Acoramidis Hydrochloride

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.

12.3 Pharmacokinetics The systemic exposures (C max and AUC) increase in a less than dose proportional manner following single and multiple doses of acoramidis. Over the dose range from 89 mg twice daily to 712 mg twice daily, AUC increases only 130%. Acoramidis steady state is achieved by 4 days with approximately 1.3-fold accumulation at the approved recommended dosage. At steady state, a dose of 712 mg twice daily results in a mean (SD) C max of 13700 (6090) ng/mL and AUC 0-12h of 47200 (10300) ng.h/mL. Absorption The time to C max of acoramidis (T max ) is approximately 1 hour following oral administration. Effect of Food No clinically significant differences in acoramidis pharmacokinetics were observed following administration of a high-fat meal (800-1000 total calories, ≥ 50% fat). Distribution The apparent steady-state volume of distribution for acoramidis is 654 liters. Acoramidis is 96% bound to human plasma proteins in vitro. Acoramidis primarily binds to TTR. Elimination The effective half-life of acoramidis is approximately 6 hours with a steady state apparent clearance of 16 L/hr. Metabolism Acoramidis is primarily metabolized by glucuronidation via UGT1A9, UGT1A1 and UGT2B7. Acoramidis-β-D-glucuronide (Acoramidis-AG) is the predominant metabolite of acoramidis (8% of total circulating drug related moieties). Acoramidis-AG is approximately 1/3 as pharmacologically active compared with acoramidis, has a low potential for covalent binding, and does not contribute to pharmacological activity. Excretion After a single oral dose of radiolabeled acoramidis 712 mg to healthy adult subjects, approximately 32% of the dose radioactivity was recovered in feces (15% unchanged), and approximately 68% was recovered in urine (<10% unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of acoramidis were observed based on age, race/ethnicity (including Japanese and non-Japanese), sex, or renal impairment. The effect of hepatic impairment (Child Pugh A, B, or C) on acoramidis pharmacokinetics is unknown. Drug Interaction Studies Clinical Studies Following the administration of acoramidis (712 mg, BID) in a clinical study in healthy adult volunteers, there was not a clinically significant increase in exposure to the organic anion transporter-1 (OAT1) substrate (adefovir) and to OAT3 substrate (oseltamivir carboxylate). Concomitant diuretic use in patients does not affect steady-state plasma acoramidis concentrations. In Vitro Studies Cytochrome P450 Enzymes: Acoramidis is a time-dependent inhibitor of CYP2C9, but does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, or CYP3A4/5. Acoramidis does not induce CYP1A2, CYP2B6, or CYP3A4. UDP-Glucuronosyl Transferase (UGT): Acoramidis is a substrate of multiple UGT enzymes including UGT1A9, UGT1A1, and UGT2B7. Transporter Systems: Acoramidis is a substrate for OAT1 and breast cancer resistance protein (BCRP). Acoramidis inhibits OAT1 and OAT3, but does not inhibit MATE1, OCT1, OCT2, OATP1B1, OATP1B3, MATE2-K, BCRP, P-gp, or BSEP.