10-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

☒ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

For the fiscal year ended December 31, 2021

☐TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

FOR THE TRANSITION PERIOD FROM TO

Commission File Number 001-39351

NUVATION BIO INC.

(Exact name of Registrant as specified in its Charter)

(Address of principal executive offices) (Zip Code)

Registrant’s telephone number, including area code: (332) 208-6102

Securities registered pursuant to Section 12(b) of the Act:

Title of each class TradingSymbol(s) Name of each exchangeon which registered

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 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 ☒

The aggregate market value of the voting common stock, par value $0.0001 per share, held by non-affiliates of the registrant computed by reference to the closing sales price for the registrant’s common stock on June 30, 2021, as reported on the New York Stock Exchange was approximately $1,340,000,971.

In determining the market value of the voting stock held by any non-affiliates, shares of common stock of the registrant beneficially owned by directors and officers have been excluded. This determination of affiliate status is not necessarily a conclusive determination for other purposes.

As of February 18, 2022, the registrant had 218,059,125 shares of Class A common stock and 1,000,000 shares of Class B common stock outstanding.

DOCUMENTS INCORPORATED BY REFERENCE:

Certain portions of the registrant's definitive proxy statement relating to the Company's Annual Meeting of Stockholders, to be filed with the Securities and Exchange Commission within 120 days of the registrant's fiscal year ended December 31, 2021, are incorporated by reference into Part III of this Annual Report on Form 10-K where indicated.

Table of Contents

Page

PART I

Item 1. Business 3

Item 1A. Risk Factors 57

Item 1B. Unresolved Staff Comments 98

Item 2. Properties 98

Item 3. Legal Proceedings 98

Item 4. Mine Safety Disclosures 98

PART II

Item 6. Selected Financial Data 99

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 107

Item 8. Consolidated Financial Statements and Supplementary Data 107

Item 9A. Controls and Procedures 107

Item 9B. Other Information 108

Item 9C. Disclosure Regarding Foreign Jurisdictions That Prevent Inspections 108

PART III

Item 10. Directors, Executive Officers and Corporate Governance 108

Item 11. Executive Compensation 108

Item 14. Principal Accounting Fees and Services 109

PART IV

Item 15. Exhibits, Financial Statement Schedules 109

CAUTIONARY INFORMATION REGARDING FORWARD-LOOKING STATEMENTS

This Annual Report on Form 10-K for the year ended December 31, 2021, contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, or the Securities Act, and Section 21E of the Securities Exchange Act of 1934, as amended, or the Exchange Act, which are subject to the “safe harbor” created by those sections, concerning our business, operations, and financial performance and condition as well as our plans, objectives, and expectations for business operations and financial performance and condition. Any statements contained herein that are not of historical facts may be deemed to be forward-looking statements. You can identify these statements by words such as “anticipate,” “assume,” “believe,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “should,” “will,” “would,” and other similar expressions that are predictions of or indicate future events and future trends. These forward-looking statements are based on current expectations, estimates, forecasts, and projections about our business and the industry in which we operate and management’s beliefs and assumptions and are not guarantees of future performance or development and involve known and unknown risks, uncertainties, and other factors that are in some cases beyond our control. As a result, any or all of our forward-looking statements in this Annual Report on Form 10-K may turn out to be inaccurate. Factors that could materially affect our business operations and financial performance and condition include, but are not limited to, those risks and uncertainties described herein under “Item 1A—Risk Factors.” You are urged to consider these factors carefully in evaluating the forward-looking statements and are cautioned not to place undue reliance on the forward-looking statements. The forward-looking statements are based on information available to us as of the filing date of this Annual Report on Form 10-K. Unless required by law, we do not intend to publicly update or revise any forward-looking statements to reflect new information or future events or otherwise. You should, however, review the factors and risks we describe in the reports we will file from time to time with the Securities and Exchange Commission, or the SEC, after the date of this Annual Report on Form 10-K.

SUMMARY RISK FACTORS

Below is a summary of material factors that make an investment in our securities speculative or risky. Importantly, this summary does not address all of the risks and uncertainties that we face. Additional discussion of the risks and uncertainties summarized in this risk factor summary, as well as other risks and uncertainties that we face, can be found under the section titled “Risk Factors” in Item 1A of this Annual Report on Form 10-K. The below summary is qualified in its entirety by that more complete discussion of such risks and uncertainties. You should consider carefully the risks and uncertainties described in the section titled “Risk Factors” as part of your evaluation of an investment in our securities:

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We have a limited operating history and have incurred significant losses since inception and anticipate that we may continue to incur losses for the foreseeable future, and may never achieve or maintain profitability.

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We will need substantial funding to pursue our business objectives. If we are unable to raise capital when needed or on favorable terms, we could be forced to delay, reduce or terminate our product development, other operations or commercialization efforts. Additionally, raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish proprietary rights.

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If we do not obtain regulatory approval for and successfully commercialize our product candidates in one or more indications or we experience significant delays in doing so, we may never generate any revenue or become profitable.

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Our approach to the discovery and development of product candidates based on our Drug-Drug Conjugate platform is unproven and is based on novel technology, and we do not know whether we will be able to develop any products of commercial value, or if competing technological approaches will limit the commercial value of our product candidates or render our platform obsolete.

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Clinical trials are very expensive, time-consuming and difficult to design and implement, and involve uncertain outcomes. Furthermore, results of earlier preclinical studies and clinical trials may not be predictive of results of future preclinical studies or clinical trials.

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We may encounter substantial delays in our preclinical studies or clinical trials or we may fail to demonstrate safety and efficacy to the satisfaction of applicable regulatory authorities.

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If any of our product candidates receives marketing approval and we, or others, later discover that the drug is less effective than previously believed or causes undesirable side effects that were not previously identified, its ability to market the drug could be compromised.

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We may become exposed to costly and damaging liability claims, either when testing our product candidates in the clinic or at the commercial stage, and our product liability insurance may not cover all damages from such claims.

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We have never commercialized a product candidate and we may lack the necessary expertise, personnel and resources to successfully commercialize any of our products that receive regulatory approval on our own or together with collaborators.

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We face substantial competition, which may result in others discovering, developing or commercializing products before or more successfully than we do.

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Even if we obtain regulatory approval for our product candidates, they will remain subject to ongoing regulatory oversight.

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We rely on third parties to perform the chemistry work associated with our drug discovery and preclinical activities and to conduct our preclinical studies and future clinical trials, and our business could be substantially harmed if these third parties cease performing services or perform in an unsatisfactory manner.

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We do not have our own manufacturing capabilities and will rely on third parties to produce clinical and commercial supplies of NUV-422 and our other current and future product candidates.

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If we are not able to establish collaborations, we may have to alter some of our future development and commercialization plans. If we are not able to establish further collaborations, we may have to alter some of our future development and commercialization plans.

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Our business operations and current and future relationships with investigators, healthcare professionals, consultants, third-party payors and customers will be subject, directly or indirectly, to federal and state healthcare fraud and abuse laws, false claims laws, transparency laws, health information privacy and security laws and other healthcare laws and regulations. If we are unable to comply, or have not fully complied, with such laws, we could face substantial penalties.

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If we are unable to obtain, maintain, protect and enforce sufficient patent and other intellectual property rights for our product candidates and technology, or if the scope of patent and other intellectual property rights obtained is not sufficiently broad, we may not be able to compete effectively in our market.

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Our reliance on third parties requires us to share our trade secrets, which increases the possibility that a competitor will discover them or that our trade secrets will be misappropriated or disclosed.

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We may become involved in lawsuits to protect or enforce our patents or other intellectual property, which could be expensive, time-consuming and unsuccessful, and issued patents covering our technology and product candidates could be found invalid or unenforceable if challenged.

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Third parties may initiate legal proceedings alleging that we are infringing, misappropriating or otherwise violating their intellectual property rights, the outcome of which would be uncertain and could negatively impact the success of our business.

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Intellectual property litigation could cause us to spend substantial resources and distract our personnel from their normal responsibilities.

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Our business, operations and clinical development plans and timelines and supply chain could be adversely affected by the effects of health epidemics, including the ongoing COVID-19 pandemic, on the manufacturing, clinical trial and other business activities performed by us or by third parties with whom we conduct business, including our CMOs, CROs, shippers and others.

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Our future success depends on our ability to retain Dr. Hung and our other key employees, consultants and advisors and to attract, retain and motivate qualified personnel.

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The dual-class structure of our common stock has the effect of concentrating voting power with our Chief Executive Officer, which limits other stockholders’ ability to influence the outcome of important transactions, including a change in control.

PART I

Item 1. Business.

Business Combination of Panacea Acquisition Corp. and Nuvation Bio Inc.

On February 10, 2021, (the “Closing Date”), Nuvation Bio Inc., a Delaware corporation (“Legacy Nuvation Bio”), Panacea Acquisition Corp. (“Panacea”), and Panacea Merger Subsidiary Corp, a Delaware corporation and a direct, wholly owned subsidiary of Panacea (“Merger Sub”) consummated the transactions contemplated by an Agreement and Plan of Merger among them dated October 20, 2020 (“Merger Agreement”).

Pursuant to the terms of the Merger Agreement, a business combination of Panacea and Legacy Nuvation Bio was effected through the merger of Merger Sub with and into Legacy Nuvation Bio, with Legacy Nuvation Bio surviving as a wholly owned subsidiary of Panacea (the “Merger”). On the Closing Date, Legacy Nuvation Bio changed its name to Nuvation Bio Operating Company Inc. and Panacea changed its name to Nuvation Bio Inc. (the “Company” or “Nuvation Bio”).

In connection with the closing of the Merger, our Class A common stock and warrants to purchase shares of our Class A common stock began trading on The New York Stock Exchange under the symbols “NUVB” and “NUVB.WS,” respectively, on February 11, 2021. The disclosure in Items 1 and 1A of this report gives effect to the Merger and includes the operations of Legacy Nuvation Bio prior to the Merger.

Business Overview

Nuvation Bio is a clinical-stage biopharmaceutical company developing differentiated and innovative therapeutic candidates focused on treating patients with the most difficult-to-treat cancers, for which conventional therapies have failed. We are advancing up to six wholly owned compounds that have resulted from our drug discovery and development programs, which include NUV-422 a cyclin-dependent kinase (“CDK”) inhibitor, NUV-868 a bromodomain and extra-terminal (“BET”) inhibitor, NUV-569 a Wee1 inhibitor, an A2A adenosine receptor inhibitor program, and a drug-drug conjugate (“DDC”) platform.

We were founded in 2018 by our chief executive officer, David Hung, M.D., who founded Medivation, Inc. and led its successful development of oncology drugs Xtandi® and talazoparib (now marketed as Talzenna®), leading to its $14.3 billion sale to Pfizer Inc. (“Pfizer”) in 2016.

We leverage our team’s extensive expertise in medicinal chemistry, preclinical discovery, manufacturing, drug development and commercialization to bring forward novel small molecules that improve the activity and overcome the liabilities of currently marketed drugs to address major unmet needs in oncology.

The foundations of our approach include:

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The pursuit of validated targets: We identify and pursue oncology targets validated by strong clinical or preclinical data that provide a high degree of confidence in generating clinically meaningful benefit. We focus on targets where there has been some progress by others in generating clinical candidates or FDA-approved drugs, and we then attempt to design novel therapeutic candidates to overcome the encountered safety liabilities or limitations in efficacy. As an example, in preclinical studies, our lead product candidate, NUV-422, has demonstrated improvements in potency and selectivity of the CDK target class to reduce off-target toxic effects and to overcome specific drug-resistance mechanisms and improve anti-tumor activity.

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Innovative medicinal chemistry expertise. We use our medicinal chemistry proficiency to generate differentiated therapeutic candidates, focused on improving their safety, anti-tumor activity and pharmacologic profiles over other standard of care (“SOC”) therapies. We also use innovative medicinal chemistry approaches to generate novel classes of molecules such as our DDCs.

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Human capital management: We believe our employees are our greatest assets, and we recognize that attracting, motivating and retaining talent at all levels is vital to our continued success. We are building

a culture that fosters a productive, professional and inclusive work environment, where our employees can thrive, have fun, and be inspired to perform their best work.

The following table summarizes our product candidate pipeline:

Our lead product candidate, NUV-422, is a selective small molecule inhibitor of CDK 2, 4 and 6. Relative to currently approved CDK4/6 inhibitors, NUV-422 also targets CDK2, a cell cycle checkpoint altered in multiple tumor types including high-grade gliomas, breast cancer and prostate cancer. NUV-422 has been designed to limit CDK1 inhibition, a potential cause of toxicity, and has shown favorable blood-brain barrier penetration in preclinical studies. We believe that a CDK2/4/6 inhibitor that limits CDK1 inhibition can bring greater benefit to a broader patient population. In October 2020, the U.S. Food and Drug Administration ("FDA") cleared our first investigational new drug (“IND”) application for NUV-422 to treat high-grade gliomas and we initiated a Phase 1/2 clinical trial for this indication in December 2020. In December 2021, the FDA cleared two additional INDs for NUV-422 for the treatment of advanced breast cancer (“aBC”) and for the treatment of prostate cancer, respectively. Additional trials and trial expansion are planned for NUV-422 in 2022. The FDA granted Orphan Drug Designation to NUV-422 for the treatment of malignant gliomas and Fast Track Designation for the treatment of high-grade gliomas.

Our second product candidate is NUV-868, a BD2-selective oral small molecule BET inhibitor. NUV-868 inhibits the protein BRD4, a key member of the BET family that epigenetically regulates a number of important proteins that control tumor growth and differentiation, including oncogenes such as c-myc. Notably, BET proteins have critical biological functions and are found to be altered in many human cancers (Bechter and Schoffski, 2020). We have designed NUV-868 to potentially reduce the therapeutic limiting toxicities of BRD4 inhibitors currently in development by optimizing BD2 versus BD1 selectivity. NUV-868 is almost 1,500 times more selective for BD2 than BD1. Non-selective BD1/2-inhibitors in development have been associated with tolerability issues, potentially due to BD1 inhibition, especially in the gastrointestinal (“GI”) tract and bone marrow (Faivre et al 2020). NUV-868 in combination with androgen receptor-directed therapies may help to overcome resistance in prostate cancer. In addition, NUV-868 in combination with PARP inhibitors may have synergistic activity to increase efficacy across multiple solid tumors. In January 2022, the FDA cleared an IND for NUV-868 for the treatment of advanced solid tumors, and we intend to initiate a Phase 1 trial for this indication in mid-2022.

We are also developing several other therapeutic candidates, including NUV-569. NUV-569 is a differentiated oral small molecule selective inhibitor of Wee1 kinase, an important regulator of DNA damage repair. Wee1 inhibitors increase the efficacy of DNA-damaging therapies by forcing cancers to replicate before they can repair their damaged DNA. Inhibition of this kinase can cause a tumor cell to divide before it has finished repairing its DNA, causing catastrophic DNA damage and programmed cell death. NUV-569 is designed to limit off-target effects by improving its kinase selectivity, which may improve tolerability including reduction of bone marrow and GI toxicity. Because Wee1 inhibitors synergize with DNA-damaging therapies like radiation and certain types of chemotherapy to increase anti-tumor activity, Wee1 inhibitors like NUV-569 may have wide applicability in treating many different types of cancer. We intend to submit an IND for NUV-569 by the end of 2022 and initiate Phase 1 trials in patients with

advanced solid tumors following IND clearance. We are also continuing to evaluate additional Wee1 inhibitors for the potential to increase efficacy and further widen the therapeutic window.

Our adenosine receptor inhibitors are designed to have high affinity for the A2A adenosine receptor, which plays multiple critical roles in human physiology and pathophysiology including anti-cancer immunity. Accumulation of adenosine in the tumor microenvironment may be a critical factor in limiting the activity of currently available immuno-oncology drugs, including anti-PD(L)1 drugs and anti-cancer chimeric antigen receptor T cells. Thus, targeting the adenosine receptor may overcome this blockade, leading to improved anti-cancer activity in tumors which are resistant to immuno-oncology drugs and adoptive T cell therapies. We intend to nominate a clinical development candidate by the end of 2022.

Our DDC platform is a novel therapeutic approach within the drug-conjugate class of anti-cancer therapies with parallels to Antibody-Drug Conjugates (“ADCs”). ADCs have been effective treatments in oncology, with ten drugs approved by the FDA and an estimated $11.0 billion in worldwide sales expected in 2023. We believe our DDC candidates could expand the therapeutic potential for the drug-conjugate class due to inherently differentiated properties versus ADCs, including a simpler manufacturing process, the potential to cross the cell membrane and recognize intracellular targets, and the potential for oral or intravenous ("IV”) dosing. We are designing DDCs to selectively deliver potent anti-cancer therapeutics to cancer cells to exert greater toxicity against these target tumor cells than against healthy non-target tissues. Utilizing this platform, we are able to conjugate tissue-selective targeted small molecules with anti-tumor agents to create unique therapeutic candidates. We have accomplished this by synthetically fusing a proven anti-cancer small molecule drug to a second small molecule that selectively binds distinct receptors that are preferentially expressed in cancer cells. These tissue-specific receptors create a “sink” that not only may concentrate the targeted drug in cancer cells but may also magnify the effects of the drug in those cells, while preventing similar effects in cells that do not express the targeted receptor. We believe this would allow our DDC candidates to limit some of the adverse effects commonly seen with many cancer drugs, such as bone marrow suppression and GI toxicity. Because this program at its core fuses the active sites of two or more small molecules to each other to generate a new small molecule with improved activity and targeted specificity, they are called DDCs. We intend to nominate a DDC clinical development candidate by year end 2022.

Strategy

We strive to deliver meaningful benefit to patients with serious unmet medical needs in oncology by developing novel and differentiated therapies. The core elements of our strategy include:

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Rapidly advance the development of our lead product candidate, NUV-422, a CDK2/4/6 inhibitor, toward regulatory approval for the treatment of various cancers.We have advanced NUV-422 through preclinical studies that have informed a robust clinical development plan. We plan to explore NUV-422 both as a monotherapy and in combination with SOC agents. In December 2020, we began a monotherapy Phase 1/2 study (Protocol NUV-422-02) for NUV-422 in high-grade gliomas and later amended the protocol in the second quarter of 2021 to include hormone receptor-positive/human epidermal growth factor receptor-2-negative locally advanced or metastatic breast cancer (HR+ HER2- aBC) and metastatic castration-resistant prostate cancer (“mCRPC”). This Phase 1/2 study (NUV-422-02) includes expansion cohorts in glioblastoma, HR+ Her2- aBC with and without active brain metastases and mCRPC that will begin in 2022. NUV-422-02 also includes a pre-surgical sub-study in patients with recurrent glioblastoma to evaluate NUV-422 concentrations and pharmacodynamic effects in brain tumor tissue. In addition, in 2022, we plan to initiate a Phase 1b/2 combination study with fulvestrant in patients with HR+ HER2- aBC who have received prior hormonal therapy combined with an approved CDK 4/6 inhibitor, as well as a Phase 1b/2 combination study with enzalutamide in patients with mCRPC who have received prior treatment with abiraterone acetate. We are evaluating other potential indications and clinical studies for NUV-422.

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Advance our deep oncology pipeline of novel and differentiated therapeutic candidates developed against clinically validated targets. We design our product candidates to have optimized properties including their ability to limit specific adverse effects of competitive compounds and/or to enhance their anti-tumor potential by targeting additional drivers of tumor resistance. Overall, in addition to the three INDs already submitted and cleared for NUV-422 and the initial IND cleared for NUV-868, we anticipate submitting multiple IND applications to the FDA over the next six years to expand and move our programs forward. We plan to advance NUV-868, a BD2-selective oral small molecule BET

inhibitor, into the clinic by mid-2022 and to submit an IND for NUV-569, a differentiated oral small molecule selective inhibitor of Wee1 kinase, by year end 2022.

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Advance candidates from our DDC platform to expand our oncology-focused pipeline. We are developing a pipeline of new chemical entities that leverage the tissue-specific targeting capabilities of small molecule nuclear hormone receptor binders, including androgen and estrogen receptor binders, fused to warheads that include PARP inhibitors and known chemotherapeutic agents. We intend to nominate a DDC clinical development candidate by year end 2022.

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Continue to leverage our deep insights in medicinal chemistry to pursue innovative clinical candidates. We have established medicinal chemistry expertise that have enabled us to rapidly pursue our current pipeline and platform. We intend to leverage these capabilities to pursue both new and validated targets in patients with serious unmet medical needs.

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Evaluate strategic opportunities to accelerate development timelines and maximize value of our product candidate pipeline.We currently own the exclusive worldwide development and commercial rights to each of our product candidates. We intend to evaluate collaborations that could maximize the value of our product candidate pipeline, either through the evaluation of our product candidates in combination with compounds owned by third parties or through geographic collaborations outside of the U.S. that allow us to leverage the existing infrastructure of other companies.

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Build a fully integrated global oncology company. We intend to continue building a fully integrated research, development and commercialization focused company. Our team's track record of success underscores their proven expertise in discovering, developing and delivering innovative medicines to patients. If our therapeutic candidates are approved, we intend to establish a focused commercial infrastructure and selectively expand our global commercial capabilities.

Programs

Overview of NUV-422: CDK2/4/6 Inhibitor Program

Our lead product candidate, NUV-422, is a potent and selective small molecule inhibitor targeting CDK2, CDK4 and CDK6. These are members of the CDK family of proteins that play a critical role in the regulation of tumor growth. Inhibition of cell cycle kinases CDK4 and CDK6 results in significant therapeutic effect in patients with HR+ HER2- aBC, and these results have led to the approvals of three CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib. Although these advancements have greatly expanded the treatment options for breast cancer patients, insensitivity to CDK4/6 inhibition has been found in some patients with primary or acquired resistance. As a result, therapeutic resistance and disease progression continue to limit the efficacy and duration of clinical benefit of these therapies. One known mechanism by which some breast cancer patients become resistant to currently approved CDK inhibitors is through CDK2 signaling, which allows cancer cells to bypass CDK4/6 inhibition. Beyond breast cancer, CDK2 activation is known to drive tumorigenesis in multiple solid tumors including brain cancer and prostate cancer, and increased CDK2 activity is associated with lower overall patient survival and recurrence. NUV-422 selectively inhibits CDK4/6, similar to the approved CDK4/6 inhibitors, but also potently inhibits CDK2. Since its initial discovery in our chemistry program, we have advanced NUV-422 through preclinical studies and have initiated clinical studies in multiple advanced solid tumors, including recurrent/refractory glioblastoma, HR+ HER2- aBC with and without active brain metastases, and mCRPC. We are exploring NUV-422 as both a monotherapy and in combination with SOC agents. We began a monotherapy Phase 1/2 study (Protocol NUV-422-02) in December 2020 in high-grade gliomas and later amended the protocol in the second quarter of 2021 to include HR+ HER2- aBC and mCRPC. We are continuing to enroll patients in the monotherapy Phase 1 dose escalation portion of the study and data from this portion of the study is expected to be shared in the second half of 2022. The FDA granted Orphan Drug Designation to NUV-422 for the treatment of malignant gliomas and Fast Track Designation for the treatment of high-grade gliomas.

CDK2 as a novel mechanism of resistance to standard therapies and an oncogenic driver in multiple cancers

The CDK family of proteins regulates cell cycle progression and transcriptional regulation. Recent advances in treatments using CDK inhibitors have focused on inhibition of CDK4 and CDK6, but preclinical studies and clinical trials suggest CDK2 may play an important role as a driver of tumor cell growth and an underlying mechanism of both primary and acquired resistance to CDK4/6 inhibitors. CDK2 is an essential regulator of cell division and multiple

events within the cell cycle, including centrosome duplication, DNA synthesis and G1-to-S-phase transition. CDK2 can bind both cyclin E and cyclin A, which play roles in the cell cycle. Cyclin D typically binds CDK4/6 and is thus a target of CDK4/6 inhibitors, but in the absence of CDK4/6, cyclin D can activate CDK2, which subsequently drives cell cycle progression.

We believe that CDK2 plays a key role in patients who either do not respond to current therapies or develop primary or secondary resistance to ongoing treatment. We and others have shown that CDK2 function can drive multiple cancers, including in gliomas, breast cancer and prostate cancer. CDK2 expression is elevated in multiple patient tumor tissues, and increased CDK2 expression correlates with a worse survival outcome (Tadasse, et al 2020, Wang et al2016). It was also recently shown that nearly 70% of high-grade glioma patients carry a homozygous deletion of CDKN2A, which encodes for p14 and p16, which are tumor suppressors that inhibit CDK4/6 directly and CDK2 through p21 (Reinhardt, et al 2018, Verhaak, et al 2010). These results, some of which are depicted in the diagram and graphs below, suggest that targeting CDK2, in addition to CDK4/6 in these cancers may lead to a blockade of an important aberrant mechanism of tumor growth and resistance to therapy leading to an improvement of clinical outcomes.

CDKN2A-DELETION DRIVES PRIMARY HIGH-GRADE GLIOMAS

(1)

Appay et al., 2020

(2)

Wang et al., 2016

In addition to primary resistance and de novo tumorigenesis, there are preclinical and clinical data suggesting that CDK2 may be involved in acquired resistance to cancer therapy. Metastatic breast cancer patients enrolled in the PALOMA-3 study who did not benefit from palbociclib therapy demonstrated overexpression of c-myc and cyclin E1 (Turner et al 2018). Since c-myc acts upstream to activate CDK2 and cyclin E1 binds CDK2 to drive the cell cycle, these results suggest CDK2 may be responsible for tumor resistance to palbociclib treatment. Taken together, these preclinical and clinical data demonstrate that CDK2 plays a unique role in promoting tumor growth in multiple types of cancer and that targeting CDK2 in addition to CDK4/6 may help patients overcome the CDK2-mediated resistance to approved therapies, including palbociclib and other CDK4/6 inhibitors.

CDK2 DRIVES RESISTANCE TO CDK4/6 INHIBITORS

Limitations of Other CDK Inhibitors

While CDK4/6 inhibitors demonstrated significant clinical benefit in patients with hormone-receptor-positive breast cancer including an improvement in overall survival, emerging preclinical and clinical evidence suggests that targeting CDK2 in addition to CDK4/6 may provide further benefit to cancer patients whose tumors may be driven by CDK2. These may include breast cancer that does not benefit from treatment with approved CDK4/6 inhibitors and other cancers wherein CDK2 dysregulation may contribute to tumor growth and worse clinical outcomes. It has been reported that of the three CDK4/6 inhibitors approved by the FDA for the treatment of patients with hormone receptor-positive breast cancer (ribociclib, palbociclib, abemaciclib), only abemaciclib demonstrated some anti-CDK2 activity, albeit extremely weak activity, in the hundreds of nanomolar half-maximal inhibitory concentration (“IC50”) range (Chen, et al, 2016). The IC50 is a measure of how much of a particular drug or other substance (inhibitor) is required for 50% inhibition of a specific biological or biochemical function, and IC50 values in the hundreds of nanomolar range are considered a sign of relatively weak inhibition. As evidenced by the recently reported divergent outcomes in the breast cancer adjuvant trials of palbociclib (PALLAS and PENELOPE-B studies) and abemaciclib (MonarchE study), patients who received treatment with abemaciclib experienced significant improvement in invasive disease-free survival and distant relapse-free survival (Johnston, et al, 2020), while no such effect was reported for patients in palbociclib trials (Mayer, et al 2020). Moreover, only abemaciclib received approval by the FDA as monotherapy for metastatic breast cancer patients, while ribociclib and palbociclib are only approved in combination with hormonal therapy, suggesting a potential benefit of even weak CDK2 inhibition in addition to CDK4/6 inhibition.

We and others have shown that it is critical to target CDK2, CDK4 and CDK6, while limiting CDK1 inhibition, which is a ubiquitously expressed CDK, the inhibition of which is known to cause severe toxicities in animal models and in patients. Dinaciclib is a potent inhibitor of CDK1 in addition to CDK2 with IC50 for both in the low nanomolar range, indicating strong inhibition. When tested as a once weekly intravenous infusion in a clinical trial (Nemunaitis, et al 2013), despite early signs of anti-tumor activity, 60% of patients experienced grade 3-4 adverse events, including nausea, vomiting, liver enzyme elevation, hyperbilirubinemia and hematological adverse events (neutropenia, anemia). Consequently, clinical development of dinaciclib has been discontinued.

To our knowledge, there is one clinical-stage CDK2/4/6 inhibitor:

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PF-06873600 (Pfizer) is a CDK2/4/6 inhibitor in a Phase 2 clinical trial being evaluated as a monotherapy and in combination with fulvestrant. While PF-06873600 inhibits CDK2/4/6, it also strongly inhibits CDK1 with an IC50 in the single-digit nanomolar range, which could result in a poor therapeutic index. We believe that limiting CDK1 inhibition is critical to developing a safe and efficacious next-generation CDK inhibitor drug.

In addition to a CDK2/4/6 inhibitor, Pfizer is also developing a CDK2-selective inhibitor (PF-07104091) which is being combined with palbociclib (CDK4/6 inhibitor) in HR+HER2- aBC validating the approach of inhibiting CDK2 in addition to CDK4 and CDK6.

NUV-422 Differentiation

NUV-422 is a next-generation CDK inhibitor discovered in our chemistry program, which potently inhibits CDK2, CDK4 and CDK6, while limiting CDK1 inhibition as shown in the table below. NUV-422 is approximately equal to approved drugs ribociclib, palbociclib and abemaciclib in its ability to inhibit CDK4 and CDK6, but it additionally inhibits CDK2, like PF-06873600. But importantly, unlike PF-06873600, NUV-422 does not potently inhibit CDK1, demonstrating at least a 10-fold lower IC50 for CDK1 than CDK2, but even greater than that for CDK4/6. We believe this positions NUV-422 as a promising next-generation CDK inhibitor with superior CDK2/4/6 vs CDK1 selectivity. In preclinical studies, we have shown that NUV-422 exhibits good drug-like properties, with oral bioavailability, suitable pharmacokinetic and drug metabolism profiles, and a nonclinical safety profile consistent with the class of CDK4/6 inhibitors, as well as a scalable manufacturing process. We have shown that NUV-422 demonstrates strong anti-proliferative activity across multiple human cancer cells.

NUV-422: POTENT INHIBITOR OF CDK2/4/6

IC50 Values: Lower value indicates stronger inhibition

Our Current Opportunities for NUV-422

Overview of Recurrent or Refractory High-Grade Gliomas

Cancer is the second leading cause of mortality in the U.S. and accounts for nearly one in four deaths. Primary tumors of the central nervous system (“CNS”) remain among the most difficult to treat, with a 5-year overall survival of approximately 35%. Gliomas represent 75% of malignant primary brain tumors and glioblastoma multiforme (“GBM”) accounts for over half of all gliomas. Compared to other areas of oncology, relatively few advances have been made in the treatment of brain cancers. Temozolomide (“TMZ”) is commonly used in front-line settings in combination with radiation, and it was first approved more than fifteen years ago in 2005. Bevacizumab approval soon followed in 2009 for recurrent GBM, but its use remains controversial due to conflicting clinical trial results. Consequently our initial proposed indication, recurrent or refractory high-grade gliomas, remains a significant unmet medical need with the first de facto option for recurrent GBM patients being clinical trials. Based on the preclinical data we have generated and clinical data others have generated, including patient biopsy, genetic sequencing and survival data, there is a strong biological rationale for targeting CDK2 in gliomas, including GBM. Coupled with preclinical data demonstrating preferential accumulation of NUV-422 in the brain without evidence of CNS toxicity, we believe that NUV-422 has the potential to bring significant clinical benefit to high-grade glioma patients.

Clinical Rationale for Targeting CDK2/4/6 in Gliomas

There is evidence suggesting CDK inhibition may be a promising therapeutic strategy in gliomas due to the role of CDKN2A deletion and CDK2 overexpression. Loss of CDKN2A occurs in majority of GBM(Brennan et al 2013). CDKN2A deletion and CDK2 overexpression are associated with worse survival in primary high-grade gliomas

(Appay et al., 2020, Wang et al., 2016). Abemaciclib (a potent inhibitor of CDK4/6 and weak inhibitor of CDK2) demonstrated an improvement of PFS in ND GBM patients in Phase 2 (Wen et al, 2021).

Preclinical Data

The in vitro anti-proliferative activity of NUV-422 was evaluated in six glioma cell lines, five of which have known CDKN2A deletions. Treatment with NUV-422 resulted in dose-dependent growth inhibition of all six glioma cell lines, with mean absolute IC50values in the nanomolar range.

The in vivo antitumor activity of NUV-422 and TMZ was evaluated in a cell line-derived xenograft model, which harbors a CDKN2A deletion, implanted subcutaneously in the flank of immunocompromised mice. NUV-422 was administered orally once daily (“QD”) at 30 mg/kg. NUV-422 treatment resulted in reduced tumor volume (p < 0.0001) of tumors compared to the vehicle-treated group. In contrast, SOC TMZ had no significant effect on tumor growth compared to the vehicle-treated group. These results are illustrated in the following chart.

NUV-422 INHIBITS TUMOR GROWTH BETTER THAN SOC TMZ IN GLIOBLASTOMA XENOGRAFT MODEL

Following a single 30 mg/kg and 100 mg/kg oral dose of NUV-422 in rats, the brain-to-plasma concentration ratios at six hours post-dose ranged from 11 to 12. These data, set forth in the following table, demonstrate high blood-brain barrier (“BBB”) penetration of NUV-422.

HIGH CONCENTRATIONS OF NUV-422 IN THE BRAIN

Clinical Development Plan for NUV-422 in Brain Tumors

We have successfully completed IND-enabling studies of NUV-422, our lead product candidate. The molecule has favorable pharmacological properties with a wide therapeutic index and has demonstrated a consistent nonclinical safety profile supportive of advancement into clinical trials. Most importantly, based on preclinical data, NUV-422 is unique among CDK inhibitors in that it is much more brain-penetrant and maintains a longer half-life in the brain than in the plasma, approximately 12 times the exposure in the brain compared to the plasma. We believe these characteristics will allow NUV-422 to more potently engage the intended targets in brain tumors compared to other CDK inhibitors that have been tested in brain tumors to date.

In October 2020, the FDA accepted our first IND application for NUV-422 for the treatment of patients with high-grade gliomas, including GBM. In December 2020, we began a monotherapy Phase 1/2 study (Protocol NUV-422-02) in high-grade gliomas and later amended the protocol in the second quarter of 2021 to include HR+ HER2- aBC (with and without brain metastases) and mCRPC. We are continuing to enroll patients in the monotherapy Phase 1 dose escalation portion of the study and data from this portion of the study is expected to be shared in the second half of 2022. After the determination of the recommended Phase 2 dose, the Phase 2 portion will enroll recurrent GBM,HR+ HER2- aBC, and mCRPC patients. This study is designed to evaluate safety and efficacy of NUV-422 as a monotherapy in these advanced solid tumors. This trial design is depicted below.

NUV-422-02: Seamless Phase 1/2 Trial Design

As part of the Phase 1 portion of the NUV-422-02 study, a surgical sub-study will be initiated to characterize the pharmacokinetics of NUV-422 in resected tumor tissue. In this sub-study, thirty patients with recurrent IDH-WT GBM requiring surgery per standard of care will be enrolled. Twenty patients will be randomized to receive NUV-422 for approximately 8 to 21 days before surgery. Ten patients will be randomized to receive no drug before surgery and can proceed to surgery per Investigator discretion. After recovery (14 – 21 days post-surgery), all 30 patients in this surgical cohort will have the option to receive NUV-422, if deemed appropriate by the Investigator.

After the determination of the recommended Phase 2 dose, the Phase 2 portion will enroll up to 40 patients with recurrent IDH-WT GBM with known CDKN2A/B/C status into Cohort 1. For these recurrent GBM patients, radiographic tumor assessments will be performed based on RANO criteria [Wen et al, 2010] to determine the primary objective of overall response rate (ORR) and duration of response (DOR).

NUV-422-02 rGBM Monotherapy Phase 1/2

The FDA granted Orphan Drug Designation to NUV-422 for the treatment of malignant gliomas and Fast Track Designation for the treatment of high-grade gliomas.

Overview of Metastatic Breast Cancer

Breast cancer is the most frequent malignancy in women worldwide, and the second most common cancer worldwide, with an estimated 1.8 million new diagnoses per year. In the U.S., breast cancer has the highest prevalence among all cancers. The Surveillance, Epidemiology, and End Results (“SEER”) Program at National Cancer Institute estimates that in 2020, there will be 276,000 new cases of breast cancer in the U.S. alone, and more than 40,000 deaths. Treatment options for breast cancer depend on many factors, including the stage of cancer. Breast cancer is a heterogeneous disease which is grouped into several clinical subtypes based on the expression of three proteins: ER, progesterone receptor (“PR”) and HER2. Both ER and PR are hormone receptors, and tumors that express either of these receptors are referred to as hormone receptor-positive. The ACS estimates that approximately 75-80% of all breast cancers express estrogen receptor (“ER+”) highlighting the central role of ER signaling in driving a large majority of breast cancer. Although early-stage non-metastatic disease is curable in approximately 70-80% of patients, advanced breast cancer with distant organ metastases is considered incurable with currently available therapies (Harbeck, et al 2019). Advanced breast cancer comprises inoperable locally advanced breast cancer, which has not spread to distant organs, and metastatic (stage IV) breast cancer; common sites of spread are bone, lungs, liver and brain. Currently, it is a treatable but virtually incurable disease, with metastases to distant sites, including the brain, being the cause of death in almost all patients, and a median overall survival of two to three years. Patients with metastatic breast cancer receive treatments that aim to relieve their symptoms and to prolong quality-adjusted life expectancy.

For patients with advanced ER+ breast cancer, endocrine therapy has been the backbone of treatment with a focus on developing a new generation of selective ER modulators (“SERMs”), aromatase inhibitors (“AIs”) and selective ER degraders (“SERDs”) due to emerging resistance to approved drugs. This resistance to endocrine treatment is due to multiple mechanisms, including changes in ER signaling and activation of other molecular pathways, such as CDK, mammalian target of rapamycin (“mTOR”), phosphoinositide 3-kinase (“PI3K”), mitogen-activated protein kinase (“MAPK”) and others (McAndrew & Finn, 2020). Recently, several agents targeting these mechanisms have been approved by the FDA: mTOR inhibitor (everolimus [2012]), followed by the approval of 3 CDK4/6 inhibitors (palbociclib [2015], ribociclib [2018] and abemaciclib [2018]), and more recently the PI3K inhibitor alpelisib for a subgroup of patients with PI3K alterations (2019). For a select group of patients with homologous recombination-deficient (“HR-D”) breast cancer, talazoparib, an oral PARP inhibitor, was approved by the FDA in 2018. All three approved CDK4/6 inhibitors—palbociclib, abemaciclib and ribociclib—are used in the metastatic setting. While patients with HR+ HER2- advanced breast cancer derive significant clinical benefit with first line treatment with a CDK4/6 inhibitor in combination with hormonal therapy, the majority eventually experience progression of their disease.

In 2019, worldwide sales for endocrine and targeted therapies treating ER+ breast cancer patients totaled $9.6 billion, with CDK4/6 inhibitors accounting for more than $6.0 billion. Given the incidence rate and cost of treatment, by 2027 the market size for adjuvant therapy, first line treatments and second line treatments in ER+ breast cancer could total $25 billion, $8 billion and $4 billion, respectively, with CDK4/6 inhibitors expected to account for approximately $14.0 billion.

Clinical Rationale for Targeting CDK2/4/6 in Breast Cancer Patients with Brain Metastases and Other Tumors.

It is estimated that at least 15% and as high as 50% of breast cancer patients will develop brain metastases during the course of their disease (Leone et al 2019). Patients with breast cancer brain metastasis (BCBM) have a poor prognosis with short overall survival and low quality of life. The prevalence of BCBM is increasing as treatment of primary cancers and imaging techniques improve. In addition, the brain is a “sanctuary site” for breast cancer cells treated with drugs that have poor penetration into the CNS. Thus, although a multitude of systemic treatment options exist for extracranial breast metastases, brain metastases continue to pose treatment challenges in clinical practice. For ER+ mBC patients, though recent Phase 3 trials demonstrated a PFS and even an overall survival benefit for CDK4/6 inhibitors in the first or second-line setting, there is limited evidence to inform their CNS-specific activity (Nguyen, et al 2019). Many studies included patients with stable and treated brain metastases or excluded patients with brain metastasis altogether, thus, the potential utility of CDK4/6 inhibitors for the prevention of CNS metastases remains unknown. A study of abemaciclib in BCBM patients demonstrated a slightly over 24% intracranial clinical benefit rate with 5% intracranial response rate (Tolaney et al 2020). While brain exposure was favorable in some of the patients, the overall low response rate in and outside the brain demonstrated that inhibition of CDK4/6 alone may not be enough for substantial control of the disease in this patient population. In addition, analyses of breast cancer metastases identified CDKN2A/p16 as a gene potentially associated with development of brain metastases. Patients with a higher p16 score had higher risk of brain metastases and worse overall survival (Furet, et al., 2017). Thus, targeting CDK2 in addition to CDK4/6 may present an important therapeutic strategy in ER+ mBC. In addition, up to 50% of patients with advanced HER2+ breast cancer who develop brain metastases, and a combination strategy of CDK2/4/6 inhibition with HER2-targeted therapy may warrant further investigation.

Overall, brain metastases develop in nearly 30% of patients with solid tumors. Cancers of the lung, breast and skin (melanoma) most frequently develop brain metastases and account for 67–80% of patients. Brain metastases from solid extracranial tumors represent an unmet need of increasing relevance as their incidence is rising considerably and is now estimated to be approximately 10 times higher than for primary malignant brain tumors. Thus, we may opt to study the effect of NUV-422 on brain metastases in patients whose primary tumor location is other than breast (e.g., lung, skin, and/or gastrointestinal tract).

Clinical Rationale for Targeting CDK2/4/6 in ER+ mBC

It was recently reported in the PALOMA-3 trial of ER+ mBC patients that cyclin E1 overexpression is a potential resistance mechanism to palbociclib (Turner, et al 2019). The efficacy of palbociclib plus fulvestrant was approximately halved in patients with high cyclin E1 expression compared to patients with low cyclin E1 expression (median PFS of 7.6 vs 14.1 months, respectively). Since Cyclin E is a known binding partner to CDK2 leading to cell cycle progression, these results reinforce that CDK2 is a key bypass kinase of CDK4/6 inhibition that may be responsible for driving resistance to palbociclib.

Preclinical Data

The activity of NUV-422 as a single agent and in combination with approved and investigational SERDs was explored in several clinically relevant breast cancer models.

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In a cell line derived xenograft model, the in vivo antitumor activity of NUV-422 alone and in combination with fulvestrant (Faslodex), an approved SERD, was evaluated. NUV-422 was administered orally QD at 30 mg/kg. NUV-422 treatment resulted in several tumor regressions compared to the vehicle-treated group. While fulvestrant alone had a significant effect on tumor volume, the combination of NUV-422 and fulvestrant results in several deep regressions in tumor volume. These results are illustrated in the figure below.

NUV-422 IS SUPERIOR TO FULVESTRANT IN XENOGRAFT MODEL OF ER+ METASTATIC BREAST CANCER

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In a patient-derived xenograft model that harbored an ESR1 mutation and that was derived from a patient previously treated with a combination of letrozole and palbociclib, NUV-422 (30 mg/kg QD) treatment resulted in reduced tumor volume (p<0.0001) compared to the vehicle-treated group. Additionally, NUV-422 resulted in significantly reduced tumor volume when compared to comparator standard-of-care agents fulvestrant (p <0.0001) and palbociclib (p=0.0004). These results are illustrated in the figure below.

NUV-422 INHIBITS GROWTH OF AN ESR1 MUTANT BREAST CANCER MODEL DERIVED FROM A PATIENT THAT RECEIVED PRIOR CDK THERAPY

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The in vivo antitumor activity of NUV-422 alone and in combination with elacestrant, an investigational oral SERD, was evaluated in an ESR1 mutant patient-derived xenograft model. NUV-422 was administered orally QD at 30 mg/kg. NUV-422 treatment resulted in reduced tumor volume (p<0.0001) compared to the vehicle-treated group. Additionally, NUV-422 resulted in significantly reduced tumor volume when compared to comparator standard-of-care agents fulvestrant (p<0.0001) and palbociclib (p<0.0001). Lastly, NUV-422 in combination with elacestrant resulted in deep tumor regressions. These results are illustrated in the figure below.

NUV-422 IN COMBINATION WITH AN INVESTIGATIONAL ORAL SERD, ELACESTRANT, CAUSES DEEP REGRESSIONS IN AN ESR1 MUTANT PATIENT-DERIVED XENOGRAFT MODEL

Development Plan for NUV-422 in aBC

For metastatic or advanced breast cancer, we are exploring NUV-422 as both a monotherapy and in combination with SOC agent, fulvestrant. We began a monotherapy Phase 1/2 study (Protocol NUV-422-02) in December 2020 in high-grade gliomas and later amended the protocol in the second quarter of 2021 to include HR+ HER2- aBC. We are continuing to enroll patients in the monotherapy Phase 1 dose escalation portion of the study and data from this portion of the study. After the determination of the recommended Phase 2 dose, the Phase 2 portion will enroll recurrent HR+ HER2- aBC with and without active brain metastases. Up to 40 patients will be enrolled into each of these aBC cohorts. Eligible patients must have received at least 1 but not more than 4 prior lines of systemic therapy for aBC including at least 1 prior line of hormonal therapy in combination with an approved CDK4/6 inhibitor. The primary objective is ORR and DOR based on radiographic tumor assessments performed per RECIST 1.1 criteria for both cohorts. For the aBC active brain metastases cohort, efficacy will be determined by radiographic tumor assessments performed by RANO-BM criteria [Lin et al, 2015], which will be used to derive intracranial ORR and DOR.

NUV-422-02 2L+ aBC Monotherapy Phase 1/2

In December 2021, the FDA cleared an IND for NUV-422 for the treatment of HR+ HER2- aBC. In 2022, we plan to initiate a Phase 1b/2 study in patients with HR+ HER2- aBC who have received prior hormonal therapy combined with an approved CDK 4/6 inhibitor. This study will begin with a Phase 1b dose escalation portion designed to evaluate safety and tolerability of the NUV-422 plus fulvestrant combination and to determine a recommended Phase 2 combination dose of NUV-422. The Phase 2 portion is a randomized, non-comparative study designed to evaluate the safety and efficacy of NUV-422 in combination with fulvestrant relative to NUV-422 monotherapy and fulvestrant monotherapy. Up to 200 patients may be enrolled into the Phase 2 portion across three arms. The primary endpoint for Phase 2 portion is ORR based on radiographic tumor assessments performed per RECIST 1.1 criteria.

NUV-422-03 Phase 1b/2 HR+ HER2- aBC study NUV-422 In Combination with Fulvestrant

Additional Preclinical data suggests broad potential for NUV-422 in endocrine-independent breast cancer.

The in vivo antitumor activity of NUV-422 was evaluated in an ER+ and an ER- model of Her2+ breast cancer. NUV-422 inhibited tumor growth in both models as a single agent and in combination with Tucatinib (Tukysa). Additionally, in the ER+ HER2+ model, the triple combination of NUV-422, tucatinib, and fulvestrant caused tumor regressions. The results are illustrated in the figure below.

NUV-422, AS A SINGLE AGENT, AND IN COMBINATION WITH SOC AGENTS, TUCATINIB AND FULVESTRANT, CAUSES REGRESSION OF HER2+ BREAST CANCER XENOGRAFTS

Prostate Cancer Overview

Prostate cancer is reported as the second and third leading cause of cancer death for men in the U.S. and in Europe, respectively. SEER cancer statistics estimated that approximately 175,000 men in the U.S. and 450,000 men in the EU5 would be diagnosed with prostate cancer in 2020, potentially resulting in a $15 billion market opportunity given the costs of treatment.

For early stage prostate cancer, the SOC is a radical prostatectomy, the removal of the prostate via surgery, or radiation therapy. While potentially curative, prostatectomy and/or radiation can result in serious side effects, including urinary and fecal incontinence and erectile dysfunction, as a result of damage to surrounding vital structures, blood vessels and nerves. Given the invasive nature of the procedure, prostatectomy surgery also brings the risk of complications with anesthesia, bleeding and infection.

mCRPC is the most advanced form of the disease, and there are approximately 35,000 to 45,000 new incidences of mCRPC each year. Men with mCRPC have a poor prognosis and a predicted survival rate of fewer than two years from the initial time of progression.

Current SOC for men with castration-resistant prostate cancer provides that patients should initially receive a combination of androgen deprivation therapy (“ADT”) and either abiraterone, which works by decreasing androgen levels, or enzalutamide, which works by blocking androgen binding to AR. If the disease progresses despite these second-generation hormonal therapies, chemotherapy is considered the next treatment option. Treatment with chemotherapy is generally postponed for as long as possible due to its effect on patient’s quality of life and the potential for severe side effects including neuropathies, nausea, diarrhea, decreased mental capacity and increased risk of infections.

Clinical Rationale for Targeting CDK2/4/6 in mCRPC.

The role of CDK2 as a crucial factor in development of metastases in patients with prostate cancer has been supported by an extensive analysis of patient gene sequencing data and clinical outcomes (Yin, et al 2018). This analysis identified CDK2 and CDKN2C as one of the most important genes in transcriptional dysregulation in prostate cancer when expression of CDK2 was significantly associated with recurrence of prostate cancer (p = 0.00793). The importance of CDK2 in cancer growth is further supported by knockout experiments suggesting that CDK2 is critical to the cell invasion. While a clinical trial of abemaciclib plus abiraterone in later line prostate cancer (CYCLONE 2) is ongoing and an additional study may be initiated soon in earlier line prostate cancer (CYCLONE 3). A randomized study of palbociclib with ADT in metastatic hormone-sensitive prostate cancer (mHSPC) patients demonstrated that addition of this CDK4/6 inhibitor to ADT did not improve prostate specific antigen endpoints or PFS in this population (Palmbos, et al 2021). Thus, targeting CDK2 in combination with hormonal therapy may be able to address an important unmet medical need in mCRPC patients who progress on current SOC therapy.

Preclinical Data

The in vivo antitumor activity of NUV-422 alone and in combination with enzalutamide (Xtandi), an approved prostate cancer drug, was evaluated in a patient-derived xenograft model, implanted subcutaneously in the flank of immunocompromised mice. NUV-422 was administered orally QD at 30 mg/kg. Treatment with NUV-422 alone resulted in reduced tumor volume compared to the vehicle-treated group. As illustrated in the figure below, while enzalutamide alone had very little effect on reducing tumor volume, the combination of NUV-422 and enzalutamide resulted in an enhanced antitumor effect, where all treated animals had marked tumor regression and half of the animals had complete tumor regression.

DEEP TUMOR REDUCTIONS OBSERVED IN ENZALUTAMIDE-RESISTANT PATIENT-DERIVED XENOGRAFT PROSTATE MODEL

The in vivo antitumor activity of NUV-422 was evaluated in an androgen receptor variant, ARv-7, harboring cell line-derived prostate xenograft model, implanted subcutaneously in the flank of immunocompromised mice. NUV-422 was administered orally QD at 30 mg/kg. Treatment with NUV-422 alone resulted in reduced tumor volume (p<0.001) when compared to the vehicle-treated group, as well as approved SOC groups, enzalutamide (p<0.001) or abiraterone (p<0.001). Abiraterone or enzalutamide did not cause significant growth inhibition in this model. The results are illustrated in the figure below.

NUV-422 EXHIBITS ANTI-TUMOR ACTIVITY IN AN ARV-7 PROSTATE CANCER MODEL RESISTANT TO ANTI-ANDROGEN THERAPIES

The in vivo antitumor activity of NUV-422 alone and in combination with enzalutamide, an approved prostate cancer drug, was evaluated in an androgen-sensitive cell line-derived xenograft model, implanted subcutaneously in the flank of immunocompromised mice. NUV-422 was administered orally QD at 30 mg/kg. As shown in the figure below, treatment with NUV-422 alone, and in combination with enzalutamide, resulted in significantly reduced tumor volume (p<0.001) compared to the vehicle-treated group. NUV-422 in combination with enzalutamide resulted in further growth inhibition when compared to the single agent groups.

NUV-422 IN COMBINATION WITH ENZALUTAMIDE CAUSES SIGNIFICANT TUMOR GROWTH INHIBITION IN ANDROGEN-SENSITIVE PROSTATE CANCER XENOGRAFT

Development Plan for NUV-422 in mCRPC

For mCRPC, we are exploring NUV-422 as both a monotherapy and in combination with SOC agent, enzalutamide. We began a monotherapy Phase 1/2 study (Protocol NUV-422-02) in December 2020 in high grade gliomas and later amended the protocol in the second quarter of 2021 to include mCRPC. We are continuing to enroll patients in the monotherapy Phase 1 dose escalation portion of the study and data from this portion of the study. After the determination of the recommended Phase 2 dose, the Phase 2 portion will enroll up to 40 mCRPC patients who have disease progression or rising PSA on prior therapies that include prior anti-androgen therapies and at least 1 prior line of taxane-based chemotherapy for castration-resistant disease. The primary objective is ORR and DOR based on radiographic tumor assessments performed per RECIST 1.1 criteria and Prostate Cancer Clinical Trials Working Group 3 (PCWG3) guidelines as well as a decrease in the prostate-specific antigen (PSA) to ≥ 50% less than the baseline PSA.

NUV-422-02 mCRPC Monotherapy Phase 1/2

In December 2021, the FDA cleared an IND for NUV-422 for the treatment of prostate cancer. In 2022, we plan to initiate a Phase 1b/2 study in patients with mCRPC who have received prior treatment with abiraterone acetate. This study will begin with a Phase 1b dose escalation portion designed to evaluate safety and tolerability of NUV-422 plus enzalutamide combination and to determine a recommended Phase 2 combination dose of NUV-422. The Phase 2 portion will be an open-label, single-arm study designed to evaluate safety and efficacy of NUV-422 in combination with enzalutamide in previously treated mCRPC patients who can have measurable or nonmeasurable disease. A minimum of 20 patients with measurable disease will be enrolled into the Phase 2 portion. The primary endpoint is ORR based on radiographic tumor assessments performed per RECIST 1.1 criteria and PCWG3 guidelines as well as PSA-response rate (PSA-RR) defined as the proportion of treated patients who achieve PSA response per PCWG3 guidelines.

NUV-422-04 Phase 1b/2 Study in mCRPC: NUV-422 combination with enzalutamide

Overview of NUV-868: BET Inhibitor Program

NUV-868 for Advanced Solid Tumors

NUV-868, a BD2-selective oral small molecule BET inhibitor, inhibits BRD4, a key member of the BET family that epigenetically regulates proteins that control tumor growth and differentiation. BETs consist of two sub-domains:

BD1, the inhibition of which is known to contribute to toxicity, and BD2, the inhibition of which is known to be important for efficacy. BET inhibitors have historically targeted both BD1 and BD2 less selectively, causing gastrointestinal toxicity and bone marrow suppressive effects like thrombocytopenia. NUV-868 is almost 1,500 times more selective for BD2 than BD1 and is designed to alleviate the therapeutic limiting toxicities observed by other non-BD2 selective BET inhibitors. NUV-868 in combination with androgen receptor-directed therapies may help to overcome resistance in prostate cancer. In addition, NUV-868 in combination with PARP inhibitors may have synergistic activity to increase efficacy across multiple solid tumors. We intend to initiate a Phase 1 trial of NUV-868 in patients with advanced solid tumors in mid-2022.

BET Inhibition in Advanced Solid Tumors

The BET family of proteins have critical biological functions and are found to be altered in many human cancers (Bechter and Schoffski, 2020). Genetic screening and nonclinical studies have implicated BET proteins in both hematologic malignancies and in solid tumors. BET proteins have been shown to drive transcription of a variety of oncogenes (reviewed in (Taniguchi, 2016)). For example, BRD4 was found to be enriched at super-enhancer regions of genes that play a major role in oncogenesis (Loven et al, 2013). Inhibition of BRD4 led to defects in transcription along with decreased mRNA of super-enhancer driven genes, including the Myconcogene (Loven et al, 2013). Besides genetic alterations, overexpression and perturbation of physiological BET function have been described. Chromosomal translocations involving BRD4 and BRD3 have been identified in particularly aggressive forms of nuclear protein in testis (NUT) midline carcinomas (NMC) (French et al, 2001; French et al, 2008). Overexpression of both BRD2 and BRD4 have been observed in glioblastoma cell lines and stem cells (Pastori et al, 2014). Furthermore, gene amplification and overexpression of BRD4 have been observed in patients with some ovarian cancers (Goundiam et al, 2015). Together, these observations suggest that the BET protein family plays multiple roles in oncogenesis.

BET proteins are epigenetic readers that turn on specific genes by binding unique regions of the genome through their ability to read specific chemical tags on chromatin. In some instances, BET proteins turn on oncogenes that are abnormally expressed in a variety of human cancers, such as c-myc. C-myc is believed to play a role in promoting the growth of up to 70% of all cancers. BET inhibitors have the potential to downregulate the expression of such driver oncogenes. These observations have resulted in the generation and clinical investigation of BET inhibitors in several cancer subtypes.

BET Inhibition with Anti-Androgen Therapy

The androgen receptor (AR) plays a pivotal role in castration-resistant prostate cancer, and androgen deprivation therapy is an effective strategy for suppressing the progression of most prostate cancers (Fujita and Nonomura, 2019). Enzalutamide is a nonsteroidal antiandrogen approved for the treatment of castration-resistant and metastatic castration-sensitive prostate cancer. The drug has been studied extensively in the clinic and, along with available real-world data since its approval, shows strong evidence of its efficacy and tolerability (Scott, 2018). Many patients with castration-resistant prostate cancer eventually develop resistance to antiandrogens, including enzalutamide, through a variety of mechanisms related to the AR, including mutation and overexpression (Fujita and Nonomura, 2019). A potential therapeutic strategy to overcome antiandrogen resistance is through BET inhibition, specifically inhibition of BRD4, which has been shown to drive transcription of the AR (Faivre et al, 2017). Data from a nonclinical study showed that a dual AR and BET inhibitor reduced transactivation of the AR mutant that mediates enzalutamide resistance, inhibited proliferation of AR-positive prostate cancer cells, and suppressed growth of prostate cancer xenografts in vivo (Yu et al, 2020). Additional nonclinical data provide evidence that combining BET inhibitors with AR antagonists, such as enzalutamide, could prevent resistance to these antagonists (Asangani et al, 2016). Published results from a Phase 1b/2a study of ZEN-3694 in combination with enzalutamide in patients with mCRPC showed promising preliminary efficacy results (progression-free survival [PFS] of 9 months, with a PFS of 10 months in patients with prior progression on enzalutamide monotherapy) (Aggarwal et al, 2020).

BET Inhibition with PARP Inhibition

Poly (ADP-ribose) polymerase (PARP) inhibitors block DNA repair and replication in cancer cells. Originally, PARP inhibitors were shown to target cells deficient in breast cancer gene 1 or breast cancer gene 2 (BRCA)-dependent homologous recombination pathways (Farmer et al, 2005); however, nonclinical and clinical evidence suggests that PARP inhibitors may also be effective in cancers lacking BRCA 1/2 mutations through alternative mechanisms (Keung et al, 2020; Kim et al, 2019; Ledermann et al, 2014; Mirza et al, 2016), expanding the potential

population who might benefit from PARP inhibition. Several PARP inhibitors have now been approved for solid organ cancers, including ovarian, breast, prostate, and pancreatic cancers; however, their long-term use may be limited due to the development of resistance (reviewed in (Kim et al, 2021). Combination therapies that include drugs with other mechanisms of action are being investigated to potentially overcome common mechanisms of resistance to PARP inhibitors. Several nonclinical studies have provided evidence that BET inhibitors in combination with PARP inhibitors may provide synergistic activity against ovarian, breast, prostate, pancreatic, and small cell lung cancers and in cholangiocarcinoma (Fehling et al, 2020; Fiorentino et al, 2020; Karakashev et al, 2017; Lui et al, 2020; Miller et al, 2019; Mio et al, 2019; Pawar et al, 2018; Wilson et al, 2018; Yang et al, 2017). Two clinical studies are currently ongoing to test combination treatment using investigational BET inhibitors alongside approved PARP inhibitors: a Phase 2 study of ZEN-3694 + talazoparib in patients with metastatic or recurrent triple negative breast cancer (TNBC) (NCT03901469) and a Phase 1/2 study of PLX2853 + olaparib in patients with mCRPC (NCT04556617).

Our Solution—NUV-868

NUV-868, our lead candidate from our BET program, is a small molecule BD2-selective BETi for the treatment of solid tumors that is almost 1,500 times more selective for BD2 than BD1, which may potentially enable this molecule to reduce the toxicities associated with other non-BD2 selective inhibitors. Given BET’s promise as an oncology target, there are several BET inhibitors in development for several cancers. Other BET inhibitors that are not as selective for BD2, have been associated with toxicities including gastrointestinal and thrombocytopenia. The selectivity of several BET inhibitors that are currently in development is shown in the table below.

NUV-868 IS A MORE SELECTIVE BD2 INHIBITOR

IC50 values of NUV-868 and other BET inhibitors in development

1. Faivre et al 2020; 2. Various assays used; 3. Internal Nuvation Bio data; 4. https://ash.confex.com/ash/2020/webprogram/Paper140138.html;5.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474678/; 6. https://www.nature.com/articles/s41388-018-0150-2; 7. 2016-EORTCposter-ZenithEpigenetics.pdf

Preclinical Data

In two AML xenograft models, including a Kasumi-1 and an MV-4-11 model, NUV-868 demonstrated anti-tumor activity as compared to vehicle across three doses (5 mg/kg, 10 mg/kg and 20 mg/kg twice daily (BID)) out to

21 days, as shown in the graphs below. Notably, near complete tumor regression was observed in the 10-20 mg/kg NUV-868 groups.

NUV-868 IS HIGHLY POTENT IN KILLING AML CELLS IN IN VIVO XENOGRAFT MODELS

The pharmacodynamic effects of NUV-868 was evaluated in a systemic MV-4-11 model. NUV-868 was evaluated at a dose of 20 mg/kg BID. mRNA was isolated from control-treated and NUV-868 treated animals after 5 days of treatment. As demonstrated below, NUV-868 treatment reduced expression of tumor-promoting genes, c-Myc and BCL-2, and upregulated Hexim-1 which is indicative of BET inhibition.

NUV-868 DOWNREGULATES TUMOR PROMOTING GENES, SUCH AS C-MYC, AND UPREGULATES HEXIM-1, AN INDICATOR OF BET PROTEIN INHIBITION

The in vivo antitumor activity of NUV-868 alone and in combination with enzalutamide, an approved prostate cancer drug, was evaluated in an androgen-sensitive cell line-derived xenograft model, implanted subcutaneously in the flank of immunocompromised mice. NUV-868 was administered orally BID at 20 mg/kg. Treatment with NUV-868 alone, and in combination with enzalutamide, resulted in reduced tumor volume (p<0.001) compared to the vehicle-treated group. The combination resulted in significant growth inhibition than enzalutamide (p<0.01) or NUV-868 alone (p<0.05).

NUV-868 IN COMBINATION WITH ENZALUTAMIDE SIGNIFICANTLY INHIBITS GROWHT OF ANDROGEN-SENSITIVE PROSTATE CANCER XENOGRAFTS

NUV-868 in combination with AR directed therapies may help to overcome resistance in prostate cancer. Inhibition of BRD4 has been shown to drive transcription of the AR (Faivre et al, 2017). BET inhibitors given with AR antagonists, such as enzalutamide, may prevent resistance to these antagonists (Asangani et al, 2016).

NUV-868 as a single agent causes tumor reductions in an enzalutamide-resistant patient-derived prostate cancer xenograft model as noted in the graph below. Additionally, NUV-868 re-sensitized tumors back to enzalutamide and the combination caused deep tumor reductions in this model.

NUV-868 CAUSES TUMOR REDUCTIONS IN AN ENZALUTAMIDE-RESISTANT PATIENT-DERIVED PROSTATE CANCER XENOGRAFT MODEL

NUV-868 in combination with PARP inhibitors may have synergistic activity to increase efficacy across multiple solid tumors. Several nonclinical studies have provided evidence that BETi in combination with PARPi may provide synergistic activity against ovarian, breast, prostate, pancreatic, and small cell lung cancers (Fehling et al, 2020; Fiorentino et al, 2020; Karakashev et al, 2017; Lui et al, 2020; Miller et al, 2019; Mio et al, 2019; Pawar et al, 2018; Wilson et al, 2018; Yang et al, 2017). As noted in the figure below, NUV-868 + olaparib suppresses HR-proficient ovarian tumor growth better than olaparib alone. NUV-868 + olaparib increases double stranded DNA breaks (γH2AX) in an HR-proficient ovarian tumor model.

COMBINATION OF NUV-868 + OLAPARIB INCREASES DOUBLE STRANDED DNA BREAKS (gH2AX) IN AN HR-PROFICIENT OVARIAN TUMOR MODEL

The in vivo antitumor activity of NUV-868 alone and in combination with olaparib was evaluated in a patient-derived xenograft model, harboring a BRCA mutation derived from a patient that was previously treated with olaparib. NUV-868 was administered orally at 10 mg/kg BID. As illustrated in the graph below, while olaparib alone had very little effect on reducing tumor volume, the combination of NUV-868 and olaparib resulted in an enhanced antitumor effect when compared to the vehicle group (p<0.05).

COMBINATION OF NUV-868 AND OLAPARIB SUPPRESSES GROWTH OF A HR-DEFICIENT OVARIAN CANCER MODEL DERIVED FROM A PATIENT PREVIOUSLY TREATED WITH OLAPARIB

NUV-868’s BD2 selectivity may limit gut toxicity observed with other dual BD1 / BD2 BET inhibitors. In tissue samples from a rat small intestine treated with vehicle and non-selective BET inhibitor, ABBV-075, treatment with ABBV-075 led to a marked reduction in healthy goblet cells, which are central in protecting the mucous membrane in the GI tract (Faivre et al 2020). By comparison, a notably higher dose (30 mg/kg) of NUV-868 showed no apparent evidence of goblet cell loss in mice. These results are shown in the images below. We believe this data supports the potential for NUV-868 to limit the gastrointestinal toxicities that are associated with other BET inhibitors.

HIGH SELECTIVITY FOR BD2 OVER BD1 REDUCES THE GUT TOXICITY OBSERVED WITH OTHER BET INHIBITORS

ABBV-075 (Dual BD1 / BD2) Faivre et al 2020 NUV-868 (BD2 Selective)

The other main toxicity associated with BET inhibitors is thrombocytopenia. While most non-selective BET inhibitors lower platelet levels and cause thrombocytopenia, NUV-868 has demonstrated higher platelet levels as a function of reversing platelet suppression associated with untreated tumor burden and a lack of bone marrow-suppressive side effects. In the table below, platelet counts are measured in a MV 4-11 AML xenograft hematology panel 24 hours post the final dose of NUV-868 on day 21 across three dose levels. As compared to treatment with vehicle, platelet counts are higher for the NUV-868 cohorts across the low (5 mg/kg), medium (10 mg/kg) and high (20 mg/kg) doses.

NUV-868 REVERSES PLATELET SUPPRESSION IN AML

MV 4-11 AML Xenograft Hematology Panel

(24-hours post final dose on Day 21)

Clinical Development Plan for NUV-868 in Advanced Solid Tumors

In January 2022, the FDA cleared an IND for NUV-868 for the treatment of advanced solid tumors. With the clearance of this IND, we will be initiating a Phase 1/2 study of NUV-868 as a monotherapy and in combination with olaparib or enzalutamide in multiple tumor types. This protocol (NUV-868-01) will initiate in mid-2022 with a Phase 1 monotherapy dose escalation study in advanced solid tumor patients. A Phase 1b study will then be initiated exploring NUV-868 in combination with olaparib in previously treated ovarian cancer, pancreatic cancer, mCRPC, and TNBC patients and in combination with enzalutamide for mCRPC patients followed by a Phase 2b study to further explore safety and efficacy once the recommended Phase 2 combination dose is determined. A Phase 2 monotherapy study will also be initiated in mCRPC patients as well to further explore safety and efficacy. The primary endpoints

for the Phase 1 and Phase 1b portions will be safety, tolerability, and the determination of the recommended phase 2 monotherapy or combination dose. In the Phase 2 and 2b portions, the primary objective is PSA-RR for the mCRPC cohorts and ORR by RECIST 1.1 for the ovarian, pancreatic, and TNBC cohorts.

NUV-868-01 Phase 1/1b Study: Monotherapy & Combination

Overview of NUV-569: Wee1 Program

NUV-569 is a differentiated oral small molecule selective inhibitor of Wee1 kinase, an important regulator of DNA damage repair. Wee1 inhibitors increase the efficacy of DNA-damaging therapies by forcing cancers to replicate before they can repair their damaged DNA. NUV-569 is a highly potent Wee1 kinase inhibitor that synergizes with DNA-damaging agents to enhance cancer cell death. NUV-569 is designed to limit off-target effects by improving its kinase selectivity. NUV-569 has low inhibition of PLK1, which may improve tolerability including reduction of bone marrow and GI toxicity.

Background on Wee1 and DNA Damage Repair

DNA damage occurs frequently throughout the cell cycle, and even more frequently in rapidly dividing cancer cells, as a result of the challenge of endogenous and exogenous DNA insults and stressors. In response to DNA damage, cells have evolved a network of complex, coordinated DNA damage response (“DDR”). The DDR involves a network of DNA repair pathways and DNA damage checkpoints that are linked through various signaling mechanisms responsible for sensing and responding to specific types of DNA damage that affect DNA repair, cell cycle regulation replication stress responses and apoptosis. Defects in the DDR result in genomic instability and ultimately promote the cloning of cancer cells.

Wee1 is one of many kinases involved in regulation of signaling within the cell cycle and DNA damage identification and repair within the DDR. Specifically, Wee1 is a tyrosine kinase that allows cells with DNA damage to repair and survive by activating the G2/M cell cycle checkpoint through inhibition of the phosphorylation of CDK1/2, thus suspending the process of cell division in healthy cells. In cancer cells, tumors activate their Wee1 checkpoint in order to arrest the process of cell division, thus allowing them to repair their damaged DNA and replicate, resulting in tumor growth. Inhibition of cellular regulation and repair mechanisms within the cell cycle and DDR, such as Wee1, may potentially play a crucial role in the induction of apoptosis, improve the efficacy of DNA-damaging cancer therapies to which cancer cells have already developed multiple mechanisms of resistance, and may improve the efficacy of DNA-damaging radiation treatment. Specifically, Wee1 inhibitors force tumor cells to replicate prior to DNA repair, leading to incorrect DNA replication and ultimately tumor cell death.

Wee1 Inhibitors in Clinical Development and Limitations

We are aware of several clinical-stage and preclinical-stage Wee1 inhibitors being developed for patients with solid tumors, including product candidates from AstraZeneca, Zentalis, DebioPharm, Impact Therapeutics, and

Schrodinger. To our knowledge, there is not a commercially available Wee1 inhibitor and the most advanced Wee1 inhibitor is currently in Phase 2 development with Phase 3s in the planning stages. There are 15 industry sponsored ongoing trials evaluating molecules targeting Wee1 inhibitors with several Phase 1 signal-seeking basket trials are ongoing (ClinicalTrials.gov; Citeline).

Adavosertib (AZD1775), which is manufactured by AstraZeneca (AZD), is currently the most advanced, being studied as a monotherapy and in combination with chemotherapy, anti-PD-L1 (durvalumab), and PARPi. AZD is planning a Phase 3 pivotal study for adavosertib in uterine carcinoma. Data from adavosertib Phase 1 and 2 trials have been published and have demonstrated the following efficacy data:

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Adavosertib with multiple chemotherapy regimens in platinum-refractory ovarian cancer, Phase 2: NCT02272790

In the 94 pts treated (median treatment duration 3 months; range 0–16 months), outcomes were greatest with adavosertib (weeks [W]1–3) + carboplatin cohort with ORR of 67% and median PFS (mPFS) of 10.1 months for this cohort (Moore et al, ASCO, 2019).

•

Adavosertib monotherapy in advanced refractory solid tumors with CCNE1 amplification; Phase 2: NCT03253679

ORR of 25.9% and a median PFS of 4.7 mos; OS rate was 55% (Fu et al., AACR, 2021)

•

Adavosertib + durvalumab in advanced solid tumors; Phase 1: NCT02617277

Two confirmed PR (soft tissue and esophageal tumors) with DCR of 36% (Patel et al, ASCO 2019)

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Adavosertib + olaparib in PARPi-resistant ovarian cancer; Phase 2 (EFFORT): NCT03579316 (Westin et al, ASCO 2021)

Adavosertib monotherapy demonstrated ORR of 23%, SD of 66%, and mPFS of 5.5 mos

Adavosertib + olaparib demonstrated ORR of 29%, SD of 66%, and mPFS of 6.4 mos

•

Adavosertib vs. active monitoring for TP53 and RAS mutant metastatic colorectal cancer, Phase 2: EudraCT Number 2012-005111-1

Adavosertib arm demonstrated a mPFS of 3.6mos (HR 0.35; p=0.0022) with an immature mOS of 13.1 mos while the active monitoring arm demonstrated a mPFS of 1.8mos and mOS of 11.3 mos (Seligmann et al, ESMO 2021)

•

Adavosertib + carboplatin in Platinum-refractory ES-SCLC; Phase 2: NCT02937818

No responses observed; 30% of pts had disease control at 12 weeks with mPFS of 2.6 mos and mOS of 4.67 mos (Results posted on clinicaltrials.gov)

Although AZD1775 has shown encouraging clinical efficacy data in patients with uterine serous carcinoma and ovarian and pancreatic cancers, we believe it has the following limitations with regards to its safety profile.

•

Potent inhibition of polo-like kinase 1 (“PLK1”). PLK1 is a cell kinase that phosphorylates Wee1 as the cell approaches the G2/M cell cycle checkpoint thus promoting and enabling the cell replication process. Potent PLK1 inhibition may be responsible for gastrointestinal and bone marrow toxicity. AZD1775 is a highly potent inhibitor of PLK1, having demonstrated an IC50 of 15 nanomolar in biochemical studies, and thus may contribute to bone marrow and GI toxicity.

•

Liver enzyme inhibition.AZD1775 inhibits liver enzyme CYP3A4, which is responsible for elimination of drug and drug metabolites from the body.

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Tolerability.In a Phase 1 clinical trial in patients with locally advanced pancreatic cancer, AZD1775 in combination with gemcitabine, an FDA-approved chemotherapy, and radiation, eight patients (24%) experienced a dose-limiting toxicity, most commonly anorexia, nausea, or fatigue, thus preventing continuous dosing of AZD1775.

Other Wee1 inhibitors are also currently in early phase development. Zentalis has multiple ongoing studies for ZN-c3 as a monotherapy and in combination. The company is pursuing a fast-to-market strategy in uterine serous

carcinoma (USC), where the ongoing Phase II trial has registrational intent. Zentalis is also planning to start a tumor agnostic biomarker-driven Phase II trial with registrational potential. In a Phase 1/2 study of ZN-c3 in advanced solid tumors an ORR of 43% in the USC population was observed (Zentalis PR 6/28/2021; Zentalis Nov 2021 presentation). Phase I solid tumor basket studies are ongoing for Debio-0123 + carboplatin (Debiopharm) and IMP7068 monotherapy (Impact Therapeutics) (ClinicalTrials.gov; Citeline).

Our Solution—NUV-569

NUV-569, our lead candidate from our Wee1 program, is a differentiated oral small molecule selective inhibitor of Wee1 kinase, an important regulator of DNA damage repair. NUV-569 is a highly potent Wee1 kinase inhibitor that synergizes with DNA-damaging agents to enhance cancer cell death. NUV-569 is designed to limit off-target effects by improving its kinase selectivity. NUV-569 has low inhibition of PLK1, which may improve tolerability including reduction of bone marrow and GI toxicity. Specifically, in our preclinical studies NUV-569 demonstrated single digit nanomolar inhibition of Wee1, an approximate 45-fold lower PLK1 inhibition than AZD1775 and 9-fold lower potency in inhibiting proliferation of rat gut epithelial cells (IEC6) than AZD1775, which we believe suggests NUV-569 may have better GI tolerability than AZD1775. The following table demonstrates the favorable potency and selectivity profile of NUV-569 compared to AZD1775.

NUV-569’S HIGHLY POTENT AND SELECTIVE PROFILE = LESS TOXICITY

Preclinical Results

Wee1 inhibition can synergize with chemotherapy and radiation therapy leading to mitotic catastrophe and eventually, cell death. In an in vitro preclinical study of pancreatic cancer in combination with gemcitabine and radiation therapy, we observed NUV-569's anti-tumor activity and potency in inducing apoptosis in pancreatic cancer cells, as shown in the figure below.

NUV-569 FURTHER ENHANCES CANCER CELL DEATH IN COMBINATION WITH BOTH GEMCITABINE AND RADIATION

Enhancement of chemotherapy cytotoxicity by NUV-569 was observed in additional pancreatic models and triple negative breast cancer (TNBC) models. As demonstrated in the figure below, the cytotoxicity of SOC agent, gemcitabine, was enhanced by NUV-569 addition in several pancreatic cancer cell lines. Similarly, the addition of NUV-569 enhanced the cytotoxicity of SOC, carboplatin, in several TNBC models.

NUV-569 SYNERGIZES WITH SOC GEMCITABINE IN PANCREATIC CANCER CELLS AND CARBOPLATIN IN BREAST CANCER CELLS TO ENHANCE CANCER CELL DEATH

The in vivo antitumor activity of NUV-569 alone and in combination with carboplatin, was evaluated in a TNBC cell line-derived xenograft model. NUV-569 was administered orally BID at 30 mg/kg and 70 mg/kg, in combination with carboplatin. As illustrated in the figure below, while carboplatin alone had very little effect on reducing tumor volume, the combination of NUV-569 and carboplatin resulted in an enhanced antitumor effect when compared to the vehicle-treated and the carboplatin-treated group. In an in vivo model of ovarian cancer, the combination treatment of

NUV-569 and gemcitabine resulted in tumor regressions when compared to the vehicle-treated and gemcitabine-treated groups.

NUV-569 SYNERGIZES WITH SOC CARBOPLATIN AND GEMCITABINE TO INHIBIT TUMOR GROWTH IN BREAST AND OVARIAN CANCER XENOGRAFTS

Next Steps

We intend to submit an IND for NUV-569 by the end of 2022 and initiate Phase 1 trials in patients with advanced solid tumors following IND clearance. We are also continuing to evaluate additional Wee1 inhibitors for the potential to increase efficacy and further widen the therapeutic window.

Overview of Our A2AAdenosine Receptor Program

NUV-1182, an A2A adenosine receptor inhibitor, boosts immune function and may enhance the efficacy of IO-targeted therapies. A2Aadenosine receptor plays multiple critical roles in human physiology and pathophysiology including anti-cancer immunity. Accumulation of adenosine in the tumor microenvironment may be a critical factor in limiting the activity of currently available immuno-oncology drugs, including anti-PD1/PD-L1 drugs and anti-cancer chimeric T cells. Targeting A2A adenosine receptor may overcome this blockade, leading to improved anti-cancer activity in tumors which are resistant to immuno-oncology drugs and T cell therapies.

In our preclinical studies, our adenosine receptor inhibitors, NUV-035, NUV-115 and NUV-1182, have high affinity for the A2A adenosine receptor demonstrating single digit nanomolar binding affinity. Our preclinical studies demonstrate that NUV-035, NUV-115 and NUV-1182 have desirable pharmacokinetic profiles, with high exposure following a single oral dose in mice. Furthermore, in a melanoma cell line derived xenograft model, daily oral dosing with NUV-1182 enhanced the tumor suppressive activity when combined with either an anti-PD1 antibody or an anti-PD-L1 antibody.

NUV-1182 IS A POTENT AND SELECTIVE A2A ADENOSINE RECEPTOR INHIBITOR

The in vivo antitumor activity of NUV-1182 and other adenosine inhibitors include competitor molecules such as AB-928 (Arcus Biosciences) and CPI-444 (Corvus Pharmaceuticals), was evaluated in a melanoma cell line derived syngeneic xenograft model. As demonstrated in the figure below, NUV-1182 enhanced the tumor suppressive activity when combined with an anti-PD1 antibody, compared to anti-PD1 alone. NUV-035 and NUV-115, other adenosine receptor antagonists, also demonstrated enhanced anti-tumor activity when combined with anti-PD1.

NUVATION A2A ADENOSINE RECEPTOR INHIBITORS INCREASE THE ANTI-TUMOR ACTIVITY OF IMMUNE CHECKPOINT INHIBITORS IN AN IN VIVO MELANOMA XENOGRAFT MODEL

Our A2A adenosine receptor inhibitors have an attractive PK profile, with good oral bioavailability and do not effectively cross the blood-brain barrier. Brain to plasma ratios range from 0.02 to 0.2, demonstrating that our compounds do not effectively cross the blood-brain barrier. Our compounds are currently being tested in several syngeneic tumor models, with tumor volume and tumor infiltrating immune cell profiling and mechanism of action studies.

NUVATION A2A INHIBITORS HAVE AN ATTRACTIVE ORAL PHARMACOKINETIC PROFILE AND DO NOT CROSS THE BLOOD-BRAIN BARRIER

Overview of Our DDC Technology Platform

The foundations of our DDCs are built by employing tissue-targeting small molecules fused to anti-cancer warheads of existing drugs with well-understood mechanisms of action. For example, our PARP-AR DDC, NUV-1156, is composed of the AR binder Xtandi (enzalutamide) fused to the warhead of the PARP inhibitor Lynparza® (olaparib) to address advanced stage prostate cancers with the potential to move into earlier lines typically treated with surgical prostatectomy. Our PARP-ER DDC, NUV-1176, is composed of a PARP inhibitor warhead that is fused to the binding domain of an ER-targeting small molecule to address ER+ breast and ovarian cancer. NUV-1511 is a DDC that fuses a targeting agent to a widely used chemotherapy agent. In preclinical models, NUV-1156 and NUV-1176 potently kill tumor cell lines without killing healthy cells in the bone marrow and the gastrointestinal tract. In in vivo models of prostate and breast cancer, NUV-1511 caused significant tumor growth inhibition and regression when compared to the targeting ligand or the chemotherapy-treated groups. We intend to nominate our first clinical development candidate from our DDC platform in the second half of 2022.

Traditional Cancer Therapeutics

Cancer treatment has traditionally included chemotherapy, radiation, surgery or a combination of these approaches. Over the last twenty years, new paradigms of cancer research and treatment have emerged to address the limitations of existing treatments. Monoclonal antibodies, or proteins that bind to antigen targets on tumor cells and inhibit tumor growth, represent one of the most successful approaches. More recently, engineered versions of monoclonal antibody-based therapies have emerged, including ADCs and bispecific antibodies, which collectively aim to exert the tumor-specific power of monoclonal antibodies to drive a larger clinical impact than conventional approaches.

ADCs

ADCs exert their antitumor activity by using monoclonal antibodies to deliver potent cytotoxins directly to tumors. ADCs have three primary components: (1) a monoclonal antibody that recognizes an antigen on the tumor and is responsible for directing the therapy to the tumor; (2) a cytotoxic molecule that causes cell death, typically by interrupting a critical cell function such as replication; and (3) a linker that attaches the cytotoxin to the antibody. The two main attributes of ADC therapeutics are:

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Targeting Only Diseased Tissue. ADCs are designed with a monoclonal antibody that binds to antigen targets that are preferably expressed on the outside of tumor cells and not on healthy tissues.

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Increased Therapeutic Window. The cytotoxin payload of the ADC attached to the targeting monoclonal antibody is directed to specific cancer epitopes on the cell surface, allowing an improved therapeutic index by delivering the cytotoxin to the cancer more than non-target tissues.

As a result of these two main attributes, ADCs can offer greater antitumor potency while still maintaining an acceptable tolerability profile. Despite these benefits, limitations remain, including:

•

Intravenous Delivery. ADCs are administered intravenously into the systemic circulation where they home to tumors. While the cytotoxic payload is designed to only cleave when internalized by the targeted

tumor cell, challenges with linker chemistry can result in instability and cause the cytotoxic payload to be released within circulation, causing systemic toxicities.

•

Inability to Reach Intracellular Targets. Monoclonal antibodies are not capable of penetrating the cell membrane due to their size and are limited to targeting antigens that are present on the surface of a tumor cell.

•

Complex Manufacturing. ADCs are complex biologics that require the refinement of several properties in tandem and are expensive to manufacture. They often present significant manufacturing challenges, particularly at a large scale, and generally have a lower gross margin than a small molecule.

Our Solution—DDCs

Our DDC platform has generated orally bioavailable or IV small molecules that fuse the binding domains of two different drugs to target two different targets, simultaneously. Our platform leverages our drug discovery and chemistry expertise to find the minimum target binding sites of drug X and drug Y and fuse them together, while maintaining activity. Our DDCs are designed to selectively bind to intracellular as well as surface cell membrane targets that are expressed more highly in specific target tissues and to potently deliver anti-cancer warheads to these target tissues. The figure below depicts our DDC approach.

DRUG-DRUG CONJUGATES ARE DESIGNED TO BIND TWO DIFFERENT TARGETS SIMULTANEOUSLY

Key benefits of our DDCs include:

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Tissue-selective targeting improves therapeutic index vs. untargeted warhead;

•

Oral or IV delivery;

•

Binds intracellular and cell membrane targets;

•

Highly cell permeable; and

•

Simpler and less expensive to manufacture

We believe our DDC technology will be broadly applicable and can be replicated across many other existing therapies to transform the SOC across multiple indications for oncology.

We are currently in preclinical development and intend to nominate our first lead clinical development candidate in the second half of 2022.

NUV-1156: Targeting AR and PARP for Prostate Cancer

NUV-1156 is an oral small molecule that is composed of a PARP inhibitor warhead that is fused to the binding domain of an AR-targeting small molecule. In preclinical models, NUV-1156 demonstrated the ability to kill tumor

cells associated with high AR-expression, sparing healthy cells in bone marrow and the gastrointestinal tract that do not have high levels of AR expression.

We are exploring the use of PARP-AR DDCs in prostate cancer, initially focused on mCRPC where there is an urgent unmet medical need. The ability of our PARP-AR DDC to kill prostate cancer cells resistant to current therapies suggests that this drug could play a role in advanced stage prostate cancer, particularly in the Xtandi and Zytiga resistant setting.

Additionally, we believe PARP-AR DDCs could play a role in early-stage prostate cancer where the SOC for newly diagnosed, early-stage patients is radical prostatectomy and radiation therapy which often results in serious side effects, including urinary incontinence, erectile dysfunction and fecal incontinence. We believe a PARP-AR DDC could potentially allow early-stage patients to avoid surgical radical prostatectomy and radiation therapy, which we believe could be a major transformation for the treatment of prostate cancer.

NUV-1156 Drug Design and Mechanism of Action

Our PARP-AR DDCs kill cells via an AR-targeted mechanism. NUV-1156 consists of the warhead from the PARP inhibitor Lynparza (olaparib) which is fused to an AR-binding domain of Xtandi (enzalutamide). We believe this drug design will potentially allow for a PARP inhibitor to be potently delivered to high AR-expressing tumors, like prostate cancer, while potentially reducing the off-target toxicities associated with other PARP inhibitors, namely toxicity in the bone marrow and gastrointestinal tract, which are low AR-expressing tissues. The figure below depicts the components of NUV-1156.

NUV-1156 IS A DDC THAT TARGETS AR AND PARP

PARP Inhibitor Overview

Mechanisms of Action

The rapid cell division and attendant required DNA replication seen in cancers causes an increase in single stranded DNA breaks. PARP is the most abundant DNA repair enzyme in the nucleus. Because cancers have an increase in DNA breaks related to their rapid division, their DNA breaks must be repaired by PARP if the cancers are to be able to faithfully replicate their DNA. Furthermore, approximately one-third of tumors have intrinsic DNA repair defects, such as BRCA-mutations and other HR-D. Tumors with HR-D struggle to repair and faithfully replicate DNA. When HR-D is combined with PARP inhibition, DNA repair is so compromised that cancer cells can no longer survive. This is the fundamental reason that all current commercially available PARP inhibitors have superior outcomes in HR-D vs. homologous recombination proficient (“HR-P”) cancers. This mechanism of action of PARP inhibitors has been shown to further enhance the effects of DNA-damaging anti-cancer therapies, such as chemotherapy or radiation.

Existing PARP Inhibitors and Our Opportunity

PARP inhibitors Lynparza (olaparib), Rubraca (rucaparib camsylate), Zejula (niraparib) and Talzenna (talazoparib tosylate) have been approved by the FDA for multiple oncology indications, including ovarian, breast, prostate and pancreatic cancer. Sales of these FDA-approved PARP inhibitors were approximately $1.7 billion in 2019 and are forecasted to be over $7.0 billion in 2025, with Lynparza (olaparib) accounting for $1.2 billion and over $4.0 billion in the 2019 and 2025 totals, respectively.

Despite the commercial success of PARP inhibitors, broader adoption is limited by their high rates of GI and bone marrow toxicity which is largely a result of off-target cell killing. Adverse grade 3-4 events from this class of drugs include anemia, thrombocytopenia, neutropenia and alopecia. Other common adverse reactions include nausea, vomiting, diarrhea, fatigue and decreased appetite. We believe a DDC that fuses the warhead of a PARP inhibitor to an AR-binding domain of Xtandi (enzalutamide) will allow us to take advantage of the powerful and proven selectivity of AR therapy in AR-driven tumors by possibly minimizing the toxicities associated with PARP inhibitors in low AR-expressing cells in the gastrointestinal tract and bone marrow and broadening the tumor types (both HR-D and HR-P) in which this approach could be effective.

AR Selectively Expressed in AR-Specific Tissue

The growth and survival of prostate cancer cells depends heavily on the AR. Testosterone fuels prostate cancer cell growth by using the binding of androgens to ARs to trigger abnormal cell growth and tumor progression. In men, AR protein expression is limited primarily to the sex organs, with medium to high AR expression levels seen across the testis, prostate, epididymis and seminal vesicle tissues. In contrast, AR expression is either low or not detected in the bone marrow and the gastrointestinal tract, two organs strongly associated with PARP-inhibitor toxicity.

Existing AR Inhibitors and Our Opportunity

Xtandi (enzalutamide) is an AR inhibitor that acts on different steps in the AR signaling pathway. Xtandi has been shown to potently bind to the AR and effectively compete for this receptor against its native ligand testosterone. Zytiga (abiraterone) is an inhibitor of androgen synthesis and results in decreased AR signaling through ligand depletion. Between 15% and 25% of patients do not respond to either AR signaling pathway inhibitors abiraterone or enzalutamide, and the vast majority of the responsive patients will ultimately become resistant, resulting in limited survival. Zytiga was approved for the treatment of mCRPC in 2011 and generated sales of $2.8 billion in 2019. Xtandi was approved for the treatment of mCRPC in 2012 and generated sales of approximately $3.7 billion in 2019.

Prostate Cancer Overview

See “Prostate Cancer Overview” for NUV-422, above.

Preclinical Data

In an Xtandi (enzalutamide)-resistant prostate cancer model, NUV-1156 demonstrated the ability to inhibit growth of enzalutamide-resistant prostate cancer cells more than Lynparza (olaparib), Xtandi (enzalutamide) or the combination of olaparib and enzalutamide. Cell proliferation, as measured by IC50, was more than 30,000 nanomolar for enzalutamide, nearly 8,000 nanomolar for olaparib and over 6,000 nanomolar for olaparib + enzalutamide. In contrast, NUV-1156 had an IC50 of 201 nanomolar, demonstrating that forming a DDC of a PARP inhibitor with a targeting agent that targets a receptor highly expressed in prostate cancer leads to orders of magnitude superior therapeutic effects compared to either agent alone, or even a combination of the two agents given in their native state. These results are shown in the table below.

NUV-1156 DDC POTENTLY KILLS PROSTATE CANCER CELLS RESISTANT TO CURRENT SOC

As shown in the figure below, unlike Lynparza (olaparib) which is only approved in HR-D cancers and is not effective in HR-P tumors, NUV-1156 potently kills prostate cancer cells and triple negative breast cancer cells, whether they are HR-D or HR-P. We believe this underscores the superior potency of NUV-1156 as well as the potential for NUV-1156 to be used more broadly than current commercially available PARP inhibitors, which are limited to HR-D driven tumor types.

UNLIKE CURRENT PARP INHIBITORS, NUV-1156 KILLS HR-DEFICIENT AND HR-PROFICIENT CANCER CELL LINES WITH EQUALLY HIGH POTENCY

In an Xtandi (enzalutamide)-resistant prostate cancer cell model, NUV-1156 demonstrated the ability to kill cancer cells while sparing healthy gastrointestinal cells in vitro. In the figure below, the grey bars represent prostate cancer cells (22Rv1 prostate cancer cell line model) and the blue bars represent gastrointestinal epithelial cells, or healthy tissue (IEC-6, a standard model for healthy rat gastrointestinal epithelial cells). In this enzalutamide-resistant model, Xtandi (enzalutamide) had no toxicity on IEC-6 gastrointestinal cells but had little efficacy on Xtandi-resistant prostate cancer cells, a suboptimal effect. Lynparza (olaparib) fared even worse, having little efficacy on Xtandi-resistant prostate cancer, but killing gastrointestinal epithelial cells three times more potently than it kills prostate

cancer cells. As compared to Lynparza (olaparib) and Xtandi (enzalutamide), NUV-1156 was observed to be significantly more potent and selective for prostate cancer cells than either Lynparza or Xtandi alone, killing Xtandi-resistant prostate cancer with low nanomolar potency while having little toxicity on healthy gastrointestinal epithelial cells. These results are shown in the figure below.

NUV-1156 KILLS ENZALUTAMIDE-RESISTANT PROSTATE CANCER (HIGH AR) CELLS BUT SPARES HEALTHY COLON (LOW AR) CELLS IN VITRO

In addition to NUV-1156, several other PARP-AR DDCs have demonstrated potent growth inhibition of prostate cancer cells lines, while sparing healthy gastrointestinal cells in vitro. In the figure below, the in vitro IC50 values for several PARP-AR DDCs are shown ranging from less than <150 nM to <250 nM in the prostate cancer cell line 22RV1, and from <30 nM to <150 nM in the prostate cancer cell line LNCaP. In contrast, in vitro IC50 values for the normal gastrointestinal epithelial cell line IEC6 are >30,000 nM. This leads to 22RV1/IEC6 selectivity ratios of up to 250-fold.

NEW AR-DDCS ARE EVEN MORE POTENT AND SELECTIVE THAN NUV-1156 AT KILLING PROSTATE CANCER CELLS (22RV1 AND LNCAP) COMPARED TO GUT EPITHELIAL CALLS (IEC6)

Thus, in preclinical models, PARP-AR DDCs have demonstrated the ability to kill high AR-expressing tissues like prostate cancer while sparing low AR-expressing tissues like healthy gastrointestinal epithelial cells. This level

of specificity may potentially allow a prostate-specific DDC to kill prostate cancer cells in the prostate while sparing other low AR-expressing cells like nerve and blood vessel cells, which are directly impacted during prostate ablation procedures like radical prostatectomy and radiation therapy, the current SOC for early stage prostate cancer. While prostatectomy and radiation ablation are potentially curative, these interventions can result in serious side effects, including erectile dysfunction, urinary incontinence and/or fecal incontinence, or other sequelae of invasive surgery, as a result of damage to the tissues surrounding or within the prostate like healthy blood vessels and nerve cells. We believe that PARP-AR DDCs have the potential to become a non-surgical/non-radiation curative alternative for these patients, representing a large potential market opportunity.

NUV-1176: Targeting ER and PARP for ER+ Breast Cancers

NUV-1176 is an oral small molecule that is composed of a PARP inhibitor warhead that is fused to the binding domain of an ER targeting small molecule. In preclinical models, NUV-1176 potently kills both HR-D and HR-P ER+ tumor cell lines without killing healthy gastrointestinal epithelial cells. We are exploring the use of NUV-1176 for ER+ breast cancer and ovarian cancer. We are currently in preclinical development and intend to nominate our first lead clinical development candidate in the second half of 2022.

Overview of ER+ Breast Cancers

See “Overview of Breast Cancer” for NUV-422, above.

ER Selectively Expressed in ER-Specific Tissue

In women, ER protein expression is limited primarily to the sex organs, with median to high ER expression levels seen across the fallopian tube, breast, vagina, uterine, cervix and endometrium tissues. In contrast, ER expression is either low or not detected in the bone marrow and intestine, organs strongly associated with current commercially available PARP-inhibitor toxicity. Given that ER is more highly expressed in tumors that arise in female sex organ tissues like breast or ovarian cancer than tissues like the bone marrow or gastrointestinal tract, we believe an ER-targeted DDC will have improved anti-tumor activity while limiting the toxicity profile associated with current commercially available PARP inhibitors.

Preclinical data

We have developed NUV-1176, an ER-targeted DDC that is composed of a PARP inhibitor warhead that is fused to the binding domain of an ER-targeting small molecule. In preclinical models, as shown below, NUV-1176 has demonstrated the ability to potently kill both HR-D and HR-P ER+ tumor cell lines with minimal effects on healthy gastrointestinal cells.

NUV-1176, AN ER-TARGETED DDC, POTENTLY KILLS BOTH HR-D AND HR-P ER+ BREAST CANCER CELLS WITH MINIMAL EFFECTS ON HEALTHY COLON CELLS

NUV-1511: A Targeted DDC Derived from a Widely Used Chemotherapy Agent for Prostate and Breast Cancer

NUV-1511 is a DDC that fuses a targeting agent to a widely used chemotherapy agent that suppresses the growth of prostate and breast cancer. We believe NUV-1511 may be able to limit the adverse side effects of the chemotherapy agent while effectively targeting prostate and breast tumors.

Preclinical data

The anti-tumor efficacy of NUV-1511 was evaluated in a prostate cancer cell line derived xenograft model. As shown in the figure below, NUV-1511 demonstrated significant tumor growth inhibition with IV dosing and two different dosing regimens. Of note, the DDC targeting ligand or chemotherapy agent alone did not inhibit tumor growth to the extent of NUV-1511.

NUV-1511 was also examined in an ER+/PR+ breast cancer cell line derived xenograft model. As shown below, both dosing regimens of NUV-1511 caused significant tumor regressions. The DDC targeting ligand or the chemotherapeutic agent were less effective in inhibiting tumor growth.

NUV-1511, A DDC DERIVATIVE OF A WIDELY USED CHEMO AGENT, CAUSES REGRESSIONS OF PROSTATE AND BREAST CANCER XENOGRAFTS

DDCs have the Potential to Achieve Significant Plasma Exposure Following Oral Dosing in Preclinical Models

As shown in the figure below, following single oral dosing in mice, several new DDCs, with various nuclear hormone receptor targeting and various warheads, have achieved enhanced plasma concentrations and exposure compared with NUV-1156, with plasma exposure, (AUC), exceeding 1000 nM*hr.

NEW DDCS HAVE IMPROVED ORAL BIOAVAILIBILITY COMPARED WITH NUV-1156

Intellectual Property

Our commercial success depends in large part on our ability to obtain and maintain patent protection in the U.S. and other countries for our investigational products, to operate without infringing valid and enforceable patents and proprietary rights of others, and to prevent others from infringing on our proprietary or intellectual property rights.

We seek to protect our proprietary position by pursuing patents that cover the compositions of matter, formulations, methods of use or methods of synthesis relating to our investigational products, as well as other discoveries, technologies, inventions and improvements that may be commercially important to our business. We generally seek patent protection in the U.S. and in foreign jurisdictions such as Australia, Brazil, Canada, Europe, China, Japan, India, Israel, New Zealand, Mexico, Singapore, South Africa, Republic of Korea, Hong Kong and Taiwan.

As of December 31, 2021, our company-owned patent portfolio consists of approximately 6 issued U.S. patents, 35 pending U.S. patent applications, 9 pending PCT applications, and 168 pending foreign patent applications.

NUV-422, our lead investigational product, is covered by an issued patent in the U.S. that claims the composition of matter of NUV-422. This patent is expected to expire in 2039 (not including patent term extension that

may be available to extend the term of the patent). Corresponding patent applications covering the composition of matter of NUV-422 are pending in certain foreign jurisdictions. We also have pending patent applications directed towards specific therapeutic indications and certain solid forms of NUV-422, which if issued, are anticipated to expire in 2042.

Because of the extensive time required for development, testing and regulatory review of an investigational product, it is possible that, before a product can be commercialized, any patent protection for such product may expire or remain in force for only a short period following commercialization, thereby reducing the commercial advantage the patent provides. In the U.S., the term of a patent covering an FDA-approved product may, in certain cases, be eligible for a patent term extension under the Hatch-Waxman Act as compensation for the loss of patent term during the FDA regulatory review process. The period of extension may be up to five years, but cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval. Only one patent among those eligible for an extension may be extended and the amount of available extension to any patent term extension-eligible patent depends on a variety of factors, including the date on which the patent issues and certain dates related to the regulatory review period. Possible extensions may be available in Europe and in certain other jurisdictions to extend the term of a patent that covers an approved product. While we intend to seek patent term extensions in any jurisdictions where they are available to us, there is no guarantee that the applicable authorities, including the FDA or the USPTO, will agree with our assessment of whether such extensions should be granted, and even if granted, the length of such extensions.

We also rely on trade secrets to protect our technology and product candidates, especially where we do not believe patent protection is appropriate or obtainable. We seek to protect our proprietary information, in part, using confidentiality agreements with our partners, collaborators, employees and consultants.

Our commercial success may depend in part on not infringing upon the proprietary rights of third parties. It is uncertain whether the issuance of any third party patent would require us to alter our development or commercial strategies, obtain licenses or cease certain activities. Our failure to obtain a license to proprietary rights that we may require to develop or commercialize our future drug products may have a material adverse impact on us.

The intellectual property positions for biotechnology and pharmaceutical companies like us are generally uncertain and can involve complex legal, scientific and factual issues. For information regarding the risks related to our intellectual property, please see “Risk Factors—Risks Related to Our Intellectual Property.”

Manufacturing and Supply

We do not own or operate, and currently have no plans to establish, any manufacturing facilities. We rely, and expect to continue to rely, on third parties for the manufacture of our investigational products for preclinical and clinical testing, as well as for commercial manufacture if any of our investigational products obtain marketing approval. We also rely, and expect to continue to rely, on third parties to package, label, store and distribute our investigational products, as well as for our commercial products if marketing approval is obtained. We believe that this strategy allows us to maintain a more efficient infrastructure by eliminating the need for us to invest in our own manufacturing facilities, equipment and personnel while also enabling us to focus our expertise and resources on the development of our investigational products.

To date, we have obtained APIs and drug product for our investigational products from single-source third-party CMOs. We are in the process of developing our supply chain for each of our investigational products and intend to put in place framework agreements under which CMOs will generally provide us with necessary quantities of API and drug product on a project-by-project basis based on our development needs, and which agreements will provide us with intellectual property rights necessary to conduct the business. We seek to use a different CMO for each investigational product and will consider further diversification of drug product and supply organizations as circumstances warrant. Overall, as we advance our investigational products through development, we will start by seeking multiple sources for raw materials and address other potential points of concern over time.

Commercialization

We intend to retain significant development and commercial rights to our investigational products and, if marketing approval is obtained, to commercialize our investigational products on our own, or potentially with a partner, in the U.S. and other regions. We intend to build the necessary infrastructure and sales, marketing and commercial product distribution capabilities for the U.S., and potentially other regions, following further advancement

of our investigational products. Clinical data, the size of the addressable patient population and the size of the commercial infrastructure and manufacturing needs and economics related to the foregoing may all influence or alter our commercialization plans.

Competition

The pharmaceutical and biotechnology industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products. While we believe that our technology, development experience and scientific knowledge provide us with competitive advantages, we face potential competition from many different sources, including large pharmaceutical and biotechnology companies, academic institutions, government agencies and other public and private research organizations that conduct research, seek patent protection and establish collaborative arrangements for the research, development, manufacturing and commercialization of cancer therapies. Any investigational products that we successfully develop and commercialize will compete with new therapies that may become available in the future.

We compete in the segments of the pharmaceutical, biotechnology and other related markets that develop small molecules and drug conjugates as treatments for cancer patients. There are many other companies that have commercialized and/or are developing such treatments for cancer including large pharmaceutical and biotechnology companies, such as AstraZeneca plc, Bristol-Myers Squibb Company (“BMS”), Eli Lilly, Merck, Novartis Pharmaceuticals Corporation ("Novartis"), Pfizer, Regeneron Pharmaceuticals, Inc. in partnership with Sanofi Genzyme (“Sanofi”) and Roche.

For our CDK2/4/6 and/or CDK 2 alone inhibitors, we are aware of several clinical-stage and preclinical stage CDK inhibitors being developed as monotherapy or in combination with other drugs, including, but not limited to, product candidates being developed by Pfizer, Fosun Pharma, Cyclacel, Adastra/Cothera Bio, Blueprint Medicines, Aucentra, ARC Therapeutics, and Regor Therapeutics.. In addition, CDK 4/6 inhibitors from Pfizer, Novartis and Eli Lilly are commercially available for patients with breast cancer and are also in clinical trials for other types of cancer. G1 Therapeutics received approval with its CDK4/6 inhibitor to decrease the incidence of chemotherapy-induced myelosuppression extensive-stage small cell lung cancer and is exploring trilaciclib in other oncology indications, including additional breast indications.

For our BET inhibitor, we are aware of several clinical-stage BET inhibitors being developed for patients with hematological malignancies and solid tumors, including, but not limited to, product candidates from Constellation Pharma/MorphoSys Company, Plexxikon, Zenith Epigenetics, Incyte, Boehringer Ingelheim, Abbvie, BMS, Jacobio, Foghorn Therapeutics, Sierra Oncology, Betta Pharmaceuticals and Ranok Therapeutics. In addition, there are a number of BET inhibitors at the preclinical stage. To our knowledge, there is currently no commercially available BET inhibitor and the most advanced BET inhibitor is in a Phase 3 clinical trial (pelabresib for myelofibrosis).

For our Wee1 inhibitor, we are aware of several clinical-stage and preclinical-stage Wee1 inhibitors being developed for patients with solid tumors, including product candidates from AstraZeneca, Zentalis, DebioPharm, Impact Therapeutics, and Schrodinger. To our knowledge, there is currently no commercially available Wee1 inhibitor and the most advanced Wee1 inhibitor is currently in Phase 2 development with Phase 3s in the planning stages.

For our adenosine receptor antagonist, we are aware of several other clinical-stage adenosine antagonists being developed, including, but not limited to, product candidates from Ligand Pharmaceuticals/Corvus Pharmaceuticals, CStone Pharmaceuticals, Dizal (Jiangsu) Pharmaceuticals, Arcus Biosciences/Gilead, Evotec/Exscientia, Incyte, iTeos Therapeutics, Palobiofarma, and Novartis. To our knowledge, there is currently no adenosine receptor antagonist approved for the treatment of cancer and the most advanced adenosine receptor antagonist is in Phase 2 development.

Our DDC programs targeting hormone receptors in cancer cells apply to types of cancer that may depend on hormone receptors for their growth, such as ER+ mBC, prostate cancer and ovarian cancer. All of these tumors have commercially available therapies including therapies from AstraZeneca, Bayer, Clovis Oncology, Dendreon, Eli Lilly, GSK, Janssen Pharmaceutical Companies, Novartis, Pfizer, Roche and Sanofi. In addition, many new product candidates are being developed as monotherapy or in combination with other drugs for these tumors type, and the most advanced of these development programs are in Phase 3 and may lead to near-term regulatory approval and subsequent commercialization. These development programs include those of the companies named above as well as numerous others. Some of these drugs and drug candidates target hormone receptor pathways directly, while many others may affect cancer cell growth through different mechanisms of action.

Many of the companies against which we are competing or against which we may compete in the future have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved drugs than we do. Mergers and acquisitions in the pharmaceutical, biotechnology and diagnostic industries may result in even more resources being concentrated among a smaller number of our competitors. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and enrolling subjects for our clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

We could see a reduction or elimination of our commercial opportunity if our competitors develop and commercialize products that are safer or more effective, have fewer or less severe side effects, are more convenient or are less expensive than any products that we or our collaborators may develop. Our competitors also may obtain FDA or foreign regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we or our collaborators are able to enter the market. The key competitive factors affecting the success of all of our investigational products, if approved, are likely to be their degree of efficacy, tolerability profile, convenience and price, the effectiveness of companion diagnostics (if required), the level of biosimilar or generic competition and the availability of reimbursement from government and other third-party payors.

Government Regulation

Government authorities in the U.S. at the federal, state and local level and in other countries regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of drug and biological products. Generally, before a new drug can be marketed, considerable data demonstrating its quality, safety and efficacy must be obtained, organized into a format specific for each regulatory authority, submitted for review and approved by the regulatory authority.

U.S. Drug Development

In the U.S., the FDA regulates drugs under the Food, Drug, and Cosmetic Act (“FDCA”). Drugs also are subject to other federal, state and local statutes and regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources. Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or post-market may subject an applicant to administrative or judicial sanctions. These sanctions could include, among other actions, the FDA’s refusal to approve pending applications, withdrawal of an approval, a clinical hold, untitled or warning letters, product recalls or market withdrawals, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement and civil or criminal penalties. Any agency or judicial enforcement action could have a material adverse effect on us.

Our product candidates are considered small molecule drugs and must be approved by the FDA through the new drug application (“NDA”) process before they may be legally marketed in the U.S. The process generally involves the following:

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completion of extensive preclinical studies in accordance with applicable regulations, including studies conducted in accordance with GLP;

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submission to the FDA of an IND, which must become effective before human clinical trials may begin;

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approval by an independent institutional review board ("IRB") or ethics committee at each clinical trial site before each trial may be initiated;

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performance of adequate and well controlled human clinical trials in accordance with applicable IND regulations, current Good Clinical Practice ("GCP") requirements and other clinical trial-related protocols and regulations to establish substantial evidence of the safety and efficacy of the investigational product for each proposed indication;

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submission to the FDA of an NDA after completion of all pivotal trials;

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determination by the FDA within 60 days of its receipt of an NDA to accept the filing for substantive review;

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satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities where the drug will be produced to assess compliance with current good manufacturing practices ("cGMP") requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

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potential FDA audit of the preclinical study and/or clinical trial sites that generated the data in support of the NDA filing to assess compliance with GCP;

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FDA review and approval of the NDA, including consideration of the views of any FDA advisory committee, prior to any commercial marketing or sale of the drug in the U.S.; and

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compliance with any post-approval requirements, including the potential requirement to implement a risk evaluation and mitigation strategy ("REMS") and the potential requirement to conduct post-approval studies.

The data required to support an NDA are generated in two distinct developmental stages: preclinical and clinical. The preclinical and clinical testing and approval process requires substantial time, effort and financial resources, and we cannot be certain that any approvals for any current and future product candidates will be granted on a timely basis, or at all.

Preclinical Studies and IND

The preclinical developmental stage generally involves laboratory evaluations of drug chemistry, formulation and stability, as well as studies to evaluate toxicity in animals, which support subsequent clinical testing. The sponsor must submit the results of the preclinical studies, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND. An IND is a request for authorization from the FDA to administer an investigational product to humans and must become effective before human clinical trials may begin.

Preclinical studies include laboratory evaluation of product chemistry and formulation, as well as in vitro and animal studies to assess the potential for adverse events and in some cases to establish a rationale for therapeutic use. The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations for safety/toxicology studies. An IND sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical studies, among other things, to the FDA as part of an IND. Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue after the IND is submitted. An IND automatically becomes effective 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions related to one or more proposed clinical trials and places the trial on clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. As a result, submission of an IND may not result in the FDA allowing clinical trials to commence.

Clinical Trials

The clinical-stage of development involves the administration of the investigational product to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCP requirements, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters to be used to monitor subject safety and assess efficacy. Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND. Furthermore, each clinical trial must be reviewed and approved by an IRB for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB must also approve the informed consent form that must be provided to each clinical trial

subject or his or her legal representative and must monitor the clinical trial until completed. There also are requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries.

A sponsor who wishes to conduct a clinical trial outside of the U.S. may, but need not, obtain FDA authorization to conduct the clinical trial under an IND. If a foreign clinical trial is not conducted under an IND, the sponsor may submit data from the clinical trial to the FDA in support of an NDA. The FDA will generally accept a well-designed and well conducted foreign clinical trial not conducted under an IND if the clinical trial is conducted in compliance with GCP and the FDA is able to validate the data through an onsite inspection, if deemed necessary. An NDA based solely on foreign clinical data meeting U.S. criteria for marketing approval may be approved if (1) the foreign data are applicable to the U.S. population and U.S. medical practice, (2) the studies have been performed by clinical investigators of recognized competence and (3) the FDA is able to validate the data through an onsite inspection or other appropriate means, if deemed necessary

Clinical trials in the U.S. generally are conducted in three sequential phases, known as Phase 1, Phase 2 and Phase 3, and may overlap.

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Phase 1 clinical trials generally involve a small number of healthy volunteers or disease-affected patients who are initially exposed to a single dose and then multiple doses of the product candidate. The primary purpose of these clinical trials is to assess the metabolism, pharmacologic action, tolerability and safety of the drug.

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Phase 2 clinical trials involve studies in disease-affected patients to determine the dose and dosing schedule required to produce the desired benefits. At the same time, safety and further pharmacokinetic and pharmacodynamic information is collected, possible adverse effects and safety risks are identified, and a preliminary evaluation of efficacy is conducted.

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Phase 3 clinical trials generally involve a large number of patients at multiple sites and are designed to provide the data necessary to demonstrate the effectiveness of the product for its intended use, its safety in use and to establish the overall benefit/risk relationship of the product and provide an adequate basis for product approval. These trials may include comparisons with placebo and/or other comparator treatments. The duration of treatment is often extended to mimic the actual use of a product during marketing.

Post-approval trials, sometimes referred to as Phase 4 clinical trials, are conducted after initial marketing approval. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.

Progress reports detailing the results of the clinical trials, among other information, must be submitted at least annually to the FDA. Sponsor is also responsible for submitting written IND safety reports, including reports of serious and unexpected suspected adverse events, findings from other studies suggesting a significant risk to humans exposed to the drug, findings from animal or in vitro testing that suggest a significant risk for human subjects, and any clinically significant increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, if at all. The FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients. Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee. This group provides recommendations for whether a trial may move forward at designated check-points based on access to certain data from the trial.

Concurrent with clinical trials, companies usually complete additional animal safety studies and also must develop additional information about the chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process, as performed by the manufacturing facility, must be capable of consistently producing quality batches of our product candidates. Additionally, appropriate packaging must be selected and tested, and stability studies must be

conducted to demonstrate that our product candidates do not undergo unacceptable deterioration over their labeled shelf life.

NDA Review Process

Following completion of the clinical trials, data is analyzed to assess whether the investigational product is safe and effective for the proposed indicated use or uses. The results of preclinical studies and clinical trials are then submitted to the FDA as part of an NDA, along with proposed labeling, chemistry and manufacturing information to ensure product quality and other relevant data. In short, the NDA is a request for approval to market the drug in the U.S. for one or more specified indications and must contain proof of safety and efficacy for a drug.

The application must include both negative and ambiguous results of preclinical studies and clinical trials, as well as positive findings. Data may come from company-sponsored clinical trials intended to test the safety and efficacy of a product’s use or from a number of alternative sources, including studies initiated by investigators. To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of the investigational product to the satisfaction of FDA. FDA approval of an NDA must be obtained before a drug may be legally marketed in the U.S.

Under the Prescription Drug User Fee Act (“PDUFA”), as amended, each NDA must be accompanied by a user fee. FDA adjusts the PDUFA user fees on an annual basis. PDUFA also imposes an annual program fee for each marketed human drug. Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first application filed by a small business. Additionally, no user fees are assessed on NDAs for products designated as orphan drugs, unless the product also includes a non-orphan indication.

The FDA reviews all submitted NDAs before it accepts them for filing and may request additional information rather than accepting the NDA for filing. The FDA must make a decision on accepting an NDA for filing within 60 days of receipt. Once the submission is accepted for filing, the FDA begins an in-depth review of the NDA. Under the goals and policies agreed to by the FDA under PDUFA, the FDA has 10 months, from the filing date, in which to complete its initial review of a new molecular-entity NDA and respond to the applicant, and six months from the filing date of a new molecular-entity NDA designated for priority review. The FDA does not always meet its PDUFA goal dates for standard and priority NDAs, and the review process is often extended by FDA requests for additional information or clarification.

Before approving an NDA, the FDA will conduct a pre-approval inspection of the manufacturing facilities for the new product to determine whether they comply with cGMP requirements. The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications. The FDA also may audit data from clinical trials to ensure compliance with GCP requirements. Additionally, the FDA may refer applications for novel drug products or drug products which present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions, if any. The FDA is not bound by recommendations of an advisory committee, but it considers such recommendations when making decisions on approval. The FDA likely will reanalyze the clinical trial data, which could result in extensive discussions between the FDA and the applicant during the review process. After the FDA evaluates an NDA, it will issue an approval letter or a Complete Response Letter. An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications. A Complete Response Letter indicates that the review cycle of the application is complete, and the application will not be approved in its present form. A Complete Response Letter usually describes all of the specific deficiencies in the NDA identified by the FDA. The Complete Response Letter may require additional clinical data, additional pivotal Phase 3 clinical trial(s) and/or other significant and time-consuming requirements related to clinical trials, preclinical studies and/or manufacturing. If a Complete Response Letter is issued, the applicant may either resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application. Even if such data and information are submitted, the FDA may decide that the NDA does not satisfy the criteria for approval. Data obtained from clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data.

Orphan Drugs

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug or biological product intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals

in the U.S., or more than 200,000 individuals in the U.S. and for which there is no reasonable expectation that the cost of developing and making the product available in the U.S. for this type of disease or condition will be recovered from sales of the product.

Orphan drug designation must be requested before submitting an NDA. After the FDA grants orphan drug designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Orphan drug designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.

If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan drug exclusivity, which means that the FDA may not approve any other applications to market the same drug for the same indication for seven years from the date of such approval, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity by means of greater effectiveness, greater safety or providing a major contribution to patient care or in instances of drug supply issues. However, competitors may receive approval of either a different product for the same indication or the same product for a different indication but that could be used off-label in the orphan indication. Orphan drug exclusivity also could block the approval of one of our product candidates for seven years if a competitor obtains approval before we do for the same product, as defined by the FDA, for the same indication we are seeking approval, or if a product candidate is determined to be contained within the scope of the competitor’s product for the same indication. If one of our product candidates designated as an orphan drug receives marketing approval for an indication broader than that which is designated, it may not be entitled to orphan drug exclusivity. Orphan drug status in the European Union has similar, but not identical, requirements and benefits.

Expedited Development and Review Programs

The FDA has a fast track program that is intended to expedite or facilitate the process for reviewing new drugs that meet certain criteria. Specifically, new drugs are eligible for fast track designation if they are intended to treat a serious or life-threatening condition and preclinical or clinical data demonstrate the potential to address unmet medical needs for the condition. Fast track designation applies to both the product and the specific indication for which it is being studied. The sponsor can request the FDA to designate the product for fast track status any time before receiving NDA approval, but ideally no later than the pre-NDA meeting with the FDA.

Any product submitted to the FDA for marketing, including under a fast track program, may be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval. Any product is eligible for priority review if it treats a serious or life-threatening condition and, if approved, would provide a significant improvement in safety and effectiveness compared to available therapies.

A product may also be eligible for accelerated approval, if it treats a serious or life-threatening condition and generally provides a meaningful advantage over available therapies. In addition, it must demonstrate an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (“IMM”), which is reasonably likely to predict an effect on IMM or other clinical benefit. As a condition of approval, the FDA may require that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials. FDA may withdraw drug approval or require changes to the labeled indication of the drug if confirmatory post-market trials fail to verify clinical benefit or do not demonstrate sufficient clinical benefit to justify the risks associated with the drug. If the FDA concludes that a drug shown to be effective can be safely used only if distribution or use is restricted, it may require such post-marketing restrictions as it deems necessary to assure safe use of the product.

Additionally, a drug may be eligible for designation as a breakthrough therapy if the product is intended, alone or in combination with one or more other drugs or biologics, to treat a serious or life-threatening condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over currently approved therapies on one or more clinically significant endpoints. The benefits of breakthrough therapy designation include the same benefits as fast track designation, plus intensive guidance from the FDA to ensure an efficient drug development program. Fast track designation, priority review, accelerated approval and breakthrough therapy designation do not change the standards for approval, but may expedite the development or approval process. Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

Post-approval Requirements

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