TOKYO and BOTHELL, Wash., April
19, 2021 /PRNewswire/ -- Astellas Pharma Inc. (TSE:
4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas")
and Seagen Inc. (Nasdaq:SGEN) today announced the U.S. Food and
Drug Administration (FDA) filed two supplemental Biologics License
Application (sBLA) submissions for PADCEV® (enfortumab
vedotin-ejfv) for review as part of the Real-Time Oncology Review
(RTOR) pilot program. The applications were granted Priority
Review, with a target action date of August
17, 2021. The review of both applications will also be
conducted under Project Orbis, an initiative of the FDA Oncology
Center of Excellence.
The FDA's RTOR program aims to explore a more efficient
review process to ensure that safe and effective treatments are
available to patients as early as possible. Project Orbis provides
a framework for concurrent submission and review of oncology drugs
among participating international partners. The first sBLA is based
on the phase 3 EV-301 trial and seeks to convert PADCEV's
accelerated approval to regular approval. The second sBLA, based on
the pivotal trial EV-201's cohort 2, requests an expansion of the
current indication to include patients with locally advanced or
metastatic urothelial cancer who have been previously treated with
a programmed death receptor-1 (PD-1) or programmed death-ligand 1
(PD-L1) inhibitor and are ineligible for cisplatin. Results from
EV-301 were published in the New England Journal of
Medicine. Results from EV-301 and EV-201 cohort 2 were
presented at the 2021 American Society of Clinical Oncology
Genitourinary Cancers Symposium.
"With our recent regulatory submissions, we intend to provide
the highest level of clinical evidence supporting PADCEV use –
overall survival data from a randomized phase 3 trial – and expand
availability in multiple countries where there is unmet medical
need," said Andrew Krivoshik, M.D.,
Ph.D., Senior Vice President and Oncology Therapeutic Area Head,
Astellas.
"These FDA filings, along with regulatory submissions outside of
the United States under our
collaboration with Astellas, are important steps in our shared goal
of bringing PADCEV to more patients with advanced urothelial
cancer," said Roger Dansey, M.D.,
Chief Medical Officer of Seagen.
Health authorities in Australia
and Canada will evaluate data from
EV-301 and EV-201 for initial registrations under Project Orbis. In
March, the companies announced regulatory submissions in
Japan and the European Union.
Urothelial cancer is the most common type of bladder cancer (90
percent of cases) and can also be found in the renal pelvis (where
urine collects inside the kidney), ureter (tube that connects the
kidneys to the bladder) and urethra.1 Globally,
approximately 573,000 new cases of bladder cancer and more than
212,000 deaths are reported annually.2
In 2019, PADCEV received accelerated approval in the U.S. 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
urothelial cancer setting. PADCEV is currently only approved for
use in the U.S.
About the EV-301 Trial
The EV-301 trial (NCT03474107)
is a global, multicenter, open-label, randomized phase 3 trial
designed to evaluate enfortumab vedotin versus physician's choice
of chemotherapy (docetaxel, paclitaxel or vinflunine) in
approximately 600 patients with locally advanced or metastatic
urothelial cancer who were previously treated with a PD-1/L1
inhibitor and a platinum-based therapy.3 The primary
endpoint is overall survival and secondary endpoints include
progression-free survival, overall response rate, duration of
response and disease control rate, as well as assessment of
safety/tolerability and quality-of-life parameters.
About the EV-201 Trial
The EV-201 trial (NCT03219333) is a single-arm, dual-cohort,
pivotal phase 2 clinical trial of enfortumab vedotin for patients
with locally advanced or metastatic urothelial cancer who have been
previously treated with a PD-1 or PD-L1 inhibitor, including those
who have also been treated with a platinum-containing chemotherapy
(cohort 1) and those who have not received a platinum-containing
chemotherapy in this setting and who are ineligible for cisplatin
(cohort 2). The trial enrolled 128 patients in cohort 1 and 91
patients in cohort 2 at multiple centers
internationally.4 The primary endpoint is confirmed
objective response rate per blinded independent central review.
Secondary endpoints include assessments of duration of response,
disease control rate, progression-free survival, overall survival,
safety and tolerability.
PADCEV (enfortumab vedotin-ejfv) U.S. Important Safety
Information
Warnings and Precautions
Skin reactions: Severe cutaneous adverse reactions,
including fatal cases of Stevens-Johnson syndrome (SJS) or toxic
epidermal necrolysis (TEN), occurred in patients treated with
PADCEV. SJS and TEN occurred predominantly during the first cycle
of treatment but may occur later.
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), dermatitis bullous,
dermatitis exfoliative, 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 closely throughout treatment for skin
reactions. Consider topical corticosteroids and antihistamines as
clinically indicated. Withhold PADCEV and consider referral for
specialized care for severe (Grade 3) skin reactions, suspected
SJS, or TEN. Permanently discontinue PADCEV in patients with
confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin
reactions.
Hyperglycemia occurred in patients treated with PADCEV,
including death and diabetic ketoacidosis, 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.
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 (10%), hemoglobin
decreased (10%), phosphate decreased (10%), lipase increased (9%),
sodium decreased (8%), glucose increased (8%), urate increased
(7%), neutrophils decreased (5%).
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. is a
pharmaceutical company conducting business in more than 70
countries around the world. We are promoting the Focus Area
Approach that is designed to identify opportunities for the
continuous creation of new drugs to address diseases with high
unmet medical needs by focusing on Biology and Modality.
Furthermore, we are also looking beyond our foundational Rx focus
to create Rx+® healthcare solutions that combine our
expertise and knowledge with cutting-edge technology in different
fields of external partners. Through these efforts, Astellas stands
on the forefront of healthcare change to turn innovative science
into value for patients. For more information, please visit our
website at https://www.astellas.com/en.
About Seagen
Seagen Inc. is a global biotechnology
company that discovers, develops and commercializes transformative
cancer medicines to make a meaningful difference in people's lives.
Seagen is headquartered in the Seattle,
Washington area, and has locations in California, Canada, Switzerland and the European Union. For more
information on our marketed products and robust pipeline, visit
www.seagen.com and follow @SeagenGlobal on Twitter.
About the Astellas and Seagen Collaboration
Astellas
and Seagen are co-developing enfortumab vedotin under a
collaboration that was entered into in 2007 and expanded in
2009.
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.
Seagen Forward Looking Statements
Certain statements
made in this press release are forward looking, such as those,
among others, relating to the potential conversion of PADCEV's
current accelerated approval in the U.S. to regular approval and
the potential expansion of the current PADCEV label to include
patients with locally advanced or metastatic urothelial cancer who
have been previously treated with a PD-1/L1 inhibitor and are
ineligible for cisplatin; the potential to obtain regulatory
approvals in Japan, the European
Union, Australia and Canada; 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, without limitation, the
possibility that the sBLA submissions based on the EV-301 and
EV-201 second cohort clinical trials may not be ultimately
approved by the FDA in a timely manner or at all; that the results
of the EV-301 clinical trial may not be sufficient to convert
PADCEV's accelerated approval in the U.S. to regular approval and
that the results of the second cohort of the EV-201 clinical trial
may not be sufficient to support the requested label expansion;
that, even if PADCEV receives regular approval and even if the
PADCEV label is expanded based on the results of the second cohort
of the EV-201 clinical trial, the product labeling may not be as
broad or desirable as requested or anticipated; and that
regulatory approvals of PADCEV in Japan, the European Union, Australia and Canada may not be obtained or may not be
obtained with product labeling that is as broad or desirable as
requested or anticipated, and that setbacks in the development and
commercialization of PADCEV could occur as a result of the
difficulty and uncertainty of pharmaceutical product development,
the risk of adverse events or safety signals, adverse regulatory
actions or other factors. More information about the risks and
uncertainties faced by Seagen is contained under the caption "Risk
Factors" included in the company's Annual Report on Form 10-K for
the year ended December 31, 2020
filed with the Securities and Exchange Commission. Seagen 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.
References
1 American Society of Clinical Oncology. Bladder
cancer: introduction (9-2020).
https://www.cancer.net/cancer-types/bladder-cancer/introduction.
Accessed April 13, 2021.
2 World Health Organization, International Agency
for Research on Cancer. Globocan 2020 world fact sheet.
https://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf.
Accessed April 13, 2021.
3 Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab
Vedotin in Previously Treated Advanced Urothelial Carcinoma. N
Engl J Med. 2021; 10.1056/NEJMoa2035807.
4 Balar AV, McGregor BA, Rosenberg JE, et al.
EV-201 Cohort 2: Enfortumab vedotin in cisplatin-ineligible
patients with locally advanced or metastatic urothelial cancer who
received prior PD-1/PD-L1 inhibitors [abstract]. In 2021
Genitourinary Cancers Symposium; 2021 Feb
11-13; Alexandria, VA. ASCO
GU; 2021. Abstract 394.
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