First Regulatory Approval of Cobimetinib in Switzerland

Additional regulatory applications in the US and EU currently under review

On 27 August 2015, Exelixis, Inc. announced that Swissmedic, the Swiss licensing and supervisory authority of Switzerland, has approved cobimetinib for use in combination with vemurafenib as a treatment for patients with advanced melanoma. Cobimetinib is a selective inhibitor of MEK that was discovered by Exelixis and is the subject of a worldwide collaboration agreement between Exelixis and Genentech, a member of the Roche Group. The trade name for cobimetinib in Switzerland is Cotellic™.

Roche’s Swiss regulatory submission for cobimetinib was based on data from coBRIM, the phase III pivotal trial of cobimetinib and vemurafenib conducted in 495 patients with previously untreated unresectable, locally advanced or metastatic melanoma with a BRAF V600 mutation.

The resulting approval is the first for cobimetinib worldwide, and additional regulatory applications are under review in other territories. Genentech filed its New Drug Application (NDA) for cobimetinib with the US Food and Drug Administration (FDA) in December 2014 and the Prescription Drug User Fee Act date is 11 November, 2015. Separately, Roche filed a Marketing Authorization Application with the European Medicines Agency in late 2014, and Roche anticipates a regulatory decision before the end of 2015.

After discovering cobimetinib internally, Exelixis advanced the product to investigational new drug (IND) status. In late 2006, the company entered into its worldwide collaboration with Genentech, under which Exelixis received initial upfront and milestone payments for signing the agreement and submitting the IND.

Following the determination of the maximum tolerated dose in phase I by Exelixis, Genentech exercised its option to further develop cobimetinib. Under the terms of the collaboration, Exelixis is eligible to receive royalties on sales of cobimetinib outside the United States. If cobimeitnib is approved in the United States, Exelixis is entitled to an initial equal share of US profits and losses, which will decrease as sales increase, and will share in US marketing and commercialisation costs. In November 2013, Exelixis exercised its option to co-promote cobimetinib in the United States and, under the terms of the agreement, the company is prepared to field up to 25% of the US sales force.

About the coBRIM study

The pivotal coBRIM study is an international, randomised, double-blind, placebo-controlled, phase III study evaluating the safety and efficacy of the combination therapy. A total of 495 patients with unresectable, locally advanced or metastatic melanoma with a BRAF V600 mutation were randomised to receive vemurafenib once daily at the approved dosage and either cobimetinib or a placebo for 3 weeks followed by one week off cobimetinib/placebo. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent. Investigator-assessed progression-free survival (PFS) was the primary endpoint. Secondary endpoints include PFS by independent review committee, objective response rate, overall survival, duration of response and other safety, pharmacokinetic and quality of life measures.

The Swissmedic approval was based on an updated analysis of the coBRIM study data that showed median PFS among patients with previously untreated BRAF V600 mutation-positive advanced melanoma of 12.3 months with combination therapy with cobimetinib and vemurafenib and 7.2 months with vemurafenib monotherapy. Patients responded better to treatment with cobimetinib and vemurafenib than those given vemurafenib alone. In this updated analysis, the objective response rate (ORR) of the cobimetinib and vemurafenib combination was 70% compared to 50% for vemurafenib monotherapy). With further follow-up from the primary analysis, the complete response rate was 15%. The safety profile of cobimetinib and vemurafenib was consistent with safety data previously reported from the phase Ib BRIM7 study. The most common adverse events in the combination arm were diarrhoea, rash, nausea, fever, sun sensitivity, liver lab abnormalities, elevated creatine phosphokinase and vomiting.

About the cobimetinib and vemurafenib combination

Cobimetinib is a selective inhibitor that blocks the activity of MEK, a protein kinase that is part of a key pathway (the RAS-RAF-MEK-ERK pathway) that promotes cell division and survival. This pathway is frequently activated in human cancers including melanoma, where mutation of BRAF causes abnormal activation in about 50% of tumours. About 50% of patients with BRAF mutation positive melanoma experience a tumour response when treated with a BRAF inhibitor, however development of resistance and subsequent tumour progression limits treatment benefit. Clinical and preclinical analyses indicated that reactivation of the MEK-ERK pathway may underlie development of resistance to BRAF inhibitors in many progressing tumours, and that co-treatment with a BRAF and MEK inhibitor delays the emergence of resistance in the preclinical setting, providing the rationale for testing the combination of vemurafenib and cobimetinib in clinical trials. In addition to the combination with vemurafenib in melanoma, cobimetinib is also being investigated in combination with several investigational medicines, including an immunotherapy, in several tumour types, including non-small cell lung cancer, colorectal cancer, triple-negative breast cancer and melanoma.

The BRAF V600 mutation-positive form of melanoma is associated with high-risk characteristics of the disease, including early onset, the absence of chronic skin damage, and decreased survival.

Forward-looking statements

The press release by Exelixis contains forward-looking statements. Words such as “anticipate,” “look forward,” “if,” “entitled,” “eligible,” “will,” “prepared,” or other similar expressions, identify forward-looking statements, but the absence of these words does not necessarily mean that a statement is not forward-looking. In addition, any statements that refer to expectations, projections or other characterisations of future events or circumstances are forward-looking statements. These forward-looking statements are based upon Exelixis’ current plans, assumptions, beliefs, expectations, and projections. Exelixis’ actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of risks and uncertainties. The forward-looking statements made in the press release speak only as of the date of press release. Exelixis expressly disclaims any duty, obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in Exelixis’ expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based.