ArQule Announces Publication of Preclinical Data for ARQ 531, a Reversible Inhibitor of Both Wild Type and Mutant BTK
August 13 2018 - 4:01PM
Business Wire
Data Support ARQ 531 as a Potential First- and
Best-In-Class Reversible BTK Inhibitor, with the Potential to
Address Emerging Resistance to Irreversible BTK Inhibitors
ArQule, Inc. (Nasdaq:ARQL), today announced the publication of
preclinical study data for ARQ 531, the Company’s
rationally-designed, reversible inhibitor of both wild type and
C481S-mutant Bruton’s tyrosine kinase (BTK). The studies, published
in Cancer Discovery, were conducted in collaboration with
researchers at The Ohio State University. Data from these studies
demonstrated efficacy in in vitro and in vivo hematologic
malignancy models that recapitulate the most common mechanisms of
resistance to irreversible BTK inhibitors, including ibrutinib.
Highlights from the manuscript (link here) include:
Differentiated Crystal Structure and
Biochemical Profile
- The crystal structure of ARQ 531 bound
to BTK elucidates the mechanism of BTK inhibition that is not
dependent on the specific amino acid residue at position 481 (eg. C
or S)
- Recombinant BTK biochemical assays of
ARQ 531 and ibrutinib show similar inhibition for wild type BTK,
however ibrutinib has dramatically lower inhibition, binding
affinity and residence time for mutant BTK
“Relapsed and refractory patients that develop resistance to
ibrutinib have poor outcomes and limited treatment options,” said
Brian Schwartz, M.D., Chief Medical Officer and Head of R&D at
ArQule. “ARQ 531 was rationally-designed and selected to address
this unmet need by inhibiting both wild type and mutant BTK. The
published crystal structure and biochemistry clearly demonstrate
the mechanism by which ARQ 531 maintains binding and inhibition of
mutant BTK in conditions where ibrutinib cannot.”
Established Activity in Multiple Cellular
and Murine Models of Hematological Malignancies
- Exhibited dose dependent toxicity in
human primary CLL cells (mutant and wild type)
- Inhibited CLL cell migration in
vitro
- Established superiority to ibrutinib in
an engraftment murine model of CLL
- Showed activity against other B-cell
signaling pathways
- Demonstrated efficacy in a murine model
of Richter’s transformation
John Byrd, M.D., the Warren Brown Chair of Leukemia Research at
The Ohio State University stated, “The inhibition profile of ARQ
531 may confer distinct advantages over ibrutinib, potentially
expanding the patient population beyond those with a C481S mutation
who may benefit from treatment. Targeting multiple kinases in the B
cell activation pathway may provide more durable responses to
treatment while also delaying the emergence of treatment
resistance. Jennifer Woyach, M.D., Associate Professor of Medicine
at The Ohio State University, added, “I am particularly encouraged
by the CLL mouse model data which established the superior efficacy
of ARQ 531 compared to ibrutinib and the efficacy of ARQ 531 in the
model of Richter’s transformation as this is an extremely
aggressive disease with very few treatment options.”
About ArQule
ArQule is a biopharmaceutical company engaged in the research
and development of targeted therapeutics to treat cancers and rare
diseases. ArQule’s mission is to discover, develop and
commercialize novel small molecule drugs in areas of high unmet
need that will dramatically extend and improve the lives of our
patients. Our clinical-stage pipeline consists of five drug
candidates, all of which are in targeted, biomarker-defined patient
populations, making ArQule a leader among companies our size in
precision medicine. ArQule’s pipeline includes: ARQ 531, an orally
bioavailable, potent and reversible inhibitor of both wild type and
C481S-mutant BTK, in Phase 1 for patients with B-cell malignancies
refractory to other therapeutic options; Miransertib (ARQ 092), a
selective inhibitor of the AKT serine/threonine kinase, in a phase
1/2 company-sponsored study for Overgrowth Diseases, in a Phase 1
study for ultra-rare Proteus syndrome conducted by the National
Institutes of Health (NIH), and in Phase 1b in combination with the
hormonal therapy, anastrozole, in patients with advanced
endometrial cancer; ARQ 751, a next generation AKT inhibitor, in
Phase 1 for patients with AKT1 and PI3K mutations; Derazantinib, a
multi-kinase inhibitor designed to preferentially inhibit the
fibroblast growth factor receptor (FGFR) family, in a
registrational trial for iCCA; and ARQ 761, a β-lapachone analog
being evaluated as a promoter of NQO1-mediated programmed cancer
cell necrosis, in Phase 1/2 in multiple oncology indications in
partnership with the University of Texas Southwestern Medical
Center. ArQule’s current discovery efforts are focused on the
identification and development of novel kinase inhibitors,
leveraging the Company’s proprietary library of compounds.
About BTK and ARQ 531
Bruton’s tyrosine kinase, BTK, is a therapeutic target that has
been clinically proven to inhibit B-cell receptor signaling in
blood cancers. ARQ 531 is an orally bioavailable, potent and
reversible BTK inhibitor. Biochemical and cellular studies have
shown that ARQ 531 inhibits both the wild type and C481S-mutant
forms of BTK. The C481S mutation is a known resistance mechanism
for first generation irreversible BTK inhibitors. In preclinical
studies, ARQ 531 has demonstrated good oral bioavailability as well
as favorable pharmacokinetic, pharmacodynamic and metabolic
properties.
Forward Looking Statements
This press release contains forward-looking statements regarding
preclinical experiments and with ARQ 531. These statements are
based on the Company's current beliefs and expectations and are
subject to risks and uncertainties that could cause actual results
to differ materially. Positive information about pre-clinical
results does not ensure that clinical trials will be successful.
For example, ARQ 531 may not demonstrate promising therapeutic
effect in man; in addition, it may not exhibit an adequate safety
profile in planned or later stage or larger scale clinical trials
as a result of known or as yet unanticipated side effects. The
results achieved in later stage trials may not be sufficient to
meet applicable regulatory standards or to justify further
development. Problems or delays may arise during clinical trials or
in the course of developing, testing or manufacturing ARQ 531 that
could lead the Company to discontinue development. Even if later
stage clinical trials are successful, unexpected concerns may arise
from subsequent analysis of data or from additional data. Obstacles
may arise or issues may be identified in connection with review of
clinical data with regulatory authorities. Regulatory authorities
may disagree with the Company's view of the data or require
additional data or information or additional studies. In addition,
we and are collaborators are utilizing diagnostic tests to identify
patients in the Phase 1 trial with the BTK C481S mutation and
expect to utilize diagnostic tests in other clinical trials with
ARQ 531. We or our collaborators may need to develop and register
these or other diagnostic tests as companion diagnostics with the
FDA. We or our collaborators may encounter difficulties in
developing and obtaining regulatory approval for companion
diagnostics, including issues relating to access to certain
technologies, selectivity/specificity, analytical validation,
reproducibility, or clinical validation. Any delay or failure by
our collaborators or us to develop or obtain regulatory approval of
companion diagnostics could delay or prevent approval of our
product candidates. Drug development involves a high degree of
risk. Only a small number of research and development programs
result in the commercialization of a product. For more detailed
information on the risks and uncertainties associated with the
Company's drug development and other activities, see the Company's
periodic reports filed with the Securities and Exchange
Commission. The Company does not undertake any obligation to
publicly update any forward-looking statements.
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version on businesswire.com: https://www.businesswire.com/news/home/20180813005595/en/
Corporate Contact:ArQule, Inc.Marc Schegerin, MDSenior
Vice President, Head of Strategy, Finance and
CommunicationIR@arqule.comorMedia Contact:LifeSci Public
RelationsAllison Blum, Ph.D.,
646-627-8383Allison@lifescipublicrelations.com
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