COTI-2

COTI-2 is a novel small molecule that acts by inhibition of AKT/PKB (Protein kinase B) phosphorylation which leads to caspase-9 activation in cancer cells resulting in apoptosis or programmed cell death. COTI-2 is easily synthesized and has good in vitro and in vivo efficacy against multiple cancers including small cell lung cancer, non-small cell lung cancer, colon cancer, brain cancer, ovarian cancer, endometrial cancer, and pancreatic cancer, markets that could represent more than $21 billion by 2018. COTI is currently evaluating partners to share in the risk/reward of development via a licensing agreement for COTI-2.

How does COTI-2 work?
• COTI-2 promotes tumor cell death by interfering with AKT2 in the
• PI3K/AKT/mTOR pathway.
• Experimental evidence indicates that COTI-2 prevents the activation of AKT2,
• thereby preventing its cancer promoting activities.
• Human cancer cells exposed to COTI-2 exhibit reduced levels of activated
• AKT2 compared to untreated cells.
• COTI-2 did not exhibit any activity towards cells in which AKT2 activity was
• removed by silencing RNA. Therefore, in the absence of its target (AKT2)
• COTI-2 was unable to promote death in cancer cells. This indicates that
• AKT2 is the specific target of COTI-2.

Current Status of the COTI-2 Development Program
• Experimental evidence indicated that COTI-2 was highly effective against
• several human cancer cell lines.
• COTI-2 was also highly effective against human colon cancer cell lines with
• abnormal/mutated KRAS, which were otherwise not sensitive to Erbitux^®.
• COTI-2 has demonstrated a good in vitro and in vivo pharmacokinetic profile.
• COTI-2 has demonstrated low toxicity in vitro and in vivo.
• COTI-2 was highly effective as a single agent in multiple animal models of
• human cancers, including SCLC, colon, brain, ovarian, pancreatic cancer and
• leukemia.
• COTI-2 was highly effective as a combination agent in multiple animal
• models of human cancers, including endometrial, ovarian, and
• pancreatic cancer.

How does COTI-2 differ from other cancer treatments?
• Treatment by conventional cancer chemotherapy involves the killing of all
• growing and dividing cells (cancer or otherwise) in the body. This often
• leads to significant toxic side effects in patients.
• Unlike conventional chemotherapy, COTI-2 specifically targets and destroys
• tumor cells.
• COTI-2 targets tumor cells with abnormally high levels of active AKT2.
• COTI-2 has demonstrated very low toxicity in normal human cells compared
• to human cancer cells.
• COTI-2 has demonstrated very low toxicity in rodents.
• Many studies have shown that the activation of AKT2 causes tumor cells to
• become resistant to chemotherapeutic drugs and signal molecule inhibitors.
• (e.g., Gleevec^®, Iressa^®,and Herceptin^®).
• Unlike the conventional therapeutic agents paclitaxel and cisplatin, COTI-2
• did not induce resistance in cancer cells. COTI-2 was actually highly effective
• against paclitaxel and cisplatin resistance cancer cells.
• The combined scientific evidence indicates that COTI-2 is an ideal agent for
• combination therapy with current standard agents.

Projected Developmental Activities for the Next 12 to 18 Months
• Optimize the oral formulation and bioavailability of COTI-2 (in progress).
• Complete FDA enabling research for the first-in-man multicentre
• United States based Phase 1 Clinical Trial.
• Document oral pharmacokinetic properties and human toxicity in a Phase 1
• Clinical Trial.
• Document preliminary human efficacy data and evaluate activated AKT2 as a
• potential biomarker for COTI-2 therapy during the Phase 1 Clinical Trial.