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Sobetirome(GC-1) 100x100mcg
  • Sobetirome(GC-1) 100x100mcg
  • Sobetirome(GC-1) 100x100mcg
Sobetirome(GC-1) 100x100mcg

Sobetirome(GC-1) 100x100mcg

€120,00 EUR
Taxes included.

                                             NOT FOR HUMAN CONSUMPTION

Sobetirome is the first‐in-class orally active thyroid-hormone-receptor-β (THR-β) selective agonist discovered at the University of California San Francisco and originally licensed to QuatRx Pharmaceuticals. It has been evaluated for dyslipidaemia, non-alcoholic steatohepatitis / metabolic-dysfunction-associated steatohepatitis (NASH/MASH), demyelinating disorders and X-linked adrenoleukodystrophy (X-ALD). Direct development of the parent drug beyond early-phase trials has stalled, but two derivative programmes remain active:

  • VK2809 – a liver-targeted cleavable pro-drug (under Viking Therapeutics) now entering phase 3 for MASH.

  • Sob-AM2 – a CNS-penetrant amide pro-drug under academic development for X-ALD and MCT8-deficiency syndromes.

2 | Medicinal chemistry and physicochemical properties

Feature Parent sobetirome VK2809 (PCP-sulphate pro-drug) Sob-AM2 (CNS pro-drug)
Core scaffold 3,5-dimethyl-4-(4´-hydroxy-3´-isopropyl-benzyl)-phenoxy-acetic acid Phosphonate ester masked with 2-vinylphenyl group (requires CYP3A4) N-methyl-acetamide masking the carboxylate
Selectivity (β : α) ~22 : 1 retained after hepatic activation retained
cLogP 4.4 5.1 (pro-drug) 4.8
Purpose of pro-drug – restrict activation to hepatocytes, minimise systemic exposure enhance blood–brain-barrier penetration

Sobetirome’s two iodine atoms of endogenous triiodothyronine (T3) are replaced by isosteric methyl groups, eliminating de-iodinase activation and lowering α-receptor affinity.

3 | Mechanistic pharmacology

Selective THR-β agonism reproduces the beneficial hepatic actions of T3 while sparing heart, bone and muscle (THR-α–rich). Key downstream effects:

  • ↑ LDL-receptor transcription → accelerated LDL-C clearance.

  • ↑ Fatty-acid oxidation genes (CPT-1α, PPARα targets) → reduced hepatic steatosis.

  • ↑ Bile-acid synthesis (CYP7A1) → enhanced cholesterol disposal.

  • In the CNS, THR-β activation promotes oligodendrocyte maturation and remyelination.

4 | Pharmacokinetics and pharmacodynamics

Parameter (parent) Typical value Note
Oral bioavailability ≈ 75 % rapid absorption, food-independent
T½ (plasma) 5–7 h terminal phase
Hepatic AUC / systemic AUC 3–4 : 1 favourable liver targeting
VK2809 T½ 22 h (pro-drug) once-daily dosing; active moiety identical to sobetirome
Sob-AM2 brain : plasma ratio ×3 parent sustained CNS exposure

5 | Clinical development and efficacy

5.1 Dyslipidaemia (parent molecule)

A randomised phase 1 multiple-dose study (100 µg daily, 14 days, n = 24) reduced LDL-C by 41 % versus 5 % for placebo without tachycardia or thyrotoxic symptoms. Further advancement paused when eprotirome, a class peer, revealed cartilage toxicity in dogs; no such signal was observed for sobetirome itself.

5.2 MASH / NASH (VK2809)

  • VOYAGE phase 2b (n = 337; 52 weeks, doses 1–10 mg):

    • ≥30 % MRI-PDFF liver-fat reduction in up to 88 % of patients.

    • MASH resolution without fibrosis worsening in 63–75 % (placebo = 29 %).

    • ≥1-stage fibrosis improvement in 44–57 %.

    • Safety: largely grade 1–2 GI events; no increase in heart-rate, bone or thyroid adverse signals.
      Phase 3 design (initiation 2H 2025) will compare once-daily 5 mg and 10 mg VK2809 against placebo in 2 000 biopsy-confirmed MASH patients (F2–F3).

5.3 Central nervous system indications

  • Multiple sclerosis: Sobetirome accelerated remyelination and restored motor performance in three murine demyelination models. Combination with clemastine showed additive benefit.

  • X-ALD / MCT8 deficiency: In Abcd1–/– mice, Sob-AM2 lowered very-long-chain fatty acids (VLCFAs) in brain and spinal cord by ≥40 % and improved gait metrics; parent sobetirome achieved ~20 % reduction.ScienceDirectOxford Academic First-in-human pilot studies were cancelled because of sponsor changes, but an NIH-funded translational programme is advancing intranasal Sob-AM2 for paediatric CALD (expected IND 2026).OHSU NowAmerican Chemical Society Publications

6 | Safety and tolerability profile

Across >600 human exposures to sobetirome or VK2809:

  • Cardiovascular: ≤4 bpm resting-heart-rate increase; no QTc prolongation.

  • Thyroid axis: Dose-dependent suppression of TSH and modest fall in free T4; clinical hyperthyroidism not observed.

  • Bone/ cartilage: No density loss in 12-month rat studies; long-term human monitoring ongoing.

  • Liver enzymes: Mild, transient ALT/AST elevation in <5 %.

  • Other: GI discomfort (nausea, diarrhoea) in 8–15 %, generally grade 1.NATAPPubMedScienceDirect

7 | Competitive landscape of THR-β agonists (2025)

Agent Development stage Key efficacy (MRI-PDFF) Histology benefit Regulatory status
Resmetirom Phase 3 complete −49 % (100 mg, 12 wk) 25 % fibrosis-1 improvement (52 wk) FDA accelerated approval 03-2024
VK2809 Phase 3 starting −56 % (10 mg QOD, 12 wk) 44–57 % fibrosis-1 improvement (52 wk) Fast Track; no BLA yet
TERN-501 Phase 2a −41 % NA Ongoing
Eprotirome Discontinued – – Off-market (toxicity)

8 | Unresolved questions and research priorities

  1. Long-term skeletal safety with chronic THR-β activation.

  2. Optimal CNS delivery — can Sob-AM2 achieve sustained brain exposure without systemic thyrotoxicity?

  3. Combination therapy — synergy with GLP-1 analogues or ACC inhibitors for MASH.

  4. Biomarkers — standardised serum and imaging markers to titrate dose while avoiding subclinical thyrotoxicity.

  5. Paediatric development — dosing paradigms for growing skeleton and brain.