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S3-E19 – What Can NAIL-NIT Retrospective Analysis Tell Us About NASH?

NAIL-NIT co-leads Stephen Harrison and Mazen Noureddin and retrospective analysis co-leads Naim Alkhouri and Jörn Schattenberg join Louise and Roger to discuss designs and plans for NAIL-NIT retrospective analysis.

The content focus of this 2nd Anniversary episode is to look at what the retrospective analysis from the NAIL-NIT consortium can achieve in terms of moving the shift beyond the biopsy in NASH diagnostics forward. The other focus was to announce that Jörn Schattenberg will become our weekly Key Opinion Leader starting with this episode, while other commitments will force Stephen Harrison to reduce his participation to approximately 50% of episodes.

The first part of the discussion focuses on Stephen’s role in the podcast, including his feelings about its formation and what it has accomplished to date, plus comments from all the other panelists about Stephen’s role in the podcast and, in some cases, their professional lives. The last part of this section was what MiC Wilson, SurfingNASH’s audio engineer par excellence, dubbed “The Stephen Harrison Drinking Game.” In this game, panelists each provided one phrase they associated with Stephen. If you are reading this before you listen, take a minute to write down the one “Harrisonism” that comes to mind for you. (Because this is a NAFLD podcast, the drink for the game is black coffee, hot or iced. Depending on how you take your coffee, you can add a non-dairy milk and/or a low glycemic index sweetener.)

After the game ends, the group shifts to discussing NAIL-NIT. Stephen begins by discussing the motivation behind the effort – a chance to “break down stovepipes” (a Harrisonism that didn’t make the Drinking Game list!) to create a multi-study data set that can be commonly analyzed to address some of the biggest issues around NITs that we face today. As Stephen describes it, “We want to find the right tests for the right situation at the right time to answer the right question whether that’s diagnosis, whether that’s monitoring for therapeutic efficacy or it’s prognosis.”

He goes on to discuss a two-step process. Step 1 is the analysis of retrospective data from completed and existing clinical trials, which should provide guidance on the best way to construct a prospective study that can “nail” the right NIT for each situation within the next 5-6 years.

Mazen discusses the patient perspective: what happens for the patient (and physician) who clearly has NASH (maybe even F3) but cannot get into a trial because the biopsy does not reveal presence of ballooning. He started discussing this with Stephen one day at a conference, and that discussion led over time to the NAIL-NIT initiative. Mazen goes on to note the valuable work that LITMUS, NIMBLE and the Goldmine project at UCSD have done, but feels that this is the time – and NAIL-NIT is the project – to pull all this together into a focused, eventually conclusive effort. When Mazen finishes, Naim and Jörn discuss their excitement about the overall project and its goals.

Mazen shifts the tone of the conversation by asking Naim and Jörn to describe their “passionate first project.” Naim answers by focusing on the thresholds that correspond to histological response for the different NITs. Jörn focuses on questions of effect size, particularly as it relates to differences in placebo response across the different trials.

Naim then goes on to quote Nassim Taleb, developer of the Black Swan theory and author of the recent book, “Skin in the Game.” In this book, Taleb discusses ideas he describes as “IYI”, intellectual yet idiot. Naim provides examples of IYI concepts in NASH drug development and treatment. His first example is the situation where an F3 patient cannot be enrolled in a trial due to lack of balloon hepatocytes. As Naim notes, F3 is “aggressive disease” and he asks, “what else do you need to know?” A second situation is where a 0 score on ballooning is required to describe a patient’s NASH as having reached resolution. Roger goes on to recall recent discussions (S3 E14, for example) that focused on how semi-quantitative rules developed for single patient assessments became the core of quantitative analyses, for which they were ill-suited.

Mazen goes on to note that in a future of 10-15 Phase 3 trials, we will never be able to complete the number of trials we will need with the sample sizes they will require if we are tethered to biopsy and ballooning. Step[hen harkens back to Roger’s comment to describe the path by which we got here, quoting the English author Rupert Sheldrake on the concept of “morphic resonance” in the context of NASH diagnosis: you can know something is NASH even if the specific metrics do not prove it. (You might have to listen to the episode to understand.)

After Jörn discusses the project’s ability to shape the prospective trial, Louise asks whether the group plans to analyze presenting symptoms. She points out that a goal of research should be to develop a questionnaire a primary care physician can administer to the patient that will point those at higher risk toward additional evaluation.

From there, the discussion focuses on other implications of the trial on drug development and patient diagnosis and care. There is not enough room to describe all of it. Listen on to learn why a 5-year timeline to get the answer both makes sense and might be imperative.

Make sure to allow the energy and “get it done” (another Harrisonism) tone of the conversation to sink in…

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