10-K
Table of Contents
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM
10-K
(Mark One)
For the fiscal year ended December 31, 2021
OR
For the transition period from
to
Commission file number:
001-40671
NUVALENT, INC.
(Exact name of registrant as specified in its charter)
One Broadway, 14th FloorCambridge, MA 02142
(Address of principal executive offices) (Zip Code)
(857)
357-7000
(Registrant’s telephone number, including area code)
Securities registered pursuant to Section 12(b) of the Act:
Title of each class TradingSymbol(s) Name of each exchangeon which registered
Class A Common Stock, $0.0001 Par Value NUVL Nasdaq Global Select Market
Securities registered pursuant to Section 12(g) of the Act:
None
Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒
Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐ No ☒
Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐
Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation
S-T
(§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes ☒ No ☐
Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a
non-accelerated
filer, a smaller reporting company or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule
12b-2
of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☒
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☐
Indicate by check mark whether the registrant is a shell company (as defined in Rule
12b-2
of the Exchange Act). Yes ☐ No ☒
As of June 30, 2021, the last business day of the registrant’s most recently completed second fiscal quarter, there was no established public market for the registrant’s Class A common stock. The registrant therefore cannot calculate the aggregate market value of its voting and
non-voting
common equity held by
non-affiliates
as of such date. The registrant’s Class A common stock began trading on The Nasdaq Global Select Market on July 29, 2021.
As of February 28, 2022, there were 42,878,747 shares of the registrant’s Class A Common Stock, $0.0001 par value per share, outstanding and 5,435,254 shares of the registrant’s Class B Common Stock, $0.0001 par value per share, outstanding.
DOCUMENTS INCORPORATED BY REFERENCE
Portions of the registrant’s Proxy Statement for its 2022 Annual Meeting of Stockholders, which the registrant intends to file with the Securities and Exchange Commission not later than 120 days after the registrant’s fiscal year ended December 31, 2021, are incorporated by reference into Part III of this Annual Report on Form
10-K.
Table of Contents
Nuvalent, Inc.
Index
Page
PART I
Item 1. Business 8
Item 1A. Risk Factors 79
Item 1B. Unresolved Staff Comments 145
Item 2. Properties 145
Item 3. Legal Proceedings 145
Item 4. Mine Safety Disclosures 145
PART II
Item 6. [Reserved] 147
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 157
Item 8. Financial Statements and Supplementary Data 158
Item 9A. Controls and Procedures 178
Item 9B. Other Information 179
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 179
PART III
Item 10. Directors, Executive Officers and Corporate Governance 180
Item 11. Executive Compensation 180
Item 14. Principal Accounting Fees and Services 180
PART IV
Item 15. Exhibits, Financial Statement Schedules 181
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CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS AND INDUSTRY DATA
This Annual Report on Form
10-K
(Annual Report) of Nuvalent, Inc. contains express or implied forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, Section 27A of the Securities Act of 1933, as amended (the Securities Act), and Section 21E of the Securities Exchange Act of 1934, as amended (the Exchange Act), that are based on our management’s belief and assumptions and on information currently available to our management. These statements relate to future events or our future operational or financial performance, and involve known and unknown risks, uncertainties and other factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by these forward-looking statements. Forward-looking statements contained in this Annual Report include, among other things, statements about:
• the timing, scope or likelihood of foreign regulatory filings and approvals;
• the pricing and reimbursement of our product candidates, if approved;
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• our financial performance;
• the rate and degree of market acceptance of our product candidates;
• regulatory developments in the United States (the U.S.) and foreign countries;
• the impact of laws and regulations;
• developments relating to our competitors and our industry;
In some cases, you can identify forward-looking statements by terminology such as “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “expect,” “estimate,” “seek,” “predict,” “future,” “project,” “potential,” “continue,” “target” or the negative of these terms or other comparable terminology. These statements are only predictions. You should not place undue reliance on forward-looking statements because they involve known and unknown risks, uncertainties, and other factors, which are, in some cases, beyond our control and which could materially affect results. Factors that may cause actual results to differ materially from current expectations include, among other things, those listed under the section titled “Risk Factors” and elsewhere in this Annual Report. If one or more of these risks or uncertainties were to occur, or if our underlying assumptions prove to be incorrect, actual events or results may vary significantly from those implied or projected by the forward-looking statements. No forward-looking statement is a guarantee of future performance. You should read this Annual Report and the documents that we reference in this Annual Report and have filed with the Securities and Exchange Commission (the SEC) thereto completely and with the understanding that our actual future results may be materially different from any future results expressed or implied by these forward-looking statements.
The forward-looking statements in this Annual Report represent our views as of the date of this Annual Report. We do not undertake any obligation to publicly update any forward-looking statement except to the extent required by applicable law. You should therefore not rely on these forward-looking statements as representing our views as of any date subsequent to the date of this Annual Report.
This Annual Report also contains estimates, projections and other information concerning our industry, our business and the markets for our product candidates. Information that is based on estimates, forecasts, projections, market research or similar methodologies is inherently subject to uncertainties and actual events or circumstances may differ materially from events and circumstances that are assumed in this information. Unless
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otherwise expressly stated, we obtained this industry, business, market and other data from our own internal estimates and research as well as from reports, research surveys, studies, and similar data prepared by market research firms and other third parties, industry, medical and general publications, government data and similar sources. All of the market data used in this Annual Report involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such data. Industry publications and third-party research, surveys and studies generally indicate that their information has been obtained from sources believed to be reliable, although they do not guarantee the accuracy or completeness of such information. Our estimates of the potential market opportunities for our product candidates include several key assumptions based on our industry knowledge, industry publications, third-party research and other surveys, which may be based on a small sample size and may fail to accurately reflect market opportunities. While we believe that our internal assumptions are reasonable, no independent source has verified such assumptions.
Except where the context otherwise requires or where otherwise indicated, the terms “Nuvalent,” “we,” “us,” “our,” “our company,” “the company,” and “our business” in this Annual Report refer to Nuvalent, Inc. and its consolidated subsidiary.
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SUMMARY OF RISK FACTORS
Below is a summary of the principal factors that make an investment in our common stock speculative or risky. This summary does not address all of the risks that we face. Additional discussion of the risks summarized in this risk factor summary, and other risks that we face, can be found below under the section titled “Risk Factors” and should be carefully considered, together with other information in this Annual Report and our other filings with the SEC before making investment decisions regarding our common stock.
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PART I
ITEM 1. BUSINESS
Overview
We are a clinical stage biopharmaceutical company focused on creating
precisely
targeted therapies for patients with cancer. We leverage our team’s deep expertise in chemistry and structure-based drug design to develop innovative small molecules that are designed with the aim to overcome the limitations of existing therapies for clinically proven kinase targets. Through addressing the limitations of existing therapies, we believe our programs have the potential to drive deeper, more durable responses with minimal adverse events. We believe these potential benefits will support opportunities for clinical utility earlier in the treatment paradigm.
We focus our discovery efforts on small molecule inhibitors of kinases, a class of cellular targets that can play a central role in cancer growth and proliferation. In particular, we focus on “clinically proven” kinase targets, or those for which therapies have been developed by others to target those kinases, and that such drugs have demonstrated sufficient clinical efficacy and safety data to be approved by the FDA or similar regulatory agency and are established and used in the clinical setting. Currently available kinase inhibitors face multiple limitations, which can include kinase resistance, or the emergence of new mutations in the kinase target that can enable resistance to existing therapies; kinase selectivity, or the potential for existing therapies to inhibit other structurally similar kinase targets and lead to
off-target
adverse events; and limited brain penetrance, or the ability for the therapy to treat disease that has spread or metastasized to the brain. By prioritizing target selectivity, we believe our drug candidates have the potential to overcome resistance, minimize adverse events, optimize brain penetrance to address brain metastases, and drive more durable responses.
We are advancing a robust pipeline of product candidates with parallel lead programs in cancers driven by genomic alterations in the ROS proto-oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK) kinases (
i.e.,
ROS1-positive and
ALK-positive,
respectively), along with multiple discovery-stage research programs. We hold worldwide development and commercialization rights to our product candidates.
Our first lead product candidate,
NVL-520,
is a novel ROS1-selective inhibitor designed with the aim to address the clinical challenges of emergent treatment resistance, central nervous system (CNS)-related adverse events, and brain metastases that may limit the use of currently available ROS1 tyrosine kinase inhibitors (TKI). Preclinical data has shown that
NVL-520
was brain-penetrant, inhibited wild-type ROS1 fusions, remained active in the presence of mutations conferring resistance to approved and investigational ROS1 inhibitors, and displayed strong selectivity for both wild-type ROS1 and its resistance variants as compared to the structurally related tropomyosin receptor kinase B (TRKB), thereby minimizing the potential for
off-target
TRKB-related CNS adverse events.
We are currently enrolling patients in the Phase 1 portion of our
ARROS-1
clinical trial, a
first-in-human
Phase 1/2, multicenter, open-label, dose-escalation and expansion study evaluating
NVL-520
as an oral monotherapy in patients with advanced ROS1-positive
non-small
cell lung cancer (NSCLC) and other solid tumors.
ARROS-1
is comprised of two study components, beginning with a Phase 1 dose-escalation portion to evaluate the safety and tolerability of
NVL-520
in patients with advanced ROS1-positive solid tumors previously treated with at least one ROS1 TKI, as well as to determine the recommended Phase 2 dose (RP2D), characterize the pharmacokinetic profile, and evaluate preliminary anti-tumor activity of
NVL-520.
Once the RP2D is determined, the study may transition directly into a Phase 2 portion designed to support potential registration of
NVL-520
in both ROS1-positive patients with NSCLC who are
TKI-naïve
and who have been previously treated with ROS1 kinase inhibitors.
Our second lead product candidate,
NVL-655,
is a brain-penetrant
ALK-selective
inhibitor, designed with the aim to address the clinical challenges of emergent treatment resistance,
CNS-related
adverse events, and brain metastases that may limit the use of first-, second-, and third-generation ALK inhibitors. Preclinical data has shown that
NVL-655
was brain-penetrant, inhibited wild-type ALK fusions, remained active in the presence of mutations conferring resistance to approved and investigational ALK inhibitors, and displayed strong selectivity
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for both wild-type ALK and its resistance variants as compared to the structurally related TRKB, thereby minimizing the potential for
off-target
TRKB-related CNS adverse events. We have submitted an IND for
NVL-655
and the FDA has confirmed that clinical investigation of
NVL-655
may proceed. We plan to initiate the Phase 1 portion of our planned
ALKOVE-1
study, a
first-in-human
Phase 1/2 clinical trial investigating
NVL-655
in advanced
ALK-positive
NSCLC and other solid tumors, in the second quarter of 2022.
In addition to our lead programs, we have prioritized a number of additional small molecule research programs following an assessment of medical need, including a second ALK inhibitor program designed with the aim to address emerging compound resistance mutations and a HER2 Exon 20 insertions program. We expect to nominate product candidates for these programs in 2022.
Within the past decade, the increase in the utilization of cancer genomic profiling has resulted in the identification of specific genomic alterations, such as ROS1 fusions and ALK fusions, that can drive the growth and proliferation of a tumor. The successful development of targeted therapies matched to individual genomic alterations has given rise to the current era of precision oncology, where treatment decisions driven by the genomic profile of a patient’s cancer are increasingly becoming the standard of care.
In particular, kinase inhibitors have fueled the targeted therapy revolution and remain at the leading edge of precision oncology. However, the clinical utility of currently approved kinase inhibitors is limited by three key challenges: kinase resistance, kinase selectivity, and, for some tumor types, limited CNS activity.
Our approach is to create innovative molecular structures and nominate product candidates that have the potential to overcome the limitations of existing therapies for clinically proven kinase targets. Our structures are designed to precisely engage the target kinase and remain active in tumors that have developed resistance, enabling our product candidates to treat both the original tumor and tumors with emergent resistance mutations. In addition, we prioritize structures that are highly selective for their target kinases in order to minimize adverse events and drive durable responses. Where appropriate, we optimize for brain penetrance to improve treatment options for patients with brain metastases.
By addressing the limitations of existing therapies, we believe our programs have the potential to drive deeper, more durable responses with minimal adverse events. We believe these potential benefits will support opportunities for clinical utility earlier in the treatment paradigm.
Our approach
Our approach is built on three core principles:
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Our approach has enabled us to identify two product candidates in two years, and we expect to nominate two more product candidates in 2022. With the continued increase in the adoption of kinase inhibitors as the standard of care across a broadening set of indications, we believe that opportunities to apply our established approach of efficient drug discovery and development will continue to grow.
Our programs
We are currently advancing two parallel lead programs in addition to multiple early-stage discovery programs as summarized in Figure 1 below. We hold worldwide development and commercialization rights to our product candidates.
Figure 1. Our pipeline of kinase inhibitor product candidates
NVL-520
(ROS1-Selective inhibitor)
The ROS1 kinase is a clinically proven target in oncology, with two therapies that target the ROS1 kinase that have received FDA marketing approval for the treatment of ROS1-positive NSCLC: Xalkori
®
(crizotinib), a dual ROS1/ALK inhibitor marketed by Pfizer Inc. (Pfizer); and Rozlytrek
®
(entrectinib), a dual ROS1/TRK inhibitor marketed by F.
Hoffmann-La
Roche AG (Roche) and its partners. We believe
NVL-520
is a differentiated product candidate for patients with advanced NSCLC driven by a ROS1 fusion (
i.e.,
ROS1-positive).
NVL-520
is a brain-penetrant ROS1-selective inhibitor designed to remain active in tumors that have developed resistance to currently available ROS1 inhibitors, including tumors with the prevalent G2032R resistance mutation and those with the S1986Y/F, L2026M, or D2033N resistance mutations. We optimized
NVL-520
for brain penetrance to potentially improve treatment options for patients with brain metastases. Importantly, we observed that
NVL-520
selectively inhibits ROS1 over the structurally related tropomyosin receptor kinase (TRK) family to potentially avoid
TRK-related
CNS adverse events seen with dual TRK/ROS1 inhibitors and drive more durable responses for patients with ROS1-mutant variants. The Phase 1 portion of our
ARROS-1
study, a Phase 1/2 clinical trial investigating
NVL-520
in advanced ROS1-positive NSCLC and other solid tumors, is open and enrolling.
NVL-655
(ALK-Selective
inhibitor)
The ALK kinase is a clinically proven target in oncology, with five therapies that target the ALK kinase that have received FDA marketing approval for the treatment of
ALK-positive
NSCLC: Xalkori (crizotinib) and Lorbrena
®
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(lorlatinib), each marketed by Pfizer; Zykadia
®
(ceritinib), marketed by Novartis AG (Novartis); Alecensa
®
(alectinib), marketed by Roche and Chugai Pharmaceutical Co., Ltd. (Chugai); and Alunbrig
®
(brigatinib), marketed by Takeda Pharmaceutical Company Limited (Takeda). We believe
NVL-655
is a differentiated product candidate for patients with advanced NSCLC driven by an ALK fusion (
i.e.
,
ALK-positive).
NVL-655
is a brain-penetrant
ALK-selective
inhibitor designed with the aim to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors,
including tumors with the G1202R resistance mutation or compound resistance mutations G1202R/L1196M
(GRLM), G1202R/G1269A (GRGA), or G1202R/L1198F (GRLF and, together with GRLM and GRGA, referred to as G1202R+). We believe we have optimized
NVL-655
for brain penetrance and ALK selectivity to potentially improve treatment
options for patients with brain metastases and avoid CNS adverse events related to
off-target
inhibition of the structurally related TRK family. We have submitted an IND for
NVL-655
and the FDA has confirmed that clinical investigation of
NVL-655
may proceed. We plan to initiate the Phase 1 portion of our planned
ALKOVE-1
study, a
first-in-human
Phase 1/2 clinical trial investigating
NVL-655
in advanced
ALK-positive
NSCLC and other solid tumors, in the second quarter of 2022.
Discovery programs
In addition to our lead programs, we have prioritized a number of additional small molecule research programs following assessment of medical need, including a second ALK inhibitor program designed with the aim to address emerging compound resistance mutations and a HER2 Exon 20 insertions program. Our key discovery programs are summarized below:
ALK IXDN
The ALK I1171X (X = N, S, or T) / D1203N (IXDN) compound mutations are emerging mutations that confer resistance to all available ALK inhibitor therapies for NSCLC. For patients treated with current first-line standard of care alectinib, the most prevalent ALK drug-resistance mutations are G1202R and I1171X. Following second-line treatment with lorlatinib, IXDN compound mutations have been observed. There are no approved therapies for the treatment of NSCLC with IXDN compound mutations. We are advancing toward a novel, selective, brain-penetrant ALK inhibitor designed with the aim to remain active in tumors harboring IXDN compound resistance mutations. We expect to nominate a product candidate in 2022.
HER2 Exon 20 insertions
Mutations in human epidermal growth factor receptor 2 (HER2 or ERBB2) occur in up to 4% of metastatic NSCLCs, with
in-frame
deletions, insertions, or duplications in exon 20 accounting for 90% of cases (collectively, HER2 Exon 20 Insertions). Approximately 20% of patients with HER2 mutant NSCLC present with brain metastases, with the percentage increasing upon treatment. There are no approved targeted therapies for NSCLC patients with HER2 Exon 20 Insertions. We are advancing toward a novel, selective, brain-penetrant HER2 inhibitor to treat patients with HER2 Exon 20 Insertions, including those with brain metastases, and to minimize adverse events and dose-limiting toxicities related to
off-target
inhibition of HER2 family member epidermal growth factor receptor (EGFR). We expect to nominate a product candidate in 2022.
Our team
We have assembled a management team of biopharmaceutical industry veterans with extensive experience in developing novel oncology therapies from research through commercialization. Our team is led by our Chief Executive Officer, James R. Porter, Ph.D., who has over 20 years of experience, including at Infinity Pharmaceuticals, Inc. (Infinity) and Verastem Oncology. Our Chief Financial Officer, Alexandra Balcom, M.B.A., C.P.A., has over 16 years of industry experience and was previously at SQZ Biotechnologies Company and Agios Pharmaceuticals, Inc. Our Chief Medical Officer, Christopher D. Turner, M.D., has over 20 years of experience in drug development, including at ARIAD Pharmaceuticals, Inc. and Blueprint Medicines Corporation. Our Chief Legal Officer, Deborah Miller, Ph.D., J.D., has over 20 years of legal experience managing the entire pharmaceutical lifecycle from early discovery through litigation, including at Sumitomo Dainippon Pharma America, Inc. and Infinity. Our Senior Vice President of Product Development & Regulatory
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Affairs, Darlene Noci, A.L.M., has over 20 years of experience in global drug development in rare diseases and oncology, including at Genzyme Corporation and EMD Serono, the North America biopharma business of Merck KgaA, Darmstadt, Germany.
Our seasoned leadership team has broad experience at both large global organizations, including C.H. Boehringer Sohn AG & Ko. KG, Pfizer, Sanofi S.A., EMD Serono, GlaxoSmithKline plc, and BeiGene, Ltd., as well as established biotech companies, including Infinity, Agios Pharmaceuticals Inc., Blueprint Medicines Corporation, and ARIAD Pharmaceuticals, Inc. Together, our leadership team has contributed directly to the regulatory approval of 12 therapies, including 5 kinase inhibitors, 9 oncology therapeutics, and 10 small molecules: CLOLAR
®
/Evoltra
®
(clofarabine), FABRAZYME
®
(agalsidase beta), COPIKTRA
®
(duvelisib), BRUKINSA
®
(zanubrutinib), MOZOBIL
®
(plerixafor injection), BAVENCIO
®
(avelumab), TIBSOVO
®
(ivosidenib tablets), TIVICAY
®
(dolutegravir), ICLUSIG
®
(ponatinib), GAVRETO
TM
(pralsetinib), ALUNBRIG
®
(brigatinib) and PYRUKYND
®
(mitapivat).
Our discovery approach leverages the experience and ongoing support of our scientific founder and head scientific advisor Matthew Shair, Ph.D., Professor of Chemistry and Chemical Biology at Harvard University. In leading his laboratory at Harvard, Dr. Shair has integrated organic chemistry, human disease biology, and drug development to focus on the development of novel small molecule therapeutics, and he has developed ways to efficiently assemble complex small molecules.
Our scientific advisors include additional researchers who publish widely cited research on topics relevant to the study and treatment of cancer, lead clinical units at experienced precision medicine cancer centers in the U.S., and are actively involved in our drug development process and programs. Our strong scientific advisory board includes:
• Pasi Jänne, M.D., Ph.D., clinical advisor, Dana Farber Cancer Institute;
• Alexander Drilon, M.D., clinical advisor, Memorial Sloan Kettering;
• Nancy Kohl, Ph.D., translational research advisor, independent consultant.
We have also established collaborations through service agreements with global CROs to provide scale and expertise in research chemistry, chemical manufacturing, biology, pharmacology and toxicology, and clinical studies.
Our values
Our three core values are:
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Our strategy
Our goal is to be a leading biopharmaceutical company that translates our deep expertise in structure-based drug design to discover, develop, and deliver novel, selective therapeutics that enable durable responses for patients with cancer. The key elements of our strategy include:
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Background
Cancer is a group of diverse diseases defined by aberrant cell growth and proliferation of abnormal cells. The initiation of cancer can occur when the tightly regulated balance of healthy cell homeostasis is disrupted through a variety of mechanisms, including genomic alterations that lead to dysregulation of key cellular functions.
Historically, cancers were classified by their tissue of origin and stage of clinical progression. However, the advent and increasing adoption of genomic profiling for tumors has enabled expansion of this classification to include recognition of the different molecular origins of cancer. We now understand that tumors, even those arising at different sites throughout the body, often bear genomic alterations in a recurring subset of cancer-associated genes, referred to collectively as oncogenes, that often express signaling proteins for cell proliferation and survival. Furthermore, a subset of these genomic alterations that affect oncogenes appear to be critical drivers of cancer initiation and growth and are therefore referred to as driver alterations. The ability to identify driver alterations within a tumor and the successful development of targeted therapies against them has given rise to the current era of precision oncology, where treatment decisions driven by the genomic profile of a patient’s cancer are increasingly becoming the standard of care.
The genes encoding for kinases represent a key category of oncogenes in which driver alterations have been identified and successfully targeted. Kinases are enzymes that regulate the biological activity of proteins, including critical cellular functions such as metabolism, cell cycle regulation, survival, and differentiation, and are subcategorized by the protein residue on which they act (
e.g.,
tyrosine, serine, or threonine). Genomic alterations impacting kinase function can be oncogenic, as dysregulation of key cellular functions can cause normal cells to transform to cancer cells. Cancer cells can be highly dependent on these oncogenic kinase alterations for survival, a concept known as oncogene addiction. As a result, in tumors where an oncogenic driver alteration in a kinase oncogene can be identified, kinase inhibition is a rational and proven approach to disrupt oncogene addiction and lead to arrested cellular growth and proliferation in a targeted manner.
Since the FDA approval of the first targeted kinase inhibitor in 2001, there has been exponential focus on the development of kinase inhibitors for the treatment for cancer. As of January 31, 2022, there were 74 kinase inhibitors approved by the FDA to treat patients with cancer and 34 of these approvals have occurred since 2017. The majority of the currently approved kinase inhibitors are small molecules that target tyrosine kinases and are referred to as TKIs. The success of TKIs and other kinase inhibitors in oncology is driven by observed clinical benefit, as many patients with tumors driven by oncogenic kinases have demonstrated rapid and measurable tumor shrinkage when treated with a corresponding targeted kinase inhibitor. As a result of their clinical impact, the worldwide sales of small molecule kinase inhibitors in oncology were reported to be $40 billion in 2020 and are estimated to grow to more than $80 billion by 2026.
Limitations of kinase inhibitors
Kinase inhibitors have fueled the targeted therapy revolution and remain at the leading edge of precision oncology. Although advancements in precision oncology have improved outcomes for patients, many patients who initially respond to kinase inhibitors develop resistance to treatment, experience treatment-limiting adverse events, or develop brain metastases that may not be controlled by their initial therapy. This highlights the opportunity for better genomically-driven therapeutics that can overcome kinase resistance, improve kinase selectivity, and, for some tumor types, improve activity in the CNS.
The kinase resistance problem
A common feature of a cancer cell is its ability to gain new mutations in order to sustain its continuous oncogenic signaling and fuel its growth and proliferation. While treatment with currently available kinase inhibitors may provide an initial therapeutic effect, it often results in the emergence of cancer cells harboring new mutations in the kinase target. These new mutations can change the shape and the chemical properties of the kinase binding
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pocket, resulting in resistance to therapy. For example, “solvent-front” mutations occur in the solvent-exposed region of the kinase binding pocket where an inhibitor is traditionally designed to fit. Mutations in this solvent-exposed region often cause physical changes to the pocket that disrupt the ability of the kinase inhibitor to bind to its target, leading to the loss of response to the therapy and disease progression. A majority of patients with advanced or metastatic cancer who initially respond to targeted therapies are estimated to eventually develop acquired resistance.
Compounds that are designed to address known resistance mutations to currently approved kinase inhibitors could lead to more durable responses and advance earlier in the treatment paradigm. As an example, the EGFR inhibitor Tagrisso
®
(osimertinib) was originally developed to treat NSCLC patients that have progressed on first generation inhibitors Iressa
®
(gefitinib) or Tarceva
®
(erlotinib) and have developed EGFR T790M, a resistance mutation. Osimertinib was subsequently compared to gefitinib or erlotinib in first
-
line EGFR NSCLC and demonstrated a statistically significant improvement in progression free survival, attributed in part to preventing the emergence of the EGFR T790M resistance mutation. Today, osimertinib has supplanted the first-generation kinase inhibitors as the standard of care for this patient population. Likewise, the
BCR-ABL
inhibitor Tasigna
®
(nilotinib) was initially approved for the treatment of patients with chronic myelogenous leukemia (CML) who were resistant or intolerant to the first-generation inhibitor Gleevec
®
(imatinib) and was subsequently approved for the treatment of newly diagnosed patients.
The kinase selectivity problem
The drug binding sites of different kinases are often very similar in structure, making it challenging to design molecules that uniquely inhibit a single specific target at therapeutic doses. The similarities between kinases often leads to
off-target
inhibition, which may contribute to adverse events, dose-limiting toxicities, and insufficient
on-target
inhibition, ultimately decreasing the duration of clinical response.
Compounds that are designed with greater selectivity could improve tolerability, lead to more durable responses, and advance earlier in the treatment paradigm. As an example, in separate clinical trials, the
RET-selective
inhibitor Retevmo
®
(selpercatinib) demonstrated more than twice the response rate and median duration of response in a RET fusion-positive NSCLC patient population compared to the investigational multi-kinase inhibitor, cabozantinib. In another example, clinical adoption of the multi-kinase inhibitor Iclusig
®
(ponatinib) for CML patients is limited due to
off-target
vascular adverse events. Ponatinib is not recommended for first-line use despite demonstrating activity against the
BCR-ABL
T315I mutation that confers resistance to all first-line agents, including Gleevec
®
(imatinib). This highlights the importance of addressing both kinase resistance and kinase selectivity in parallel to maximize potential opportunities for more durable responses and to advance earlier in the treatment paradigm.
The brain penetration problem
Patients with oncogenic alterations in kinases often present with or develop brain metastases. Approximately 200,000 brain metastases are diagnosed annually in the U.S., accounting for 20% of cancer deaths. Across tumor types, lung cancers and breast cancers constitute the majority of brain metastases. Among lung cancer patients with brain metastases, up to 25% of patients exhibit brain metastases at diagnosis, up to another 50% during the course of disease, and even more at the time of autopsy. Overall, patients presenting with metastatic brain cancer have a poor prognosis with median survival of approximately two months, which may be due to the poor blood-brain barrier (BBB) permeability of currently available therapies.
The growing incidence and unfavorable prognosis of patients with brain metastases highlight the need for therapies that penetrate the BBB to control or prevent disease in the brain. To address the needs of patients presenting with or at risk of developing brain metastases, drug designs must be optimized for structural and physical properties that allow passage through the BBB while also meeting the challenges of kinase resistance to ensure target engagement in the brain, and kinase selectivity to avoid
off-target
CNS adverse events.
Our approach
We aim to create
precisely
targeted therapies for patients with cancer, designed to overcome the limitations of existing therapies for clinically proven kinase targets. By addressing the limitations of existing therapies, we
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believe our programs have the potential to drive deeper, more durable responses with minimal adverse events. These potential benefits may also support opportunities for clinical utility earlier in the treatment paradigm.
As discussed below, our approach is built on three core principles:
• Patient-driven focus.
• Efficient drug discovery and development.
Our approach has enabled us to identify two product candidates in two years, and we expect to nominate two more product candidates in 2022. With the continued increase in the adoption of kinase inhibitors as the standard of care across a broadening set of indications, we believe that opportunities to apply our established approach to efficient drug discovery and development will continue to grow.
Patient-driven focus
Our goal is to benefit patients, and that is where our process begins. We partner with physician-scientists to assess current and emerging patient needs across potential therapeutic targets. We prioritize clinically proven kinase targets where we believe those needs can be addressed through the design of a highly selective small molecule kinase inhibitor.
Through the combination of clinical insights and our internal drug design and development expertise, we anchor each development program with a detailed target product profile that includes well-defined selection criteria informed by real-world medical needs. Key recurring challenges informing our target product profiles include kinase resistance, kinase selectivity, and limited CNS activity. By aligning with our physician-scientist partners on both the medical needs and target product profile from the beginning, we believe we are able to clearly define the criteria required for molecules that may achieve deep, durable responses with minimal adverse events for patients.
Deep expertise in chemistry and structure-based drug design to achieve precise selectivity (“threading the needle”)
We harness our team’s deep expertise in chemistry and structure-based drug design to develop product candidates that specifically meet our
pre-defined
target product profiles with potential to become differentiated therapies that can advance to earlier lines of treatment. This requires the design of innovative structures that are able to ‘thread the needle’ between achieving high affinity for the kinase target of interest, including drug-resistant variants, while avoiding
off-target
kinases, in the CNS or in the periphery, associated with dose-limiting toxicities. We believe our purpose-built product candidates have the potential to concurrently address the challenges of kinase resistance, kinase selectivity, and brain penetration.
Addressing kinase resistance
In addition to selectively inhibiting the wild-type kinase, our product candidates are designed to remain active even in the presence of structural changes arising from resistance mutations. This allows our product candidates to potentially treat both the original tumor and tumors with emergent resistance mutations. Figure 2 below illustrates how the unique design of our product candidates may address the challenge of kinase resistance by continuing to bind target kinases, despite structural changes.
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Figure 2. Our ability to address the kinase resistance problem
Addressing kinase selectivity
Many kinases are structurally similar, increasing the potential for
off-target
binding and related adverse events. We pursue innovative small molecules that can exploit subtle, structural differences across closely related kinases. By prioritizing selectivity, we are able to design inhibitors that have a high affinity for their target kinase relative to other,
off-target
kinases in order to minimize adverse events and drive durable responses, as illustrated in Figure 3 below.
Figure 3. Our ability to address the kinase selectivity problem
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Addressing brain penetration
We pursue product candidates with optimal physical-chemical properties to pass through the BBB, limit recognition by efflux transporters that can actively pump out drug molecules, and reach clinically efficacious concentrations in the brain. Our molecules are designed to achieve these properties while retaining the ability to address kinase resistance to ensure target inhibition, and exquisite kinase selectivity to avoid
off-target
CNS adverse events.
In summary, we believe a core aspect of our differentiation is the ability to navigate competing molecular challenges in the design of innovative small molecules that address multiple limitations of currently existing therapies to overcome resistance, minimize adverse events, optimize CNS activity, and drive more durable responses. We believe that this ability not only allows us to clearly define an addressable market opportunity, but also provides us with the possibility to move into earlier lines of treatment.
Efficient drug discovery and development
We believe our approach may enable us to develop drugs with an increased probability of clinical success while potentially reducing the cost and risk of drug discovery and development.
We prioritize clinically proven kinase targets in well-defined patient populations, to leverage existing tools and processes for the investigation of clinically proven kinase targets to advance drug discovery and development in an efficient manner. Prior clinical experience with approved inhibitors provides increased confidence in observing early objective measures of tumor responses that could inform the pursuit of an expedited development path. Moreover, learnings from earlier generations of kinase inhibitors may be leveraged to accelerate patient identification and enrollment in clinical trials.
We streamline the discovery process through clear,
pre-defined
selection criteria within our target product profiles. Once we have developed product candidates that meet these criteria, we continue to advance our programs with discipline and focus our resources on opportunities with the greatest potential for immediate impact.
We design our clinical trials with the goal to efficiently advance clinical development of our product candidates. Pending supportive data, we plan to engage regulators about expedited drug development pathways, such as Fast Track designation, Breakthrough Therapy designation, Priority Review, and other collaborative mechanisms. We believe the profile of our product candidates may allow us to develop breakthrough therapies that have the potential to drive more durable responses and to advance earlier in the treatment paradigm.
Our ROS1 program,
NVL-520
Overview
NVL-520
is a differentiated oral small molecule ROS1-selective inhibitor that we are evaluating for the potential treatment of ROS1-positive NSCLC and other solid tumors.
We designed
NVL-520
with the aim to overcome several limitations observed with currently available ROS1 inhibitors. Our preclinical data demonstrates that
NVL-520
can inhibit both wild-type ROS1 fusions and ROS1 fusions that have developed key resistance mutations, including G2032R. In addition,
in vitro
and
in vivo
studies of
NVL-520
have demonstrated its ability to penetrate the brain as well as its superior selectivity for ROS1 over
off-target
kinases, including the TRK family of kinases, which could help minimize toxicity demonstrated by currently available therapies and therapies in development. We believe this preclinical profile suggests the potential for
NVL-520
to be a differentiated ROS1-selective inhibitor that may be able to move earlier in the treatment paradigm.
Clinical investigation of
NVL-520
is ongoing in the Phase 1 portion of our
ARROS-1
study, a
first-in-human
Phase 1/2 clinical trial investigating
NVL-520
in advanced ROS1-positive NSCLC and other solid tumors.
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Background and limitations of current ROS1 therapies
ROS1 is an oncogene that encodes the receptor tyrosine kinase ROS1, which can be aberrantly activated by gene rearrangement to drive tumor cell proliferation, survival, and metastasis. In NSCLC, ROS1 rearrangements leading to constitutively active ROS1 fusions (
e.g.,
CD74-ROS1 fusion) are detected in up to 3% of patients. At the time of diagnosis, up to 40% of these patients present with accompanying brain metastases. Beyond NSCLC, ROS1 rearrangements have also been reported across a wide range of solid tumors as well as in some lymphomas.
As of February 28, 2022, currently available ROS1 inhibitors include the
FDA-approved
therapies Xalkori
®
(crizotinib) and Rozlytrek
®
(entrectinib). In addition, investigational therapies lorlatinib and repotrectinib are both in active clinical development for ROS1-positive NSCLC. Although these therapies have the potential to improve the lives and outcomes for patients with ROS1-positive NSCLC, many patients still progress. This highlights the significant remaining challenges, including:
Figure 4. Safety implications of TRK inhibition
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Target selection & target product profile development: ROS1
Based on the identified limitations, we believe there is a significant medical need for therapeutic agents that could overcome these obstacles, and ultimately provide more durable anti-tumor activity for patients with ROS1-positive cancers.
We have defined, in collaboration with our physician-scientist partners, the following product profile for a ROS1 inhibitor that would address current clinical needs and the limitations of available therapies, and potentially support utility earlier in the treatment paradigm. These criteria include:
Our solution:
NVL-520,
a ROS1-selective inhibitor
We have designed
NVL-520
with the aim to specifically address the target product profile for a novel ROS1-selective inhibitor that can overcome the limitations of current therapies.
In our preclinical studies, we have observed
NVL-520
to be a potent, highly selective, and brain-penetrant ROS1 inhibitor that meets our target profile goals and, thus, we believe it is a promising candidate for clinical development. Potency as used in this Annual Report refers to the amount of drug required to produce a pharmacological effect of given intensity and is not a measure of therapeutic efficacy. All statements of the potency, selectivity, and brain penetrance of
NVL-520
in this Annual Report have been made based on preclinical
in vitro
or
in vivo
studies that are described in “—Preclinical results” below.
In our preclinical studies, we observed that
NVL-520:
• inhibits wild-type ROS1 fusions;
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• is selective for ROS1 over other off-target kinases; and
• is brain-penetrant in pharmacokinetic and pharmacology studies.
To better understand the potential to differentiate
NVL-520
from currently approved and investigational ROS1 inhibitors, we also assessed the ROS1 inhibitors crizotinib, entrectinib, lorlatinib, and repotrectinib in our preclinical studies where possible, under the same study conditions. Although no
head-to-head
clinical studies have been conducted for these therapies and drug candidates, based on our preclinical evaluation, we observed the drug profiles summarized in Figure 5 below. We believe that this preclinical profile suggests the potential to differentiate
NVL-520
from approved or investigational ROS1 inhibitors by addressing the medical needs as defined in our product profile.
Figure 5.
NVL-520
is designed with the aim to address medical needs for ROS1-positive NSCLC patients
*No
head-to-head
clinical studies have been conducted for these therapies and drug candidates versus
NVL-520.
Clinical investigation of
NVL-520
is ongoing. Illustrative representation of the potential ability for currently approved and investigational ROS1 inhibitors to address medical needs for ROS1-positive NSCLC patients. Medical needs have been identified in discussion with our physician-scientist partners. Characterization of wild-type ROS1 fusion activity, G2032R ROS1 activity, and TRKB sparing activity is based on preclinical experiments conducted by Nuvalent. These preclinical experiments were not powered to determine the statistical significance of differences in measurements between any of the inhibitors tested. TRKB sparing activity refers to whether the drug or drug candidate selectively inhibits its primary development target(s) compared to TRKB. For this analysis, the primary development target for crizotinib, entrectinib, and repotrectinib is considered to be ROS1 wild-type, and the primary development target for lorlatinib, a dual ALK/ROS1 inhibitor, is considered to be ALK G1202R (ALK GR). The primary development targets for
NVL-520
include both ROS1 wild-type and the ROS1 G2032R resistance mutation. 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.
Based on the preclinical data described below, we believe that
NVL-520
has the potential to remain active even in the presence of common resistance mutations, deliver a favorable tolerability profile, and ultimately drive durable responses in both the CNS and in the periphery as a differentiated ROS1-selective inhibitor. The
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preclinical data described below are included in the active IND for
NVL-520,
and we believe support the investigation of
NVL-520
in patients with previously treated ROS1-positive advanced solid tumors as well as patients with ROS1-positive advanced solid tumors who have not previously received a kinase inhibitor.
Preclinical results
Activity against wild-type ROS1 fusions
We have conducted
in vitro
and
in vivo
experiments in models of wild-type ROS1 fusion-driven NSCLC, where we observed that
NVL-520
is a potent preclinical inhibitor of ROS1 and is active against wild-type ROS1 fusions, as summarized in Figure 6. The currently approved and investigational ROS1 inhibitors crizotinib, entrectinib, lorlatinib, and repotrectinib were also tested in this
in vitro
study under the same experimental conditions.
In vitro
measurements of IC
50
(the concentration required for 50% inhibition of cell viability) were not powered to determine the statistical significance of differences in measurements between any of the inhibitors tested.
NVL-520
potently inhibited Ba/F3 cells expressing the CD74-ROS1 fusion with an IC
50
of 1.2 nM. Inhibitory activity of
NVL-520
against the wild-type ROS1 fusion was confirmed
in vivo
, where
NVL-520
induced dose-dependent regression with statistically significant tumor growth inhibition versus vehicle (p<0.0001) in the NSCLC patient-derived xenograft (PDX) preclinical model
LU-01-0414,
which harbors an SDC4-ROS1 fusion.
Figure 6. Preclinical activity of
NVL-520
against wild-type ROS1 fusions
in vitro
and
in vivo
*(Left, in vitro) Ba/F3 cells were engineered to express the CD74-ROS1 fusion. Cells were treated with various currently approved and investigational ROS1 inhibitors under the same experimental conditions
(3-fold
dilution series, testing in duplicate). Cell viability for each experimental group is reported as half-maximal inhibitory concentration (IC
50
) measured after
72-hour
incubation using
CellTiter-Glo
reagent and represents the geometric mean of two or more independent experiments with geometric standard deviation of
≤
1.90. In vitro measurements of IC
50
were not powered to determine the statistical significance of differences in measurements between any of the inhibitors tested. An IC
50
of
0-49
nM is indicated as green, an IC
50
of 50 - 499 nM would be indicated as yellow, and
≥
500 nM would be indicated as red.
(Right, in vivo) SDC4-ROS1 patient-derived xenograft (PDX) tumors were implanted in Balb/c nude mice. Mice were treated with
NVL-520
(0.04 mg/kg BID, 0.2 mg/kg BID, or 1 mg/kg BID), or vehicle as a control. Vehicle was 20%
HP-ß
-CD
and was used to formulate
NVL-520.
Average tumor volume (mm3) ± SEM is plotted (n=5 per group). Number of mice was selected assuming signal/noise ratio of
≥
2.0, 5% significance level, and 80% power versus vehicle.
NVL-520
treatment induced significant tumor growth inhibition
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compared to vehicle with values ranging from 94% to 115% and adjusted
p-values
<0.0001 for all doses shown
(2-way
repeat measure ANOVA with Geisser-Greenhouse correction followed by Dunnett’s multiple comparison test).
BID = dosing two times per day, PO = oral administration.
No
head-to-head
clinical studies have been conducted for these therapies and drug candidates versus
NVL-520.
Clinical investigation of
NVL-520
is ongoing.
Activity against resistance mutations (G2032R, S1986Y/F, L2026M, D2033N)
We have conducted
in vitro
and
in vivo
experiments in preclinical models of ROS1 fusion-driven NSCLC harboring resistance mutations, where we have observed that
NVL-520
potently inhibits ROS1 in the presence of resistance mutations.
In vitro