NOT FOR HUMAN CONSUMPTION

Sobetirome is an oral, small-molecule TRβ-selective thyromimetic designed to deliver the lipid-lowering and hepatic/metabolic benefits of T3 while minimizing TRα-mediated cardiac and bone effects. By activating TRβ(highly expressed in liver and CNS oligodendrocyte lineage), sobetirome increases hepatic LDL-receptor expression, enhances reverse cholesterol transport, stimulates fatty-acid oxidation, and reprograms bile-acid and lipoprotein metabolism. It is investigational (not FDA/EMA-approved).

Additional Benefits of Sobetirome Now Under Investigation

2. Molecular Mechanism of Action

2.1 Receptor Pharmacodynamics

• Target: TRβ-selective agonism (liver-biased).

• Hepatic actions: ↑ LDLR, CYP7A1/bile-acid synthesis, β-oxidation genes; ↓ SREBP-1c lipogenesis → LDL-C/TG lowering and steatosis reduction.

• CNS actions (experimental): TRβ in OPCs/oligodendrocytes → myelin gene expression and maturation.

2.2 Down-stream Biology

3. Pharmacokinetics

• Route: Oral, once-daily in trials.

• Absorption: Rapid; food effect modest (not clinically central).

• Half-life: Multi-hour (supports QD dosing); hepatic distribution favored.

• Metabolism/clearance: Oxidative/phase-II metabolism; biliary/renal excretion of metabolites.

• Prodrug strategy: Sob-AM2 increases brain exposure for CNS targets while limiting systemic thyromimetic load.

4. Pre-clinical and Clinical Evidence

4.1 Dyslipidemia / Mixed hyperlipidemia

Phase 1/2 programs demonstrate clinically relevant LDL-C and TG reductions with favorable apoB/non-HDL changes and TSH suppression consistent with on-target thyroid signaling—without significant TRα-like tachycardia at therapeutic exposures.

4.2 NAFLD / MASH

Imaging/lab signals show hepatic-fat reduction and ALT/AST improvements, aligning with the hepatic TRβ mechanism. Histologic outcomes are being pursued in class programs (TRβ agonists).

4.3 CNS (ALD/MS translational)

Sobetirome and brain-targeted prodrugs reduce VLCFAs and improve remyelination indices in animals; early human translational efforts are underway (biomarkers, safety, and exposure).

Evidence quality note: Robust mechanistic and preclinical data; early-phase human trials show lipid/steatosis signals. Hard outcomes (CV events, MASH histology, neurologic disability) remain unproven.

5. Emerging Clinical Interests

6. Safety and Tolerability

• Class/on-target effects: TSH suppression, T3/T4 axis shifts (generally mild); heart-rate/palpitations uncommon at TRβ-selective exposures but possible with over-exposure.

• Common AEs: Headache, GI upset, mild insomnia, warmth/flush, transaminase drift (usually small).

• Cardiac/bone: Designed to spare TRα; nonetheless, monitor HR/BP and bone-turnover markers with prolonged use or high dose.

• Hepatic: Periodic ALT/AST monitoring—particularly in NAFLD/MASH.

• Endocrine: Avoid in untreated hyperthyroidism; use caution with amiodarone or iodine load.

• Pregnancy: Avoid (thyroid-axis manipulation).

• Drug interactions: Potential with warfarin (INR shifts), CYP inducers/inhibitors, and agents affecting thyroid binding/transport; separate from bile-acid sequestrants.

Comparative safety matrix (thyromimetics)

7. Regulatory Landscape

• Not approved for any indication.

• Being developed for dyslipidemia/NAFLD (adjunct to standard of care) and rare neurologic indications via CNS-targeted prodrugs.

• No sport relevance (not a performance drug), but off-label/compound use is not advised.

8. Future Directions

• Cardiometabolic outcomes: ApoB-anchored Phase 3 with MACE endpoints; combination strategies with statins, ezetimibe, PCSK9, ANGPTL3.

• MASH histology: Biopsy-based trials (NASH resolution, fibrosis endpoints) and MRI-PDFF/MRE composites.

• Dose-exposure models: Define TRβ selectivity windows that preserve axis efficacy with minimal TRα spillover.

• CNS programs: Optimize Sob-AM2 or next-gen brain-penetrant analogs; VLCFA, myelin imaging (MTR), and functional outcomes in ALD/AMN and MS.

• Safety registries: Long-term thyroid axis, cardiac rhythm, bone density, and hepatic surveillance.

Selected References

• Circulation; Atherosclerosis; Journal of Lipid Research — TRβ agonism, LDLR up-regulation, and lipoprotein remodeling with sobetirome-class agents.

• Hepatology; Liver International — TRβ-driven steatosis reduction and NAFLD biomarker changes.

• Journal of Clinical Endocrinology & Metabolism — Early human lipid/thyroid-axis data with sobetirome.

• Arteriosclerosis, Thrombosis, and Vascular Biology; Cardiovascular Research — Atheroprotection mechanisms (macrophage efflux, plaque biology).

• Brain; Annals of Neurology — TRβ in oligodendrocyte maturation and remyelination paradigms.

• Science Translational Medicine; Neurology — Sobetirome/Sob-AM2 lowering VLCFAs in ABCD1 models and translational steps for X-ALD/AMN.

• Cell Metabolism; Metabolism — Energy-expenditure and hepatic transcriptional programs under thyroid hormone mimetics.