Acoramidis – Introduction
- Acoramidis, a selective transthyretin stabilizer, is indicated for the treatment of cardiomyopathy of the wild-type or variant transthyretin-mediated amyloidosis (ATTR-CM) to reduce cardiovascular death and cardiovascular-related hospitalization in adults.
- Gastrointestinal adverse reactions (i.e., diarrhea and abdominal pain) were the most common adverse reactions reported in clinical trials.71564
- Acoramidis appears to be more potent, have better TTR binding affinity, and improved TTR stabilization when compared to other TTR stabilizers, such as tafamidis.71555 Acoramidis was FDA-approved in November 2024.
Indications
- Reduction of cardiovascular mortality
- Transthyretin amyloid cardiomyopathy
For the treatment of wild type or variant transthyretin amyloid cardiomyopathy for the reduction of cardiovascular mortality and cardiovascular-related hospitalization
Note: Acoramidis is designated as an orphan drug by the FDA for this indication
Oral dosage
Adults:
712 mg PO twice daily.71564
Maximum Dosage Limits:
•Adults
1424 mg/day PO.
•Geriatric
1424 mg/day PO.
•Adolescents
Safety and efficacy have not been established.
•Children
Safety and efficacy have not been established.
•Infants
Safety and efficacy have not been established.
•Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Precautions
- Breast-feeding
- Pregnancy
Interactions
- Amobarbital
- Apalutamide
- Aspirin, ASA; Butalbital; Caffeine
- Barbiturates
- Bosentan
- BUPivacaine; Meloxicam
- Butalbital; Acetaminophen
- Butalbital; Acetaminophen; Caffeine
- Butalbital; Acetaminophen; Caffeine; Codeine
- Butalbital; Aspirin; Caffeine; Codeine
- carBAMazepine
- Diclofenac
- Diclofenac; miSOPROStol
- Encorafenib
- Enzalutamide
- Etravirine
- Fexinidazole
- Fosphenytoin
- Lonafarnib
- Lopinavir; Ritonavir
- Lorlatinib
- Lumacaftor; Ivacaftor
- Lumacaftor; Ivacaftor
- Meloxicam
- Meloxicam; Rizatriptan
- Methadone
- Methohexital
- Mitapivat
- Mitotane
- Nateglinide
- Nirmatrelvir; Ritonavir
- OXcarbazepine
- PENTobarbital
- PHENobarbital
- PHENobarbital; Hyoscyamine; Atropine; Scopolamine
- Phenytoin
- Primidone
- rifAMPin
- Rifapentine
- Ritonavir
- Secobarbital
- St. John’s Wort, Hypericum perforatum
- Warfarin
Amobarbital: (Major) Avoid concomitant use of acoramidis and barbiturates due to the risk of decreased acoramidis exposure which may reduce its efficacy. 28596 41911 49229 49236 49352 55436 57046 71454 71564
Apalutamide: (Major) Avoid concomitant use of acoramidis and apalutamide due to the risk of decreased acoramidis exposure which may reduce its efficacy. 62874 71564
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concomitant use of acoramidis and barbiturates due to the risk of decreased acoramidis exposure which may reduce its efficacy. 28596 41911 49229 49236 49352 55436 57046 71454 71564
Barbiturates: (Major) Avoid concomitant use of acoramidis and barbiturates due to the risk of decreased acoramidis exposure which may reduce its efficacy. 28596 41911 49229 49236 49352 55436 57046 71454 71564
Bosentan: (Moderate) Monitor for an increase in bosentan-related adverse reactions if concomitant use of acoramidis is necessary. Concomitant use may increase bosentan exposure. Bosentan is a CYP2C9 substrate and acoramidis is a CYP2C9 inhibitor. 28496 71564
BUPivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with acoramidis is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and acoramidis is a CYP2C9 inhibitor. 65019 71564
Butalbital; Acetaminophen: (Major) Avoid concomitant use of acoramidis and barbiturates due to the risk of decreased acoramidis exposure which may reduce its efficacy. 28596 41911 49229 49236 49352 55436 57046 71454 71564
Butalbital; Acetaminophen; Caffeine: (Major) Avoid concomitant use of acoramidis and barbiturates due to the risk of decreased acoramidis exposure which may reduce its efficacy. 28596 41911 49229 49236 49352 55436 57046 71454 71564
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concomitant use of acoramidis and barbiturates due to the risk of decreased acoramidis exposure which may reduce its efficacy. 28596 41911 49229 49236 49352 55436 57046 71454 71564
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concomitant use of acoramidis and barbiturates due to the risk of decreased acoramidis exposure which may reduce its efficacy. 28596 41911 49229 49236 49352 55436 57046 71454 71564
carBAMazepine: (Major) Avoid concomitant use of acoramidis and carbamazepine due to the risk of decreased acoramidis exposure which may reduce its efficacy. 71454 71564
Diclofenac: (Moderate) Monitor for an increase in diclofenac-related adverse effects if concomitant use with acoramidis is necessary; a diclofenac dosage decrease may be required based on response. Concomitant use may increase diclofenac exposure. Diclofenac is a CYP2C9 substrate and acoramidis is a CYP2C9 inhibitor. 45871 71564
Diclofenac; miSOPROStol: (Moderate) Monitor for an increase in diclofenac-related adverse effects if concomitant use with acoramidis is necessary; a diclofenac dosage decrease may be required based on response. Concomitant use may increase diclofenac exposure. Diclofenac is a CYP2C9 substrate and acoramidis is a CYP2C9 inhibitor. 45871 71564
Encorafenib: (Major) Avoid concomitant use of acoramidis and encorafenib. Concurrent use may decrease acoramidis exposure which may reduce its efficacy. 63317 71564
Enzalutamide: (Major) Avoid concomitant use of acoramidis and enzalutamide. Concurrent use may decrease acoramidis exposure which may reduce its efficacy. 51727 71564
Etravirine: (Major) Avoid concomitant use of acoramidis and etravirine due to the risk of decreased acoramidis exposure which may reduce its efficacy. Acoramidis is a UGT substrate and etravirine is a UGT inducer. 61985 71564
Fexinidazole: (Major) Avoid concomitant use of acoramidis and fexinidazole due to the risk of decreased acoramidis exposure which may reduce its efficacy. Acoramidis is a UGT substrate and fexinidazole is a UGT inducer. 66812 71564
Fosphenytoin: (Major) Avoid concomitant use of acoramidis and phenytoin/fosphenytoin due to the risk of decreased acoramidis exposure which may reduce its efficacy. Additionally, concomitant use may increase phenytoin exposure and the risk for phenytoin toxicity. Phenytoin is a CYP2C9 substrate and UGT inducer; acoramidis is a UGT substrate and CYP2C9 inhibitor. 28535 71454 71564
Lonafarnib: (Major) Avoid coadministration of lonafarnib and acoramidis; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, closely monitor patients for lonafarnib-related adverse reactions. Lonafarnib is a CYP2C9 substrate and acoramidis is a CYP2C9 inhibitor. 66129 71564
Lopinavir; Ritonavir: (Major) Avoid concomitant use of acoramidis and ritonavir due to the risk of decreased acoramidis exposure which may reduce its efficacy. Acoramidis is a UGT substrate and ritonavir is a UGT inducer. 71454 71564
Lorlatinib: (Major) Avoid concomitant use of acoramidis and lorlatinib due to the risk of decreased acoramidis exposure which may reduce its efficacy. Acoramidis is a UGT substrate and lorlatinib is a UGT inducer. 63732 71564
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of acoramidis and lumacaftor; ivacaftor. Concurrent use may decrease acoramidis exposure which may reduce its efficacy. 59891 71564
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of acoramidis and lumacaftor; ivacaftor. Concurrent use may decrease acoramidis exposure which may reduce its efficacy. 59891 71564
Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with acoramidis is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and acoramidis is a CYP2C9 inhibitor. 65019 71564
Meloxicam; Rizatriptan: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with acoramidis is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and acoramidis is a CYP2C9 inhibitor. 65019 71564
Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of acoramidis is necessary. If acoramidis is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; acoramidis is a CYP2C9 inhibitor. Concomitant use with acoramidis can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. 33136 71564
Methohexital: (Major) Avoid concomitant use of acoramidis and barbiturates due to the risk of decreased acoramidis exposure which may reduce its efficacy. 28596 41911 49229 49236 49352 55436 57046 71454 71564
Mitapivat: (Major) Avoid concomitant use of acoramidis and mitapivat due to the risk of decreased acoramidis exposure which may reduce its efficacy. Acoramidis is a UGT substrate and mitapivat is a UGT inducer. 67403 71564
Mitotane: (Major) Avoid concomitant use of acoramidis and mitotane. Concurrent use may decrease acoramidis exposure which may reduce its efficacy. 41934 71564
Nateglinide: (Moderate) Monitor for an increase in nateglinide-related adverse effects, such as hypoglycemia, if concomitant use with acoramidis is necessary; a nateglinide dosage reduction may be required. Concomitant use may increase nateglinide exposure. Nateglinide is a CYP2C9 substrate and acoramidis is a CYP2C9 inhibitor. 45644 71564
Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of acoramidis and ritonavir due to the risk of decreased acoramidis exposure which may reduce its efficacy. Acoramidis is a UGT substrate and ritonavir is a UGT inducer. 71454 71564
OXcarbazepine: (Major) Avoid concomitant use of acoramidis and oxcarbazepine due to the risk of decreased acoramidis exposure which may reduce its efficacy. Acoramidis is a UGT substrate and oxcarbazepine is a UGT inducer. 29014 71564
PENTobarbital: (Major) Avoid concomitant use of acoramidis and barbiturates due to the risk of decreased acoramidis exposure which may reduce its efficacy. 28596 41911 49229 49236 49352 55436 57046 71454 71564
PHENobarbital: (Major) Avoid concomitant use of acoramidis and barbiturates due to the risk of decreased acoramidis exposure which may reduce its efficacy. 28596 41911 49229 49236 49352 55436 57046 71454 71564
PHENobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of acoramidis and barbiturates due to the risk of decreased acoramidis exposure which may reduce its efficacy. 28596 41911 49229 49236 49352 55436 57046 71454 71564
Phenytoin: (Major) Avoid concomitant use of acoramidis and phenytoin/fosphenytoin due to the risk of decreased acoramidis exposure which may reduce its efficacy. Additionally, concomitant use may increase phenytoin exposure and the risk for phenytoin toxicity. Phenytoin is a CYP2C9 substrate and UGT inducer; acoramidis is a UGT substrate and CYP2C9 inhibitor. 41239 71454 71564
Primidone: (Major) Avoid concomitant use of acoramidis and barbiturates due to the risk of decreased acoramidis exposure which may reduce its efficacy. 28596 41911 49229 49236 49352 55436 57046 71454 71564
rifAMPin: (Major) Avoid concomitant use of acoramidis and rifampin due to the risk of decreased acoramidis exposure which may reduce its efficacy. 71454 71564
Rifapentine: (Major) Avoid concomitant use of acoramidis and rifapentine. Concurrent use may decrease acoramidis exposure which may reduce its efficacy. 28483 71564
Ritonavir: (Major) Avoid concomitant use of acoramidis and ritonavir due to the risk of decreased acoramidis exposure which may reduce its efficacy. Acoramidis is a UGT substrate and ritonavir is a UGT inducer. 71454 71564
Secobarbital: (Major) Avoid concomitant use of acoramidis and barbiturates due to the risk of decreased acoramidis exposure which may reduce its efficacy. 28596 41911 49229 49236 49352 55436 57046 71454 71564
St. John’s Wort, Hypericum perforatum: (Major) Avoid concomitant use of acoramidis and St. John’s wort. Concurrent use may decrease acoramidis exposure which may reduce its efficacy. 56579 71564
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with acoramidis is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The active metabolite of warfarin, the S-enantiomer, is a CYP2C9 substrate and acoramidis is a CYP2C9 inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. 28549 71564
Adverse Reactions
- Abdominal pain
- Diarrhea
An increase in serum creatinine and decrease in eGFR have occurred with acoramidis therapy. These changes in serum creatinine and eGFR generally occur within 4 weeks of starting therapy, then stabilize; the changes are reversible upon discontinuation of acoramidis therapy.
In an acoramidis clinical trial, a mean increase in serum creatinine of 0.2 mg/dL and a mean decrease in eGFR of 8.2 mL/minute/1.73m2 was observed in acoramidis-treated subjects compared to a mean increase in serum creatinine of 0 mg/dL and a mean decrease in eGFR of 0.7 mL/minute/1.73m2 in placebo-treated subjects at Day 28 of therapy.71564
Transthyretin (TTR) stabilizers, including acoramidis, may decrease serum concentrations of free thyroxine without an accompanying change in thyroid stimulating hormone (TSH). The reduction in free thyroxine concentrations may be a result of a reduction in thyroxine binding or displacement from TTR.71564
Gastrointestinal adverse reactions reported in acoramidis-treated subjects in a clinical trial included diarrhea (11.6%) and abdominal pain (5.5%) compared to 7.6% and 1.4% in placebo-treated subjects, respectively.
The majority of these gastrointestinal adverse reactions were categorized as mild and resolved without drug discontinuation. Additionally, discontinuation of study drug due to an adverse event occurred in 9.3% of acoramidis-treated subjects compared to 8.5% of placebo-treated subjects.
Mechanism of Action
- Acoramidis is a selective transthyretin (TTR) stabilizer. Acoramidis exerts its therapeutic effect in the rate-limiting step of amyloidgenesis by binding to the thyroxine binding sites on TTR, stabilizing the tetramer and slowing dissociation of the tetramer into its constituent monomers.
- Due to either a reduction in thyroxine binding to or displacement from TTR, a reduction in thyroxine serum concentrations without an accompanying change to thyroid stimulating hormone (TSH) may occur with acoramidis therapy.
- A reduction in free thyroxine has occurred with TTR stabilizers.71564 Near-complete TTR stabilization (more than 90%) has been observed with acoramidis in both wild-type and variant TTR.7155571594
Pharmacodynamics:
- In transthyretin-mediated amyloidosis (ATTR-CM) clinical trials, changes in serum TTR concentrations or in vitro TTR stabilization assays are utilized as pharmacodynamic markers of TTR stabilization.
- Compared to baseline serum TTR concentrations, individuals with wild-type or variant ATTR-CM treated with acoramidis experienced an increase in mean serum TTR concentrations by Day 28 of therapy.
- Based upon in vitro TTR stabilization assays, acoramidis-treated individuals had near-complete TTR stabilization as early as Day 28 and through completion of a 30-month study in individuals with wild-type and variant ATTR-CM.715647155571594
Pharmacokinetics
- Acoramidis is administered orally. Based on in vitro data, 96% of acoramidis is protein bound, and it primarily binds to transthyretin (TTR). The steady-state Vd for acoramidis is 654 L. Metabolism of acoramidis occurs primarily by glucuronidation via UGT1A9, UGT1A1, and UGT2B7.
- The predominant metabolite of acoramidis, beta-D-glucuronide (Acoramidis-AG), accounts for 8% of total circulating drug.
- Acoramidis-AG has approximately one-third of the pharmacological activity of acoramidis, has low potential for covalent binding, and does not contribute to pharmacological activity.
- Approximately 32% of acoramidis is recovered in feces and 68% in the urine with 15% and less than 10%, respectively, as unchanged drug. The half-life of acoramidis is approximately 6 hours with an apparent steady-state clearance of 16 L/hour.71564
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C9, UGT1A9, UGT1A1, UGT2B7, OAT1, OAT3 and breast cancer resistance protein (BCRP).
Acoramidis is a time-dependent inhibitor of CYP2C9 and a substrate of UGT1A9, UGT1A1, UGT2B7, OAT1, and BCRP. Additionally, acoramidis is an inhibitor of OAT1 and OAT3.71564
Pharmacodynamics:
In a 30-month clinical trial, acoramidis demonstrated a smaller increase in N-terminal prohormone of brain natriuretic peptic (NT-proBNP) and troponin I compared to placebo. At Month 30, the increase in NT-proBNP with acoramidis was approximately half that of placebo.71564
Monitoring Parameters
Monitoring Parameters
- laboratory monitoring not necessary
Classifications
- Cardiovascular System
- Selective Transthyretin Stabilizers
