Takeda Receives Positive CHMP Opinion for ADCETRIS® (brentuximab vedotin) as Consolidation Treatment in Post-Transplant Hodgkin Lymphoma

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 current conditional approval of ADCETRIS® (brentuximab vedotin) and
recommended its approval for the treatment of adult patients with CD30+
Hodgkin lymphoma at increased risk of relapse or progression following
autologous stem cell transplantation (ASCT). On average 50 percent of
Hodgkin lymphoma patients relapse after ASCT and those patients with
additional risk factors can be at even higher risk of relapse. ADCETRIS
after ASCT is a new treatment paradigm based on the largest randomized
study ever conducted in relapsed or refractory Hodgkin lymphoma. The
AETHERA Phase 3 trial is the first completed study that has explored
consolidation treatment immediately following ASCT as a way of extending
the effect of transplant for prevention of relapse among people with
Hodgkin lymphoma. The use of ADCETRIS in this setting may provide a
meaningful treatment option where none currently exist for patients.
“While ASCT is the standard of care following failure of frontline
chemotherapy in Hodgkin lymphoma, we know that many patients will
unfortunately see their disease return. Early eradication of residual
disease through treatment with ADCETRIS has the highest chance of
preventing the disease from returning in these patients,” said Dirk
Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area
Unit, Takeda Pharmaceutical Company. “This opinion, in addition to the
recent five year overall survival data in relapsed or refractory Hodgkin
lymphoma, further establishes the role of ADCETRIS in improving outcomes
for patients. We look forward to the European Commission’s authorization
of this new indication and bringing this medicine to physicians and
patients in the European Union.”
The CHMP positive opinion for ADCETRIS will now be reviewed by the
European Commission (EC). If the CHMP recommendation is formally adopted
by the EC, which has the authority to approve medicines for the European
Union (EU), ADCETRIS will be approved for marketing of this indication
in the 28 member states of the EU, Norway Liechtenstein and Iceland.
This opinion is based on the results of the Phase 3 AETHERA study. The
AETHERA trial met its primary endpoint with ADCETRIS (plus best
supportive care) treatment resulting in a statistically significant
improvement in progression-free survival (PFS) versus placebo (plus best
supportive care) 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. An updated analysis
conducted after three years of follow up showed sustained PFS
improvement (per Independent Review Facility; HR=0.58; 95%CI
(0.41,0.81). A pre-specified interim analysis of overall survival showed
no statistically significant difference between the treatment arms. The
safety profile of ADCETRIS in the AETHERA trial was generally consistent
with the existing prescribing information.
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: Hodgkin lymphoma and non-Hodgkin lymphoma.
Hodgkin lymphoma 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 expresses CD30.
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 proprietary technology by Seattle
Genetics. 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 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 systemic anaplastic large cell lymphoma (sALCL).
In January 2016, the European Commission approved a Type II variation to
include data on the retreatment of adult patients with Hodgkin lymphoma
or sALCL who previously responded to ADCETRIS and who later relapse.
ADCETRIS has received marketing authorization by regulatory authorities
in more than 60 countries. See important safety information below.
ADCETRIS is being evaluated broadly in more than 45 ongoing clinical
trials, including the Phase 3 ALCANZA trial in CD30+ cutaneous T cell
lymphoma (CTCL) and two additional Phase 3 studies, one in frontline
classical Hodgkin lymphoma (ECHELON-1) and one in frontline CD30+ mature
T-cell lymphomas (ECHELON-2), as well as trials in many additional types
of CD30-expressing malignancies.
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
Takeda Pharmaceutical
Company Limited is a global, R&D-driven pharmaceutical company committed
to bringing better health and a brighter future to patients by
translating science into life-changing medicines. Takeda focuses its
research efforts on oncology, gastroenterology and central nervous
system therapeutic areas. It also has specific development programs in
specialty cardiovascular diseases as well as late-stage candidates for
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 its 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 https://www.takeda.com/news.
Additional information about Takeda is available through its corporate
website, www.takeda.com,
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.
INDICATIONS
ADCETRIS® is indicated for the treatment of
adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL):
1. following autologous stem cell transplant (ASCT) or
2. following
at least two prior therapies when ASCT or multi-agent chemotherapy is
not a treatment option.
ADCETRIS is indicated for the treatment of adult patients with relapsed
or refractory systemic anaplastic large cell lymphoma (sALCL).
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
ADCETRIS is contraindicated for patients with hypersensitivity to
brentuximab vedotin and its excipients. In addition, combined use of
bleomycin and ADCETRIS causes pulmonary toxicity, and is contraindicated.
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 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 and patients should be 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 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. If anaphylaxis occurs, administration of ADCETRIS should be
immediately and permanently discontinued and appropriate medical therapy
should be administered. If an infusion-related reaction 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 infusion-related
reaction should be premedicated for subsequent infusions.
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 that
is predominantly sensory. Cases of peripheral motor neuropathy have also
been reported. ADCETRIS-induced PN is typically cumulative. Patients
should be monitored for symptoms of PN, such as hypoesthesia,
hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic
pain, or weakness. Dose modification for PN should be instituted
accordingly.
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 and toxic epidermal
necrolysis (TEN) have been reported with brentuximab vedotin. Fatal
outcomes have been reported. If SJS or TEN occurs, treatment with
ADCETRIS should be discontinued and appropriate medical therapy should
be administered.
Hepatic function: Elevations in alanine aminotransferase (ALT)
and aspartate aminotransferase (AST) have been reported. Liver function
should be routinely monitored in patients receiving brentuximab vedotin.
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. Antidiabetic 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 (MMAE
exposure increased approximately 1.9-fold), hepatic impairment (MMAE
exposure increased approximately 2.3-fold), and by low serum albumin
concentrations (MMAE clearance was 2-fold lower). 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.
INTERACTIONS
Patients who are receiving strong CYP3A4
inhibitors concomitantly with ADCETRIS should be closely monitored for
adverse events. Coadministration of ADCETRIS with CYP3A4 inducers did
not alter the metabolism of ADCETRIS; however, it reduced exposure to
MMAE by approximately 31%. ADCETRIS is not expected to alter the
exposure to drugs that are metabolized by CYP3A4 enzymes.
PREGNANCY: Women of childbearing potential should be using 2
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.
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.
ADVERSE REACTIONS
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.
In the clinical studies of ADCETRIS, adverse reactions defined as very
common (≥1/10) were: infection, neutropenia, peripheral sensory
neuropathy, diarrhea, nausea, vomiting, alopecia, pruritus, myalgia,
fatigue, pyrexia, and infusion-related reactions. Adverse reactions
defined as common (≥1/100 to <1/10) were: Sepsis/septic shock (including
fatal events), 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.