ASC-43F

As drugmakers edge closer towards the first FDA approval in non-alcoholic steatohepatitis (NASH), Ascletis Pharma's Gannex unit on Tuesday unveiled an interim Phase II readout that CEO Jinzi Wu said positions its ASC41 as a potential best-in-class THRB agonist. The once-daily oral treatment - currently at the centre of a trade-secret dispute with Viking Therapeutics - led to statistically significant reductions in fat content in patients with biopsy-confirmed NASH.The interim analysis is based on data from 42 patients who completed 12 weeks of treatment. ASC41 was associated with up to a 68.2% mean relative reduction in liver fat content, based on MRI-PDFF, with just over 93% of patients across the two treatment cohorts achieving ≥30% relative improvement. Ascletis notes that this level of reduction, particularly for the THRβ agonist class, is associated with higher likelihood of histologic improvement in NASH. The trial, conducted in China, is targeting about 180 patients overall, randomised to one of two oral doses of ASC41 (2mg or 4mg) or placebo.Key biomarker dataThe company also reported significant and clinical meaningful reductions in ALT and AST liver injury markers, results that "notably differentiate ASC41 from other THRβ agonists currently at clinical or registration stages." Compared to placebo, ASC41 was associated with average reductions of up to 37.8% in ALT and 41.5% in AST at the 12-week mark, versus placebo. The drug also improved the hepatic lipid profile, lowering LDL cholesterol, total cholesterol and triglycerides by up to 23.4%, 20% and 42.6%, respectively. There was a significant placebo-adjusted mean reduction in lipoprotein (a) as well in patients receiving ASC41.Two patients given ASC41 experienced drug-related Grade 2 treatment-emergent adverse events (TEAEs), while one dropped out of the study due to one Grade 1 drug-related TEAE. Otherwise, no serious side effects were reported, with ASC41 demonstrating "excellent gastrointestinal tolerability," the company said.Upcoming Madrigal decision While Ascletis thinks Tuesday's data may position its THRB agonist as best-in-class, it's not likely to be first-in-class. Madrigal Pharmaceuticals has been ramping up preparations for the launch of its once-daily, oral THR-β agonist resmetirom, which the FDA is expected to decide on by March 14 – without plans to convene an advisory panel first. While analysts estimate that resmetirom could generate anywhere from $3 billion to over $5 billion at its peak, investors are likely to remain wary until the drug officially obtains FDA approval given repeated setbacks with other NASH hopefuls in the past.The resmetirom application is based in part on the Phase III MAESTRO-NASH results, where the 100mg dose significantly improved liver fibrosis in 26% of patients versus 14% for placebo, and achieved NASH resolution in 30% of patients versus 10% for placebo. One key opinion leader (KOL) interviewed by FirstWord last year put the odds of US approval of resmetirom at about 90% based on the MAESTRO-NASH data.Trade squabbleMeanwhile, Viking filed a pair of complaints about a year ago in the US, claiming that ASC41 and another Ascletis NASH candidate – ASC43F, which targets THRβ and farnesoid X receptor –  were based on stolen trade secrets revolving around its own THRβ drug, VK2809. Mid-stage data from the VOYAGER study showed that VK2809 met the primary endpoint by significantly reducing liver fat content by up to 52% after 12 weeks. One KOL told FirstWord last year that the VOYAGER data made him optimistic about THRβ agonism as a mechanism for addressing early NASH patients.Ascletis, which argues ASC41 was developed using its in-house formulation technology, has said Viking's allegations have no merit and that it plans to defend itself against the complaints.