The fixed drug combination was tested on animals in order to evaluate the safety and maximize the efficacy of the drug combination. Before reaching clinical trial, the drug doses underwent fine tuning adjustment in animal studies to obtain the safest dose while not compromising on drug efficacy.
TL-118 was tested in various animal models including pancreatic cancer, breast cancer, colorectal cancer, melanoma, and Neuroblastoma. It demonstrated efficacy in terms of tumor size and animal survival, as well as direct effects on angiogenesis inhibition.
The experimental model used to titrate the product components was a mouse breast cancer tumor model resistant to cytotoxic agents (EMT6/CTX model). Hence, all effects were attributed to anti-angiogenic activity.
Figure 1 depicts a representative study conducted by an external CRO which was performed in a blinded manner (10 animals per group). The experiment compared between TL-118 and its preceding formulation TL-112 (which contains the same active pharmaceutical ingredients with different formulation).
In another study, the anti-angiogenic efficacy of TL-118 was evaluated by assessment of in vivo changes in perfusion to liver metastases, using Functional MRI in a mouse Colon Cancer Liver Metastases model. Results illustrated below (Figure 2, 3 and Figure 4) show that TL-118 significantly reduced tumor volume and tumor perfusion emphasizing its anti angiogenic properties. In addition, the anti-angiogenic effect suppressed the growth of liver metastases which resulted in a significant prolongation of animal survival. These effects were compared to the leading antiangiogenic drug, Avastin (= its murine analog – B20) and Rapamaycin, and demonstrated unequivocal TL-118 superiority.
In an additional study, The efficacy of TL-118 was evaluated utilizing an orthotopic pancreatic mouse model in which syngeneic pancreatic cancer cells (PANC02) were implanted in the pancreas of test animals (figure 5). Treatment began on day 5 when all animals had already developed tumors. This study shows that TL-118 on its own is superior to the standard of care, Gemcitabine (GEM). Moreover, the combination of both drugs, Gem and TL-118, led to complete response and no tumors were evident in treated animals, suggesting synergy between TL-118 and GEM.