A Study to Evaluate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy - APOLLO-B

Oct 30, 2023
Font Size
A
A
A
Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Trial Sponsor:
Alnylam Pharmaceuticals
Date Published:
10/26/2023
Date Updated:
10/30/2023
Original Posted Date:
10/30/2023
References

Contribution To Literature:

The APOLLO-B trial showed that intravenous patisiran is superior to placebo for improving quality of life endpoints at 12 months among patients with ATTR-CM.

Description:

The goal of the trial was to compare the safety and efficacy of patisiran compared with placebo among patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM).

Study Design

Eligible patients with variant or wild-type ATTR were randomized in a 1:1 randomized double-blind fashion to either patisiran (n = 181) or matching placebo (n = 178). Patisiran was administered at a dose of 0.3 mg/kg, maximum dose 30 mg, intravenously every 3 weeks for 12 months.

  • Total number of enrollees: 359
  • Duration of follow-up: 12 months
  • Median patient age: 76 years
  • Percentage female: 10%

Inclusion criteria:

  • Age 18-85 years
  • Subjects with diagnosed ATTR-cardiac amyloidosis (wild-type or variant), defined as the presence of transthyretin amyloid deposits on analysis of tissue biopsy specimens or fulfillment of validated nonbiopsy diagnostic criteria for ATTR cardiac amyloidosis
  • Cardiac involvement confirmed by echocardiography

Exclusion criteria:

  • New York Heart Association (NYHA) class III and an ATTR amyloidosis stage of 3 (defined as an N-terminal pro–B-type natriuretic peptide [NT-proBNP] level of >3000 pg/mL occurring concomitantly with an estimated glomerular filtration rate of <45 mL/min/1.73 m2 of body surface area)
  • NYHA class of IV
  • Six-minute walk distance (6MWD) of <150 m
  • A polyneuropathy disability score >II
  • Cardiomyopathy not associated with ATTR amyloidosis (e.g., cardiomyopathy due to ischemic or valvular heart disease)

Other salient features/characteristics:

  • Wild-type ATTR-CM: 81%
  • NT-proBNP: 2000 pg/mL
  • NYHA class: I: 7%, II: 85%
  • Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) score at baseline: 70
  • Concomitant tafamidis use at baseline: 25%
  • ATTR amyloidosis stage 1: 67%

Principal Findings:

The primary endpoint, change at 12 months compared with baseline in 6MWD for patisiran vs. placebo, was: -8.5 vs. -21.4 m; difference: 14.69 (p = 0.02).

Secondary outcomes for patisiran vs. placebo:

  • Change in KCCQ-OS from baseline: -3.4 vs. 0.3, difference 3.7 (p = 0.04)
  • Change in NT-proBNP from baseline: 131 vs. 518 (p < 0.05)
  • All-cause mortality/cardiovascular events/change in 6MWD: win ratio 1.27 (95% confidence interval 0.99–1.61)
  • All-cause mortality (safety analysis): 3% vs. 4%

Reduction in serum transthyretin levels with patisiran was 86.8%, which was sustained irrespective of baseline use of tafamidis and wild-type vs. variant ATTR.

Interpretation:

The results of this trial indicate that patisiran 0.3 mg/kg (maximum dose 30 mg) given intravenously every 3 weeks for 12 months is superior to placebo for improving quality of life endpoints among patients with ATTR-CM. Approximately 25% of patients were already on tafamidis at baseline.

Patisiran is an RNA interference agent with a lipid nanoparticle delivery system that targets the common 3′ untranslated region of TTR messenger RNA in the liver to reduce circulating transthyretin protein levels in both variant and wild-type ATTR amyloidosis. On the other hand, tafamidis and acromidis are transthyretin stabilizers. Patisiran has the potential to be an effective and safe agent for the treatment of ATTR-CM, possibly in combination with transthyretin stabilizers, although this needs to be further assessed. Long-term data are also awaited. In addition, the cost-effectiveness of this therapy deserves further study; prior studies in polyneuropathy patients indicate annual treatment costs of approximately $500,000/patient.

References:

Maurer MS, Kale P, Fontana M, et al., on behalf of the APOLLO-B Trial Investigators. Patisiran Treatment in Patients With Transthyretin Cardiac Amyloidosis. N Engl J Med 2023;389:1553-65.

Editorial: Merlini G. A Step Forward in Solving Amyloidosis. N Engl J Med 2023;389:1615-7.

Clinical Topics: Cardiovascular Care Team, Heart Failure and Cardiomyopathies

Keywords: Cardiac Amyloidosis, Cardiomyopathies


< Back to Listings