Data Presented on Two Novel Millennium Investigational Oncology Drugs at ASCO
Results build on data recently published in Nature for NEDD8-Activating Enzyme (NAE) Inhibitor
MLN4924 is a small molecule aimed at inhibiting the NEDD8-Activating Enzyme (NAE), a Millennium-discovered target upstream of the proteasome. Data providing the preclinical rationale for the advancement of the molecule into clinical trials were recently published in the journal Nature (April 2009). MLN4924 is currently in Phase I clinical trials evaluating its use in the treatment of patients with both solid tumors and hematologic malignancies.
MLN8237 is an oral compound designed to selectively inhibit Aurora A kinase and was discovered and developed by Millennium scientists. Millennium initiated Phase II trials of the compound in March 2009 for the potential treatment of patients with hematologic malignancies; a Phase II trial in patients with ovarian cancer began in April 2009.
“The MLN4924 results build on the pre-clinical research published in Nature and are the first time evidence of NAE inhibition has been demonstrated in man,” said Nancy Simonian, M.D., Chief Medical Officer, Millennium. “Both the MLN4924 and MLN8237 programs are using pharmacodynamic tools, which assist us in translating our pre-clinical findings into cancer patients.”
MLN4924, a Novel NAE Inhibitor, Induces Pharmacodynamic Changes in Blood and Skin
In this Phase I trial in patients with advanced solid tumors, researchers are evaluating the pharmacodynamic effects of MLN4924. The effects are being evaluated by measuring the accumulation of proteins that are indicative of the inhibition of NAE. John Kauh, M.D., Emory University, presented the following results:
- Pharmacokinetic analysis indicated that MLN4924 exposure increased in a dose-proportional manner.
- Skin biopsies and peripheral blood samples demonstrated pharmacodynamic response even at the lowest doses evaluated in the study.
- Treatment-emergent dose-limiting toxicities have included liver enzyme elevations and hypophosphatemia.
Patients in the study received a daily infusion of MLN4924 for five days of a 21-day cycle. Dose escalation is ongoing to establish the maximum tolerated dose of MLN4924. This trial continues to enroll patients. A second Phase I trial treating patients with lymphoma or multiple myeloma is also ongoing.
Phase I pharmacokinetic and pharmacodynamic study of MLN8237, a novel, selective Aurora A kinase inhibitor in patients with advanced solid tumors
In this Phase I study, researchers are investigating the safety, pharmacokinetics and pharmacodynamics of MLN8237 administered orally in patients with advanced solid tumors. Andres Cervantes-Ruiperez, M.D., Ph.D., Hospital Clinical Universitario, presented the following results from 31 patients:
- 50 mg PO BID for seven days of a 21-day cycle was the maximum tolerated dose; the most frequent dose-limiting toxicities were neutropenia with or without stomatitis.
- A pharmacodynamic response consistent with Aurora A inhibition was observed in tumor and skin.
- Anti-tumor activity was seen in one large, treatment-resistant, pliomorphic liposarcoma patient, with treatment ongoing for more than one year.
Patients received MLN8237 orally once daily or twice daily for seven days, followed by a 14-day recovery period. Additional cohorts are planned for this study to evaluate different dosing regimens. The results of this study support future Phase II development.
The Aurora A kinase Inhibitor MLN8237 Combined with Rituximab Induces Additive/Synergistic Anti-tumor Activity in Preclinical B-cell non-Hodgkin's lymphoma models
In this preclinical study, researchers explored the anti-tumor effects of MLN8237 in vivo in preclinical models of human diffuse large B-cell lymphoma (DLBCL). MLN8237 was used as both a single agent and in combination with rituximab. Mengkung Zhang, Ph.D., Millennium: The Takeda Oncology Company, presented the following results:
- MLN8237, as a single agent, induced significant dose-dependent anti-tumor activity in three DLBCL lymphoma models.
- MLN8237 combined with rituximab demonstrated significant additive-to-synergistic anti-tumor activity as well as long-term survival benefit in multiple disseminated and primary diffuse large B-cell lymphoma models.
- MLN8237 is currently being tested as a single agent in a Phase I clinical trial in patients with DLBCL.
Three human DLBCL models were examined in mice. Tumor bearing animals were treated for 21 days with MLN8237 administered orally once daily at 3 to 20 mg/kg; rituximab at 10 mg/kg every seven days, or the two agents combined.
About Millennium
Millennium: The Takeda Oncology Company, a leading biopharmaceutical company based in Cambridge, Mass., markets VELCADE, a first-in-class proteasome inhibitor, and has a robust clinical development pipeline of product candidates. Millennium Pharmaceuticals, Inc. was acquired by Takeda Pharmaceutical Company Ltd. in May, 2008. The Company's research, development and commercialization activities are focused in oncology. Additional information about Millennium is available through its website, www.millennium.com.
Editors' Note: This press release is also available under the Media section of the Company's website at: www.millennium.com.
Contact: Millennium: The Takeda Oncology Company
Manisha Pai, 617-510-9193
Manisha.Pai@mpi.com
or
Lisa Adler, 617-413-1296
Lisa.Adler@mpi.com
