TXR-311 Shows Promising Preclinical Efficacy and Safety in Hepatocellular Carcinoma

Ghassan K. Abou-Alfa, MD

The novel investigational agent TXR-311 has been selected as an in vivo candidate for the potential treatment of patients with hepatocellular carcinoma (HCC) after demonstrating significant efficacy compared with the standard of care in preclinical studies, announced twoXAR Pharmaceuticals.¹

TXR-311 has demonstrated activity in validation studies and has selectivity for killing HCC tumor cells. The activity observed with this agent appears greater than with the standard of care treatment, sorafenib (Nexavar). TXR-311 significantly inhibited the growth in 2 xenograft tumor models that were HCC patient-derived, as well as demonstrated efficacy in in vivo studies compared with the standard of care.

"While we have some beneficial treatments for HCC, this tumor type is a growing problem worldwide, and more options are needed," said Ghassan K. Abou-Alfa, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, in a statement. "These early results are interesting and exciting because they showed safety and efficacy comparability against sorafenib but with a completely novel mechanism of action."

These preclinical data, which were presented during the American Association for Cancer Research (AACR) Virtual Meeting II, evaluated both HCC and pancreatic ductal adenocarcinoma models that were built with an artificial intelligence (AI) platform. The efficacy predictions were made from a library of >50,000 molecules.²

The company announced that they have identified 10 novel mechanisms of action for HCC and pancreatic ductal adenocarcinoma each as part of a larger oncology drug discovery program. The program utilized an AI-driven drug discovery approach that is able to build an in-silico disease model with multiple sets of biological, clinical, and chemical data. Overall, TXR-311 appeared to be the most promising of these mechanisms of action and will move forward to lead optimization studies for patients with HCC.

In the 2 validation studies, the novel agent inhibited proliferation and viability of 5 HCC tumor cell lines that had IC50 values 70-fold lower than those of sorafenib. The selectivity against primary human hepatocytes was greater than 500-fold. The drug also demonstrated in vitro activity at low µm concentrations in pancreatic ductal adenocarcinoma cancer cells.

"We are pleased that our TRX-311 in vivo data was selected for presentation at AACR. This study is another demonstration that our approach to drug discovery is effective in identifying novel molecules that have high likelihood of showing positive safety and efficacy signals in preclinical studies," said Andrew A. Radin, co-founder and chief executive officer of twoXAR Pharmaceuticals, in a statement.¹ "We are thrilled with the progress of our HCC clinical program thus far and look forward to advancing additional drug candidates in disease areas with similar unmet needs."

TXR-311 will be evaluated for drug pharmacokinetics and pharmacodynamics in future studies, as well as studies aimed to establish the pharmacokinetics/pharmacodynamics/efficacy relationships.²

HCC, which is a complex and heterogeneous disease, is the most common type of primary liver cancer, although the exact cause of the disease remains unknown. It is often difficult to both diagnose and treat patients with HCC, and the disease has been associated with poor outcomes. HCC is associated mostly with underlying chronic liver disease, such as hepatitis, alcoholic steatohepatitis and non-alcoholic steatohepatitis.¹

_References

_{1. twoXAR Pharmaceuticals Presents Positive Preclinical Safety and Efficacy Data for its Novel Investigational Cancer Treatment TXR-311. News Release. twoXAR Pharmaceuticals. June 22, 2020. Accessed June 26, 2020. https://prn.to/384KPyn}

_{2. Hakim I, Chua MS, Wei W, et al. Computational discovery and preclinical validation of therapeutic leads with novel MOAs for hepatocellular carcinoma and pancreatic ductal adenocarcinoma. AACR Virtual Meeting II; June 22 – 24, 2020.}