Roche Bearer Share : FDA grants Roche?s cobimetinib priority review for use in combination with Zelboraf (vemurafenib) in advanced melanoma

Basel, 19 February 2015

Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced the U.S. Food and Drug Administration (FDA) has accepted and granted priority review for the company's New Drug Application (NDA) for cobimetinib in combination with Zelboraf® (vemurafenib) for the treatment of people with BRAF V600 mutation-positive advanced melanoma. The FDA will make a decision on approval by August 11, 2015.

"We are pleased the FDA has accepted our application for cobimetinib in combination with Zelboraf and granted it priority review status," said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. "We look forward to working with the FDA to bring this new treatment option to people with BRAF mutation-positive advanced melanoma as soon as possible."

A priority review designation is granted to medicines that the FDA determines have the potential to provide significant improvements in the treatment, prevention or diagnosis of a disease. The NDA is based on results of the coBRIM Phase III study, which showed the MEK inhibitor cobimetinib plus Zelboraf reduced the risk of disease worsening or death by half in people who received the combination (hazard ratio [HR]=0.51, 95 percent confidence interval [CI] 0.39-0.68; p

CoBRIM is an international, randomized, double-blind, placebo-controlled Phase III study evaluating the safety and efficacy of 60 mg once daily of cobimetinib in combination with 960 mg twice daily of Zelboraf, compared to 960 mg twice daily of Zelboraf alone. In the study, 495 patients with BRAF V600 mutation-positive unresectable locally advanced or metastatic melanoma (detected by the cobas® 4800 BRAF Mutation Test) and previously untreated for advanced disease were randomized to receive Zelboraf every day on a 28-day cycle plus either cobimetinib or placebo on days 1-21. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent. Investigator-assessed PFS was the primary endpoint. Secondary endpoints include PFS by independent review committee, overall response rate, overall survival, duration of response and other safety, pharmacokinetic and quality of life measures.

There was a higher overall frequency of Grade 3 or higher adverse events in the combination arm (65 vs. 59 percent), with close to half of these due to lab value abnormalities (mainly increased blood levels of liver enzymes and CPK). Common adverse events (occurring in more than 20 percent) observed at a higher frequency (all grades) in the combination arm compared to the Zelboraf arm included diarrhea (57 vs. 28 percent), nausea (39 vs. 24 percent), photosensitivity (28 vs. 16 percent), lab value abnormalities (increased alanine aminotransferase [ALT, 24 vs. 18 percent], increased aspartate aminotransferase [AST, 22 vs. 13 percent], increased CPK [30 vs. 3 percent]) and vomiting (21 vs. 12 percent). Common adverse events observed at a lower frequency in the combination arm included hair loss (14 vs. 29 percent), thickening of the outer layer of the skin (10 vs. 29 percent) and joint pain (33 vs. 40 percent). Most instances of each common adverse event were Grade 1 or 2 in severity. 1

Other select adverse events that were lower in the combination arm included cutaneous squamous cell carcinomas (3 vs. 11 percent; all grades) and keratoacanthomas (1

Melanoma is less common, but more aggressive and deadlier than other forms of skin cancer.2,3 BRAF is mutated in approximately half of melanomas.4 When melanoma is diagnosed early, it is generally a curable disease,5,6 but most people with advanced melanoma have a poor prognosis.3 More than 232,000 people worldwide are currently diagnosed with melanoma each year7 and more than 70,000 people worldwide die every year from melanoma and non-melanoma skin cancers.8 In recent years, there have been significant advances in treatment for metastatic melanoma and people with the disease have more options. However, it continues to be a serious health issue with a high unmet need and a steadily increasing incidence over the past 30 years.9

Cobimetinib is designed to selectively block the activity of MEK,10 one of a series of proteins inside cells that make up a signalling pathway that helps regulate cell division and survival.11 Cobimetinib binds to MEK while Zelboraf binds to mutant BRAF, another protein on the pathway, to interrupt abnormal signalling that can cause tumours to grow.12,13

Cobimetinib (GDC-0973, XL518) was discovered by Exelixis Inc. and is being developed in collaboration with Exelixis. Cobimetinib is also being investigated in combination with several investigational medicines, including an immunotherapy, in several tumour types such as non-small cell lung cancer and colorectal cancer, triple-negative breast cancer and melanoma

Zelboraf  was the first prescription treatment for patients with unresectable or metastatic melanoma with BRAF V600 mutation as detected by a validated test, such as Roche's cobas 4800 BRAF Mutation Test. Zelboraf is not indicated for use in patients with wild-type BRAF melanoma.14 It is now approved in more than 80 countries and has been used to treat more than 11,000 patients worldwide. Zelboraf was co-developed under a 2006 license and collaboration agreement between Roche and Plexxikon, now a member of the Daiichi Sankyo Group.

Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world's largest biotech company, with truly differentiated medicines in oncology, immunology, infectious diseases, ophthalmology and neuroscience. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner in diabetes management. Roche's personalised healthcare strategy aims at providing medicines and diagnostics that enable tangible improvements in the health, quality of life and survival of patients. Founded in 1896, Roche has been making important contributions to global health for more than a century. Twenty-four medicines developed by Roche are included in the World Health Organization Model Lists of Essential Medicines, among them life-saving antibiotics, antimalarials and chemotherapy.

In 2014, the Roche Group employed 88,500 people worldwide, invested 8.9 billion Swiss francs in R&D and posted sales of 47.5 billion Swiss francs. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. For more information, please visit roche.com.

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