Thursday, June 9, marks #NASHDay 2022, the 5th annual celebration of International NASH Day by the world’s largest liver patient advocacy organization, the Global Liver Institute. With over 200 affiliated organizations and sponsors, many holding their own events, International NASH Day is not only a major day for education and communication, but also in a sense NASH’s “New Year’s Day,” a moment to take stock of the last year and make resolutions for the future.
To celebrate the occasion, Surfing NASH’s esteemed co-founder and frequent panelist Stephen Harrison joined co-hosts Jörn Schattenberg, Louise Campbell and Roger Green to celebrate the event and ponder a seemingly simple question: what one crucial thing — trend, event, insight — most signifies what the last year has meant in we sometimes call “NASH-Ville?”
Stephen went first. His primary focus was on a substantial change in strategy in the design of Phase 3 trials. Previously, the corporate sponsor would conduct a single, large Phase 3 trial with F2 and F3 NASH patients. The initial phase of the trial would include 1,000 – 1,200 patients with the goal of achieving sub-part H approval based on conditional endpoints. This trial would keep enrolling patients until there were enough patients in the trial for 4-7 years to prove an outcome-based endpoint and achieve full approval. In the new design, two trials transpire in parallel: the original trial with F2 and F3 patients and a trial with well-compensated cirrhotic patients focused solely on achieving an outcome. This design has a number of benefits: ease of recruitment, lower cost, and the ability to achieve outcome-based endpoints in cirrhotic patients more quickly. Most strikingly, it leads to a change in endpoint strategy so that the sponsor can evaluate distinct “co-endpoints,” as Stephen puts it, instead of needing to achieve dual endpoints. This way, the sponsor can succeed by achieving fibrosis improvement with only a stable NAS score or a decline in NAS score with no worsening of cirrhosis. It is an attractive approach and one that is ready to launch with the support of regulators, sponsors and researchers alike. All three panelists expressed admiration and appreciation for the benefits of this approach. When Roger described it as akin to a “tapestry” woven from many visions for improving clinical trial design, Stephen noted how many people needed to collaborate for this to come to fruition. He made his next point, that the Fatty Liver community is coming together by engaging Delphi processes, sharing data and generally being open to solving our most pressing challenges collaboratively. Stephen ends his section of the meeting by noting the excellent chance we may see a drug approved in 2023 and, if we do, the energy and momentum that will bring to education, patient outreach, guidelines and pathways, and further drug and diagnostic development.
Jörn went next. He focused on the extraordinary breadth of pivotal conferences during the year, many with their own key moments. He cited NASH-TAG, where regulators joined in the “fireside chats” to reconsider drug approval criteria, and the recent Barcelona meeting, which pulled together the range of stakeholders to ask how we will serve patients best after we have a drug. This led Roger to note the breadth of groups lining up behind this issue, including not only the typical Fatty Liver stakeholders but also medical societies, like AGA and American Heart, that play at most a limited role in primary treatment of Fatty Liver disease.
Louise focused on advances in diagnostics and discussions, thinking not only about better devices or tests but about discussions on how best to use non-invasive methods to screen, diagnose and stage patients. What she found striking is that these discussions are taking place before drugs are approved, which suggests the possibility that shorter after we have drugs to prescribe, we will have systems and protocols to get the drugs to the patients that need them most. Louise contrasted thought development in NASH to Hep C, where the drugs came along before we knew how to find the patients. Jörn commented that Louise’s Hep C experience gave her a unique perspective on this set of issues. Louise noted that many people who were involved in the fight against Hep C were now bringing there experiences to Fatty Liver.
Rounding out the group, Roger talks about the Law of Unintended Consequences and the Intercept Complete Response Letter from FDA. He recalled the initial thoughts that the failure to approve obeticholic acid would signal a perilous downturn in interest in Fatty Liver disease. Instead, he suggested, the passion of the community coupled with lack of funds led stakeholders to ask better questions and focus on more practical issues, which has led to the convergence we are seeing today.
In the end, Stephen noted that the stakeholder champions — and particularly the providers — will not tolerate “No” for an answer. Jörn expanded on this determination by stating, “this disease is not going away,” and recalling patients who suffered from HCC and died too young. The commitment to these patients drives the providers’ determination that Jörn and Stephen described.
In the end, Roger asked the group to make a bold prediction about what will happen next year, when the group gets together on the eve of International NASH Day once again to survey the past year. The predictions were bold and boldly optimistic, but you will need to listen to or view the episode to learn what they were.