Terns Pharmaceuticals touts safety data from an ex-Eli Lilly candidate in the hunt for NASH treatment
While many others have tried — and failed — to get a NASH candidate across the finish line, Terns Pharmaceuticals thinks its FXR agonist will eventually earn its wings without the safety issues that have slowed others down. Now, a mid-stage safety readout could help add some validity to those hopes.
No patients in the Phase IIa LIFT study discontinued TERN-101 due to side effects, CMO Erin Quirk said during a call with investors on Monday morning. That includes pruritus, an uncomfortable itching sensation that frequently leads patients to drop out of other FXR agonist studies.
“This is the first of several important milestones that provide validation for Terns’ pipeline over the next 12 months or so,” CEO Senthil Sundaram said.
NASH, or nonalcoholic steatohepatitis, refers to fat buildup in the liver that causes inflammation and scarring. TERN-101 targets FXR, a nuclear receptor in the liver, intestine and kidneys that regulates the hepatic expression of various genes involved in lipid metabolism, inflammation and fibrosis.
Eleven out of the 74 patients treated with TERN-101 came down with pruritus, including four in the highest dose group, Terns said. Patients received one of three doses — 5 mg, 10 mg or 15 mg — over 12 weeks. There were no treatment-related serious adverse events, as two cases of Covid-19 and a UTI that sent patients to the hospital were not linked to the candidate.
“TERN-101 is more highly liver-distributed than other FXR agonists that have been studied in NASH patients,” Quirk said during the call, adding that data suggest the candidate primarily activates FXR in the liver, rather than the intestine or other organs. “We believe that TERN-101’s differentiated safety and tolerability profile and improved target engagement, relative to other FXR agonists, is because of its activity in the liver.”
Other NASH candidates have run into trouble with raised LDL cholesterol, which in turn can raise cardiovascular risk. No change in LDL cholesterol was reported in the first two dose groups, but a statistically significant change (15.9%) was seen in the 15 mg group.
Researchers also noted improvements in a biomarker known as corrected T1 (cT1) relaxation time, an MRI-based test measuring free-water content in liver tissue. Improvements of at least 80 milliseconds were seen in a significant proportion of patients in the 5 mg and 10 mg groups at Week 12 compared to placebo, and significant decreases in cT1 were reported at Week 6 for all dose groups, according to Terns.
“LIFT is the first controlled NASH trial to show significant cT1 improvement as early as Week 6,” Quirk said.
Mean relative changes in MRI proton density fat fraction (MRI-PDFF), an imaging marker that measures liver fat content, were -8.4% in the placebo arm, -15.1% in the 5 mg arm, -19.7% in the 10 mg arm, and -12.9% in the 15 mg arm at Week 12. While the relative changes were significant at Week 6 for the 10 and 15 mg groups compared to placebo, they weren’t statistically significant at Week 12, Terns said.
Mean changes in alanine transaminase levels (ALT), which can indicate a liver problem, were -5.3% (placebo), -2.6% (5 mg), -18% (10 mg), and -13.2% (15 mg).
Terns $TERN stock was up 9% upon sharing the news early Monday morning, then slipped 4% about an hour later.
Terns bagged the rights to TERN-101 back in 2018, along with two other NASH candidates from Eli Lilly. Its TERN501, a thyroid hormone receptor beta agonist, is currently in Phase I, and a combination trial of the two is expected to kick off in the first half of next year.
While 2019 was initially dubbed “The Year of NASH” by Goldman Sachs, the year quickly turned into the year of NASH failures, the most notable among them Gilead’s. CymaBay went from a $1 billion company to a $100 million company after they found their drug appeared to be making patients worse. Cirius withdrew an $86 million IPO bid after a bad readout.
The bad luck continued into 2020, as Intercept, which pulled ahead with positive Phase III results, wound up with a rejection for their long-watched NASH drug last June. And after failing a Phase III showdown, Genfit exited NASH altogether and made plans to lay off 40% of its workforce back in October.
AbbVie currently has a Phase I FXR agonist for NASH, which it inherited in the Allergan buyout.
At first, the idea behind Terns — named after the small, tough water bird — was to partner a California-based discovery team with a small development group in China to efficiently develop new drugs primarily for the Chinese market. But back in January, a spokesperson for the company told Endpoints News that the company has since shifted to focus more on building a headquarters and development team in California.
While Terns continues to “have an eye on additional global markets,” their current focus is on the US, where clinical trials for their three lead programs will occur, the spokesperson said.