News Release

Takeda Announces Presentation of New Analysis from Phase 3 AETHERA Clinical Trial for ADCETRIS® (Brentuximab Vedotin) in Hodgkin Lymphoma Patients at Risk of Relapse Following ASCT

– Results from Post Hoc Sub-analysis of AETHERA Study Show Improved Progression-free Survival in Primary Refractory Patients Treated with ADCETRIS Following Transplant Compared to Placebo –

Lugano, Switzerland, June 23, 2015 – Takeda Pharmaceutical Company Limited (TSE: 4502) announced today that results from a new sub-analysis of the Phase 3 AETHERA clinical trial were presented at the 13th International Conference on Malignant Lymphoma (ICML) Annual Meeting taking place in Lugano, Switzerland, June 17-20, 2015. Results from the initial analysis of AETHERA, presented at the 2014 American Society of Hematology (ASH) Annual Meeting, demonstrated statistically significant improvement in progression-free survival (PFS) with ADCETRIS® (brentuximab vedotin) versus placebo. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, which is expressed in classical Hodgkin lymphoma and systemic anaplastic large cell lymphoma (sALCL), a type of T-cell lymphoma. ADCETRIS is currently not approved in the AETHERA treatment setting.

The sub-analysis further evaluates the role of ADCETRIS in the treatment of patients at high-risk of residual disease following autologous stem cell transplant (ASCT), including those who did not achieve a complete response following first-line treatment. Results demonstrated that primary refractory patients who were treated with ADCETRIS had significant improvement in two-year PFS compared with patients who received a placebo [60 percent compared to 42 percent, respectively; hazard ratio (HR)=0.55; n=196].

“Through our robust ongoing clinical development program, we have continued to see the benefit of ADCETRIS, particularly in Hodgkin lymphoma patient populations that would typically face a poor prognosis. The results of the AETHERA analysis presented at this year’s ICML meeting provide further evidence of the benefit of ADCETRIS in this treatment setting, particularly among certain high-risk patient populations,” said Dirk Huebner, M.D., Senior Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company. “Takeda’s presence at ICML is part of our commitment to focus our research on hematological malignances that have high unmet medical need, and we thank the patients and their families for their participation in this trial.”

The Phase 3 AETHERA trial was designed to evaluate the potential of single agent ADCETRIS to extend PFS following ASCT in patients with Hodgkin lymphoma who have at least one risk factor for progression. In addition to the primary endpoint of PFS, secondary endpoints included overall survival (OS), safety and tolerability. Eligible patients must have had any of the following: a history of refractory Hodgkin lymphoma, have relapsed within one year from receiving frontline chemotherapy and/or have had disease outside of the lymph nodes at the time of pre-ASCT relapse. These factors are consistently reported to be associated with poor prognosis after transplant. Patients received ADCETRIS or placebo every three weeks for up to approximately one year. This international multi-center trial was conducted at 78 sites in the United States, Eastern and Western Europe and Russia.

Analysis of Primary-Refractory Hodgkin Lymphoma Patients in a Randomized, Placebo-Controlled Study of Brentuximab Vedotin Consolidation after Autologous Stem Cell Transplant (Abstract #120, presented June 19, 2015)
This sub-analysis found that ADCETRIS consolidation following ASCT improved PFS in primary-refractory Hodgkin lymphoma patients, as well as across several subgroups of this population at increased risk of progression following ASCT. Furthermore, two-year PFS and three-year OS rates compared favorably with historical controls. Key findings from the study were presented by lead author Craig H. Moskowitz, M.D., Memorial Sloan-Kettering Cancer Center, New York City.

  • 329 patients were randomized to receive 16 cycles of ADCETRIS or placebo at 78 sites in the U.S. and Europe; primary refractory patients comprised 60 percent of the intent-to-treat population (n=99 in the ADCETRIS arm and n=97 in the placebo arm).
  • The median age of patients included in the sub-analysis was 33 years for those in the ADCETRIS group and 31 years for those in the placebo group.
  • Reasons for discontinuation of the AETHERA trial included completion of all 16 cycles of treatment (51 percent for ADCETRIS and 49 percent for placebo), progressive disease (20 percent for ADCETRIS and 43 percent for placebo), and adverse events (26 percent for ADCETRIS and 6 percent for placebo).
  • In the sub-analysis, three-year OS rates were not different between treatment arms (81 percent for ADCETRIS and 79 percent for placebo; HR=1.19).

A second AETHERA-related sub-analysis titled, “Brentuximab Vedotin in Patients at Increased Risk of Hodgkin Lymphoma Progression Post Autologous Stem Cell Transplant: Evaluation of Healthcare Resource Utilization in the AETHERA trial” (Abstract #177, Poster) was also presented as a poster at ICML by lead author Vijayveer Bonthapally, PhD, Global Outcomes Epidemiology Research, Takeda Oncology. Preliminary results suggest a trend toward lower healthcare resource utilization rates among patients in the AETHERA clinical trial, including a lower hospitalization rate per patient and a shorter duration of hospital stays, among the ADCETRIS-treated patients compared to placebo.”

About ADCETRIS®
ADCETRIS® (brentuximab vedotin) is an antibody drug conjugate (ADC) comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics' proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.
ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. ADCETRIS has received marketing authorization by regulatory authorities in 55 countries. See important safety information below.
Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

About Hodgkin Lymphoma
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell generally expresses CD30.
According to the American Cancer Society, approximately 9,200 cases of Hodgkin lymphoma will be diagnosed in the United States during 2014 and more than 1,200 will die from the disease. Globally, there are more than 62,000 cases of Hodgkin lymphoma diagnosed each year. Although frontline combination chemotherapy can result in durable response rates, up to 30 percent of these patients relapse or are refractory to frontline treatment and have few therapeutic options beyond ASCT.

ADCETRIS Global Important Safety Information
ADCETRIS® is indicated for the treatment of adult patients with relapsed or refractory (r/r) CD30+ Hodgkin lymphoma:

  1. Following autologous stem cell transplant or
  2. Following at least two prior therapies when autologous stem cell transplantation is not a treatment option

ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).
ADCETRIS is contraindicated for patients who are hypersensitive to ADCETRIS. In addition, combined use of bleomycin and ADCETRIS causes pulmonary toxicity, and is contraindicated.
ADCETRIS can cause serious side effects, including:

  • Progressive multifocal leukoencephalopathy (PML): John Cunningham virus (JCV) reactivation resulting in PML and death has been reported in patients treated with ADCETRIS. Patients should be closely monitored for new or worsening neurological, cognitive, or behavioral signs or symptoms, which may be suggestive of PML.
  • Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported. Patients should be closely monitored for new or worsening abdominal pain.
  • Pulmonary Toxicity: Cases of pulmonary toxicity have been reported in patients receiving ADCETRIS. In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnoea), a prompt diagnostic evaluation should be performed.
  • Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteraemia, sepsis/septic shock (including fatal outcomes), and herpes zoster, and opportunistic infections such as Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with ADCETRIS. Patients should be carefully monitored during treatment for emergence of possible serious and opportunistic infections.
  • Infusion-related reactions: Immediate and delayed infusion-related reactions, as well as anaphylaxis, have occurred with ADCETRIS. Patients should be carefully monitored during and after an infusion.
  • Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS. Patients with rapidly proliferating tumor and high tumor burden are at risk of TLS and should be monitored closely and managed according to best medical practice.
  • Peripheral neuropathy (PN): ADCETRIS treatment may cause PN that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. Patients should be monitored for symptoms of PN, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness.
  • Hematological toxicities: Grade 3 or Grade 4 anemia, thrombocytopenia, and prolonged (equal to or greater than one week) Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose.
  • Febrile neutropenia: Febrile neutropenia has been reported. Patients should be monitored closely for fever and managed according to best medical practice.
  • Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN): SJS and TEN have been reported. Fatal outcomes have been reported.
  • Hyperglycemia: Hyperglycemia has been reported during trials in patients with an elevated body mass index (BMI) with or without a history of diabetes mellitus. Any patient who experiences an event of hyperglycemia should have their serum glucose closely monitored.
  • Renal and hepatic impairment: There is limited experience in patients with renal and hepatic impairment. Population pharmacokinetic analysis indicated that MMAE clearance might be affected by moderate and severe renal impairment, and by low serum albumin concentrations. Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported. Liver function should be routinely monitored in patients receiving brentuximab vedotin.
  • Sodium content in excipients: This medicinal product contains a maximum of 2.1 mmol (or 47mg) of sodium per dose. To be taken into consideration for patients on a controlled sodium diet.

Serious adverse drug reactions were: neutropenia, thrombocytopenia, constipation, diarrhea, vomiting, pyrexia, peripheral motor neuropathy and peripheral sensory neuropathy, hyperglycemia, demyelinating polyneuropathy, tumor lysis syndrome, and Stevens-Johnson syndrome.
ADCETRIS was studied as monotherapy in 160 patients in two Phase 2 studies. Across both studies, adverse reactions defined as very common (≥1/10) were: infections, neutropenia, peripheral sensory neuropathy, diarrhea, nausea, vomiting, alopecia, pruritis, myalgia, fatigue, pyrexia, and infusion-related reactions. Adverse reactions defined as common (≥1/100 to <1/10) were: upper respiratory tract infection, herpes zoster, pneumonia, anemia, thrombocytopenia, hyperglycemia, peripheral motor neuropathy, dizziness, demyelinating polyneuropathy, cough, dyspnea, constipation, rash, arthralgia, back pain, and chills.
These are not all of the possible side effects with ADCETRIS. Please refer to Summary of Product Characteristics (SmPC) before prescribing.

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