Publication provides comprehensive assessment
of NVL-655's preclinical activity and includes preliminary clinical
case studies
CAMBRIDGE, Mass., Sept. 13,
2024 /PRNewswire/ -- Nuvalent, Inc. (Nasdaq: NUVL), a
clinical-stage biopharmaceutical company focused on
creating precisely targeted therapies for
clinically proven kinase targets in cancer, today announced the
publication of a manuscript in Cancer Discovery, a journal
of the American Association for Cancer Research, which describes
the design and characterization of NVL-655 and details Nuvalent's
approach to rationally targeting ALK. NVL-655 is currently being
studied in the ongoing ALKOVE-1 Phase 1/2 clinical trial for
patients with advanced ALK-positive non-small cell lung cancer
(NSCLC) and other solid tumors.
The manuscript, entitled "NVL-655 is a selective and
brain-penetrant inhibitor of diverse ALK mutant oncoproteins,
including lorlatinib-resistant compound mutations," is published
online and can be accessed here:
https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-24-0231/748436/NVL-655-Is-a-Selective-and-Brain-Penetrant
"Currently available ALK tyrosine kinase inhibitors (TKIs) are
important treatment options for patients with ALK-driven lung
cancer. However, limitations including treatment-emergent drug
resistance, off-target neurological adverse events, and inadequate
control of brain metastases, support the need for continued
development in this disease," said senior author Alexander Drilon, MD, Chief of the Early Drug
Development Service at Memorial Sloan Kettering Cancer Center, and
investigator in the ALKOVE-1 trial. "As detailed in this
publication, preclinical characterization and preliminary clinical
data provide a compelling rationale for the ongoing clinical
investigation of NVL-655 and evaluation of its potential to address
the limitations of available ALK TKIs for patients with
ALK-positive NSCLC."
The manuscript details the design principles underlying the
activity of NVL-655 against ALK single and compound resistance
mutations, including the most commonly occurring resistance
mutation, ALK G1202R. Additionally, it outlines a molecular
rationale for the selectivity of NVL-655 for ALK over the
structurally related tropomyosin receptor kinase (TRK) family,
whose inhibition has been associated with neurological adverse
events that can be dose limiting. Preclinical characterization of
the activity and selectivity of NVL-655 is presented, including
in vivo xenograft studies, preclinical assessments of brain
penetrance and intracranial activity, and a comparison of eight ALK
TKIs across multiple biochemical and cellular assays.
The manuscript further documents three case studies from the
ALKOVE-1 trial of patients with ALK fusion-positive lung cancers
who had received a range of ALK TKIs, including lorlatinib, and
presented with brain metastases or with tumors that harbored ALK
G1202R. NVL-655 elicited tumor responses in these patients without
accompanying CNS effects attributed to off-target TRK inhibition.
These findings support the potential for NVL-655 as a future
treatment for these patient populations that may also enhance
tolerability through improved selectivity for ALK.
"With this publication in Cancer Discovery, we are
pleased to have now also elucidated our focused approach for
ALK-positive NSCLC. Along with our parallel lead program for
ROS1-positive NSCLC, these selective inhibitors form the foundation
for our pipeline of precisely targeted therapies which aim
to deliver potential best-in-class activity against recalcitrant
targets through solving for multiple, and at times competing,
challenges in structure-based drug design," said Joshua Horan, Ph.D., Vice President, Chemistry
at Nuvalent. "We are grateful to our collaborators for their
contributions to this manuscript and to the continued advancement
of NVL-655."
Enrollment is ongoing in the global Phase 2 portion of the
ALKOVE-1 Phase 1/2 clinical trial, designed with registrational
intent. Updated data from the Phase 1 portion of the trial will be
presented at the European Society for Medical Oncology (ESMO)
Congress 2024 in Barcelona, Spain
during a Proffered paper session on Saturday
September 14, 2024 from 9:30 – 9:40
a.m. CEST.
About NVL-655
NVL-655 is a novel brain-penetrant ALK-selective inhibitor
created with the aim to overcome limitations observed with
currently available ALK inhibitors. NVL-655 is designed to remain
active in tumors that have developed resistance to first-, second-,
and third-generation ALK inhibitors, including tumors with single
or compound treatment-emergent ALK mutations such as G1202R. In
addition, NVL-655 is designed for central nervous system (CNS)
penetrance to improve treatment options for patients with brain
metastases, and to avoid inhibition of the structurally related
tropomyosin receptor kinase (TRK) family. Together, these
characteristics have the potential to avoid TRK-related CNS adverse
events seen with dual TRK/ALK inhibitors and to drive deep, durable
responses for patients across all lines of therapy. NVL-655 has
received breakthrough therapy designation for the treatment of
patients with locally advanced or metastatic ALK-positive non-small
cell lung cancer (NSCLC) who have been previously treated with two
or more ALK tyrosine kinase inhibitors and orphan drug designation
for ALK-positive NSCLC. NVL-655 is currently being evaluated
in the Phase 2 portion of the ALKOVE-1 Phase 1/2 clinical trial, a
first-in-human study of NVL-655 in patients with advanced
ALK-positive NSCLC and other solid tumors (NCT05384626).
About Nuvalent
Nuvalent, Inc. (Nasdaq: NUVL) is a clinical-stage
biopharmaceutical company focused on creating precisely
targeted therapies for patients with cancer, designed to overcome
the limitations of existing therapies for clinically proven kinase
targets. Leveraging deep expertise in chemistry and structure-based
drug design, we develop innovative small molecules that have the
potential to overcome resistance, minimize adverse events, address
brain metastases, and drive more durable responses. Nuvalent is
advancing a robust pipeline with investigational candidates for
ROS1-positive, ALK-positive, and HER2-altered non-small cell lung
cancer, and multiple discovery-stage research programs.
Forward-Looking Statements
This press release contains forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of
1995, as amended, including, without limitation, implied and
express statements regarding Nuvalent's strategy, business plans,
and focus; the expected timing of data announcements; the clinical
development program for NVL-655; the potential clinical effect of
NVL-655; the design and enrollment of the ALKOVE-1 trial, including
its intended pivotal registration-directed design; the potential of
Nuvalent's pipeline programs, including NVL-655; Nuvalent's
research and development programs for the treatment of cancer; and
risks and uncertainties associated with drug development. The words
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Nuvalent may not fully enroll the ALKOVE-1 trial or that enrollment
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entitled "Risk Factors" in Nuvalent's Quarterly Report on Form 10-Q
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SOURCE Nuvalent, Inc.