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New 12-week data shows an investigative oral drug provided significant benefit in key outcomes associated with NASH disease relief.
An orally-administered investigative drug provided significant fat reduction over a 12-week span in treated patients with non-alcoholic steatohepatitis (NASH), according to new phase 2a data.1
Terns Pharmacueticals announced in a press release Wednesday findings indicating that the company’s TERN-501, a thyroid hormone receptor-beta (THR-β) agonist under development for the treatment of NASH, achieved its primary and secondary endpoints in the DUET clinical trial. Chief among the outcomes was a mean liver fat content reduction of 45% among treated patients with NASH at 12 weeks, versus only 4% reduction in patients receiving placebo.
The findings indicate a potential pathway toward TERN-501 being considered as the first drug approved by the US Food and Drug Administration (FDA) for the treatment of NASH, a chronic liver disease estimated to impact 1 in 20 people globally.
The DUET trial, a randomized, double-blind, placebo-controlled assessment into the efficacy and safety of TERN-501 for the treatment of noncirrhotic NASH as both a monotherapy and in combination with the company’s liver-distributed farnesoid X receptor (FXR) agonist, TERN-101. The trial included 160 adults with eligibility criteria including body mass index (BMI) ≥25 kg/m2 and pre-cirrhotic NASH per liver biopsy and/or imaging and clinical criteria. Additional criteria included a liver fat content per ≥10% magnetic resonance imaging proton density fat fraction (MRI-PDFF).
Investigators sought a primary endpoint of relative change in MRI-PDFF from baseline to week 12 for TERN-501 monotherapy versus placebo; secondary endpoints included relative change in MRI-PDFF from baseline to 12 for TERN-501 plus TERN-101 versus placebo.
Dose ranges included TERN-501 1 mg (n = 23), 3 mg (n = 19), 6 mg (n = 22), and placebo (n = 21). Approximately two-thirds (64%) of patients receiving TERN-501 reported MRI-PDFF response. The team reported a liver fat reduction per MRI-PDFF of 45% in the 6 mg arm at week 12, versus 4% among the placebo arm (P <.001).
Each of the 3 TERN-501 monotherapy doses were associated with significantly greater proportions of patients achieving ≥30% MRI-PDFF reduction versus placebo at 12 weeks. Such levels of liver fat reduction were associated with improvements in NASH severity based on liver biopsies, investigators noted.
What’s more, investigators reported significant benefit with TERN-501 for an MRI marker of liver fibro-inflammation correlated with liver disease clinical outcomes; the clinical benefit of TERN-501 was additionally “modestly improved” in combination with 10 mg TERN-101 per ≥30% MRI-PDFF responder rates versus monotherapy TERN-501 at week 12.
As previously covered on HCPLive, pharmaceutical prospects for NASH or non-alcoholic fatty liver disease (NAFLD) have been limited in an era of emerging novel, targeted therapy options in hepatology. Arun Jesudian, MD, a transplant hepatologist NewYork-Presbyterian Hospital/Weill Cornell Medical College, previously explained that the mechanism and characteristics of disease are well understood; the issue lies in identifying the right potential agent.
“I think the easy answer is that NAFLD and Nash is a complicated disease to treat medically,” Jesudian told HCPLive. “Clearly, we know fat leads to inflammation and fibrosis and scarring in the liver. But how to address that in terms of medications is a complicated undertaking.”2
Principal DUET investigator Mazen Noureddin, MD, MHSc, professor of clinical medicine at the Academic Institute of Houston Methodist and director of the Houston Research Institute, said in the Terns statement that THR-β is representative of a key target for the treatment of NASH, “as it is the only class of treatment to have demonstrated both resolution of steatohepatitis and improvement in fibrosis in a registrational NASH study.”
“TERN-501's impressive efficacy within a short duration and excellent safety profile is compelling especially with its once-daily, oral dosing as well as its cardiovascular and GI safety profile, the latter of which has adversely affected other NASH modalities in development,” Noureddin said. “These results add to the growing body of evidence of the safety and efficacy profile of TERN-501 and its promise as a therapy to treat the multiple facets of this disease.”