Acoramidis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh; Meghana Kodali, MBBS, MPH
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Overview
Acoramidis is a transthyretin stabilizer that is FDA approved for the treatment of Acoramidis is a transthyretin stabilizer that is FDA approved for the treatment of the cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce death and cardiovascular-related hospitalization.. Common adverse reactions include diarrhea and upper abdominal pain, which were categorized as mild and resolved without drug discontinuation..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
- Acoramidis is indicated for the treatment of cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis (ATTR-CM) – 712 mg PO bid
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Acoramidis in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non-Guideline-Supported Use of Acoramidis in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of Acoramidis have not been established in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Acoramidis in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non-Guideline-Supported Use of Acoramidis in pediatric patients.
Contraindications
None
Warnings
There is limited information regarding warnings.
Adverse Reactions
Clinical Trials Experience
- Acoramidis has been evaluated for safety in 421 participants with ATTR-CM in a randomized, double-blind, placebo-controlled trial of 30 months.
- Higher frequency of gastrointestinal (GI) adverse reactions were observed as follows –
- Diarrhea: 11.6% (treatment group) versus 7.6% (placebo group)
- Upper abdominal pain: 5.5% (treatment group) versus 1.4% (placebo group)
- Majority of these GI adverse reactions were classified as mild and disappeared without drug discontinuation.
- Similar clinical trial was discontinued due to increased serum creatinine and decreased eGFR, which occurred within 4 weeks of therapy initiation.
- Serum creatinine: mean increase of 0.2 mg/dl (treatment group) versus 0.0 mg/dl (placebo group)
- eGFR: mean decrease of 8.2 mL/min/1.73 m2 (treatment group) versus 0.7 mL/min/1.73 m2 (placebo group)
- These changes were reversible after drug discontinuation.
Postmarketing Experience
There is limited information about post-marketing experience.
Drug Interactions
UDP-glucuronosyltransferases (UGT) Inducers and Strong CYP3A Inducers
- Acoramidis is metabolized by UGT enzyme-mediated glucuronidation. Concurrent use with UGT inducers can decrease acoramidis exposure.
- Although acoramidis is not metabolized by CYP3A, UGT enzymes can be induced by strong CYP3A inducers.
- Avoid simultaneous use of acoramidis with UGT inducers and strong CYP3A inducers.
Sensitive Cytochrome P450 2C9 (CYP2C9) Substrates
- Acoramidis inhibits CYP2C9 and results in an increase in CYP2C9 substrate concentrations during concomitant use.
- Frequent monitoring is advised for evidence of increased exposure when they are co-administered.
Use in Specific Populations
Pregnancy
- Insufficient data on acoramidis use in pregnant women.
- Animal reproductive studies in rats and rabbits found no embryofetal abnormalities at doses up to 34 and 13 times the clinical exposure at the maximum recommended human dose (MRHD) of acoramidis, respectively.
- However, the following changes were observed in pregnant rabbits at 34 times the clinical exposure at MRHD –
- increased pre-implantation loss
- maternal toxicity (26% reduced body weight gain)
- Pregnant rats had the following changes in a pre- and postnatal developmental toxicity study at 43 times the clinical exposure at MRHD –
- maternal death
- body weight reduction
- decreased number of females with live-born pups (due to increase in resorbed litters)
- Decreased body weight gain from the neonatal period to weaning and learning deficits were observed in the offspring of dams given 43 times the clinical exposure at MRHD.
- No adverse effects on pre- and postnatal development were observed at 18 times the clinical exposure at the MRHD.
- Report pregnancies to the BridgeBio reporting line at 1-844-550-2246.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on the usage of acoramidis in pregnant women.
Labor and Delivery
There is no FDA guidance on the use of acoramidis during labor and delivery.
Nursing Mothers
No available data on the presence of acoramidis in human or animal milk or its effects on breastfed infants or maternal milk production. There is no FDA guidance on the use of acoramidis in nursing mothers.
Pediatric Use
The safety and effectiveness of acoramidis have not been established in pediatric patients.
Geriatic Use
No dosage adjustment is required for elderly patients (≥65 years). In the clinical study of 632 randomized subjects, 97% were aged 65 or older, with a median age of 78 years.
Gender
There is no FDA guidance on the use of acoramidis with respect to specific gender populations.
Race
There is no FDA guidance on the use of acoramidis with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of acoramidis in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of acoramidis in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of acoramidis in women of reproductive potential and males.
Immunocompromised Patients
There is no FDA guidance on the use of acoramidis in patients who are immunocompromised.
Administration and Monitoring
Administration
The recommended dosage of acoramidis is 712 mg orally twice daily, with or without food. Swallow tablets whole; do not cut, crush, or chew.
Monitoring
Patient monitoring is required for evidence of increased exposure (for example, signs of exposure-related toxicity) when acoramidis is co-administered with sensitive CYP2C9 substrates.
IV Compatibility
There is limited information regarding the compatibility of acoramidis and IV administrations.
Overdosage
There is no clinical experience with overdose. In case of suspected overdose, treatment should be symptomatic and supportive.
If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Acoramidis Pharmacology in the drug label.
Mechanism of Action
- Acoramidis is a selective stabilizer of transthyretin (TTR) that binds TTR at thyroxine binding sites, slowing the dissociation of the TTR tetramer into its constituent monomers, which is the rate-limiting step in amyloidogenesis.
Structure
- Acoramidis hydrochloride (HCl) is a transthyretin stabilizer.
- Chemical name: 3-[3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy]-4-fluorobenzoic acid hydrochloride.
- Molecular formula: C15H18FN2O3Cl
- Molecular weight: 328.77 g/mol
- It is a white to tan solid.
- Solubility: ≥ 12 micrograms/mL from pH 1.2 to 6.8 in aqueous media.
- Inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and silicon dioxide.
- Film coating and printing ink ingredients: black iron oxide, glyceryl monocaprylocaprate, hypromellose, polyvinyl alcohol, propylene glycol, talc, titanium dioxide, and vinyl alcohol graft copolymer.
Pharmacodynamics
TTR Stabilization
- Pharmacodynamic markers of TTR stabilization: changes in serum TTR level or in vitro TTR stabilization assays
- Mean serum TTR levels were increased by Day 28 in patients treated with acoramidis.
- Similarly, near-complete in vitro TTR stabilization was observed as early as Day 28 and through completion of a 30-month study in ATTR-CM patients treated with acoramidis.
Free thyroxine
- Acoramidis may reduce serum concentrations of free thyroxine without any change in thyroid-stimulating hormone (TSH).
- Transthyretin stabilizers have been associated with decreased free thyroxine levels, likely due to reduced binding to or displacement from transthyretin (TTR).
NT-proBNP and Troponin I
- NT-proBNP (0.5 vs. 1) and Troponin I increase were lower in a clinical study of acoramidis versus placebo during the 30th month.
Cardiac Electrophysiology
- No QTc interval prolongation at 1.2 times the steady state peak plasma concentrations (Cmax) at the recommended dose of acoramidis.
Pharmacokinetics
- Systemic exposures (Cmax and AUC) increase less than dose proportionally following single and multiple doses of acoramidis.
- AUC increases only 130% over the dose range from 89 mg twice daily to 712 mg twice daily.
- Steady state is achieved by 4 days with approximately 1.3-fold accumulation at the approved recommended dosage.
- A dose of 712 mg twice daily results in a mean (SD) Cmax of 13700 (6090) ng/mL and AUC0-12h of 47200 (10300) ng.h/mL at the steady state.
Absorption
- Time to Cmax of acoramidis (Tmax): approximately 1 hour following oral administration.
Effect of Food
- Administration of a high-fat meal (800-1000 total calories, ≥ 50% fat): No clinically significant differences observed.
Distribution
- Steady-state volume of distribution: 654 liters
- It is 96% bound to human plasma proteins in vitro.
Elimination
- Effective half-life: approximately 6 hours.
- Steady state apparent clearance: 16 L/hr
Metabolism
- Primarily metabolized by glucuronidation via UGT1A9, UGT1A1 and UGT2B7.
- Acoramidis-β-D-glucuronide (Acoramidis-AG) is the predominant metabolite of acoramidis, constituting 8% of total circulating drug-related moieties.
- Acoramidis-AG has the following properties:
- Approximately 1/3 as pharmacologically active compared with acoramidis
- Has a low potential for covalent binding
- No contribution to pharmacological activity
Excretion
- After a single oral dose of radiolabeled acoramidis 712 mg to healthy adult subjects, radioactivity was recovered as follows –
- Feces: approximately 32% of the dose (15% unchanged)
- Urine: approximately 68% (<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
- After the recommended dosage (712 mg, BID) of acoramidis in a clinical study in healthy adult volunteers, no clinically significant increase in exposure to the organic anion transporter-1 (OAT1) substrate (adefovir) and to OAT3 substrate (oseltamivir carboxylate) was observed.
- Concomitant diuretic use in patients does not affect steady-state plasma concentrations of acoramidis.
In vitro Studies
- Cytochrome P450 Enzymes: Acoramidis has the following actions.
- Time-dependent inhibition: CYP2C9
- Does not inhibit: CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, or CYP3A4/5.
- 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). It has the following actions:
- Inhibits: OAT1 and OAT3
- Does not inhibit: MATE1, OCT1, OCT2, OATP1B1, OATP1B3, MATE2-K, BCRP, P-gp, or BSEP.
Nonclinical Toxicology
Carcinogenesis
- In a 2-year carcinogenicity study, no evidence of increased incidence of neoplasia was observed in male rats dosed up to approximately equivalent to (50 mg/kg) and in female rats dosed up to 11 times (350 mg/kg) the AUC at the MRHD, respectively.
- No evidence of an increased incidence of neoplasia was observed in transgenic (Tg.rasH2) mice following repeated daily administration for 26 weeks at daily doses up to 300 mg/kg.
Mutagenesis
- No evidence of mutagenicity or clastogenicity was observed in an Ames assay or in vivo rat micronucleus and alkaline comet assay.
Impairment of Fertility
- In a male and female fertility study of rats, no effects were observed on fertility, reproductive performance, or mating behavior in male or female rats at doses up to approximately 38 times (1,000 mg/kg/day) the AUC at the MRHD.
Clinical Studies
- Study type: multicenter, international, randomized, double-blind, placebo-controlled study (NCT03860935).
- Participants: 611 adult patients with wild-type or variant (hereditary or de novo) ATTR-CM, randomized (2:1) to receive acoramidis 712 mg (n=409) or placebo (n=202) twice daily for 30 months.
- Stratification of treatment assignment was done by –
- Type of ATTR-CM [variant (ATTRv-CM) or wild-type (ATTRwt-CM)]
- NT-proBNP level
- estimated glomerular filtration rate (eGFR)
- Study Characteristics –
- Mean age: 77 years
- Males: 90.8%
- White: 87.9%
- Black or African American: 4.7%
- Asian: 2.1%
- Other race: 5.3%
- History of permanent pacemaker: 19%
- History of atrial fibrillation: 58%
- No significant imbalance in baseline characteristics was observed between the two treatment groups
- Initiation of open-label tafamidis after 12 months (median time - 17 months) in the study was as follows –
- Treatment group: 61(14.9%) participants
- Placebo group: 46 (22.8%) participants
- Results:
- Primary composite endpoints: all-cause mortality (ACM) and cumulative frequency of cardiovascular-related hospitalizations (CVH) over 30 months.
- Statistically significant reduction (p=0.018) observed in ACM and cumulative frequency of CVH in the treatment versus the placebo group by the stratified Finkelstein-Schoenfeld (F-S) test.
- ACM was reported in 19% and 26% of participants in the treatment and the placebo group, respectively.
- Majority (79%) of deaths were cardiovascular.
- CVH was reported in 27% and 43% of participants in the treatment and the placebo group, respectively.
- Majority (59%) of CVH were heart failure hospitalizations reported in 13% and 26% of the participants in the treatment and the placebo group, respectively.
- Functional capacity and health status assessments were performed by the 6MWD and the Kansas City Cardiomyopathy Questionnaire-Overall Summary score (KCCQ-OS), respectively.
- At month 30, the LS mean difference (95% CI) in change from baseline in 6MWD was 40 [21, 58] meters (p < 0.0001), and change from baseline in KCCQ-OS was 10 [6, 14] points (p < 0.0001) (Figure 1 and Figure 2).
- The changes from baseline in 6MWT and KCCQ-OS were analyzed using the mixed model for repeated measures (MMRM) with treatment group, visit, genotype (ATTRv-CM vs. ATTRwt-CM), NT-proBNP level (≤ 3000 vs. > 3000 pg/mL), eGFR level (≥ 45 vs. < 45 mL/min/1.73 m2) and treatment group-by-visit interaction as factors, and baseline value as covariate.
- Cox regression analysis indicated a 35.5% decrease in the risk of the composite of ACM or first CV hospitalization (hazard ratio: 0.645 [95% CI: 0.500, 0.832]).
- Kaplan-Meier plot of time to the first event of ACM or CVH is shown in Figure 3.
- Treatment effects by prespecified subgroups are shown in Figure 4.
How Supplied
Mode of Supply
- Acoramidis tablets are available as 356 mg, white, film-coated, oval tablets printed with the BridgeBio company logo followed by “ACOR” in black ink on one side.
- They are supplied in a carton of 112 tablets: 4 blister cards (each containing 28 tablets).
Storage
- Store at a controlled room temperature of 20°C to 25°C (68°F to 77°F) in the original blister card until used to protect from moisture.
- Excursions permitted to 15°C to 30°C (59°F to 86°F).
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Pregnancy
Advise patients who are exposed to ATTRUBY during pregnancy to contact the BridgeBio reporting line at 1-844-550-2246. Advise patients to inform their healthcare provider of a known or suspected pregnancy.
Precautions with Alcohol
Alcohol-Acoramidis interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
ATTRUBY is the brand name in the US.
Look-Alike Drug Names
There is limited information regarding acoramidis Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.