) won FDA approval Dec 21 2023 as Wainua for hATTR-PN and EU approval Mar 10 2025 as Wainzua. Post-close commercial ramp: FY2024 global net sales $85M (US launch year), FY2025 $212M. The pivotal ATTR-CM CARDIO-TTRansform Phase 3 outcome trial (>1,400 pts) had NOT read out as of Jun 2026 -- Ionis now guides the readout to H2 2026 (slipped from earlier "as early as 1H 2025"). ATTR-CM is the far larger indication that underpins the $2.9B sales milestones and the partners' >$5B peak-sales case; the CM readout remains the deal's key open value driver. Strategic logic intact: AZ rebuilds CV franchise; Ionis monetizes its wholly-owned LICA asset via a resourced commercial partner.