Long-term safety and pharmacodynamics of acoramidis in ATTR-CM

In the open-label extension AG10-202 study, acoramidis for 45 months was generally well tolerated by patients with symptomatic transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) and resulted in sustained TTR stabilization and reduced NT-proBNP.

This summary is based on the publication of Masri A, Aras M, Grogan M, et al. - Acoramidis for Transthyretin Amyloid Cardiomyopathy: Open-Label Extension Study Long-Term Follow-Up. J Card Fail. 2025 Apr 9:S1071-9164(25)00162-9 [Online ahead of print]. doi: 10.1016/j.cardfail.2025.03.017.

Introduction and methods

Background

Transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal disease characterized by the deposition of amyloid fibrils, which consist of misfolded transthyretin (TTR) aggregates, in the myocardium. Acoramidis (AG10), a highly selective, potent, oral stabilizer of the TTR protein, reduced CV death and CV hospitalization in ATTR-CM patients and has been approved by the FDA and EMA [1-4]. The phase 2 study AG10-201 among patients with symptomatic ATTR-CM showed treatment with acoramidis for 28 days was well tolerated and resulted in reaching target plasma TTR levels and near-complete TTR stabilization [3].

Aim of the study

In an open-label extension (OLE) study of the AG10-201 study, the authors investigated the safety and pharmacodynamics of long-term acoramidis treatment in patients with symptomatic ATTR-CM.

Methods

The AG10-201 study was a multicenter, double-blind, placebo-controlled, parallel-group, dose-ranging, phase 2 RCT conducted in the US in which 49 adult patients with ATTR-CM, NYHA class HF symptoms II–III, and a history of HF (i.e., ≥1 prior HF hospitalization or clinical evidence of HF) were randomized in a 1:1:1 ratio to acoramidis 400 mg twice daily, acoramidis 800 mg twice daily, or placebo for 28 days.

In the currently ongoing AG10-202 OLE study, 47 participants (96%) were enrolled, who received acoramidis 800 mg twice daily. Of them, 25 (53.2%) completed the month 45 visit, whereas 22 (46.8%) discontinued the OLE study due to, among others, adverse events, death, or physician decision. Median follow-up time since enrollment in the AG10-201 study was 55 months (IQR: 18.6–55.3).

Outcomes

The primary endpoints of the current analysis were safety and tolerability, including assessments of vital signs, physical examination, clinical laboratory tests, ECG, and adverse events, at 45 months. Secondary endpoints included pharmacodynamic assessment of TTR stabilization at 45 months, as examined with 2 ex vivo assays (i.e., fluorescent probe exclusion (FPE) and Western blotting), and change in NT-proBNP levels from baseline to 45 months.

Main results

Safety

• All 47 participants experienced a treatment-emergent adverse event, most frequently a fall (n=22; 47%), acute kidney injury (n=13; 28%), and acute cardiac failure (n=12; 26%).
• Of the treatment-emergent adverse events, 5 (10.6%) were deemed to be treatment-related and 1 (2.1%) of these was serious.
• During follow-up, no potential clinical safety concerns were observed.

Pharmacodynamics

• Treatment with acoramidis increased the mean serum TTR level from 20.70 mg/dL at baseline to 29.68 mg/dL at 45 months, representing a mean increase of 47.6% (SD: 33.3%).
• Western blotting showed the mean TTR percent stabilization at 45 months was 86.0% (SD: 9.8%). In patients with wild-type ATTR-CM, the mean TTR percent stabilization was 100.0% (SD: 10.6%) at 14 days and 87.6% (SD: 9.0%) at 45 months, whereas it was 94.7% (SD: 12.9%) and 78.8% (SD: 11.6%), respectively, in those with variant ATTR-CM.
• The FPE assay confirmed these findings, with a mean TTR percent stabilization at 45 months of 99.3% (SD: 12.0%) in the overall study population, 99.3% (SD: 13.4%) in patients with wild-type ATTR-CM, and 98.9% (SD: 1.9%) in those with variant ATTR-CM.
• The median change in NT-proBNP level from baseline to 45 months was −307 pg/mL (IQR: −679 to 204), representing a median decrease of 22.9% (IQR: –31.3% to 19.1%).

Conclusion

The OLE phase of the AG10-201 study (named AG10-202) demonstrated that 45-month treatment with acoramidis was generally well tolerated by patients with symptomatic ATTR-CM and resulted in sustained TTR stabilization and reduced NT-proBNP levels. The authors point out the small sample size of their study and note that “[t]he ongoing OLE study of ATTRibute-CM will provide further insights into a larger cohort of patients.”

Find this article online at J Card Fail.

References

1. Miller M, Pal A, Albusairi W et al. Enthalpy-driven stabilization of transthyretin by AG10 mimics a naturally occurring genetic variant that protects from transthyretin amyloidosis. J Med Chem 2018;61:7862-7876.
2. Gillmore JD, Judge DP, Cappelli F et al. Efficacy and safety of acoramidis in transthyretin amyloid cardiomyopathy. N Engl J Med 2024;390:132-142.
3. Judge DP, Heitner SB, Falk RH et al. Transthyretin stabilization by AG10 in symptomatic transthyretin amyloid cardiomyopathy. J Am Coll Cardiol 2019;74:285-295.
4. Penchala SC, Connelly S, Wang Y et al. AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. Proc Natl Acad Sci U S A 2013;110:9992-7.