Over the horizon: early stage trials for NASH
Another dozen or so drugs are in early stage trials. Most notably, VBL Therapeutics is currently testing lecinoxoids VB 201 and VB 703, antagonists for Toll-like receptors 2 and 4 (TLR-2 and TLR-4), which play a role in nonalcoholic fatty liver disease. In an exploratory trial, VB 201 demonstrated significant reduction of vascular inflammation, suggesting that lecinoxoids can restrict liver inflammation and ameliorate liver fibrosis. VBL Therapeutics has also developed related compounds which could offer greater efficacy than VB 201: VB 703 has demonstrated promising preclinical results in NASH and renal fibrosis models.
Combination drug treatments
However, combinations drug treatments are likely to offer some of the most promising results: for instance, a mouse model study combining elafibranor with obeticholic acid showed that the combination exerted additive effects on metabolic and histological endpoints, and led to profound transcriptome changes associated with further improvements in lipid handling and insulin signaling, suppression of immune responses and reduced extracellular matrix formation1.
In 2018, Novartis announced a clinical agreement with Pfizer which will include a study combining tropifexor and one or more Pfizer compounds for the treatment of NASH, including an Acetyl CoA-Carboxylase Inhibitor (PF-05221304, a Diacylglycerol O-Acyltransferase 2 (DGAT2) Inhibitor (PF-06865571, and a Ketohexokinase (KHK) Inhibitor (PF-06835919). Tropifexor is an FXR agonist and in FLIGHT-FXR study in NASH patient’s results showed improvements in biomarkers of NASH. The trial will complete in April 2020.
Gilead Sciences also has a large, seven-group, placebo-controlled, parallel group phase II trial (ATLAS; NCT03449446) underway using various combinations of its three drugs; selonsertib (which failed to reduce fibrosis in NASH patients in STELLAR 3 and STELLAR 4 trials), GS 0976 and GS 9674. As indicated above, results so far are “mixed”.
Merck Inc. was a late comer to the NASH scene and recently licensed NGM 313 from NGM Biotherapeutics which successfully completed a proof of concept trial in NAFLD and is to be advanced into NASH in a Phase IIb trial. Dong-A has launched its DPP-4 Type 2 diabetes drug Suganon (evogliptin) in the Republic of Korea and has signed a deal with Allergan/Tobira to test its drug in combination with cenicriviroc in phase III trials.
Advances in NASH detection
Finally, detecting the disease is also a key challenge. NASH is asymptomatic and can remain undetected until the disease has progressed. Blood tests may not always spot signs of the disease, and for now the only means of proving a firm diagnosis of NASH is a liver biopsy, yet only a small percentage of patients undergo this procedure. It is uncomfortable, expensive and potentially risky with a limited number of specialists able to perform it. However new tests for the disease are in development. These include a biomarker test from Genfit and the BreathID diagnostic test from Exalenz BioScience which are both in late stage trials.
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References
- Roth JD, Veidal SS, Fensholdt LKD, Rigbolt KTG, Papazyan R, Nielsen JC, et al. Combined obeticholic acid and elafibranor treatment promotes additive liver histological improvements in a diet-induced ob/ob mouse model of biopsy-confirmed NASH. Sci Rep. 2019;9(1):9046.
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