Delving into the Latest Updates on Eprotirome with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

THR-β

Mechanism

THR-β agonists(Thyroid hormone receptor beta-1 agonists)

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication-

Inactive Indication

Heterozygous familial hypercholesterolemiaHypercholesterolemiaObesity+ [1]

Originator Organization

Karo Bio USA, Inc.

Active Organization-

Inactive Organization

Karo Healthcare AB

Karo Bio USA, Inc.Alkem Pharma GmbH

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

Login to view timeline

Structure

Molecular FormulaC18H17Br2NO5

InChIKeyVPCSYAVXDAUHLT-UHFFFAOYSA-N

CAS Registry355129-15-6

Eprotirome is a liver selective thyroid hormone that can reduce several independent risk factors for cardiovascular disease, while an euthyroid state is preserved in the extrahepatic tissue.
The purpose of this Phase III study is to assess the long-term efficacy and safety of Eprotirome in Patients with heterozygous Familial Hypercholesterolaemia who are on optimal standard of care.

Start Date01 Oct 2011

Sponsor / Collaborator

Karo Healthcare AB

100 Clinical Results associated with Eprotirome

Login to view more data

100 Translational Medicine associated with Eprotirome

Login to view more data

100 Patents (Medical) associated with Eprotirome

Login to view more data

30

Literatures (Medical) associated with Eprotirome

01 Aug 2020·ThyroidQ1 · MEDICINE

Thyroid Hormone Analogues: An Update

Q1 · MEDICINE

Review

Author: Zucchi, Riccardo

The development of thyroid hormone (TH) analogues was prompted by the attempt to exploit the effects of TH on lipid metabolism, avoiding cardiac thyrotoxicosis. Analysis of the relative distribution of the α and β subtypes of nuclear TH receptors (TRα and TRβ) showed that TRα and TRβ are responsible for cardiac and metabolic responses, respectively. Therefore, analogues with TRβ selectivity were developed, and four different compounds have been used in clinical trials: GC-1 (sobetirome), KB-2115 (eprotirome), MB07344/VK2809, and MGL-3196 (resmetirom). Each of these compounds was able to reduce low-density lipoprotein cholesterol, but a phase 3 trial with eprotirome was interrupted because of a significant increase in liver enzymes and the contemporary report of cartilage side effects in animals. As a consequence, the other projects were terminated as well. However, in recent years, TRβ agonists have raised new interest for the treatment of nonalcoholic fatty liver disease (NAFLD). After obtaining excellent results in experimental models, clinical trials have been started with MGL-3196 and VK2809, and the initial reports are encouraging. Sobetirome turned out to be effective also in experimental models of demyelinating disease. Aside TRβ agonists, TH analogues include some TH metabolites that are biologically active on their own, and their synthetic analogues. 3,5,3'-triiodothyroacetic acid has already found clinical use in the treatment of some cases of TH resistance due to TRβ mutations, and interesting results have recently been reported in patients with the Allan-Herndon-Dudley syndrome, a rare disease caused by mutations in the TH transporter MCT8. 3,5-diiodothyronine (T2) has been used with success in rat models of dyslipidemia and NAFLD, but the outcome of a clinical trial with a synthetic T2 analogue was disappointing. 3-iodothyronamine (T1AM) is the last entry in the group of active TH metabolites. Promising results have been obtained in animal models of neurological injury induced by β-amyloid or by convulsive agents, but no clinical data are available so far.

01 Oct 2019·EndocrineQ3 · MEDICINE

Thyroid hormone metabolites and analogues

Q3 · MEDICINE

Review

Author: Lanni, Antonia ; Petito, Giuseppe ; Goglia, Fernando ; Senese, Rosalba ; Cioffi, Federica

Several metabolic products that derive from L-thyroxine (T4) and 3,3'5-L-triiodothyronine (T3), the main thyroid hormones secreted by the thyroid gland, possess biologic activities. Among these metabolites or derivatives showing physiological actions some have received greater attention: diiodothyronines, iodothyronamines, acetic acid analogues. It is known that increased thyroid hormone (T3 and T4) levels can improve serum lipid profiles and reduce body fat. These positive effects are, however, counterbalanced by adverse effects on the heart, muscle and bone, limiting their use. In addition to the naturally occurring metabolites, thyroid hormone analogues have been developed that either have selective effects on specific tissues or bind selectively to thyroid hormone receptor (TR) isoform. Among these GC-1, KB141, KB2115, and DITPA were deeply investigated and displayed promising therapeutic results in the potential treatment of conditions such as dyslipidemias and obesity. In this review, we summarize the current knowledge of metabolites and analogues of T4 and T3 with reference to their possible clinical application in the treatment of human diseases.

01 Oct 2017·EndocrinologyQ2 · MEDICINE

Role of the Bile Acid Transporter SLC10A1 in Liver Targeting of the Lipid-Lowering Thyroid Hormone Analog Eprotirome

Q2 · MEDICINE

Article

Author: Carlsson, Bo ; Visser, Theo J ; van de Graaf, Stan F. J ; Brigante, Giulia ; van Mullem, Alies ; Peeters, Robin P ; Farina, Stefania ; van Gucht, Anja L. M ; Donkers, Joanne M ; Kersseboom, Simone

The thyroid hormone (TH) analog eprotirome (KB2115) was developed to lower cholesterol through selective activation of the TH receptor (TR) β1 in the liver. Interestingly, eprotirome shows low uptake in nonhepatic tissues, explaining its lipid-lowering action without adverse extrahepatic thyromimetic effects. Clinical trials have shown marked decreases in serum cholesterol levels. We explored the transport of eprotirome across the plasma membrane by members of three TH transporter families: monocarboxylate transporters MCT8 and MCT10; Na-independent organic anion transporters 1A2, 1B1, 1B3, 1C1, 2A1, and 2B1; and Na-dependent organic anion transporters SLC10A1 to SLC10A7. Cellular transport was studied in transfected COS1 cells using [14C]eprotirome and [125I]TH analogs. Of the 15 transporters tested initially, the liver-specific bile acid transporter SLC10A1 showed the highest eprotirome uptake (greater than a sevenfold induction after 60 minutes) as well as TRβ1-mediated transcriptional activity. Uptake of eprotirome by SLC10A1 was Na+ dependent and saturable with a Michaelis constant of 8 μM. Eprotirome transport was inhibited by known substrates for SLC10A1 (e.g., cholate and taurocholate), and by TH analogs such as triiodothyropropionic acid and triiodothyroacetic acid. However, no significant SLC10A1-mediated transport was observed of these [125I]TH analogs. We also studied the plasma disappearance and biliary excretion of [14C]eprotirome injected in control and Slc10a1 knockout mice. Although eprotirome is also transported by mouse Slc10a1, the pharmacokinetics of eprotirome were not affected by Slc10a1 deficiency. In conclusion, we have demonstrated that the liver-specific bile acid transporter SLC10A1 effectively transports eprotirome. However, Slc10a1 does not appear to be critical for the liver targeting of this TH analog in mice. Therefore, the importance of SLC10A1 for liver uptake of eprotirome in humans remains to be elucidated.

100 Deals associated with Eprotirome

Login to view more data

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB05035

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Heterozygous familial hypercholesterolemia	Phase 3	-	Karo Healthcare AB	01 Oct 2011
Primary hypercholesterolemia	Phase 3	SE	Karo Healthcare AB	01 Sep 2006
Hypercholesterolemia	Phase 3	-	Alkem Pharma GmbH	-
Obesity	Phase 3	SE	Karo Bio USA, Inc.	-

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00593047 (Pubmed \| Br Dent J)	Phase 2	Dyslipidemias	-	Eprotirome 25 microg	(pzsgctcaff) = colgjwwnho djszyafrwe (sbtyutrxpj )	-	11 Mar 2010
				Eprotirome 50 microg	(pzsgctcaff) = tsxeowbwhu djszyafrwe (sbtyutrxpj )