TTR (transthyretin)

Acoramidis hydrochloride (AG10, 0.1-10 μM, TTR ~ 5 μM) stabilized WT and mutant TTR in whole serum more effectively than it did V122I- and WT-TTR [1]. Between 10 and 100 μM, Acoramidis hydrochloride (AG10) raises mitochondrial QO2 in a concentration-dependent manner [3]. Two typical off-targets in drug development, the potassium channel hERG (IC50 > 100 μM) and several cytochrome P450 isozymes (IC50 > 50 μM) (low toxicity), are minimally inhibited by acoramidis hydrochloride (AG10) [1].

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.

Western Blot Analysis[1].
Cell Types: Human serum (TTR ∼5 µM).
Tested Concentrations: 0.1 and 10 μM.
Incubation Duration: 72 h.
Experimental Results: Was Dramatically more effective than tafamidis in stabilizing TTR. The concentration of AG10 to 10 µM resulted in stabilization of almost all of TTR in serum.

Animal/Disease Models: Wistar rats[1].
Doses: 50 mg/kg/d (Toxicity Analysis).
Route of Administration: Oral gavage, daily for 28 d.
Experimental Results: demonstrated the plasma Cmax of ∼40 µM and histopathological evaluation of liver, kidney, heart, spleen, thymus, and lung demonstrated no signs of pathologic processes in the AG10-treated animals

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, Akramidis 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.

[1]. AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9992-7.

[2]. First-in-Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers. Clin Pharmacol Drug Dev. 2020 Jan;9(1):115-129.

[3]. Evidence that tyrphostins AG10 and AG18 are mitochondrial uncouplers that alter phosphorylation-dependent cell signaling. J Biol Chem. 2004 Mar 19;279(12):10910-8.

Acoramidis hydrochloride is the hydrochloride form of Acoramidis, a potent, highly selective, and 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 transporter of thyroxine and retinol, secreted into the bloodstream by the liver. Accumulation of TTR amyloid fibrils can lead to thickening and stiffening of the ventricular walls, potentially causing heart failure. Acoramidis hydrochloride is a small molecule drug, with clinical trials up to Phase IV (covering all indications), and was first approved in 2024 for the treatment of amyloidosis and male infertility.
Acolamid is a potent, highly selective, and orally bioavailable transthyretin (TTR) stabilizer with potential disease-modifying effects. After oral administration, acolamid 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 causing 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. Patients with ATTR-CM accumulate protein deposits in their hearts, causing stiffening of the heart walls and preventing the left ventricle from properly relaxing and filling with blood (a condition known as cardiomyopathy). As the disease progresses, the heart may become unable to pump blood adequately, 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 transthyretin gene, leading to protein deposition within the heart. In wild-type ATTR-CM, there is no mutation in the transthyretin gene. While the true prevalence of ATTR-CM is unclear, estimates of the number of patients are increasing as understanding of the disease and diagnostic tools improve. Efficacy: A multicenter, international, randomized, double-blind, placebo-controlled study (NCT03860935) evaluated the efficacy and safety of Attruby 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) within 30 months. At 30 months, the survival rate in the Attruby group was higher than that in the placebo group (81% vs 74%), and the incidence of CVH in the Attruby group was lower than that in the placebo group (0.3 times per year on average 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.
Recognition
Attruby has received Orphan Drug Designation for this indication.

C15H18CLFN2O3

328.766426563263

328.098

C, 54.80; H, 5.52; Cl, 10.78; F, 5.78; N, 8.52; O, 14.60

2242751-53-5

Acoramidis;1446711-81-4

135307127

White to light yellow solid powder

3

5

6

22

356

0

Cl.FC1=CC=C(C(=O)O)C=C1OCCCC1C(C)=NNC=1C

MGFZEARHINUOMX-UHFFFAOYSA-N

InChI=1S/C15H17FN2O3.ClH/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);1H

3-[3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy]-4-fluorobenzoic acid;hydrochloride

Acoramidis hydrochloride; 2242751-53-5; AG10 hydrochloride; AG-10 hydrochloride; VY9C88C2NV;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO: 62.5 mg/mL (190.10 mM)
H2O: < 0.1 mg/mL

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.33 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (6.33 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (6.33 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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