Nuvalent(NUVL) - 2021 Q4 - Annual Report

PART I Business Nuvalent, Inc. is a clinical-stage biopharmaceutical company specializing in precisely targeted therapies for cancer, focusing on innovative small molecule kinase inhibitors to overcome limitations of existing treatments Overview and Pipeline Nuvalent is a clinical-stage biopharmaceutical company creating precisely targeted cancer therapies by designing small molecule kinase inhibitors to overcome limitations of existing drugs, with lead candidates NVL-520 and NVL-655 in or entering Phase 1/2 clinical trials - Nuvalent is a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for patients with cancer by developing innovative small molecules designed to overcome limitations of existing therapies for clinically proven kinase targets[28][29] Nuvalent's Product Pipeline Status | Product Candidate | Target | Indication | Development Stage | | :--- | :--- | :--- | :--- | | NVL-520 | ROS1-Selective Inhibitor | Advanced ROS1-positive NSCLC & other solid tumors | Phase 1/2 (ARROS-1 study enrolling) | | NVL-655 | ALK-Selective Inhibitor | Advanced ALK-positive NSCLC & other solid tumors | Phase 1/2 (ALKOVE-1 study to initiate Q2 2022) | | ALK IXDN Program | ALK Inhibitor | NSCLC with IXDN compound resistance mutations | Discovery (Candidate nomination expected 2022) | | HER2 Program | HER2 Inhibitor | NSCLC with HER2 Exon 20 Insertions | Discovery (Candidate nomination expected 2022) | Our Approach and Strategy Nuvalent's strategy centers on a patient-driven focus, leveraging deep expertise in chemistry and structure-based drug design for precise selectivity, and employing efficient drug discovery processes to advance lead candidates and build an integrated biopharmaceutical company - The company's approach is built on three core principles: a patient-driven focus in partnership with physician-scientists, deep expertise in chemistry and structure-based drug design to achieve precise selectivity, and efficient drug discovery and development targeting clinically proven kinases[40] - Key strategic goals include advancing NVL-520 and NVL-655 through clinical trials designed to support potential regulatory approval, progressing discovery-stage programs to nominate two more candidates in 2022, and building a fully integrated biopharmaceutical company to commercialize its products[57] NVL-520 (ROS1 Program) NVL-520 is an oral, brain-penetrant ROS1-selective inhibitor designed to overcome resistance and off-target effects in ROS1-positive NSCLC, currently being evaluated in the ARROS-1 Phase 1/2 clinical trial - 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 the prevalent G2032R mutation[44] - Preclinically, NVL-520 demonstrated high selectivity for ROS1 over the structurally related TRK family, aiming to avoid TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors[97][115] - The ARROS-1 study, a Phase 1/2 clinical trial, is currently enrolling patients to evaluate NVL-520 in advanced ROS1-positive NSCLC and other solid tumors, with a design intended to support potential registration[127][128] NVL-655 (ALK Program) NVL-655 is an oral, brain-penetrant ALK-selective inhibitor designed to address resistance to current ALK inhibitors and minimize CNS adverse events, with a Phase 1/2 clinical trial (ALKOVE-1) planned for Q2 2022 - NVL-655 is a brain-penetrant ALK-selective inhibitor designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including those with G1202R+ compound mutations[46] - Preclinical data indicates NVL-655 is selective for ALK over the structurally related TRK family, potentially minimizing TRK-related CNS adverse events associated with other ALK inhibitors like lorlatinib[151][171] - The company plans to initiate the ALKOVE-1 study, a first-in-human Phase 1/2 clinical trial for NVL-655 in advanced ALK-positive NSCLC and other solid tumors, in the second quarter of 2022[142] Competition, IP, and Manufacturing Nuvalent faces substantial competition from major pharmaceutical companies in the ROS1 and ALK inhibitor markets, protects its intellectual property through patent applications with expirations no earlier than 2041, and relies entirely on third-party contract manufacturing organizations - Competitors in the ROS1 space include Pfizer (Xalkori, lorlatinib), Roche (Rozlytrek), and Turning Point Therapeutics (repotrectinib); in the ALK space, competitors include Pfizer (Xalkori, Lorbrena), Novartis (Zykadia), Roche (Alecensa), and Takeda (Alunbrig)[212][213] - The company owns pending PCT and U.S. patent applications for its ROS1 and ALK programs, with any resulting patents expected to expire no earlier than 2041; it also has pending applications for its HER2 and ALK IXDN programs[222] - Nuvalent relies entirely on third-party contract manufacturing organizations (CMOs) for the manufacture of its product candidates for preclinical, clinical, and future commercial supply, and does not own or operate any manufacturing facilities[225] Government Regulation The company's operations are subject to extensive government regulation in the U.S. by the FDA and in other countries, encompassing drug approval processes, expedited review programs, post-approval compliance, and healthcare fraud and data privacy laws - In the U.S., drug development requires completing preclinical studies, submitting an IND to the FDA, and conducting Phase 1, 2, and 3 clinical trials before submitting a New Drug Application (NDA) for marketing approval[237] - The FDA provides several expedited programs to facilitate and hasten the review of drugs for serious conditions, including Fast Track designation, Breakthrough Therapy designation, Priority Review, and Accelerated Approval[270][271][274] - In the European Union, marketing authorization is obtained through a centralized procedure via the European Medicines Agency (EMA) or through national procedures; the EU also has programs for conditional approval and PRIME designation for priority medicines[350][351][353] - The company is subject to healthcare fraud and abuse laws, including the federal Anti-Kickback Statute and False Claims Act, as well as data privacy regulations like HIPAA in the U.S. and the GDPR in Europe[319][376] Risk Factors The company faces significant risks including a limited operating history, ongoing net losses, dependence on the success of its early-stage product candidates NVL-520 and NVL-655, substantial regulatory hurdles, reliance on third parties for manufacturing and clinical trials, intense competition, and the need for additional capital - The company is in early development stages with a limited operating history, no approved products, and a history of significant net losses, which are expected to continue[399][403] - Future success is substantially dependent on the clinical development and commercialization of its two lead candidates, NVL-520 and NVL-655, which face high risks of failure in clinical trials[416] - The company relies on third parties for manufacturing and conducting clinical trials, which introduces risks related to production difficulties, supply chain disruptions, and lack of direct control over trial execution[661][666] - The ongoing COVID-19 pandemic poses a risk of adversely impacting business operations, including potential delays in clinical trials due to enrollment difficulties, site disruptions, and regulatory interruptions[466] Unresolved Staff Comments The company reports that it has no unresolved staff comments from the Securities and Exchange Commission - None[729] Properties The company's corporate headquarters are located in leased office space in Cambridge, Massachusetts, under a month-to-month lease, which is considered adequate for current needs - The company's corporate headquarters are in Cambridge, Massachusetts, where it leases office space on a month-to-month basis[730] Legal Proceedings As of December 31, 2021, the company was not a party to any material legal proceedings - As of December 31, 2021, the company was not involved in any material legal proceedings[731] Mine Safety Disclosures This item is not applicable to the company - Not applicable[732] PART II Market for Registrant's Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities Nuvalent's Class A common stock began trading on the Nasdaq Global Select Market under the symbol "NUVL" on July 29, 2021, with its IPO on August 2, 2021, raising net proceeds of approximately $174.3 million, and the company has never paid dividends - The company's Class A common stock began trading on the Nasdaq Global Select Market under the symbol "NUVL" on July 29, 2021[734] - On August 2, 2021, the company completed its IPO, raising net proceeds of approximately $174.3 million[737][738] - The company has never declared or paid cash dividends and does not intend to in the foreseeable future, retaining earnings for business development[741] Management's Discussion and Analysis of Financial Condition and Results of Operations For the year ended December 31, 2021, Nuvalent reported a net loss of $46.3 million, driven by increased R&D and G&A expenses, and held $288.1 million in cash, cash equivalents, and marketable securities expected to fund operations into 2024 Results of Operations (2021 vs. 2020) | (in thousands) | Year Ended Dec 31, 2021 | Year Ended Dec 31, 2020 | Change | | :--- | :--- | :--- | :--- | | Research and development | $35,559 | $15,403 | $20,156 | | General and administrative | $10,258 | $1,502 | $8,756 | | Total operating expenses | $45,817 | $16,905 | $28,912 | | Loss from operations | ($45,817) | ($16,905) | ($28,912) | | Net loss | ($46,338) | ($14,556) | ($31,782) | Research & Development Expenses by Program (2021 vs. 2020) | (in thousands) | Year Ended Dec 31, 2021 | Year Ended Dec 31, 2020 | Change | | :--- | :--- | :--- | :--- | | NVL-520 | $11,411 | $4,583 | $6,828 | | NVL-655 | $7,302 | $2,948 | $4,354 | | Discovery programs | $7,388 | $3,835 | $3,553 | | Personnel-related | $8,067 | $3,024 | $5,043 | | Other | $1,391 | $1,013 | $378 | | Total R&D Expenses | $35,559 | $15,403 | $20,156 | - As of December 31, 2021, the company had cash, cash equivalents, and marketable securities of $288.1 million, which is expected to fund operating expenses and capital expenditure requirements into 2024[781][791] Quantitative and Qualitative Disclosures About Market Risk As a smaller reporting company, Nuvalent is not required to provide the information for this item - The company is a smaller reporting company and is not required to provide the information under this item[800] Financial Statements and Supplementary Data The consolidated financial statements for the years ended December 31, 2021, and 2020, audited by KPMG LLP, are presented, showing a $46.3 million net loss for 2021 and $288.1 million in cash, cash equivalents, and marketable securities as of year-end Consolidated Balance Sheet Highlights (as of Dec 31) | (in thousands) | 2021 | 2020 | | :--- | :--- | :--- | | Cash, cash equivalents & marketable securities | $288,111 | $10,332 | | Total Assets | $293,824 | $10,646 | | Total Liabilities | $8,787 | $6,615 | | Total Stockholders' Equity (Deficit) | $285,037 | ($31,323) | Consolidated Statement of Operations Highlights (Year Ended Dec 31) | (in thousands) | 2021 | 2020 | | :--- | :--- | :--- | | Total operating expenses | $45,817 | $16,905 | | Loss from operations | ($45,817) | ($16,905) | | Net loss | ($46,338) | ($14,556) | - In August 2021, the company completed its IPO, receiving net proceeds of approximately $174.3 million; in connection with the IPO, all outstanding convertible preferred stock was converted into common stock[826] Changes in and Disagreements With Accountants on Accounting and Financial Disclosure The company reports no changes in or disagreements with its accountants on accounting and financial disclosure - None[899] Controls and Procedures Management concluded that the company's disclosure controls and procedures were effective at a reasonable assurance level as of December 31, 2021, with no material changes to internal controls during the fourth quarter - Management concluded that as of December 31, 2021, the company's disclosure controls and procedures were effective at the reasonable assurance level[900] - A management report on internal control over financial reporting is not included, as permitted for newly public companies[901] Other Information The company reports no other information for this item - None[903] PART III Directors, Executive Officers and Corporate Governance Information regarding directors, executive officers, and corporate governance will be incorporated by reference from the company's definitive proxy statement for its 2022 Annual Meeting of Stockholders - Information required by this item is incorporated by reference from the company's 2022 Proxy Statement[906] Executive Compensation Information regarding executive compensation will be incorporated by reference from the company's definitive proxy statement for its 2022 Annual Meeting of Stockholders - Information required by this item is incorporated by reference from the company's 2022 Proxy Statement[907] Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters Information regarding security ownership will be incorporated by reference from the company's definitive proxy statement for its 2022 Annual Meeting of Stockholders - Information required by this item is incorporated by reference from the company's 2022 Proxy Statement[908] Certain Relationships and Related Transactions, and Director Independence Information regarding certain relationships, related transactions, and director independence will be incorporated by reference from the company's definitive proxy statement for its 2022 Annual Meeting of Stockholders - Information required by this item is incorporated by reference from the company's 2022 Proxy Statement[909] Principal Accounting Fees and Services Information regarding principal accounting fees and services will be incorporated by reference from the company's definitive proxy statement for its 2022 Annual Meeting of Stockholders - Information required by this item is incorporated by reference from the company's 2022 Proxy Statement[910] PART IV Exhibits, Financial Statement Schedules This section lists the financial statements included from page 158 and provides an index of all exhibits filed with the report, incorporating them by reference - This item lists the financial statements included in the report and incorporates the Exhibit Index by reference[912][914] Form 10-K Summary The company did not provide a Form 10-K summary - None[915]