Additional Presentation: Phase 2 Results From an Investigational study of Ixazomib plus Cyclophosphamide and Low-Dose Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma

Orlando, FL (Press Release) – Takeda Pharma­ceu­tical Company Limited (TSE:4502) today announced results from the TOURMALINE-MM1 trial presented at the 57^th Annual Meeting and Exposition of the American Society of Hematology (ASH), showing that treat­ment with NINLARO^® (ixazomib) capsules is effective in extending pro­gres­sion free survival (PFS) with a man­age­able tolerability profile in patients with re­lapsed and/or refractory multiple myeloma. The TOURMALINE-MM1 trial is an inter­na­tional, ran­dom­ized, double-blind, placebo-controlled Phase 3 clin­i­cal trial designed to eval­u­ate once-weekly oral ixazomib plus lena­lido­mide and dexa­meth­a­sone compared to placebo plus lena­lido­mide and dexa­meth­a­sone.

NINLARO was recently approved by the U.S. Food and Drug Admin­istra­tion (FDA) in com­bi­na­tion with lena­lido­mide and dexa­meth­a­sone for the treat­ment of patients with multiple myeloma who have received at least one prior ther­apy. The approval was based on the Phase 3 TOURMALINE-MM1 data, which were highlighted at today’s ASH press briefing. Ixazomib data will be featured in 18 presentations at this year’s ASH meeting, in­­clud­ing an oral presentation on Phase 2 data from an inves­ti­ga­tional study eval­u­ating the all-oral com­bi­na­tion of ixazomib plus cyclophosphamide and low-dose dexa­meth­a­sone (ICd) in newly diag­nosed multiple myeloma patients.

“The data presented at ASH this year are the first major output from the com­pre­hen­sive ixazomib clin­i­cal trial pro­gram, TOURMALINE, demonstrating Takeda’s ongoing commitment to providing effective and convenient treat­ment options for patients with multiple myeloma,” said Andy Plump, M.D., Ph.D, Takeda Chief Medical and Scientific Officer. “The breadth and depth of the TOURMALINE pro­gram allows us to gather im­por­tant data across a broad range of patients that live with multiple myeloma and to expand on the efficacy and safety profile of our oral pro­te­a­some inhibitor, ixazomib. We will con­tinue this and other im­por­tant clin­i­cal trials and look forward to sharing results over the next few years.”

The com­pre­hen­sive ixazomib clin­i­cal devel­op­ment pro­gram, TOURMALINE, in­cludes a total of five pivotal trials – four investigating every major multiple myeloma patient pop­u­la­tion and one in light-chain amyloid­osis.

Ixazomib, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Lena­lido­mide and Dexamethasone (IRd), Significantly Extends Progression-Free Survival (PFS) for Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): The Phase 3 Tourmaline-MM1 Study (Abstract #727)

TOURMALINE-MM1 (n= 722) is the first double-blind, placebo-controlled trial with a pro­te­a­some inhibitor and has met the pri­mary end­point at the first interim analysis. Trial results dem­onstrate a statistically sig­nif­i­cant (35%) im­prove­ment in PFS, with patients treated in the ixazomib arm living for a sig­nif­i­cantly longer time without their disease worsening compared to patients in the control arm (20.6 months vs. 14.7 months in control group; Hazard Ratio [HR] 0.742; p = 0.012). Overall response rate (ORR) was 78.3% in the ixazomib arm and median duration of response was 20.5 months, vs. 71.5% and 15 months in the control group. Median PFS in high-risk patients (HR 0.543; HR 0.596 in patients with del(17p)) was similar to that in the over­all patient pop­u­la­tion and in standard-risk patients. Adverse events observed with IRd were con­sis­tent with reported safety profiles for the individual agents. The most common gr ≥3 adverse events in­cluded neu­tro­penia, anemia, thrombo­cytopenia, and pneu­monia. Gastrointestinal events in­cluded diarrhea, nausea, and vomiting. Peripheral neu­rop­athy (PN) rates were 28% in the IRd arm vs. 21% in the control arm, 35% vs. 21% had rash events, 8% vs. 10% had acute renal failure, and 4% vs. 3% had heart failure.

“The TOURMALINE-MM1 trial eval­u­ated ixazomib plus lena­lido­mide and dexa­meth­a­sone in some of the most common patient types in the re­lapsed / refractory multiple myeloma setting who are in urgent need of new treat­ment options due to the complex nature of this disease. This trial enabled us to gather efficacy and safety data across a large variety of patients such as older patients, patients with mod­er­ate renal im­pair­ment, light chain disease, and high risk cytogenetics,” said lead investigator and presenter Philippe Moreau, M.D., University of Nantes, France.”

The TOURMALINE-MM1 trial is cur­rently ongoing. Patients con­tinue to be treated to pro­gres­sion in this trial and will be eval­u­ated for long-term out­comes.

Takeda has submitted addi­tional review appli­ca­tions for ixazomib to regu­la­tory author­i­ties around the world, in­­clud­ing the European Medicines Agency (EMA), based on the TOURMALINE-MM1 data.

Randomized Phase 2 Study of the All-Oral Combination of Investigational Proteasome Inhibitor (PI) Ixazomib Plus Cyclophosphamide and Low-Dose Dexamethasone (ICd) in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Who Are Transplant-Ineligible (Abstract #26)

Takeda also presented pre­lim­i­nary data from an open-label, multi­center, Phase 2 study that in­ves­ti­gates the all-oral triplet com­bi­na­tion of ixazomib plus cyclophosphamide and low-dose dexa­meth­a­sone (ICd) as a first line ther­apy for patients not eli­gible for trans­plant. Preliminary data dem­onstrated com­parable activity across treat­ment arms with a man­age­able toxicity profile in line with pre­vi­ous ixazomib studies and with man­age­able myelosuppression. This is the first study to assess ICd for the frontline treat­ment of multiple myeloma.

The Phase 2 study (n = 70) ran­dom­ized patients receiving ixazomib, low-dose dexa­meth­a­sone and two dif­fer­en­t doses of cyclophosphamide 300 mg/m2 (ICd-300, n = 36) or 400 mg/m2 (ICd-400, n = 34), with a mean duration follow-up of 7.0 months in both arms. Preliminary results across treat­ment arms dem­onstrated best unconfirmed com­plete response plus very good partial response (CR+VGPR) of 27% (ICd-300) and 23% (ICd-400), as well as early over­all response rates (ORR) of 80% (ICd-300) and 73% (ICd-400). Toxicity was man­age­able in both the ICd-300 and ICd-400 arms, but toxicity rates appeared higher with ICd-400. Thrombo­cyto­penia events occurred in 5 patients (no gr ≥3) in the ICd-300 arm and 4 patients (3 gr ≥3) in the ICd-400 arm. Most common adverse events (>15% all patients) in­cluded anemia, neu­tro­penia, nausea, PN, diarrhea, vomiting, con­sti­pa­tion, and fatigue. Most common gr ≥3 adverse events were neu­tro­penia, anemia and pneu­monia; no Grade 3 PN was observed.

“Research has shown that the com­bi­na­tion of a pro­te­a­some inhibitor with cyclophosphamide and dexa­meth­a­sone is active in patients with multiple myeloma. As treat­ment practices for multiple myeloma can vary across regions, it is im­por­tant that we gain an under­stand­ing of the utility of ixazomib in a number of com­bi­na­tion settings,” said lead investigator and presenter Meletios A. Dimopoulos, M.D., National and Kapodistrian University of Athens, School of Medicine. “Preliminary data suggest that this may be a viable all-oral triplet regi­men. We are committed to gathering addi­tional data of ixazomib in this inves­ti­ga­tional setting.”

About NINLARO (ixazomib) capsules

NINLARO (ixazomib) is the first and only oral pro­te­a­some inhibitor approved by the U.S. Food and Drug Admin­istra­tion (FDA) in com­bi­na­tion with lena­lido­mide and dexa­meth­a­sone for the treat­ment of patients with multiple myeloma who have received at least one prior ther­apy. NINLARO is admin­istered orally, once-weekly on days 1, 8, and 15 of a 28-day treat­ment cycle. NINLARO is cur­rently under review by the European Medicines Agency (EMA) and was granted an accelerated assess­ment by the Committee for Medicinal Products for Human Use (CHMP). NINLARO also received Break­through Therapy status by the U.S. FDA for re­lapsed or refractory systemic light-chain (AL) amyloidosis, a related ultra orphan disease, in 2014.

The TOURMALINE clin­i­cal devel­op­ment pro­gram further reinforces Takeda’s ongoing commitment to devel­op­ing inno­va­tive ther­a­pies for people living with multiple myeloma world­wide and the health­care professionals who treat them. Five global Phase 3 trials are ongoing:

• TOURMALINE-MM1, investigating ixazomib vs. placebo, in combination with lenalidomide and dexa­meth­a­sone in relapsed and/or refractory multiple myeloma
• TOURMALINE-MM2, investigating ixazomib vs. placebo, in combination with lenalidomide and dexa­meth­a­sone in patients with newly diagnosed multiple myeloma
• TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)
• TOURMALINE-MM4, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT
• TOURMALINE-AL1, investigating ixazomib plus dexa­meth­a­sone vs. physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis
• In addition to the TOURMALINE program, a large number of investigator initiated studies are evaluating ixazomib for patients globally.

For addi­tional in­­for­ma­tion on the ongoing Phase 3 studies please visit www.clinicaltrials.gov. To learn more about NINLARO, please visit www.NINLARO.com or call 1-844-N1POINT (1-844-617-6468).

Important Safety Information

WARNINGS AND PRECAUTIONS

• Thrombocytopenia has been reported with NINLARO. During treatment, monitor platelet counts at least monthly, and consider more frequent monitoring during the first three cycles. Adjust dosing as needed. Platelet nadirs occurred between Days 14-21 of each 28-day cycle and recovered to baseline by the start of the next cycle.
• Gastrointestinal Toxicities, including diarrhea, constipation, nausea and vomiting, were reported with NINLARO and may occasionally require the use of antidiarrheal and antiemetic medications, and supportive care. Adjust dosing for severe symptoms.
• Peripheral Neuropathy (predominantly sensory) was reported with NINLARO. Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.
• Peripheral Edema was reported with NINLARO. Monitor for fluid retention. Investigate for underlying causes when appropriate and provide supportive care as necessary. Adjust dosing as needed.
• Cutaneous Reactions: Rash, most commonly maculo-papular and macular rash, was reported with NINLARO. Manage rash with supportive care or with dose modification.
• Hepatotoxicity has been reported with NINLARO. Monitor hepatic enzymes regularly during treatment and adjust dosing as needed
• Embryo-fetal Toxicity: NINLARO can cause fetal harm. Women should be advised of the potential risk to a fetus, to avoid becoming pregnant, and to use contraception during treatment and for an additional 90 days after the final dose of NINLARO.

ADVERSE REACTIONS

The most common adverse reac­tions occurring in greater than or equal to 20% of patients treated with NINLARO were diarrhea, con­sti­pa­tion, thrombo­cytopenia, periph­eral neu­rop­athy, nausea, periph­eral edema, vomiting and back pain.

SPECIAL POPULATIONS

• Hepatic Impairment: Reduce the NINLARO starting dose to 3mg in patients with moderate or severe hepatic impairment
• Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease requiring dialysis. NINLARO is not dialyzable.
• Lactation: Advise women to discontinue nursing while on NINLARO.

DRUG INTERACTIONS: Avoid concomitant admin­istra­tion of NINLARO with strong CYP3A inducers.

INDICATION

NINLARO (ixazomib) is indicated in com­bi­na­tion with lena­lido­mide and dexa­meth­a­sone for the treat­ment of patients with multiple myeloma who have received at least one prior ther­apy.

Please see the accompanying full Prescribing Information for NINLARO.

About Multiple Myeloma

Multiple myeloma is a cancer of the plasma cells, which are found in the bone marrow. In multiple myeloma, a group of plasma cells, or myeloma cells, becomes can­cer­ous and multiplies, in­creas­ing the number of plasma cells to a higher than normal level. Because plasma cells circulate widely in the body, they have the poten­tial to affect many bones in the body, possibly resulting in compression fractures, lytic bone lesions and related pain. Multiple myeloma can cause a number of serious health problems affecting the bones, immune system, kidneys and red blood cell count, with some of the more common symp­toms in­­clud­ing bone pain and fatigue, a symp­tom of anemia. Multiple myeloma is a rare form of cancer, with more than 26,000 new cases in the U.S. and 114,000 new cases globally per year.

About Takeda

Located in Osaka, Japan, Takeda (TSE:4502) 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.