– Opinion based on positive Phase 3 ALCANZA study results which
demonstrated a highly statistically significant improvement in rate of
objective response lasting at least four months, median
progression-free survival and overall response rate, and decrease in
symptom burden in ADCETRIS arm –
CAMBRIDGE, Mass. & OSAKA, Japan–(BUSINESS WIRE)–Takeda Pharmaceutical Company Limited (TSE:
4502) today announced that the European Medicines Agency’s (EMA)
Committee for Medicinal Products for Human Use (CHMP) has adopted a
positive opinion for the extension of the marketing authorization of
ADCETRIS® (brentuximab vedotin) and recommended its approval
for the treatment of adult patients with CD30-positive cutaneous T-cell
lymphoma (CTCL) after at least one prior systemic therapy. ADCETRIS is
an antibody-drug conjugate (ADC) directed at CD30 which is expressed on
skin lesions in approximately 50 percent of patients with CTCL. ADCETRIS
is currently not approved for the treatment of CTCL.
“This opinion represents a crucial first step forward for European
patients living with CTCL, a debilitating disease that can have a
significant impact on their quality of life,” said Julia Scarisbrick,
M.D., Department of Dermatology, University Hospital Birmingham,
Birmingham, UK. “The results of the ALCANZA trial demonstrate impressive
efficacy along with a manageable safety profile when compared with
methotrexate and bexarotene, commonly used therapies. If approved in
Europe, ADCETRIS would offer a novel treatment option for
CD30-expressing CTCL patients.”
“Today’s positive CHMP opinion is an important milestone for the CTCL
community, and further reinforces the role ADCETRIS may have in
improving outcomes for patients with CD30-positive malignancies” said
Jesus Gomez Navarro, M.D., Vice President, Head of Oncology Clinical
Research and Development, Takeda. “For patients with CTCL, there is a
significant need for additional treatment options that increase the
opportunity to achieve durable responses. We look forward to the
European Commission’s review of the CHMP positive opinion of this new
indication and the possibility to bring ADCETRIS to appropriate CTCL
patients in the European Union.”
The CHMP positive opinion for ADCETRIS will now be reviewed by the
European Commission (EC), which has the authority to approve medicines
for use in the 28 countries of the European Union (EU), Norway,
Liechtenstein and Iceland.
The positive CHMP opinion is based on the results of the randomized,
open-label Phase 3 ALCANZA study designed to evaluate single-agent
ADCETRIS versus a control arm of investigator’s choice of standard of
care therapies (methotrexate or bexarotene) in patients with
CD30-positive CTCL. The trial achieved its primary endpoint and the
ADCETRIS treatment arm demonstrated a highly statistically significant
improvement in the overall response rate lasting at least four months
(ORR4) versus the control arm as assessed by an independent review
facility (p-value <0.0001). The ORR4 was 56.3 percent in the ADCETRIS arm compared to 12.5 percent in the control arm. The key secondary endpoints specified in the protocol, including complete response rate, progression-free survival and reduction in the burden of symptoms during treatment, as measured by the Skindex-29 questionnaire1, were
all highly statistically significant in favor of the ADCETRIS arm. The
safety profile associated with ADCETRIS from the ALCANZA trial was
generally consistent with the existing prescribing information. The most
common adverse events of any grade include: peripheral neuropathy,
nausea, diarrhea, fatigue, vomiting, alopecia, pruritis, pyrexia,
decreased appetite and hypertriglyceridemia. In the ADCETRIS arm, the
most common grade 3 or 4 events were peripheral sensory neuropathy (no
grade 4 events), fatigue, diarrhea, nausea, vomiting and pruritis. In
the control arm, the most common grade 3 or 4 events were
hypertriglyceridemia, pruritis, fatigue and pyrexia.
Lymphoma is a general term for a group of cancers
that originate in the lymphatic system. There are two major categories
of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Cutaneous
lymphomas are a category of non-Hodgkin lymphoma that primarily involve
the skin. According to the Cutaneous Lymphoma Foundation, CTCL is the
most common type of cutaneous lymphoma and typically presents with red,
scaly patches or thickened plaques of skin that often mimics eczema or
chronic dermatitis. Progression from limited skin involvement may be
accompanied by skin tumor formation, ulceration and exfoliation,
complicated by itching and infections. Advanced stages are defined by
involvement of lymph nodes, peripheral blood and internal organs.
According to published literature, CD30 is expressed on CTCL lesions in
approximately 50 percent of patients with the disease.
The standard treatment for CTCL includes skin-directed therapies,
radiation and systemic therapies or a combination of these. The systemic
therapies currently approved for treatment have demonstrated 30 to 45
percent objective response rates, with low complete response rates.
ADCETRIS 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-positive tumor cells.
ADCETRIS injection for intravenous infusion has received FDA approval
for four indications: (1) regular approval for patients with pcALCL and
CD30-expressing MF and who have received prior systemic therapy, (2)
regular approval for the treatment of patients with classical Hodgkin
lymphoma after failure of autologous hematopoietic stem cell
transplantation (auto-HSCT) or after failure of at least two prior
multi-agent chemotherapy regimens in patients who are not auto-HSCT
candidates, (3) regular approval for the treatment of classical Hodgkin
lymphoma patients at high risk of relapse or progression as
post-auto-HSCT consolidation, and (4) accelerated approval for the
treatment of patients with systemic anaplastic large cell lymphoma
(sALCL) after failure of at least one prior multi-agent chemotherapy
regimen. The sALCL indication is approved under accelerated approval
based on overall response rate. Continued approval for the sALCL
indication may be contingent upon verification and description of
clinical benefit in confirmatory trials.
Health Canada granted ADCETRIS approval with conditions for relapsed or
refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional
approval for post-ASCT consolidation treatment of Hodgkin lymphoma
patients at increased risk of relapse or progression.
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 Hodgkin
lymphoma 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. The European Commission extended the
current conditional marketing authorization of ADCETRIS and approved
ADCETRIS for the treatment of adult patients with CD30-positive Hodgkin
lymphoma at increased risk of relapse or progression following ASCT.
ADCETRIS has received marketing authorization by regulatory authorities
in more than 65 countries for relapsed or refractory Hodgkin lymphoma
and sALCL. See important safety information below.
ADCETRIS is being evaluated broadly in more than 70 clinical trials,
including a Phase 3 study in frontline Hodgkin lymphoma (ECHELON-1) and
another Phase 3 study in frontline CD30-positive peripheral T-cell
lymphomas (ECHELON-2), as well as trials in many additional types of
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 is solely responsible for development costs.
About Takeda Pharmaceutical Company
Company Limited is a global, research and development-driven
pharmaceutical company committed to bringing better health and a
brighter future to patients by translating science into life-changing
medicines. Takeda focuses its R&D efforts on oncology, gastroenterology
and central nervous system therapeutic areas plus vaccines. Takeda
conducts R&D both internally and with partners to stay at the leading
edge of innovation. New innovative products, especially in oncology and
gastroenterology, as well as our presence in Emerging Markets, fuel the
growth of Takeda. More than 30,000 Takeda employees are committed to
improving quality of life for patients, working with our partners in
health care in more than 70 countries. For more information, visit http://www.takeda.com/news.
Additional information about Takeda is available through its corporate
and additional information about Takeda Oncology, the brand for the
global oncology business unit of Takeda Pharmaceutical Company Limited,
is available through its website, www.takedaoncology.com.
ADCETRIS (brentuximab vedotin) Important Safety Information (European
ADCETRIS is contraindicated for patients with hypersensitivity to
brentuximab vedotin and its excipients. In addition, combined use of
ADCETRIS with bleomycin is contraindicated as it causes pulmonary
SPECIAL WARNINGS & PRECAUTIONS
Progressive multifocal leukoencephalopathy (PML): John Cunningham
virus (JCV) reactivation resulting in PML and death can occur in
patients treated with ADCETRIS. PML has been reported in patients who
received ADCETRIS after receiving multiple prior chemotherapy regimens.
Patients should be closely monitored for new or worsening neurological,
cognitive, or behavioral signs or symptoms, which may be suggestive of
PML. Suggested evaluation of PML includes neurology consultation,
gadolinium-enhanced magnetic resonance imaging of the brain, and
cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or
a brain biopsy with evidence of JCV. ADCETRIS dosing should be held for
any suspected case of PML and should be permanently discontinued if a
diagnosis of PML is confirmed.
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, which
may be suggestive of acute pancreatitis. Patient evaluation may include
physical examination, laboratory evaluation for serum amylase and serum
lipase, and abdominal imaging, such as ultrasound and other appropriate
diagnostic measures. ADCETRIS should be held for any suspected case of
acute pancreatitis. ADCETRIS should be discontinued if a diagnosis of
acute pancreatitis is confirmed.
Pulmonary Toxicity: Cases of pulmonary toxicity, some with fatal
outcomes, have been reported in patients receiving ADCETRIS. Although a
causal association with ADCETRIS has not been established, the risk of
pulmonary toxicity cannot be ruled out. New or worsening pulmonary
symptoms should be promptly evaluated and treated appropriately.
Serious infections and opportunistic infections: Serious infections such
as pneumonia, staphylococcal bacteremia, 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
Infusion-related reactions (IRR): Immediate and delayed IRR, as
well as anaphylaxis, have occurred with ADCETRIS. Patients should be
carefully monitored during and after an infusion. If anaphylaxis occurs,
administration of ADCETRIS should be immediately and permanently
discontinued and appropriate medical therapy should be administered. If
an IRR occurs, the infusion should be interrupted and appropriate
medical management instituted. The infusion may be restarted at a slower
rate after symptom resolution. Patients who have experienced a prior IRR
should be premedicated for subsequent infusions. IRRs are more frequent
and more severe in patients with antibodies to ADCETRIS.
Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS.
Patients with rapidly proliferating tumor and high tumor burden are at
risk of TLS. These patients should be monitored closely and managed
according to best medical practice.
Peripheral neuropathy (PN): ADCETRIS treatment may cause PN, both
sensory and motor. ADCETRIS-induced PN is typically cumulative and
reversible in most cases. Patients should be monitored for symptoms of
PN, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a
burning sensation, neuropathic pain, or weakness. Patients experiencing
new or worsening PN may require a delay and a dose reduction or
discontinuation of ADCETRIS.
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 if febrile neutropenia develops.
Stevens-Johnson syndrome (SJS): SJS and toxic epidermal
necrolysis (TEN) have been reported with ADCETRIS. Fatal outcomes have
been reported. If SJS or TEN occurs, treatment with ADCETRIS should be
discontinued and appropriate medical therapy should be administered.
Gastrointestinal (GI) Complications: GI complications, some with
fatal outcomes, including intestinal obstruction, ileus, enterocolitis,
neutropenic colitis, erosion, ulcer, perforation and haemorragh, have
been reported. New or worsening GI symptoms should be promptly evaluated
and treated appropriately.
Hepatotoxicity: Elevations in alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) have been reported. Serious cases of
hepatotoxicity, including fatal outcomes, have also occurred. Liver
function should be tested prior to treatment initiation and routinely
monitored in patients receiving ADCETRIS. Patients experiencing
hepatotoxicity may require a delay, dose modification, or
discontinuation of 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. However, any patient who experiences an
event of hyperglycemia should have their serum glucose closely
monitored. Anti-diabetic treatment should be administered as appropriate.
Renal and Hepatic Impairment: There is limited experience in
patients with renal and hepatic impairment. Available data indicate that
MMAE clearance might be affected by severe renal impairment, hepatic
impairment, and by low serum albumin concentrations. The recommended
starting dose in patients with hepatic impairment or severe renal
impairment is 1.2 mg/kg administered as an intravenous infusion over 30
minutes every 3 weeks. Patients with renal or hepatic impairment should
be closely monitored for adverse events.
Sodium content in excipients: This medicinal product contains a maximum
of 2.1 mmol (or 47 mg) of sodium per dose. To be taken into
consideration for patients on a controlled sodium diet.
Patients who are receiving a strong CYP3A4 and
P-gp inhibitor, concomitantly with ADCETRIS may have an increased risk
of neutropenia and should be closely monitored. Co-administration of
ADCETRIS with a CYP3A4 inducer did not alter the plasma exposure of
ADCETRIS but it appeared to reduce plasma concentrations of MMAE
metabolites that could be assayed. ADCETRIS is not expected to alter the
exposure to drugs that are metabolized by CYP3A4 enzymes.
PREGNANCY: Women of childbearing potential should be using two
methods of effective contraception during treatment with ADCETRIS and
until 6 months after treatment. There are no data from the use of
ADCETRIS in pregnant women, although studies in animals have shown
reproductive toxicity. ADCETRIS should not be used during pregnancy
unless the benefit to the mother outweighs the potential risks to the
fetus. If a pregnant woman needs to be treated, she should be clearly
advised on the potential risk to the fetus.
LACTATION (breast-feeding): There are no data as to whether
ADCETRIS or its metabolites are excreted in human milk, therefore a risk
to the newborn/infant cannot be excluded. With the potential risk, a
decision should be made whether to discontinue breast-feeding or
discontinue/abstain from therapy with ADCETRIS.
FERTILITY: In nonclinical studies, ADCETRIS treatment has
resulted in testicular toxicity, and may alter male fertility. Men being
treated with this medicine are advised not to father a child during
treatment and for up to 6 months following the last dose.
Serious adverse drug reactions were: pneumonia, acute respiratory
distress syndrome, headache, neutropenia, thrombocytopenia,
constipation, diarrhea, vomiting, nausea, pyrexia, peripheral motor
neuropathy, peripheral sensory neuropathy, hyperglycemia, demyelinating
polyneuropathy, tumor lysis syndrome, and Stevens-Johnson syndrome.
In the clinical studies of ADCETRIS, adverse reactions defined as very
common (≥1/10) were: infection, upper respiratory tract infection,
neutropenia, PN (sensory and motor), cough, dyspneoa, diarrhea, nausea,
vomiting, constipation, abdominal pain, alopecia, pruritus, myalgia,
arthralgia, fatigue, chills, pyrexia, infusion-related reactions and
weight decreased. Adverse reactions defined as common (≥1/100 to <1/10) were: Sepsis/septic shock, herpes zoster, pneumonia, herpes simplex, anemia, thrombocytopenia, hyperglycemia, dizziness, demyelinating
polyneuropathy, ALT/AST increased, rash, and back pain.
ADCETRIS (brentuximab vedotin) U.S. Important Safety Information
BOXED WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
virus infection resulting in PML and death can occur in ADCETRIS-treated
ADCETRIS concomitant with bleomycin due to
pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).
Warnings and Precautions
Peripheral neuropathy (PN): ADCETRIS causes PN that is
predominantly sensory. Cases of motor PN have also been reported.
ADCETRIS-induced PN is cumulative. Monitor for symptoms such as
hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning
sensation, neuropathic pain, or weakness. Institute dose modifications
Anaphylaxis and infusion reactions: Infusion-related reactions
(IRR), including anaphylaxis have occurred with ADCETRIS. Monitor
patients during infusion. If an IRR occurs, interrupt the infusion and
institute appropriate medical management. If anaphylaxis occurs,
immediately and permanently discontinue the infusion and administer
appropriate medical therapy. Premedicate patients with a prior IRR
before subsequent infusions. Premedication may include acetaminophen,
an antihistamine, and a corticosteroid.
Hematologic toxicities: Prolonged (≥1 week) severe neutropenia
and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS.
Febrile neutropenia has been reported with ADCETRIS. Monitor complete
blood counts prior to each ADCETRIS dose. Consider more frequent
monitoring for patients with Grade 3 or 4 neutropenia. Monitor
patients for fever. If Grade 3 or 4 neutropenia develops, consider
dose delays, reductions, discontinuation, or G-CSF prophylaxis with
Serious infections and opportunistic infections: Infections
such as pneumonia, bacteremia, and sepsis or septic shock (including
fatal outcomes) have been reported in ADCETRIS-treated patients.
Closely monitor patients during treatment for bacterial, fungal, or
Tumor lysis syndrome: Closely monitor patients with rapidly
proliferating tumor and high tumor burden.
Increased toxicity in the presence of severe renal impairment: The
frequency of ≥Grade 3 adverse reactions and deaths was greater in
patients with severe renal impairment compared to patients with normal
renal function. Avoid use in patients with severe renal impairment.
Increased toxicity in the presence of moderate or severe hepatic
impairment: The frequency of ≥Grade 3 adverse reactions and deaths
was greater in patients with moderate or severe hepatic impairment
compared to patients with normal hepatic function. Avoid use in
patients with moderate or severe hepatic impairment.
Hepatotoxicity: Serious cases, including fatal outcomes, have
occurred in ADCETRIS-treated patients. Cases were consistent with
hepatocellular injury, including elevations of transaminases and/or
bilirubin, and occurred after the first ADCETRIS dose or rechallenge.
Preexisting liver disease, elevated baseline liver enzymes, and
concomitant medications may increase the risk. Monitor liver enzymes
and bilirubin. Patients with new, worsening, or recurrent
hepatotoxicity may require a delay, change in dose, or discontinuation
PML: JC virus infection resulting in PML and death has been
reported in ADCETRIS-treated patients. First onset of symptoms
occurred at various times from initiation of ADCETRIS therapy, with
some cases occurring within 3 months of initial exposure. Other
possible contributory factors other than ADCETRIS include prior
therapies and underlying disease that may cause immunosuppression.
Consider PML diagnosis in patients with new-onset signs and symptoms
of central nervous system abnormalities. Hold ADCETRIS if PML is
suspected and discontinue ADCETRIS if PML is confirmed.
Pulmonary toxicity: Noninfectious pulmonary toxicity events
including pneumonitis, interstitial lung disease, and acute
respiratory distress syndrome, some with fatal outcomes, have been
reported. Monitor patients for signs and symptoms, including cough and
dyspnea. In the event of new or worsening pulmonary symptoms, hold
ADCETRIS dosing during evaluation and until symptomatic improvement.
Serious dermatologic reactions: Stevens-Johnson syndrome (SJS)
and toxic epidermal necrolysis (TEN), including fatal outcomes, have
been reported with ADCETRIS. If SJS or TEN occurs, discontinue
ADCETRIS and administer appropriate medical therapy.
Gastrointestinal (GI) complications: Acute pancreatitis,
including fatal outcomes, has been reported in ADCETRIS-treated
patients. Other fatal and serious GI complications, including
perforation, hemorrhage, erosion, ulcer, intestinal obstruction,
enterocolitis, neutropenic colitis, and ileus have been reported in
Tsuyoshi Tada, +81 (0)
Kate Burd, +41 79 514 9533
Sara Noonan, +1 617-551-3683