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ArQule Announces Publication of Preclinical Data for ARQ 531, a Reversible Inhibitor of Both Wild Type and Mutant BTK

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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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