Agios Pharmaceuticals, a company focused on discovering and developing novel drugs to treat cancer and inborn errors of metabolism (IEMs), has announced that the first patient has been dosed in a phase I study of AG-120 in patients with advanced hematologic malignancies with an isocitrate dehydrogenase-1 (IDH1) mutation. AG-120 is an orally available, selective, potent inhibitor of the mutated IDH1 protein, making it the first targeted therapeutic candidate to treat patients with cancers that harbor the IDH1 mutation.

“Today’s announcement marks the second cancer metabolism clinical program that we’ve initiated in less than six months, both of which utilize a precision medicine approach that could potentially set up a rapid clinical development pathway,” said David Schenkein, M.D., chief executive officer of Agios. “Initiation of this study also represents a significant milestone for Agios, as we have exclusive U.S. rights for the IDH1 program, as well as for our partner Celgene, who has an option on IDH1 program rights in the rest of the world. Most importantly, we believe this program has the potential to change the treatment of cancer and help patients.”

Groundbreaking research by Agios' scientists established for the first time that the mutated metabolic gene IDH1 has novel enzyme activity consistent with a cancer-causing gene or oncogene. This discovery shows that the mutated form of IDH1 produces a metabolite, 2-hydroxyglutarate (2HG), which may contribute to the formation and malignant progression of many forms of cancer, including hematologic malignancies such as acute myeloid leukemia and solid tumors such as gliomas (the most common type of brain cancer), chondrosarcomas and cholangiocarcinomas.

“We expect that this study will generate important insights about the utility of AG-120 among this genetically defined patient population, for whom there are very few treatment options available,” said Richard Stone, M.D., Dana-Farber Cancer Institute. “This research furthers the field of cancer metabolism and advances potential treatment options for patients whose cancers harbor genetic abnormalities.”

AG-120 is a part of Agios’ global strategic collaboration with Celgene, a biotechnology company. Established in 2010, the goal of the collaboration is to discover, develop and deliver novel, disease-altering oncology therapies based on Agios’ cancer metabolism research platform. The parties also are collaborating on the development of AG-221, an oral, selective, potent inhibitor of the mutated IDH2 protein.

The phase I, multicenter, open-label, dose-escalation clinical trial of AG-120 is designed to assess the safety and tolerability of AG-120 as a single agent. The study is expected to only enroll subjects with an IDH1-mutant hematologic malignancy, including acute myelogenous leukemia (AML) and myelodysplastic syndrome. Key objectives in the study include determining maximum tolerated dose, pharmacokinetics, pharmacodynamics (including inhibition of 2HG) and preliminary anti-tumor activity. Disease-specific expansion cohorts will be enrolled at the maximally tolerated or biologically relevant dose.

The connection between cancer and metabolism has been the central focus for scientists at Agios, who were the first to identify the neo-activity of IDH1 mutations to produce 2HG in research published in Nature in 2009. These insights revealed the potential of IDH1 and IDH2 mutations as novel therapeutic targets in cancer. Mutations in both IDH1 and IDH2 have been linked to numerous hematologic and solid tumor malignancies.

Agios and its collaborators recently demonstrated that IDH1 and IDH2 mutations initiate and drive cancer growth by blocking differentiation, or maturation, of primitive cells. Agios believes that inhibition of these mutated proteins may lead to clinical benefit for the subset of cancer patients whose tumors carry them.

Agios also is conducting a phase I study of AG-221, evaluating its safety, pharmacokinetics, pharmacodynamics and clinical activity in patients with advanced hematologic malignancies that harbor an IDH2 mutation.