Key physicochemical and pharmacological characteristics of resmetirom and semaglutide relevant to MASH therapy.
| Parameter | Resmetirom (MGL-3196) | Semaglutide |
|---|---|---|
| Drug class/primary target | Selective THR-β agonist | Long-acting GLP-1 receptor agonist |
| CAS number | 920509-32-6 | 910463-68-2 |
| Molecular formula | C17H12Cl2N6O4 | C187H291N45O59 |
| Molecular weight | 600.45 g·mol–1 | 4,113.58 g·mol–1 |
| 2-D structure | See Figure 1 | See Figure 2 |
| Physical appearance | White to off-white crystalline powder | White lyophilised powder (pen) or tablets (with SNAC) |
| Aqueous solubility (25°C) | < 0.1 mg·mL–1 (practically insoluble) | Highly soluble ≥ 1 mg·mL–1, pH ≈ 7.4 |
| Solubility in DMSO/buffers | DMSO ≈ 45 mg·mL–1 EtOH ≈ 2 mg·mL–1 | Fully soluble in isotonic aqueous buffers |
| LogP (cLogP)* | ≈ 4.8 | n/a (large peptide) |
| pKa (dominant) | 4.7 (carboxylic acid) | Multiple; isoelectric point ≈ 4.8 |
| Formulation in trials | Immediate-release oral tablets 40/80/100 mg | Prefilled s.c. pens 0.25–2.4 mg; oral 3/7/14 mg (SNAC-enhanced) |
| Typical MASH study dose | 80–100 mg orally once daily | 0.4 mg s.c. daily (phase II); 2.4 mg s.c. weekly in obesity |
| Oral bioavailability | ≈ 30% | ≈ 1% (oral); s.c. ≈ 89% |
| Plasma protein binding | > 99% | > 99% |
| Elimination half-life | ≈ 35 h | ≈ 160 h (≈ 7 days) |
| Main metabolism/clearance | Hepatic oxidation & conjugation; biliary/fecal excretion | Proteolysis followed by β-oxidation; renal (54%) peptide fragments |
| Principal route(s) of administration | Oral | s.c.; oral (with SNAC) |
| Key therapeutic signals in MASH | ↓ MRI-PDFF, ↑ MASH resolution (≈ 30%), early fibrosis improvement | MASH resolution up to 59%, ≥ 13% weight loss, fibrosis signal weight-dependent |
| Most frequent adverse events | Mild pruritus, transient GI discomfort, reversible ↓ TSH | Nausea, vomiting, diarrhoea, gall-bladder events, and rare pancreatitis |
| Development status (mid-2024) | Licensed for use in non-cirrhotic MASH in March 2024 in the USA | Phase III ESSENCE-NASH ongoing; already marketed for T2DM & obesity |
| Representative trade names approved by the FDA | Rezdiffra (tablets) | Rybelsus (tablets), Ozempic (injection), Wegovy (injection) |
| Storage | 2–8°C, protected from moisture/light | 2–8°C (pens); room temperature ≤ 30°C for ≤ 56 days (in-use pens) |
| Mechanism of action | Hepatic | Systemic |
| Direct improvement of insulin resistance | No | Yes |
| Extra-hepatic benefits | Improves atherogenic dyslipidemia by strong LDL-C & ApoB lowering | Glycaemic & cardio-nephro-metabolic benefits |
ApoB: apolipoprotein B; EtOH: ethanol; FDA: Food and Drug Administration; GI: gastrointestinal; GLP-1: glucagon-like peptide-1; LDL-C: low-density lipoprotein cholesterol; MASH: metabolic dysfunction-associated steatohepatitis; MRI-PDFF: magnetic resonance imaging-proton density fat fraction; NASH: nonalcoholic steatohepatitis; s.c.: subcutaneous; SNAC: sodium N-[8-(2-hydroxybenzoyl)amino] caprylate; T2DM: type 2 diabetes mellitus; THR-β: thyroid hormone receptor-β; TSH: thyroid-stimulating hormone. * LogP (cLogP) refers to the logarithm of the octanol-water partition coefficient, a measure of the fat-solubility of a drug.