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CO-1686 is a novel, oral, targeted covalent (irreversible) inhibitor of the cancer-causing mutant forms of epidermal growth factor receptor (EGFR) currently being studied for the treatment of non-small cell lung cancer (NSCLC). CO-1686 was designed to selectively target both the initial activating EGFR mutations and the T790M resistance mutation, while sparing wild-type, or normal EGFR at anticipated therapeutic doses, with an improved toxicity profile. Accordingly, it has the potential to be a first-line treatment in NSCLC patients with activating EGFR mutations and a second or later-line treatment in NSCLC patients who become resistant to EGFR-directed therapy due to the emergence of the T790M secondary mutation.

CO-1686 is the subject of a global Phase II study. We are studying CO-1686 in expansion cohorts of NSCLC patients who have failed EGFR-directed therapy, such as Tarceva® or Iressa®, and have developed the T790M mutation, which is the dominant resistance mechanism to Tarceva/Iressa.

We have designed an accelerated clinical development program for CO-1686. Pending positive initial efficacy data, we intend to pursue the development of CO-1686 as both a second or later-line therapy for EGFR-mutated NSCLC patients who become resistant to EGFR-directed therapy due to the emergence of the T790M secondary mutation and as a first-line treatment for EGFR-mutated NSCLC. We own global development and commercialization rights to CO-1686.

Lung Cancer and EGFR Mutations

Lung cancer is the most common cancer worldwide with 1.35 million new cases annually, with NSCLC accounting for almost 85 percent of all lung cancers. NSCLC progresses rapidly with a five-year survival rate in advanced NSCLC patients of less than five percent. EGFR activating mutations occur in approximately 10 to 15 percent of NSCLC cases in Caucasian patients and approximately 30 to 35 percent in East Asian patients. These patients often experience significant tumor response to Tarceva and Iressa, which are first-generation EGFR inhibitors. However, most patients ultimately progress on these therapies, with approximately 60 percent of patients developing acquired resistance from a second, "gatekeeper" mutation, T790M. Currently, no targeted therapies are approved for treatment of this mutation.

Design of CO-1686 – a Targeted Covalent Drug

The most commonly used small molecule drugs, while able to inhibit the activity of disease-causing proteins, are generally only able to form transient binding interactions with the disease targets, and are thus considered reversible. A covalent drug, however, forms a strong and durable bond with its protein target, known as a covalent bond. Covalent drugs, such as CO-1686, are designed to form their covalent bond in a highly directed and controlled manner with a specific site on the disease target. Directed bond formation is key to achieving a distinct selectivity profile that is difficult to achieve with reversible small molecules. CO-1686 was designed to potently inhibit the mutant forms of EGFR, while sparing normal EGFR, providing efficacy without "off-target" side effects or side effects due to inhibition of normal receptor functions.

Development of a Companion Diagnostic

We are collaborating with QIAGEN on the development and commercialization of a companion diagnostic to identify patients with the T790M mutation. The diagnostic test will be developed in parallel with the clinical development of CO-1686, with the goal of filing a premarket approval (PMA) application with the FDA in a time frame that would allow for regulatory approval of the companion diagnostic concurrent with CO-1686 approval.

CO-1686 Scientific Presentations