The US Food and Drug Administration (FDA) on Monday issued draft guidance on developing drugs to treat patients who have noncirrhotic nonalcoholic steatohepatitis (NASH) with liver fibrosis.
“Currently, there are no approved drugs for the treatment of NASH. Given the high prevalence of NASH, the associated morbidity, the growing burden of end-stage liver disease, and the limited availability of livers for organ transplantation, FDA believes that identifying therapies that will slow the progress or, halt, or reverse NASH and NAFLD will address an unmet medical need,” FDA writes.
However, FDA acknowledges that there are knowledge gaps that present challenges to developing drugs to treat NASH. One particular challenge is that there are currently no criteria for identifying which patients with nonalcoholic fatty liver (NAFL) will progress to NASH.
Because of this, FDA says that sponsors should focus on developing treatments noncirrhotic NASH with liver fibrosis until there are methods for identifying the subset of patients who are at risk of progression.
FDA also encourages sponsors to develop and validate biomarkers for diagnosing and grading NASH and liver fibrosis, as liver biopsy is currently the only reliable method for diagnosing the disease.
The guidance itself provides recommendations for preclinical and clinical development as well as trial design and endpoint selection to support approval of drugs to treat noncirrhotic NASH with liver fibrosis.
FDA notes that the guidance is not meant to cover the development of drugs to treat cirrhosis caused by NASH or the development of in vitro
diagnostics that may be used in developing drugs to treat the disease.
For Phase 3 studies, FDA says that sponsors should enroll patients with a histological diagnosis of NASH with liver fibrosis made within six months of enrollment, taking into consideration patients’ standard of care and background therapy for other chronic conditions. FDA also says that patients’ weight should be stable for three months prior to enrollment.
FDA also says that Phase 3 studies for NASH should be double-blind and placebo-controlled with the goal of slowing, halting or reversing disease progression and improving clinical outcomes.
“Because of the slow progression of NASH and the time required to conduct a trial that would evaluate clinical endpoints such as progression to cirrhosis or survival, the FDA recommends sponsors consider … liver histological improvements as endpoints reasonably likely to predict clinical benefit to support accelerated approval,” FDA writes.
Those endpoints include resolution of steatohepatitis on overall histopathological reading and no worsening of liver fibrosis on NASH Clinical Research Network (CRN) fibrosis score and/or improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis score) and no worsening of steatohepatitis.
For NASH treatments granted accelerated approval on the basis of liver histology, FDA says that randomized, double-blind, placebo-controlled trials to verify clinical benefits should be underway when the marketing application is submitted.
The guidance also provides some caveats for pediatric development, as “Pediatric NASH appears to have different histological characteristics as well as a different natural history when compared to adult NASH. For reasons that are currently unknown, disease characteristics and progression in pediatric patients may be different.”
As such, FDA says that extrapolation of efficacy from adults “is not appropriate at this time,” and that longitudinal natural history data for pediatric patients are needed.
FDA says it plans to further address issues related to pediatric noncirrhotic NASH in an upcoming guidance.
, Federal Register Notice