Newsletter Fall 2018 - Brian E. Harvey, MD, Ph.D, A Perspective on the Development of the Treatment of Our Next Epidemic



Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world [1]. The phenotypes of the disease extend from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), the latter of which progresses to liver fibrosis and end-stage cirrhosis [2]. NASH is also associated with an increased risk of cardiovascular (CV) morbidity and mortality, as well as metabolic diseases such as Type 2 diabetes mellitus (T2D) [3]. Cirrhosis associated with NASH increases the risk of hepatocellular carcinoma. Currently, liver biopsy is the only generally acceptable method to diagnose NASH and to accurately assess progression to cirrhosis [4]. There are currently no FDA-approved treatments for NASH [5].


FDA Regulatory Environment

With nearly 100 companies interested in developing NASH treatments, the FDA is faced with not only the challenge of promoting the development of such treatments by providing advice to drug Sponsors, but also the challenge of protecting patients from committing to long-term clinical trials that could potentially treat NASH less effectively. 


Industry leaders in this field have provided the FDA with a robust package of studies on their products for NASH treatment. They have provided animal studies that support the mechanism of action of their products, as well as pre-clinical data that support first-in-human (FIH) studies, Phase 1 Single (SAD) and Multiple Ascending Dose (MAD) studies, Phase 2a Dose Ranging studies, and Phase 2b studies with NASH endpoints (e.g., liver biopsy and corresponding MRI-based measurements at either 24 or 36 weeks).


The FDA has advised Sponsors to submit certain data in order to allow their clinical trials to progress to Phase 3 and beyond. As one example, the FDA staff who have attended recent academic hepatology and liver-related meetings stated that compelling liver biopsy evidence of drug effect is necessary at the Phase 2b stage. Providing this evidence would allow clinical trials regulated under an Investigational New Drug (IND) Application [6] by the FDA to proceed to Phase 3. 


In addition, many Sponsors reported that the FDA GI Division has advised them to submit data from the “Full Chronic Toxicology Package under GLP” for review prior to enrolling patients into Phase 3.


The agency has also encouraged Sponsors to “roll over the Phase 2b patients into long-term extension trials” in order to increase the size of the Safety Database with an adequate number of patients exposed at 12 months, 24 months, and beyond.


Lastly, the FDA has asked NASH Sponsors with Phase 2 patient data containing both liver biopsy and corresponding MRI-based measurements to submit this data to the agency early. This early submission would allow for an informal validation “pilot” of the MRI-based NASH endpoints and the degree of correlation with liver biopsy across Sponsors. This agency analysis of pooled Sponsor Phase 2 data could potentially hasten the acceptance of MRI “biomarkers” and remove the requirement for liver-biopsy-based clinical trials for FDA drug approval.   


Despite these advisements from the FDA, there continues to be no official agency guidance document for NASH treatment development. However, the FDA has been active at conferences in providing detailed advice on designing clinical trials that would have an increased chance of generating data that would support agency approval of a drug or biologic product. For example, during the FDA presentation on NASH at a recent “Liver Forum,” a public/private/academic partnership formed to promote the exchange of ideas regarding clinical trials in liver disease [7], the FDA representative stated that the critical aspect of such a development program is the choice of endpoints for the proposed pivotal clinical trial. There are several potential pathways that can be used, which involve traditional clinical endpoints, intermediate clinical endpoints, and surrogate endpoints reasonably likely to predict clinical benefit in patients [8].

At this Liver Forum, FDA’s Dr. Dimick-Santos provided examples endpoints. Traditional clinical endpoints include a “reduction in all-cause mortality,” “prevention of liver transplantation” (e.g., model for end-stage liver disease [MELD] score increase from ≤12 [listing for liver transplant] to 15), and a “reduction of decompensation events” [9]. The FDA examples for potential surrogate endpoints for NASH are a “complete resolution of steatohepatitis,” “no worsening of liver fibrosis,” “at least 1 point improvement in fibrosis using the Brunt/Kleiner Scale” [10], and “no worsening of steatohepatitis, defined as no increase in ballooning or inflammation on NAS (NAFLD Activity Score) Score” [11]. A surrogate reasonably likely to predict clinical benefit could be used as the basis of an Accelerated Approval by the FDA. However, the Accelerated Approval must be followed by a Verification Trial with a traditional clinical endpoint. An alternative for verification is a “seamless” Phase 3/4 design where patients are rolled over at the end of Phase 3 into a Phase 4 verification trial. 


The FDA also advised Sponsors on whether to conduct one or two pivotal trials to support product approval. In order for one Phase 3 trial to be persuasive, the FDA Guidance “Providing Clinical Evidence and Effectiveness for Human Drug and Biologic Products” states that such a trial is “generally limited to situations in which a trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity, or prevention of a disease with potentially serious outcome and conformation of the results in a second trial would be practically or ethically impossible” [12]. Specifically, this should be a large, multicenter trial, with internal consistency across study site, evidence of an effect on multiple endpoints, and statistically persuasive efficacy results (i.e., a “robust p-value”).   


Alternatively, if a Sponsor plans for two seamless Phase 3/4 trials for the Accelerated Approval pathway, then the Sponsor must control the alpha (α) level to be ≤0.05 for each of the Phase 3/4 trials. For example, if α=0.01 for Phase 3 (using liver histology-based endpoints), then α must be <0.04 for Phase 4 (using traditional clinical endpoints). However, if the Sponsor plans only one seamless Phase 3/4 Trial to submit for FDA Approval, then the overall α must be <0.05 and split between Phase 3 (α << 0.05) and Phase 4 (α << 0.05) [13].  


Current examples of Sponsors conducting development programs for NASH treatments can be found on

·         REGENERATE (Intercept Pharmaceuticals)

·         RESOLVE-IT (Genfit)

·         Phase 2 Study of MGL-3196 in Patients with NASH (Madrigal Pharmaceuticals, Inc.)

·         STELLAR-3 (Gilead Sciences)

·         A Study of BMS-986036 in Subjects with NASH (Bristol-Myers Squibb)

·         AURORA (Tobira Therapeutics, Inc.)


Unanswered Questions, Potential Challenges, & Hope for the Future

Although there are significant resources focused on developing NASH treatments, unknowns regarding disease pathophysiology, long-term health benefits from improving short-term aspects of NASH, and the potentially negative impact of chronic use of these medications still remain. For example:

·         The natural history of NASH is unclear (e.g., percentage of progression to cirrhosis).

·         Mechanisms underlying NASH include the accumulation of fat in liver, inflammation, and progress to cirrhosis. How will regulators judge treatments if treatments target only one or two mechanisms, but not all aspects of disease?

·         Liver biopsy is currently the only generally acceptable method to diagnose NASH and to accurately assess progression to cirrhosis. Increased screening (e.g., FibroScan, MRI, biomarkers) for liver disease in populations at increased risk for NASH, such as those with T2D, obesity, hyperlipidemia, and abnormal Liver Function Tests (LFTs), could identify potential patients and refer them for liver biopsy. This could potentially increase the number of patients available for NASH trials.    

·         The FDA has expressed a willingness to consider the liver biopsy endpoint as part of an Accelerated Approval, which would then be verified with traditional clinical endpoints in a “Verification Trial” as part of a Phase 4 Post-Approval Commitment by the Sponsor.  Despite FDA approval for NASH treatments, will “Payers” wait until there is patient outcomes data from these confirmatory clinical trials before committing to reimbursement for these important medications, as they did and continue to do in some patients with Hepatitis C? 


Reports from the hepatology community note that as the number of hepatitis C patients who undergo liver transplant decreases, the percentage of NASH-related cirrhosis events leading to liver transplant continues to increase. The hope is with the identification of the significant public health impact of this disease, as well as focused efforts to find safe and effective treatments, overall healthcare costs can be reduced by reducing liver transplants, which could drive positive reimbursement decisions. The missing piece of this puzzle is a rational, integrated healthcare marketplace, where patient savings downstream can be shared with those who pay to treat disease at the earlier stages. Meanwhile, positive clinical trial results from a growing number of Sponsors continue to provide hope for the future.