Coming Soon: NASH Treatment Approaching the Horizon
Nonalcoholic steatohepatitis is an increasingly common cause of cirrhosis, hepatocellular carcinoma and liver-related mortality. Along its progression, severe nonalcoholic steatohepatitis includes the development of clinically significant or advanced fibrosis. Currently, there are no approved therapeutics to treat this disease, but that will be changing soon.
Physicians can look forward to a very exciting future when it comes to NASH therapy. There are a number of cutting-edge options in mid-to-late stage development for NASH and NASH with fibrosis. Additionally, our understanding of the pathogenesis of the disease and our ability to detect disease activity through noninvasive testing are advancing incrementally at a rapid pace.
Our understanding of the pathogenesis of the disease is that it is multifactorial. There are multiple and duplicative pathways that lead to the classic liver biopsy findings of NASH and our understanding of the natural history of NASH is also continuing to evolve. We understand now that it does not always progress in a steady manner. There are periods of quiescence and even improvement in the disease, and then periods when it’s more rapidly progressive.
Regarding therapies currently in clinical trials, it is important to understand that there are two primary endpoints for a viable treatment. Phase 3 trials require a histological endpoint of either NASH resolution without fibrosis progression or improvement in fibrosis without worsening of NASH. We will likely have the first FDA approved therapy for NASH with fibrosis in the first quarter of 2020 based on the reports from the REGENERATE trial of Ocaliva, but there are many other exciting candidates to follow.
Intercept – Ocaliva (Obeticholic Acid)
Investigators of the REGENERATE trial have enrolled more than 2,000 patients with biopsy-proven NASH with fibrosis. At 18 months, 23.1% of patients who received 25 mg of obeticholic acid daily demonstrated an improvement of fibrosis by one stage or more with no worsening of NASH compared with 11.9% in the placebo control group (P = .0002). Additionally, a numerically greater proportion of treated patients achieved NASH resolution with no fibrosis progression.
Genfit – Elafibranor
The RESOLVE-IT trial began in the first quarter of 2016 and comprised patients with NASH and fibrosis stage 2 or stage 3. An interim analysis of the first 1,000 enrolled patients is planned after 72 weeks of daily treatment with elafibranor 120 mg or placebo. In the previous phase 2b trial, treated patients experienced improvement in circulating markers of liver dysfunction such as alanine aminotransferase, gamma-glutamyl transferase and alkaline phosphatase.
Madrigal Pharmaceuticals – MGL-3196
Based on treatment activity and a favorable safety profile, investigators have begun enrollment for a phase 3 trial of MGL-3196 in patients with NASH along with a phase 3 clinical program in a broader segment of patients with dyslipidemia including patients with earlier stages of fatty liver disease. Results from the phase 2 clinical trial revealed significant reduction of liver fat on magnetic resonance imaging-estimated proton density fat fraction at 12 weeks of treatment, which was sustained through 36 weeks compared with placebo (37% vs. 8.9%; P < .0001).
Allergan – Cenicriviroc
Enrollment for a phase 3 trial of cenicriviroc is ongoing since completion of its phase 2 CENTAUR study in June 2017. In the phase 2 trial, patients in the placebo group who switched to treatment demonstrated fibrosis improvement without worsening of NASH compared with placebo (24% vs. 17%), and those who remained in the treatment group from baseline demonstrated a greater improvement in stage 1 or better fibrosis reduction compared with those who received placebo for 2 years (39% vs. 29%).
As these newer therapies reach FDA approval and approval in other countries, safe and easy noninvasive tests will be as important for diagnosis as for follow-up. One of the things we want to be able to tell is if the patient is responding to therapy, so we know whether to keep them on therapy or if it is safe to stop therapy.
When it comes to the diagnosis of NASH, physicians have both wet or blood biomarkers as well as radiographic biomarkers to use. Our development of noninvasive tests is in the context of distinguishing NASH from NAFLD, which is vital because there are about 100 million Americans with fatty liver but only about 20-30 million Americans with NASH. These tests provide the potential to find that one in four patients with fatty liver who is at risk for disease progression.
The first thing that frontline doctors who are seeing these patients need to realize is that patients can have moderate to severe liver disease and be completely asymptomatic and they can also have normal to near-normal liver enzymes. What they need to keep in mind is that there are risk factors for people that have fatty liver that are likely to progress. The top risk factor is metabolic syndrome. Looking at ethnicity, individuals of Hispanic descent have a genetic predisposition. Identifying high-risk factors in patients provides the “low-hanging fruit” to catch liver disease and slow if not reverse its progression.
Disclosures: Harrison reports he has received grants or research support from Allergan, Conatus, Cymabay, Galectin, Galmed, Genfit, Gilead, Immuron, Intercept, Madrigal and TaiwanJ; is on speakers bureau for AbbVie and Alexion; and is a consulting advisor for Allergan, Chronic Liver Disease Foundation, Cirius, CiVi, Cymabay, Echosens, Genfit, Gilead, Hightide, Innovate, Intercept, IQVIA, Madrigal, Medpace, Novartis, Novo Nordisk, Perspectum, Pfizer, Pippin and PPD.