BLA Based on Clinical Trial Results from the
Phase 3 ALCANZA and Phase 2 Investigator-Sponsored Studies in
Cutaneous T-Cell Lymphoma
Seattle Genetics, Inc. (Nasdaq: SGEN) announced today that it
has submitted a supplemental Biologics License Application (BLA) to
the U.S. Food and Drug Administration (FDA) based on data from the
phase 3 ALCANZA trial and two phase 2 investigator-sponsored trials
of ADCETRIS (brentuximab vedotin) in patients with cutaneous T-cell
lymphoma (CTCL). ADCETRIS is currently not approved for the
treatment of CTCL.
“The submission of the supplemental BLA requesting label
expansion for ADCETRIS as a treatment in CTCL patients who require
systemic therapy is an important milestone. CTCL is an incurable
and disfiguring disease in need of new therapeutic options,
particularly those that achieve durable responses,” said Jonathan
Drachman, M.D., Chief Medical Officer and Executive Vice President,
Research and Development of Seattle Genetics. “Results from the
phase 3 ALCANZA trial demonstrated that CTCL patients treated with
ADCETRIS had superior outcomes across all primary and secondary
endpoints compared to patients in the control arm who were treated
with either methotrexate or bexarotene standard of care agents. In
addition to the ALCANZA results, data from two
investigator-sponsored trials also support ADCETRIS use in this
disease setting. We believe these data are clinically meaningful
and support a label expansion for ADCETRIS in CTCL, which would be
the fourth indication for this program.”
In November 2016, based on preliminary analysis of ALCANZA, the
FDA granted ADCETRIS Breakthrough Therapy Designation (BTD) for the
treatment of patients with CD30-expressing mycosis fungoides and
primary cutaneous anaplastic large cell lymphoma who require
systemic therapy and have received one prior systemic therapy.
These represent the most common subtypes of CTCL. Based on
discussions with the FDA following the BTD, additional data from
investigator-sponsored phase 2 trials have been incorporated into
the supplemental BLA to support the potential for a broader label
in CTCL.
The supplemental BLA is primarily based on positive results from
a phase 3 trial called ALCANZA that were presented at the 58th
American Society of Hematology (ASH) annual meeting in December
2016 and published in the Lancet in June 2017. Results from the
ALCANZA trial in 128 CTCL patients requiring systemic therapy
included:
- The trial achieved its primary endpoint
with the ADCETRIS treatment arm demonstrating a highly
statistically significant improvement in the rate of objective
response lasting at least four months (ORR4) versus the control arm
as assessed by an independent review facility. ORR4, as assessed by
Global Response Score, was 56.3 percent in the ADCETRIS arm
compared to 12.5 percent in the control arm (p-value
<0.0001).
- Key secondary endpoints specified in
the protocol, including complete response rate, progression-free
survival and reduction in the burden of symptoms during treatment
(Skindex-29), 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.
About CTCL
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 mimic 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.
The standard treatment for systemically pretreated CTCL includes
skin-directed therapies, radiation and systemic therapies. The
systemic therapies currently approved for treatment have
demonstrated 30 to 45 percent objective response rates, with low
complete response rates.
About ADCETRIS
ADCETRIS is being evaluated broadly in more than 70 ongoing
clinical trials, including three Phase 3 studies, the ongoing
ECHELON-1 trial in frontline classical Hodgkin lymphoma and the
ongoing ECHELON-2 trial in frontline mature T-cell lymphomas, as
well as the completed ALCANZA trial in cutaneous T-cell lymphoma,
from which data were submitted in a supplemental BLA.
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 for intravenous injection has received approval from
the FDA for three indications: (1) 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, (2) regular
approval for the treatment of classical Hodgkin lymphoma patients
at high risk of relapse or progression as post-auto-HSCT
consolidation, and (3) 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.
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 67 countries for relapsed or refractory Hodgkin
lymphoma and sALCL. 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 is solely
responsible for development costs.
About Seattle Genetics
Seattle Genetics is an innovative biotechnology company that
develops and commercializes novel antibody-based therapies for the
treatment of cancer. The company’s industry-leading antibody-drug
conjugate (ADC) technology harnesses the targeting ability of
antibodies to deliver cell-killing agents directly to cancer cells.
ADCETRIS® (brentuximab vedotin), the company’s lead product, in
collaboration with Takeda Pharmaceutical Company Limited, is the
first in a new class of ADCs and is commercially available globally
in 67 countries for relapsed classical Hodgkin lymphoma (HL) and
relapsed systemic anaplastic large cell lymphoma (sALCL). Seattle
Genetics is also advancing enfortumab vedotin, an ADC for
metastatic urothelial cancer, in a planned pivotal trial in
collaboration with Astellas. Headquartered in Bothell, Washington
and with European and international operations in Zug, Switzerland,
Seattle Genetics has a robust pipeline of innovative therapies for
blood-related cancers and solid tumors designed to address
significant unmet medical needs and improve treatment outcomes for
patients. The company has collaborations for its proprietary ADC
technology with a number of companies including AbbVie, Astellas,
Bayer, Celldex, Genentech, GlaxoSmithKline and Pfizer. More
information can be found at www.seattlegenetics.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
ADCETRIS is contraindicated with concomitant bleomycin due to
pulmonary toxicity (e.g., interstitial infiltration and/or
inflammation).
Warnings and Precautions
- Peripheral neuropathy (PN): ADCETRIS
treatment causes a PN that is predominantly sensory. Cases of motor
PN have also been reported. ADCETRIS-induced PN 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.
- Anaphylaxis and infusion reactions:
Infusion-related reactions, including anaphylaxis, have occurred
with ADCETRIS. Monitor patients during infusion. If an
infusion-related reaction occurs, interrupt the infusion and
institute appropriate medical management. If anaphylaxis occurs,
immediately and permanently discontinue the infusion and administer
appropriate medical therapy. Patients who experienced a prior
infusion-related reaction should be premedicated for 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
dose of ADCETRIS and 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 subsequent doses.
- Serious infections and opportunistic
infections: Infections such as pneumonia, bacteremia, and sepsis or
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.
- 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
the use of ADCETRIS 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 the use of ADCETRIS in patients with
moderate or severe hepatic impairment.
- Hepatotoxicity: Serious cases of
hepatotoxicity, including fatal outcomes, have occurred with
ADCETRIS. Cases were consistent with hepatocellular injury,
including elevations of transaminases and/or bilirubin, and
occurred after the first dose of ADCETRIS or rechallenge.
Preexisting liver disease, elevated baseline liver enzymes, and
concomitant medications may also increase the risk.
- Monitor liver enzymes and bilirubin.
Patients experiencing new, worsening, or recurrent hepatotoxicity
may require a delay, change in dose, or discontinuation of
ADCETRIS.
- Progressive multifocal
leukoencephalopathy (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. 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. Hold ADCETRIS if PML is suspected and
discontinue ADCETRIS if PML is confirmed.
- Pulmonary toxicityEvents of
noninfectious pulmonary toxicity including pneumonitis,
interstitial lung disease, and acute respiratory distress syndrome,
some with fatal outcomes, have been reported. Monitor patients for
signs and symptoms of pulmonary toxicity, 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:
Fatal and serious GI complications, including perforation,
hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis,
neutropenic colitis, and ileus have been reported in
ADCETRIS-treated patients. Lymphoma with preexisting GI involvement
may increase the risk of perforation. In the event of new or
worsening GI symptoms, perform a prompt diagnostic evaluation and
treat appropriately.
- Embryo-fetal toxicity: Based on the
mechanism of action and findings in animals, ADCETRIS can cause
fetal harm when administered to a pregnant woman. Females of
reproductive potential should avoid pregnancy during ADCETRIS
treatment and for at least 6 months after the final dose of
ADCETRIS.
Adverse Reactions
In two uncontrolled single-arm trials of ADCETRIS as monotherapy
in 160 patients with relapsed classical HL and sALCL, 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.
In a placebo-controlled trial of ADCETRIS in 329 patients with
classical HL at high risk of relapse or progression post-auto-HSCT,
the most common adverse reactions (≥20%) in the ADCETRIS-treatment
arm (167 patients), regardless of causality, were: neutropenia,
peripheral sensory neuropathy, thrombocytopenia, anemia, upper
respiratory tract infection, fatigue, peripheral motor neuropathy,
nausea, cough, and diarrhea.
Drug Interactions
Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp
inhibitors, has the potential to affect the exposure to monomethyl
auristatin E (MMAE).
Use in Specific Populations
MMAE exposure and adverse reactions are increased in patients
with moderate or severe hepatic impairment or severe renal
impairment. Avoid use.
Advise females of reproductive potential to avoid pregnancy
during ADCETRIS treatment and for at least 6 months after the final
dose of ADCETRIS.
Advise males with female sexual partners of reproductive
potential to use effective contraception during ADCETRIS treatment
and for at least 6 months after the final dose of ADCETRIS.
Advise patients to report pregnancy immediately and avoid
breastfeeding while receiving ADCETRIS.
For additional Important Safety Information, including Boxed
WARNING, please see the full Prescribing Information for ADCETRIS
at www.seattlegenetics.com or
www.ADCETRIS.com.
Forward-Looking Statements
Certain of the statements made in this press release are forward
looking, such as those, among others, relating to the therapeutic
potential, and the possibility of market approval of ADCETRIS
(brentuximab vedotin) for uses including CTCL and other
CD30-expressing lymphomas for which ADCETRIS has not received
regulatory approval. 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 that
the supplemental BLA submission 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 or delayed. In addition,
our regulatory plans may change as a result of consultation with
the FDA or other regulatory authorities. More information about the
risks and uncertainties faced by Seattle Genetics is contained
under the caption “Risk Factors” included in the company’s
Quarterly Report on Form 10-Q for the quarter ended March 31, 2017
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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version on businesswire.com: http://www.businesswire.com/news/home/20170620005551/en/
Seattle Genetics, Inc.Investors:Peggy Pinkston,
425-527-4160ppinkston@seagen.comorMedia:Tricia Larson,
425-527-4180tlarson@seagen.com
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