3-year acoramidis (AG10) results in ATTR-CM: data from an ongoing OLE

Take-home messages:

  • ATTR-CM is an under-recognised, progressive and fatal disease
  • AG10 at a median of 38 months showed an adverse event profile consistent with baseline disease severity and patient characteristics
  • AG10 stabilised or improved NT-proBNP in patients with ATTR-CM at all time points beyond 12 months

Transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy (ATTR-CM) is an infiltrative cardiomyopathy that occurs when unstable transthyretin (TTR) tetramers dissociate and aggregate as amyloid plaques in the myocardium. The prognosis is fatal and there are few treatment options available.1,2 At the American College of Cardiology Scientific Sessions 2022 (ACC.22), Dr Ahmad Masri, Director of the Cardiac Amyloidosis Program, Oregon Health & Science University, presented interim phase II open-label extension (OLE) results for AG10, a TTR stabiliser, in patients with ATTR-CM.

Dr Masri began by introducing ATTR-CM as a growing diagnostic and treatment priority. It is an under‑recognised cause of many cardiac morbidities; for instance, studies have identified undiagnosed ATTR amyloidosis in 7% of patients with idiopathic bilateral carpal tunnel release3 and in 10%-13% of patients with heart failure (HF) with preserved ejection fraction.4,5 It is also rapidly progressive, with an estimated survival at 36 months of just 50% when untreated.6

AG10, Dr Masri explained, was designed to mimic a naturally occurring T199M mutation in TTR that stabilises TTR tetramers to prevent their dissociation.7 A phase II study, completed in 2018, tested the efficacy, safety and pharmacodynamics of a range of doses of AG10 versus placebo for 28 days in adult patients with ATTR-CM, NYHA class II/III and ≥1 prior hospitalisation for HF or clinical evidence of HF.8 In the ongoing OLE, patients were invited to continue or switch to AG10 800 mg twice daily, for up to 60 months.9

Phase II and OLE study design:

Dr Masri presented the results, available as of 31 August 2021, at a median follow-up of 38 months since initial randomisation and 35 months since open-label AG10 initiation:

Serum TTR levels increased by 41% from baseline at Month 30

Serum TTR concentration increased from 21.55 mg/dL baseline to 30.06 mg/dL at Month 30.

Median NT-proBNP was stable or improving throughout the OLE

At Month 30:

  • NT-proBNP had decreased by a median of 437 pg/mL versus baseline
  • 68% of evaluable participants (15/22) had NT-proBNP levels lower than their baseline levels

No safety signals of clinical concern were identified

The pattern of treatment-emergent adverse events (TEAEs) was consistent with the underlying disease, disease progression, concurrent illnesses and the age of participants.

  • All participants experienced at least one TEAE
  • 31 participants (66%) experienced at least one serious TEAE
  • The most common serious TEAEs (≥10%) were acute cardiac failure (19.1%), acute kidney injury (14.9%), fall (10.6%) and congestive heart failure (10.6%)
  • Overall, adverse events with an outcome of death, cardiac transplant or transition to hospice were reported for 11 participants (23%)

“These results provide additional optimism for the results of the ongoing phase III study of acoramidis expected next year”, Dr Masri told the audience, before sharing additional details of the phase III study - ATTRibute-CM.

ATTRibute-CM began in 2019, assigning patients with ATTR-CM and NYHA class I-III to 800 mg AG10 twice daily or placebo twice daily, and includes an OLE in which all patients can continue or switch to AG10.10

At 12 months, AG10 versus placebo showed:

  • no improvement in 6-minute walking distance versus placebo (12-month primary endpoint)
  • positive improvement in the Kansas City Cardiomyopathy Questionnaire overall score
  • positive reduction in NT-proBNP
  • positive improvement in serum TTR

Data from ATTRibute-CM are expected to be published in mid-202310 and will provide further insight into the potential benefits of AG10 as a treatment for ATTR-CM.

NT-proBNP: N-terminal pro B-type natriuretic peptide; NYHA: New York Heart Association

Based on: Masri, A. Long-term safety and tolerability of acoramidis (AG10) in symptomatic transthyretin amyloid cardiomyopathy: updated analysis from an ongoing phase 2 open-label extension study. Presented at ACC.22, 2-4 April 2022, Washington, DC, US

Top image: Design Cells
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