Preclinical data presented today during the virtual meeting II of the American Association for Cancer Research (AACR), being held June 22 – 24, 2020, shows that an investigational drug called TXR-311 demonstrated significant efficacy and good tolerability in in vivo studies for the potential treatment of hepatocellular carcinoma (HCC).
The results were, according to the investigators, comparable to that of sorafenib (Nexavar®; Bayer), which is standard-of-care for the treatment of patients with HCC, a disease which occurs most often in people with chronic liver diseases, such as cirrhosis caused by hepatitis B or hepatitis C infection and and alcoholic and non–alcoholic steatohepatitis (NASH).
HCC, also called hepatoma, is the most common type of liver cancer, accounting for approximately 75% of all liver cancers, is considered a multifactorial disorder and does not cause symptoms in the early stage, which often leads to a delay in diagnosis, leading to poor survival. This makes the disease dificult to treat.
The disease is the fourth most common cause of cancer-related death worldwide with >80% of cases occuring in low-resource and middle-resource countries, particularly in Eastern Asia and sub-Saharan Africa, where medical and social care resources are often constrained. 
Despite advances made with the introduction of multi-kinase inhibitor therapies with similar mechanisms of action, including cabozantinib (Cabometyx™ and Cometriq™; Exelixis), regorafenib (Stivarga®; Bayer) and lenvatinib (Lenvima®; Eisai), and the immune checkpoint inhibitor nivolumab (Opdivo®; Bristol-Myers Squibb), the 5-year survival rate and median survival, at 18%, remains one of the lowest of all cancer types. Combined with treatment options relatively unchanged over the past 10 years, the disease represents a major unmet mendical need
The investigational drug TXR-311, which has a confirmed novel Mechanism of Action, is being developed by twoXAR Pharmaceuticals.
“While we have some beneficial treatments for hepatocellular carcinoma, this tumor type is a growing problem worldwide and more options are needed,” said Ghassan K. Abou-Alfa, M.D., medical oncologist at Memorial Sloan Kettering.
“These early results are interesting and exciting because they showed safety and efficacy comparability against sorafenib but with a completely novel mechanism of action,” he added.
In validation studies in two HCC patient-derived xenograft (PDX) tumor models, the investiogators found that TXR-311 inhibited proliferation and viability of five different HCC tumor cell lines with IC50 values that were 70-fold lower than IC50 values for sorafenib, but displayed greater than 500-fold selectivity against primary human hepatocytes.
TRX-311 also demonstrated in vivo efficacy comparable to sorafenib with good tolerability.
“We are pleased that our TXR-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,” noted Andrew A. Radin, co-founder and Chief Executive Officer of twoXAR.
“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,” he said.
TXR-311 also showed in vitro activity at low µm concentrations in pancreatic ductal adenocarcinoma (PDAC), another disase with low survival rate.
Based on the ourcomes of the pre-clinical validation studies, the investigators agree that TXR-311 presents a first-in-class lead for further development as a potential HCC therapy.
As part of a larger oncology drug discovery program, scientists at twoXAR, a company focusing on drug discovery and development, build in-silico disease models based on the company’s AI-driven drug discovery approach.
Using diverse, proprietary algorithms, deep learning principles and detailed HCC disease-specific data, as well as clinical and chemical data, the scientists were able to explore a library of existing drug molecules allowing them to discover associations between biology and biomedical data. This resulted in novel, high-value drug discovery hits which generated a set of 10 molecules with predicted efficacy against HCC. Each of the discovered molecules discplayed a potential treatment of HCC based on a novel MOA.
On of these investiugational agents, TXR-311, showed the most promising results and was chosen to proceed into lead optimization studies for HCC.
 Hakim I, Chua MS, Wei W, Ma Li, So S, Noblin E, Mujahid S, Daugherty AC, Heuer TS. Computational discovery and preclinical validation of therapeutic leads with novel MOAs for hepatocellular carcinoma and pancreatic ductal adenocarcinoma. Annualk meeting of the American Association for Cancer Research (AACR), June 22 – 24, 2020, Session LBPO.ET02 – Late-Breaking Research: Experimental and Molecular Therapeutics 2; LB-110 / 13 [Abstract][Poster]
 Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16(10):589-604. doi:10.1038/s41575-019-0186-y [Article]