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Clovis, Avila to Co-develop Targeted NSCLC Drug with Companion Test in Deal Worth up to $209M

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By Turna Ray

Biopharmaceutical firm Clovis Oncology has partnered with targeted drugmaker Avila Therapeutics to develop and commercialize Avila's epidermal growth factor receptor mutant-selective inhibitor (EMSI) program in non-small cell lung cancer.

Avila's EGFR mutant-selective inhibitor, currently in pre-clinical development for NSCLC, has been shown to target the T790 mutant form of EGFR, which is linked to resistance to two leading targeted lung cancer treatments, Genentech/OSI's Tarceva (erlotinib) and AstraZeneca's Iressa (gefitinib). Early clinical trials also suggest that the investigational drug targets the initial activating EGFR mutations, including L858R and exon 19 deletions.

The drug targets these pathways "while also sparing the wild-type, [or] normal, EGFR and may thus treat refractory NSCLC while minimizing dose-limiting side effects," Avila and Clovis said in a statement. "Because the program targets both the sensitive activating mutations as well as the primary resistance mechanism, T790M, it has the potential to treat both first- and second-line NSCLC patients with EGFR mutations, for whom there is great unmet medical need."

Under the terms of the partnership, Clovis will lead accelerated clinical development of the drug in conjunction with a companion diagnostic to identify T790M mutated EGFR in NSCLC patients. "Clovis will be fully responsible for all aspects of development and commercialization, including development of companion diagnostics to prospectively identify patients with clinically arising resistance mutations of the EGFR," the companies said.

The financial terms of the agreement dictate that Clovis will give Avila research support and an upfront fee. Additionally, Avila will receive tiered royalties on product sales, share in selected sublicense income, and be eligible to receive development, regulatory, and sales-based milestone payments, with a total potential value of $209 million.

According to the companies, the T790M mutation appears to be the main mechanism in EGFR-mutant lung cancers causing patients to become resistant to EGFR kinase inhibitors, such as Tarceva and Iressa. This mechanism of action "may well explain why the dramatic responses seen in these cases are of relatively short duration," said Daniel Haber, director of the Massachusetts General Hospital Cancer Center, in a statement provided by the companies.

Haber led a team of researchers that initially discovered EGFR mutations in lung cancer. He added in the statement that a drug that can simultaneously inhibit mutations in EGFR and bind to normal EGFR has the potential to "to be of major clinical significance."

According to Clovis CEO Patrick Mahaffy, the company plans to file an investigational new drug application with the US Food and Drug Administration "as rapidly as possible" in order to proceed with an accelerated development timeline.

A spokesperson for Clovis told Pharmacogenomics Reporter that after the diagnostic is clinically validated in trials, the company plans to submit the test to the FDA for Class 3 pre-market approval at the same time the new drug application for the EGFR mutant-selective inhibitor is submitted to the agency. The company hopes that the drug and diagnostic will "ideally be approved together."

The FDA encourages companies to ink drug/diagnostic partnerships as early as possible in the development cycle of a drug. Additionally, with an eye toward advancing genomically guided personalized medicine products, the agency is aligning its drug and diagnostics divisions to allow for simultaneous review of the drug and companion diagnostic (PGx Reporter 11/11/09).

Approximately 85 percent of the 1.39 million new lung cancer cases yearly are NSCLC, a form of the disease that progresses rapidly; 5 percent of patients with advanced NSCLC have a five-year survival rate. Additionally, activating EGFR mutations have been shown to drive NSCLC malignancy in 10 percent to 15 percent of patients of European descent and approximately 30 percent of patients of East Asian descent.

As such, several drug firms are exploring pharmacogenomic strategies to personalize NSCLC treatments.

AstraZeneca is paying for genetic testing for UK patients considering treatment with Iressa before the National Institute of Health and Clinical Excellence appraises the cost-effectiveness of the drug.

After a study showed that Iressa had low efficacy in the general NSCLC population, AstraZeneca in 2005 withdrew its application in the EU. The company reapplied for marketing approval in 2008 with efficacy data in EGFR-positive patients, and last year the drug was approved for marketing in Europe as a treatment for locally advanced or metastatic NSCLC patients whose tumors have EGFR mutations. Around the time AstraZeneca pulled its application in the EU, the FDA restricted marketing Iressa to new patients. The company has not announced plans to pursue relabeling the drug with a companion test in the US (PGx Reporter 04/07/10).

Additionally, Biodesix recently presented data showing that its serum-based Veristrat test is able to identify NSCLC patients most likely to benefit with Tarceva treatment. Biodesix believes that its test has additional utility with other EGFR inhibitors and tumor types and the company is planning to conduct additional studies to expand the intended use of VeriStrat (PGx Reporter 05/05/10).

Since Clovis and Avila plan to develop the EGFR mutant-selective inhibitor as a treatment for first- and second-line NSCLC treatment, they pointed out that both Iressa and Tarceva have "significant" toxicities, such as skin rashes and diarrhea, related to inhibition of the wild-type EGFR in skin and intestine, respectively. Iressa is available in Europe as a first-line drug for NSCLC, and Tarceva is indicated as a second-line treatment for NSCLC.

Clovis and Avila are also developing the investigational treatment for patients who are resistant to standard-of-care EGFR inhibitors. "Acquired resistance to Tarceva and Iressa occurs after a median of 12 months, driven in approximately 50 percent of cases by" T790 mutations, the companies note. "Patients with tumors containing this secondary resistance EGFR mutation are clinically resistant to both first generation EGFR inhibitors (Tarceva and Iressa) as well as second generation pan-ErbB inhibitors currently in clinical development."

Pfizer is developing neratinib, an investigational pan-ErbB inhibitor that came to the company through its acquisition of Wyeth. The drug is being developed in patients with HER2-positive breast cancer, as well as other solid tumors, including NSCLC (PGx Reporter 12/09/09).

"By inhibiting both T790M and the initial activating mutations, the EMSI program offers the prospect of effective drug treatment for first and second-line NSCLC patients with activating EGFR mutations," the companies said. "With sparing of the wild-type EGFR, the EMSI program could also offer a much improved therapeutic window compared to current therapies in a first-line setting."

Beyond NSCLC, both Clovis and Avila are involved in other research in the area of personalized medicine. Clovis is collaborating with Ventana Medical Systems to develop a companion diagnostic to identify pancreatic cancer patients most likely to benefit from the investigational drug candidate CO-101 due to their low tumor expression of hENT1.

Avila is focused on developing targeted covalent drugs in the area of viral infection, cancer, and autoimmune diseases, using a "protein silencing" approach through its proprietary Avilomics platform.

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