Thyroid Hormone Analogs: Recent Developments

Abstract

Background:

Thyroid hormone exerts its function on virtually all tissues in the human body through binding to the thyroid hormone receptor (TR), making it an interesting vehicle for therapeutic intervention in nonthyroid conditions with metabolic consequences, as well as genetic thyroid hormone signaling disorders. Since the 1990s, several thyroid hormone analogs have been developed that have tissue specificity. Given the recent approval of two thyroid hormone analogs, the aim of this review is to give an update on developments in the field since 2020.

Summary:

Although initial therapeutic use of thyroid hormone analogs for nonthyroid conditions with metabolic consequences focused on cardiovascular disease and dyslipidemia, nowadays the primary focus is on the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Clinical trials with MGL-3196 (resmetirom) showed significant improvement on hepatic steatosis, fibrosis, and lipids, which led to approval by the U.S. Food and Drug Administration in 2024 for the treatment of MASH. Results are currently awaited for prodrug VK2809, exerting organ specificity through prodrug conversion in the liver, ultimately targeting MASH. For the treatment of genetic thyroid hormone signaling disorders (resistance to thyroid hormone β [RTHβ] and monocarboxylate transporter 8 [MCT8] deficiency), different thyroid hormone analogs have been tested. 3,5,3ʹ-triiodothyroacetic acid (Triac), an endogenous thyroid hormone analog, has been prescribed on a compassionate use basis for RTHβ. In MCT8 deficiency, 3,5-diiodothyropropionic acid has been explored in patients, and Sob-AM2, a prodrug of which the active compound accumulates in the brain, has been investigated in preclinical studies. Recently, the European Medicines Agency has granted market authorization for Triac, being the first approved medicine for this rare disease.

Conclusions:

Ongoing strategies to enhance organ specificity of thyroid hormone analogs should include not only TR specificity but also other determinants of tissue selectivity, such as tissue-specific transporters or enzymes that activate the prodrug. This, together with the recent approval of two thyroid hormone analogs, may ensure a promising future for the development and application of thyroid hormone analogs.

Introduction

Thyroid hormones are important for the metabolism and development of virtually all tissues within the human body.^1,2 The thyroid gland is responsible for the production of thyroid hormones, producing predominantly the inactive precursor thyroxine (T4) and, to a lesser extent, the active hormone 3,3ʹ,5-triiodothyronine (T3).² Thyroid hormone production is stimulated by thyrotropin (TSH), secreted by the pituitary. In turn, TSH is regulated by thyrotropin-releasing hormone (TRH) from the hypothalamus.³ Thyroid hormone homeostasis is achieved via a negative feedback loop, where TRH and TSH are inhibited by circulating T4 concentrations, which are locally converted to T3 at the hypothalamic and pituitary levels, respectively (Fig. 1A).^2,3

FIG. 1.

Thyroid hormone action within the human body. (A) The hypothalamus–pituitary–thyroid axis regulates thyroid hormone synthesis and homeostasis. Thyrotropin-releasing hormone (TRH) stimulates thyrotropin (TSH), which in turn stimulates secretion of triiodothyronine (T3) and thyroxine (T4) by the thyroid gland, which in turn exerts negative feedback on TRH and TSH production by the hypothalamus and pituitary, respectively. (B) Thyroid hormone enters the cell through thyroid hormone transporters. Within the cell, they are metabolized by deiodinases (DIO). DIO1 and DIO2 are activating deiodinases, converting the inactive precursor T4 to the active T3, while DIO3 is an inactivating enzyme, converting T4 to reverse T3 (rT3) and T3 to diiodothyronine (T2). Within the nucleus, the active T3 binds to the thyroid hormone receptor (TR) that is bound to retinoid X receptor (RXR) and corepressors at the thyroid hormone response element (TRE). Upon T3 binding, corepressors (co-R) are replaced by coactivators (co-A), leading to transcription of thyroid hormone-dependent target genes. (C) Distribution of TRα- and TRβ-expressing tissues within the human body. Created in BioRender. Freund, M. (2025) https://BioRender.com/v96lei0.

The intracellular availability of thyroid hormones is regulated through different transmembrane transporter proteins and deiodinases, which activate or inactivate thyroid hormones (Fig. 1B).^1,2,4
–6 Intracellular bioactive T3 exerts its genomic actions through binding to nuclear thyroid hormone receptors (TRs) that regulate the transcription of T3-dependent target genes.^1,2 TRs bind to thyroid hormone response elements (TREs), located at the promotor region of T3-dependent target genes. Binding of T3 to the TR results in a dissociation of corepressors and recruitment of coactivators, enabling the transcription machinery to initiate transcription (Fig. 1B).¹ There are two TR types, TRα and TRβ, that differ in their tissue distribution.^1,7 TRα is predominantly expressed in brain, heart, skeletal muscle, and bone, while TRβ is mainly expressed in liver, kidney, and pituitary (Fig. 1C). An imbalance in circulating thyroid hormone concentrations affects all tissues. However, thyroid hormone analogs could potentially uncouple the beneficial and negative effects of thyroid hormones by targeting their thyromimetic activity to specific tissues.

In the past decades, there has been growing interest in developing thyroid hormone analogs for therapeutic application in various disorders (Fig. 2), ranging from nonthyroid conditions with metabolic consequences to genetic disorders in thyroid hormone signaling. Consequently, there have been multiple reviews highlighting several aspects in this field, including an elegant review on thyroid hormone analogs published in this journal in 2020.^8

–12 Therefore, this review will focus on the latest developments in the field from 2020 onward. We will discuss the pharmacological treatment for various nonthyroid conditions with metabolic consequences and for genetic disorders in thyroid hormone signaling. We will highlight two thyroid hormone analogs, MGL-3196 (resmetirom) and 3,5,3ʹ-triiodothyroacetic acid (Triac), that were recently approved by regulatory agencies.^13,14

FIG. 2.

Developmental timeline of thyroid hormone analogs within different fields irrespective of application. The preclinical phase is defined as the period from the start of drug development to either the first administration in humans or the termination of preclinical studies. The clinical phase is defined as the interval between the first clinical administration in human subjects to the present date or termination of clinical studies. The drug approval by the regulatory agency coincides with the moment of the official press release issued by the respective authority. DITPA, 3,5-diiodothyropropionic acid; MAFLD, metabolic dysfunction-associated fatty liver disease; MASH, metabolic dysfunction-associated steatohepatitis; MCT8, monocarboxylate transporter 8; RTHβ, resistance to thyroid hormone β. Created in BioRender. Freund, M. (2025) https://BioRender.com/x08xfhg.

Brief Historical Overview

A shared underlying principle in the development of thyroid hormone analogs is the goal to achieve tissue-specific thyromimetic actions.⁹ The clinical observation that thyrotoxicosis leads to an increased heart rate, weight loss, and lipid reduction triggered the exploration of thyroid hormone analogs as a treatment for cardiovascular disease and dyslipidemia.⁹ However, treatment with dextrothyroxine, the synthetic mirror form of T4, in euthyroid patients with coronary artery disease proved to be counter effective, with a higher mortality, due to the TRα-mediated thyrotoxicosis.¹⁵ This prompted the development of thyroid hormone analogs that mimic the beneficial thyromimetic effects, without inducing thyrotoxic side effects.

3,5-diiodothyropropionic acid

3,5-diiodothyropropionic acid (DITPA) was one of the first analogs that was designed and tested for cardiovascular disease and dyslipidemia.¹⁶ DITPA is structurally different to T3 based on the absence of iodine at the outer ring and the amino group within the amino acid side chain (Fig. 3). It is a nonselective TR agonist with a TRβ binding affinity that is similar to TRα, albeit 350-fold smaller compared with T3.¹⁷ Considering its inotropic effects with small effects on heart rate, it was selected as a candidate for therapeutic use for heart failure.¹⁷ An initial pilot clinical trial showed positive effects on cardiac function as well as a reduction in serum cholesterol and triglycerides.¹⁸ Although a randomized controlled phase II trial also showed positive hemodynamic and metabolic effects, including a reduction in body weight, DITPA was poorly tolerated without evidence for symptomatic benefit.^19,20

FIG. 3.

Chemical structure of synthetic (A) and endogenous (B) thyroid hormone analogs. For every compound, differences in molecular structure compared with triiodothyronine (T3) are depicted using color coding: blue for synthetic and red for endogenous compounds. Missing structural elements are highlighted with a blue dot. For the three prodrugs, the structural element that is enzymatically altered for the active analog is depicted with a green background. Created in BioRender. Freund, M. (2025) https://BioRender.com/yxptgd7.

Another potential use of thyroid hormone analogs was for the treatment of dyslipidemia. In the liver, T3 stimulates the breakdown of triglyceride-containing lipid droplets via increased lipolysis and consecutive beta-oxidation in the mitochondria.¹⁰ The favorable effects on cholesterol levels are exploited through decreased secretion, increased clearance, and conversion of cholesterol into bile acids.²¹ Hence, several groups aimed to develop such molecules with liver-specific thyromimetic activity, thereby enabling favorable effects on lipids while avoiding thyromimetic effects in other tissues (e.g., the heart). To achieve this goal, they exploited the expression of TRβ in the liver to develop molecules with a preferential selectivity of TRβ over TRα. Although the ligand-binding domains (LBDs) are highly similar, there are some differences between the two receptor types. For example, TRα has a serine at position 277, whereas TRβ has an asparagine at the equivalent position.²² Moreover, in TRβ helices, H3 and H11 seem to be more flexible, allowing larger molecules as ligands.^22,23 Such differences in the molecular structure of the TRs can be exploited to generate compounds with a higher affinity for TRβ. Two well-known examples are sobetirome and eprotirome, which were developed in the 1990s and 2000s, respectively.⁹

Sobetirome

GC-1 [3,5-dimethyl-4-(4′-hydroxy-3′-isopropylbenzyl)-phenoxy acetic acid], or sobetirome, has enhanced TRβ specificity through different modifications, such as the amino acid side chain being replaced by an oxoacetic chain, enhancing the polar interaction with the arginine residues in the TRβ pocket (Fig. 3).²⁴ Furthermore, the iodine atoms, as well as the oxygen atom linking both aromatic rings of T3, are changed into alkyl groups, allowing sobetirome to form more stable interactions with TRβ. Sobetirome has a similar affinity for TRβ as T3, while the affinity for TRα is 10-fold lower, explaining the beneficial effects in the liver, while having limited effects on the heart in a clinical study (Table 1).^39,44,45

Table 1.

Overview of Thyroid Hormone Analogs Applied in Clinical Setting

Compound	Thyromimetic action^a	Clinical indication	(Pre)clinical study	Clinical study protocol^b	Prominent findings^c
DITPA; 3,5-diiodothyropropionic acid	No TR selectivity TR potency <T3 (350-fold)	Dyslipidemia / Heart failure	Animal models¹⁷		↑ cardiac output \| ↓ left ventricular end-diastolic pressure
			Pilot study¹⁸	n = 22 \| adult \| 4 week treatment \| 1.9–3.8 mg/kg/day \| placebo-controlled	↑ cardiac index \| ↓ total cholesterol \| ↓ triglycerides \| ↓ TSH
			Phase II clinical trial^19,20	n = 86 \| adult \| 24 week treatment \| 90–360 mg/day \| placebo-controlled	↑ cardiac index \| ↓ body weight \| ↓ total cholesterol \| ↓ triglycerides \| ↓ TSH ! poorly tolerated
		MCT8 deficiency	Animal models^25 –27		↓ TSH \| ↓ T4 \| ↓ (r)T3 \| ↑ cerebral markers of thyroid hormone deprivation ! placental passage
			Compassionate use²⁸	n = 4 \| aged 8.5–25 months \| 26–40 month treatment \| 2.1–2.4 mg/kg/day	↓ T3 \| ↓ SHBG \| ↓ heart rate
			Compassionate use (NCT04143295)	recruiting \| aged <12 years (incl. fetal period)
Eprotirome; KB-2115	TRβ selectivity (20-fold)TR potency T3-like for TRβ	Dyslipidemia	Phase II clinical trial²⁹	n = 24 \| adult \| 5 day treatment \| 50–2000 mcg/day \| placebo-controlled	↓ total and LDL cholesterol \| ↓ T4
			Phase II clinical trial²⁹	n = 24 \| adult \| 2 week treatment \| 50–200 mcg/day \| placebo-controlled	↓ total and LDL cholesterol \| ↓ T4
			Phase II clinical trial³⁰	n = 189 \| 12 week treatment \| 25–100 mcg/day \| placebo-controlled	↓ total and LDL cholesterol \| ↓ triglycerides \| ↓ T4
			Phase II clinical trial³¹	n = 98 \| adult \| 12 week treatment \| 100–200 mcg/day \| placebo-controlled	↓ total and LDL cholesterol \| ↓ triglycerides \| ↓ T4
			Phase III clinical trial³²	n = 236 \| planned for 52–76 weeks \| 50–100 mcg/day \| placebo-controlled	↓ total and LDL cholesterol \| ↓ triglycerides \| ↓ T4 ! increased liver enzymes ! prematurely terminated due to cartilage side effects in dogs
Resmetirom; MGL-3196	TRβ selectivity (30-fold)TR potency <T3 for TRβ (14-fold)	Dyslipidemia	Animal studies³³		↓ total and LDL cholesterol \| ↓ liver size
		Dyslipidemia	Phase I clinical trial³⁴	n = 120 \| 14 day treatment \| 50–200 mg/day	↓ LDL cholesterol \| ↓ HDL \| ↓ apoB \| ↓ T4
		MAFLD/MASH	Phase II clinical trial³⁵	n = 125 \| adult \| 36 week treatment \| 80 mg/day \| placebo-controlled	↓ liver fat \| ↓ total and LDL cholesterol \| ↓ triglycerides
			Phase III clinical trial³⁶	n = 1143 \| adult \| 52 week treatment \| 80–100 mg/day \| placebo-controlled	↓ total and LDL cholesterol \| ↓ triglycerides \| ↓ liver fat
			Phase III clinical trial³⁷	n = 966 \| adult \| 52 week treatment \| 80–100 mg/day \| placebo-controlled	↑ MASH resolution \| ↑ fibrosis improvement \| ↓ total and LDL cholesterol \| ↓ triglycerides
		MASH cirrhosis	Phase III clinical trial (NCT05500222)	recruiting \| adult \| 3 year treatment \| 80 mg/day \| placebo-controlled
Sobetirome; GC-1; QRX-431	TRβ selectivity (6.6-fold)TR potency T3-like for TRβ and <T3 for TRα (10-fold)	MCT8 deficiency	Animal models³⁸		↓ T4 \| ↓ T3 \| ↑ cerebral T3-target genes
		Dyslipidemia	Animal models^39 –43		↓ total and LDL cholesterol \| ↓ fat mass \| ↓ hepatic steatosis
		Dyslipidemia	Phase Ib clinical trial^44,45	n = 24 \| adult \| 2 week treatment\| 100 mcg/day	↓ total and LDL cholesterol
Sob-AM2	Intra-cerebral prodrug conversion by FAAH to Sobetirome	MCT8 deficiency	Animal models^38,46		↓ T4 \| ↓ T3 \| ↑ cerebral T3-target genes ! placental passage
Triac; tiratricol; 3,3′,5-triiodothyroacetic acid	TRβ selectivity (2–3 fold)TR potency >T3 for TRβ1 (3–6 fold) and TRβ2 (7-fold	MCT8 deficiency	Animal models^47 –49		↑ T3-dependent neural differentiation \| ↑ white matter volume \| ↑ myelination \| ↑ brain network function ! effects only present with treatment initiation before post-natal day 21
			Real-world retrospective cohort study⁵⁰	n = 67 \| aged 0.5–66 years \| 0.2–6.5 year treatment \| 15–105 mcg/kg/day	↓ T3 \| ↓ (f)T4 \| ↓ TSH \| ↓ heart rate \| ↑ weight \| ↓ SHBG \| ↑ creatinine \| ∼ CK
			Phase II clinical trial⁵¹	n = 45 \| aged 0.8–66.8 years \| 12 month treatment \| 6.4–84.3 mcg/kg/day	↓ (r)T3 \| ↓ (f)T4 \| ↓ TSH \| ↓ heart rate \| ↑ weight \| ↓ blood pressure weight \| ↓ SHBG \| ↑ CK \| ∼ total cholesterol
			Phase II clinical trial (NCT02396459)	n = 23 \| aged 6–30 months \| 5 year treatment \| 30–200 mcg/kg/day
			Phase III clinical withdrawal trial (NCT05579327)	recruiting \| aged >4 years \| 16–26 week treatment \| placebo-controlled
		RTHβ	Case-reports^11,52	n = 34 \| aged 0–52 years \| 7 day – 5.5 year treatment \| 700–4200 mcg/day	↓ TSH \| ↓ (f)T4 \| ↓ goiter size \| ↓ heart rate \| ↓ perspiration
VK2809; MB-07811	TRβ selectivity (12-fold)TR potency <T3 (fold unknown)Intra-hepatic prodrug conversion by CYP3A4 to VK2809A	Dyslipidemia	Animal studies^53 –55		↓ total and LDL cholesterol\| ↓ triglycerides
		Dyslipidemia	Phase I clinical trial⁵⁶	n = 56 \| adult \| 2 week treatment \| 0.25–40 mg/day	↓ total and LDL cholesterol\| ↓ triglycerides! increased liver enzymes
		MAFLD/MASH	Phase IIa clinical trial⁵⁷	n = 45 \| adult \| 12 week treatment \| 20–40 mcg/day \| placebo-controlled	↓ liver fat
		MAFLD/MASH	Phase IIb clinical trial⁵⁸	n = 178 \| adult \| 52 week treatment \| 1 mg/day – 10 mg/every other day \| placebo-controlled	↓ liver fat \| ↑ fibrosis improvement

Thyromimetic action is characterized by the selectivity of the compound to TRβ over TRα (TR selectivity) and its binding affinity to TR relative to T3 (TR potency). TR potency is classified as greater than T3 (<T3), lower than T3 (<T3), or equivalent to T3 (T3-like).

For clinical studies, if available, information is given on the number of patients included, age at baseline, treatment duration and treatment dose. All clinical trials are single-arm open-label studies, unless stated otherwise.

Changes in primary and secondary outcomes are presented as decreased (↓), increased (↑), or unchanged (∼). Relevant additional findings are reported in cursive, following an exclamation mark (!).

CK, creatine kinase; FAAH, fatty-acid-amide hydrolase; LDL, Low-density lipoprotein; MAFLD, Metabolic dysfunction-associated fatty liver disease; MASH, Metabolic dysfunction-associated steatohepatitis; MCT8, Monocarboxylate transporter 8; RTH, Resistance to thyroid hormone; SHBG, sex hormone-binding globulin; TFT, Thyroid function test; TR, Thyroid hormone receptor; TSH, thyroid stimulating hormone; (r)T3, (reverse) triiodothyronine; (f)T4, (free) thyroxine.

Eprotirome

In KB-2115 (3-[[3,5-dibromo-4-[4-hydroxy-3-(1-methylethyl)-phenoxy]-phenyl]-amino]-3-oxopropanoic acid), or eprotirome, the iodine atoms at the inner ring of T3 are replaced by bromine atoms, while the outer ring iodine is replaced by an isopropyl (Fig. 3).²⁹ The preferential actions of eprotirome on the liver are not only explained by its modest TRβ selectivity but likely also by its selective hepatic uptake through transporter solute carrier family 10A1 (SLC10A1), also known as Na⁺-taurocholate cotransporting polypeptide.⁵⁹ In double-blind randomized placebo-controlled trials (RCTs) in patients with statin-treated dyslipidemia and familial hypercholesterolemia, eprotirome showed substantial positive changes in total and low-density lipoprotein (LDL) cholesterol and triglycerides without effects on high-density lipoprotein (Table 1).^29,30,32 Similar results were obtained in an RCT with primary hypercholesterolemia, who were not on lipid-lowering therapy.³¹ Long-term dosing of eprotirome in dogs showed adverse effects on cartilage, leading to the company’s decision to withdraw the drug from further development.³²

Thyroid Hormone Analogs as Pharmacological Treatment in Metabolic Dysfunction-Associated Steatotic Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) and the more severe metabolic dysfunction-associated steatohepatitis (MASH) display a worrisome increase in prevalence across the world.⁶⁰ Fat accumulation in the liver (steatosis) due to metabolic abnormalities is a state called MASLD; once inflammation is present in MASLD, it is called MASH. If these conditions remain untreated, they may progress to cirrhosis, cancer, and liver failure. As such, there is a clinical need for treatment. Thyroid hormone exerts both metabolic effects in the liver (stimulation of lipolysis, beta-oxidation, and lipophagy) as well as anti-inflammatory and antifibrotic effects.¹⁰ Therefore, these effects can be exploited by thyroid hormone analogs in the treatment of MASLD and MASH.

Resmetirom

To obtain MGL-3196 (2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile), also known as resmetirom, the phenolic outer ring of T3 is changed into a dihydropyridazinyloxy heterocycle, where a isopropyl replaces the iodine atom, while in the second ring two chlorine atoms replace iodine in T3, and the amino acid side chain is replaced by a triazine-carbonitrile heterocycle (Fig. 3).³³ Together, these changes attain a 30-fold selectivity for TRβ over TRα, although the affinity for TRβ is also reduced compared with T3 and other compounds such as sobetirome, explaining the need for higher doses. Further hepatic selectivity is conferred by liver uptake through the liver transporter solute carrier organic anion transporter family member 1B1 (OATP1B1).⁶¹ Animal studies showed positive effects of resmetirom on total lipids and LDL cholesterol, and in a first-in-human study, these effects were also observed in healthy subjects (Table 1).^33,34

Several clinical trials have investigated the effects of resmetirom on different outcomes. In the placebo-controlled phase II MGL-3196-05 trial in 116 patients with MASH, resmetirom sustainably reduced hepatic fat, as assessed by magnetic resonance imaging (MRI) after 12 weeks of treatment.³⁵ Clinically relevant reduction of multiple atherogenic lipids, decreased liver enzymes, and inflammatory markers underscored these positive effects. Next, the placebo-controlled phase III (MAESTRO-NAFLD-1) trial in 972 patients with MASH showed that resmetirom was safe and well-tolerated with a treatment duration of 52 weeks.³⁶ Similar effects were observed in the reduction of hepatic fat, LDL, and triglycerides levels as in the earlier study, with a dose-dependent effect. Reported adverse events were diarrhea and nausea at the initiation of treatment. Only a minor reduction in free T4 concentration was observed, and no effects on TSH and free T3 concentrations were reported. Another phase III study, the MAESTRO-NASH trial in 966 patients with MASH showed a higher resolution of MASH after 52 weeks of treatment with resmetirom (and improvement in fibrosis).³⁷ These two phase III trials were pivotal for the approval of resmetirom for the treatment of MASH with moderate to advanced liver fibrosis by the Food and Drug Administration of the United States.¹³ Currently, one additional study evaluates the effect of resmetirom in patients with well-compensated MASH cirrhosis (NCT05500222), of which the completion is expected in 2027.

VK2809

VK2809 (MB07811) (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4′-hydroxy-3′-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1–3]-dioxaphosphonane is a liver-specific prodrug (Fig. 3).⁵³ After first-pass hepatic extraction, this prodrug is converted into the active compound VK2809A (MB07344) (3,5-dimethyl-4-(4′-hydroxy-3′-isopropylbenzyl)phenoxy)methylphosphonic acid) through the oxidation of the benzylic methine proton by cytochrome P3A4 (CYP3A4). VK2809A is highly similar to sobetirome, albeit with a lower affinity for the TRs. Preliminary results of the phase IIa randomized, double-blind, placebo-controlled trial (NCT02927184) in 45 patients with MAFLD showed reduced hepatic fat as assessed by MRI after 12 weeks of treatment (Table 1).⁵⁷ Recently, the first results of the phase IIb VOYAGE trial (NCT04173065) with VK2809 were reported, in which 178 patients with MASH were treated for 12 months.⁵⁸ For all but the lowest dose, a significant reduction of steatosis after 3 months of treatment and improvement in liver fibrosis were observed after 52 weeks. No major safety issues were reported. Detailed results are awaited, as no follow-up studies have been announced.

Other analogs

Based on the success of resmetirom in the treatment of MASH, new analogs are still being developed. In 2020, compound IS25 (2-(4-(4-amino-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid) and its prodrug TG68 (2-(4-(4-acetamido-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid) were discovered (Fig. 3).^62,63 The structure of IS25 is highly similar to sobetirome, and with computational analysis, it was inferred that the specificity for TRβ was higher than for TRα. One of the newest thyroid hormone analogs is ZTA-261 (2-[4-[(4-hydroxynaphthalen-1-yl)methyl]-3,5-bis(trifluoromethyl)phenyl]acetic acid), a derivate of sobetirome, where the outer aromatic ring is changed into a naphthol to increase hydrophobic interaction with TR (Fig. 3).⁶⁴ The affinity for TRβ is similar to T3, but with a 100-fold lower affinity for TRα. Animal studies for these compounds showed significant reductions of serum and liver lipids, but clinical studies have not been planned.^64
–66

The anticipated added value of TRβ-specific analogs has ultimately led to the approval of resmetirom as the first treatment for MASH. Hence, both the European and American guidelines recommend treatment with resmetirom in adults with moderate to advanced liver fibrosis.^67,68 However, further clinical studies are needed to compare resmetirom to other therapies that have been shown to be effective. Although no head-to-head trials have been performed, other treatments such as vitamin E or glucagon-like-polypeptide-1 agonists seem equally or even more effective and are often available for lower costs.^69

–72

Still, with several clinical studies awaiting results and new compounds continuing to be developed, there is a promising future for even more advanced treatments for MASH via thyroid hormone analogs.

Thyroid Hormone Analogs in Resistance to Thyroid Hormone Beta

Resistance to thyroid hormone β (RTHβ) is typically caused by a heterozygous pathogenic variant in the LBD of TRβ (encoded by the THRB gene), with a prevalence of 1:19,000–40,000 individuals.^73,74 Mutant TRβ interferes with the normal function of wild-type TRβ, a phenomenon called dominant negative inhibition.^74
–76 TRβ-expressing tissues (e.g., pituitary, liver) are insensitive (resistant) to thyroid hormones, while TRα-expressing tissues (e.g., heart, bone) retain normal sensitivity. Due to reduced sensitivity of the hypothalamus–pituitary axis to thyroid hormones, patients with RTHβ demonstrate a distinctive biochemical profile, characterized by elevated (F)T4 and (F)T3 concentrations with nonsuppressed TSH concentrations.

Patients with RTHβ may exert clinical features of tissue-specific hypothyroidism (e.g., elevated cholesterol concentrations) and thyrotoxicity (e.g., anxiety and palpitations).^74,77 Recently, a 2–3 times elevated risk of mortality rate and ∼10-times risk of atrial fibrillation in untreated patients with RTHβ was reported.^78,79 Hence, there is a clear need for therapies that overcome the resistance in TRβ-expressing tissues while accomplishing a euthyroid state in TRα-expressing tissues. Ideally, a compound should have sufficient thyromimetic potency to overcome the reduced binding affinity of mutant TRβ, without further increasing thyromimetic action on TRα.^11,12

Triac

3,5,3ʹ-triiodothyroacetic acid, also called tiratricol or Triac, is an endogenous T3 metabolite found in human serum at concentrations ∼50-fold lower than T3 (Fig. 3).⁸⁰ In Triac, the amino acid side chain is replaced by an acetic acid, although the endogenous metabolism pathway has not been entirely elucidated. Compared with T3, Triac has a higher affinity for TRβ, which is also retained in a subset of TRβ mutants, while affinity of Triac for TRα is similar to T3.^81

–84 Therefore, Triac has been explored as potential treatment in patients with RTHβ, mostly reported as case reports or case series (Table 1).¹¹ Most patients favorably responded by a reduction in (F)T4 and TSH concentrations along with alleviation of thyrotoxic symptoms, such as goiter, tachycardia, and excessive perspiration.¹¹ Currently, the place of Triac in the treatment of RTHβ is not clear.⁸⁵ Clinical trials are necessary to investigate the effectiveness of Triac on different outcomes, including cardiovascular morbidity, in patients with RTHβ.

Thyroid Hormone Analogs in MCT8 Deficiency

Monocarboxylate transporter 8 (MCT 8) is a very specific thyroid hormone transporter, facilitating transport of T3 and T4.⁴ Pathogenic variants within SLC16A2, the gene encoding MCT8, lead to MCT8 deficiency, estimated to occur in 1:70,000 male individuals.^86
–88 Patients with MCT8 deficiency exhibit a characteristic biochemical profile of elevated (F)T3, low-normal (F)T4, and a nonsuppressed TSH concentrations.⁸⁹ Due to the essential role of MCT8 in thyroid hormone transport across the blood–brain barrier, defective MCT8 results in cerebral hypothyroidism.^90
–92 Since thyroid hormones are crucial for brain development,⁹¹ patients with MCT8 deficiency have severe intellectual and motor disabilities.^89,93 Simultaneously, tissues independent on MCT8 (i.e., liver, heart, muscle) are exposed to elevated T3 concentrations, leading to thyrotoxic symptoms such as tachycardia and elevated blood pressure and contributing to a low body weight.^89,93 Treatment of MCT8 deficiency should focus on increasing thyroid hormone availability in the brain while alleviating signs and symptoms of peripheral thyrotoxicosis. Thyroid hormone analogs that enter the cell independent of MCT8 may serve this therapeutic goal by alleviating the T3-mediated thyrotoxicosis through TSH suppression and by bypassing the defect at the blood–brain barrier.

DITPA

DITPA was first explored as a potential therapeutic compound in MCT8 deficiency when Di Cosmo et al. showed that in Mct8 KO mice, reflecting only the thyrotoxic phenotype of MCT8 deficiency, DITPA enters the cell independent of MCT8 (Table 1).²⁵ Subsequent research by Ferrara et al. showed a successful decrease in serum TSH and T3 concentrations in the same mouse model.²⁶ DITPA use in MCT8 deficiency has been reported in four patients between 8.5 and 25 months old who were treated for 26–40 months on a compassionate use basis.²⁸ All four patients showed a reduction in T3 upon DITPA initiation, although thyrotoxicity-related clinical effects varied, with some experiencing improvements in heart rate and body weight, while others showed no significant changes.²⁸ Potential rescue of the neurodevelopmental disorder in MCT8 deficiency is currently the topic of investigation during an ongoing trial (NCT04143295) that allows DITPA treatment to start prenatally.

Sob-AM2

2-[4-[[4-Hydroxy-3-(1-methylethyl)phenyl]methyl]-3,5-dimethylphenoxy]-N-methylacetamide, or Sob-AM2, is an amide prodrug of sobetirome where the negatively charged carboxylate group is replaced by an amide, thereby increasing the permeability of the blood–brain barrier (Fig. 3).^94,95 Sob-AM2 can be metabolized in the brain by fatty acid amide hydrolase and leads to a ∼20-fold increase in cerebral sobetirome concentrations while limiting circulating concentrations.⁹⁶ In 30-day old Mct8/Dio2 dKO mice, reflecting the thyrotoxic and neurological components of MCT8 deficiency, sobetirome and Sob-AM2 led to equivalent reductions in T4 and T3 concentrations and equal activation of cerebral T3-dependent target genes (Table 1).³⁸ The same murine model has been used to show that Sob-AM2 is able to cross the placenta and stimulate fetal cerebral T3-dependent target genes as well.⁴⁶ Although Sob-AM2 shows promising potential in targeting the neurological aspects of MCT8 deficiency, clinical experience is lacking, with no clinical trials planned in the near future.

Triac

Preclinical findings in cells and murine models demonstrated that Triac can enter cells independently of MCT8.⁴⁷ Several studies in Mct8/Oatp1c1 dKO, mimicking the thyrotoxic and neurological phenotype of MCT8 deficiency, demonstrated that Triac has the potential to fully rescue neurological impairment by restoring T3-dependent neural differentiation, white matter loss, myelination, and brain network dysfunction (Table 1).^47
–49 These effects were only observed when treatment was initiated before the third postnatal week in mice, indicating that (partial) rescue of the neurological phenotype might be possible in humans, given that treatment is initiated in early postnatal life.⁴⁹

In a single-arm phase II trial (Triac Trial I) in 46 pediatric and adult patients with MCT8 deficiency, Triac treatment for 12 months substantially reduced T3 concentrations.⁵¹ Secondary outcomes on thyrotoxicity improved as well, including body weight, heart rate, premature atrial contractions, blood pressure, and tissue-specific biochemical markers.⁵¹ These results were validated in a real-world retrospective cohort study of 67 patients with MCT8 deficiency, indicating that the amelioration of thyrotoxicosis in MCT8 deficiency is safe and sustainable.⁵⁰ The potential impact of Triac treatment on neurocognitive development in MCT8 deficiency is currently being investigated in a phase II clinical trial (NCT02396459), involving pediatric male patients under 30 months old, with results expected this year. In December 2024, the European Medicines Agency approved Triac as a drug for peripheral thyrotoxicosis treatment in MCT8 deficiency, being the first approved medicine for this rare disease.¹⁴

Ongoing or Other Developments

New applications for thyroid hormone analogs are continuously being explored. This is exemplified in the work undertaken by Li et al. (2024), which proposes sobetirome as an anti-inflammatory strategy in acute lung injury and acute respiratory distress syndrome⁹⁷ building on a previous study by Yu et al. (2018), indicating that sobetirome significantly alleviates pulmonary fibrosis.⁹⁸ In glycogen storage disease type Ia, caused by deficient glucose-6-phosphatase, VK2809 has shown promising results in decreasing hepatic triglyceride levels, potentially mitigating the increased risks of hepatosteatosis present in this disease.⁹⁹ All abovementioned studies use murine models to reflect the respective disease entities, and developments have not yet progressed toward clinical applications. Nevertheless, these studies underscore the extensive reach of thyroid hormone signaling, highlighting the potential of thyroid hormone analogs for therapeutic application across a wide spectrum of diseases.

The beneficial effects of sobetirome and Sob-AM2 in several demyelinating murine models have opened the door for the potential use of thyroid hormone analogs as pro-remyelinating therapy targeting demyelinating diseases, such as multiple sclerosis, multiple system atrophy, and Pitt–Hopkins syndrome.^100

–103 Also for X-linked adrenoleukodystrophy, a genetic disorder with central nervous system demyelination and adrenal insufficiency, sobetirome has previously been shown to effectively lower very long-chain fatty acid accumulation in serum and tissues through upregulation of the ABCD2 gene in different murine models, addressing the presumed pathogenic mechanism behind the disease.^104,105 However, two previously planned clinical trials for X-linked adrenoleukodystrophy (NCT01787578, NCT03196765) were withdrawn, allegedly due to the need for revisions in the original protocol and lack of funding, respectively.

In the field of RTH syndromes, thyroid hormone analogs targeting specific mutants or corepressors have gained attention. One study developed a compound, called 16 g, that, apart from showing high TRβ selectivity, also shows efficient binding to one specific TRβ (H435R) mutant.¹⁰⁶ Another study by Romartinez-Alonso et al., focusing on resistance to thyroid hormone α, has identified ES08 as a compound to dissociate aberrant corepressor binding, which is a key mechanism underlying dominant negative inhibition in RTH.¹⁰⁷ Such studies highlight the potential to develop disease- and mutation-specific thyroid hormone analogs.

Future Perspectives

Since the discovery of sobetirome in the 90s as the first synthetic thyroid hormone analog specifically aimed at the TRβ isoform, the field of thyroid hormone analogs has expanded. Numerous thyroid hormone analogs have been developed with varying success rates. Although the original aim, namely a treatment for cardiovascular disease and dyslipidemia, is not prioritized anymore, the recent and first-ever approval of two thyroid hormone analogs shows the potential of this class of drugs.

Ongoing strategies to enhance organ specificity of thyroid hormone analogs should include not only TR specificity but also other determinants of tissue selectivity, such as tissue-specific transporters or enzymes that inactivate the drug or activate the prodrug. If the decades of experience in thyroid hormone analog development can be used in a fruitful way, we anticipate that the recent regulatory approvals of two thyroid hormone analogs are signposts to a promising future for this class of drugs.

Footnotes

Authors’ Contributions

M.F.T.F., F.v.d.M., and W.E.V.: Conceptualization (equal), investigation (equal), visualization (equal), writing—original draft (equal), and writing—review and editing (equal). S.G. and F.S.v.G.: Conceptualization (supporting) and writing—review and editing (equal).

Author Disclosure Statement

Erasmus Medical Center (Rotterdam, the Netherlands), which employs all authors, receives royalties from Egetis Therapeutics, the company manufacturing Triac. The authors do not benefit personally from these royalties. M.E.T.F., F.v.d.M., S.G., and W.E.V. have no conflicts of interest to disclose. F.S.v.G. is a paid consultant for Egetis Therapeutics and has no further conflicts of interest to disclose.

Funding Information

M.E.T.F., F.v.d.M., S.G., and F.S.v.G. have no funding information to declare. W.E.V. received funding from the Sherman Foundation.

References

Mullur

, Liu

, Brent

. Thyroid hormone regulation of metabolism. Physiol Rev, 2014; 94(2):355–382.

Yen

. Physiological and molecular basis of thyroid hormone action. Physiol Rev, 2001; 81(3):1097–1142.

Ortiga-Carvalho

, Chiamolera

, Pazos-Moura

, et al. Hypothalamus-pituitary-thyroid axis. Compr Physiol, 2016; 6(3):1387–1428.

Groeneweg

, van Geest

, Peeters

, et al. Thyroid hormone transporters. Endocr Rev, 2020; 41(2):bnz008; doi: 10.1210/endrev/bnz008

Becker

, Güth-Steffens

, Lazarow

, et al. Identification of human TRIAC transmembrane transporters. Thyroid, 2024; 34(7):920–930.

Chen

, Yildiz

, Markova

, et al. 3,3′,5-Triiodothyroacetic acid transporters. Thyroid, 2024; 34(8):1027–1037.

Cheng

, Leonard

, Davis

. Molecular aspects of thyroid hormone actions. Endocr Rev, 2010; 31(2):139–170.

Zucchi

. Thyroid hormone analogues: An update. Thyroid, 2020; 30(8):1099–1105; doi: 10.1089/thy.2020.0071

Baxter

, Webb

. Thyroid hormone mimetics: Potential applications in atherosclerosis, obesity and type 2 diabetes. Nat Rev Drug Discov, 2009; 8(4):308–320.

10.

Ratziu

, Scanlan

, Bruinstroop

. Thyroid hormone receptor-beta analogues for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). J Hepatol, 2025; 82(2):375–387; doi: 10.1016/j.jhep.2024.10.018

11.

Groeneweg

, Peeters

, Visser

, et al. Therapeutic applications of thyroid hormone analogues in resistance to thyroid hormone (RTH) syndromes. Mol Cell Endocrinol, 2017; 458:82–90.

12.

Visser

. Therapeutic applications of thyroid hormone analogues. Ann Endocrinol (Paris), 2021; 82(3–4):170–172.

13.

FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease. U.S. Food & Drug Administration: 2024.

14.

First treatment for peripheral thyrotoxicosis in patients with Allan-Herndon-Dudley syndrome. European Medicines Agency: 2024.

15.

The Coronary Drug Project. Findings leading to further modifications of its protocol with respect to dextrothyroxine. The coronary drug project research group. JAMA, 1972; 220(7):996–1008.

16.

Arsanjani

, McCarren

, Bahl

, et al. Translational potential of thyroid hormone and its analogs. J Mol Cell Cardiol, 2011; 51(4):506–511; doi: 10.1016/j.yjmcc.2010.12.012

17.

Pennock

, Raya

, Bahl

, et al. Cardiac effects of 3,5-diiodothyropropionic acid, a thyroid hormone analog with inotropic selectivity. J Pharmacol Exp Ther, 1992; 263(1):163–169.

18.

Morkin

, Pennock

, Spooner

, et al. Pilot studies on the use of 3,5-diiodothyropropionic acid, a thyroid hormone analog, in the treatment of congestive heart failure. Cardiology, 2002; 97(4):218–225; doi: 10.1159/000063110

19.

Goldman

, McCarren

, Morkin

, et al. DITPA (3,5-diiodothyropropionic acid), a thyroid hormone analog to treat heart failure: Phase II trial veterans affairs cooperative study. Circulation, 2009; 119(24):3093–3100.

20.

Ladenson

, McCarren

, Morkin

, et al. Effects of the thyromimetic agent diiodothyropropionic acid on body weight, body mass index, and serum lipoproteins: A pilot prospective, randomized, controlled study. J Clin Endocrinol Metab, 2010; 95(3):1349–1354.

21.

Sinha

, Bruinstroop

, Singh

, et al. Nonalcoholic fatty liver disease and hypercholesterolemia: Roles of thyroid hormones, metabolites, and agonists. Thyroid, 2019; 29(9):1173–1191; doi: 10.1089/thy.2018.0664

22.

Wagner

, Huber

, Shiau

, et al. Hormone selectivity in thyroid hormone receptors. Mol Endocrinol, 2001; 15(3):398–410.

23.

Borngraeber

, Budny

, Chiellini

, et al. Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor. Proc Natl Acad Sci U S A, 2003; 100(26):15358–15363; doi: 10.1073/pnas.2136689100

24.

Chiellini

, Apriletti

, Yoshihara

, et al. A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor. Chem Biol, 1998; 5(6):299–306.

25.

Di Cosmo

, Liao

, Dumitrescu

, et al. A thyroid hormone analog with reduced dependence on the monocarboxylate transporter 8 for tissue transport. Endocrinology, 2009; 150(9):4450–4458.

26.

Ferrara

, Liao

, Ye

, et al. The thyroid hormone analog DITPA ameliorates metabolic parameters of male mice with Mct8 deficiency. Endocrinology, 2015; 156(11):3889–3894.

27.

Ferrara

, Liao

, Gil-Ibáñez

, et al. Placenta passage of the thyroid hormone analog DITPA to male wild-type and Mct8-deficient mice. Endocrinology, 2014; 155(10):4088–4093.

28.

Verge

, Konrad

, Cohen

, et al. Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency. J Clin Endocrinol Metab, 2012; 97(12):4515–4523.

29.

Berkenstam

, Kristensen

, Mellstrom

, et al. The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans. Proc Natl Acad Sci U S A, 2008; 105(2):663–667; doi: 10.1073/pnas.0705286104

30.

Ladenson

, Kristensen

, Ridgway

, et al. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med, 2010; 362(10):906–916; doi: 10.1056/NEJMoa0905633

31.

Angelin

, Kristensen

, Eriksson

, et al. Reductions in serum levels of LDL cholesterol, apolipoprotein B, triglycerides and lipoprotein(a) in hypercholesterolaemic patients treated with the liver-selective thyroid hormone receptor agonist eprotirome. J Intern Med, 2015; 277(3):331–342; doi: 10.1111/joim.12261

32.

Sjouke

, Langslet

, Ceska

, et al. Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): A randomised, double-blind, placebo-controlled phase 3 study. Lancet Diabetes Endocrinol, 2014; 2(6):455–463; doi: 10.1016/S2213-8587(14)70006-3

33.

Kelly

, Pietranico-Cole

, Larigan

, et al. Discovery of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a highly selective thyroid hormone receptor beta agonist in clinical trials for the treatment of dyslipidemia. J Med Chem, 2014; 57(10):3912–3923; doi: 10.1021/jm4019299

34.

Taub

, Chiang

, Chabot-Blanchet

, et al. Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-beta agonist. Atherosclerosis, 2013; 230(2):373–380; doi: 10.1016/j.atherosclerosis.2013.07.056

35.

Harrison

, Bashir

, Guy

, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet, 2019; 394(10213):2012–2024; doi: 10.1016/S0140-6736(19)32517-6

36.

Harrison

, Taub

, Neff

, et al. Resmetirom for nonalcoholic fatty liver disease: A randomized, double-blind, placebo-controlled phase 3 trial. Nat Med, 2023; 29(11):2919–2928; doi: 10.1038/s41591-023-02603-1

37.

Harrison

, Bedossa

, Guy

, et al.; MAESTRO-NASH Investigators. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med, 2024; 390(6):497–509; doi: 10.1056/NEJMoa2309000

38.

Bárez-López

, Hartley

, Grijota-Martínez

, et al. Sobetirome and its amide prodrug Sob-AM2 exert thyromimetic actions in Mct8-deficient brain. Thyroid, 2018; 28(9):1211–1220.

39.

Trost

, Swanson

, Gloss

, et al. The thyroid hormone receptor-beta-selective agonist GC-1 differentially affects plasma lipids and cardiac activity. Endocrinology, 2000; 141(9):3057–3064.

40.

Grover

, Egan

, Sleph

, et al. Effects of the thyroid hormone receptor agonist GC-1 on metabolic rate and cholesterol in rats and primates: Selective actions relative to 3,5,3′-triiodo-L-thyronine. Endocrinology, 2004; 145(4):1656–1661.

41.

Villicev

, Freitas

, Aoki

, et al. Thyroid hormone receptor beta-specific agonist GC-1 increases energy expenditure and prevents fat-mass accumulation in rats. J Endocrinol, 2007; 193(1):21–29.

42.

Perra

, Simbula

, et al. Thyroid hormone (T3) and TRbeta agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats. Faseb J, 2008; 22(8):2981–2989.

43.

Cable

, Finn

, Stebbins

, et al. Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist. Hepatology, 2009; 49(2):407–417; doi: 10.1002/hep.22572

44.

Lin

, Klepp

, Hanley

. Sobetirome is a TRβ- and liver-selective thyromimetic that can affect substantial LDL-C lowering without significant changes in heart rate or the thyroid axis in euthyroid men [abstract]. The Endocrine Society Annual Meeting ENDO: San Francisco, USA; 2008. pp. OR36-33.

45.

Tancevski

, Rudling

, Eller

. Thyromimetics: A journey from bench to bed-side. Pharmacol Ther, 2011; 131(1):33–39; doi: 10.1016/j.pharmthera.2011.04.003

46.

Valcárcel-Hernández

, Guillén-Yunta

, Scanlan

, et al. Maternal administration of the CNS-selective sobetirome prodrug Sob-AM2 exerts thyromimetic effects in murine MCT8-deficient fetuses. Thyroid, 2023; 33(5):632–640.

47.

Kersseboom

, Horn

, Visser

, et al. In vitro and mouse studies supporting therapeutic utility of triiodothyroacetic acid in MCT8 deficiency. Mol Endocrinol, 2014; 28(12):1961–1970.

48.

Reinwald

, Weber-Fahr

, Cosa-Linan

, et al. TRIAC treatment improves impaired brain network function and white matter loss in thyroid hormone transporter Mct8/Oatp1c1 deficient mice. Int J Mol Sci, 2022; 23(24):15547.

49.

Chen

, Salveridou

, Liebmann

, et al. Triac treatment prevents neurodevelopmental and locomotor impairments in thyroid hormone transporter Mct8/Oatp1c1 deficient mice. Int J Mol Sci, 2023; 24(4):3452.

50.

van Geest

, Groeneweg

, van den Akker

ELT

, et al. Long-term efficacy of T3 analogue triac in children and adults with MCT8 deficiency: A real-life retrospective cohort study. J Clin Endocrinol Metab, 2022; 107(3):e1136–e1147.

51.

Groeneweg

, Peeters

, Moran

, et al. Effectiveness and safety of Triac in children and adults with MCT8 deficiency: An international, multicentre, single group, open-label, phase 2 trial. Lancet Diabetes Endocrinol, 2019; 7(9):695–706.

52.

Carbone

, Verrienti

, Cito

, et al. Effective TRIAC treatment of a THRβ-mutated patient with thyroid hormone resistance. Endocrine, 2024; 85(2):598–600.

53.

Erion

, Cable

, Ito

, et al. Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index. Proc Natl Acad Sci U S A, 2007; 104(39):15490–15495; doi: 10.1073/pnas.0702759104

54.

Ito

, Zhang

, Cable

, et al. Thyroid hormone beta receptor activation has additive cholesterol lowering activity in combination with atorvastatin in rabbits, dogs and monkeys. Br J Pharmacol, 2009; 156(3):454–465.

55.

Boyer

, Jiang

, Jacintho

, et al. Synthesis and biological evaluation of a series of liver-selective phosphonic acid thyroid hormone receptor agonists and their prodrugs. J Med Chem, 2008; 51(22):7075–7093; doi: 10.1021/jm800824d

56.

Lian

, Hanley

, Schoenfeld

. A phase 1 randomized, double-blind, placebo-controlled, multiple ascending dose study to evaluate safety, tolerability and pharmacokinetics of the liver-selective TR-beta agonist VK2809 (MB07811) in hypercholesterolemic subjects. Jacc, 2016; 67(13):1932; doi: 10.1016/S0735-1097(16)31933-7

57.

Loomba

, Neutel

, Mohseni

, et al. LBP-20-VK2809, a novel liver-directed thyroid receptor beta agonist, significantly reduces liver fat with both low and high doses in patients with non-alcoholic fatty liver disease: A phase 2 randomized, placebo-controlled trial. J Hepatol, 2019; 70(1):e150–e151; doi: 10.1016/S0618-8278(19)30266-X

58.

Results from the 52-week phase 2b VOYAGE trial of VK2809 in patients with biopsy-confirmed non-alcoholic steatohepatitis and fibrosis: A randomized, placebo-controlled trial. Gastroenterol Hepatol (N Y), 2024; 20(12 Suppl 11):13–14.

59.

Kersseboom

, van Gucht

ALM

, van Mullem

, et al. Role of the bile acid transporter SLC10A1 in liver targeting of the lipid-lowering thyroid hormone analog eprotirome. Endocrinology, 2017; 158(10):3307–3318; doi: 10.1210/en.2017-00433

60.

Guo

, Wu

, Mao

, et al. Global burden of MAFLD, MAFLD related cirrhosis and MASH related liver cancer from 1990 to 2021. Sci Rep, 2025; 15(1):7083; doi: 10.1038/s41598-025-91312-5

61.

Hones

, Sivakumar

, Hoppe

, et al. Cell-specific transport and thyroid hormone receptor isoform selectivity account for hepatocyte-targeted thyromimetic action of MGL-3196. Int J Mol Sci, 2022; 23(22):13714; doi: 10.3390/ijms232213714

62.

Runfola

, Sestito

, Bellusci

, et al. Design, synthesis and biological evaluation of novel TRbeta selective agonists sustained by ADME-toxicity analysis. Eur J Med Chem, 2020; 188:112006; doi: 10.1016/j.ejmech.2019.112006

63.

Wang

, Chen

, Wang

, et al. Drug discovery targeting thyroid hormone receptor beta (THRbeta) for the treatment of liver diseases and other medical indications. Acta Pharm Sin B, 2025; 15(1):35–51; doi: 10.1016/j.apsb.2024.07.025

64.

Nambo

, Nishiwaki-Ohkawa

, Ito

, et al. Synthesis and preclinical testing of a selective beta-subtype agonist of thyroid hormone receptor ZTA-261. Commun Med (Lond), 2024; 4(1):152; doi: 10.1038/s43856-024-00574-z

65.

Caddeo

, Kowalik

, Serra

, et al. TG68, a novel thyroid hormone receptor-beta agonist for the treatment of NAFLD. Int J Mol Sci, 2021; 22(23):13105; doi: 10.3390/ijms222313105

66.

Caddeo

, Serra

, Sedda

, et al. Potential use of TG68—A novel thyromimetic—for the treatment of non-alcoholic fatty liver (NAFLD)-associated hepatocarcinogenesis. Front Oncol, 2023; 13:1127517; doi: 10.3389/fonc.2023.1127517

67.

Chen

, Morgan

, Rotman

, et al. Resmetirom therapy for metabolic dysfunction-associated steatotic liver disease: October 2024 updates to AASLD Practice Guidance. Hepatology, 2025; 81(1):312–320; doi: 10.1097/HEP.0000000000001112

68.

European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol, 2024; 81(3):492–542; doi: 10.1016/j.jhep.2024.04.031

69.

Sherker

, Hoofnagle

. Letter to the Editor: Resmetirom therapy for metabolic dysfunction-associated steatotic liver disease-October 2024 updates to AASLD practice guidance. Hepatology, 2025; 81(6):E158–E159; doi: 10.1097/HEP.0000000000001264

70.

Sanyal

, Chalasani

, Kowdley

, et al.; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med, 2010; 362(18):1675–1685; doi: 10.1056/NEJMoa0907929

71.

Newsome

, Buchholtz

, Cusi

, et al.; NN9931-4296 Investigators. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med, 2021; 384(12):1113–1124; doi: 10.1056/NEJMoa2028395

72.

Loomba

, Hartman

, Lawitz

, et al.; SYNERGY-NASH Investigators. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med, 2024; 391(4):299–310; doi: 10.1056/NEJMoa2401943

73.

Sakurai

, Takeda

, Ain

, et al. Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor beta. Proc Natl Acad Sci U S A, 1989; 86(22):8977–8981.

74.

Pappa

, Refetoff

. Resistance to thyroid hormone beta: A focused review. Front Endocrinol (Lausanne), 2021; 12:656551.

75.

Dumitrescu

, Refetoff

. The syndromes of reduced sensitivity to thyroid hormone. Biochim Biophys Acta, 2013; 1830(7):3987–4003.

76.

Chatterjee

, Nagaya

, Madison

, et al. Thyroid hormone resistance syndrome. Inhibition of normal receptor function by mutant thyroid hormone receptors. J Clin Invest, 1991; 87(6):1977–1984.

77.

Forrest

, Hanebuth

, Smeyne

, et al. Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor beta: Evidence for tissue-specific modulation of receptor function. Embo J, 1996; 15(12):3006–3015.

78.

Campi

, Censi

, Prodam

, et al. Increased cardiovascular morbidity and reduced life expectancy in a large Italian cohort of patients with resistance to thyroid hormone β (RTHβ). Eur J Endocrinol, 2024; 191(4):407–415.

79.

Okosieme

, Usman

, Taylor

, et al. Cardiovascular morbidity and mortality in patients in Wales, UK with resistance to thyroid hormone β (RTHβ): a linked-record cohort study. Lancet Diabetes Endocrinol, 2023; 11(9):657–666.

80.

Groeneweg

, Peeters

, Visser

, et al. Triiodothyroacetic acid in health and disease. J Endocrinol, 2017; 234(2):R99–R121.

81.

Takeda

, Suzuki

, Liu

, et al. Triiodothyroacetic acid has unique potential for therapy of resistance to thyroid hormone. J Clin Endocrinol Metab, 1995; 80(7):2033–2040.

82.

Schueler

, Schwartz

, Strait

, et al. Binding of 3,5,3′-triiodothyronine (T3) and its analogs to the in vitro translational products of c-erbA protooncogenes: Differences in the affinity of the alpha- and beta-forms for the acetic acid analog and failure of the human testis and kidney alpha-2 products to bind T3. Mol Endocrinol, 1990; 4(2):227–234.

83.

Martínez

, Nascimento

, Nunes

, et al. Gaining ligand selectivity in thyroid hormone receptors via entropy. Proc Natl Acad Sci U S A, 2009; 106(49):20717–20722.

84.

Messier

, Langlois

. Triac regulation of transcription is T(3) receptor isoform- and response element-specific. Mol Cell Endocrinol, 2000; 165(1–2):57–66.

85.

Persani

, Rodien

, Moran

, et al. 2024 European Thyroid Association Guidelines on diagnosis and management of genetic disorders of thyroid hormone transport, metabolism and action. Eur Thyroid J, 2024; 13(4):e240125; doi: 10.1530/ETJ-24-0125

86.

Friesema

, Grueters

, Biebermann

, et al. Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet, 2004; 364(9443):1435–1437; doi: 10.1016/S0140-6736(04)17226-7

87.

Dumitrescu

, Liao

, Best

, et al. A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet, 2004; 74(1):168–175.

88.

Visser

, Vrijmoeth

, Visser

, et al. Identification, functional analysis, prevalence and treatment of monocarboxylate transporter 8 (MCT8) mutations in a cohort of adult patients with mental retardation. Clin Endocrinol (Oxf), 2013; 78(2):310–315.

89.

Groeneweg

, van Geest

, Abaci

, et al. Disease characteristics of MCT8 deficiency: An international, retrospective, multicentre cohort study. Lancet Diabetes Endocrinol, 2020; 8(7):594–605; doi: 10.1016/S2213-8587(20)30153-4

90.

López-Espíndola

, García-Aldea

, Gómez de la Riva

, et al. Thyroid hormone availability in the human fetal brain: Novel entry pathways and role of radial glia. Brain Struct Funct, 2019; 224(6):2103–2119.

91.

Bernal

. Action of thyroid hormone in brain. J Endocrinol Invest, 2002; 25(3):268–288.

92.

Bernal

, Morte

, Diez

. Thyroid hormone regulators in human cerebral cortex development. J Endocrinol, 2022; 255(3):R27–R36.

93.

van Geest

, Groeneweg

, Visser

. Monocarboxylate transporter 8 deficiency: Update on clinical characteristics and treatment. Endocrine, 2021; 71(3):689–695; doi: 10.1007/s12020-020-02603-y

94.

Ferrara

, Meinig

, Placzek

, et al. Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration. Bioorg Med Chem, 2017; 25(10):2743–2753.

95.

Placzek

, Ferrara

, Hartley

, et al. Sobetirome prodrug esters with enhanced blood-brain barrier permeability. Bioorg Med Chem, 2016; 24(22):5842–5854.

96.

Meinig

, Ferrara

, Banerji

, et al. Targeting fatty-acid amide hydrolase with prodrugs for CNS-selective therapy. ACS Chem Neurosci, 2017; 8(11):2468–2476.

97.

, Xia

, He

, et al. The thyroid hormone analog GC-1 mitigates acute lung injury by inhibiting M1 macrophage polarization. Adv Sci (Weinh), 2024; 11(44):e2401931.

98.

, Tzouvelekis

, Wang

, et al. Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. Nat Med, 2018; 24(1):39–49.

99.

Zhou

, Waskowicz

, Lim

, et al. A liver-specific thyromimetic, VK2809, decreases hepatosteatosis in glycogen storage disease type Ia. Thyroid, 2019; 29(8):1158–1167.

100.

Bohlen

, Cleary

, Das

, et al. Promyelinating drugs promote functional recovery in an autism spectrum disorder mouse model of Pitt-Hopkins syndrome. Brain, 2023; 146(8):3331–3346.

101.

Chaudhary

, Marracci

, Calkins

, et al. Thyroid hormone and thyromimetics inhibit myelin and axonal degeneration and oligodendrocyte loss in EAE. J Neuroimmunol, 2021; 352:577468.

102.

Hartley

, Banerji

, Tagge

, et al. Myelin repair stimulated by CNS-selective thyroid hormone action. JCI Insight, 2019; 4(8):e126329.

103.

Meszaros

, Himmler

, Schneider

, et al. Sobetirome rescues alpha-synuclein-mediated demyelination in an in vitro model of multiple system atrophy. Eur J Neurosci, 2024; 59(2):308–315; doi: 10.1111/ejn.16215

104.

Genin

, Gondcaille

, Trompier

, et al. Induction of the adrenoleukodystrophy-related gene (ABCD2) by thyromimetics. J Steroid Biochem Mol Biol, 2009; 116(1–2):37–43.

105.

Hartley

, Kirkemo

, Banerji

, et al. A thyroid hormone-based strategy for correcting the biochemical abnormality in X-linked adrenoleukodystrophy. Endocrinology, 2017; 158(5):1328–1338.

106.

, Yao

, Zhao

, et al. Discovery of a highly selective and H435R-sensitive thyroid hormone receptor β agonist. J Med Chem, 2022; 65(10):7193–7211.

107.

Romartinez-Alonso

, Agostini

, Jones

, et al. Structure-guided approach to relieving transcriptional repression in resistance to thyroid hormone α. Mol Cell Biol, 2022; 42(2):e0036321.