continuing color re. your (seemingly insightful) comment....
Item 8.01. Other Events.
Exelixis, Inc. (“Exelixis”) is reporting the expansion by Roche and Genentech, Exelixis’ collaborator and a member of the Roche Group, of the clinical development program for the MEK inhibitor cobimetinib (GDC-0973/XL518). As disclosed on ClinicalTrials.gov, Roche and Genentech are initiating the following new clinical trials of cobimetinib in combination with other agents:
• A Phase 1b, Open-Label, Dose-Escalation Study of the Safety, Tolerability, and Pharmacokinetics of MEHD7945A and Cobimetinib in Patients with Locally Advanced or Metastatic Solid Tumors with Mutant KRAS (NCT01986166);
• A Phase 1b, Open-Label Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Onartuzumab in Combination with Vemurafenib and/or Cobimetinib in Patients with Advanced Solid Malignancies (NCT01974258); and
• A Phase 1b Study of the Safety and Pharmacology of MPDL3280A Administered with Cobimetinib in Patients with Locally Advanced or Metastatic Solid Tumors (NCT01988896).
These new phase 1b clinical trials are being conducted by Roche and Genentech under Exelixis’ worldwide co-development agreement with Genentech and are being initiated on the basis of a strong scientific rationale and encouraging preclinical data.
MEHD7945A is a dual specificity antibody targeting EGFR and HER3. Mutation of KRAS and subsequent activation of the MAP kinase pathway independent of EGFR/HER3 may limit the efficacy of agents such as MEHD7945A in KRAS mutant tumors. Co-administration of a MAP kinase inhibitor such as cobimetinib to block signaling downstream of KRAS is therefore a rational combination approach to the treatment of KRAS mutant tumors.
Onartuzumab is an antibody directed against the receptor tyrosine kinase MET. Activation of MET by its ligand HGF limits the response to agents such as vemurafenib (as published by Straussman et. al. in Nature, Volume 487 (19 July 2012), page 500, and Wilson et. al., in Nature, Volume 487 (19 July 2012), page 505), and conversely, activation of MAP kinase via KRAS mutation may limit the efficacy of MET pathway blockade. In preclinical KRAS mutant xenograft models, combinations of onartuzumab and cobimetinib demonstrated superior tumor growth control to either agent administered alone (Yang et. al., poster presented at American Association of Cancer Research Annual Meeting, April 6-10, 2013).
MPDL3280A is an antibody directed against PD-L1, the ligand for PD1. The PD-L1/PD1 pathway restrains T-cell activation in response to tumor antigens. In preclinical syngeneic tumor models, combinations of cobimetinib and an anti-PD-L1 antibody were superior to either agent alone. Notably, cobimetinib did not significantly interfere with T-cell activation in response to PD-L1 inhibition (Irving et. al., poster presented at the Society for Immunotherapy of Cancer Annual Meeting, November 7-10, 2013).
Exelixis discovered cobimetinib internally and advanced the compound to investigational new drug (“IND”) status. In late 2006, Exelixis entered into the worldwide co-development agreement with Genentech, under which Exelixis received initial upfront and milestone payments for signing the agreement and submitting the IND. Exelixis was responsible for development of cobimetinib through the end of phase 1, at which point Genentech exercised its option to further develop the compound.
Under the terms of the co-development agreement, Exelixis is entitled to an initial equal share of U.S. profits and losses for cobimetinib, which will decrease as sales increase, and will share equally in the U.S. marketing and commercialization costs. The profit share has multiple tiers—Exelixis is entitled to 50% of profits from the first $200 million of U.S. actual sales, decreasing to 30% of profits from U.S. actual sales in excess of $400 million. Exelixis is entitled to low double-digit royalties on ex-U.S. net sales. Exelixis also has the option to co-promote in the United States. The co-promotion option would allow Exelixis to provide up to 25% of the total sales force for cobimetinib in the United States. Exelixis must exercise the co-promotion option within 12 months of receiving notification of the first patient dosed in the first phase 3 clinical trial of cobimetinib. Exelixis received notification of dosing from Genentech on January 14, 2013, which triggered the beginning of the period in which Exelixis can exercise its co-promotion option. |
