TOKYO and BOTHELL, Wash., Dec.
18, 2019 /PRNewswire/ -- Astellas Pharma
Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Seattle
Genetics, Inc. (Nasdaq:SGEN) today announced that the U.S.
Food and Drug Administration (FDA) granted accelerated approval to
PADCEV™ for the treatment of adult patients with locally
advanced or metastatic urothelial cancer who have previously
received a PD-1/L1 inhibitor and a platinum-containing chemotherapy
before (neoadjuvant) or after (adjuvant) surgery or in a locally
advanced or metastatic setting. PADCEV is approved under the FDA's
Accelerated Approval Program based on tumor response rate.
Continued approval may be contingent upon verification and
description of clinical benefit in confirmatory trials. PADCEV is
the first FDA approved treatment in the U.S. for these patients. It
is a first-in-class antibody-drug conjugate (ADC) that is directed
against Nectin-4, a protein located on the surface of cells and
highly expressed in bladder cancer.1,3
"Metastatic urothelial cancer is an aggressive and devastating
disease with limited treatment options, and the approval of PADCEV
is a significant advance for these patients who previously had
limited options after initial therapies failed," said Jonathan E. Rosenberg, M.D., Medical Oncologist,
Chief, Genitourinary Medical Oncology Service, Memorial Sloan
Kettering Cancer Center in New
York. "The PADCEV clinical trial enrolled a range of
patients whose cancer was difficult to treat, including those whose
disease had spread to the liver."
"The FDA approval of PADCEV is welcome news for patients with
bladder cancer," said Andrea
Maddox-Smith, Chief Executive Officer, Bladder Cancer
Advocacy Network. "Though new medicines for bladder cancer have
been approved in recent years, most people living with advanced
stages of this disease face a difficult journey with few treatment
options."
"This approval underscores our commitment to develop novel
medicines that address unmet patient needs, and we're grateful to
the patients and physicians whose participation led to this
outcome," said Andrew Krivoshik,
M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area
Head, Astellas.
"PADCEV is the first antibody-drug conjugate approved for
patients facing this aggressive disease, and it is the culmination
of years of innovative work on this technology," said Roger Dansey, M.D., Chief Medical Officer,
Seattle Genetics.
PADCEV was evaluated in the pivotal trial EV-201, a single-arm
phase 2 multi-center trial that enrolled 125 patients with locally
advanced or metastatic urothelial cancer who received prior
treatment with a PD-1 or PD-L1 inhibitor and a platinum-based
chemotherapy.1 In the study, the primary endpoint of
confirmed objective response rate (ORR) was 44 percent per blinded
independent central review (55/125; 95% Confidence Interval [CI]:
35.1, 53.2). Among patients treated with the single agent PADCEV,
12 percent (15/125) experienced a complete response, meaning no
cancer could be detected at the time of assessment, and 32 percent
(40/125) experienced a partial response, meaning a decrease in
tumor size or extent of cancer in the body. The median duration of
response (DoR), a secondary endpoint, was 7.6 months (95% CI: 6.3,
not estimable [NE]). The most common serious adverse reactions
(≥3%) were urinary tract infection (6%), cellulitis (5%), febrile
neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury
(3%), dyspnea (3%), and rash (3%). The most common adverse reaction
leading to discontinuation was peripheral neuropathy (6%). The most
common adverse reactions (≥20%) were fatigue (56%), peripheral
neuropathy (56%), decreased appetite (52%), rash (52%), alopecia
(50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye
(40%), pruritus (26%) and dry skin (26%). The most common Grade ≥3
adverse reactions (≥5%) were rash (13%), diarrhea (6%) and fatigue
(6%).
The FDA's Accelerated Approval Program allows approval of a
medicine based on a surrogate endpoint if the medicine fills an
unmet medical need for a serious condition. A global,
randomized phase 3 confirmatory clinical trial (EV-301) is underway
and is also intended to support global registrations.
About PADCEV
PADCEV is a first-in-class
antibody-drug conjugate (ADC) that is directed against Nectin-4, a
protein located on the surface of cells and highly expressed in
bladder cancer.1,2 Nonclinical data suggest the
anticancer activity of PADCEV is due to its binding to Nectin-4
expressing cells followed by the internalization and release of the
anti-tumor agent monomethyl auristatin E (MMAE) into the cell,
which result in the cell not reproducing (cell cycle arrest) and in
programmed cell death (apoptosis). PADCEV is co-developed by
Astellas and Seattle Genetics.
PADCEV Support Solutions offers access and reimbursement support
to help patients access PADCEV. For more information, go to
PADCEV Support Solutions at PADCEVSupportSolutions.com.
About Bladder and Urothelial
Cancer
Approximately 80,000 people in the U.S. will be
diagnosed with bladder cancer this year.4 Urothelial
cancer accounts for 90 percent of all bladder cancers and can also
be found in the renal pelvis, ureter and urethra.5
Important Safety Information
Warnings and Precautions
- Hyperglycemia occurred in patients treated with PADCEV,
including death and diabetic ketoacidosis (DKA), in those with and
without pre-existing diabetes mellitus. The incidence of Grade 3-4
hyperglycemia increased consistently in patients with higher body
mass index and in patients with higher baseline A1C. In one
clinical trial, 8% of patients developed Grade 3-4 hyperglycemia.
Patients with baseline hemoglobin A1C ≥8% were excluded. Closely
monitor blood glucose levels in patients with, or at risk for,
diabetes mellitus or hyperglycemia. If blood glucose is elevated
(>250 mg/dL), withhold PADCEV.
- Peripheral neuropathy (PN), predominantly sensory,
occurred in 49% of the 310 patients treated with PADCEV in clinical
trials; 2% experienced Grade 3 reactions. In one clinical trial,
peripheral neuropathy occurred in patients treated with PADCEV with
or without preexisting peripheral neuropathy. The median time to
onset of Grade ≥2 was 3.8 months (range: 0.6 to 9.2). Neuropathy
led to treatment discontinuation in 6% of patients. At the time of
their last evaluation, 19% had complete resolution, and 26% had
partial improvement. Monitor patients for symptoms of new or
worsening peripheral neuropathy and consider dose interruption or
dose reduction of PADCEV when peripheral neuropathy occurs.
Permanently discontinue PADCEV in patients that develop Grade ≥3
peripheral neuropathy.
- Ocular disorders occurred in 46% of the 310 patients
treated with PADCEV. The majority of these events involved the
cornea and included keratitis, blurred vision, limbal stem cell
deficiency and other events associated with dry eyes. Dry eye
symptoms occurred in 36% of patients, and blurred vision occurred
in 14% of patients, during treatment with PADCEV. The median time
to onset to symptomatic ocular disorder was 1.9 months (range: 0.3
to 6.2). Monitor patients for ocular disorders. Consider artificial
tears for prophylaxis of dry eyes and ophthalmologic evaluation if
ocular symptoms occur or do not resolve. Consider treatment with
ophthalmic topical steroids, if indicated after an ophthalmic exam.
Consider dose interruption or dose reduction of PADCEV for
symptomatic ocular disorders.
- Skin reactions occurred in 54% of the 310 patients
treated with PADCEV in clinical trials. Twenty-six percent (26%) of
patients had maculopapular rash and 30% had pruritus. Grade 3-4
skin reactions occurred in 10% of patients and included symmetrical
drug-related intertriginous and flexural exanthema (SDRIFE),
bullous dermatitis, exfoliative dermatitis, and palmar-plantar
erythrodysesthesia. In one clinical trial, the median time to onset
of severe skin reactions was 0.8 months (range: 0.2 to 5.3). Of the
patients who experienced rash, 65% had complete resolution and 22%
had partial improvement. Monitor patients for skin reactions.
Consider appropriate treatment, such as topical corticosteroids and
antihistamines for skin reactions, as clinically indicated. For
severe (Grade 3) skin reactions, withhold PADCEV until improvement
or resolution and administer appropriate medical treatment.
Permanently discontinue PADCEV in patients that develop Grade 4 or
recurrent Grade 3 skin reactions.
- Infusion site extravasation Skin and soft tissue
reactions secondary to extravasation have been observed after
administration of PADCEV. Of the 310 patients, 1.3% of patients
experienced skin and soft tissue reactions. Reactions may be
delayed. Erythema, swelling, increased temperature, and pain
worsened until 2-7 days after extravasation and resolved within 1-4
weeks of peak. One percent (1%) of patients developed extravasation
reactions with secondary cellulitis, bullae, or exfoliation. Ensure
adequate venous access prior to starting PADCEV and monitor for
possible extravasation during administration. If extravasation
occurs, stop the infusion and monitor for adverse reactions.
- Embryo-fetal toxicity PADCEV can cause fetal harm when
administered to a pregnant woman. Advise patients of the potential
risk to the fetus. Advise female patients of reproductive potential
to use effective contraception during PADCEV treatment and for 2
months after the last dose. Advise male patients with female
partners of reproductive potential to use effective contraception
during treatment with PADCEV and for 4 months after the last
dose.
Adverse Reactions
Serious adverse reactions occurred
in 46% of patients treated with PADCEV. The most common serious
adverse reactions (≥3%) were urinary tract infection (6%),
cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis
(3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal
adverse reactions occurred in 3.2% of patients, including acute
respiratory failure, aspiration pneumonia, cardiac disorder, and
sepsis (each 0.8%).
Adverse reactions leading to discontinuation occurred in 16% of
patients; the most common adverse reaction leading to
discontinuation was peripheral neuropathy (6%). Adverse reactions
leading to dose interruption occurred in 64% of patients; the most
common adverse reactions leading to dose interruption were
peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse
reactions leading to dose reduction occurred in 34% of patients;
the most common adverse reactions leading to dose reduction were
peripheral neuropathy (12%), rash (6%) and fatigue (4%).
The most common adverse reactions (≥20%) were fatigue (56%),
peripheral neuropathy (56%), decreased appetite (52%), rash (52%),
alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry
eye (40%), pruritus (26%) and dry skin (26%). The most common Grade
≥3 adverse reactions (≥5%) were rash (13%), diarrhea (6%) and
fatigue (6%).
Lab Abnormalities
In one clinical trial, Grade 3-4
laboratory abnormalities reported in ≥5% were: lymphocytes
decreased, hemoglobin decreased, phosphate decreased, lipase
increased, sodium decreased, glucose increased, urate increased,
neutrophils decreased.
Drug Interactions
- Effects of other drugs on PADCEV Concomitant use
with a strong CYP3A4 inhibitor may increase free MMAE exposure,
which may increase the incidence or severity of PADCEV toxicities.
Closely monitor patients for signs of toxicity when PADCEV is given
concomitantly with strong CYP3A4 inhibitors.
Specific Populations
- Lactation Advise lactating women not to breastfeed
during treatment with PADCEV and for at least 3 weeks after the
last dose.
- Hepatic impairment Avoid the use of PADCEV in patients
with moderate or severe hepatic impairment.
For more information, please see the full Prescribing
Information for PADCEV here.
About Astellas
Astellas Pharma Inc., based in
Tokyo, Japan, is a company
dedicated to improving the health of people around the world
through the provision of innovative and reliable pharmaceutical
products. For more information, please visit our website at
https://www.astellas.com/en.
About Seattle Genetics
Seattle Genetics, Inc.
is an emerging multi-product, global biotechnology company that
develops and commercializes transformative therapies targeting
cancer to make a meaningful difference in people's lives. The
company is headquartered in Bothell,
Washington, and has a European office in Switzerland. For more information on our
robust pipeline, visit www.seattlegenetics.com and follow
@SeattleGenetics on Twitter.
About the Astellas and Seattle Genetics
Collaboration
Seattle Genetics and Astellas are
co-developing PADCEV (enfortumab vedotin) under a collaboration
that was entered into in 2007 and expanded in 2009. Under the
collaboration, the companies are sharing costs and profits on a
50:50 basis worldwide.
Astellas Cautionary Notes
In this press release,
statements made with respect to current plans, estimates,
strategies and beliefs and other statements that are not historical
facts are forward-looking statements about the future performance
of Astellas. These statements are based on management's current
assumptions and beliefs in light of the information currently
available to it and involve known and unknown risks and
uncertainties. A number of factors could cause actual results to
differ materially from those discussed in the forward-looking
statements. Such factors include, but are not limited to: (i)
changes in general economic conditions and in laws and regulations,
relating to pharmaceutical markets, (ii) currency exchange rate
fluctuations, (iii) delays in new product launches, (iv) the
inability of Astellas to market existing and new products
effectively, (v) the inability of Astellas to continue to
effectively research and develop products accepted by customers in
highly competitive markets, and (vi) infringements of Astellas'
intellectual property rights by third parties.
Information about pharmaceutical products (including products
currently in development), which is included in this press release
is not intended to constitute an advertisement or medical
advice.
Seattle Genetics Forward Looking
Statements
Certain statements made in this press
release are forward looking, such as those, among others, relating
to the continued FDA approval of PADCEV™ (enfortumab
vedotin-ejfv) for the treatment of adult patients with locally
advanced or metastatic urothelial cancer who have previously
received a PD-1/L1 inhibitor, and a platinum-containing
chemotherapy in the neoadjuvant/adjuvant, locally advanced or
metastatic setting; the conduct of an ongoing randomized phase 3
confirmatory clinical trial (EV-301) intended to verify the
clinical benefit of PADCEV and support global registrations; and
the therapeutic potential of PADCEV including its efficacy, safety
and therapeutic uses. 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 the
possibility that EV-301 and subsequent clinical trials may fail to
establish sufficient efficacy; that adverse events or safety
signals may occur; that utilization and adoption of PADCEV by
prescribing physicians may be limited by the availability and
extent of reimbursement or other factors; and that adverse
regulatory actions may occur. 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 September
30, 2019 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, except as required by
law.
1 Padcev [package insert]. Northbrook, IL: Astellas, Inc.
2 Rosenberg JE, O'Donnell PH, Balar AV, et al.
Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After
Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1
Therapy. J Clin Oncol 2019;37(29):2592600.
3 Challita-Eid P, Satpayev D, Yang P, et al.
Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a
Highly Potent Therapeutic Agent in Multiple Preclinical Cancer
Models. Cancer Res 2016;76(10):3003-13.
4 American Society of Clinical Oncology. Bladder cancer:
introduction (10-2017). https://www.cancer.net/cance
rtypes/bladdercancer/introduction. Accessed 05-09-2019.
5 National Cancer Institute. Surveillance,
Epidemiology, and End Results Program. Cancer stat facts: bladder
cancer. https://seer.cancer.gov/statfacts/html/urinb.html. Accessed
05-01-2019.
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SOURCE Astellas Pharma US, Inc.