Arvinas, Inc. (Nasdaq: ARVN) and Pfizer Inc. (NYSE: PFE) today
announced an update on Phase 1 dose escalation data of ARV-471, a
novel PROTAC® estrogen receptor (ER) degrader, which is being
co-developed for the treatment of patients with locally advanced or
metastatic ER-positive/human epidermal growth factor receptor 2
(HER2)-negative breast cancer (ER+/HER2-). These data were
presented as a virtual spotlight poster session at the 2021 San
Antonio Breast Cancer Symposium (SABCS) and showed:
- ARV-471 demonstrated antitumor activity in CDK4/6
inhibitor-pretreated patients with a clinical benefit rate (CBR) of
40% in 47 evaluable patients. This heavily pretreated patient group
had a median of four prior therapies.
- Three patients exhibited confirmed partial responses (PR) among
the 38 patients with response evaluation criteria in solid tumors
(RECIST) measurable lesions and at least one on-treatment tumor
assessment.
- ARV-471 continues to demonstrate a favorable tolerability
profile. Robust ER degradation was observed at all dose levels,
reaching 89% reduction of ER.
Erika P. Hamilton, MD, Director of the Breast Cancer and
Gynecologic Cancer Research Program and Principal Investigator,
Sarah Cannon Research Institute, provided an overview of these
data.
“These results continue to suggest that ARV-471 has the
potential to become a first-in-category treatment, and a new
standard of care, for ER+/HER2- breast cancer patients,” said John
Houston, Ph.D., Chief Executive Officer at Arvinas. “The profile we
see emerging for this drug candidate continues to validate our
PROTAC® protein degrader platform, with ARV-471 showing clear
signals of clinical benefit in a heavily pretreated patient
population, including tumor shrinkage and good tolerability.”
These data support and further validate the evaluation of
ARV-471 as a potential treatment for metastatic breast cancer that
is ongoing in a Phase 1b combination study with
IBRANCE® (palbociclib) and a Phase 2 monotherapy dose
expansion study.
“We are excited by these results and believe ARV-471 is a
promising ER-targeting investigational medicine,” said Chris
Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer
Global Product Development. “It is encouraging to see ARV-471
continuing to show durable efficacy and tolerability in heavily
pre-treated patients with ER+ breast cancer who have limited
treatment choices.”
ARV-471 Clinical Update
Enrollment
As of the data cut-off date of September 30, 2021, 60 adult
patients with locally advanced or metastatic ER+/HER2- breast
cancer were treated in the Phase 1 dose escalation portion of the
study with total daily ARV-471 doses ranging from 30 mg to 700 mg.
This patient group is heavily pretreated, with a median of four
prior therapies. All patients were previously treated with
cyclin-dependent kinase (CDK) 4/6 inhibitors; 80% of patients
received prior fulvestrant; and 78% received prior
chemotherapy.
Efficacy
Of 47 patients who were evaluable for clinical benefit
(confirmed complete response, PR, or stable disease ≥ 24 weeks) the
CBR was 40%. As of the data cutoff date, 14 patients were
continuing to receive study treatment, including two patients who
had been on treatment for over 18 months. Three confirmed PRs were
observed among the 38 patients with baseline RECIST measurable
disease and at least one on-treatment tumor assessment.
Safety
Patients were treated in the monotherapy escalation at total
daily doses of 30 mg (n=3), 60 mg (n=3), 120 mg (n=7), 180/200 mg
(n=11), 360 mg (n=15), 500 mg (n=17), and 700 mg (n= 4). All
patients in the 700 mg cohort received ARV-471 twice-daily, a
subset of patients who received 500 mg as a total daily dose
received ARV-471 twice-daily, and other all doses were administered
once-daily. A maximum tolerated dose was not reached and no dose
limiting toxicities or Grade ≥4 treatment-related adverse events
(TRAEs) were observed. Of the 60 patients, 37% had Grade 1 TRAEs
and 57% had Grade ≤2 TRAEs, and the most common TRAEs were nausea
(29%), fatigue (20%), and vomiting (10%). No Grade 1 or 2 TRAEs led
to discontinuation or dose reduction of ARV-471. Four patients
experienced six Grade 3 TRAEs that were potentially related to
ARV-471, including: headache lasting 1-day, single occurrence of
asymptomatic increased amylase and lipase, nausea and asymptomatic
QTc prolongation, and post-biopsy venous embolism. The patient with
the venous embolism was the only Grade 3 patient who discontinued
ARV-471 due to a TRAE, and the patient with Grade 3 nausea was the
only patient with a dose reduction due to a TRAE (reduced from 500
mg to 400 mg daily).
ER Degradation
In paired biopsies from 14 patients across all doses up to 500
mg daily, robust ER degradation of up to 89% was observed,
regardless of ESR1 mutation status. Median and mean ER degradation
across dose levels were 67% and 64%, respectively.
Pharmacokinetics
ARV-471 demonstrated a dose-related increase in plasma exposure,
with doses from 30 mg to 500 mg daily, resulting in steady-state
Cmax and AUC24 that exceeded the exposure associated with tumor
regression in preclinical breast cancer models. Mean exposure on
day 15 exceeded the nonclinical efficacious range at doses ≥60 mg
daily.
Anticipated 2021/2022 Milestones
- ARV-471 currently is being evaluated as a treatment for
metastatic breast cancer in a Phase 1 dose escalation study, a
Phase 1b combination study with IBRANCE® (palbociclib), and a
Phase 2 monotherapy dose expansion study.
- In 2022, we expect to:
- Initiate Phase 3 studies across lines of therapy in metastatic
breast cancer, as both monotherapy and in combination.
- Initiate two additional trials of ARV-471, including a Phase 1b
combination trial with everolimus in 2L/3L metastatic breast
cancer, potentially as part of a planned umbrella study to explore
multiple combination agents, and a Phase 2 neoadjuvant trial in
early breast cancer.
- Present data from the ongoing Phase 1b combination study with
IBRANCE® (palbociclib) and from the ongoing Phase 2 monotherapy
dose expansion study.
Investor Conference Call Details Arvinas will
host a conference call and webcast at 8:30 AM ET on Friday,
December 10, 2021, to discuss these data. Pfizer Oncology
executives will also participate in this call. Participants are
invited to listen by dialing (844) 467-7654 (domestic) or (602)
563-8497 (international) five minutes prior to the start of the
call and providing the passcode 9122219.
Supporting materials for the conference call and webcast will be
available on the Arvinas’ website
at www.arvinas.com under Events + Presentations. A
replay of the webcast will be archived on the Arvinas website
following the presentation.
About ARV-471ARV-471 is an investigational
orally bioavailable PROTAC® protein degrader designed to
specifically target and degrade the estrogen receptor (ER) for the
treatment of patients with locally advanced or metastatic ER+/HER2-
breast cancer.
In preclinical studies, ARV-471 demonstrated near-complete ER
degradation in tumor cells, induced robust tumor shrinkage when
dosed as a single agent in multiple ER-driven xenograft models, and
showed superior anti-tumor activity when compared to a standard of
care agent, fulvestrant, both as a single agent and in combination
with a CDK4/6 inhibitor. In July 2021, Arvinas announced a global
collaboration with Pfizer for the co-development and
co-commercialization of ARV-471; Arvinas and Pfizer will equally
share worldwide development costs, commercialization expenses, and
profits.
About ArvinasArvinas is a clinical-stage
biopharmaceutical company dedicated to improving the lives of
patients suffering from debilitating and life-threatening diseases
through the discovery, development, and commercialization of
therapies that degrade disease-causing proteins. Arvinas uses its
proprietary PROTAC® Discovery Engine platform to engineer
proteolysis targeting chimeras, or PROTAC® targeted protein
degraders, that are designed to harness the body’s own natural
protein disposal system to selectively and efficiently degrade and
remove disease-causing proteins. In addition to its robust
preclinical pipeline of PROTAC® protein degraders against validated
and “undruggable” targets, the company has three clinical-stage
programs: ARV-110 and ARV-766 for the treatment of men with
metastatic castrate-resistant prostate cancer; and ARV-471 for the
treatment of patients with locally advanced or metastatic ER+/HER2-
breast cancer. For more information, visit www.arvinas.com.
Arvinas Forward-Looking StatementsThis press
release contains forward-looking statements that involve
substantial risks and uncertainties, including statements regarding
the development and regulatory status of ARV-471 and other
candidates in our pipeline, and the timing of clinical trials and
data from those trials and plans for registration for our product
candidates, the therapeutic potential of our product candidates,
and the potential commercialization of any of our product
candidates. All statements, other than statements of historical
facts, contained in this press release, including statements
regarding our strategy, future operations, prospects, plans and
objectives of management, are forward-looking statements. The words
“anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,”
“might,” “plan,” “predict,” “project,” “target,” “potential,”
“will,” “would,” “could,” “should,” “continue,” and similar
expressions are intended to identify forward-looking statements,
although not all forward-looking statements contain these
identifying words.
We may not actually achieve the plans, intentions or
expectations disclosed in our forward-looking statements, and you
should not place undue reliance on our forward-looking statements.
Actual results or events could differ materially from the plans,
intentions and expectations disclosed in the forward-looking
statements we make as a result of various risks and uncertainties,
including but not limited to: whether we and Pfizer will be able to
successfully conduct and complete clinical development for ARV-471,
initiate and complete other clinical trials for our product
candidates, and receive results from our clinical trials on our
expected timelines, or at all and other important factors discussed
in the “Risk Factors” sections contained in our quarterly and
annual reports on file with the Securities and Exchange Commission.
The forward-looking statements contained in this press release
reflect our current views with respect to future events, and we
assume no obligation to update any forward-looking statements
except as required by applicable law. These forward-looking
statements should not be relied upon as representing our views as
of any date subsequent to the date of this release.
About
IBRANCE® (palbociclib) 125
mg tablets and capsulesIBRANCE is an oral inhibitor of
CDKs 4 and 6,1 which are key regulators of the cell cycle that
trigger cellular progression.2,3 In the U.S., IBRANCE is
indicated for the treatment of adult patients with HR+, HER2-
advanced or metastatic breast cancer in combination with an
aromatase inhibitor as initial endocrine based therapy in
postmenopausal women or in men; or with fulvestrant in patients
with disease progression following endocrine therapy.
The full U.S. Prescribing Information for the IBRANCE tablets
and the IBRANCE capsules can be
found here and here.
IMPORTANT
IBRANCE®(palbociclib) SAFETY
INFORMATION FROM THE U.S. PRESCRIBING
INFORMATIONNeutropenia was the most
frequently reported adverse reaction in PALOMA-2 (80%) and PALOMA-3
(83%). In PALOMA-2, Grade 3 (56%) or 4 (10%) decreased neutrophil
counts were reported in patients receiving IBRANCE plus letrozole.
In PALOMA-3, Grade 3 (55%) or Grade 4 (11%) decreased neutrophil
counts were reported in patients receiving IBRANCE plus
fulvestrant. Febrile neutropenia has been reported in 1.8% of
patients exposed to IBRANCE across PALOMA-2 and PALOMA-3. One death
due to neutropenic sepsis was observed in PALOMA-3. Inform patients
to promptly report any fever.
Monitor complete blood count prior to starting IBRANCE, at the
beginning of each cycle, on Day 15 of first 2 cycles and as
clinically indicated. Dose interruption, dose reduction, or delay
in starting treatment cycles is recommended for patients who
develop Grade 3 or 4 neutropenia.
Severe, life-threatening, or fatal interstitial
lung disease (ILD) and/or pneumonitis can occur in
patients treated with CDK4/6 inhibitors, including IBRANCE when
taken in combination with endocrine therapy. Across clinical trials
(PALOMA-1, PALOMA-2, PALOMA-3), 1.0% of IBRANCE-treated patients
had ILD/pneumonitis of any grade, 0.1% had Grade 3 or 4, and no
fatal cases were reported. Additional cases of ILD/pneumonitis have
been observed in the post-marketing setting, with fatalities
reported.
Monitor patients for pulmonary symptoms indicative of
ILD/pneumonitis (e.g., hypoxia, cough, dyspnea). In patients who
have new or worsening respiratory symptoms and are suspected to
have developed pneumonitis, interrupt IBRANCE immediately and
evaluate the patient. Permanently discontinue IBRANCE in patients
with severe ILD or pneumonitis.
Based on the mechanism of action, IBRANCE can
cause fetal harm. Advise females of
reproductive potential to use effective contraception during
IBRANCE treatment and for at least 3 weeks after the last dose.
IBRANCE may impair fertility in
males and has the potential to cause genotoxicity.
Advise male patients to consider sperm preservation before taking
IBRANCE. Advise male patients with female partners of reproductive
potential to use effective contraception during IBRANCE treatment
and for 3 months after the last dose. Advise females to inform
their healthcare provider of a known or suspected pregnancy. Advise
women not to breastfeed during IBRANCE
treatment and for 3 weeks after the last dose because of the
potential for serious adverse reactions in nursing infants.
The most common adverse
reactions (≥10%) of any grade
reported in PALOMA-2 for IBRANCE plus
letrozole vs placebo plus letrozole were neutropenia (80% vs 6%),
infections (60% vs 42%), leukopenia (39% vs 2%), fatigue (37% vs
28%), nausea (35% vs 26%), alopecia (33% vs 16%), stomatitis (30%
vs 14%), diarrhea (26% vs 19%), anemia (24% vs 9%), rash (18% vs
12%), asthenia (17% vs 12%), thrombocytopenia (16% vs 1%), vomiting
(16% vs 17%), decreased appetite (15% vs 9%), dry skin (12% vs 6%),
pyrexia (12% vs 9%), and dysgeusia (10% vs 5%).
The most frequently reported Grade ≥3 adverse
reactions
(≥5%) in PALOMA-2 for
IBRANCE plus letrozole vs placebo plus letrozole were neutropenia
(66% vs 2%), leukopenia (25% vs 0%), infections (7% vs 3%), and
anemia (5% vs 2%).
Lab abnormalities of any grade occurring
in PALOMA-2 for IBRANCE plus letrozole
vs placebo plus letrozole were decreased WBC (97% vs 25%),
decreased neutrophils (95% vs 20%), anemia (78% vs 42%), decreased
platelets (63% vs 14%), increased aspartate aminotransferase (52%
vs 34%), and increased alanine aminotransferase (43% vs 30%).
The most common adverse reactions
(≥10%) of any grade reported
in PALOMA-3 for IBRANCE plus fulvestrant
vs placebo plus fulvestrant were neutropenia (83% vs 4%),
leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs
29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs
13%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), vomiting
(19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased
appetite (16% vs 8%), and pyrexia (13% vs 5%).
The most frequently reported Grade ≥3 adverse
reactions
(≥5%) in PALOMA-3 for
IBRANCE plus fulvestrant vs placebo plus fulvestrant were
neutropenia (66% vs 1%) and leukopenia (31% vs 2%).
Lab abnormalities of any grade occurring
in PALOMA-3 for IBRANCE plus fulvestrant
vs placebo plus fulvestrant were decreased WBC (99% vs 26%),
decreased neutrophils (96% vs 14%), anemia (78% vs 40%), decreased
platelets (62% vs 10%), increased aspartate aminotransferase (43%
vs 48%), and increased alanine aminotransferase (36% vs 34%).
Avoid concurrent use of strong CYP3A
inhibitors. If patients must be administered a strong
CYP3A inhibitor, reduce the IBRANCE dose to 75 mg. If the strong
inhibitor is discontinued, increase the IBRANCE dose (after 3-5
half-lives of the inhibitor) to the dose used prior to the
initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit
juice may increase plasma concentrations of IBRANCE and should be
avoided. Avoid concomitant use of strong CYP3A
inducers. The dose of sensitive CYP3A
substrates with a narrow therapeutic index may need
to be reduced as IBRANCE may increase their exposure.
For patients with severe hepatic
impairment (Child-Pugh class C), the recommended dose
of IBRANCE is 75 mg. The pharmacokinetics of
IBRANCE have not been studied in
patients requiring hemodialysis.
About Pfizer OncologyAt Pfizer Oncology, we are
committed to advancing medicines wherever we believe we can make a
meaningful difference in the lives of people living with cancer.
Today, we have an industry-leading portfolio of 24 approved
innovative cancer medicines and biosimilars across more than 30
indications, including breast, genitourinary, colorectal, blood and
lung cancers, as well as melanoma.
About Pfizer: Breakthroughs That Change Patients’
LivesAt Pfizer, we apply science and our global resources
to bring therapies to people that extend and significantly improve
their lives. We strive to set the standard for quality, safety and
value in the discovery, development and manufacture of health care
products, including innovative medicines and vaccines. Every day,
Pfizer colleagues work across developed and emerging markets to
advance wellness, prevention, treatments and cures that challenge
the most feared diseases of our time. Consistent with our
responsibility as one of the world's premier innovative
biopharmaceutical companies, we collaborate with health care
providers, governments and local communities to support and expand
access to reliable, affordable health care around the world. For
more than 170 years, we have worked to make a difference for all
who rely on us. We routinely post information that may be important
to investors on our website at www.Pfizer.com. In addition, to
learn more, please visit us on www.Pfizer.com and follow us on
Twitter at @Pfizer and @Pfizer News, LinkedIn, YouTube and like us
on Facebook at Facebook.com/Pfizer.
Pfizer Forward-Looking StatementsThe
information contained in this release is as of December 10, 2021.
Pfizer assumes no obligation to update forward-looking statements
contained in this release as the result of new information or
future events or developments.
This release contains forward-looking information about ARV-471
and a global collaboration between Pfizer and Arvinas to develop
and commercialize ARV-471, including their potential benefits, that
involves substantial risks and uncertainties that could cause
actual results to differ materially from those expressed or implied
by such statements. Risks and uncertainties include, among other
things, the uncertainties inherent in research and development,
including the ability to meet anticipated clinical endpoints,
commencement and/or completion dates for clinical trials,
regulatory submission dates, regulatory approval dates and/or
launch dates, as well as the possibility of unfavorable new
clinical data and further analyses of existing clinical data; risks
associated with interim data; the risk that clinical trial
data are subject to differing interpretations and assessments by
regulatory authorities; whether regulatory authorities will be
satisfied with the design of and results from the clinical studies;
whether and when any applications may be filed for ARV-471 for any
potential indications in any jurisdictions; whether and when
regulatory authorities may approve any potential applications that
may be filed for ARV-471 in any jurisdictions, which will depend on
myriad factors, including making a determination as to whether the
product’s benefits outweigh its known risks and determination of
the product’s efficacy and, if approved, whether ARV-471 will be
commercially successful; decisions by regulatory authorities
impacting labeling, manufacturing processes, safety and/or other
matters that could affect the availability or commercial potential
of ARV-471; whether the collaboration between Pfizer and Arvinas
will be successful; uncertainties regarding the impact of COVID-19
on Pfizer’s business, operations and financial results; and
competitive developments.
A further description of risks and uncertainties can be found in
Pfizer’s Annual Report on Form 10-K for the fiscal year ended
December 31, 2020 and in its subsequent reports on Form 10-Q,
including in the sections thereof captioned “Risk Factors” and
“Forward-Looking Information and Factors That May Affect Future
Results”, as well as in its subsequent reports on Form 8-K, all of
which are filed with the U.S. Securities and Exchange Commission
and available at www.sec.gov and www.pfizer.com.
1 IBRANCE® (palbociclib) Prescribing Information. New
York. NY: Pfizer Inc: 2019.
2 Weinberg, RA. pRb and Control of the Cell Cycle Clock.
In: Weinberg RA, ed. The Biology of Cancer. 2nd ed. New York,
NY: Garland Science; 2014:275-329.
3 Sotillo E, Grana X. Escape from Cellular Quiescence. In:
Enders GH, ed. Cell Cycle Deregulation in Cancer. New York, NY:
Humana Press; 2010:3-22.
Arvinas Contacts
Investors:Jeff Boyle, Arvinas Investor
Relations+1 (347) 247-5089Jeff.Boyle@arvinas.com
Media:Kirsten Owens, Arvinas Communications+1
(203) 584-0307Kirsten.Owens@arvinas.com
Pfizer Media Contacts
Investors:+1 (212) 733-4848IR@pfizer.com
Media:+1 (212)
733-1226PfizerMediaRelations@pfizer.com
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