-Olivia Stricker, PhD

Meetings are back baby!  This was the first event that I have been to since the pandemic where it felt 100% back to normal.  It was great to get back to it and have others there to get back to it with.

In heading to Nashville, DiaPharma/I was in search of answers to the following questions.  I can say I am satisfied with what I was able to take home as answers.


Q1:  We have been told for 10+ years that CK18 is a promising exploratory biomarker with better specificity and sensitivity than others.  We want to understand how and when CK18 is being used as a biomarker in drug safety protocols of the liver, preclinically and clinically.

A1:  It’s good news for CK18. While at this meeting, we heard favorable comments about its utility from a variety of large pharmas, as well as concrete examples of where and how CK18 is being used in several points of the drug development process.

The most insightful example of CK18’s utility came from Dominic Williams of AstraZeneca.  Dr. Williams gave a super engaging talk about the journey taken to explore the source of elevated ALT levels in 17 of 43 subjects in a Phase 2 trial.  Using DILISym and in vitro work, his team determined that an increase in bile acids, due to a decrease in transporter expression, was driving apoptosis of hepatocytes.  This apoptosis was measured in clinical samples using VLVbio’s M30 Apoptosense® ELISA.  This finding supported the in vitro investigation for mechanism of toxicity and allowed the clinical trial to move forward.  In the next phase of the trial, M30® measurements will be included in the trial protocol to explore high ALT signals.


Q2:  Complex in vitro platforms (organoids, spheroids, organ-on- a-chip) have been around for a while.  InSphero, Emulate, CN Bio, etc. have been part of every liver-specific meeting I have been to since starting my role at DiaPharma, 4 years ago.  How fast are these platforms being adopted and what endpoints are rising to the top?  Can CK18 be used as a biomarker within these systems to provide better mechanistic insight as a DILI predictor?  Is there interest in CK18 as a translational marker?

A2:  Most important thing first…. I now know these platforms are called Microphysiological Systems (MPSs).  While there was a public focus on expanding this market (highlighted by the FDA’s Modernization Act), behind the scenes and over drinks it was indicated that animal models are going nowhere fast. It’s clear there is a public facing push to reduce animal use, but there’s also a tremendous amount of value per animal in the ability to have organ systems connected, as well as, to dose over longer periods of time.

That being said, the growth in the MPS space from last year to this year is undeniable.  It felt like there was twice as many MPS companies at the expo hall this year.  I really need to count to see if that is real.  There was also a ton of talks about the systems and data being shared.  MPSs have even sprouted new technology companies focused on QC, monitoring spheroids and organoids for automation, and developing higher-throughput workflows.

Icing on the cake, I saw a BMS poster with CN Bio chips that used CK18 (M65 Epideath® ELISA) as a biomarker.  CK18 was 3rd on the list, but the author pointed out that at lower drug concentrations it could have performed even better.  The drug concentrations used for the poster were hammer strength.  The author also indicated that caspase-cleaved CK18 (M30 Apoptosense® ELISA) had been successfully used with spheroids in their lab.  Success!  I now have examples that CK18 was successfully used in these systems and that there were enough cells on these platforms to give detectable signals for the CK18 kits.  Also, sensitive readouts might be more useful at lower drug concentrations, so no need to sledgehammer.


Q3:  I have seen several gene therapy talks about how frequently high ALT is seen in subjects yet have not seen any drug safety talks about AAV vectors.  I got the impression that the ALT increases with gene therapy are not of concern. What research groups, if any, are interested in doing studies related to liver safety with these populations?  Are gene therapies reserved for those with healthy livers?

A3:  I asked this question in several sessions and the overall vibe was that in the current cases the benefit outweighs the risk.  It was also indicated that known elevations in ALT were not sustained or above a threshold that triggers Hy’s law.  Therefore, from a drug safety perspective, AAV vector-induced liver toxicity might not be a super concern for this group.


Q4:  DiaPharma is in southwest Ohio, downstream of East Palestine and the train disaster.  What is the level of concern regarding the chemicals (vinyl chloride) in the area and in our water source?
    I only had one conversation about this with Environmental Working Group (EWG).  EWG is a non-profit that measures pollutants in drinking water. They ask the question, “what does safe really mean?”.  The EWG representative told me that following the train derailment, 17 contaminants were measured in the water in East Palestine, Ohio and was deemed fine. He said “clearly, it’s not ‘fine’”.  Then gave me a hug.  It was nice.  I wasn’t that worried before, but I am now.

It will be exciting to continue this conversation at SOT 2024, in Salt Lake City.

Next up, the 2023 American Thoracic Society meeting in DC.  All things sputum, neutrophils and NETosis.  Come find me at the DiaPharma booth.


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