Preclinical data continue to support NVL-330's
broad activity against HER2 oncogenic alterations, selectivity over
wild-type EGFR, and differentiated brain-penetrant
profile
Zidesamtinib shown to be effective at
suppressing on-target ROS1 resistance mutations in preclinical
mutagenesis screens
CAMBRIDGE, Mass., April 8,
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 presentation of new
preclinical data for its novel HER2-selective inhibitor, NVL-330,
and novel ROS1-selective inhibitor, zidesamtinib (NVL-520). The two
posters will be presented at the American Association for Cancer
Research (AACR) Annual Meeting taking place from April 5 – 10 in San
Diego. The posters will also be available on the Nuvalent
website at www.nuvalent.com following the presentations.
"Today's presentations continue to reinforce the differentiated
profiles of our drug candidates," said Henry Pelish, Ph.D., Senior Vice President of
Drug Discovery at Nuvalent. "In comparative in vitro and
in vivo analyses of NVL-330 with currently approved and
investigational HER2-targeting agents, NVL-330 demonstrated a
differentiated preclinical profile by achieving higher CNS
penetration and deeper intracranial response. Importantly, in these
preclinical studies, NVL-330 also demonstrated potency against a
broad range of HER2 oncogenic alterations and selectivity over
wild-type EGFR, in line with our goal of designing molecules that
can thread the needle between multiple competing challenges."
Dr. Pelish continued, "In our ongoing ARROS-1 clinical trial of
zidesamtinib, preliminary Phase 1 data has demonstrated a
differentiated profile combining activity against ROS1 resistance
mutations, CNS penetrance, and TRK avoidance which we believe has
the potential to translate to deep, durable responses for patients
with ROS1-driven cancers. A new preclinical mutagenesis screen
reinforces this potential, showing that on-target resistance is
unlikely following treatment with zidesamtinib at its average
observed clinical concentration."
In 2024, the company expects to initiate a Phase 1 trial for its
HER2 program and to share updated data from the ARROS-1 trial at a
medical meeting.
AACR Presentation Overviews:
Title: Preclinical characterization of NVL-330, a
selective and brain penetrant HER2 tyrosine kinase inhibitor with
broad activity on HER2 oncogenic alterations
Authors: Yuting Sun*1, Kristin L. Andrews1, Anupong
Tangpeerachaikul1, Tuan M.
Nguyen1, Baudouin
Gerard1, Nancy E.
Kohl2, Joshua C.
Horan1, Henry E.
Pelish1
Abstract Number: 1979
Session Category: Experimental and Molecular
Therapeutics
Session Title: Kinase and Phosphatase Inhibitors 2
Session Date and Time: Monday April 8, 2024, from 9:00
– 12:30 p.m. PT
Location: Poster Section 25
Presentation summary:
- NVL-330 had broad preclinical activity on HER2 oncogenic
alterations, including HER2 exon20ins, HER2 activating point
mutations, and amplified wild-type HER2.
- In a preclinical comparison with the selective
tyrosine kinase inhibitor, zongertinib, NVL-330 demonstrated:
- Similar potency and selectivity over wild-type EGFR;
and,
- Higher CNS penetrance.
- In a preclinical comparison with antibody drug
conjugate, T-DXd (Enhertu), NVL-330 demonstrated:
- Deeper response and higher CNS penetrance in an
intracranial tumor model; and,
- Activity in cells with acquired resistance to T-DXd.
Title: Mutagenesis screens support potential
best-in-class profile for selective, brain-penetrant, and
TRK-sparing ROS1 inhibitor zidesamtinib (NVL-520)
Authors: Anupong Tangpeerachaikul*1,
Franklin Gu1,
Henry E.
Pelish1
Abstract Number: LB182
Session Title: Late-Breaking Research: Experimental and
Molecular Therapies 2
Session Date and Time: Monday April 8, 2024, from 1:30
– 5:00 p.m. PT
Location: Poster Section 52
Presentation summary:
- Comparison of the clinical concentration of zidesamtinib
to its efficacious in vitro concentration suggests a potential for
a deep and sustained inhibition of ROS1 and ROS1 G2032R fusions in
humans, including in the CNS.
- Zidesamtinib effectively suppressed on-target resistance in ENU
mutagenesis screens with both ROS1 and ROS1 G2032R fusions,
predicting that on-target resistance is unlikely when used as
either a first-line or a later-line therapy.
- On-target resistance is predicted to be more likely for
earlier-generation ROS1 inhibitors crizotinib, entrectinib,
and potentially repotrectinib as a first-line therapy.
- These mutagenesis screens provide additional preclinical
support for zidesamtinib's potential to drive deep and durable
responses for patients with ROS1-driven cancers.
*Presenter, corresponding author; 1Nuvalent, Inc.,
Cambridge, MA, USA;
2Kohl Consulting, Wellesley,
MA, USA
About NVL-330
NVL-330 is a novel brain-penetrant
HER2-selective tyrosine kinase inhibitor designed to address the
combined medical need of treating HER2-mutant tumors, including
those with HER2 exon 20 insertion mutations, avoiding treatment
related adverse events due to off-target inhibition of wild-type
EGFR, and treating brain metastases.
About zidesamtinib (NVL-520)
Zidesamtinib is a novel
brain-penetrant ROS1-selective inhibitor created with the aim to
overcome limitations observed with currently available ROS1
inhibitors. Zidesamtinib is designed to remain active in tumors
that have developed resistance to currently available ROS1
inhibitors, including tumors with treatment-emergent ROS1 mutations
such as G2032R. In addition, zidesamtinib 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/ROS1 inhibitors
and to drive deep, durable responses for patients across all lines
of therapy. Zidesamtinib has received breakthrough therapy
designation for the treatment of patients with ROS1-positive
metastatic non-small cell lung cancer (NSCLC) who have been
previously treated with 2 or more ROS1 tyrosine kinase inhibitors
and orphan drug designation for ROS1-positive NSCLC. Zidesamtinib
is currently being investigated in the ARROS-1 trial (NCT05118789),
a first-in-human Phase 1/2 clinical trial for patients with
advanced ROS1-positive NSCLC and other solid tumors.
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-positive
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 development programs for zidesamtinib
(NVL-520) and NVL-330; the potential benefits of zidesamtinib and
NVL-330; the potential of Nuvalent's pipeline programs, including
zidesamtinib and NVL-330; Nuvalent's research and development
programs for the treatment of cancer; and risks and uncertainties
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development and commercialization involve a high degree of risk,
and only a small number of research and development programs result
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reliance on these statements or the scientific data presented.
Any forward-looking statements in this press release are based
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obligation to update any forward-looking statements.
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