-Supplemental BLA Based on Clinical Trial
Results from the Phase 3 ALCANZA and Phase 2 Investigator-Sponsored
Studies in CTCL-
-FDA Previously Granted ADCETRIS Breakthrough
Therapy Designation in CTCL-
-PDUFA Action Date is December 16, 2017-
Seattle Genetics, Inc. (Nasdaq: SGEN) announced today that the
U.S. Food and Drug Administration (FDA) has accepted for filing a
supplemental Biologics License Application (BLA) 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). In November 2016, 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. The FDA granted
Priority Review for the application and the Prescription Drug User
Fee Act (PDUFA) target action date is December 16, 2017. ADCETRIS
is currently not approved for the treatment of CTCL.
“The FDA’s filing of our supplemental BLA with Priority Review
status represents a significant milestone towards our goal of
making ADCETRIS available to CTCL patients who require systemic
therapy,” said Jonathan Drachman, M.D., Chief Medical Officer and
Executive Vice President, Research and Development of Seattle
Genetics. “Results from our positive phase 3 ALCANZA trial
demonstrated that using ADCETRIS in this setting significantly
improved the rate of objective responses lasting at least four
months with a manageable safety profile. Data from two
investigator-sponsored trials in a broader patient population were
included in the submission to further support ADCETRIS use in this
disease setting. We look forward to working with the FDA during the
review of our application for ADCETRIS in CTCL, which, if approved,
would be the fourth indication for this product.”
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 online 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: anemia, peripheral sensory neuropathy, nausea,
diarrhea, fatigue and neutropenia.
Based on discussions with the FDA, additional data from two
investigator-sponsored phase 2 trials have also been incorporated
into the supplemental BLA to support the potential for a broader
label in CTCL.
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. The most common subtypes
of CTCL include mycosis fungoides and primary cutaneous anaplastic
large cell lymphoma. 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 four phase 3 studies: the ECHELON-1
trial in frontline classical Hodgkin lymphoma from which positive
top-line results were recently reported, the ongoing ECHELON-2
trial in frontline mature T-cell lymphomas, the completed ALCANZA
trial in cutaneous T-cell lymphoma that supported the supplemental
BLA to the FDA, and the recently initiated CHECKMATE 812 trial of
ADCETRIS in combination with Opdivo (nivolumab) for
relapsed/refractory Hodgkin lymphoma.
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 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 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 toxicity: Events 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 June 30, 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/20170816005171/en/
Seattle Genetics, Inc.Investors:Peggy Pinkston,
425-527-4160ppinkston@seagen.comorMedia:Tricia Larson,
425-527-4180tlarson@seagen.com
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