NASH Pathway to Approval – Light at the End of the Tunnel
Not long ago, there was very little regulatory guidance or recommendations regarding a pathway for nonalcoholic steatohepatitis (NASH) drug approval. NASH is a chronic hepatic disease that can lead to cirrhosis, liver failure and need for transplant, and currently there is no FDA-approved treatment for NASH, creating a large unmet need for patients. On the bright side, there is a bountiful pipeline of drugs in development for this disease. Many investigational products are being developed under an accelerated process that uses surrogate endpoints such as tissue biopsy results for initial approval followed by clinical outcome measures for full approval. However, it was not until recently that the acceptable endpoint definitions and consensus on patient I/E criteria were described. Academic and industry led partnerships have spearheaded discussion forums for all stakeholders to advance the regulatory science of NASH. To this end, hepatic focused research societies such as the Liver Forum, AASLD and EASL have developed a set of study design considerations for NASH trials. In addition, both the FDA and EMA released draft guidance documents within the past year, providing a clear pathway to approval.
The Liver Forum helped define key terminology for NASH clinical trial endpoints such as NASH resolution. While previous Phase IIb trials may have used more lenient criteria, it is now widely accepted that NASH resolution is defined as a histological ballooning injury store of 0, inflammation score of 0-1 and steatosis score of 0-3 according the NAFLD Activity Score (NAS). More recently, meeting proceedings from a joint AASLD/EASL Workshop addressed standards for reporting results from NAFLD clinical trials. They suggest reporting absolute change in primary and secondary endpoints rather than percent change only as well as absolute number and proportion of patients that improved, remained stable, or worsened on treatment and placebo. Another key recommendation is to report the performance of noninvasive imaging and soluble biomarkers in relation to histological biopsy results. This information is needed to eventually replace the liver biopsy with a simpler, noninvasive measurement.
Regulatory Authority Recommendations
The FDA released two sets of draft guidance for NASH drug development, distinguishing between non-cirrhotic (fibrosis stages 1-3) and cirrhotic (stage 4) disease states. Recommended early phase endpoints for non-cirrhotic NASH include imaging changes in AST and ALT, imaging measures of liver stiffness or hepatic fat content or disease-specific biomarkers such as de novo lipogenesis fractional rates. Participant inclusion criteria for these early studies can be based on histological diagnosis of NASH or a combination of biochemical criteria and/or imaging evidence of steatosis in addition to known risk factors for NASH. For late phase studies, clinical endpoints include NASH resolution with no worsening of fibrosis and/or ≥1 stage improvement in the fibrosis stage with no worsening of NASH for pre-cirrhotic NASH indication. Cirrhotic NASH endpoints for Phase III studies are ≥1 stage improvement in the fibrosis stage with no worsening of NASH, rates of hepatic decompensation events and MELD progression. Hard endpoints are captured as all-cause mortality, liver transplant and hospitalization rates.
In late 2018, the EMA issued considerations for drugs to treat NASH in a reflection paper. In contrast to the FDA guidance, the European authority takes a more judicious view by recommending co-primary endpoints of both NASH resolution and fibrosis improvement for anti-inflammatory drugs; and 2-stage improvement in fibrosis for anti-fibrotic therapies.
Hurdles to Overcome
There are still many challenges to face for NASH drug development. High screen failure rates of 40-60% are not uncommon for clinical trials with biopsy requirements. Steps to mitigate screen fails include robust patient pre-screening with non-invasive techniques such as FibroScan or opting for imaging-based inclusion criteria over biopsy-proven NASH (for Phase IIa studies).
Another issue to contend with is the large placebo response for histological endpoints. A meta-analysis by Han et al. found that one quarter of patients given placebo had an improvement in NAS by ≥2 points, and improvements in fibrosis scores of approximately 20%. Spontaneous disease regression can contribute to the observed placebo response. External influencing factors may include diet, exercise, and modest amounts of alcohol consumption during the trial. A lead-in period prior to the baseline biopsy may minimize the placebo effect. Meanwhile, 2-stage fibrosis improvement would drastically reduce the placebo response and could be considered as a secondary endpoint to negate false negative studies.
While the liver biopsy remains the reference standard for disease diagnosis, the ultimate goal is to have a noninvasive soluble biomarker to stage the disease, akin to HbA1c for diabetes and cholesterol for cardiovascular disease. Biomarkers of inflammatory cytokines, apoptosis (cytokeratin 18) and fibrotic factors show promise, however more validation is required.
The Road Ahead
Despite these challenges, there is a light at the end of the tunnel! Clarification of agency expectations and unified definitions has certainly helped to foster the influx of NASH drugs in development. However, the true test will come from a review of upcoming new drug applications. The first approval for a NASH treatment is anticipated by the end of the year, with more to follow suit in 2020.