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About liver disease

Nitazoxanide in fibrosis

We are also conducting a clinical-stage program based on drug repurposing to develop an anti-fibrotic drug candidate, with a priority given to liver fibrosis. Our lead drug candidate in this program, nitazoxanide, or NTZ, is an approved anti-parasitic agent that has shown promising activity against fibrosis in preclinical disease models. We are currently evaluating NTZ in an investigator-initiated Phase 2 proof-of-concept clinical trial for the treatment of NASH-induced significant or severe fibrosis.

NTZ phase 2 trial in NASH-induced fibrosis

In December 2018 we announced the launch of an investigator-initiated Phase 2 proof-of-concept clinical trial repurposing nitazoxanide, or NTZ, an approved drug currently commercialized as an anti-parasitic, for the treatment of significant to severe fibrosis in NASH patients. The primary objective of the study is to evaluate the safety and tolerability of NTZ in patients with NASH-induced fibrosis. Secondary objectives include evaluating the anti-fibrotic effect of NTZ by several approaches, including a method to quantify hepatic fibrogenesis flux rates.

As part of our pre-clinical program, we studied the effects of the administration of NTZ in both disease models and human fibroblasts1 from different organs. In April 2017, we presented at the EASL International Liver Congress (ILC), the results of this research supporting the potential efficacy of NTZ in two disease models. In these in-vivo models, we observed that administration of NTZ significantly attenuated liver fibrosis development.

If the Phase 2 trial demonstrates anti-fibrotic activity in these patients, we plan to develop NTZ as a standalone monotherapy in fibrotic diseases, as well as a combination therapy with elafibranor as part of our strategy in NASH.

NTZ in combination with elafibranor (ELA) in NASH models

NASH is a complex and multifaceted disease and several drug classes with complementary mechanisms of action may be required for optimal management of NASH, liver fibrosis and comorbidities. Therefore, there is an increasing need for therapies based on drug combinations. To address this need, and as part of our comprehensive strategy, we evaluated the potential synergy of NTZ and ELA in combination therapy in models of fibrosing NASH. In April 2018, at the EASL ILC, we presented results from studies of combination therapy with elafibranor in which NTZ had a synergistic effect in primary human stellate cells and in a model of NASH with fibrosis.

Altogether these findings indicate that NTZ may be a good candidate for a NASH combination therapy with ELA, thus establishing the rationale for proof-of-concept studies in patients with NASH and advanced fibrosis.

About the identification and repurposing of nitazoxanide (NTZ)

Progressive liver fibrosis can result from chronic liver injury of any etiology, including viral infection, alcoholic liver disease and NASH2. Cirrhosis, the terminal stage of progressive liver fibrosis, results in over 1 million deaths annually worldwide3, and annual direct and indirect costs for the care of cirrhosis exceeds $12 billion in the United States alone4.

Complications of cirrhosis include: functional liver failure, portal hypertension-induced variceal bleeding, ascites, hepatic encephalopathy, systemic bacterial infection, liver cancer, especially HCC. As approved therapies directly targeting and reversing advanced liver fibrosis are still lacking, there is an urgent need for anti-fibrotic drugs to prevent progression to liver failure and the associated morbidity and mortality.

Our research program designed to discover novel anti-fibrotic molecules uses a phenotypic screening approach5 combined with the use of a compound library composed of FDA-approved drugs. In our model, we evaluated the compounds for their capacity to interfere with the activation of quiescent hepatic stellate cells into myofibroblasts, which are the major fibrogenic cell type in the liver.

After screening the pharmacopea, and investigating the drug candidate profiles in medical literature, we identified nitazoxanide, or NTZ; currently commercialized and prescribed in the United States and several other countries as an anti-parasitic; as a potent anti-fibrotic agent that we believe can be repurposed for the treatment of fibrosis.

1Fibroblasts are cells in connective tissues that, when activated, play a significant role in the development of fibrosis.
2Higashi, T., Friedman, S. L., and Hoshida, Y. (2017), ‘Hepatic stellate cells as key target in liver fibrosis’, Adv Drug Deliv Rev, 121, 27-42
3Tsochatzis, E. A., Bosch, J., and Burroughs, A. K. (2014), ‘Liver cirrhosis’, Lancet, 383 (9930), 1749-61
4Ge, P. S. and Runyon, B. A. (2016), ‘Treatment of Patients with Cirrhosis’, N Engl J Med, 375 (8), 767-77
5The phenotypic method does not rely on knowledge of the identity of a specific drug target or a hypothesis about its role in a disease, but rather focuses on the modulation of a disease-linked phenotype.

 
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