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{{DrugProjectFormSinglePage
{{DrugProjectFormSinglePage
|authorTag=Parth Vikram Singh
|authorTag=Parth Vikram Singh; [[User:Meghana Kodali|Meghana Kodali, MBBS, MPH]]
|genericName=acoramidis
|genericName=Acoramidis
|aOrAn=a
|aOrAn=a
|drugClass=transthyretin stabilizer
|drugClass=transthyretin stabilizer
|indicationType=treatment
|indicationType=treatment
|indication=ATTRUBY 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 [[cardiovascular|death]] and cardiovascular-related hospitalization.
|indication=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 [[cardiovascular|death]] and cardiovascular-related hospitalization.
|adverseReactions=• 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.
|adverseReactions=[[diarrhea]] and upper [[abdominal pain]], which 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).
• Increase in Serum [[Creatinine]] and Decrease in eGFR
|blackBoxWarningTitle='''<span style="color:#FF0000;">TITLE</span>'''
|blackBoxWarningTitle='''<span style="color:#FF0000;">TITLE</span>'''
|blackBoxWarningBody=''<span style="color:#FF0000;">Condition Name:</span>'' (Content)
|blackBoxWarningBody=''<span style="color:#FF0000;">Condition Name:</span>'' (Content)
|fdaLIADAdult=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.
|fdaLIADAdult=* Acoramidis is indicated for the treatment of cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis (ATTR-CM) – '''712 mg PO bid'''
 
The recommended dosage of ATTRUBY is 712 mg orally twice daily (with or without food). Swallow tablets whole; do not cut, crush, or chew.
 
ATTRUBY is available as 356 mg acoramidis, white, film-coated, oval tablets, printed with the BridgeBio company logo followed by “ACOR” in black ink on one side.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Acoramidis in adult patients.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Acoramidis in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Acoramidis in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non-Guideline-Supported Use'' of Acoramidis in adult patients.
|fdaLIADPed=The safety and effectiveness of ATTRUBY have not been established in pediatric patients.
|fdaLIADPed=The safety and effectiveness of Acoramidis have not been established in pediatric patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Acoramidis in pediatric patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Acoramidis in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Acoramidis in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non-Guideline-Supported Use'' of Acoramidis in pediatric patients.
|contraindications=None.
|contraindications=None
|clinicalTrials=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.
|warnings=There is limited information regarding warnings.
 
|clinicalTrials=* Acoramidis has been evaluated for safety in 421 participants with ATTR-CM in a randomized, double-blind, placebo-controlled trial of 30 months.  
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).
* Higher frequency of gastrointestinal (GI) adverse reactions were observed as follows –
 
** Diarrhea: 11.6% (treatment group) versus 7.6% (placebo group)
Laboratory Tests
** 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.
Increase in Serum Creatinine and Decrease in eGFR:
* Similar clinical trial was discontinued due to increased serum creatinine and decreased eGFR, which occurred within 4 weeks of therapy initiation.  
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 m2 was observed in the ATTRUBY and placebo groups, respectively, at Day 28. The changes in serum creatinine and eGFR were reversible after treatment discontinuation.
** Serum creatinine: mean increase of 0.2 mg/dl (treatment group) versus 0.0 mg/dl (placebo group)
|drugInteractions=.  
** eGFR: mean decrease of 8.2 mL/min/1.73 m2 (treatment group) versus 0.7 mL/min/1.73 m2 (placebo group)
• UDP-glucuronosyltransferases (UGT) Inducers and Strong CYP3A Inducer.
* These changes were reversible after drug discontinuation.
 
|postmarketing=There is limited information about post-marketing experience.
o Acoramidis is metabolized by UGT enzyme-mediated glucuronidation.  
|drugInteractions====UDP-glucuronosyltransferases (UGT) Inducers and Strong CYP3A Inducers===
o 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.
* Acoramidis is metabolized by UGT enzyme-mediated glucuronidation. Concurrent use with UGT inducers can decrease acoramidis exposure.
o Avoid concomitant use of ATTRUBY with UGT inducers and strong CYP3A inducers.
* 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.
 
o 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.) when ATTRUBY is co administered with sensitive CYP2C9 substrates.
|useInPregnancyFDA=Available data with acoramidis use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproductive studies in rats and rabbits, no embryofetal abnormalities were observed at exposures up to 34 times and 13 times the clinical exposure at the maximum recommended human dose, respectively. 
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
 
Data
Animal Data
In pregnant rats, oral administration of acoramidis (0, 50, 350, and 1,000 mg/kg/day) throughout organogenesis did not result in any adverse effects on embryofetal development at up to 1,000 mg/kg/day, approximately 34 times the clinical exposure at the maximum recommended human dose (MRHD) based on AUC.
In pregnant rabbits, oral administration of acoramidis (0, 25, 75, and 200 mg/kg/day) throughout organogenesis resulted in increased pre-implantation loss at 200 mg/kg/day, a dose that caused maternal toxicity (26% reduced body weight gain). No embryofetal abnormalities were observed at 200 mg/kg/day, approximately 13 times the clinical exposure at the MRHD based on AUC.
In a pre- and postnatal developmental toxicity study, pregnant rats received oral administration of acoramidis at doses of 0, 50, 350, or 1,000 mg/kg/day throughout pregnancy and lactation (Gestation Day 6 to Lactation Day 20). Maternal death, body weight reduction, and decreased number of females with live born pups (due to increase in resorbed litters) were observed at 1,000 mg/kg/day, approximately 43 times the clinical exposure at the MRHD based on AUC. Decreased body weight gain from the neonatal period to weaning and learning deficits were observed in the offspring of dams given 1,000 mg/kg/day. No adverse effects on pre- and postnatal development were observed at 350 mg/kg/day, approximately 18 times the clinical exposure at the MRHD based on AUC.
|useInNursing=There are no available data on the presence of acoramidis in either human or animal milk or the effects of the drug on the breastfed infant or maternal milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ATTRUBY and any potential adverse effects on the breastfed child from ATTRUBY or from the underlying maternal condition.
|useInPed=The safety and effectiveness of ATTRUBY have not been established in pediatric patients.
|useInGeri=No dosage adjustment is required for elderly patients (≥65 years).
 
Of the total number of participants randomized in the clinical study (n=632), 97% were 65 years and over, with a median age of 78 years.
|administration=The recommended dosage of ATTRUBY is 712 mg orally twice daily (with or without food). Swallow tablets whole; do not cut, crush, or chew.
|monitoring=monitoring of patients for evidence of increased exposure (for example, signs of exposure related toxicity) when ATTRUBY is co administered with sensitive CYP2C9 substrates.
|overdose=There is no clinical experience with overdose. In case of suspected overdose, treatment should be symptomatic and supportive.
|mechAction=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.
|structure=ATTRUBY contains 356 mg acoramidis equivalent to 400 mg acoramidis HCl.
 
Acoramidis HCl is a transthyretin stabilizer. The chemical name of acoramidis HCl is 3- [ 3- ( 3,5-dimethyl-1H-pyrazol-4-yl ) propoxy ] -4-fluorobenzoic acid hydrochloride. The molecular formula is C15H18FN2O3Cl, and the molecular weight is 328.77 g/mol.
 
Acoramidis HCl is a white to tan solid. The solubility of acoramidis is ≥ 12 micrograms/mL from pH 1.2 to 6.8 in aqueous media.
 
ATTRUBY is supplied as a white, film-coated, oval tablet, contains 356 mg acoramidis, printed with the BridgeBio company logo followed by “ACOR” in black ink on one side.
 
The inactive ingredients are croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and silicon dioxide. The film coating and printing ink contain black iron oxide, glyceryl monocaprylocaprate, hypromellose, polyvinyl alcohol, propylene glycol, talc, titanium dioxide, and vinyl alcohol graft copolymer.
|PD=• TTR Stabilization
 
o Changes in serum TTR level or in vitro TTR stabilization assays were utilized as pharmacodynamic markers of TTR stabilization. Increases in mean serum TTR levels were observed by Day 28 in ATTR-CM patients treated with ATTRUBY. Near-complete in vitro TTR stabilization was observed as early as Day 28 and through completion of a 30-month study of patients with ATTR-CM (wild-type and variant) treated with the recommended dosage.
 
• Free thyroxine
 
o ATTRUBY may decrease serum concentrations of free thyroxine without an accompanying change in thyroid stimulating hormone (TSH). A reduction in free thyroxine values has been observed with transthyretin stabilizers probably due to reduced thyroxine binding to or displacement from transthyretin (TTR).
• NT-proBNP and Troponin I
 
o In a clinical study of ATTRUBY in patients with ATTR-CM, at Month 30, the increase in N-terminal prohormone of brain natriuretic peptide [NT-proBNP] and troponin I was lower with ATTRUBY versus placebo. The increase in NT-proBNP at Month 30 for ATTRUBY was about half that of placebo.
 
• Cardiac Electrophysiology
 
o At approximately 1.2 times the steady state peak plasma concentrations (Cmax) at the recommended dose, ATTRUBY does not prolong the QTc interval to any clinically relevant extent.
|PK=The systemic exposures (Cmax 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) Cmax of 13700 (6090) ng/mL and AUC0-12h of 47200 (10300) ng.h/mL.
• Absorption
The time to Cmax of acoramidis (Tmax) 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
o 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.
o 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.
o 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.
|nonClinToxic=• Carcinogenesis
 
o There was no evidence of increased incidence of neoplasia in a 2-year carcinogenicity study in male rats dosed up to 50 mg/kg and in female rats dosed up to 350 mg/kg, which provided exposures approximately equivalent to and 11 times the AUC at the maximum recommended human dose (MRHD), respectively. There was no evidence of an increased incidence of neoplasia in transgenic (Tg.rasH2) mice following repeated daily administration for 26 weeks at daily doses up to 300 mg/kg.
• Mutagenesis
 
o There was no evidence of mutagenicity or clastogenicity for acoramidis in an Ames assay or in vivo rat micronucleus and alkaline comet assay.
• Impairment of Fertility
 
o In a male and female fertility study, rats were orally administered acoramidis at 0, 50, 350, and 1,000 mg/kg/day. Male rats were given acoramidis prior to and during cohabitation for a total of up to 52 days. Female rats were given acoramidis prior to and during cohabitation until implantation of the embryo (Gestational Day 7) for a total of up to 34 days. There were no effects on fertility, reproductive performance, or mating behavior in male or female rats at doses up to 1,000 mg/kg/day, approximately 38-times the AUC at the MRHD.
|clinicalStudies=The efficacy of ATTRUBY was demonstrated in a multicenter, international, randomized, double-blind, placebo-controlled study in 611 adult patients with wild-type or variant (hereditary or de novo) ATTR-CM (NCT03860935).
 
Participants were randomized (2:1) to receive ATTRUBY 712 mg (n=409) or placebo (n=202) twice daily for 30 months. Treatment assignment was stratified by type of ATTR-CM [variant (ATTRv-CM) or wild-type (ATTRwt-CM)], NT-proBNP level, and estimated glomerular filtration rate (eGFR). The mean age of study participants was 77 years, 90.8% were male, 87.9% were White, 4.7% Black or African American, 2.1% Asian, 5.3% race other, 19% had a history of permanent pacemaker and 58% had a history of atrial fibrillation. No significant imbalance in baseline characteristics was observed between the two treatment groups.
 
Participants were permitted to initiate open-label tafamidis after 12 months in the study. A total of 107 participants received tafamidis: 61 (14.9%) in the ATTRUBY arm and 46 (22.8%) in the placebo arm. The median time to initiation of tafamidis for these 107 participants was 17 months.
 
The primary composite endpoint included all-cause mortality (ACM) and cumulative frequency of cardiovascular-related hospitalizations (CVH) over 30 months, analyzed hierarchically using the stratified Finkelstein-Schoenfeld (F-S) test. The F-S test demonstrated a statistically significant reduction (p=0.018) in ACM and cumulative frequency of CVH in the ATTRUBY arm versus the placebo arm. All-cause mortality was reported in 19% and 26% of participants in the ATTRUBY and placebo groups, respectively. The majority (79%) of the deaths were cardiovascular. CVH was reported in 27% and 43% of participants in the ATTRUBY and placebo groups, respectively. The mean number of CVH events was 0.3 vs 0.6 per year. The majority (59%) of CVH were heart failure hospitalizations reported in 13% and 26% of the participants in the ATTRUBY and placebo groups, respectively.
 
The treatment effect of ATTRUBY on functional capacity and health status was assessed 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)
|howSupplied=Tablets 356 mg, are white, film-coated, oval tablets, printed with the BridgeBio company logo followed by “ACOR” in black ink on one
Tablets are supplied as a carton of 112 tablets: 4 blister cards (each containing 28 tablets).
|storage=At controlled room temperature 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Store in original blister card until use to protect from moisture.
|packLabel=PATIENT INFORMATION
ATTRUBYTM (ah-troo-be)
(acoramidis)
tablets
What is ATTRUBY?
ATTRUBY is a prescription medicine used to treat adults with a disease that affects the heart muscle called cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis (ATTR-CM), to reduce death and hospitalization related to heart problems.
It is not known if ATTRUBY is safe and effective in children.
Before taking ATTRUBY, tell your healthcare provider about all your medical conditions, including if you:
are pregnant or plan to become pregnant. It is not known if ATTRUBY will harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ATTRUBY. You may also report your pregnancy by calling the BridgeBio reporting line at 1-844-550-2246.
are breastfeeding or plan to breastfeed. It is not known if ATTRUBY passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with ATTRUBY.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How should I take ATTRUBY?
Take ATTRUBY exactly as your healthcare provider tells you to.
Take ATTRUBY tablets by mouth 2 times a day, with or without food.
Swallow tablets whole. Do not cut, crush, or chew tablets.
What are the possible side effects of ATTRUBY?
The most common side effects of ATTRUBY were mild and include:
stomach-area (abdominal) pain
diarrhea
These are not all of the possible side effects of ATTRUBY.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store ATTRUBY?
Store ATTRUBY tablets at room temperature between 68°F to 77°F (20°C to 25°C).
Store in original blister card until use to protect from moisture.
Keep ATTRUBY and all medicines out of the reach of children.
General information about the safe and effective use of ATTRUBY.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ATTRUBY for a condition for which it was not prescribed. Do not give ATTRUBY to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ATTRUBY that is written for health professionals.
What are the ingredients in ATTRUBY?
Active ingredient: acoramidis
Inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and silicon dioxide. The film coating and printing ink contain black iron oxide, glyceryl monocaprylocaprate, hypromellose, polyvinyl alcohol, propylene glycol, talc, titanium dioxide, and vinyl alcohol graft copolymer.
 
 
Distributed by: BridgeBio Pharma, Inc., Palo Alto, CA 94304


For more information about ATTRUBY, go to www.ATTRUBY.com or call 1-844-550-2246"
===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.
|FDAPregCat=B
|useInPregnancyFDA=* 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.
|useInPregnancyAUS=There is no Australian Drug Evaluation Committee (ADEC) guidance on the usage of acoramidis in pregnant women.
|useInLaborDelivery=There is no FDA guidance on the use of acoramidis during labor and delivery.
|useInNursing=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.
|useInPed=The safety and effectiveness of acoramidis have not been established in pediatric patients.
|useInGeri=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.
|useInGender=There is no FDA guidance on the use of acoramidis with respect to specific gender populations.
|useInRace=There is no FDA guidance on the use of acoramidis with respect to specific racial populations.
|useInRenalImpair=There is no FDA guidance on the use of acoramidis in patients with renal impairment.
|useInHepaticImpair=There is no FDA guidance on the use of acoramidis in patients with hepatic impairment.
|useInReproPotential=There is no FDA guidance on the use of acoramidis in women of reproductive potential and males.
|useInImmunocomp=There is no FDA guidance on the use of acoramidis in patients who are immunocompromised.
|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.
|IVCompat=There is limited information regarding the compatibility of acoramidis and IV administrations.
|overdose=There is no clinical experience with overdose. In case of suspected overdose, treatment should be symptomatic and supportive.


ChatGPT said:
If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
This Patient Information has been approved by the U.S. Food and Drug Administration.
|mechAction=* 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.
|PD====''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).


Issued: 11/2024
===''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.


PATIENT INFORMATION
===''Cardiac Electrophysiology''===
ATTRUBY™ (ah-troo-be)
* No QTc interval prolongation at 1.2 times the steady state peak plasma concentrations (Cmax) at the recommended dose of acoramidis.
(acoramidis)
|PK=* Systemic exposures (Cmax and AUC) increase less than dose proportionally following single and multiple doses of acoramidis.
tablets
* 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.


What is ATTRUBY?
===''Absorption''===
ATTRUBY is a prescription medicine used to treat adults with a disease that affects the heart muscle called cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis (ATTR-CM). It helps reduce death and hospitalization related to heart problems.
* Time to Cmax of acoramidis (Tmax): approximately 1 hour following oral administration.
It is not known if ATTRUBY is safe and effective in children.


Before taking ATTRUBY, tell your healthcare provider about all your medical conditions, including if you:
===''Effect of Food''===
* Administration of a high-fat meal (800-1000 total calories, ≥ 50% fat): No clinically significant differences observed.


Are pregnant or plan to become pregnant. It is not known if ATTRUBY will harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ATTRUBY. You may also report your pregnancy by calling the BridgeBio reporting line at 1-844-550-2246.
===''Distribution''===
* Steady-state volume of distribution: 654 liters
* It is 96% bound to human plasma proteins in vitro.  


Are breastfeeding or plan to breastfeed. It is not known if ATTRUBY passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with ATTRUBY.
===''Elimination''===
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
* Effective half-life: approximately 6 hours.
* Steady state apparent clearance: 16 L/hr


How should I take ATTRUBY?
===''Metabolism''===
Take ATTRUBY exactly as your healthcare provider tells you to.
* Primarily metabolized by glucuronidation via UGT1A9, UGT1A1 and UGT2B7.
Take ATTRUBY tablets by mouth 2 times a day, with or without food.
* Acoramidis-β-D-glucuronide (Acoramidis-AG) is the predominant metabolite of acoramidis, constituting 8% of total circulating drug-related moieties.
Swallow tablets whole. Do not cut, crush, or chew tablets.
* 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


What are the possible side effects of ATTRUBY?
===''Excretion''===
The most common side effects of ATTRUBY were mild and include:
* 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)


Stomach-area (abdominal) pain
===''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.


Diarrhea
===''Drug Interaction Studies''===
These are not all of the possible side effects of ATTRUBY.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.


How should I store ATTRUBY?
====''Clinical Studies''====
Store ATTRUBY tablets at room temperature between 68°F to 77°F (20°C to 25°C).
* 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.
Store in the original blister card until use to protect from moisture.
* Concomitant diuretic use in patients does not affect steady-state plasma concentrations of acoramidis.
Keep ATTRUBY and all medicines out of the reach of children.


General information about the safe and effective use of ATTRUBY.
====''In vitro Studies''====
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ATTRUBY for a condition for which it was not prescribed. Do not give ATTRUBY to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ATTRUBY that is written for health professionals.
* 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.
|nonClinToxic====''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.


What are the ingredients in ATTRUBY?
===''Mutagenesis''===
Active ingredient: acoramidis
* No evidence of mutagenicity or clastogenicity was observed in an Ames assay or in vivo rat micronucleus and alkaline comet assay.
Inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and silicon dioxide. The film coating and printing ink contain black iron oxide, glyceryl monocaprylocaprate, hypromellose, polyvinyl alcohol, propylene glycol, talc, titanium dioxide, and vinyl alcohol graft copolymer.


Distributed by: BridgeBio Pharma, Inc., Palo Alto, CA 94304.
===''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.
|clinicalStudies=* 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.
|howSupplied====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).
|fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling (Patient Information).
|fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling (Patient Information).


Pregnancy
===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.
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.
|alcohol=Alcohol-Acoramidis interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|alcohol=Alcohol-Acoramidis interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=ATTRUBY is the brand name in the US.
|brandNames=ATTRUBY is the brand name in the US.
|lookAlike=There is limited information regarding acoramidis Look-Alike Drug Names in the drug label.
}}
}}
__NOEDITSECTION__
__NOEDITSECTION__

Latest revision as of 01:48, 8 April 2025

Acoramidis
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh; Meghana Kodali, MBBS, MPH

Disclaimer

WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

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

Pregnancy Category (FDA): B

  • 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

{{#ask: Page Name::Acoramidis |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Acoramidis |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

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.


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