Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biopharmaceutical
company creating a new class of drugs based on targeted protein
degradation using its PROTAC® Discovery Engine, today announced
clinical program updates for its PROTAC® protein degraders ARV-471
and ARV-110. For ARV-471, interim Phase 1 data show potential for
best-in-class safety and tolerability, estrogen receptor (ER)
degradation superior to that previously reported for the current
standard of care agent (fulvestrant), and robust efficacy signals
in heavily pretreated patients with locally advanced or metastatic
ER positive / HER2 negative (ER+/HER2-) breast cancer. The efficacy
signals include one Response Evaluation Criteria in Solid Tumors
(RECIST) confirmed partial response (PR), two additional patients
with unconfirmed PRs, and a clinical benefit rate (CBR) of 42%. For
ARV-110, the ongoing dose escalation portion of the Phase 1/2 trial
in men with metastatic castration-resistant prostate cancer (mCRPC)
has provided additional evidence of anti-tumor activity and patient
benefit, including a prostate specific antigen reduction of more
than 50% (PSA50) rate of 40% in a molecularly defined patient
population. Arvinas has initiated a Phase 2 dose expansion to
explore a two-pronged development strategy, including the potential
for accelerated approval in molecularly defined, late-line
patients, and broader development in less-heavily pretreated mCRPC
patients with fewer androgen receptor (AR)-independent mechanisms
of tumor resistance.
Both ARV-471 and ARV-110 have been well tolerated, neither has
reached a maximum tolerated dose, and the Phase 1 dose escalation
trials for both programs continue. A Phase 1b combination trial of
ARV-471 and Ibrance® (palbociclib) is expected to begin in December
2020, and a Phase 2 expansion cohort for ARV-471 is scheduled to
begin in the first half of 2021.
“After initiating our clinical efforts just last year, we now
have what we believe are clear signals of efficacy in both of our
clinical-stage development programs,” said John Houston, Ph.D.,
Chief Executive Officer at Arvinas. “The clinical benefits we’ve
seen in both patient populations, including tumor shrinkage and low
incidence of adverse effects, are compelling and reinforce our
belief that our PROTAC protein degraders could dramatically change
the lives of patients who have few or no therapeutic options.”
“Based on data to date, we believe ARV-471 is the most promising
ER-targeting therapy in the clinic, showing early signs of
efficacy, a favorable tolerability profile, and better ER
degradation than that previously reported for fulvestrant, the
current standard of care,” said Ron Peck, Ph.D., Chief Medical
Officer at Arvinas. “It is exciting to see that ARV-110 continues
to be active and well tolerated in what we believe is the most
heavily pretreated patient population that has ever been studied
with an AR-directed therapy. Our recently initiated ARDENT Phase 2
cohort expansion is specifically designed to investigate the
potential of a precision medicine approach in molecularly defined,
late-line patients with few available treatment options, while also
fully characterizing the safety and activity of ARV-110 in earlier
line patients irrespective of molecular profile, setting ARV-110 on
a potential two-pronged registrational path.”
ARV-471 Clinical Update
As of the data cut-off date of November 11, 2020, 21 adult
patients with locally advanced or metastatic ER+/HER2- breast
cancer completed at least one treatment cycle with ARV-471 (orally,
once-daily) in the Phase 1 clinical trial. 100% of these patients
were previously treated with a cyclin-dependent kinase (CDK) 4/6
inhibitor, 71% of patients received prior fulvestrant, and 23% of
patients were pretreated with investigational selective estrogen
receptor degraders (SERDs). Overall, patients had a median of five
prior therapies.
In metastatic breast cancer, prior treatment with CDK4/6
inhibitors predicts high tumor ER-independence, rendering
ER-targeting therapies ineffective. However, one patient in the
ARV-471 trial had a confirmed PR with a 51% reduction in target
lesion size as assessed by RECIST. Two additional patients had
unconfirmed PRs and one additional patient demonstrated stable
disease with >50% target lesion shrinkage. For evaluation of
CBR, 12 patients had sufficient follow-up to be included. Five of
12 patients (42%) achieved CBR (CBR defined as PRs + complete
responses + stable disease at 6 months). Three of these five
patients had previously received fulvestrant, and another was
treated with two investigational SERDs.
ARV-471 has been well tolerated at all dose levels, as of the
data cut-off date. The most common treatment-related Grade 1-2
adverse events were nausea (24%), arthralgia (19%), fatigue (19%),
and decreased appetite (14%). None of these led to discontinuation
or dose reduction of ARV-471. No patients reported
treatment-related Grade 3 of 4 adverse events, and no dose-limiting
toxicities (DLTs) have been reported. A maximum tolerated dose
(MTD) has not been reached and dose escalation continues.
The plasma exposures of ARV-471 have been dose proportional up
to and including 360 mg orally once daily and have substantially
exceeded Arvinas’ predicted thresholds of efficacy based on
preclinical studies. The estimated half-life of ARV-471 is 28
hours, supporting a once-daily schedule of administration. Analysis
of five paired tumor biopsies at doses up to 120 mg provide
compelling proof of mechanism for ARV-471, which has demonstrated
ER degradation up to 90% (average of 62%) at those doses, while
dose escalation continues.
The combined profile of ARV-471, including efficacy signals in a
highly refractory population, excellent tolerability profile, and
high levels of ER degradation, support a potential best-in-class
ER-targeting therapy.
A Phase 2 dose expansion of ARV-471 is expected to begin in the
first half of 2021. Arvinas also expects to initiate a Phase 1b
cohort expansion of ARV-471 in combination with Ibrance®
(palbociclib) in December 2020. This trial will evaluate the safety
and tolerability of ARV-471 in combination with palbociclib and
seek to identify a recommended combination dose. Arvinas expects to
begin two additional studies of ARV-471 in the second half of 2021:
a combination trial of ARV-471 and another targeted therapy in
2L/3L metastatic breast cancer, and a window of opportunity study
in adjuvant breast cancer. The combined data from these studies
will inform Arvinas’ global development strategy and path forward
toward the goal for ARV-471 to become the leading endocrine therapy
in ER+/HER2- breast cancer.
ARV-110 Clinical Update
In the Phase 1 clinical trial in men with mCRPC, ARV-110
continues to show promising activity in a very late-line
population, with PSA reductions >50% observed at doses greater
than 280 mg, the last reported cohort.
In the dose escalation, ARV-110 exposures have risen dose
proportionally, and at 420 mg oral daily dosing, exposures in
nearly all patients have surpassed a threshold associated with
tumor responses with ARV-110 in enzalutamide-resistant preclinical
models of prostate cancer. Increases in exposure are associated
with increased frequency of PSA reductions.
In the Phase 1 dose escalation trial, 76% of patients had been
treated with prior chemotherapy, and 82% previously received both
abiraterone and enzalutamide. Patients had a median of five prior
lines of therapy. Multiple lines of therapy in nonmetastatic and
metastatic castrate resistant prostate cancer are associated with a
decreased responsiveness to AR-directed therapies and an increase
in tumor heterogeneity, including in genetic mutations, which
reduce the tumor’s dependence on the AR signaling axis. Genetic
profiling of trial patient tumors has led to significant learnings
about the ARV-110 Phase 1 patient population, especially regarding
genetic variability. 84% of patients in the trial have non-AR gene
mutations, and as such, they would not be expected to respond. In
addition, rates of specific AR mutations have been found to be
higher than reported in publications that have characterized
prevalence of AR mutations in men with mCRPC.
Despite the highly heterogeneous nature of the Phase 1 patient
population, Arvinas has identified a molecularly defined, late-line
population with a particularly strong response to ARV-110. Two of
five patients (40%) with T878 or H875 mutations in AR had PSA
reductions >50%, including one patient with a confirmed PR by
RECIST and tumor size reduction of 80%.
In addition, two of 15 patients (13%) with wild-type AR also had
PSA reductions >50%, representing activity in a broader patient
population. In the full group of patients with exposures above the
minimum threshold Arvinas predicted to be efficacious by
preclinical studies, four of 28 (14%) had PSA reductions >50%.
These PSA50 rates are higher than would be expected from approved
AR-directed therapies in such late-line patients. Specifically,
PSA50 response rates from standard-of-care AR-directed therapies
generally decrease to 8-15% in mCRPC patients with fewer prior
therapies than the patients in the ARV-110 trial.
The dual signals of ARV-110 activity in a molecularly defined
population (T878/H875) and in wild-type patients supports Arvinas’
two-pronged strategy for ARV-110 development and suggest a robust
opportunity to address unmet need in patients with mCRPC.
A daily dose of 420 mg was selected as a Phase 2 expansion dose
based on pharmacokinetics, safety profile, and the activity signals
in both T878/H875 and wild-type patients. In the ARDENT Phase 2
expansion, T878/H875 patients will be enriched in a subgroup to
ensure sufficient patient numbers to support the potential for
accelerated approval in this population. A separate subgroup will
enrich for less-pretreated patients (i.e., no prior chemotherapy
and with only one previous second-generation AR-directed therapy,
such as enzalutamide or abiraterone), to ensure sufficient numbers
of patients whose tumors are expected to be more AR-dependent, less
genetically complex, and more responsive to ARV-110.
The ARDENT Phase 2 expansion (N = ~100) began enrolling in
October 2020, and Arvinas expects to provide interim data from the
trial in the second half of 2021. In 2021, Arvinas also expects to
begin at least one Phase 1b combination trial with a
standard-of-care prostate cancer therapy and provide complete data
from the Phase 1 dose escalation.
Anticipated 2020/2021 Milestones
ARV-471
- Initiation of a Phase 1b trial in
combination with Ibrance® (palbociclib) (December 2020)
- Initiation of a Phase 2 dose
expansion (1H21)
- Completion of the Phase 1 dose
escalation (1H21)
- Safety data from the Phase 1b trial
in combination with Ibrance® (palbociclib) (2H21)
- Initiation of a window of
opportunity study in adjuvant breast cancer (2H21)
- Initiation of a combination trial of
ARV-471 and another targeted therapy in 2L/3L metastatic breast
cancer (2H21)
ARV-110
- Completion of the Phase 1 dose
escalation (1H21)
- Interim data from the ARDENT Phase 2
dose expansion at 420 mg (2H21)
- Initiation of combination trial(s)
with standards-of-care (2021)
Other clinical milestones
- First-in-human start for ARV-766, an
AR degrader with a different profile from ARV-110 (1H21)
Arvinas Webcast Investor MeetingArvinas will
host a conference call and webcast at 8:00 AM ET on Monday,
December 14, 2020 to discuss these data. 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 9681734. A live webcast presentation will be
available here or on the Company’s 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-110ARV-110 is an investigational
orally bioavailable PROTAC® protein degrader designed to
selectively target and degrade the androgen receptor (AR). ARV-110
is being developed as a potential treatment for men with metastatic
castration-resistant prostate cancer.
ARV-110 has demonstrated activity in preclinical models of AR
mutation or overexpression, both common mechanisms of resistance to
currently available AR-targeted therapies.
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.
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 two clinical-stage
programs: ARV-110 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.
Forward-Looking StatementsThis press release
contains forward-looking statements that involve substantial risks
and uncertainties, including statements regarding the development
and regulatory status of our product candidates ARV-110, ARV-471,
ARV-766, and other candidates in our pipeline, the conduct of and
plans for our ongoing Phase 1/2 clinical trials for ARV-110 and
ARV-471, our planned Phase 1b combination trial for ARV-471, our
planned Phase 1b combination trials for ARV-110, the plans for
presentation of data from our Phase 1/2 clinical trials for ARV-110
and ARV-471, the planned first-in-human start for ARV-766,and the
potential advantages and therapeutic potential 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 will be able to
successfully conduct Phase 1/2 clinical trials for ARV-110 and
ARV-471 and Phase 1b combination trials for ARV-110 or ARV-471,
complete our clinical trials for our other 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 press release.
Contacts for Arvinas
Investors
Will O’Connor, Stern Investor Relations ir@arvinas.com
MediaKirsten Owens, Arvinas
Communicationskirsten.owens@arvinas.com
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