Q&A: Phase 1b trial will assess oral-administered vascular adhesion protein-1 inhibitor for NASH
Terns Pharmaceuticals Inc. announced initiation of a phase 1b clinical trial assessing TERN-201 for the treatment of patients with nonalcoholic steatohepatitis.
According to a press release, TERN-201 is an orally administered inhibitor of vascular adhesion protein-1 (VAP-1). The AVIATION trial is a multi-center, randomized, double-blind, dose-ranging, placebo-controlled, phase 1b clinical study of the safety, pharmacokinetics, pharmacodynamics and efficacy of TERN-201 in patients with presumed non-cirrhotic NASH and a cT1 value of greater than 800ms. Researchers will compare the safety and tolerability of TERN-201 vs. placebo, each administered for 12 weeks. The first part of the trial has already begun with a 10-mg dose compared with placebo. Part 2 will include additional TERN-201 dose cohorts based on the interim evaluation of the 10-mg dose. The trial is to include about 20 patients assigned each dose of TERN-201 and about 10 patients assigned placebo.
Healio Gastroenterology spoke with Erin Quirk, MD, President, Chief Medical Officer and Head of Research and Development at Terns, about the AVIATION trial, its goals and the next steps in research.
Healio: Can you provide some background info?
Quirk: VAP-1 is a transmembrane protein expressed in endothelial cells and the inner surface of blood cells in multiple different organs. As the liver is damaged during the process of NASH, we know that VAP-1 becomes highly overexpressed in the blood vessels of the liver. That increased expression of VAP-1 leads to further inflammation and fibrosis in a few ways. First, VAP-1 serves as an attachment point for white blood cells and facilitates their deceleration, binding and transmigration from the blood into the liver. Therefore, VAP-1 plays an important role in getting white blood cells into the liver, which then can carry out the inflammatory cascade. So that's one way that VAP-1 overexpression leads to increased inflammation in the liver in the setting of NAFLD/NASH.
VAP-1 also has an enzymatic function; it's an amine oxidase and it converts primary amines in the blood into reactive oxygen species, specifically hydrogen peroxide and aldehyde. Those reactive oxygen species then cause further oxidative stress in the liver and contribute to worsening inflammatory pathways and the production of fibrosis. When TERN-201 binds to and then inhibits VAP-1, it stops the migration of white blood cells into the liver, which is an upstream way of reversing inflammation, if you think about it, stopping the migration of the very cells that cause inflammation into the liver. In addition, VAP-1 inhibition stops the production of this reactive oxygen species that leads to further stress and damage in the liver and the production of fibrosis.
Quirk: TERN-201 has been introduced into human studies in a phase 1 trial where we were able to show sustained VAP-1 inhibition, in the plasma, as well as good safety and tolerability in healthy volunteers. So, there is some level of VAP-1 expression in the blood. TERN-201 even at the lowest dose studied knocked down that enzymatic VAP-1 activity in the blood in healthy volunteers. Now, we know that NASH patients express more of VAP-1 than healthy people do, particularly in their livers. The purpose of the AVIATION trial is primarily to assess the safety and tolerability of TERN-201 in that patient population of interest.
Healio: What are the key goals of the study?
Quirk: The primary endpoint is safety and tolerability through 12 weeks of TERN-201 treatment. The study has a secondary endpoint assessing pharmacokinetics of the drug in patients with NASH, and importantly to test how much we can inhibit the enzymatic activity of VAP-1 in the blood with TERN-201 in this patient population, which should have more VAP-1 expression and activity than healthy volunteers. As a result, it might take a little bit more drug to have the same effect on NASH patients because there's more VAP-1 expressed compared to the healthy volunteers treated in the phase 1 trial. The study also has several exploratory and pharmacodynamic efficacy endpoints that we're looking at including blood and imaging markers of inflammation and fibrosis.
Healio: What is the study design?
Quirk: It's an adaptive design, that's one of the A's in AVIATION. The study is an acronym, AVIATION stands for Assessing VAP-1 Inhibition: Trial In Overweight NASH. Because VAP-1 expression can also be influenced by adipose tissue, we're including overweight and obese patients in the trial. We're trying to recruit a patient population that will skew higher in terms of their VAP-1 expression level. It's an adaptive trial because it's a two-part study. In the first part of the study, we're only looking at two arms. We anticipate having the results of part one in the first half of 2022. Based on what we observe, we’ll then move on to part two of the study, which will assess different dose ranges of TERN-201. We would expect having those results in the second half of 2022.
We are looking at imaging technique corrected T1 (cT1) parametric liver MRI scans, which is a marker of fibroinflammation. Based on results of our phase 2a LIFT study, we saw significant cT1 improvements in patients treated with our farnesoid X receptor (FXR) agonist TERN-101, also in development for the treatment of NASH. Similarly, we will be looking at markers of fibroinflammation in the AVIATION trial.
Healio: What will be the next steps after you get the results?
Quirk: Once we have the results of the AVIATION study, we would look to advance TERN-201 in combination with a metabolically active agent for NASH, something that we would expect to have a high impact on liver fat content.