− Positive opinion reinforces the role of ADCETRIS in earlier line of treatment in Hodgkin lymphoma −
Cambridge, Mass. and Osaka, Japan, May 27, 2016 – Takeda Pharmaceutical Company Limited (TSE: 4502) today announced that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for the extension of the current conditional approval of ADCETRIS® (brentuximab vedotin) and recommended its approval for the treatment of adult patients with CD30+ Hodgkin lymphoma at increased risk of relapse or progression following autologous stem cell transplantation (ASCT). On average 50 percent of Hodgkin lymphoma patients relapse after ASCT and those patients with additional risk factors can be at even higher risk of relapse. ADCETRIS after ASCT is a new treatment paradigm based on the largest randomized study ever conducted in relapsed or refractory Hodgkin lymphoma. The AETHERA Phase 3 trial is the first completed study that has explored consolidation treatment immediately following ASCT as a way of extending the effect of transplant for prevention of relapse among people with Hodgkin lymphoma. The use of ADCETRIS in this setting may provide a meaningful treatment option where none currently exist for patients.
“While ASCT is the standard of care following failure of frontline chemotherapy in Hodgkin lymphoma, we know that many patients will unfortunately see their disease return. Early eradication of residual disease through treatment with ADCETRIS has the highest chance of preventing the disease from returning in these patients,” said Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company. “This opinion, in addition to the recent five year overall survival data in relapsed or refractory Hodgkin lymphoma, further establishes the role of ADCETRIS in improving outcomes for patients. We look forward to the European Commission’s authorization of this new indication and bringing this medicine to physicians and patients in the European Union.”
The CHMP positive opinion for ADCETRIS will now be reviewed by the European Commission (EC). If the CHMP recommendation is formally adopted by the EC, which has the authority to approve medicines for the European Union (EU), ADCETRIS will be approved for marketing of this indication in the 28 member states of the EU, Norway Liechtenstein and Iceland.
This opinion is based on the results of the Phase 3 AETHERA study. The AETHERA trial met its primary endpoint with ADCETRIS (plus best supportive care) treatment resulting in a statistically significant improvement in progression-free survival (PFS) versus placebo (plus best supportive care) as assessed by an independent central review committee (hazard ratio=0.57; p-value=0.001), which equates to a 75 percent improvement in PFS. PFS was assessed after a minimum of two years post initiation of treatment for all study patients. An updated analysis conducted after three years of follow up showed sustained PFS improvement (per Independent Review Facility; HR=0.58; 95%CI (0.41,0.81). A pre-specified interim analysis of overall survival showed no statistically significant difference between the treatment arms. The safety profile of ADCETRIS in the AETHERA trial was generally consistent with the existing prescribing information.
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.
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 in CD30+ cutaneous T cell lymphoma (CTCL) and two additional Phase 3 studies, one in frontline classical Hodgkin lymphoma (ECHELON-1) and one in frontline CD30+ mature T-cell lymphomas (ECHELON-2), as well as trials in many additional types of CD30-expressing malignancies.
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 Pharmaceutical Company
Takeda Pharmaceutical Company Limited is a global, R&D-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its research efforts on oncology, gastroenterology and central nervous system therapeutic areas. It also has specific development programs in specialty cardiovascular diseases as well as late-stage candidates for vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. New innovative products, especially in oncology and gastroenterology, as well as its presence in emerging markets, fuel the growth of Takeda. More than 30,000 Takeda employees are committed to improving quality of life for patients, working with our partners in health care in more than 70 countries. For more information, visit http://www.takeda.com/news/.
Additional information about Takeda is available through its corporate website, http://betterhealth.takeda.com/, and additional information about Takeda Oncology, the brand for the global oncology business unit of Takeda Pharmaceutical Company Limited, is available through its website, http://www.takedaoncology.com/.
ADCETRIS® is indicated for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL):
1. following autologous stem cell transplant (ASCT) or
2. following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option.
ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).
IMPORTANT SAFETY INFORMATION
ADCETRIS is contraindicated for patients with hypersensitivity to brentuximab vedotin and its excipients. In addition, combined use of bleomycin and ADCETRIS causes pulmonary toxicity, and is contraindicated.
SPECIAL WARNINGS & PRECAUTIONS
Progressive multifocal leukoencephalopathy (PML): John Cunningham virus (JCV) reactivation resulting in PML and death can occur in patients treated with ADCETRIS. PML has been reported in patients who received ADCETRIS after receiving multiple prior chemotherapy regimens.
Patients should be closely monitored for new or worsening neurological, cognitive, or behavioral signs or symptoms, which may be suggestive of PML. Suggested evaluation of PML includes neurology consultation, gadolinium-enhanced magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or a brain biopsy with evidence of JCV. ADCETRIS dosing should be held for any suspected case of PML and should be permanently discontinued if a diagnosis of PML is confirmed.
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, which may be suggestive of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. ADCETRIS should be held for any suspected case of acute pancreatitis. ADCETRIS should be discontinued if a diagnosis of acute pancreatitis is confirmed.
Pulmonary Toxicity: Cases of pulmonary toxicity have been reported in patients receiving ADCETRIS. Although a causal association with ADCETRIS has not been established, the risk of pulmonary toxicity cannot be ruled out and patients should be treated appropriately.
Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteremia, 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. If anaphylaxis occurs, administration of ADCETRIS should be immediately and permanently discontinued and appropriate medical therapy should be administered. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. The infusion may be restarted at a slower rate after symptom resolution. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions.
Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS. Patients with rapidly proliferating tumor and high tumor burden are at risk of TLS. These patients 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. ADCETRIS-induced PN is typically cumulative. Patients should be monitored for symptoms of PN, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Dose modification for PN should be instituted accordingly.
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): SJS and toxic epidermal necrolysis (TEN) have been reported with brentuximab vedotin. Fatal outcomes have been reported. If SJS or TEN occurs, treatment with ADCETRIS should be discontinued and appropriate medical therapy should be administered.
Hepatic function: Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported. Liver function should be routinely monitored in patients receiving brentuximab vedotin.
Hyperglycemia: Hyperglycemia has been reported during trials in patients with an elevated body mass index (BMI) with or without a history of diabetes mellitus. However, any patient who experiences an event of hyperglycemia should have their serum glucose closely monitored. Antidiabetic treatment should be administered as appropriate.
Renal and Hepatic Impairment: There is limited experience in patients with renal and hepatic impairment. Available data indicate that MMAE clearance might be affected by severe renal impairment (MMAE exposure increased approximately 1.9-fold), hepatic impairment (MMAE exposure increased approximately 2.3-fold), and by low serum albumin concentrations (MMAE clearance was 2-fold lower). The recommended starting dose in patients with hepatic impairment or severe renal impairment is 1.2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Patients with renal or hepatic impairment should be closely monitored for adverse events.
Sodium content in excipients: This medicinal product contains a maximum of 2.1 mmol (or 47 mg) of sodium per dose. To be taken into consideration for patients on a controlled sodium diet.
Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse events. Coadministration of ADCETRIS with CYP3A4 inducers did not alter the metabolism of ADCETRIS; however, it reduced exposure to MMAE by approximately 31%. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.
PREGNANCY: Women of childbearing potential should be using 2 methods of effective contraception during treatment with ADCETRIS and until 6 months after treatment. There are no data from the use of ADCETRIS in pregnant women, although studies in animals have shown reproductive toxicity. ADCETRIS should not be used during pregnancy unless the benefit to the mother outweighs the potential risks to the fetus. If a pregnant woman needs to be treated, she should be clearly advised on the potential risk to the fetus.
LACTATION (breast-feeding): There are no data as to whether ADCETRIS or its metabolites are excreted in human milk, therefore a risk to the newborn/infant cannot be excluded.
FERTILITY: In nonclinical studies, ADCETRIS treatment has resulted in testicular toxicity, and may alter male fertility. Men being treated with this medicine are advised not to father a child during treatment and for up to 6 months following the last dose.
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.
In the clinical studies of ADCETRIS, adverse reactions defined as very common (≥1/10) were: infection, neutropenia, peripheral sensory neuropathy, diarrhea, nausea, vomiting, alopecia, pruritus, myalgia, fatigue, pyrexia, and infusion-related reactions. Adverse reactions defined as common (≥1/100 to <1/10) were: Sepsis/septic shock (including fatal events), 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.
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