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FDA Simultaneously Approves Roche/Plexxikon's Drug, Companion Dx for BRAF-Mutated Melanoma


By Turna Ray

The US Food and Drug Administration this week approved Roche's personalized melanoma drug Zelboraf alongside a companion genetic test, highlighting the process as a model for future Rx/Dx co-development strategies.

The approval of the drug and the test "is a great example of how companion diagnostics can be developed and used to ensure patients are exposed to highly effective, more personalized therapies in a safe manner," said Alberto Gutierrez, director of the Office of In Vitro Diagnostic Device Evaluation and Safety in the FDA’s Center for Devices and Radiological Health, in a statement.

FDA reviewed Zelboraf under its priority review program, which enables a six-month review period for drugs for which no adequate therapy exists. Zelboraf was approved in three months — well ahead of the drug's Oct. 28 target date while the test, Roche's Cobas 4800 BRAF V600 Mutation Test, was approved ahead of its Nov. 12 goal date, FDA said.

The label for Zelboraf (vemurafenib) indicates the drug "for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test."

Roche plans to launch Zelboraf, developed under a 2006 licensing agreement between Roche and Daiichi Sankyo subsidiary Plexxikon, and the BRAF V600E test within the next two weeks.

A six-month course of treatment with Zelboraf costs $56,400. The average price for the test will vary by laboratory, but will likely cost between $120 and $150 per test. A Roche Molecular Diagnostics spokesperson said that three labs are currently offering the test: Clarient, based in Aliso Viejo, Calif.; Laboratory Corporation of America, based in Burlington, NC; and the Carolinas Medical Center, based in Charlotte, NC.

The BRAF protein is involved in cell proliferation, but is mutated in 50 percent of late-stage melanoma patients. Since Zelboraf inhibits the mutated BRAF protein, the BRAF V600 Mutation test identifies patients who are most likely to respond to the drug.

The simultaneous approval of Zelboraf and the companion test is in line with FDA recommendations for Rx/Dx development. The simultaneous approval in 1998 of Roche's HER2 positive breast cancer drug Herceptin and Dako's HercepTest to pick out best responders was the first example of a successful drug/diagnostic combination product, but such approvals have been rare in the intervening years.

The FDA in July released a companion diagnostic draft guidance that highlighted its thinking that the drug and the test should ideally be taken through regulatory approval in parallel (PGx Reporter 7/13/2011). This week, in announcing its approval of Zelboraf and the BRAF mutation test, the agency noted that the comment period for the draft guidance is still open.

Improved Response

While FDA is touting the approval of Zelboraf and the test as a success story, the drug's development wasn't entirely without challenges.

The association between BRAF mutations and melanoma was first reported in Nature in 2002 by Helen Davies of the the Wellcome Trust Sanger Institute and colleagues from other institutions.

Urged by this finding, Berkeley, Calif.-based Plexxikon began Phase I trials in 2006 for Zelboraf with investment from Roche. Then called PLX 4032, researchers soon discovered that patients, even those with BRAF mutations, weren't responding to the drug because they weren't properly absorbing its formulation. The sponsors briefly halted clinical studies from 2007 to 2008 while Roche reformulated the drug into a more potent form.

At the American Society of Clinical Oncology's annual meeting in 2009, Roche and Plexxikon presented data from a Phase I study showing promising early results. In that study, patients with BRAF mutations who were treated with Zelboraf experienced tumor shrinkage in sites where cancerous lesions commonly spread, such as the liver, lung, and bone.

Additionally, Zelboraf kept patients' disease from getting worse for six months, whereas metastatic melanoma patients usually experience progression-free survival of less than two months. After reporting these results, Roche announced it would develop a tissue-based PCR test to gauge BRAF mutations in clinical trials for the drug.

As Zelboraf progressed through later-stage studies, the pronounced benefit in the BRAF-mutated melanoma subpopulation to the drug became apparent. At ASCO's annual meeting in June, Roche presented data from the Phase III BRIM3 trial, which found that after six months of treatment, 84 percent of study participants who received vemurafenib were alive compared to 64 percent who received chemotherapy.

At the time of data analysis, median overall survival for patients receiving Zelboraf had not been reached and was 7.9 months for those receiving chemotherapy. Zelboraf-treated patients had a response rate of 48.4 percent versus to 5.5 percent for those who received chemotherapy.

In clinical trials, the most common Zelboraf-related side effects were joint pain, rash, hair loss, fatigue, nausea, and skin sensitivity to sun exposure. A skin-related cancer called cutaneous squamous cell carcinoma developed in approximately 26 percent of patients treated with Zelboraf, but this was treated with surgery.

The drug label issued this week cautions patients taking Zelboraf to avoid sun exposure. The FDA issued a Medication Guide to inform health care professionals and patients of the risks associated with Zelboraf therapy.

Accelerated Timeframe

Personalized medicine proponents have often claimed that pharmacogenomics strategies, such as the development program for Zelboraf, can help drugmakers run more efficient development programs by avoiding late-stage attrition and shortening timelines. Traditionally, the development of a drug from discovery to market launch is estimated to take between 15 to 20 years and cost more than $1 billion.

Under the terms of Roche and Plexxikon's 2006 agreement, Roche has paid up to $700 million to develop Zelboraf. Under the terms of the 2006 collaboration, Roche paid Plexxikon $40 million upfront and $6 million in guaranteed research funding over the following two years. Additionally, as part of the deal, Plexxikon was entitled to receive up to $660 million upon completion of milestones, as well as royalties on potential product sales.

The development program – from Roche filing the investigational new drug application with FDA to receiving regulatory approval of the combination product – took under five years. If one considers the time frame from the first published report linking BRAF mutations to melanoma in 2002, the development program for Zelboraf was still significantly faster than for drugs developed without the aid of companion tests.

Susan Wilson, a spokesperson from Roche subsidiary Genentech, told PGx Reporter that the availability of a valid biomarker target and companion test sped up the development process for the drug. In fact, "the development program for Zelboraf is the fastest we've ever conducted," she said.

"Because we were able to identify a certain subset of the population, it did speed up the development process and develop a companion diagnostic in lockstep with the medicine and actually validate the test with the medicine along the way," Wilson said.

She cautioned, however, that other PGx-guided drug development programs may not have the same experience. "In this case it did allow us to move quickly, because we were able to identify the most-likely-to-benefit patient population early and plan our development program accordingly," Wilson said. "However, it does depend on the disease state. Even with the personalized approach, it could still take years and years for certain medicines to come to market because of the nature of the disease, how long people might be living with the disease, and what other treatment options are available."

The FDA highlighted that this is the second melanoma drug it has approved this year that improves overall survival for a population of patients with limited treatment options. The agency approved Bristol-Myers Squibb's Yervoy, or ipilimumab, in late March after the drug was shown in clinical trials to extend survival in late-stage melanoma patients by 10 months.

"This has been an important year for patients with late-stage melanoma. Zelboraf is the second new cancer drug approved that demonstrates an improvement in overall survival," said Richard Pazdur, director of FDA's Office of Oncology Drug Products, in a statement.

At the ASCO annual meeting this year, Roche and BMS announced that they would investigate whether combining Yervoy and Zelboraf could further improve outcomes in molecularly defined subpopulations of melanoma patients (PGx Reporter 06/08/2011).

The National Cancer Institute estimates that 68,130 people were newly diagnosed with melanoma in the US during 2010, and approximately 8,700 people died from the disease that year.

Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at tray [at] genomeweb [.] com.