– Data Featured as Oral Presentation at ASH 2014 –

San Francisco (Press Release) –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, MN. “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 inno­va­t in medicine. Additional in­­for­ma­tion about Takeda is avail­able through its corporate website, www.takeda.com.

Source: Takeda Pharma­ceu­ticals.