As an attendee at the recent Global Nonalcoholic Steatohepatitis (NASH) Congress in London, England, I was among a good mix of academics and industry. Much of the conference focused on noninvasive bio-markers, genetics, nutrition, compounds and clinical trials. Unfortunately for me, there was little focus on imaging. One of the most interesting presentations discussed the differences in the stances between the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
For the most part, they are relatively aligned in their expectations for NASH clinical trials. For example, neither require histology for a Phase IIa study, but both require histology for Phase IIb/III studies. The primary endpoints that both agencies will consider for registration trials are resolution of NASH with no worsening of fibrosis and improvement in fibrosis with no worsening of NASH. A couple of the differences to highlight are:
- The EMA expects patients to have at least one attempt at weight loss.
- The EMA expects the two endpoints to be co-primary endpoints, while the FDA will accept them as alternative endpoints.
Many of the presenters referenced the 2015 “Cuba study” (Vilar-Gomez et al. 2015) which demonstrated that weight loss can have a fairly sizable effect on NASH. The study demonstrated that a greater than 5% weight loss led to improved steatosis, while a 7-10% reduction produced a reduction in hepatitis, and a >10% reduction in weight produced resolution of nonalcoholic fatty liver disease (NAFLD) activity score (NAS) 90% of the time along with a regression in fibrosis 45% of the time.
The results from Madrigal Pharmaceuticals’ phase 2 trial of MGL-3196 were presented, where biopsies and proton density fat-fraction (PDFF) were collected at screening and week 36. There was a reduction of at least 30% in MRI-PDFF in 77% of patients at week 36. In the 36-week open label extension study, 87% of patients saw ≥ 30% reduction in MRI-PDFF. And, relating back to the previous discussion on weight loss, 47% of patients, who had less than 5% weight loss, showed a 2-point reduction in the NAS, which measures steatosis, inflammation, and cellular ballooning.
The 30% reduction in MRI-PDFF as an endpoint comes from a 2017 publication out of UCSD where they performed a secondary analysis of the MOZART trial data (Lin et al. 2017). It was found that of the 35 patients who had a paired liver biopsy and MRI-PDFF assessment, 10 showed histological improvement. Those that improved histologically had a mean reduction in MRI-PDFF of 29.3% compared with a gain of 2.0% in the non-responders. Therefore, it is believed that a reduction in MRI-PDFF of at least 30% should be linked to histological improvement.
Finally, a significant number of presentations at this conference focused on mechanisms of action. That is, there are many different pathways for the liver to form lipids, with multiple steps in the creation of those lipids. In addition to pathways to generate lipids, there are other pathways that may lead to inflammation or fibrosis. By altering those pathways, it is possible to change the course of fatty liver disease. That is the general goal for all of the compounds in development. By activating or inhibiting different cell receptors, certain pathways can be enhanced or inhibited. Since there are so many different pathways that all lead to NASH, the question arose as to whether NASH is really a single disease or whether it has many different etiologies.
If there are different causes of the disease, then it is possible that the best treatment may be a combination of different compounds. Novartis presented plans to study their FXR agonist, Tropifexor, in combination with other Novartis compounds, along with compounds from Allergan, Conatus, and Pfizer. All of these compounds have different mechanisms of action, so potentially hitting multiple pathways could lead to a better outcome. Pre-clinical results presented confirmed this hypothesis. Clinical studies are in early stages and should provide interesting results.
Although the conference did not have a large imaging component, it was still very informative and provided the opportunity to meet and converse with a dynamic group of industry and academia representatives. I look forward to the next NASH conference in April 2019- the NASH Summit in Boston.
Lin, S. C., E. Heba, R. Bettencourt, G. Y. Lin, M. A. Valasek, O. Lunde, G. Hamilton, C. B. Sirlin and R. Loomba (2017). "Assessment of treatment response in non-alcoholic steatohepatitis using advanced magnetic resonance imaging." Aliment Pharmacol Ther 45(6): 844-854.
Vilar-Gomez, E., Y. Martinez-Perez, L. Calzadilla-Bertot, A. Torres-Gonzalez, B. Gra-Oramas, L. Gonzalez-Fabian, S. L. Friedman, M. Diago and M. Romero-Gomez (2015). "Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis." Gastroenterology 149(2): 367-378.e365.