On June 24, 2015 Agios Pharmaceuticals reported dose administration for the first patient in a Phase 1, open-label, dose-escalation and expansion study of single agent AG-881, a small molecule that has shown in preclinical studies to fully penetrate the blood-brain barrier and inhibit isocitrate dehydrogenase-1 (IDH1) and IDH2 mutations in cancer models (Press release, Agios Pharmaceuticals, JUN 24, 2015, View Source [SID:1234505798]). Schedule your 30 min Free 1stOncology Demo! "The initiation of this study represents a significant milestone for Agios, as it marks the third program from our portfolio of IDH inhibitors to enter the clinic in less than two years," said Chris Bowden, M.D., chief medical officer of Agios. "We look forward to producing important early data to guide our future development plans and continuing to demonstrate Agios’ leadership in cancer metabolism and drug development for IDH inhibitors."
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"We are eager to explore the profile of AG-881 as we continue to investigate the role of IDH inhibitors for the treatment of patients with IDH mutant-positive tumors," said Howard Burris, M.D., Sarah Cannon Research Institute, an investigator for the study. "The Phase 1 study of this second-generation IDH inhibitor expands the opportunities for clinical development in the genetically defined spectrum of IDH1 or IDH2 mutant-positive tumors."
About the AG-881 Phase 1 Study in Advanced Solid Tumors, including Gliomas, with an IDH1 or IDH2 Mutation
The purpose of the Phase 1 multi-center, open-label study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-881 in advanced solid tumors. AG-881 will be administered continuously as a single agent dosed orally in a 28-day cycle. The first portion of the study includes a dose-escalation phase in which cohorts of patients will receive ascending oral doses of AG-881 to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose based on safety and tolerability. The second portion of the study is a dose expansion phase where patients will receive AG-881 to further evaluate the safety, tolerability and clinical activity of the recommended Phase 2 dose. Please refer to www.clinicaltrials.gov for additional clinical trial information.
Upcoming Milestones for AG-881
A second dose-escalating and expansion trial, for patients with advanced IDH1 or IDH2 mutant-positive hematologic malignancies whose cancer has progressed on a prior IDH inhibitor therapy, is expected to begin shortly.
About IDH Mutations and Cancer
IDH1 and IDH2 are two metabolic enzymes that are mutated in a wide range of hematologic and solid tumor malignancies, including acute myeloid leukemia (AML) and gliomas. Normally, IDH enzymes help to break down nutrients and generate energy for cells. When mutated, IDH increases production of an oncometabolite 2-hydroxyglutarate (2HG) that alters the cells’ epigenetic programming, thereby promoting cancer. 2HG has been found to be elevated in several tumor types. Agios believes that inhibition of the mutated IDH proteins may lead to clinical benefit for the subset of cancer patients whose tumors carry them.
Summary of Agios and Celgene Collaboration on IDH Mutant Inhibitors
Agios and Celgene entered a global, strategic collaboration in April 2010, and to date, three potential new distinct investigational medicines have emerged – the IDH2 mutant inhibitor, AG-221; the IDH1 mutant inhibitor, AG-120; and the pan-IDH mutant inhibitor, AG-881, which was recently announced as part of a new collaboration between the companies. These three investigational medicines aim to improve treatment outcomes for patients whose cancers carry IDH mutations, including difficult-to-treat AML and glioma, a type of aggressive brain tumor with a poor prognosis.
Each of these investigational medicines carries different financial terms and rights under the collaboration:
AG-221: Celgene has worldwide development and commercialization rights for AG-221. Agios is eligible for up to $120 million in milestone payments and royalties on any net sales.
AG-120: Agios retains U.S. development and commercialization rights, while Celgene has development and commercialization rights outside the U.S. Agios is eligible to receive royalties on any net sales outside the U.S. and up to $120 million in milestone payments. Celgene is eligible to receive royalties on any net sales in the U.S.
AG-881: Joint worldwide development and 50/50 profit share collaboration. Agios is eligible to receive regulatory milestone payments up to $70 million.