Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis (APOLLO-B)

Authors, Journal, Affiliations, Type, DOI

• Maurer MS, Kale P, Fontana M, Berk JL, Grogan M, Gustafsson F, Hung RR, Gottlieb RL, Damy T, González-Duarte A, Sarswat N, Sekijima Y, Tahara N, Taylor MS, Kubanek M, Donal E, Palecek T, Tsujita K, Tang WHW, Yu W-C, Obici L, Simões M, Fernandes F, Poulsen SH, Diemberger I, Perfetto F, Solomon SD, Di Carli M, Badri P, White MT, Chen J, Yureneva E, Sweetser MT, Jay PY, Garg PP, Vest J, Gillmore JD; for the APOLLO-B Trial Investigators
• The New England Journal of Medicine
• Lead: Columbia University Irving Medical Center, New York; National Amyloidosis Centre UCL, London; Alnylam Pharmaceuticals, Cambridge MA; 69 international sites
• Phase 3, double-blind, randomized, placebo-controlled trial
• DOI: 10.1056/NEJMoa2300757

Overview

APOLLO-B is a Phase 3 RCT (n=360; 12 months) testing patisiran (0.3 mg/kg IV Q3W) vs placebo in patients with ATTR-CM (ATTRv or ATTRwt). Patisiran, an LNP-formulated siRNA targeting the 3' UTR of TTR mRNA in the liver, achieved 86.8% serum TTR knockdown. The primary endpoint (6MWT) was met (+14.69 m; P=0.02) and KCCQ-OS showed benefit (+3.7 pts; P=0.04), but both hard composite endpoints — death/cardiovascular events and death/hospitalization — were not significant, as the 12-month trial was underpowered for mortality. Exploratory data showed favourable signals for LV mass, GLS, stroke volume, NT-proBNP, and troponin I, establishing proof-of-concept for cardiac RNAi benefit. Patisiran was not approved for ATTR-CM; its successor vutrisiran (GalNAc-SC formulation) demonstrated mortality benefit in the 36-month HELIOS-B trial.

Keywords

ATTR amyloidosis, transthyretin, RNA interference, patisiran, siRNA, LNP, 6-minute walk test, KCCQ, TTR knockdown, cardiac amyloidosis, wild-type ATTR, variant ATTR, heart failure

Key Takeaways

Background

• ATTR-CM is caused by progressive myocardial amyloid deposition; median survival 2–6 years by disease stage
• Tafamidis (TTR tetramer stabilizer, ATTR-ACT 2018) reduced mortality but functional capacity and QoL still declined on average
• Patisiran targets the 3' UTR of TTR mRNA (common to both WT and variant isoforms) in hepatocytes via LNP delivery; already approved for ATTRv polyneuropathy (APOLLO trial, NEJM 2018)
• Pre-specified cardiac subgroup of APOLLO (cardiac involvement at baseline) showed favourable cardiac structural/functional effects at 18 months — mechanistic rationale for APOLLO-B

Trial Design and Patients

• Phase 3, double-blind, randomized, placebo-controlled; 1:1 allocation; 69 sites, 21 countries
• Enrollment: October 2019 – May 2021; n=360 (181 patisiran; 179 placebo)
• Patisiran: 0.3 mg/kg IV Q3W (max 30 mg); standard premedication (corticosteroids, antihistamines, acetaminophen) before each infusion; vitamin A supplementation during trial
• Duration: 12 months double-blind; open-label extension ongoing
• Key inclusion criteria: age 18–85; confirmed ATTR-CA (biopsy or validated non-biopsy criteria); cardiac involvement (IVS >12 mm on echo); history of heart failure
• Key exclusion criteria: NYHA III + NAC Stage 3 (NT-proBNP >3000 + eGFR <45) together; NYHA IV; 6MWT <150 m; neuropathy disability score >II; non-ATTR CMP (ischaemic, valvular)
• ~80% ATTRwt; 20% ATTRv (16 different pathogenic variants; 41% V122I in ATTRv subgroup)
• Median age 76 years; predominantly male; 25% on tafamidis at baseline
• Randomization stratified by: tafamidis use at baseline (yes/no); genotype (ATTRv vs ATTRwt); NYHA class + age (NYHA I–II + <75 years vs all others)
• Hierarchical endpoint testing: primary → 1st secondary → 2nd secondary → 3rd secondary (sequential alpha-spending; lower endpoints not tested if a higher one fails)

Efficacy — Primary Endpoint

• 6MWT change from baseline at 12 months (primary): patisiran −8.15 m (95% CI −16.42 to 1.50) vs placebo −21.35 m (95% CI −34.05 to −7.52); Hodges–Lehmann estimate of median difference +14.69 m (95% CI 0.69–28.69; P=0.02) ✓
• Both groups showed decline from baseline; patisiran preserved function relative to placebo but did not achieve absolute improvement
• 14.69 m is below the commonly cited 30 m MCID for ATTR-CM; clinical significance of the between-group difference is modest
• Results consistent across prespecified subgroups (ATTRv/ATTRwt; tafamidis yes/no) and in post-hoc analysis excluding neuropathy-impaired walkers

Efficacy — Secondary Endpoints

• KCCQ-OS change at 12 months (1st secondary): patisiran +0.3 pts (95% CI −2.2 to 2.8) vs placebo −3.4 pts (95% CI −5.9 to −0.9); LS mean difference +3.7 pts (95% CI 0.2–7.2; P=0.04) ✓
  • 3.7 pts difference is below the 5-point MCID; the clinical significance of health-status benefit is marginal
• Composite: death/CV events/6MWT change (2nd secondary; win ratio): win ratio 1.27 (95% CI 0.99–1.61); NS ✗ — hierarchical testing stopped here
• Composite: death/any hospitalisation/urgent HF visits (3rd secondary; HR): HR 0.88 (95% CI 0.58–1.34); NS ✗ — not formally tested (hierarchy stopped)
  • Tafamidis subgroup at baseline: HR 1.0 (95% CI 0.62–1.60)
• Deaths (efficacy analysis): 4 (2.2%) patisiran vs 10 (5.6%) placebo; HR 0.36 (95% CI 0.11–1.14); NS — trial underpowered and too short for mortality
  • Heart transplantations counted as deaths: 0 patisiran, 2 placebo
  • 1 COVID-19 death censored (1 patisiran); not counted in efficacy analysis

Efficacy — Exploratory Endpoints (hypothesis-generating; not multiplicity-controlled)

• NT-proBNP: median change patisiran +131 pg/mL (IQR −280 to 817) vs placebo +518 pg/mL (IQR 51–1544); ratio of adjusted geometric mean factor increase patisiran/placebo = 0.80 (95% CI 0.73–0.89) — less biomarker worsening with patisiran
• Troponin I: median change patisiran +3.8 pg/mL (IQR −7.1 to 19.9) vs placebo +14.5 pg/mL (IQR 0.0–32.2); ratio = 0.87 (95% CI 0.80–0.95) — less injury worsening
• LV mass (echo): change from baseline −1.00 g (95% CI −7.31 to 5.32) patisiran vs +8.45 g (95% CI 2.02–14.89) placebo; between-group LS mean difference −9.45 g (95% CI −18.48 to −0.42)
• LV GLS: LS mean change patisiran +0.36 pp vs placebo +0.90 pp (worsening); between-group difference −0.54 pp (95% CI −1.04 to −0.05)
• LV stroke volume: change patisiran +0.48 mL vs placebo −2.52 mL; between-group difference +3.00 mL (95% CI 0.61–5.38)
• Collectively these exploratory signals support amyloid regression/stabilization and preserved systolic function

Pharmacodynamics

• Mean (±SD) serum TTR reduction at 12 months: 86.8±13.6% in patisiran group
• Reduction rapid (onset within first dosing cycle) and sustained throughout 12 months
• Consistent across subgroups: tafamidis-treated (83.7±16.3%) and non-tafamidis (87.9±12.3%); ATTRv (85.2±12.7%) and ATTRwt (87.2±13.9%)
• Baseline mean serum TTR 235.32±68.05 mg/L (patisiran) and 244.77±73.17 mg/L (placebo); at 12 months: 30.93±33.60 mg/L vs 229.40±77.15 mg/L
• Note: unlike TTR stabilizers (which raise serum TTR by preventing incorporation into amyloid), patisiran substantially lowers circulating TTR — inverse pharmacodynamic direction

Safety

• Adverse events: 91% patisiran vs 94% placebo; majority mild or moderate; discontinuation 3% each group
• Adverse events ≥5% in patisiran and ≥3 pp more common than placebo: infusion-related reactions, arthralgia, muscle spasms (all infusion reactions mild or moderate; 1 discontinuation)
• Serious adverse events: similar in both groups (not significantly different)
• Most common SAEs (≥2% in either group): cardiac failure, atrial fibrillation, complete AV block, amyloidosis, syncope
• Safety deaths: 5 (3%) patisiran (sudden cardiac death 1; heart failure 1; pancreatitis 1; COVID-19 1; undetermined 1) vs 8 (4%) placebo
• No clinically relevant changes in laboratory measures, vital signs, or ECG in either group

Limitations of the Document

• Trial duration 12 months: Explicitly stated by authors; insufficient power for mortality and hospitalization endpoints; between-group differences in hard outcomes were NS
• Primary endpoint met but below MCID: 14.69 m 6MWT difference and 3.7 KCCQ-OS difference are below generally accepted MCIDs (30 m and 5 pts); clinical meaningfulness is debatable
• Modest between-group differences driven by placebo decline: Patisiran largely prevented decline rather than producing absolute improvement
• Underpowered for mortality: 4 vs 10 deaths (HR 0.36 NS) — estimated much larger sample or longer follow-up needed
• Exclusion of most severe patients: NYHA III + NAC Stage 3 excluded; 6MWT <150 m excluded — results not generalizable to advanced disease
• No patisiran vs tafamidis comparison: 25% on background tafamidis; no formal analysis of patisiran monotherapy vs tafamidis monotherapy
• Neuropathy confound in 6MWT: ATTRv patients may have neuropathy affecting walk test; post-hoc analysis excluding neuropathy impairment was consistent, mitigating but not eliminating this concern
• Industry-funded: Alnylam Pharmaceuticals sponsored, designed, and analyzed the trial; authors had confidentiality agreements

Key Concepts Mentioned

• concepts/TTR-Stabilizer-Therapy — patisiran is the comparator RNAi agent for this concept class
• entities/ATTR-Amyloidosis — the disease entity treated

Key Entities Mentioned

• entities/Patisiran — the investigational therapy
• entities/Vutrisiran — successor agent (GalNAc-SC) that went on to demonstrate mortality benefit in HELIOS-B 2025
• entities/ATTR-Amyloidosis — disease entity treated in the trial

Wiki Pages Updated

• wiki/sources/patisiran-attrcm-apollob-nejm-2023.md — created (this file)
• wiki/entities/Patisiran.md — created
• wiki/entities/ATTR-Amyloidosis.md — updated management section
• wiki/concepts/TTR-Stabilizer-Therapy.md — updated with patisiran/RNAi context
• wiki/sourceindex.md — updated
• wiki/wikiindex.md — updated