Millennium Highlights New Protein Homeostasis Data in Metastatic Melanoma and Other Solid Tumors at American Society of Cl

CHICAGO--(BUSINESS WIRE)-- Millennium: The Takeda Oncology Company with its parent company Takeda Pharmaceutical Company Limited (TSE:4502) today reported results from two ongoing Phase I studies with investigational therapy MLN4924 in metastatic melanoma and other advanced solid tumors. MLN4924, discovered by Millennium, is a small molecule inhibitor of the NEDD8-Activating Enzyme (NAE), a key component of the protein homeostasis pathway. It is the first small molecule inhibitor specifically targeting this class of enzyme to be studied clinically, and is currently being examined in Phase I clinical trials.

“In these studies, MLN4924 therapy shows promising antitumor activity in patients with advanced solid tumors, with the potential to someday address unmet medical needs in cancers such as melanoma,” said Nancy Simonian, M.D., Chief Medical Officer, Millennium. “The progress we are seeing with MLN4924 is a testament to our continued leadership in the protein homeostasis field, and represents Millennium’s dedication to developing first-in-class therapies for cancer patients.”

MLN4924 Treatment in Patients with Metastatic Melanoma

This ongoing Phase I study assessed the safety, activity, pharmacokinetics (PK), and pharmacodynamics (PD) of MLN4924 in 20 patients with unresectable stage III/IV metastatic melanoma. The primary endpoint was to determine the safety profile and establish the maximum tolerated dose (MTD) of MLN4924. Secondary endpoints were to evaluate antitumor activity of MLN4924, assess PK, and investigate PD effects in blood and tumor cells. The results, which were presented by Shailender Bhatia, M.D., Seattle Cancer Care Alliance, showed:

  • The MTD is 209 mg/m2 on Schedule A (days 1, 4, 8, and 11 every 21 days)
  • Patients with metastatic melanoma were treated with 1-hour intravenous infusions of MLN4924 on days 1, 4, 8, and 11 of 21-day cycles (Schedule A) or MLN4924 on days 1, 8, 15 (schedule B)
  • Adverse events (AEs) were mostly grade 1 or 2, including fatigue, diarrhea, nausea, myalgia, vomiting and anemia
  • Two dose-limiting toxicities (DLTs) have been recorded to date: grade 3 hyperphosphatemia and grade 3 elevated serum creatinine
  • Grade 3 or higher AEs have been reported in 35 percent of patients
  • Nine patients (45%) achieved stable disease (SD), meaning change in size of tumors was not sufficient to be classified as partial response or progressive disease; one patient had a partial response (PR)
  • SD has been maintained for up to 8 cycles in patients with prior rapidly progressive disease
  • Plasma concentrations were similar between days 1 and 11
  • Immunohistochemical analyses of collected tumor biopsies revealed increased levels of two NAE regulated proteins, Cdt-1 and Nrf-2

Analysis of NAE-regulated transcripts in peripheral blood demonstrates the expected PD effects of MLN4924-target inhibition. An expansion cohort is ongoing at the MTD on Schedule A.

MLN4924 Treatment in Patients with Advanced Solid Tumors

This ongoing Phase I study examined 35 patients with a diagnosis of a non-hematologic malignancy for which standard curative/life-prolonging treatment does not exist/is no longer effective. The study was conducted to assess the safety, activity, PK, and PD of MLN4924 in patients with advanced solid tumors across a range of two dosing schedules.

The primary endpoints of the study were to determine the dose-limiting toxicity (DLT) and MTD, describe MLN4924 PK and PD in blood, and investigate PD effects in skin and tumor tissue. Secondary endpoints were to evaluate disease response inhibition of NAE pathway activity in blood, skin, and tumor tissue.

The results, which were presented by John S. Kauh, M.D., Atlanta, Georgia, showed:

  • Schedule A MTD level was previously determined as 50 mg/m2; Schedule B MTD level was 50 mg/m2 ; Schedule C MTD level was 67 mg/m2
  • The 17 patients in dosing Schedule B were treated for a median of 3 cycles (range 1 to 9); the 18 patients in dosing Schedule C were treated for a median of 1.5 cycles (range 1 to 5)
  • Thirty-five percent of patients in Schedule B had melanoma
  • Thirty-nine percent of patients in Schedule C had colorectal cancer
  • Five patients were reported to have experienced DLT, which included grade 3 elevated ALT, grade 2 prolonged AST elevation and grades 1 and 2 hyperbilirubinemia
  • Most adverse events (AEs) were mild or moderate (grade 1 or 2), including fatigue, nausea and hypercalcemia
  • On Schedules B and C, 6 (35%) and 8 (44%) patients, respectively, experienced at least one grade 3 AE
  • A total of 11 patients on Schedule B and 9 patients on Schedule C had stable disease (SD)
  • Seven patients experienced stable disease (SD) durable for at least 4 cycles
  • Three patients with melanoma on Schedule B had SD for at least 4 cycles, one patient had SD for 6 cycles, and one patient had SD for 8 cycles
  • PD effects consistent with NAE target inhibition were observed in tumor tissue following MLN4924 infusion

Patients in Schedule A, B and C received MLN4924 on days 1-5 of 21-day cycles. To date, 17 patients have been enrolled on Schedule B and 18 patients on Schedules C. Co-administration of dexamethasone was investigated in Schedule B based on observations suggesting an acute phase reaction in patients receiving MLN4924.

About MLN4924

MLN4924, discovered by Millennium, is a small molecule inhibitor of the NEDD8-Activating Enzyme (NAE), a key component of the protein homeostasis pathway. NAE is an enzyme that controls the level of proteins critical for the regulation of cancer cell growth and survival pathways. MLN4924 is the first clinically studied small molecule inhibitor that specifically targets this class of enzyme.

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,

About Takeda

Located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to strive towards better health for patients worldwide through leading innovation in medicine. Additional information about Takeda is available through its corporate website,

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Manisha Pai, 617-510-9193
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