Aligos Therapeutics is heralding a midstage win in metabolic-dysfunction associated steatohepatitis (MASH) after three different doses of its drug candidate significantly slashed liver fat at 12 weeks. Despite the company's enthusiasm, the results failed to impress investors.
The oral asset, a thyroid hormone receptor beta agonist called ALG-055009, was evaluated among 102 patients with presumed MASH and stage 1 to 3 liver fibrosis. Top-line results from the phase 2a study, dubbed HERALD, were shared Sept. 19 before U.S. markets opened.
Since then, Aligos' stock has slipped about 20%, falling from $14.16 yesterday at close to $11.20 as of 12:15 p.m. ET Thursday.
Participants in the phase 2 MASH trial were randomized to one of four dosing arms (0.3, 0.5, 0.7 or 0.9 mg) or to receive placebo once daily for 12 weeks. Only patients weighing more than 85 kg (about 187 pounds) were enrolled in the 0.9-mg dosing cohort, with no other weight restrictions implemented on the other groups.
The dosing stratification was used to account for “the wide distribution of body weights among MASH patients,” Aligos President and CEO Lawrence Blatt, Ph.D., said on a Sept. 19 investor call.
ALG-055009 hit the study’s primary endpoint, which measured the percent of relative change from baseline in liver fat at Week 12 using a quantitative imaging biomarker scale known as the Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF), plus other noninvasive biomarkers or tests, according to Aligos.
The 0.5-mg, 0.7-mg and 0.9-mg trial groups all demonstrated statistically significant reductions in liver fat, with patients in the 0.7-mg cohort seeing the highest placebo-adjusted median relative reduction at 46.2%, Aligos said. Results seen in the lowest dose arm—0.3 mg—were not statistically significant.
MASH is a severe form of fatty liver disease that can lead to scarring, cancer or failure of the liver. Up to 70% of participants receiving ALG-055009 had a relative reduction in liver fat of 30% or more compared to baseline, according to Aligos.
“I would like to remind everyone that this data is only recently received,” Blatt said on the investor call. “To date, we have evaluated safety and primary efficacy data and a subset of the biomarker data through the treatment period of Week 12. We therefore feel confident reporting the top-line MRI-PDFF, certain biomarkers and the tolerability data today. In the coming weeks, we plan to evaluate additional biomarkers and follow up safety data.”
The asset was well tolerated with no serious adverse events or dose reductions reported, according to the California-based biotech. Most treatment-emergent adverse events were mild to moderate in severity, and patients receiving ALG-055009 had a similar incidence of gastrointestinal-related adverse events compared to placebo. The investigational treatment was actually tied to a lower incidence of diarrhea when compared to placebo.
ALG-055009 was also tied to significantly lowered levels of atherogenic lipids, such as LDL-C, lipoprotein (a) and apolipoprotein B, the biotech said.
In March, Madrigal Pharmaceuticals' resmetirom (brand name Rezdiffra) won accelerated FDA approval for patients with MASH and moderate or severe fibrosis based on a surrogate endpoint measuring the drug's effect on liver inflammation and scarring, also known as fibrosis.
While Aligos didn’t evaluate ALG-055009 in a head-to-head trial with resmetirom, Blatt said the data demonstrate a differentiated profile compared to Madrigal's approved drug.
“HERALD data demonstrated a higher placebo adjusted median liver fat reduction at week 12—46.2% for ALG-009 versus 26% placebo adjusted median relative fat reduction reported in the published literature pertaining to the MRI-PDFF Week 12 data for resmetirom,” Blatt said.
Another player in the space is Viking Therapeutics, which shared phase 2b data from its MASH candidate, also an agonist of the thyroid hormone beta receptor, last November. The asset was tied to a median relative reduction from baseline in liver fat up to 51.7%, as measured by MRI-PDFF and depending on dose level. Up to 85% of patients receiving treatment experienced at least a 30% relative reduction in liver fat content.
Aligos’ results have prompted the company to plot further clinical development, Blatt said, adding that the biotech plans to wrap up activities necessary to launch a phase 2b study by mid-2025.
The company is also in early talks with potential partners and evaluating several options to fund development, according to Blatt.
When asked on the Q&A portion of the investor call whether Aligos needed a partner to launch the phase 2b study, Blatt said it depended on the type of partnership offered.
“I always like to say, we're not going to give this drug away,” the CEO explained. “So, if partners [are] willing to financially reward the company for the value created, then we'll move forward to partner. If not, we'll find other means to finance the movement forward.”
MASH has historically been a tricky indication to crack, with numerous companies—Genfit, Novo Nordisk, Akero Therapeutics and Bristol Myers Squibb, to name a few—failing to get their therapies working both efficiently and safely enough in trials to warrant approvals. The chronic and progressive liver disease is expected to affect some 27 million Americans by 2030, a jump from 16.5 million in 2015.