The latest treatments in NASH
Recently, diabetes therapeutics called glitazones (pioglitazone in particular) have been the focus of several studies for NASH treatment and studies show that the use of glitazones can lead to improvements in steatosis, fibrosis and hepatocellular ballooning (damage to liver cells), but at the cost of significant weight gain1.
Current guidelines suggest that pioglitazone can be used for the treatment of steatohepatitis in patients with biopsy-proven NASH2. But pioglitazone and rosiglitazone, used in treating diabetes, have been withdrawn in France and Germany following evidence of increased risk of bladder cancer, cardiovascular events or hepatitis.
Other than glitazones, the most advanced new NASH treatments currently are a handful of drugs in phase III trials.
Obeticholic acid – the closest to approval
The closest to approval is a semi-synthetic bile acid analogue and selective farnesoid X receptor (FXR) agonist Ocaliva (obeticholic acid), from Intercept Pharmaceuticals partnered with Dainippon Sumitomo. This oral drug has anti-inflammatory, immunomodulatory and antifibrotic properties.
The pivotal Phase III REGENERATE study in patients with liver fibrosis due to NASH showed that 25mg Ocaliva taken once-daily met the primary endpoint of fibrosis improvement with no worsening of NASH at the planned 18-month interim analysis.
In the primary efficacy analysis, a numerically greater proportion of patients in both Ocaliva treatment arms vs placebo achieved the primary endpoint of NASH resolution with no worsening of liver fibrosis. Adverse events in the NASH trials are associated with pruritis (mostly mild to moderate) and an increase in LDL cholesterol. Based on these results, Intercept has filed in the US, with a PDUFA date extended to 26 June 2020. This was later also filed in the EU in December 2019.
In 2016 the FDA approved Ocaliva to treat the liver disease primary biliary cholangitis. In the post marketing setting, hepatic decompensation and failure have been reported in patients with advanced cirrhosis when Ocaliva was dosed more frequently than the recommended starting dosage. As a result, the Ocaliva label has been revised to include a boxed warning and a dosing table that reinforce the existing dosing schedule for such patients, who comprise two to three percent of the overall PBC population.
Elafibranor – resolving NASH without worsening fibrosis
GFT 505 (elafibranor), from Genfit, is an oral, dual PPAR agonist (alpha and delta). In the GOLDEN- 505 study, elafibranor failed to show an improvement in NASH, but Genfit argued that the Phase II study results should be measured against a revised definition of NASH resolution. A 2016 post-hoc analysis3 seems to support this view, showing that elafibranor can resolve NASH without the worsening of fibrosis, as well as reducing cardiometablic risks.
In 2019, the FDA Data Safety Monitoring Board issued a new positive recommendation for the continuation, without any modifications, of the RESOLVE-IT Phase III trial. Genfit is planning to unveil data from the RESOLVE-IT study in the first quarter of 2020. They anticipate filing an NDA with the FDA during the fourth quarter of 2020, with a European filing to follow within three to six months.
Saroglitazar – a repurposed diabetes drug
A different PPAR agonist that targets PPAR alpha and gamma, Lipaglyn (saroglitazar) from Zydus Cadila, is also in phase III trials. Zydus has initiated a 52-week Phase III EVIDENCES IV clinical trial in patients with biopsy proven NASH. A repurposed diabetes drug, saroglitazar has demonstrated good efficacy in animal models of NASH, along with associated biomarkers and has reduced hepatic steatosis, ballooning, inflammation and fibrosis in liver.
Recently completed phase II studies of saroglitazar in patients with biopsy proven NASH patients have shown improvement in liver enzymes along with favourable effects on lipid and glycemic indices. On the other hand, development of other drugs (ie aleglitazar, muraglitazar, tesaglitazar) in this class has been halted due to safety concerns. Nevertheless, Zydus filed an NDA with the Drug Controller General of India on 5 December 2019.
Cenicriviroc – blocking inflammatory and fibrogenic pathways
TAK 652 (cenicriviroc) from Allergan/Tobira Therapeutics and Takeda, is an oral immunomodulatory which blocks two chemokine receptors (CCR2 and CCR5) that play a role in the inflammatory and fibrogenic pathways in NASH. The drug has been granted FDA fast track status and is currently being evaluated in the phase IIb CENTAUR study. Cenicriviroc did not meet the primary endpoint of a mid-stage study testing it as a treatment for NASH though it did show some benefit for improving fibrosis. The design of the CENTAUR study put half of the participants on cenicriviroc and half on placebo. After one year, the experimental arm continued receiving the drug while the control arm split in two, with one piece switching to cenicriviroc. After a second year of treatment, 20% patients who switched experienced fibrosis reduction by at least one stage and no NASH worsening, whereas 13% of the patients remaining on placebo had similar outcomes. Global phase III trials are underway and results are due in 2020.
Aramchol – reducing liver fat
Also, in phase III is Aramchol, a conjugate of cholic acid and arachidic acid, a first in class member of a novel family of synthetic fatty-acid / bile-acid conjugates, from Galmed Pharmaceuticals. Aramchol affects liver fat metabolism and has been shown to significantly reduce liver fat content as well as improve metabolic parameters associated with fatty liver disease. In one-year results from the Phase IIb ARREST study, Aramchol showed liver fat reduction, biochemical improvement, NASH resolution and fibrosis reduction. In particular, compared to placebo, the Aramchol 600mg arm achieved the endpoint of NASH resolution without worsening of fibrosis. Galmed initiated a Phase III/IV study in September 2019 in obese patients with NASH to be completed in Q1 2021.
Resmetirom – reducing NASH
Recently started in phase III is Madrigal Pharma’s MGL 3196 (resmetirom), a liver-directed thyroid hormone receptor-beta agonist. In Phase II, 25% of all treated patients, and 37% of treated patients who were on adequate doses, achieved the Phase III NASH resolution endpoint: NASH resolution with at least a 2-point reduction in NASH and no fibrosis stage worsening. Both results demonstrated statistically significant differences relative to placebo. Madrigal has also initiated two Phase III studies, namely MAESTRO NASH, in patients with advanced liver fibrosis and MAESTRO NAFLD-1 with the primary endpoint of safety and reduction of cholesterol and liver fat. These trials will form the basis of a submission to the FDA for accelerated approval.
References
- Gastaldelli A, Cusi K. From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options. JHEP Reports. 2019;1(4):312–328.
- Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L. Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis. World Journal of Gastroenterology. 2018;24(30):3361–3373.
- Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology. 2016;150(5):1147-1159.e5.
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