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TMCNet:  Seattle Genetics and Takeda Highlight Long-term Follow-up Data from ADCETRIS® (Brentuximab Vedotin) Pivotal Clinical Trials in Relapsed or Refractory Hodgkin Lymphoma and Systemic Anaplastic Large Cell Lymphoma at ASH 2013

[December 09, 2013]

Seattle Genetics and Takeda Highlight Long-term Follow-up Data from ADCETRIS® (Brentuximab Vedotin) Pivotal Clinical Trials in Relapsed or Refractory Hodgkin Lymphoma and Systemic Anaplastic Large Cell Lymphoma at ASH 2013

NEW ORLEANS --(Business Wire)--

Seattle Genetics, Inc. (Nasdaq: SGEN) and Takeda Pharmaceutical Company Limited (TSE:4502) today announced updated overall survival data from two ADCETRIS (brentuximab vedotin) pivotal Phase 2 clinical trials in relapsed/refractory Hodgkin lymphoma (R/R HL) and relapsed/refractory systemic anaplastic large cell lymphoma (R/R sALCL) were presented at the 55th American Society of Hematology (ASH) Annual Meeting and Exposition taking place in New Orleans, LA, December 7-10, 2013. ADCETRIS is an antibody-drug conjugate (ADC (News - Alert)) directed to CD30. Median overall survival (OS) of 40.5 months was reported in R/R HL, and was not yet reached in R/R sALCL.

"The updated data from the pivotal ADCETRIS clinical trials demonstrate extended survival among this heavily pretreated patient population. Median overall survival in the relapsed/refractory Hodgkin lymphoma trial was 3.4 years, which includes 18 patients who remained in remission and were still being followed. In relapsed/refractory systemic ALCL, median overall survival had not yet been reached and the estimated three-year survival rate was 63 percent," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "These data strengthen the already demonstrated patient benefit associated with ADCETRIS in relapsed Hodgkin lymphoma and systemic ALCL disease settings and further support our three ongoing Phase 3 clinical trials in earlier lines of therapy: AETHERA in high risk post-transplant patients with Hodgkin lymphoma, ECHELON-1 in frontline Hodgkin lymphoma and ECHELON-2 in frontline mature T-cell lymphoma."

"In this heavily pre-treated HL and sALCL patient population, exceeding three year median survival with single-agent ADCETRIS is substantial," said Michael Vasconcelles, M.D., Senior Vice President, Head, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company. "We continue to work with regulatory agencies in our territories to expand the availability of ADCETRIS and plan to seek the inclusion of these important survival updates into our label."

Three-year Follow-up Data and Characterization of Long-term Remissions from an Ongoing Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Hodgkin Lymphoma (Abstract #4382)

A pivotal, single-arm trial was conducted in 102 R/R HL patients after autologous stem cell transplant (ASCT) to assess the efficacy and safety of single-agent ADCETRIS. In addition, the trial was designed to determine duration of response, progression-free survival (PFS) and OS. Enrolled patients had received a median of more than three prior chemotherapy regimens. Patients received 1.8 milligrams per kilogram (mg/kg) of ADCETRIS administered through a 30-minute intravenous (IV) infusion every three weeks for up to 16 cycles for patients who achieved stable disease or better.

Data highlights from the long-term survival analysis in this pivotal trial were:

  • After a median observation time of 32.7 months from the first dose of ADCETRIS, the estimated median OS was 40.5 months (95% confidence interval [CI]: 28.7 -, [range, 1.8 to 48.3 mos]).
  • Of the 34 patients who had a complete remission, the median OS had not yet been reached.
  • The estimated three year survival rate was 54 percent.
  • Of the 102 patients, 14 remained in remission per independent assessment and 18 per investigator assessment, and are still being followed on study.
  • Overall, patients received a median of nine cycles of therapy with ADCETRIS; patients who achieved an objective response (OR) received more cycles of therapy.
  • The most common adverse events (AEs) of any grade were peripheral sensory neuropathy (47 percent), fatigue (46 percent), nausea (42 percent), upper respiratory tract infection (37 percent) and diarrhea (36 percent).
  • The most common grade 3 or 4 AEs occurring in at least five percent of patients were neutropenia (20 percent), peripheral sensory neuropathy (nine percent), thrombocytopenia (eight percent) and anemia (six percent).

Three-year Survival Results from an Ongoing Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma (Abstract #1809)

A pivotal, single-arm clinical trial was conducted in 58 R/R sALCL patients to assess the efficacy and safety of single-agent ADCETRIS. In addition, the trial was designed to determine duration of response, PFS and OS. Enrolled patients had received a median of two prior chemotherapy regimens. Patients received 1.8 mg/kg of ADCETRIS administered through a 30-minute IV infusion every three weeks for up to 16 cycles for patients who achieved stable disease or better.

Data highlights from long-term patient follow up in this pivotal trial were:

  • After a median observation time of 33.4 months from the first dose of ADCETRIS, the median OS had not yet been reached.
  • The estimated survival rate of patients at three years from initiation of ADCETRIS treatment was 63 percent.
  • The median PFS was 14.6 months.
  • Of the 34 patients who achieved a complete remission on study, 16 (47 percent) remained in continued complete remission at the time of last follow-up.
  • Overall, patients received a median of seven cycles of therapy with ADCETRIS; patients who achieved an OR received more cycles of therapy.
  • The most common AEs of any grade were peripheral neuropathy (57 percent), nausea (40 percent), fatigue (38 percent), pyrexia (34 percent) and diarrhea (29 percent).
  • The most common grade 3 or 4 AEs occurring in at least five percent of patients included neutropenia (21 percent), peripheral neuropathy (17 percent), thrombocytopenia (14 percent), anemia (seven percent) and fatigue (five percent).

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 (FDA) and approval with conditions from Health Canada for two indications: (1) the treatment of patients with HL after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherap 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 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 sALCL. ADCETRIS has received marketing authorization by regulatory authorities in more than 35 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.

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. If anaphylaxis occurs, immediately and permanently discontinue the infusion.
  • 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.

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, 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): SJS has been reported with ADCETRIS.
  • 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.
  • 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 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, has been approved for two indications in more than 35 countries, including the U.S., European Union and Canada. Additionally, ADCETRIS is being evaluated broadly in more than 20 ongoing clinical trials. Seattle Genetics is also advancing a robust pipeline of clinical-stage ADC programs, including SGN (News - Alert)-CD19A, SGN-CD33A, SGN-LIV1A, 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

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.

For Seattle Genetics:

Certain of the statements made in this press release are forward looking, such as those, among others, relating to the estimated overall survival rates in HL and ALCL resulting from treatment with ADCETRIS. 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 the potential that events occur more quickly than estimated thereby reducing the overall survival rate. In addition, historical results in clinical trials for ADCETRIS may not predict results in ongoing or future clinical trials of ADCETRIS and the data resulting from additional trials with ADCETRIS may not support approvals in the studied indications. 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, 2013 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.


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