SAN FRANCISCO - Sunday, December 7th 2014 [ME NewsWire]
-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-
ASH 2014
(BUSINESS
WIRE)-- 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.
Contacts
Seattle Genetics
Investors:
Peggy Pinkston,
425-527-4160
ppinkston@seagen.com
or
Media:
Tricia Larson,
425-527-4180
tlarson@seagen.com
or
Takeda Pharmaceutical Company Limited
Elizabeth Pingpank,
+1-617-444-1495
elizabeth.pingpank@takeda.com
or
Corporate Communications Department,
+81-3-3278-2037
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