Seattle Genetics and Takeda Report Phase 3 AETHERA Clinical Trial Data from ADCETRIS® (Brentuximab Vedotin) in Post-Transplant Hodgkin Lymphoma Patients at Risk of Relapse at ASH Annual Meeting

-Randomized Phase 3 Clinical Trial with ADCETRIS Demonstrated Statistically Significant Improvement in Progression-Free Survival-

-Data Highlighted in ASH Press Program; to be Presented in an Oral Session on Monday, December 8, 2014 at 4:30 p.m. PT-

SAN FRANCISCO, CA, USA I December 6, 2014 I Seattle Genetics, Inc. (Nasdaq: SGEN) and Takeda Pharmaceutical Company Limited (TSE:4502) today reported data demonstrating that Hodgkin lymphoma (HL) patients at risk of relapse following an autologous stem cell transplant (ASCT) who received ADCETRIS (brentuximab vedotin) as consolidation therapy immediately after ASCT had significant improvement in progression-free survival (PFS) compared to patients who received placebo (median of 43 months versus 24 months, respectively; hazard ratio=0.57; p-value=0.001). The data from the AETHERA trial were featured at the 56th American Society of Hematology (ASH) Annual Meeting press program today and will be presented in an oral session on December 8, 2014. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL. ADCETRIS has been approved in more than 45 countries for the treatment of relapsed or refractory HL and systemic anaplastic large cell lymphoma (sALCL). ADCETRIS is currently not approved in the AETHERA treatment setting.

“Over the past 20 years, no improvement has been shown in the outcomes of patients treated with autologous stem cell transplant regimens for aggressive lymphomas, including Hodgkin lymphoma,” said Craig Moskowitz, M.D.Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center. “Approximately half of the patients who undergo an autologous stem cell transplant will relapse, demonstrating a significant need to identify regimens that improve patient outcomes. Data from the AETHERA clinical trial demonstrate that the addition of brentuximab vedotin use in the immediate post-transplant setting resulted in a statistically significant improvement in PFS with a manageable safety profile.”

“The outcome of the AETHERA trial is an important milestone. It demonstrates that early consolidation treatment with ADCETRIS in Hodgkin lymphoma patients at risk of relapse following an autologous transplant can result in a substantial improvement in PFS versus placebo,” said Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. “We are pleased to share these data with the physician community at ASH. We will be meeting with the FDA soon to discuss the submission of a supplemental Biologics License Application in the first half of 2015 seeking approval in this consolidation setting.”

“The AETHERA data provide compelling evidence regarding the potential utility of ADCETRIS as consolidation therapy post-transplant in these Hodgkin lymphoma patients, and we look forward to submitting these data to health authorities around the world,” said Michael Vasconcelles, M.D., Global Head, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company Limited. “Going forward, we are conducting a robust clinical development program to more fully understand the potential of CD30 targeting with ADCETRIS in frontline disease through our ongoing Phase 3 ECHELON-1 and ECHELON-2 trials in HL and mature T-cell lymphomas.”

The AETHERA Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Brentuximab Vedotin in the Treatment of Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin Lymphoma (Abstract #673, oral presentation at 4:30 p.m. PT on December 8, 2014 at the Moscone Center West Building, 3001-3003-3014-3016)

The Phase 3 AETHERA trial was designed to evaluate the potential of single agent ADCETRIS to extend PFS post-ASCT in patients with HL 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 a history of refractory HL, 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.

A total of 329 HL patients at risk of relapse were enrolled, including 165 on the ADCETRIS arm and 164 on the placebo arm. Patients received a median of 15 cycles of treatment on both arms, with an average of 12 cycles on the ADCETRIS arm and 11 cycles on the placebo arm. Key findings, which were highlighted by Dr. Moskowitz, include:

• The trial achieved its primary endpoint and demonstrated a significant increase in PFS per independent review facility (IRF), with a hazard ratio of 0.57 and a p-value of 0.001. Median PFS per IRF was 43 months for patients who received ADCETRIS versus 24 months for patients who received placebo. The two-year PFS rate per IRF was 63 percent in the ADCETRIS arm compared to 51 percent in the placebo arm.
• Per investigator, the hazard ratio was 0.50. The two-year PFS rate per investigator was 65 percent in the ADCETRIS arm compared to 45 percent in the placebo arm. The median PFS per investigator has not yet been reached for patients who received ADCETRIS versus 16 months for patients who received placebo. Very few progression events have been observed beyond two years.
• The PFS benefit was consistent across all pre-specified subgroups, including primary refractory patients, patients who relapsed within twelve months of frontline therapy and patients who relapsed after twelve months with extranodal disease.
• Patients in both arms of the study who experienced disease progression received a variety of subsequent therapies. In the ADCETRIS arm, only eight of 51 patients (16 percent) receiving subsequent therapy were treated with ADCETRIS following relapse. In the placebo arm, 72 of 85 patients (85 percent) receiving subsequent therapy were treated with single agent ADCETRIS. Twenty-four patients in the placebo arm and 13 patients in the ADCETRIS arm received stem cell transplant as subsequent therapy, the majority of which were allogeneic transplants.
• OS data are immature, and no statistically significant difference in OS has been observed between the treatment arms (hazard ratio 1.15; p-value=0.62). A further analysis of overall survival is planned in 2016.
• The most common adverse events in the ADCETRIS arm were peripheral sensory neuropathy (56 percent), neutropenia (35 percent), upper respiratory tract infection (26 percent), fatigue (24 percent) and peripheral motor neuropathy (23 percent). The most common adverse events in the placebo arm were upper respiratory tract infection (23 percent), fatigue (18 percent) peripheral sensory neuropathy (16 percent), cough (16 percent) and neutropenia (12 percent). Eighty-five percent of patients with peripheral neuropathy on the ADCETRIS arm had resolution or improvement in symptoms with a median time to improvement of 23.4 weeks.
• Grade 3 or higher adverse events in the ADCETRIS arm included neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, nausea, fatigue and diarrhea. Grade 3 or higher adverse events in the placebo arm included neutropenia, fatigue, peripheral motor neuropathy, diarrhea and peripheral sensory neuropathy. No Grade 4 peripheral neuropathy events occurred.
• One death occurred within 30 days of ADCETRIS treatment from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis. One death occurred on the ADCETRIS arm at Day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.

Submission of safety data from the AETHERA trial to the FDA is a post-marketing requirement that Seattle Genetics will fulfill in its planned supplemental BLA. Takeda plans to submit data from the AETHERA trial to regulatory agencies in its territories.

Please see Important Safety Information at the end of this press release.

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 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 for intravenous injection received accelerated approval from the U.S. Food and Drug Administration and approval with conditions from Health Canada for two indications: (1) the treatment of patients with HL after failure of ASCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates, and (2) the treatment of patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. The indications for ADCETRIS are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.

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 HL 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 more than 45 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 will be 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: HL and non-Hodgkin lymphoma. HL 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 HL 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 HL 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.

About Seattle Genetics:
Seattle Genetics is a biotechnology company focused on the development and commercialization of innovative antibody-based therapies for the treatment of cancer. Seattle Genetics is leading the field in developing antibody-drug conjugates (ADCs), a technology designed to harness the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. The company’s lead product, ADCETRIS^® (brentuximab vedotin) is an ADC that, in collaboration with Takeda Pharmaceutical Company Limited, is commercially available for two indications in more than 45 countries, including the U.S., Canada, Japan and members of the European Union. Additionally, ADCETRIS is being evaluated broadly in more than 30 ongoing clinical trials. Seattle Genetics is also advancing a robust pipeline of clinical-stage ADC programs, including SGN-CD19A, SGN-CD33A, SGN-LIV1A, SGN-CD70A, ASG-22ME and ASG-15ME. Seattle Genetics has collaborations for its ADC technology with a number of leading biotechnology and pharmaceutical companies, including AbbVie, Agensys (an affiliate of Astellas), Bayer, Genentech, GlaxoSmithKline and Pfizer. More information can be found at www.seattlegenetics.com.

About Takeda Oncology:
The Takeda Oncology Business Unit, headquartered in Cambridge, MA, is co-located with the leadership of Takeda’s globally-integrated oncology research and development enterprise, overseen by the Oncology Therapeutic Area Unit. Takeda Oncology delivers novel medicines to patients with cancer worldwide through its commitment to science, breakthrough innovation and passion for improving the lives of patients. Takeda Oncology was formerly known as Millennium: The Takeda Oncology Company. Additional information about Takeda Oncology is available through its website, www.takedaoncology.com.

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

ADCETRIS (brentuximab vedotin) U.S. Important Safety Information

BOXED WARNING
Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.

Contraindication:
Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.

Warnings and Precautions:

• Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.
• Infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy.
• Hematologic toxicities: Grade 3 or 4 anemia, thrombocytopenia and prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. Febrile neutropenia has been reported with ADCETRIS. Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. Closely monitor patients for fever. If Grade 3 or 4 neutropenia develops, manage by G-CSF support, dose delays, reductions or discontinuation.
• Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia and sepsis/septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Closely monitor patients during treatment for the emergence of possible bacterial, fungal or viral infections.
• Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
• Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
• Stevens-Johnson syndrome (SJS): SJS has been reported with ADCETRIS. If SJS occurs, discontinue ADCETRIS and administer appropriate medical therapy.
• Embryo-fetal toxicity: Fetal harm can occur. Advise pregnant women of the potential hazard to the fetus.

Adverse Reactions:
ADCETRIS was studied as monotherapy in 160 patients in two Phase 2 trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

Drug Interactions:
Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to MMAE.

Use in Specific Populations:
MMAE exposure is increased in patients with hepatic impairment and severe renal impairment. Closely monitor these patients for adverse reactions.

For additional important safety information, including Boxed WARNING, please see the full U.S. prescribing information for ADCETRIS at www.seattlegenetics.com or www.ADCETRIS.com.

ADCETRIS Global Important Safety Information

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

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.

For Seattle Genetics:
Certain of the statements made in this press release are forward looking, such as those, among others, relating to the therapeutic potential of ADCETRIS and plans for submission for supplemental regulatory approval to and obtaining regulatory approval from the FDA. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include safety and/or efficacy results of the AETHERA trial in at risk, post-ASCT Hodgkin lymphoma will not be sufficient to gain marketing approval in the United States or any other country, that we will be required to amend our submission for marketing approval or that such submission will be refused. In addition, our regulatory plans may change as a result of consultation with the FDA. More information about the risks and uncertainties faced by Seattle Genetics is contained in the company’s 10-Q for the quarter ended September 30, 2014 filed with the Securities and Exchange Commission. Seattle Genetics disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

SOURCE: Seattle Genetics