By Vlad Ratziu (Institute for Cardiometabolsim and Nutrition, Assistance Publique Hôpitaux de Paris, Sorbonne Université, France) and Nicholas Di Prospero (Janssen Pharmaceutical Research and Development, NJ USA).
Nonalcoholic fatty liver disease is the most common chronic liver disease and steatohepatitis (a.k.a. nonalcoholic or metabolic steatohepatitis, NASH), its progressive form, is responsible for a growing number of cases of cirrhosis and liver cancer leading to an increasing need for liver transplantation. Yet, despite the high unmet medical need, there is no approved medications so far. This stands in contrast with a very active field of research in NASH and the identification of many promising new molecules targeting specific mechanisms of the disease.
Major roadblocks in NASH therapeutic trials
There are several obstacles that have considerably slowed down drug development in NASH even though, on the health care provider side, engagement in treatment trials is high as are the expectations for new therapies. A major one is that these trials rely on examining liver tissue under a microscope (i.e., histology) to determine if a person has significant disease to enroll in a trial and at the end of the trial to see if the drug treatment successfully treated the disease. Unfortunately, this requires that liver biopsies (which is an invasive and uncomfortable procedure) need to be performed in order to get liver tissue to examine. In addition, sometimes the liver tissue has subtle differences and the pathologists who look at the liver tissue may not always agree on whether a person has significant disease which increases considerably screen failure rates which ultimately limits trial participation when trials are performed separately and independently. Because the disease state can change over time, tissue from a biopsy is only valid for establishing a “baseline state” for inclusion for a short period of time (i.e., 6 months only) and screen failure in one trial often means no possibility to be screened for another independent trial, unless a new biopsy is performed, a medically unjustified repetition of this invasive exam.
There are several obstacles that have considerably slowed down drug development in NASH even though, on the health care provider side, engagement in treatment trials is high as are the expectations for new therapies.
Another obstacle is the absence of a quantitative and sensitive blood tests of treatment response means that trials continue to rely on liver biopsies and histology making the trials of considerable length and necessitate a very large number of participants. Because there is no approved standard of care, it is mandatory that a group of patients are randomized to receive a placebo (i.e., something that looks like the treatment but has no active compound in it) and patient retention in a placebo group over a year or more is problematic especially when some trials need to assess clinical outcomes (like prevention of cirrhosis or liver cancer) over several years. Thus, apart from being costly, trials, as currently conducted, are inefficient and very lengthy.
Advantages or platform trials for NASH over the current paradigm
Within the EU-PEARL consortium, the work package dedicated to NASH has identified major roadblocks and bottlenecks in the current landscape of therapeutic trials and has designed an Integrated Research Platform (IRP) or platform trial which can address many issues and simultaneously accommodate multiple interventions. Adapting a platform trial to the specifics of NASH trials requires considerable planning but offers several potential advantages over the current paradigm:
- A common and uniform screening process that will reduce screen failures by allowing simultaneous consideration for inclusion in multiple trials thus maximizing chances of eligibility upon a single screening process
- A shared placebo arm that will improve timelines of recruitment and incentivize patient participation by increasing the probability of allocation to an active treatment arm with fewer patients randomized to placebo
- The use of Bayesian methods for statistical analysis that allows for early termination of ineffective arms or graduation of more effective arms for overwhelming success which saves time and resources and further reduces the number of patients needed
- A shared infrastructure leading to operational efficiencies in study start-up and study conduct, such as the development of standardized tools which will remain stable throughout the study. This reduces costs and improves the reliability of the data generated.
We have so far designed, in collaboration with other work packages from EU-PEARL, a master protocol adapted to the specifics of NASH trials for a critical stage of development: Phase 2b. Phase 2b is the preferred design as it accommodates a robust pipeline of compounds with a variety of mechanisms and has the ability to help companies make critical decisions about whether to continue to longer, complex, pivotal studies.
We have so far designed a master protocol adapted to the specifics of NASH trials for a critical stage of development: Phase 2b.
The pros and cons of each particular design choice in the master protocol are being actively discussed in order to select the model of IRP along with the endpoints and schedule of activities that would benefit most to all stakeholders. Patients’ input has been sought in meetings set up with patient representatives and ethics committee input has been solicited. A meeting with relevant representatives from both FDA and EMA will be scheduled in the forthcoming months to ensure that the overall design is suitable to help successful drugs rapidly progress to Phase 3.
Read also this interview to find out more about the expected impact of EU-PEARL on NASH prevention, diagnose and treatment.