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FDA Speeds New HER2-Targeted Drug and Companion Tests to Market

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The US Food and Drug Administration has approved a new drug for HER2-positive breast cancer patients: Genentech's Perjeta (pertuzumab). Additionally, the agency has green-lighted two companion tests that can help doctors discern which patients have HER2-overexpressing tumors and should receive the drug.

The FDA on June 8 approved Perjeta in combination with Genentech's HER2 inhibitor Herceptin (trastuzumab) and docetaxel chemotherapy as a new treatment for metastatic breast cancer patients whose tumors overexpress the HER2 protein and who have not received treatment previously with a HER2-targeted drug or chemotherapy. Roche subsidiary Genentech already markets Herceptin for the treatment of HER2-positive metastatic breast cancer and HER2-positive stomach cancer.

The FDA granted Perjeta priority review, placing it on a six-month review clock. Genentech had submitted an application for the drug in February. The company has also submitted a marketing application to the European Medicines Agency.

A few days after the approval of the new agent in the US, the FDA also approved two companion diagnostics for Perjeta developed by Dako, the immunohistochemistry-based HercepTest and the fluorescent in situ hybridization-based pharmDx Kit. Genentech and Dako worked together to pursue a parallel regulatory pathway for Perjeta and the accompanying tests.

Perjeta is a monoclonal antibody that inhibits the HER2 receptor from joining with other HER receptors, such as EGFR/HER1, HER3, and HER4, thereby stopping cancer growth by blocking cell signaling in HER2-positive cancer. Since Perjeta binds to a different region of the HER2 receptor than Herceptin, by combining the two drugs Genentech is hoping to provide a more effective blockade against the HER2 signaling that drives cancer.

In 2012, an estimated 226,870 women will be diagnosed with breast cancer and 39,510 will die from the illness. Approximately 20 percent of breast cancer patients have HER2-positive disease.

“Since trastuzumab was first approved more than a decade ago, continued research has allowed us to better understand the role HER2 plays in breast cancer,” Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement announcing Perteja’s approval.

A typical course for the combination regimen including Herceptin and Perjeta is estimated to cost in excess of $180,000.

Data from the Clinical Evaluation of Pertuzumab and Trastuzumab trial, or CLEOPATRA, was the basis for Perjeta’s FDA approval. In the study, more than 800 HER2-positive breast cancer patients were randomized to receive either the Perjeta/Herceptin/docetaxel cocktail or Herceptin/docetaxel plus a placebo.

The data, published in the New England Journal of Medicine in December by researchers led by Jose Baselga of Harvard Medical School and presented at the San Antonio Breast Cancer Symposium (PGx Reporter 12/14/2011), showed that patients receiving the Perjeta-containing regimen experienced a median progression-free survival of 18.5 months compared to 12.4 months for those receiving just Herceptin plus chemotherapy. Common side effects linked to the Perjeta regimen included diarrhea, hair loss, reduced white blood cells, nausea, fatigue, rash, and nerve damage.

In the NEJM article, Baselga et al. wrote that in CLEOPATRA, patients receiving Perteja showed a “strong trend toward prolonged survival” compared to those not receiving the drug.

Perjeta’s label comes with a boxed warning that informs physicians and patients that the drug can cause fetal death and birth defects. “Studies in animals have resulted in oligohydramnios, delayed renal development, and death,” the boxed warning states, advising doctors to discuss these risks with their patients and recommend they use contraception while on the drug.

In Light of Drug Shortages

As part of the FDA approval, Genentech is subject to post-marketing commitments related to the manufacturing process for Perjeta.

In a statement, Patrick Yang, Roche’s head of Pharma Global Technical Operations, explained that the company had “recently identified a cell growth issue that might affect [the company’s] future supply" of the drug. He added that Roche/Genentech is working with the FDA “to ensure a consistent manufacturing process that maintains drug supply for the people who need it.”

The FDA said it has only cleared for marketing lots of the drug that weren’t impacted by production issues.

“Given the need for additional treatments for metastatic breast cancer, we made the decision to approve the limited supply of this drug that is not affected by the current manufacturing issues, and not to delay its availability to patients pending resolution of the future manufacturing issues,” an agency spokesperson told PGx Reporter. “FDA anticipates that it will approve marketing for additional drug product on an ongoing basis, until Genentech resolves the manufacturing issues, and we can license future product for marketing.”

FDA’s manner of approving Perjeta in light of production issues comes during a time when supply shortages of critical drugs have been a major problem for healthcare providers. President Barack Obama last October issued an executive order to health regulators to work with drugmakers to learn of potential supply interruptions for treatments before they occur. In response, the FDA in February issued draft guidelines to help guide drugmakers on when to inform the agency of drug shortages.

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