[September 29, 2014] |
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Seattle Genetics and Takeda Announce Positive Data from Phase 3 AETHERA Clinical Trial of ADCETRIS® (Brentuximab Vedotin) for Consolidation in Post-Transplant Hodgkin Lymphoma
BOTHELL, Wash. & OSAKA, Japan --(Business Wire)--
Seattle
Genetics, Inc. (Nasdaq: SGEN) and Takeda Pharmaceutical Company
Limited (TSE:4502) today announced that patients with Hodgkin lymphoma
(HL) who received ADCETRIS (brentuximab vedotin) as consolidation
therapy immediately following an autologous stem cell transplantation
(ASCT) lived significantly longer without disease progression compared
to patients who received placebo. The phase 3 clinical trial, known as
AETHERA, compared the use of single agent ADCETRIS to placebo in 329
patients with HL who were at risk of relapse. ADCETRIS is an
antibody-drug conjugate (ADC (News - Alert)) directed to CD30, a defining marker of
classical HL. ADCETRIS has been approved in more than 45 countries for
the treatment of relapsed HL and systemic anaplastic large cell lymphoma
(sALCL). ADCETRIS is not approved in the AETHERA treatment setting.
The AETHERA trial met its primary endpoint with ADCETRIS treatment
resulting in a statistically significant improvement in progression-free
survival (PFS) versus placebo 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. A
pre-specified interim analysis of overall survival showed no
statistically significant difference between the treatment arms.
Patients on both study arms with progression of HL received a variety of
subsequent therapies. Notably, most patients on the placebo arm received
ADCETRIS after progression. A further analysis of overall survival is
planned in 2016. The safety profile of ADCETRIS in the AETHERA trial was
generally consistent with the existing prescribing information. An
abstract was previously submitted for data presentation at the American
Society of Hematology (ASH) annual meeting, December 6-9, 2014, in San
Francisco, CA (News - Alert).
"Patients with Hodgkin lymphoma who relapse or are refractory to
frontline therapy represent a significant unmet medical need. We believe
the positive top-line results of the AETHERA trial demonstrate the
ability of ADCETRIS to consolidate remissions and extend
progression-free survival in patients with Hodgkin lymphoma who are at
risk of relapse following an autologous transplant while having an
acceptable safety profile," said Clay B. Siegall, Ph.D., President and
Chief Executive Officer of Seattle Genetics. "We anticipate reporting
more complete AETHERA data at the ASH annual meeting in December and
intend to submit a supplemental Biologics License Application to the FDA
in 2015 for approval in this setting."
"The AETHERA clinical trial results may support a new treatment paradigm
for certain patients with Hodgkin lymphoma post autologous stem cell
transplant," said Michael Vasconcelles, M.D., Global Head, Oncology
Therapeutic Area Unit, Takeda Pharmaceutical Company. "As the first
randomized clinical trial of a comprehensive clinical development
program with ADCETRIS, these data also provide important information to
inform the entire ADCETRIS program. For these reasons, we are
particularly grateful to the patients, in partnership with their
families and the study investigators, for their participation in
AETHERA. We look forward to submitting these data to regulatory agencies
in our territories."
Phase 3 AETHERA Clinical Trial Design The AETHERA trial is a
randomized, double-blind, placebo-controlled phase 3 study designed to
evaluate the potential of 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, safety and tolerability. Patients must have risk factors for
residual HL, defined as a history of refractory HL, those who relapse or
progress within one year from receiving frontline chemotherapy and/or
those who have disease outside of the lymph nodes at the time of
pre-ASCT relapse. Patients received ADCETRIS or placebo every three
weeks for up to approximately one year. This international multi-center
trial is being conducted in the United States, Eastern and Western
Europe and Russia.
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 will provide safety data from the trial
to the European Medicines Agency (EMA (News - Alert)) as part of periodic safety
reports required by the EMA's conditional approval of ADCETRIS.
Please see Important Safety Information at the end of this press release.
Seattle Genetics Conference Call Details Seattle Genetics'
management will host a conference call and webcast to discuss this
announcement. The event will be held today at 5:30 a.m. Pacific Time
(PT) / 8:30 a.m. Eastern Time (ET). The live event will be available
from Seattle Genetics' website at http://www.seattlegenetics.com,
under the Investors and News section, or by calling 888-455-2263
(domestic) or 719-325-2464 (international). The access code is 9378967.
A replay of the discussion will be available beginning at approximately
7:00 a.m. PT / 10:00 a.m. ET today from Seattle Genetics' website or by
calling 888-203-1112 (domestic) or 719-457-0820 (international), using
access code 9378967. The telephone replay will be available until 8:30
a.m. PT / 11:30 a.m. ET October 1, 2014.
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 45 countries. See
important safety infomation 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 (News - Alert)-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 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):
-
Following autologous stem cell transplant or
-
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 high 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 June
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.
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