Acoramidis

12.1 Mechanism of Action Acoramidis is a selective stabilizer of transthyretin (TTR). Acoramidis binds TTR at thyroxine binding sites and slows dissociation of the TTR tetramer into its constituent monomers, the rate-limiting step in amyloidogenesis.

1 INDICATIONS AND USAGE ATTRUBY is indicated for the treatment of the cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular death and cardiovascular-related hospitalization. ATTRUBY is a transthyretin stabilizer indicated for the treatment of the cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular death and cardiovascular-related hospitalization. ( 1 , 2.1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of ATTRUBY is 712 mg orally twice daily. ( 2.1 ) 2.1 Recommended Dosage The recommended dosage of ATTRUBY is 712 mg orally twice daily (with or without food). Swallow tablets whole; do not cut, crush, or chew.

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data reflect the exposure of 421 participants with ATTR-CM to ATTRUBY 712 mg (administered as two 356 mg tablets) administered orally twice daily in a randomized, double-blind, placebo-controlled trial of 30 months fixed treatment duration. The median duration of exposure to ATTRUBY in the safety population was 29 months. There was a higher frequency of gastrointestinal (GI) adverse reactions such as diarrhea 11.6% versus 7.6% and upper abdominal pain 5.5% versus 1.4% in the ATTRUBY versus placebo group, respectively. The majority of these GI adverse reactions were categorized as mild and resolved without drug discontinuation. A similar proportion of ATTRUBY-treated and placebo-treated participants discontinued study drug because of an adverse event (9.3% and 8.5%, respectively). Laboratory Tests Increase in Serum Creatinine and Decrease in eGFR Initiation of ATTRUBY causes an increase in serum creatinine and decrease in eGFR which generally occurs within 4 weeks of starting therapy and stabilizes. In a trial of adults with ATTR-CM, a mean increase in serum creatinine of 0.2 and 0.0 mg/dL and a mean decrease in eGFR of 8.2 and 0.7 mL/min/1.73 m 2 was observed in the ATTRUBY and placebo groups, respectively, at Day 28. The changes in serum creatinine and eGFR were reversible after treatment discontinuation.

7 DRUG INTERACTIONS UDP-glucuronosyltransferases (UGT) Inducers and Strong CYP3A Inducers Acoramidis is metabolized by UGT enzyme-mediated glucuronidation. Concomitant use of UGT inducers can potentially decrease acoramidis exposure. While acoramidis is not metabolized by CYP3A, strong CYP3A inducers can also induce UGT enzymes. Avoid concomitant use of ATTRUBY with UGT inducers and strong CYP3A inducers. Sensitive Cytochrome P450 2C9 (CYP2C9) substrates Acoramidis inhibits CYP2C9 and may result in an increase in CYP2C9 substrate concentrations when these drugs are co administered. Consider more frequent monitoring of patients for evidence of increased exposure (for example, signs of exposure related toxicity) when ATTRUBY is co administered with sensitive CYP2C9 substrates.