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).

an image of a graph

Figure 1:  EMT6/CTX breast cancer tumor growth in syngeneic mice following oral treatment with TL-118 and TL-112, vs. the corresponding vehicle controls

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.

a graph of study results

Figure 2: Colorectal Cancer – liver metastases in a mouse model.

A. Tumor volume over time, B.MRI scans of control and treatment groups

a graph of study results

Figure 3:  O2/CO2 perfusion and vessel density in Colorectal Cancer – liver metastases mouse model. Left. Tumor O2 supply, Middle. Tumor CO2 evacuation, Right. New blood vessel density indicated by CD31 staining

a graph of study results

Figure 4: Survival curve of Colorectal Cancer – liver metastases in a mouse model. Survival curve of the different treatment groups (TL-PR=TL-118 Partial Response - treated animals with partial response. TL-CR=TL-118 Complete Response -treated animals with no tumors. (The animals died from repeated anesthesia,) B20=Murine Avastin , RAPA=Rapamycin)

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.

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a graph of % of tumor-bearing animals

A

a graph of Average of tumor size in the tumor bearing animals

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an image of representative tumors from the different groups

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Figure 5:  TL-118 + Gemcitabine synergy in pancreatic cancer mouse model.

A. % of tumor-bearing animals; B. Average of tumor size in the tumor bearing animals; C. Representative tumors from the different groups

Overall efficacy conclusions are:

  • Inhibition of tumor blood-vessel formation was demonstrated confirming TL-118 anti-angiogenic mechanism of action.
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  • Superior anti-cancer activity over m-Avastin or Rapamycin was demonstrated, emphasizing better activity of TL-118 drug combination over a single agent anti-angiogentic therapy.
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  • The notable synergy between TL-118 and gemcitabine (pancreatic model) paved the way for the application of such combination as first line therapy in humans.

 

 

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