Corporate Overview April 8, 2022 - Nuvalent Investors
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Corporate Overview April 8, 2022
CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS
This document 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 clinical development programs for NVL-520, NVL-655, ALK IXDN compound
resistance mutations and HER2 exon 20 insertions and the timing thereof; the potential clinical effect of NVL-520 and NVL-655; the design and enrollment of the ARROS-1
study and the timing thereof; the design and initiation of the ALKOVE-1 Phase 1/2 study and the timing thereof; the potential of Nuvalent's pipeline programs, including
NVL-520 and NVL-655; Nuvalent's research and development programs for the treatment of cancer; risks and uncertainties associated with drug development; capital
allocation; and Nuvalent’s future financial and operating results and its expectations related thereto. The words "may," "might," "will," "could," "would," "should," "expect,"
"plan," "anticipate," "aim," "goal," "intend," "believe," "expect," "estimate," "seek," "predict," "future," "project," "potential," "continue," "target" or the negative of these
terms and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.
Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a
product. You should not place undue reliance on these statements or the scientific data presented.
Any forward-looking statements in this document are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties, and
important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press
release, including, without limitation, risks associated with: risks that Nuvalent may not fully enroll the ARROS-1 study or it will take longer than expected; unexpected
concerns that may arise from additional data, analysis, or results obtained during clinical trials; the occurrence of adverse safety events; risks of unexpected costs, delays,
or other unexpected hurdles; the impact of COVID-19 on countries or regions in which Nuvalent has operations or does business, as well as on the timing and anticipated
timing and results of its clinical trials, strategy, and future operations, including the global ARROS-1 study and the planned initiation of the ALKOVE-1 Phase 1/2 study; the
timing and outcome of Nuvalent’s planned interactions with regulatory authorities; and obtaining, maintaining, and protecting its intellectual property. These and other
risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended December 31,
2021, as well as any subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Nuvalent’s views only as of
April 8, 2022 and should not be relied upon as representing its views as of any subsequent date. Nuvalent explicitly disclaims any obligation to update any forward-looking
statements.
2
Expertise in chemistry and Our mission is to bring Precisely designed solutions aiming to
structure-based drug design new medicines to overcome limitations of existing
drives wholly-owned pipeline patients with cancer therapies identified through close
of novel targeted therapies collaboration with physician-scientists
3
Significant pipeline progress and value creation to date:
Foundational Discovery Transformational Growth
$50M Series A
✓ External corporate launch
✓ Founder and head scientific advisor Matthew Shair, PhD, ✓ Team expansion to drive transition to a clinical stage company
Professor of Chemistry & Chemical Biology, Harvard University ✓ Preclinical product profiles for both NVL-520 and NVL-655
✓ Proprietary technology developed at Nuvalent to overcome presented at AACR & EORTC-NCI-AACR
dual challenges of kinase resistance and kinase selectivity
✓ $135M Series B + $191M upsized IPO (Nasdaq: NUVL)
✓ Parallel lead drug candidates nominated:
✓ First patient dosed in ARROS-1, a Phase 1/2
clinical trial of NVL-520 for patients with advanced
NVL-520 NVL-655 ROS1-positive non-small cell lung cancer (NSCLC)
ROS1-selective inhibitor ALK-selective inhibitor
and other solid tumors
✓ Established discovery team and robust pipeline ✓ Continued advancement of NVL-655 and discovery pipeline
4
Year of Operational Execution:
Double Down: Discovery & Development
Vision
❖ Clinical-stage biotech with an active R&D pipeline: Discover, Develop & Deliver
▪ Efficient conduct of the Phase 1 portion of
the ARROS-1 trial for NVL-520 Fully integrated pharmaceutical company
▪ Planned initiation of the ALKOVE-1 Phase 1/2
with the goal of translating deep expertise in
trial in advanced ALK-positive NSCLC and
chemistry & structure-based drug design
into best-in-class small molecule medicines
other tumors for NVL-655
for patients with cancer
▪ Planned portfolio expansion with internally
discovered novel drug candidates
❖ Expected cash runway into 2024 with multiple
opportunities for proof-of-concept clinical data
5
The Nuvalent Team
Significant Experience in Drug Discovery, Development and Company Building
LEADERSHIP TEAM BOARD OF DIRECTORS SCIENTIFIC ADVISORS
James Porter, Alex Balcom, Christopher Emily Drabant Conley, PhD Matthew Shair, PhD
PhD MBA, CPA Turner, MD CEO, Federation Bio Head Scientific Advisor
Chief Executive Chief Financial Chief Medical Harvard Professor of Chemistry
Gary Gilliland, MD, PhD & Chemical Biology
Officer Officer Officer
Independent
Ross Camidge, MD, PhD
Darlene Noci, Andrew Hack, MD, PhD Clinical Advisor
Deborah Miller, Ruth Adams
ALM Bain Capital Life Sciences University of Colorado
PhD, JD VP, Clinical
Sr VP, Product
Chief Legal Operations Robert Jackson, MD Alexander Drilon, MD
Development &
Officer Independent Clinical Advisor
Regulatory Affairs
Joseph Pearlberg, MD, PhD Memorial Sloan Kettering Cancer Center
Josh Horan, Benjamin Lane, Jessie Lin Deerfield Management Aaron Hata, MD, PhD
PhD VP, Corporate Translational Research Advisor
PhD Strategy & Portfolio Anna Protopapas
VP, Pharmaceutical Mass General Cancer Center
VP, Chemistry Management CEO, Mersana
Development
James Porter, PhD Pasi Jänne, MD, PhD
CEO, Nuvalent Clinical Advisor
Matthew Henry Pelish, John Soglia, PhD Dana Farber Cancer Institute
Metivier PhD VP, Translational Matthew Shair, PhD
VP, Human Development Harvard Professor of Chemistry Nancy Kohl, PhD
VP, Biology
Resources & Chemical Biology Translational Research Advisor
Independent Consultant
Sapna Srivastava, PhD
PRIOR FDA Independent Michael Meyers, MD, PhD
APPROVAL Clinical Advisor
EXPERIENCE Cameron Wheeler, PhD CMO, Syndax
Deerfield Management
6
Nuvalent is focused on creating precisely
targeted therapies to overcome key limitations
of existing therapies for clinically proven kinases
and renew hope for patients in need
• Expertise in structure-based drug design to create
innovative small molecules
• “Threading the needle”: Aim to achieve high affinity for
drug-resistant kinases while avoiding off-target kinases in
the central nervous system (CNS) and in the periphery
• Potential to minimize adverse events AND drive
more durable responses
7
ORIGINAL DRUG-RESISTANT
TUMOR TUMOR
&
Mutation in target kinase
confers resistance to
existing therapy
Kinase
Resistance EXISTING THERAPY NUVALENT THERAPY EXISTING THERAPY NUVALENT THERAPY
Structural innovations
designed to overcome
drug-resistance due to
kinase mutations
Successful inhibition of target kinase Mutation confers Designed to overcome
resistance drug-resistance mutation
8
NON-SELECTIVE THERAPY SELECTIVE NUVALENT
THERAPY
vs.
Selective inhibition
potentially minimizes
toxicities
Kinase
Selectivity
Structural innovations designed
to increase selectivity to
potentially minimize therapy-
limiting adverse events related
to off-target inhibition AND
drive more durable responses TA R G E T K I N A S E Adverse events due to TA R G E T K I N A S E
INHIBITION off-target inhibition INHIBITION
9
NVL-520
Next generation
ROS1-selective inhibitor
10
ROS1 image source: 4UXL.pdbROS1 Receptor Tyrosine Kinase
Genomic alterations lead to tumorigenesis and confer treatment resistance
R O S 1 ( U N M U TAT E D ) ONCOGENIC ROS1 R EARRANGEMENTS S E C O N D A RY R E S I S TA N C E M U TAT I O N S
Ligand-dependent
ROS1 receptor activation ROS1 gene
rearrangement Reported secondary
e.g. CD74-ROS1 mutations mapped
fusion on ROS1 kinase
domain in complex
Regulated Unregulated with crizotinib
cell signaling cell signaling (PDB:3ZBF)
Cell growth, proliferation, and differentiation Excessive cell growth and proliferation leading to tumorigenesis
• ROS1-deficient mice are viable, with males • Rearrangements may result in transmembrane or • Kinase domain mutations in ROS1 confer resistance
infertile and no detectable abnormalities intracellular ROS1 fusions to approved inhibitors such as crizotinib
in females • ROS1 fusions have been identified across multiple • “Solvent front” mutation (e.g. G2032R, D2033N) in
• In male mice, ligand NELL2 binds ROS1 in solid tumors, including NSCLC (up to 3%) adult the solvent-exposed region are the most common,
epididymis to induce epididymal glioblastoma (0.5%), pediatric low-grade and high- and cause steric hinderance to drug binding
differentiation for sperm maturation grade gliomas, spitzoid neoplasms (17%), IMT (~10%), • Additional mutations such as S1986Y/F and
• In humans, highest expression in SGC, PTC, ALCL, SOC, IHCA, cholangiocarcinoma, and “gatekeeper” mutation L2026M have been
epididymis and lung gastric and pancreatic adenocarcinoma observed
Sources: Drilon et. al. Nat Rev Clin Oncol 2021; Jordan et al., Cancer Discovery. 2017; Lin and Shaw 2017 JTO; The Human Protein Atlas; Structure image from Lin and Shaw 2017 JTO
Abbreviations: ALCL: Anaplastic large cell lymphoma; IHCA: Inflammatory hepatocellular adenoma; IMT: Inflammatory myofibroblastic tumor; SGC: Salivary gland carcinoma; PTC: Papillary thyroid carcinoma; ROS1: c-ros
oncogene 1; SOC: Serous ovarian carcinoma (SOC); TRK: tropomyosin receptor kinase
11ROS1-positive NSCLC Market Overview
Emerging resistance mutations and increasing CNS involvement limit utility of approved therapies
L I N E O F T H E R A PY S U B - PO P UL AT IO N I N C I D EN C E ( U S ) C N S D I S EA S E S TA N DA R D OF CARE
(2021)
Kinase ~3,000 – 4,500 Crizotinib
Wild-type
inhibitor naïve kinase domain
newly diagnosed ~20 – 40%
ROS1+ NSCLC patients / year Entrectinib
Non-G2032R
1 prior kinase mutation
inhibitor ~30 – 55%
ROS1+ NSCLC G2032R
~41%
mutation
Sources: Lin et al., J Thorac Oncol 2017; Gainor et al, JCO Precision Oncol 2017; Ou and Zhu Lung Cancer 2019; Patil et al, JTO 2018
12NVL-520
Differentiated Product Candidate for ROS1-positive NSCLC Patients
NUVALENT IN VITRO PRECLINICAL CHARACTERIZATION
W I L D T Y P E RO S 1 G 2 0 3 2 R RO S 1 TRKB CNS
FUSION ACTIVITY ACTIVITY S PA R I N G ACTIVITY
N VL-520 Yes
Investigational Yes Yes Yes Predicted based on preclinical
ROS1-selective inhibitor experiments
FDA APPROVED
C R I Z OT I N I B Yes No No No
Dual ALK/ROS1 Not in FDA approved label
ENTRECTINIB Yes No No Yes
Dual TRK/ROS1 In FDA label
LO R L AT I N I B No Yes
INVESTIGATIONAL
Yes No Limited selectivity at dose
Dual ALK/ROS1 In FDA label for ALK NSCLC
developed for ALK GR
Yes
R E P OT R E C T I N I B Yes Yes No Investigational: CNS activity
Dual TRK/ROS1 reported in preliminary Phase 1
data
No head-to-head clinical studies have been conducted for currently approved or investigational therapies versus NVL-520. Clinical investigation of NVL-520 is ongoing.
Other than as indicated in the CNS Activity column, data in table above is based on preclinical experiments conducted by Nuvalent. Characterization of CNS activity for each ROS1 inhibitor is based
on FDA labels and/or available clinical and preclinical data independently generated by each sponsor and not based on any preclinical experiments conducted by Nuvalent.
13T R K I N H I B I T I O N S A F E T Y I M P L I C AT I O N S
Overcoming Kinase Impairments in memory, learning and
nociception
Selectivity in NSCLC TRKB
Development of obesity caused by
ROS1 and ALK both share strong hyperphagia and hyperdipsia
structural similarities to TRK
Impairment of motor neuron afferents and
loss of dorsal root ganglia neurons
Brain penetration is needed to
address associated CNS disease TRKC
in ROS1 and ALK driven cancers Defect in proprioception
Inhibitors must be highly
Congenital insensitivity to
selective to avoid CNS toxicities pain with anhidrosis (CIPA)
from off-target inhibition of TRK TRKA
Severe sensory and
sympathetic neuropathies
Sources: Adapted from Cocco, Scaltriti and Drilon Nat Rev Clin Oncol 2018
14N V L - 5 2 0 R O S 1 - S E L E C T I V E TA R G E T P R O D U C T P R O F I L E
Wild-type ROS1 fusions
ROS1 ACTIVITY
Emergent ROS1 resistance mutations: NVL-520
G2032R, D2033N, L2026M, S1986Y/F ROS1 NSCLC
vs. TRK, to minimize CNS adverse events
Development Strategy
SELECTIVITY
vs. Other off-targets kinases
Optimize for brain penetrance to improve
CNS ACTIVITY treatment options for patients with brain
metastases
15Preclinical NVL-520 activity against ROS1
Wild-type ROS1 Fusions, in vitro and in vivo NSCLC models
NVL-520 in vitro in vivo
ROS1-selective
Target Product Profile IC50 cell viability assay SDC4-ROS1 wild-type NSCLC PDX model
Ba/F3 CD74-ROS1 NVL-520 was well-tolerated in all in vivo studies
Wild-type
ROS1 fusions WILD-TYPE 2048
ROS1 ACTIVITY ROS1 FUSION 1024 vehicle
Resistance
mutations 512
NVL-520 1.2 nM
Tumor
256 0.04 mg/kg *
TRK C R I Z OT I N I B 40 nM 128
volume
64
SELECTIVITY (mm3 )
Other off- ENTRECTINIB 23 nM 32 0.2 mg/kg *
targets 16
L O R L AT I N I B 1.3 nM
8
BID PO, n=5 1 mg/kg *
Brain
CNS ACTIVITY R E P OT R E C T I N I B 4.4 nM 4
penetration
0 7 14 21 28
Days on treatment
*p < 0.0001 vs. vehicle by 2-way repeat measure ANOVA with Geisser-Greenhouse correction followed by Dunnett’s multiple comparison test
Experiments not powered to determine the statistical significance of differences in measurements between any of the inhibitors tested. No head-to-head clinical studies
have been conducted for currently approved or investigational therapies versus NVL-520. Clinical investigation of NVL-520 is ongoing.
Source: Pelish, H.E., Tangpeerachaikul, A., Kohl, N.E., Shair, M.D., Porter, J.R., and Horan, J.C. AACR Conference 2021
16Preclinical NVL-520 activity against ROS1
Clinically Relevant Drug-Resistant Mutations, in vitro and in vivo ROS1 fusion NSCLC models
NVL-520 in vitro
ROS1
ROS1-selective IC50 cell viability assays NVL-520 CRIZOTINIB ENTRECTINIB LORLATINIB REPOTRECTINIB
STATUS
Target Product Profile
MGH9018-1 PDC, CD74-ROS1 G2032R 4.7 nM 1000 nM 590 nM 460 nM 30 nM
Ba/F3 CD74-ROS1 G2032R 3.5 nM 960 nM 1,500 nM 300 nM 25 nM
Wild-type
S1986FPreclinical ability of NVL-520 to avoid off-target TRK inhibition
Potential for Differentiation vs CNS Active Dual TRK/ROS1 Inhibitors Entrectinib and Repotrectinib
More selective
NVL-520 for ROS1 variant 730x
ROS1 fusion variants: wt: wild-type GR: G2032R
1000
ROS1-selective 240x
Target Product Profile
100
Wild-type
ROS1 fusions 7.8x
10
ROS1 ACTIVITY
Resistance
Relative selectivity ROS1
3.0x
ROS1 ROS1 ROS1
mutations for ROS1 vs. TRKB GR GR wt GR
TRK selectivity 1
IC50 (pTRKB) ROS1 ROS1 ROS1 ROS1
TRK = wt GR wt wt
0.3x
IC50 (Ba/F3 CD74-ROS1) 0.1 0.19x
SELECTIVITY
Other off- 0.047x
targets 0.034x
0.01
ROS1
Brain wt = wild-type
CNS ACTIVITY GR = G2032R
penetration 0.001
More selective
for TRKB NUV-520
NVL-520 Crizotinib Entrectinib Repotrectinib
TRKB activity as measured by a cell TRKB phosphorylation assay. Phosphorylation of intracellular TRKB was measured in Ba/F3 cells expressing full-length TRKB and stimulated by BDNF using
the phospho-TRK AlphaLISA kit. TRKB activity was also measured in additional internal assays, where results were consistent in relative terms. Compounds that showed greater selectivity in
one assay also showed greater selectivity in all other investigated assays.
Experiments not powered to determine the statistical significance of differences in measurements between any of the inhibitors tested. No head-to-head
18 clinical studies have been conducted for currently approved or investigational therapies versus NVL-520. Clinical investigation of NVL-520 is ongoing.
Source: Tangpeerachaikul, A., Horan, J.C, and Pelish, H.E. AACR-NCI-EORTC 2021Selectivity of NVL-520 for ROS1 over other kinases
Preclinical Kinome Selectivity Screen: 335 Wild Type Kinases
ALK ROS1
NVL-520
ROS1-selective
Target Product Profile S ELECTIVITY I NDEX
KINASE
Relative to ROS1-wt
Wild-type 1x ROS1
ROS1 fusions
ROS1 ACTIVITY 1 – 10x ALK
Resistance
mutations 10 – 50x LTK, FAK, PYK2, TRKB, FER
TRK >50x 328 other kinases
SELECTIVITY
Other off-
targets
Brain IC50 (kinase of interest)
CNS ACTIVITY Selectivity index =
penetration
IC50 (ROS1 wild-type)
Eid S. et al. Bioinformatics 2017
Illustration reproduced courtesy of Cell Signaling Technologies, Inc. (www.cellsignal.com)
19 Source: Pelish, H.E., Tangpeerachaikul, A., Kohl, N.E., Shair, M.D., Porter, J.R., and Horan, J.C. AACR Conference 2021Preclinical brain penetrance of NVL-520
Pharmacokinetic Data Similar to Preclinical Observations for Lorlatinib
NVL-520
ROS1-selective
Target Product Profile in vivo 0.5
Wistar Han rats
Wild-type Dose: 10 mg/kg QDx1 PO
0.4
ROS1 fusions 1h timepoint
ROS1 ACTIVITY unbound 0.3
Resistance
mutations brain:plasma
ratio 0.2
TRK
(Kp,uu) 0.1
SELECTIVITY
Other off-
targets 0.0
NVL-520 Lorlatinib
Brain
CNS ACTIVITY
penetration
Experiments not powered to determine the statistical significance of differences in measurements between any of the inhibitors tested. No head-to-head clinical studies
have been conducted for currently approved or investigational therapies versus NVL-520. Clinical investigation of NVL-520 is ongoing.
20 Source: Data on filePreclinical CNS anti-tumor activity of NVL-520
Reduction of Brain Tumors and Extended Median Survival in a Preclinical Model
vehicle
NVL-520
ROS1-selective
Target Product Profile 0
Treatment 100 NVL-520 *
Wild-type Day 2 mg/kg
ROS1 fusions
16
ROS1 ACTIVITY
Resistance Survival
mutations (%) 50 vehicle
TRK
NVL-520 2 mg/kg BID (PO)
SELECTIVITY
Other off- 0
targets 0
0 7 14 21 28 35 42 49 56 63
Treatment
Brain Day Days on treatment
CNS ACTIVITY
penetration
16
Ba/F3 CD74-ROS1 G2032R stably expressing luciferase
* Median survival was 16.5 days for vehicle group and >61 days for the NVL-520-treated group, corresponding to a significant median overall survival extension >3.7-fold
(p-value < 0.0001, log-rank Mantel-Cox test).
21 Source: Pelish, H.E., Tangpeerachaikul, A., Kohl, N.E., Shair, M.D., Porter, J.R., and Horan, J.C. AACR Conference 2021C O UN T RY I N S T IT UT I O N*
MGH (Boston, MA)
MDACC (Houston, TX)
MSKCC (New York, NY)
First-in-Human (FIH) Phase 1/2 Clinical Trial of
NVL-520 in Advanced ROS1-Positive NSCLC University of Colorado (Denver, CO)
and Other Solid Tumors (NCT05118789) Sarah Cannon (Nashville, TN)
✓ Sites selected to target global experts in TKI NSCLC early UCI Medical Center (Irvine, CA)
development (ROS1 and ALK Programs)
Vall d-Hebron (Barcelona)
✓ Phase 1 portion of ARROS-1 open and actively enrolling
Gustave-Roussy (Paris)
✓ Ongoing site expansion in the US and Europe
UMCG (Groningen)
* Non-exhaustive list of planned and active sites.
Please refer to clinicaltrials.gov for the most up to date list of sites.
22First-in-Human Phase 1/2 Clinical Trial of NVL-520 in Advanced
ROS1-Positive NSCLC and Other Solid Tumors (NCT05118789)
Phase 2 Cohorts Designed to Support Potential Registration in Kinase Inhibitor Naive or Previously Treated ROS1-positive NSCLC
Phase 2
Phase 1 PRIOR PRIOR
COHORT TUMOR TYPE DETAIL
ROS1 TKI CHEMO/I-O**
150 mg QD 2a ROS1-positive NSCLC Naive ≤1
125 mg QD Subset analysis for
2b ROS1-positive NSCLC 1* Naive G2032R
100 mg QD Subset analysis for
2c ROS1-positive NSCLC 1* 1 G2032R
75 mg QD
Subset analysis for
2d ROS1-positive NSCLC 2+ ≤1 G2032R
50 mg QD
Any ROS1-positive
25 mg QD 2e Any Any Exploratory Cohort
Solid Tumor***
✓ Safety / Tolerability
PURPOSE Cohorts 2a, 2b, 2c, and 2d were designed to support potential registration
✓ Determine/Confirm RP2D
*Either crizotinib or entrectinib; ** Platinum-based chemotherapy ± immunotherapy; *** Includes NSCLC who do not qualify for any of the other cohorts
I-O: Immunotherapy; RP2D: Recommended Phase 2 Dose; TKI: Tyrosine Kinase Inhibitor
23NVL-655
Next generation
ALK-selective inhibitor
24Anaplastic Lymphoma Kinase (ALK)
Genomic alterations lead to tumorigenesis and treatment resistance
A L K ( U N M U TAT E D ) O N C O G E N I C A L K A LT E R AT I O N S S E C O N D A RY R E S I S TA N C E M U TAT I O N S
Ligand-dependent
ALK receptor activation ALK gene
rearrangement Reported secondary
e.g. EML4-ALK mutations mapped
fusion Activating
on ALK kinase
point
domain in complex
Regulated Unregulated mutations
with crizotinib
cell signaling cell signaling
(PDB:2XP2)
Cell growth, proliferation, and differentiation Excessive cell growth and proliferation leading to tumorigenesis
• Limited data is available • Activating ALK gene rearrangements and point • Growing clinical evidence suggests that different
characterizing function and ligand- mutations have been reported in multiple solid and resistance mutation patterns may emerge depending on
stimulated activation hematologic tumor types the ALK TKI used and line of therapy
• Expression pattern in humans • ALK rearrangements define a distinct molecular • “Solvent front” mutations (e.g. G1202R, D1203N) in the
suggests a role in early nervous subtype of NSCLC, occurring in ~5% of NSCLC cases solvent-exposed region cause steric hinderance to drug
system development, with low with EML4 being the most common fusion partner binding
expression in adults • ALK tyrosine kinase inhibitors (TKIs) have • Compound mutations (“solvent front” mutation G1202R +
• Knockout mice are viable revolutionized care of ALK-positive NSCLC patients, “gatekeeper” mutation L1196M) have been observed
with multiple generations of inhibitors now available upon sequential alectinib/lorlatinib treatment
Sources: Palmer et. al. Biochem J 2009; Hallberg & Palmer Nat Rev Cancer 2013; Hallberg & Palmer Ann of Oncol 2016; Gainor et. al. Cancer Discov 2016;
25ALK-Positive NSCLC Market Overview
Emerging Resistance Mutations and Increasing CNS Involvement Limit Utility of Approved Therapies
L I N E O F T H E R A PY S U B - PO P UL AT IO N I N C I D EN C E ( U S ) C N S D I S EA S E S TA N DA R D OF CARE (2021)
Brigatinib
Kinase ~9,000 – 18,000 newly Alectinib Ceritinib
Wild-type
inhibitor naïve kinase domain
diagnosed patients / ~30 – 40% (preferred)
Crizotinib
ALK+ NSCLC year
Lorlatinib
G1202R ~35%
1 prior kinase
inhibitor I1171N/S/T ~15 – 30% > 60% Lorlatinib
ALK+ NSCLC Other
G1202R/L1196M
G1202R/G1269A
2 prior kinase
inhibitors G1202R/L1198F > 60%
ALK+ NSCLC I1171N / D1203N
Other
Sources: Ou and Zhu Lung Cancer 2019; Kris et. al. JAMA 2014; Shaw and Engelman J Clin Onc 2013; Noé et. al. J Thor Onc 2019; Peters et. al. NEJM 2017; Shaw et. al.
Lancet Onc 2017; Dagogo-Jack et. al. Clin Cancer Res 2019
26NVL-655
Differentiated Product Candidate for ALK-positive NSCLC patients
NUVALENT IN VITRO PRECLINICAL CHARACTERIZATION
WILD-TYPE ALK G1202R ALK GRLM, GRGA & GRLF TRKB CNS
FUSION ACTIVITY ACTIVITY ALK ACTIVITY SPARING ACTIVITY
N V L - 655 Yes
Investigational Yes Yes Yes Yes Predicted based on preclinical
ALK-selective inhibitor experiments
C R I Z OT I N I B Yes No No No No
Not in FDA label
CERITINIB Yes No No Yes Yes
In FDA label
FDA APPROVED
ALECTINIB Yes No No Yes Yes
In FDA label
B R I G AT I N I B Yes No No Yes Yes
In FDA label
No Yes
L O R L AT I N I B Yes Yes No Limited selectivity at dose
In FDA label
developed for ALK GR
No head-to-head clinical studies have been conducted for currently approved or investigational therapies versus NVL-655. No clinical studies have been conducted with NVL-655.
Other than as indicated in the CNS Activity column, data in table above is based on preclinical experiments conducted by Nuvalent. Characterization of CNS activity for each ALK inhibitor is
based on FDA labels and/or available clinical and preclinical data independently generated by each sponsor and not based on any preclinical experiments conducted by Nuvalent.
GR: G1202R; LM: L1196M; GA: G1269A; LF: L1198F
27N V L - 6 5 5 A L K - S E L E C T I V E TA R G E T P R O D U C T P R O F I L E
Wild-type ALK fusions
ACTIVITY Emergent ALK resistance mutations:
G1202R single and compound mutations
NVL-655
(G1202R/L1196M, G1202R/G1269A, ALK NSCLC
G1202R/L1198F)
Development Strategy
vs. TRK, to minimize CNS adverse events
SELECTIVITY
vs. Other off-target kinases
Optimize for brain penetrance to improve
CNS ACTIVITY treatment options for patients with brain
metastases
28Preclinical NVL-655 activity against ALK
Wild-type ALK Fusions, in vitro NSCLC models
NVL-655
ALK-selective
Target Product Profile
in vitro
Wild-type
ALK fusion
ALK ACTIVITY
IC50 cell viability assay (nM) NVL-655 C R I Z OT I N I B CERITINIB ALECTINIB B R I G AT I N I B L O R L AT I N I B
Resistance
mutations NCI-H2228 (EML4-ALK v3) 0.70 nM 90 nM 55 nM 13 nM 13 nM < 1.1 nM
NCI-H3122 (EML4-ALK v1) 2.0 nM 180 nM 48 nM 22 nM 22 nM 3.5 nM
TRK
Ba/F3 EML4-ALK v1 1.6 nM 270 nM 90 nM 25 nM 42 nM 4.2 nM
SELECTIVITY
Other off- IC50: 0-49 nM; 50 - 499 nM; ≥ 500 nM
targets
Brain
CNS ACTIVITY
penetration
Experiments not powered to determine the statistical significance of differences in measurements between any of the inhibitors tested. No head-to-head clinical studies
have been conducted for currently approved therapies versus NVL-655. No clinical studies have been conducted with NVL-655.
Source: Pelish, H.E., Tangpeerachaikul, A., Kohl, N.E., Shair, M.D., Porter, J.R., and Horan, J.C. AACR Conference 2021
29Preclinical NVL-655 activity against ALK
Clinically Relevant Drug-Resistant G1202R+ Mutations, in vitro and in vivo ALK fusion NSCLC models
NVL-655 in vitro
ALK-selective
IC50 cell viability assay (nM) NVL-655 C R I Z OT I N I B CERITINIB ALECTINIB B R I G AT I N I B L O R L AT I N I B
Target Product Profile
G1202R < 0.73 nM 950 nM 570 nM 1600 nM 400 nM 120 nM
Wild-type G1202R/L1196M 7.0 nM 1500 nM 1400 nM 2200 nM 820 nM 3900 nM
ALK fusion
ALK ACTIVITY G1202R/G1269A 3.0 nM 1100 nM 350 nM 1300 nM 240 nM 970 nM
Resistance G1202R/L1198F 2.0 nM 170 nM 1300 nM 2200 nM 470 nM 720 nM
mutations
IC50: 0-49 nM; 50 - 499 nM; ≥ 500 nM
TRK in vivo 2048
vehicle
2048
vehicle
1024 1024
SELECTIVITY 0.3 mg/kg
Other off- Ba/F3 EML4-ALK v1 512 512 10 mg/kg
Tumor 256 256 Lorlatinib
targets G1202R/L1196M NVL-655
CDX models volume 128 128
3
Brain (mm ) 64 64
CNS ACTIVITY 1.5 mg/kg * 32
penetration NVL-655 was 32
well-tolerated in 16 16
BID PO, n=5 BID PO, n=5
all in vivo studies 8 8
0 7 14 0 7 14
Days on treatment Days on treatment
*p < 0.0001 vs. vehicle by two-way repeat measures ANOVA followed by Tukeys post hoc comparisons of the means
Experiments not powered to determine the statistical significance of differences in measurements between any of the inhibitors tested. No head-to-head
clinical studies have been conducted for currently approved therapies versus NVL-655. No clinical studies have been conducted with NVL-655.
30 Source: Pelish, H.E., Tangpeerachaikul, A., Kohl, N.E., Shair, M.D., Porter, J.R., and Horan, J.C. AACR Conference 2021Preclinical NVL-655 activity against ALK
Clinically Relevant Drug-Resistant non-G1202R+ Mutations, in vitro and in vivo ALK fusion NSCLC models
NVL-655 in vitro
ALK-selective
Target Product Profile IC50 cell viability assay (nM) NVL-655 C R I Z OT I N I B CERITINIB ALECTINIB B R I G AT I N I B L O R L AT I N I B
L1196M 29 nM 1100 nM 79 nM 120 nM 100 nM 86 nM
Wild-type
I1171N 27 nM 320 nM 140 nM 570 nM 30 nM 59 nM
ALK fusion
ALK ACTIVITY IC50: 0-49 nM; 50 - 499 nM; ≥ 500 nM
Resistance
mutations
2048 2048
TRK
in vivo vehicle vehicle
1024 1024
SELECTIVITY Ba/F3 EML4-ALK v1 512 512
Other off- Tumor 1.5 mg/kg
I1171N CDX model
volume 256
* 256
targets
NVL-655 was (mm3) 128 NVL-655 128
well-tolerated in all 4.5 mg/kg *
Brain 7.5 mg/kg Lorlatinib
CNS ACTIVITY in vivo studies 64 * 64
penetration BID PO, n=5 BID PO, n=5 5 mg/kg *
32 32
0 7 14 0 7 14
Days on treatment Days on treatment
*p < 0.0001 vs. vehicle by two-way repeat measures ANOVA followed by Tukeys post hoc comparisons of the means
Experiments not powered to determine the statistical significance of differences in measurements between any of the inhibitors tested. No head-to-head clinical studies
have been conducted for currently approved therapies versus NVL-655. No clinical studies have been conducted with NVL-655.
Source: Tangpeerachaikul, A., Deshpande, A., Kohl, N.E., Horan, J.C, and Pelish, H.E.. AACR-NCI-EORTC 2021
31Preclinical ability of NVL-655 to avoid off-target TRK inhibition
Potential for Differentiation vs CNS Active ALK Inhibitor Lorlatinib
NVL-655 More selective ALK fusion variants: wt: wild-type GR: G1202R
ALK-selective for ALK variant GRLM: G1202R/L1196M GRGA: G1202R/G1269A
870x
1000
Target Product Profile 390x
210x 200x
91x
Wild-type 100
ALK fusion
ALK ACTIVITY
Relative selectivity
9x
Resistance for ALK vs. TRKB 10
mutations
TRK selectivity 1.4x ALK ALK ALK ALK ALK ALK ALK ALK ALK
IC50 (pTRKB) GR GRLM GRGA GRLM GRGA wt GR GRLM GRGA
1
TRK = ALK ALK ALK ALK ALK ALK ALK
IC50 (Ba/F3 EML4-ALK) wt GR GRLM GRGA wt wt GR 0.8x
SELECTIVITY 0.4x
ALK 0.2x 0.3x 0.2x
Other off- wt = wild-type 0.1 0.1x 0.1x
targets GR = G1202R 0.07x 0.06x
LM = L1196M
GA = G1269A
Brain 0.01
CNS ACTIVITY More selective NVL-655 Crizotinib Lorlatinib TPX-0131
penetration
for TRKB
TRKB activity as measured by a cell TRKB phosphorylation assay. Phosphorylation of intracellular TRKB was measured in Ba/F3 cells expressing full-length TRKB and stimulated by BDNF using
the phospho-TRK AlphaLISA kit. TRKB activity was also measured in additional internal assays, where results were consistent in relative terms. Compounds that showed greater selectivity in
one assay also showed greater selectivity in all other investigated assays.
Experiments not powered to determine the statistical significance of differences in measurements between any of the inhibitors tested. No head-to-head
clinical studies have been conducted for currently approved or investigational therapies versus NVL-655. No clinical studies have been conducted with NVL-655.
Sources: Tangpeerachaikul, A., Deshpande, A., Kohl, N.E., Horan, J.C, and Pelish, H.E. AACR-NCI-EORTC 2021;
32 Tangpeerachaikul, A., Bigot, L., Friboulet, L., and Pelish, H.E. AACR 2022.Selectivity of NVL-655 for ALK over other kinases
Preclinical Kinase Selectivity Screen: 335 Wild Type Kinases
ALK ROS1
NVL-655
ALK-selective S ELECTIVITY I NDEX
KINASE
Target Product Profile Relative to ALK wt
Wild-type 1x ALK, ROS1
ALK fusion
ALK ACTIVITY 1 – 10x LTK, PYK2, TRKB*, FAK
Resistance
SLK, TRKA, FER, MUSK,
mutations 10 – 50x
EPHA6, TRKC
TRK >50x 323 other kinases
SELECTIVITY *Due to limitations of this biochemical assay, the actual
Other off-
fold selectivity over TRKs may be greater than shown. The
targets
prior analysis presents selectivity of NVL-655 over TRKB in
Brain a more physiologically relevant context.
CNS ACTIVITY
penetration
IC50 (kinase of interest)
Selectivity index =
IC50 (ALK wild-type)
Eid S. et al. Bioinformatics 2017
Illustration reproduced courtesy of Cell Signaling Technologies, Inc. (www.cellsignal.com)
33 Source: Pelish, H.E., Tangpeerachaikul, A., Kohl, N.E., Shair, M.D., Porter, J.R., and Horan, J.C. AACR Conference 2021Preclinical brain penetrance of NVL-655
Pharmacokinetic Data Similar to Preclinical Observations for Lorlatinib
NVL-655
ALK-selective in vivo
Target Product Profile 0.5
Wistar Han rats
Dose: 10 mg/kg QDx1 PO
Wild-type
1h timepoint
0.4
ALK fusion
ALK ACTIVITY
unbound 0.3
Resistance
mutations brain:plasma
ratio 0.2
TRK (Kp,uu)
0.1
SELECTIVITY
Other off-
targets 0.0
NVL-655 Lorlatinib
Brain
CNS ACTIVITY
penetration
Experiments not powered to determine the statistical significance of differences in measurements between any of the inhibitors tested. No head-to-head clinical studies
have been conducted for currently approved or investigational therapies versus NVL-655. No clinical studies have been conducted with NVL-655.
Source: Pelish, H.E., Tangpeerachaikul, A., Kohl, N.E., Shair, M.D., Porter, J.R., and Horan, J.C. AACR Conference 2021
34Preclinical CNS anti-tumor activity of NVL-655
Reduction of Brain Tumors and Extended Median Survival in a Preclinical Model
NVL-655 Vehicle BID (PO)
ALK-selective 100
Target Product Profile 0 vehicle
Treatment NVL-655
Wild-type Survival
Day >4 fold 4.5 mg/kg
ALK fusion 50
10 (%)
ALK ACTIVITY
Resistance
mutations
0
TRK NVL-655 4.5 mg/kg BID (PO) 0 14 28 42 56
SELECTIVITY Days on treatment
Other off-
0
targets
Ba/F3 EML4-ALK v1 G1202R/L1196M stably expressing luciferase.
Treatment Median survival was 15 days for vehicle group and >65 days for the NVL-655-
Brain Day
CNS ACTIVITY treated group, corresponding to a significant median overall survival extension of
penetration >4-fold (p-value < 0.0001, log-rank Mantel-Cox test). Vehicle is 20% HP-β-CD.
10 Source: Tangpeerachaikul, A., Deshpande, A., Kohl, N.E., Horan, J.C. and Pelish, H.E.
EORTC-NCI-AACR Conference 2021
35First-in-Human Phase 1/2 Clinical Trial of NVL-655 in Advanced
ALK-Positive NSCLC and Other Solid Tumors
Phase 1 Portion Planned to Initiate in 2Q 2022
Phase 2
Phase 1
PRIOR
ALK-positive Solid Tumors with ≥1 ALK TKI* COHORT TUMOR TYPE PRIOR ALK TKI** CHEMO
and/or I -O
Dose Level 6 1 prior 2nd generation
2a ALK fusion-positive NSCLC 0 – 2 lines
(ceritinib, alectinib, or brigatinib)
Dose Level 5 2 – 3 prior 1st or 2nd generation
2b ALK fusion-positive NSCLC 0 – 2 lines
(crizotinib, ceritinib, alectinib, or brigatinib)
Dose Level 4
2 – 3 prior, with lorlatinib in 2nd or 3rd line of
2c ALK fusion-positive NSCLC 0 – 2 lines
Dose Level 3 therapy
Other ALK-positive solid tumors
Dose Level 2 & ≥ 1 prior systemic therapy (or for whom no
2d*** Any
ALK-positive NSCLC satisfactory standard therapy exists)
Dose Level 1 not eligible for 2a-c
✓ Safety / Tolerability
PURPOSE Cohorts 2a, 2b, and 2c may be expanded to support potential registration
✓ Determine/Confirm RP2D
* Patients with ALK fusion-positive NSCLC must have previously received ≥1 ALK TKI, one of which must be a 2nd or 3rd generation TKI (ceritinib, alectinib, brigatinib, or lorlatinib), while those with other solid tumors must
have previously received ≥1 prior systemic anticancer therapy or be those for whom no satisfactory standard therapy exists.
** Excluding investigational agents targeting ALK (except for cohort 2d).
*** Exploratory cohort, includes patients age ≥ 12 years with weight > 40 kg.
ALK-positive: Positive for Anaplastic Lymphoma Kinase fusion or mutation; NSCLC: Non small cell lung cancer; RP2D: Recommended Phase 2 Dose; TKI: Tyrosine Kinase Inhibitor
36Pipeline Expansion 37
Close Partnership with Physician-Scientists
• Characterize emerging medical needs for patients
• Refine understanding of safety events observed with
currently available multi-kinase inhibitors
Rigorous Target Selection
Pipeline • Combine clinical insights with internal expertise in chemistry
and structure-based drug design and development
Expansion • Prioritize opportunities with an aim to maximize patient
impact through more selective kinase inhibitor design
Rigorous Target Selection and
Disciplined Advancement of
Discovery Programs
Disciplined Program Advancement
PROGRAM 1
• Well defined selection criteria
PROGRAM 2 • Focused resource deployment on
opportunities with potential for
PROGRAM 3
immediate impact
38Key Discovery Programs
Research Programs Prioritized Following Assessment of Emerging Medical Needs
ALK IXDN Resistance Mutations HER2 Exon 20 Insertions
(DC Nomination 2022) (DC Nomination 2022)
TARGET PRODUCT PROFILE: TARGET PRODUCT PROFILE:
Selectively target ALK, ALK IX, and ALK IXDN Selectively target mutant HER2
Spare TRKB (related to CNS adverse events) Spare wild-type EGFR (related adverse
events include skin rash and diarrhea)
Strong preclinical brain penetrance (30-40%
of patients present with brain metastases) Strong preclinical brain penetrance (~20%
of patients present with brain metastases)
No FDA approved agents: No FDA approved agents:
Emergent mutations following treatment with currently Standard of Care is platinum-based chemotherapy
approved ALK inhibitors
IX: I1171X resistance mutation, (X = N, S, or T); IXDN: I1171X/D1203N compound mutation
Sources: Cocco, Scaltriti and Drilon Nat Rev Clin Oncol 2018; Ou and Zhu Lung Cancer 2019; Shaw et al., NEJM 2020; Offin et al, Cancer 2019
39Nuvalent Pipeline – Ongoing Programs
Advancing parallel lead programs in ROS1-positive and ALK-positive NSCLC, and multiple early-stage discovery programs
LEAD PRODUCT SELECTED IND ANTICIPATED COMMERCIAL
INDICATION CANDIDATE MUTATION(S) DISCOVERY ENABLING PHASE 1 PHASE 2 PHASE 3 MILESTONES RIGHTS
G2032R,
Phase 1 portion
S1986Y/F,
ROS1 NSCLC NVL-520 L2026M,
of Phase 1/2 trial
open & enrolling
D2033N
G1202R Phase 1 portion
G1202R/L1196M of Phase 1/2 trial
ALK NSCLC NVL-655 G1202R/G1269A expected to
G1202R/L1198F initiate 2Q 2022
Drug candidate
I1171X / D1203N
ALK NSCLC (X = N, S, or T)
nomination
expected in 2022
Drug candidate
Exon 20
HER2 NSCLC Insertions
nomination
expected in 2022
Additional Discovery Research Programs Ongoing
40▪ Innovative molecular structures with the potential to overcome the dual
challenges of kinase resistance and selectivity in the CNS and in the periphery
▪ Potential for differentiated inhibition of proven kinase targets with opportunities
for clinical utility earlier in the treatment paradigm
Parallel lead programs in ROS1-positive and ALK-positive NSCLC:
2022 operational focus on efficient conduct of concurrent Phase 1/2 clinical trials
Robust development pipeline leveraging established approach:
Planned portfolio expansion in 2022 with internally discovered novel drug candidates
Expected cash runway into 2024
41www.nuvalent.com
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