Cascade submitted the IND application for a THR-β agonist, CS060304, as a treatment for NASH. The US FDA approved the application in February 2024. This is the second drug candidate for NASH patients, following the first clinical-stage FXR agonist, CS0159.
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| FDA letter |
CS060304
The CS060304 target is the same as MGL-3196, a novel THR-β agonist developed by Cascade, with highly specific enrichment in liver tissue. Compared to Resmetirom, CS060304 demonstrates significantly positive preclinical data, particularly in improving NAS scores and fibrosis in NASH mouse models. It exhibits characteristics of low effective dosage, significant efficacy, and good tolerability. Its clinical trial approval is expected to provide NASH patients with a safe and effective potential treatment option, making it a potential best-in-class potent selective THR-β agonist.
The clinical trial in China will begin at the Peking Union Medical College Hospital led by Professor Zhang Shuyang.
From 2021, Cascade has filed several patents (CN115650928/CN117624069/CN116836158/CN113979963/CN116063296) covering the polycyclic THR-β agonists for NASH, dyslipidemia, atherosclerosis, or hypothyroidism. The compounds were tested to determine their selective activities for THR-α and THR-β. The animal study, was reported in the patent document as follows:
| Description in the 2022 patent |
| Description in the 2021 patent |
THR-β Agonist
Resmetirom was approved as the first THR-β agonist in 2024 by the US FDA for NASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). In 2008, Madrigal predecessor company VIA Pharmaceuticals enters into a development agreement with Hoffmann-La Roche for resmetirom. Under the Roche Agreement, Roche exclusively licensed certain patent rights and know-how relating to MGL-3196 in exchange for consideration consisting of an upfront payment, milestone payments, the remainder of which total $10 million and are tied to future commencement of Phase 3 clinical trials and regulatory approval in the United States and Europe of MGL-3196 or any derivative product, and single-digit royalty payments based on net sales of MGL-3196 and any derivative products, subject to certain reductions.There are currently several THR-β agonists being evaluated in preclinical and early-stage clinical trials in China.
Ascletis Pharma is developing two drug candidates that target the THR-β receptor. The candidates are named ASC41 (THR-β, phase 2) and ASC43F (THR-β/FXR, Fixed-Dose-Combination of ASC41 and ASC42, phase 1). In Jan 2024, Ascletis reported the results of the phase 2 study of ASC41 in patients with NASH. In 233k 12, liver fat content was reduced by 70.1% in 4 mg treated patients (n=15) and 48.8% in 2 mg treated patients (n=13), as compared with 5.8% median reduction in 14 placebo treated patients. These results were statistically significant (p<0.0001) for both ASC41 treatment groups.
ECC4703, discovered by Ecoogen, is currently in the phase 1 trial. In 2022, Eccogen reported the results of the preclinical study on the ILC 2022. In vitro EC50, maximum effect and relative selectivity of ECC4703 were measured for THR-β and THR-α against Resmetirom.ECC4703 displayed an EC50 of 3.9 nM with an Emax of 92% for THR-β and an EC50 of 110 nM with an Emax of 88% for THR-α. At this time, there have been no reports on the results of the phase 1 study.
In March 2023, Kylonova Biopharma, a company of Hegia Biomedicine, announced the completion of the phase 1 clinical study of Kylo-0603, a THR-β agonist.
Hinova Pharma is currently in the preclinical stage with their THR-β agonist, which is identified by the plate number HP515.
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