Novartis – MEK162 – MEK Inhibitor Program
In April 2010, we granted Novartis, under a License Agreement, the exclusive worldwide right to develop and commercialize MEK162. Under the agreement, we are responsible for completing our on-going Phase 1 clinical trials of MEK162 as a single agent and MEK162 in combination with paclitaxel. Additionally, we have elected to conduct further development of MEK162 as a single agent in a Phase 3 trial of patients with low-grade serous ovarian cancer. Novartis is responsible for all other development activities. Novartis is also responsible for the commercialization of products under the agreement, subject to our option to co-detail approved drugs in the U.S.
In connection with signing the agreement, Novartis paid us $45 million, comprising an up-front fee and an initial milestone payment. In May 2011, we received a $10 million clinical research milestone from Novartis after Novartis had its first patient visit in a Phase 2 clinical trial. In June 2013, we earned a $5 million clinical research milestone from Novartis after Array had its first patient visit in a Phase 3 clinical trial. We are also eligible under the agreement to receive up to approximately $408 million in additional aggregate milestone payments if all clinical, regulatory and commercial milestones specified in the agreement are achieved for MEK162 together with additional commercial milestone payments for other MEK inhibitors Novartis elects to develop under the agreement. The agreement provides Array with double-digit royalties on worldwide sales of any approved drugs, with royalties on U.S. sales at a significantly higher level. We are paying a percentage of development costs up to a maximum amount with annual caps to maintain the maximum U.S. royalty rate for MEK162. During fiscal 2013, we committed to continue our co-development contribution through fiscal 2014 and paid Novartis our first annual co-development contribution of $9.2 million. We have the right to opt out of paying our co-development contribution on an annual basis after fiscal 2014 with respect to one or more products; in which case the U.S. royalty rate would then be reduced for any such product based on a pre-specified formula, subject to a minimum that equals the royalty rate on sales outside the U.S. and we would no longer have the right to develop or co-detail such product.
The agreement with Novartis will be in effect on a product-by-product and country-by-country basis until no further payments are due with respect to the applicable product in the applicable country, unless terminated earlier. Either party may terminate the agreement in the event of a material breach of a material obligation under the agreement by the other party that remains uncured after 90 days prior notice. Novartis may terminate portions of the agreement following a change in control of Array and may terminate the agreement in its entirety or on a product-by-product basis with 180 days prior notice. Array and Novartis have each further agreed to indemnify the other party for manufacturing or commercialization activities conducted by it under the agreement, negligence or willful misconduct or breach of covenants, warranties or representations made by it under the agreement.
Development Status: There are 19 ongoing or planned clinical trials of MEK162, including three Phase 3 trials.
The first Phase 3 study is in low-grade serous ovarian cancer, or LGSOC, which Array is conducting, and began in June 2013. This study, called MILO (MEK Inhibitor in Low Grade Serous Ovarian Cancer), will evaluate the efficacy and safety of MEK162 compared to standard chemotherapy treatments in 300 patients with recurrent or persistent LGSOC following at least one prior platinum-based chemotherapy regimen and no more than three lines of prior chemotherapy regimens. The primary endpoint is progression-free survival, and the key secondary endpoint is overall survival.
The second Phase 3 study is in NRAS-mutant melanoma, which Novartis is conducting, and began in July 2013. The NRAS-mutant melanoma study, called NEMO (NRAS Melanoma and MEK Inhibitor), will evaluate the efficacy and safety of MEK162 compared to dacarbazine in 393 patients with advanced (Stage IIIC) unresectable or metastatic (Stage IV) NRAS-mutant melanoma. The primary endpoint is progression-free survival, and the key secondary endpoint is overall survival. The estimated primary completion date for the NEMO study is October 2014.
The third Phase 3 study, called COLUMBUS (COmbination of LGX818 used with MEK162 in BRAF-mutant unresectable skin cancer) will evaluate the efficacy and safety of the combination of LGX818 with MEK162 and LGX818 as a single agent compared to Zelboraf┬« (vemurafenib) in 900 patients with advanced, unresectable or metastatic BRAF-mutant melanoma. Novartis expects to begin this Phase 3 trial later in 2013.
Promising data on MEK162 in an ongoing Phase 2 trial of patients with BRAF and NRAS mutated advanced melanoma were presented at the 2012 ASCO Annual Meeting. In this trial, MEK162 showed clinical activity and good tolerability in patients with NRAS-mutant melanoma and is the first targeted therapy to show activity in this patient population. Novartis is conducting this Phase 2 open-label trial and continues to enroll patients. As of February 2012, six of the 28 patients with NRAS mutations who were evaluable for response had partial responses, including three confirmed partial responses, and 13 patients had stable disease. The disease control rate was 68% among these patients. The median progression-free survival was 3.65 months (95% CI 2.53 - 5.39 months). Common adverse events of all grades were consistent with data reported for the MEK inhibitor class and included rash, diarrhea, acneiform dermatitis, edema, creatine phosphokinase elevation, central serous retinopathy-like events, nausea and fatigue.
Additionally, preliminary data from a Phase 1b dose escalation study of MEK162 in combination with Novartis compound LGX818 in patients with BRAF-mutant cancer were presented at the 2013 ASCO Annual Meeting. This data indicated that these compounds may be safely combined with favorable clinical activity. In BRAF inhibitor na├»ve melanoma patients, the combination of LGX818 and MEK162 showed a disease control rate (complete response, partial response or stable disease) of 100%, and an overall response rate (complete response or partial response) of 88%, including one complete response. In melanoma patients who had been previously treated with another BRAF inhibitor, the disease control rate was 64%. Also in the study, 33% of colorectal cancer patients and 100% of papillary thyroid cancer patients experienced disease control. Preliminary data from the Phase 1b study also indicate that LGX818 and MEK162 may be safely combined at intended single agent doses. Unlike other BRAF inhibitor / MEK inhibitor combinations, in this study there were no febrile (fever) or photosensitivity events and a low incidence of rash was reported to date. There were no signs of increased toxicity with the combination versus single agent therapy. In fact, the combination showed early signs that it may mitigate some of the on-target adverse events common with single BRAF inhibitor therapy, including cutaneous toxicities, myalgia and arthralgia.