00:00:00 Surf's Up, Season 6, Episode 6.

On April 23, 2024, our colleague and co-founder, Stephen Harrison, passed away suddenly. This week, Surfing the MASH Tsunami remembers Stephen with two of his closest associates and continues our annual MASH Drug Development roundtable held in his honor.

00:00:04:24 - A Deep Dive into Drug Development, Part 2

The second portion of the Drug Development roundtable primarily focuses on three key issues. The first, uptake of resmetirom, starts with Naim Alkhouri discussing his experience in the Arizona Liver Health Clinics with over 650 patients in the year since resmetirom was approved and shifts to the various European panelists (Jörn Schattenberg, Louise Campbell and Sven Francque) estimating when it might be approved in their countries and how widely it might be reimbursed. The second topic, incretin agonists, focuses on exciting prospects for other incretin agonists in development, as well as some semaglutide combination therapies. The third, NIT clinical trials, covers prospects that non-biopsy clinical trials might be approved sometime in the near future.

00:16:20 - Remembering Stephen Harrison I: An Interview with Summit Clinical Research CEO Gail Hinkson

Summit CEO Gail Hinkson joins Roger Green for the first time on SurfingMASH to discuss her business partner. Gail discusses how the two originally formed Pinnacle Clinical Research and how Pinnacle led to Summit. She proceeds to discuss the current size and reach of both Pinnacle and Summit. Focusing on Summit, Gail describes the company as an Integrated Research Organization (IRO), highlighting its distinct role within the MASH firmament. In the final section of the interview, Gail discusses how Stephen's personality, goals, and vision continue to live on at Summit today.

00:34:31 - Remembering Stephen Harrison II: An Interview with Naim Alkhouri Announcing That He Is Joining Summit

Newly announced Summit Chief Academic Officer Naim Alkhouri joins this episode for a second time, but in a very different role. Naim discusses his personal history with Stephen and what he loved and respected about his "dear friend." He then makes a major announcement: he is joining Summit as Chief Academic Officer. He shares the many elements of this role, particularly his excitement that Summit can become the entity that educates a wide range of healthcare and commercial professionals on what MASH is and how it is treated. The scope of this vision, combined with what Gail discussed, portrays a level of energy, ambition and vision worthy of Stephen Harrison.

00:55:55 - Conclusion

As part of this memorial week, Roger Green forgoes the usual business report, which will return next week.

This weekend’s Newsmaker, Indiana University hepatologist and key opinion leader Naga Chalasani, joins Roger Green to discuss Early Experience with Resmetirom To Treat Metabolic-Associated Steatohepatitis with Fibrosis in a Real-World Setting, an article his group published recently in Hepatology Communications. He shares highlights from the paper and points out the one key area in which his group found room for improvement in their initial protocol.

Naga and colleagues wrote this paper after learning from Madrigal Pharmaceuticals that they were among the largest early prescribers of resmetirom and, relative to others, had achieved reimbursement with virtually all their patients and a high percentage of patients actually starting the medication. After receiving requests from other states for advice, the group decided to author this paper.

In the paper, Naga and colleagues focused on patient selection, care pathway, how IUHealth got the medicine to their patients, and experience with safety and tolerability.

In the paper, Naga and colleagues discuss their experiences in prescribing resmetirom for 113 patients in the first seven months after resmetirom's approval. Of these, IUHealth succeeded in achieving reimbursement for 110 of them. Of these patients, 83 initiated therapy, and 16% of those discontinued.

In this interview, Naga shares some of the decisions that made the group so successful in the first three areas and identifies one subsequent area where the group found an opportunity for improvement: systematic follow-up with patients after prescribing. He attributes the 16% discontinuation rate to a "prescribe and forget" policy, similar to one that was successful in HCV, where clinicians prescribed without systematic follow-up until blood levels were obtained three months later. With a "prescribe and follow up" policy that includes phone calls at 1 and 3 months, he anticipates discontinuation rates will fall to something akin to the 5% rate in Phase 3 trials.

What makes this interview so fascinating is Naga's description of the thinking that went behind specific decisions the group made in terms of patient management and pathway and suggests other options that might work as well. In all, this interview provides an excellent guide for clinics and providers on how to best integrate resmetirom into their practices.

This week’s expert, Hepatologist and Key Opinion Leader Scott Friedman, joins Roger to discuss advances in acceptance of gene therapy and knowledge in other areas of basic liver science. When discussing science, he pays particular attention to findings on the diversity of stellate cells and his interest in CAR-T as a therapy for liver disease.

This conversation starts with Scott discussing gene therapy. Specifically, he applauds the idea that gene therapy is becoming accepted in many diseases after a faulty start years ago, due to an unfortunate patient death in a badly controlled trial. He comments that this acceptance has unique benefits in liver disease because the liver can regenerate so much faster and more efficiently than other organs. He mentions some of the rare liver diseases in which patients are benefiting from gene therapy, and notes that we now have gene therapies and early-stage trials to target PNPLA3 and other genes associated with MASH and MASH cirrhosis.

Next, Scott discusses stellate cells, which he has discussed in earlier episodes of SurfingMASH. Science is increasingly demonstrating how many different types of heterogeneous stellate cells exist. As Scott puts it, these cells "come in many flavors," each of which plays a different role in cell generation or cell death. In fact, the specific therapeutic challenges that present themselves may vary as a patient moves along the pathway from F1 to F2 to F3 to F4. Further, we are learning that there may be several different forms of MASH to present differently at a cellular level. This makes tremendous sense, given that no one drug has proven successful in even a significant majority of patients yet.

As the conversation winds down, Scott shares what he describes as a "sobering note" about the state of research funding in America in 2025. As he notes, there are certain kinds of applied and developmental research that private companies do well, but other kinds of basic research that only occur when funded in public and not-for-profit sectors. As a specific example, he cites CRISPR, initially funded publicly and now in the hands of biotech companies, which is used to treat a variety of diseases more effectively than they could have been treated before, if at all. He also comments that a poor early commercial decision slowed the development of statins.