BOTHELL, WA, USA I January 13, 2012 I Seattle Genetics, Inc. (Nasdaq: SGEN – News) today announced updates to the U.S. Prescribing Information (PI) for ADCETRIS™ (brentuximab vedotin). The revised PI will include the following updated information:
A boxed warning related to the risk that JC virus infection resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in patients receiving ADCETRIS.
A discussion in the PML warning and precaution provision regarding other possible contributing factors to PML such as other prior therapies and underlying disease, symptoms to be aware of and suggested methodologies for diagnosis of PML.
A contraindication warning of the concomitant use of ADCETRIS and bleomycin due to pulmonary toxicity.
ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30 that was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in August 2011 for two indications: (1) the treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (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 systemic anaplastic large cell lymphoma (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.
“Our first priority is patient safety. By developing these agreed upon label updates with the FDA regarding PML and the contraindication with bleomycin, we aim to heighten awareness among healthcare professionals in order to most safely treat their patients with ADCETRIS. Although PML in lymphoma patients can be caused by factors such as underlying disease and prior therapies that affect the immune system, a contributory role of ADCETRIS cannot be excluded,” said Thomas C. Reynolds, M.D., Ph.D., Chief Medical Officer of Seattle Genetics. “The contraindication for the concomitant use of ADCETRIS and bleomycin is based on data suggesting an increased risk of pulmonary toxicity relative to ABVD alone that was identified in our phase I clinical trial in patients with newly diagnosed advanced Hodgkin lymphoma. We are confident that these label changes will help guide appropriate patient care while on treatment with ADCETRIS.”
PML is associated with a weakened immune system that can occur in patients with diseases such as lymphoma, leukemia and other hematologic malignancies. According to published literature, the risk of PML in persons with hematologic malignancies is estimated to be 0.07%, or approximately one in 1,400 (1). More than 2,000 patients worldwide have received treatment with ADCETRIS to date.
PML was described in the original PI for ADCETRIS based on a single case reported in a patient who had received four chemotherapy regimens prior to receiving ADCETRIS. Following the occurrence of a second case of PML, Seattle Genetics began working in conjunction with the FDA to add a boxed warning in order to heighten awareness of the potential risk of PML. There has also been a third suspected, but unconfirmed, case of PML reported in a heavily-pretreated patient receiving ADCETRIS.
In addition, based on data from a phase I clinical trial of ADCETRIS in combination with ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) for the treatment of newly diagnosed Hodgkin lymphoma patients, a contraindication for concomitant use of bleomycin and ADCETRIS will be added to the PI. This is based on data demonstrating that 40 percent of patients (10 out of 25) in the ADCETRIS plus ABVD cohorts of the trial had an event of pulmonary toxicity, compared to an overall rate of pulmonary toxicity with bleomycin-based regimens reported in published literature of 10 to 25 percent (2,3). To date, no pulmonary toxicity events have been observed in the ADCETRIS plus AVD cohorts of the trial. ADCETRIS is not approved for the front-line treatment of Hodgkin lymphoma.
When finalized, the updated PI will be posted at www.seattlegenetics.com.
About PML
PML is a rare, progressive, demyelinating disease of the central nervous system that often leads to death or severe disability. PML is caused by reactivation of the John Cunningham (JC) virus. JC virus resides in latent form in 40-80 percent of healthy adults. Reactivation of the latent infection is associated with immunocompromised conditions and may occur months following discontinuation of immunosuppressive therapy. PML has been reported in patients with Hodgkin lymphoma, HIV-positive patients, immunosuppressed cancer patients, transplantation patients and patients with autoimmune disease. There are no known interventions that can reliably prevent or adequately treat PML.
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.
Seattle Genetics and Millennium: The Takeda Oncology Company are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and the Takeda Group has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and the Takeda Group are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where the Takeda Group is solely responsible for development costs.
About Seattle Genetics
Seattle Genetics is a biotechnology company focused on the development and commercialization of monoclonal antibody-based therapies for the treatment of cancer. The FDA granted accelerated approval of ADCETRIS in August 2011 for two indications. ADCETRIS is being developed in collaboration with Millennium: The Takeda Oncology Company. In addition, Seattle Genetics has three other clinical-stage ADC programs: SGN-75, ASG-5ME and ASG-22ME. Seattle Genetics has collaborations for its ADC technology with a number of leading biotechnology and pharmaceutical companies, including Abbott, Bayer, Celldex Therapeutics, Daiichi Sankyo, Genentech, GlaxoSmithKline, Millennium, Pfizer and Progenics, as well as ADC co-development agreements with Agensys, an affiliate of Astellas, and Genmab. More information can be found at www.seattlegenetics.com.
Important Safety Information
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. Treating physicians should 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, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted.
Neutropenia: Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS.
Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.
Stevens-Johnson syndrome: Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.
Progressive multifocal leukoencephalopathy (PML): A fatal case of PML has been reported in a patient who received four chemotherapy regimens prior to receiving ADCETRIS.
Use in pregnancy: Fetal harm can occur. Pregnant women should be advised 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:
Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.
For additional important safety information, please see the full U.S. prescribing information for ADCETRIS at www.seattlegenetics.com or www.ADCETRIS.com.
Certain of the statements made in this press release are forward looking, such as those, among others, relating to continued patient 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 risks related to Seattle Genetics’ ability to demonstrate to the medical community the safety and efficacy of ADCETRIS and its potential advantages over any side effects compared to existing therapeutics and products currently in clinical development, and risks related to the FDA’s post-approval requirements for ADCETRIS, including the risk that results from Seattle Genetics’ required post-approval studies may fail to verify the clinical benefit of ADCETRIS in its approved indications. More information about the risks and uncertainties faced by Seattle Genetics is contained in Seattle Genetics’ quarterly report on Form 10-Q for the quarter ended September 30, 2011, 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.
(1) Carson, KR, et.al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. 2009. Blood 11: 4834-4840.
(2) Duggan DB, et.al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an intergroup trial. 2003. J Clin Oncol 21: 607-14.
(3) Hoskin PJ, et.al. Randomized comparison of the Stanford V regimen and ABVD in the treatment of advanced Hodgkin’s Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. 2009. J Clin Oncol 27: 5390-6.
SOURCE: Seattle Genetics
