European Commission Approves Label Variation for ADCETRIS® (Brentuximab Vedotin) to Include Data on Retreatment of Adult Patients with Relapsed or Refractory Hodgkin Lymphoma and Systemic Anaplastic Large Cell Lymphoma (sALCL)

CAMBRIDGE, Mass. & OSAKA, Japan

Takeda Pharmaceutical Company Limited (TSE:4502) today announced that the European Commission (EC) has approved a Type II variation for ADCETRIS^® (brentuximab vedotin) to include data on the retreatment of adult patients with relapsed or refractory (R/R) Hodgkin lymphoma or R/R systemic anaplastic large cell lymphoma (sALCL) who previously responded to ADCETRIS and who later relapse. The decision from the EC follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in October 2015.

ADCETRIS was granted conditional marketing authorization by the EC in 2012 for the treatment of R/R CD30+ Hodgkin lymphoma following autologous stem cell transplant (ASCT), or at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and for R/R sALCL.

The SmPC variation includes an update to the clinical sections, including safety, to include data on retreatment of adult patients who have responded to previous treatment with ADCETRIS (CR or PR) under the existing indications, but later relapsed.

The Type II variation is based on data from the Phase 2 SGN35-006 Part A study that demonstrated effective anti-tumor responses can be achieved in the majority of R/R Hodgkin lymphoma and sALCL patients with ADCETRIS retreatment. The safety and efficacy results from this trial were consistent with the positive profile demonstrated in the pivotal Phase 2 studies (SGN35-003 and SGN35-004).

“ADCETRIS has transformed the treatment landscape for relapsed/refractory Hodgkin lymphoma and sALCL patients in Europe, and has emerged as a most valuable tool to induce a remission. However, lymphoma is a relentless disease, and relapse occurs in some of these very difficult to treat patients. Now, with the opportunity for retreatment, we can offer patients with very limited options another chance to potentially benefit from ADCETRIS,” said Professor Anton Hagenbeek, M.D., Ph.D., Professor of Hematology, Department of Hematology, Academic Medical Center in the University of Amsterdam.

“The EC decision to include data on retreatment in the ADCETRIS label is important in advancing care for patients battling these diseases,” said Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda. “We look forward to continuing our ongoing clinical program of ADCETRIS in Hodgkin lymphoma and sALCL, as well as in a variety of other forms of lymphoma, with the goal of bringing this important therapy to patients who might benefit from it.”

For further details about the EC decision, please visit the EMA website: www.ema.europa.eu/ema.

SGN35-006 Part A Study
The SGN35-006 Part A study, entitled “Treatment with SGN-35 in patients with CD30-positive hematologic malignancies who have previously participated in an SGN-35 study,” was a Phase 2, multicenter, open-label study. The study was designed to evaluate ADCETRIS retreatment in patients with Hodgkin lymphoma (20 patients) or sALCL (8 patients) that recurred after a previous response to ADCETRIS (Part A). Primary objectives were safety and anti-tumor response. Secondary objectives were duration of tumor control, including duration of response and progression-free survival (PFS), overall survival (OS) and incidence of anti-therapeutic antibodies (ATA).

For more information about the trial, please visit www.clinicaltrialsregister.eu.

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 expresses CD30.

About Anaplastic Large Cell Lymphoma
Anaplastic Large Cell Lymphoma (ALCL) is a type of aggressive T-cell lymphoma, comprising about 3 percent of all non-Hodgkin lymphomas (NHL) in adults and between 10 and 30 percent of all NHL in children. There are two distinct forms/types of ALCL, including primary cutaneous ALCL and systemic ALCL (sALCL). sALCL is a clinically aggressive, systemic lymphoma that primarily involves lymph nodes and expresses CD30.

About ADCETRIS
ADCETRIS® (brentuximab vedotin) is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing proprietary technology by Seattle Genetics. 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 autologous stem cell transplant (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 systemic anaplastic large cell lymphoma (sALCL). In January 2016, the European Commission approved a Type II variation to include data on the retreatment of adult patients with Hodgkin lymphoma or sALCL who previously responded to ADCETRIS and who later relapse. ADCETRIS has received marketing authorization by regulatory authorities in more than 60 countries. See important safety information below.

ADCETRIS is being evaluated broadly in more than 45 ongoing clinical trials, including the Phase 3 ALCANZA trial and two additional Phase 3 studies, one in frontline classical Hodgkin lymphoma and one in frontline mature T-cell lymphomas, as well as trials in many additional types of CD30-expressing malignancies, including B-cell lymphomas.

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

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 2 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.

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