TTR (transthyretin)

Mechanism of Action
The first and rate-limiting step in transthyretin (TTR) amyloidogenesis is the dissociation of the TTR tetramer into its constituent monomers. This is followed by misfolding of the resulting monomer and their subsequent aggregation, leading to build-ups of larger oligomers and amyloid fibrils. When these build-ups aggregate in the heart, they can lead to heart dysfunction (transthyretin amyloidosis cardiomyopathy; ATTR-CM). Acoramidis is a highly selective stabilizer of TTR. It exerts its therapeutic effects by binding to TTR at thyroxine binding sites and stabilizing it in its tetrameric form, thereby slowing the rate-limiting step in amyloidogenesis.

Pharmacodynamics
At the recommended dosage, near-complete _in vitro_ transthyretin (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). Acoramidis may decrease serum concentrations of free thyroxine without an accompanying change in thyroid stimulating hormone - this is an effect common to TTR stabilizers, and is likely due to reduced thyroxine binding to (or displacement from) TTR.
Acoramidis is a small molecule stabilizer of transthyretin (TTR) for use in patients with TTR amyloidosis. Similar to the previously developed [tafamidis], acoramidis is used to stabilize TTR in its tetrameric form, preventing the formation of amyloidogenic monomers and the progression of amyloidosis. Although they share a mechanism of action, acoramidis is more selective for TTR and is a more potent stabilizer when compared to tafamidis. Acoramidis has been in development since at least 2013. It was brought to market by BridgeBio Pharma and approved by the FDA in November 2024 to reduce negative cardiovascular outcomes in patients with cardiomyopathy caused by TTR amyloidosis.
Acoramidis is a Transthyretin Stabilizer. The mechanism of action of acoramidis is as a Transthyretin Stabilizer, and Cytochrome P450 2C9 Inhibitor.
Acoramidis is transthyretin stabilizer used for the treatment of adults with the cardiomyopathy of both wild-type and hereditary transthyretin-mediated amyloidosis to reduce cardiovascular morbidity and mortality. Acoramidis has been associated with minor liver test abnormalities during therapy but has not been linked instances of clinically apparent liver injury.
Acoramidis is a potent, highly selective, orally bioavailable transthyretin (TTR) stabilizer with potential disease-modifying activity. Upon oral administration, acoramidis binds to and stabilizes transthyretin (TTR), thereby preventing tetramer dissociation into monomers. This prevents misfolding of the TTR protein and inhibits the formation of TTR amyloid fibrils and the subsequent deposition of these insoluble protein clusters in the heart and peripheral nerves. TTR is a transport protein for thyroxine and retinol and is secreted by the liver into the blood. The accumulation of TTR amyloid fibrils may result in thickening and stiffening of the ventricular wall, leading to heart failure.
ACORAMIDIS is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2024 and is indicated for amyloidosis and male infertility and has 3 investigational indications.

Absorption
At steady state (712 mg twice daily, reached on day 4), the mean Cmax and AUC0-12H of acoramidis are 13700 ng/mL and 47200 ng·h/mL, respectively. The Tmax after oral administration is approximately 1 hour.
Elimination Route
Following a single oral dose of 712 mg of radiolabeled acoramidis, approximately 32% of the radioactive material is excreted in feces (15% of which is the unchanged drug) and approximately 68% is excreted in urine (<10% of which is the unchanged drug).
Volume of Distribution
At steady state, the apparent volume of distribution of acoramidis is 654 L.
Clearance
At steady state, the apparent clearance of acoramidis is 16 L/h.
Protein Binding
In vitro experiments show that aclamidide binds to proteins at a rate of 96%, primarily to TTR.
Metabolism/Metabolites
Aclamidide is mainly metabolized via glucuronidation via UGT1A9, UGT1A1, and UGT2B7. The main circulating metabolite is aclamidide-β-D-glucuronide (aclamidide acylglucuronide; aclamidide-AG), accounting for 8% of the total circulating drug-related metabolites. The pharmacological activity of aclamidide-AG is approximately one-third that of the parent aclamidide drug, therefore its contribution to overall pharmacological activity is minimal.
Biological Half-Life
The effective half-life of aclamidide is approximately 6 hours.

Hepatotoxicity
Transient, mild elevations in ALT and AST were not uncommon in the registration trials of acoramidis, but elevations exceeding three times the upper limit of normal were uncommon, and the incidence was not significantly different between the acoramidis and placebo groups (0.9% vs 0.5%). Most of these were attributed to heart failure or its treatment. No patients required discontinuation of the drug due to liver dysfunction, and no patients experienced clinically significant liver injury or elevated serum transaminases with jaundice. Clinical experience with acoramidis is limited since its approval, but no published case reports have indicated that it can cause clinically significant liver injury.
Probability Score: E (Unlikely a cause of clinically significant liver injury).
Effects during Pregnancy and Lactation
◉Overview of Use During Lactation
There is currently no information regarding the use of acoramidis during lactation. If a mother needs to take acoramidis, this is not a reason to discontinue breastfeeding. Until more data becomes available, Acoramidis should be used with caution during breastfeeding, especially in newborns or preterm infants. Gastrointestinal adverse reactions, such as diarrhea, should be closely monitored in breastfed infants.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

Acoramidis is a potent, highly selective, orally bioavailable transthyretin (TTR) stabilizer with potential disease-modifying activity. After oral administration, Acoramidis binds to and stabilizes the structure of TTR, preventing the tetramer from dissociating into monomers. This prevents TTR protein misfolding, inhibits the formation of TTR amyloid fibrils, and prevents the deposition of these insoluble protein clusters in the heart and peripheral nerves. TTR is a 127-amino acid thyroxine and retinol transporter secreted into the bloodstream by the liver. Accumulation of TTR amyloid fibrils can lead to thickening and stiffening of the ventricular walls, potentially resulting in heart failure.

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Drug Indications
Treatment of Transthyretin Amyloidosis (ATTR)

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Disease or Condition

ATTR-CM is a rare but serious disease that affects the myocardium. In patients with ATTR-CM, protein deposits accumulate in the heart, causing stiffening of the heart wall and preventing the left ventricle from properly relaxing and filling with blood (a condition known as cardiomyopathy). As the disease progresses, the heart's pumping function gradually declines, eventually leading to heart failure. ATTR-CM is classified into two types: hereditary ATTR-CM (hATTR-CM) and wild-type ATTR-CM (wATTR-CM). hATTR-CM exhibits familial aggregation and is caused by a mutation in the causative gene, leading to protein deposits in the heart. wATTR-CM does not have a transthyretin gene mutation. While the true prevalence of ATTR-CM is unclear, estimates of the number of patients are increasing due to improved understanding of the disease and advancements in diagnostic tools. Efficacy: In a multicenter, international, randomized, double-blind, placebo-controlled study (NCT03860935), the efficacy and safety of Attruby were evaluated in 611 adult patients with wild-type or hereditary (variant) ATTR-CM. The primary endpoints of this study included all-cause mortality and the cumulative incidence of cardiovascular-related hospitalizations (CVH) over 30 months. At 30 months, survival was higher in the Attruby group than in the placebo group (81% vs 74%), and the incidence of CVH was lower in the Attruby group (mean 0.3 times per year vs 0.6 times per year). Safety Information: The most common adverse reactions were diarrhea and upper abdominal pain. Most gastrointestinal adverse reactions were mild and resolved without discontinuation of the drug. Designation: Attruby has received orphan drug designation for the treatment of this indication.

C15H16FN2NAO3

314.29

292.1223

C, 57.32; H, 5.13; F, 6.04; N, 8.91; Na, 7.31; O, 15.27

2242751-53-5; 1446711-81-4

Typically exists as solid at room temperature

O=C(O[Na])C1=CC=C(F)C(OCCCC2=C(C)NN=C2C)=C1

LHWRADFHHBDBQF-UHFFFAOYSA-M

InChI=1S/C15H17FN2O3.Na/c1-9-12(10(2)18-17-9)4-3-7-21-14-8-11(15(19)20)5-6-13(14)16;/h5-6,8H,3-4,7H2,1-2H3,(H,17,18)(H,19,20);/q;+1/p-1

sodium 3-(3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy)-4-fluorobenzoate

AG10 sodium; Acoramidis sodium; AG-10 sodium; AG 10 sodium

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)