Positive Preclinical Proof-of-Concept Results For Liver Cancer Candidate, TXR-311

by: Andrew A. Radin

In September 2016, we announced a collaboration with the Asian Liver Center at Stanford University School of Medicine (the Asian Liver Center). The goal of this collaboration was to identify new drug candidates targeting hepatocellular carcinoma (HCC, the major form of adult liver cancer). Today, we announced a lead candidate, TXR-311, that has shown positive results in cell-based assays. I wanted to share a bit more background on liver cancer and details on why these results are exciting.

Liver cancer: where we stand today

HCC is a primary cancer of the liver that tends to occur in patients with underlying chronic liver disease, often caused by hepatitis B or C virus infection. If a patient is diagnosed with liver cancer, the outlook is very dim; if the patient is lucky enough to be diagnosed early, the 5-year survival rate is less than one in three. Unfortunately, most patients are not diagnosed until their cancer is in advanced stages. These patients have even worse survival odds and fewer treatment options. In fact, according to the World Health Organization, 788,000 people die of liver cancer every year globally. On a personal note, the father of a good friend, who was also my mentor for 15 years, was a victim of liver cancer.

For many cancers, chemotherapy is an effective treatment. But HCC is generally resistant to chemotherapy. There is only one FDA approved drug on the market for liver cancer, sorafenib (Nexavar). While sorafenib has been shown to extend survival relative to treatment with a placebo, we think there is an opportunity to build a more effective medication. For example, there is some evidence that sorafenib may not improve outcomes in patients with advanced liver cancer (see: Sanoff, et. al. Sorafenib Effectiveness in Advanced Hepatocellular Carcinoma & Life-extending benefits of liver cancer drug Sorafenib not realistic for many patients).

An HCC-targeted missile with 500-fold specificity

Shortly after engaging with the Asian Liver Center, we used our artificial intelligence-driven approach to identify 10 drug candidates to treat liver cancer. We completed our analysis in less than one month, and then shared these candidates with the Asian Liver Center so that they could test the candidates on cultured liver cancer cells in their labs.

The objective of these experiments was to establish which of the original 10 candidates we identified might be promising liver cancer treatments, and generate preliminary preclinical data. While we had a few promising results among the 10 candidates, TXR-311 stood out as it killed liver cancer cells with high selectivity. Specifically, very low doses of TXR-311 killed five different liver cancer cell lines. But in healthy liver cells, 500 times as much TXR-311 was needed to cause cell death. In contrast, treating healthy cells with only 3 times the dose of sorafenib needed to kill liver cancer cells is enough to kill healthy cells.

In addition to this activity, data suggests that TXR-311 may target other aspects of liver cancer which we will explore in subsequent studies.

We continue to work with the Asian Liver Center to run toxicity studies and test the efficacy of TXR-311 in animal models of liver cancer, including patient-derived xenograft studies.

AI-Driven Drug Discovery

Our results in liver cancer are promising for the treatment of this challenging disease. In addition, they provide us and our collaborators additional validation that artificial intelligence-driven drug discovery can rapidly and accurately identify novel drug candidates. With several collaborations underway, I am looking forward to future announcements where we will provide updates in our other disease areas.