Takeda Presents Phase 2 Data on Maintenance with Single-Agent Investigational Ixazomib in Patients with Newly Diagnosed Multiple Myeloma

– Data Featured as Oral Presentation at ASH 2014 –

San Francisco, CA, December 7, 2014 and Osaka, Japan, December 8, 2014– Takeda Pharmaceutical Company Limited (TSE:4502) today announced results from an open-label, Phase 2 study evaluating the safety and efficacy of oral, single-agent ixazomib (MLN9708) as maintenance therapy in patients with multiple myeloma (MM) who had received ixazomib, lenalidomide and dexamethasone as induction therapy. The data from this trial demonstrate the potential feasibility of single-agent ixazomib maintenance therapy following 12 cycles of ixazomib-lenalidomide-dexamethasone, with deepening responses and an acceptable tolerability profile. These data were presented today at the 56th American Society of Hematology (ASH) annual meeting in San Francisco, CA.

“These findings suggest that treatment with single-agent ixazomib, an investigational oral proteasome inhibitor, in the maintenance setting has the potential to extend depth of response for patients following induction therapy,” said Shaji K. Kumar, MD, Mayo Clinic, Rochester, NY. “The future availability of such an agent in the maintenance setting could represent an important addition to the treatment of patients with multiple myeloma.”

“These data suggest that as an oral proteasome inhibitor, ixazomib may be an important new agent for further clinical investigation in the maintenance therapy of multiple myeloma," said Michael Vasconcelles, M.D., Head, Oncology Therapeutic Area Unit, Takeda. “Indeed, we have recently initiated enrollment into our Phase 3 TOURMALINE-MM3 study to assess the potential benefit of single-agent ixazomib following autologous stem cell transplant. We look forward to this study completing enrollment and follow up, so that important new information about the use of ixazomib in the maintenance setting may be learned.”

The primary objective of the Phase 2 component of the study was the percent of patients achieving a very good partial response [VGPR] or better (defined as complete response [CR] + VGPR). Fifty patients were enrolled in the Phase 2 cohort and received ixazomib, lenalidomide and dexamethasone as induction therapy for up to twelve 28-day cycles. Transplant-eligible patients could discontinue from the study for autologous stem cell transplant (ASCT) after six cycles. For those patients continuing on to receive ixazomib maintenance, treatment could continue until disease progression or unacceptable toxicity. All patients who received ixazomib maintenance therapy had responded to induction therapy. During induction (cycles 1–12), 29 patients discontinued study treatment, primarily to undergo autologous stem cell transplant (ASCT) (14/50). Other reasons included AEs (6/50), patient withdrawal (4/50), disease progression (2/50), and unsatisfactory response (1/50), among other factors (2/50). Twenty-one patients completed induction and progressed to the maintenance phase of the study, during which they received single-agent ixazomib for a median of 19 treatment cycles (range 3-23), with a median treatment duration of 29.0 months (range 14.3-33.3). Best overall confirmed/unconfirmed study response rates and additional results for patients who underwent any maintenance therapy were reported as follows:

CR or better was reached in 52 percent of patients (11/21) and VGPR or better was reached in 71 percent of patients (15/21).
- Forty-eight percent of patients improved their response during maintenance (10/21), including two VGPR to near-CR (2/10), five VGPR to CR (5/10), one VGPR to sCR (1/10), and two CR to sCR (2/10).
Median PFS of patients entering maintenance has not been reached.
Fifty-two percent of patients (11/21) remained on ixazomib maintenance after data cut-off.
Median time to first response (≥PR) was 0.99 months (range 0.92–5.78) and median time to best response was 7.46 months (range 1.02–24.74). Mean ixazomib relative dose intensity was 95 percent and 89.5 percent in the induction and maintenance phases, respectively.
All patients who received ixazomib maintenance were alive after follow-up of 25.1–33.9 months from study entry.

During the maintenance phase of the study with single-agent ixazomib, there were no discontinuations due to AEs and no on-study deaths. Drug-related grade 3 adverse events (AEs) were reported in 14 percent of patients during ixazomib maintenance therapy (3/21), and included one each hypokalemia, thrombocytopenia, and cataract as reported by the investigator. No grade 4 drug-related AEs were reported during maintenance.

Serious AEs were reported in 19 percent of patients during maintenance (4/21), including grade 3 acute myocardial infarction, grade 3 pneumonia, grade 3 orthostatic hypotension, and grade 2 ventricular extrasystoles; all were considered not related to treatment. Only two patients required an ixazomib dose reduction due to AEs (neuralgia, peripheral neuropathy).
All grade drug-related adverse events during maintenance included diarrhea (43 percent; 9/21), nausea (19 percent; 4/21), pain in extremity (14 percent; 3/21), anemia (10 percent; 2/21), skin and SC tissue disorders (10 percent; 2/21), headache (10 percent; 2/21), hypokalemia (10 percent; 2/21), and thrombocytopenia (10 percent; 2/21).

The abstract, titled “Long-Term ixazomib maintenance is tolerable and improves depth of response following ixazomib-lenalidomide-dexamethasone induction in patients (pts) with previously untreated multiple myeloma (MM): Phase 2 study results [Abstract #82]” was delivered as an oral presentation by Shaji K. Kumar, MD, Mayo Clinic, Rochester, MN.

About Ixazomib
Ixazomib (MLN9708) is an investigational oral proteasome inhibitor, which is being studied in multiple myeloma (MM), systemic light-chain (AL) amyloidosis and other malignancies. Ixazomib was granted orphan drug designation in MM in both the U.S. and Europe in 2011, and for AL amyloidosis in both the U.S. and Europe in 2012. It is the first oral proteasome inhibitor to enter Phase 3 clinical trials. Four global Phase 3 trials are ongoing: TOURMALINE-MM1, investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in relapsed and/or refractory MM; TOURMALINE-AL1, investigating ixazomib plus dexamethasone in patients with relapsed or refractory AL amyloidosis; TOURMALINE-MM2, investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM; and TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant. For additional information on the ongoing Phase 3 studies please visit www.tourmalinetrials.com or www.clinicaltrials.gov.

About Takeda Pharmaceutical Company Limited

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 people worldwide through leading innovation in medicine. Additional information about Takeda is available through its corporate website, www.takeda.com.

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