Ignyta and Nerviano Medical Sciences signed a license agreement in which Ignyta receives exclusive global development and commercialization rights to two new drug development programs, RXDX-103 and RXDX-104. Nerviano will receive an upfront payment of $3.5 million, as well as development- and regulatory-based milestone payments and tiered royalty payments on future net sales.

RXDX-103 is an inhibitor of the cell division cycle 7-related (Cdc7) protein kinase and RXDX-104 is a program to identify a highly selective inhibitor of the rearranged during transfection (RET) tyrosine kinase. Both are in preclinical development for the potential treatment of multiple cancers.

Currently available chemotherapies, such as anti-metabolites, topoisomerase inhibitors, and crosslinking and intercalating agents, take a broad-based approach to inhibiting the elongation step of DNA replication. Although this strategy has led to successful treatment outcomes, off-target effects can lead to dose-limiting toxicity. Cdc7 is a serine/threonine protein kinase essential for the initiation step of DNA replication during the synthesis (S) phase.

Ignyta and Nerviano said they believe that inhibiting the initiation step rather than the elongation step of DNA replication by targeting Cdc7 could offer a more targeted therapeutic strategy for disrupting DNA replication. For example, inhibition of Cdc7 has been demonstrated to selectively kill tumor cells in a P53-independent manner, while sparing noncancerous cells. RXDX-103 is a targeted cell cycle inhibitor, with high potency and selectivity against Cdc7 in vitro, and demonstrated antitumor effects both alone and in combination with chemotherapy in vivo, according to the companies.

The RET proto-oncogene is a receptor tyrosine kinase prone to gene rearrangements and other mutations, which can become oncogenic drivers in cancers such as non-small cell lung cancer and medullary thyroid cancer. Ignyta said while some marketed and development stage multi-kinase inhibitors induce non-selective RET inhibition that confers antitumor efficacy in cancer patients with RET rearrangements, such compounds often have limiting toxicities from their other mechanistic effects, such as VEGF inhibition.

This deal is an expansion of a collaboration launched last year. In November 2013, Ignyta licensed exclusive rights to two tyrosine kinase inhibitors, RXDX-101 and RXDX-102, from Nerviano.

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