Eplontersen API Manufacturers

General Description:

Eplontersen, identified by CAS number 1637600-16-8, is a notable compound with significant therapeutic applications. Eplontersen is a transthyretin-directed antisense oligonucleotide with 3 covalently linked e N-acetyl galactosamine residues for hepatic delivery. It was previously investigated as a potential treatment for hereditary transthyretin-mediated amyloidosis. Hereditary transthyretin-mediated amyloidosis is caused primarily by pathogenic variants of the TTR gene, leading to the formation and thus accumulation of insoluble and misfolded amyloid in multiple organs, although wild-type misfolded TTR has also been observed to contribute to the disease pathophysiology. As eplontersen targets both the WT and mutant TTR, it poses tremendous promises as a treatment. On December 21, 2023, the FDA approved eplontersen under the brand name WAINUA for the treatment of adult polyneuropathy of hereditary transthyretin-mediated amyloidosis. This approval was based on positive results demonstrated in the 35-week interim analysis from the Phase 3 NEURO-TTRansform study, where a consistent improvement in the Neuropathy Impairment Score +7 (mNIS+7) and the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) Score were observed.

Indications:

This drug is primarily indicated for: Eplontersen is indicated for the treatment of polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Eplontersen undergoes metabolic processing primarily in: Eplontersen is metabolized by endo- and exonucleases to short oligonucleotide fragments of varying sizes within the liver. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Eplontersen are crucial for its therapeutic efficacy: The pharmacokinetic (PK) properties of WAINUA were evaluated following subcutaneous administration of single and multiple doses (once every 4 weeks) in healthy subjects and multiple doses (once every 4 weeks) in patients with hATTR amyloidosis. Eplontersen C_max and AUC showed a slightly greater than dose-proportional increase following single subcutaneous doses ranging from 45 to 120 mg (i.e, 1- to 2.7- times the recommended dose) in healthy volunteers. Population estimates (mean ± SD) of steady-state maximum concentrations (C_max), and area under the curve (AUCτ) were 283 ± 152 ng/mL, and 2190 ± 689 ng/mL, respectively, following 45 mg monthly dosing in patients with hATTR amyloidosis. No accumulation of eplontersen C_max and AUC was observed in repeated dosing (once every 4 weeks). Following subcutaneous administration, eplontersen is absorbed with the time to maximum plasma concentrations of approximately 2 hours, based on population estimates. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Eplontersen is an important consideration for its dosing schedule: The terminal elimination half-life is approximately 3 weeks. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Eplontersen exhibits a strong affinity for binding with plasma proteins: Eplontersen is bound to human plasma proteins (>98%) in vitro. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Eplontersen from the body primarily occurs through: The mean fraction of unchanged antisense oligonucleotide (ASO) eliminated in urine was less than 1% of the administered dose within 24 hours. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Eplontersen is distributed throughout the body with a volume of distribution of: Eplontersen is expected to distribute primarily to the liver and kidney cortex after subcutaneous dosing. The population estimate for the apparent central volume of distribution is 12 L and the apparent peripheral volume of distribution is 11,100 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Eplontersen is a critical factor in determining its safe and effective dosage: The clearance was estimated at 22.6 L/h based on the population pharmacokinetic model. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Eplontersen exerts its therapeutic effects through: In Study 1, following administration of the recommended eplontersen dosage every 4 weeks to patients with hATTR amyloidosis, a decrease in serum transthyretin (TTR) levels was observed at the first assessment and the (least square) mean serum TTR at Week 35 was reduced by 81% from baseline. Similar TTR reductions were observed across subgroups including Val30Met variant status, body weight, sex, age, or race. Eplontersen also reduced the mean steady-state serum vitamin A by 71% by Week 37. At a dose 2.7-times the maximum recommended dose for eplontersen, clinically significant QTc interval prolongation was not observed. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Eplontersen functions by: Eplontersen is an antisense oligonucleotide-GalNAc conjugate that causes degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Experimental Properties:

Further physical and chemical characteristics of Eplontersen include:

• Molecular Weight: 9046.1
• Molecular Formula: C296H417N77O156P20S13Na20