10-K

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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year endedDecember 31, 2024

Commission file number 001-41989

BOUNDLESS 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: (858)766-9912

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

Title of each class TradingSymbol(s) Name of each exchange on which registered

Common stock, par value $0.0001 per share BOLD Nasdaq Global Select Market

Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes☐No☒

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or 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, 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. ☐

If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements. ☐

Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐

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 registrant's common stock held by non-affiliates of the registrant was approximately $68.4million on the last business day of the registrant’s most recently completed second fiscal quarter based on the closing price of $3.87 per share, which was the closing price of the registrant’s common stock as reported on the Nasdaq Global Select Market on such date. Shares of common stock held by each executive officer and director and by each other person who may be deemed to be an affiliate of the registrant on such date have been excluded from this computation. The determination of affiliate status for this purpose is not necessarily a conclusive determination for other purposes.

The number of shares of registrant’s Common Stock outstanding as of March 21, 2025 was 22,300,043.

DOCUMENTS INCORPORATED BY REFERENCE

Certain portions of the registrant’s definitive proxy statement for the 2025 annual meeting of stockholders to be filed with the Securities and Exchange Commission not later than 120 days after the end of the fiscal year covered by this report are incorporated by reference into Part III of this report.

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PART I

Item 1. Business 3

Item 1A. Risk Factors 44

Item 1B. Unresolved Staff Comments 89

Item 1C. Cybersecurity 89

Item 2. Properties 90

Item 3. Legal Proceedings 90

Item 4. Mine Safety Disclosures 90

PART II

Item 6. [Reserved] 92

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 102

Item 8. Financial Statements and Supplementary Data 102

Item 9A. Controls and Procedures 103

Item 9B. Other Information 103

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 104

PART III

Item 10. Directors, Executive Officers, and Corporate Governance 105

Item 11. Executive Compensation 105

Item 14. Principal Accountant Fees and Services 105

PART IV

Item 15. Exhibits and Financial Statement Schedules 106

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PART I

SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS AND MARKET AND INDUSTRY DATA

This Annual Report on Form 10-K contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended (the Securities Act) and Section 21E of the Securities Exchange Act of 1934, as amended (the Exchange Act). All statements other than statements of historical facts contained in this report are forward-looking statements, including statements regarding our future results of operations and financial position, our use of the net proceeds from the initial public offering of our common stock, the sufficiency of our cash position to fund operations and achievement of milestones, including clinical data readouts and regulatory filings, the timing and likelihood of success, plans, and objectives of management for future operations, business strategy, research and development plans, the anticipated timing, costs, design, and conduct of our ongoing and planned clinical trials and preclinical studies for our extrachromosomal DNA (ecDNA) directed therapeutic candidates (ecDTx), ecDNA diagnostic, our other discovery programs, the timing of expected data readouts, the potential safety and therapeutic benefits of our ecDTx, the potential addressable patient populations for our ecDTx, the timing and likelihood of development candidate nominations from our discovery-stage programs, the timing and likelihood of regulatory filings and approvals for our ecDTx, expected regulatory approval pathways for our ecDTx and any ecDNA diagnostic, our ability to commercialize our ecDTx, if approved, the pricing and reimbursement of our ecDTx, if approved, potential competition for our ecDTx, the potential to develop future ecDTx, the potential benefits of strategic collaborations and our intent to enter into any strategic arrangements, our intellectual property and other market exclusivity strategies.

In some cases, you can identify forward-looking statements by terms such as “anticipate,” “believe,” “contemplate,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “would,” “target,” or “will” or the negative of these terms or other similar expressions. Our forward-looking statements are only predictions. We have based our forward-looking statements largely on our current expectations and projections about future events and financial and other trends that we believe may affect our business, financial condition, and results of operations based upon information available to us as of the date of this report. Such information may be limited or incomplete. Forward-looking statements in this report speak only as of the date of this report and are subject to several risks, uncertainties, and assumptions, including those described in Part I, Item 1, “Business,” and Item 1A, “Risk Factors,” and Part II, Item 7, “Management’s Discussion and Analysis of Financial Condition and Results of Operations.” The events and circumstances reflected in our forward-looking statements may not be achieved or occur and our actual results, performance, or achievements could differ materially from those expressed or implied by our forward-looking statements. Moreover, we operate in an evolving environment. New risk factors and uncertainties may emerge from time to time, and it is not possible for management to predict all risk factors and uncertainties. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified and some of which are beyond our control, you should not place undue reliance on any forward-looking statement. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances, or otherwise. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

In addition, statements that “we believe” and similarly qualified statements reflect our beliefs and opinions on the relevant subject. These statements are based upon information available to us as of the date of this report, and while we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted an exhaustive inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain, and you are cautioned not to rely unduly upon them.

We obtained the industry, market, and competitive position data used in this report from our own internal estimates and research, as well as from independent market research, industry, and general publications and surveys, governmental agencies, and publicly available information in addition to research, surveys, and studies conducted by third parties. The content of these third-party sources, except to the extent specifically set forth in this report, does not constitute a portion of this report and is not incorporated herein. Internal estimates are derived from publicly available information released by industry analysts and third-party sources, our internal research, and our industry experience and are based on assumptions made by us based on such data and our knowledge of our industry and market, which we believe to be reasonable. In some cases, we do not expressly refer to the sources from which this data is derived. In that regard, when we refer to one or more sources of this type of data in any paragraph, you should assume that other data of this type appearing in the same paragraph is derived from the same sources, unless otherwise expressly stated or the context otherwise requires.

In addition, while we are responsible for all of the disclosure contained in this report and we believe the industry, market, and competitive position data included in this report is reliable and based on reasonable assumptions, such data involve risks and uncertainties and are subject to change based on various factors, including those discussed below under the section titled “Risk Factors Summary” and in Part I, Item 1A, “Risk Factors.” These and other factors could cause results to differ materially from those expressed in the estimates made by the independent parties or by us.

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RISK FACTORS SUMMARY

Below is a summary of the principal factors that make an investment in our common stock speculative or risky. This summary does not address all of the risks that we face. Additional discussion of the risks summarized in this risk factors summary, and other risks that we face, can be found in Part I, Item 1A., “Risk Factors,” of this Annual Report on Form 10-K, and should be carefully considered, together with other information in this report and our other filings with the U.S. Securities and Exchange Commission (SEC) before making investment decisions regarding our common stock.

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We have a limited operating history, have incurred significant operating losses since our inception and expect to incur significant losses for the foreseeable future. We may never generate any revenue or become profitable or, if we achieve profitability, we may not be able to sustain it.

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We will require substantial additional financing to finance our operations, and a failure to obtain this necessary capital when needed on acceptable terms, or at all, could force us to delay, limit, reduce or terminate our ecDTx development programs, commercialization efforts or other operations.

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We are early in our development efforts and have only one ecDTx in clinical development. All of our other ecDTx programs are still in the preclinical or discovery stage. If we are unable to successfully develop, obtain regulatory approval, and ultimately commercialize any of our current or future ecDTx, or experience significant delays in doing so, our business will be materially harmed.

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Our approach to treating cancer with oncogene amplifications by developing ecDTx directed against ecDNA is unproven, and we do not know whether we will be able to develop any products of commercial value, or if competing approaches will limit the commercial value of our ecDTx.

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Clinical and preclinical development involves a lengthy and expensive process with uncertain timelines and outcomes, and the results of preclinical studies and early clinical trials are not necessarily predictive of future results. Our ecDTx may not achieve favorable results in clinical trials or preclinical studies or receive regulatory approval on a timely basis, if at all.

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Any difficulties or delays in the commencement or completion, or the termination or suspension, of our current or planned clinical trials or preclinical studies could result in increased costs to us, delay or limit our ability to generate revenue, or adversely affect our commercial prospects.

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Use of our ecDTx could be associated with side effects, adverse events, or other properties or safety risks, which could delay or preclude regulatory approval, cause us to suspend or discontinue clinical trials, abandon an ecDTx, limit the commercial profile of an approved label, or result in other significant negative consequences that could severely harm our business, financial condition, results of operations, and prospects.

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If we are unable to successfully develop an ecDNA diagnostic to enable patient selection for our ecDTx, or if we experience significant delays in doing so, we may not realize the full commercial potential of our ecDTx.

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We face significant competition from entities that have developed or may develop product candidates for cancer, including companies developing novel treatments and technology platforms. If our competitors develop and commercialize their product candidates more rapidly than we do, or their technologies or their product candidates are more effective, safer, or less expensive than our ecDTx, our business and our ability to develop and successfully commercialize ecDTx may be adversely affected.

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We rely on third parties to conduct our clinical trials and preclinical studies, to develop an ecDNA diagnostic, and to manufacture our ecDTx, and these third parties may not perform satisfactorily, which could delay, prevent, or impair our development or commercialization efforts

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If we are unable to obtain, maintain, defend, and enforce patent or other intellectual property protection for our ecDTx, ecDNA diagnostic, or technology, or if the scope of the patent or other intellectual property protection obtained is not sufficiently broad, our competitors or other third parties could develop and commercialize products similar or identical to ours, and our ability to successfully commercialize our ecDTx may be adversely affected.

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The trading price of the shares of our common stock could be highly volatile, and purchasers of our common stock could incur substantial losses.

Item 1. Business.

The terms “we,” “us,” “our,” “our company,” “Boundless Bio,” “Boundless,” or the “Company” refer to Boundless Bio, Inc. unless otherwise stated or the context otherwise requires. All information in this report is based on our fiscal year. Unless otherwise

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stated, references to particular years, quarters, months, or periods refer to our fiscal years ending December 31 and the associated quarters, months, and periods of those fiscal years.

Overview

We are a clinical-stage oncology company dedicated to unlocking a new paradigm in cancer therapeutics that addresses the significant unmet need in patients with oncogene amplified tumors by interrogating extrachromosomal DNA (ecDNA), a root cause of oncogene amplification observed in 14 to 17% of cancer patients. Our mission is to be the foremost biopharma company interrogating ecDNA biology to deliver transformative therapies that improve and extend the lives of patients with previously intractable oncogene amplified cancers.

ecDNA are large circular units of nuclear DNA that are a primary mechanism of gene amplification and are detected only in cancer cells, not in healthy cells. Despite tremendous advancements in treating cancer broadly, patients with oncogene amplified cancers generally derive little benefit from existing therapies, such as molecular targeted therapies or immunotherapies, and have worse survival rates than patients without oncogene amplification. Using our proprietary Spyglass platform, we identify targets essential for ecDNA functionality in oncogene amplified cancer cells, then design and develop small molecule drugs called ecDNA-directed therapeutic candidates (ecDTx) to inhibit those targets, with the aim to prevent cancer cells from using amplified oncogenes to grow, adapt, and become resistant to existing therapies. Instead of directly targeting the proteins produced by amplified oncogenes, which is the approach of traditional targeted therapies, our ecDTx are intended to be synthetic lethal in tumor cells reliant on amplification biology. In the context of drug development, synthetic lethality is a therapeutic approach wherein using a drug to inhibit one target is lethal to cancer cells harboring a specific genetic alteration to a second target, but not lethal to healthy cells that lack the genetic alteration to the second target. Accordingly, our ecDTx are designed to preferentially kill amplification-dependent cancer cells, but not healthy cells. They are engineered to disrupt the underlying cellular machinery that enables functional amplification.

Our lead ecDTx, BBI-355, is a novel, oral, selective inhibitor of checkpoint kinase 1 (CHK1), which manages replication stress associated with gene amplification in cancer cells. BBI-355 demonstrated CHK1 inhibition and tumor regressions in oncogene amplified preclinical cancer models, including those enabled by ecDNA, and is currently being studied in a first-in-human, Phase 1/2 clinical trial in patients with oncogene amplified cancers. We refer to this trial as POTENTIATE (Precision Oncology Trial Evaluating Novel Therapeutic Interrupting Amplifications Tied to ecDNA). We expect to have preliminary clinical proof of concept safety and antitumor activity data of BBI-355 in the second half of 2025. Our next program is directed at a previously undrugged kinesin target that we identified as essential for proper ecDNA segregation and inheritance during cancer cell division. We are advancing our Kinesin program through drug discovery and expect to select a development candidate by mid-2025 and submit an investigational new drug application (IND) in the first half of 2026.

We have been evaluating BBI-825, a novel, oral, selective RNR inhibitor, in the Phase 1/2 STARMAP (Study Treating Acquired Resistance: MAPK Amplifications) clinical trial for patients with solid tumors, including those with BRAFV600E or KRASG12C mutated colorectal cancer that has developed resistance oncogene amplifications. In December 2024, following an assessment of preliminary pharmacokinetic data from the Part 1 portion of the trial, we made the strategic decision not to continue dose escalation of Part 1 or to proceed into the Part 2 portion of STARMAP trial. To date, BBI-825 has been generally well-tolerated in the STARMAP trial.

To assist in identifying patients that may benefit from our ecDTx, we have developed an ecDNA diagnostic, which we internally call ECHO (ecDNA Harboring Oncogenes), to detect ecDNA in patient tumor samples. This test analyzes the genomic data obtained from routine next-generation sequencing (NGS) of patient tumor samples. ECHO is currently being used as a clinical trial assay to determine ecDNA status of patients enrolled in the BBI-355 POTENTIATE trial.

Our pipeline consists of programs directed against targets critical for functional gene amplifications in cancer. We continue to identify new targets, both novel and previously clinically validated, through our proprietary Spyglass platform. To our knowledge, Spyglass is the only platform in the biopharma industry using ecDNA biology to identify specific druggable targets in oncogene amplified cancers. All of our ecDTx have been discovered internally, and we retain global rights for all of our programs.

We consider ourselves to be the world’s leading ecDNA company. To our knowledge, we are the first company developing new cancer medicines directed at ecDNA and the only company to date to bring an ecDTx into the clinic. Our efforts build on the work of our scientific founders and advisors, including Dr. Paul Mischel, who is a globally recognized leader in the ecDNA field, having authored more than 20 peer-reviewed publications on ecDNA and the team leader for the National Institute of Health’s (NIH) and Cancer Research United Kingdom’s (CRUK) Cancer Grand Challenges team devoted to ecDNA and its role in cancer. Dr. Mischel is the Chairman of our Scientific Advisory Board. We leverage this unique expertise to identify new cancer targets that are synthetic lethal in oncogene amplified cancer cells and to develop new medicines for patients with oncogene amplified cancers.

Our Pipeline and Platform

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Our lead ecDTx, BBI-355, is a novel, oral, selective small molecule CHK1 inhibitor being studied in the ongoing first-in-human, Phase 1/2 POTENTIATE clinical trial in patients with oncogene amplified cancers. CHK1 is a master regulator of cells’ response to replication stress (RS). RS is elevated in oncogene amplified cancer cells, including those with ecDNA, and, because of this, represents a key vulnerability of those cells. BBI-355 is designed to exploit the elevated RS in oncogene amplified cancer cells by disrupting proper CHK1 function in regulating RS and thereby facilitating catastrophic RS to preferentially kill cancer cells relative to healthy cells. We believe that our approach differentiates us from other biopharma industry efforts targeting CHK1 or related targets. In addition, BBI-355 is orally administered, which, unlike intravenous (IV) dosing of a CHK1 inhibitor, allows for continuous or chronic intermittent dosing, which we believe is critical for targeting ecDNA biology. BBI-355 showed inhibition of CHK1 in a host of tumor cell lines and demonstrated in vitro and in vivo single agent tumor growth inhibition or tumor regressions across a range of tumor models representing different oncogene amplifications and tumor types. BBI-355 also demonstrated synergistic tumor growth inhibition or tumor regressions when combined with targeted therapies, both in vitro and in vivo, across multiple oncogene amplification tumor settings. We expect to have preliminary clinical proof of concept safety and antitumor activity data of BBI-355 from our ongoing POTENTIATE trial in the second half of 2025.

Our next therapeutic program aims to dysregulate ecDNA segregation, which we identified as a unique node of ecDNA vulnerability via our Spyglass platform. Specifically, we are targeting a kinesin involved with the cellular mechanism for segregation of ecDNA and its resulting inheritance into dividing cells. We are advancing our Kinesin program through drug discovery and expect to nominate a development candidate by mid-2025 and submit an IND in the first half of 2026.

We continue to leverage Spyglass to identify and preclinically validate additional targets that span multiple, diverse synthetic lethal nodes in oncogene amplified cancers. In addition to the programs described above, we have preclinically validated multiple additional targets and have initiated ecDTx drug discovery efforts to identify candidates against such targets. We expect to continue to identify and preclinically validate additional cancer targets using our Spyglass platform in the future.

We believe our unique development approach has many potential benefits for patients, including:

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addressing oncogene amplified cancers, a type of cancer without effective treatment options;

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identifying patient populations most likely to benefit from our ecDTx by using a biomarker-driven approach, including our proprietary ecDNA diagnostic; and

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employing a tumor-agnostic development strategy, as appropriate, focusing on oncogene amplified cancers across a broad range of tumor types and amplified oncogene drivers.

Our Strategy

Our mission is to be the foremost biopharma company interrogating ecDNA biology to deliver transformative therapies that improve and extend the lives of patients with previously intractable oncogene amplified cancers. To accomplish this mission, our strategy is to leverage our unique expertise in ecDNA biology and its role in oncogene amplified cancer to pioneer the discovery, development,

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and commercialization of novel ecDTx for these patients who are not successfully treated by existing therapeutic options. The principal components of our strategy are to:

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Advance our lead ecDTx, BBI-355, a CHK1 inhibitor, through clinical development and regulatory approval in patients with oncogene amplified cancers, including those enabled by ecDNA. We believe that with the optimized biochemical profile of BBI-355, including its oral route of administration, along with our differentiated precision oncology development strategy and approach to identify patients with oncogene amplifications on ecDNA using our ecDNA diagnostic, we can overcome the historical challenges encountered with prior CHK1 inhibitors. We expect to have preliminary clinical proof of concept safety and antitumor activity data of BBI-355 from our ongoing POTENTIATE trial in the second half of 2025.

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Advance our Kinesin program to identify a development candidate and progress it into IND-enabling studies. Through Spyglass, we have gained a deeper understanding of unique ecDNA segregation mechanisms during cell division and identified a kinesin target essential for ecDNA segregation and inheritance, whose inhibition is synthetic lethal to ecDNA-enabled cancer cells. This program is directed to a kinesin, which is a member of a class of known druggable proteins, but for which there are no approved drugs and to our knowledge no other publicly disclosed drug discovery efforts. We have identified oral, small molecule degraders of this target and expect to nominate a development candidate by mid-2025 and submit an IND in the first half of 2026.

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Deploy our proprietary ecDNA diagnostic, ECHO, to identify patients most likely to benefit from our ecDTx. Our ecDNA diagnostic is a software algorithm intended to detect ecDNA in patient tumor samples by analyzing the genomic data of those samples available from routine NGS tests that are commonly used by commercial reference and academic laboratories for profiling patient tumors. Our ecDNA diagnostic is currently being used as a clinical trial assay to determine ecDNA status of patients enrolled in the BBI-355 POTENTIATE trial and we intend to discuss with the FDA whether it will be appropriate or required to enable commercialization of our ecDTx, if approved.

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Leverage Spyglass to continue to identify and preclinically validate additional targets to expand our therapeutic pipeline. We utilize Spyglass to identify targets that exploit cellular vulnerabilities of oncogene amplified cancers. Our target identification efforts to date have revealed multiple distinct nodes of vulnerability within the lifecycle of ecDNA. We continuously incorporate new models, tools, and technologies into our Spyglass platform to identify novel points of synthetic lethality in oncogene amplified cancers. In addition to our programs described above, we have preclinically validated multiple additional targets and have initiated ecDTx drug discovery efforts to identify potential candidates against such targets. We continue to deploy Spyglass to identify and preclinically validate additional targets for future potential ecDTx development opportunities.

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Opportunistically pursue strategic collaborations to accelerate development timelines and maximize the commercial potential of our ecDTx. The large number of potential intervention points in the ecDNA life cycle identified by our Spyglass platform has the potential to provide us with more targets, ecDTx, and clinical development strategies than we may be able to pursue on our own. We believe this abundance of potential treatment opportunities may provide an opportunity for potential strategic collaborations involving our targets, our ecDTx, our ecDNA diagnostic test, or our Spyglass platform to maximize the patient benefit and long-term value of our research and development portfolio.

Our History and Team

Our company was founded in 2018 by a leading healthcare investor, ARCH Venture Partners, and the world’s leading academic researchers in the burgeoning field of ecDNA. One of our scientific co-founders, Paul Mischel, M.D., Institute Scholar ChEM-H and Vice Chair of Research and Professor for the Department of Pathology at Stanford University, and member of the National Academy of Medicine, is internationally recognized for his expertise in ecDNA and cancer biology. Dr. Mischel serves as the Chairman of our Scientific Advisory Board.

Our other scientific co-founders include:

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Vineet Bafna, Ph.D., Professor of Computer Science & Engineering at the University of California, San Diego; co-founder of Digital Proteomics; current member of our Scientific Advisory Board.

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Howard Chang, M.D., Ph.D., Senior Vice President of Research and Chief Scientific Officer at Amgen, former Director of the Center for Personal Dynamic Regulomes and the Virginia and D.K. Ludwig Professor of Cancer Genomics at Stanford University; co-founder of Accent Therapeutics, Cartography Biosciences, Epinomics, and Orbital Therapeutics; former Howard Hughes Medical Investigator; member of the National Academy of Sciences; current member of our Scientific Advisory Board.

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Ben Cravatt, Ph.D., Professor and Gilula Chair in Biology and Chemistry at The Scripps Research Institute; co-founder of Abide Therapeutics, ActiveX Biosciences, Belharra Therapeutics, and Vividion Therapeutics; recipient of the 2022 Wolf Prize for chemistry; member of the National Academy of Sciences; current member of our Scientific Advisory Board.

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Prashant Mali, Ph.D., Professor of Bioengineering at the University of California, San Diego; co-founder of Navega Therapeutics and Shape Therapeutics.

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Roel Verhaak, Ph.D., Harvey and Kate Cushing Professor in the Department of Neurosurgery at Yale University School of Medicine.

One of our industry co-founders is Jonathan Lim, M.D., Co-founder, CEO, and Chairman of Erasca, Venture Partner at ARCH Venture Partners, and former Co-founder and CEO of Ignyta. Dr. Lim serves as the Chairman of our Board of Directors.

In support of our mission to deliver the world’s first ecDTx to patients with oncogene amplified cancers, we have assembled a highly qualified management team with deep experience in precision oncology, drug discovery and development, diagnostic development, company building, capital raising, and strategic partnerships and acquisitions. This team hails from leading oncology-focused organizations such as Ignyta, Loxo Oncology, Sierra Oncology, Halozyme Therapeutics, and Rain Oncology and from leading pharmaceutical companies such as, Genentech/Roche, Eli Lilly, and Merck.

Our management team is led by our President and Chief Executive Officer, Zachary Hornby, who formerly served as Chief Operating Officer and Chief Financial Officer at Ignyta (acquired by Roche/Genentech). At Ignyta, he led the operational team that developed Rozlytrek®, which is globally approved and commercialized for patients with NTRK+ solid tumors and ROS1+ non-small cell lung cancer. Our Chief Scientific Officer, Chris Hassig, Ph.D., brings over 20 years of oncology research, target discovery, and drug development experience to Boundless Bio. Dr. Hassig was most recently Chief Scientific Officer at Sierra Oncology (acquired by GlaxoSmithKline) where he spearheaded research efforts for the company’s pipeline against several oncology and hematology targets. Our Chief Medical Officer, Robert Doebele, M.D., Ph.D., is a medical oncologist and previously served as Chief Medical Officer and Chief Scientific Officer at Rain Oncology, where he led the early and late-stage development of multiple oncology programs using biology-based, tumor-agnostic strategies.

Evolution of Precision Oncology

Cancer is the second leading cause of mortality in the United States, accounting for approximately 1,900,000 new diagnoses and 600,000 deaths on an annual basis. There are many genetic aberrations, including mutations, fusions, and amplifications that lead to the malignant cellular growth that results in cancer.

The first approved precision oncology drugs were predominately directed at the proteins produced by oncogenes hyperactivated by gene mutations or gene fusions. These drugs targeted specific types of receptor tyrosine kinases such as BCR-ABL, HER2, EGFR, ALK, and others. Since 2001, the FDA has approved more than 50 tyrosine kinase inhibitors for the treatment of cancer. This initial class of precision oncology drugs, also known as targeted therapies, generated more than $30 billion of worldwide sales in 2023. Much of the commercial success of these targeted therapies is due to their capacity to drive deeper and more durable responses than conventional chemotherapy regimens while minimizing unwanted side effects and damage to normal healthy tissues.

An evolution in the understanding of tumor biology coupled with an improved ability to segment subsets of tumors based on genomic alterations has led to the development of new therapies that transcend single tumor or organ-targeted cancers. This improved molecular understanding of cancer resulted in the approval of therapies that address specific genomic features of tumors but are tumor type agnostic; some examples are the TRK inhibitors, including entrectinib and larotrectinib, for the treatment of tumors with NTRK gene fusions. This trend for tumor-agnostic indications represented a breakthrough in patient identification, drug development, clinical trial designs, and speed to market approvals, albeit benefiting relatively modest sized patient populations.

Despite these advances of the precision oncology field, treatment resistance is still an unfortunate inevitability in cancer. The predominant resistance mechanisms to targeted therapies are secondary mutations of the treatment target (e.g., EGFRT790M, ALKG1202R), other means of pathway activation, and oncogene or resistance gene amplifications. The quest to address resistance has given rise to a newer generation of targeted therapies and treatment modalities, mostly directed at secondary mutations and alternative pathways. However, there are still very few approved or investigational therapies in development for patients with gene amplifications.

Significant Unmet Medical Need in Oncogene Amplified Cancers

While progress in treating cancers with other forms of oncogenic driver alterations continues to advance, patients whose cancers harbor oncogene amplifications remain a high unmet medical need. Cancers with gene amplifications are characterized by the abnormal

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presence of more than two copies of any gene within the human genome; when more than eight copies of a gene are present, this is often referred to as high copy number gene amplification. Genes whose activating mutation or amplification are associated with cancer are referred to as oncogenes. According to analyses of large cancer patient databases, greater than 25% of all cancer cases involve oncogene amplifications, suggesting that in the U.S. alone the oncogene amplified cancer population may represent more than 400,000 new patients each year across multiple tumor types.

Patients whose tumors harbor oncogene amplification have significantly worse survival compared to the broader cancer population. As seen in the figure below, patients with oncogene amplifications also have significantly worse survival compared to patients with other genetic alterations of the same oncogenes.

Cancer Patients with Oncogene Amplifications Have Worse Survival Than Those with Oncogene Mutations or Fusions

Patients with primary or metastatic cancers with amplifications, point mutations, fusions, or skipping deletions, of these genes: AR, ALK, ARAF, BRAF, CCND1, CDK4, CDK6, EGFR,ERBB2, FGFR1, FGFR2, FGFR3,FGFR4, HRAS, IDH1, IDH2, KIT, KRAS, MAP2K1, MAP2K2, MAP2K4, MDM2, MET, MYC, NF1, NRAS, NTRK1, NTRK2, NTRK3, PDGFB, PDGFRA, PDGFRB, PIK3CA, RAF1, RET, ROS1

cBioPortal analysis using MSK-MET (N=14,674 patients) and MSK-IMPACT (N= 1,115 patients), p-value =< 0.0001)

A p-value is the probability that the reported result was achieved purely by chance, such that a p-value of less than or equal to 0.05 means that there is a less than or equal to 5% probability that the difference between the control group and the treatment group is purely due to chance. A p-value of 0.05 or less typically represents a statistically significant result. The FDA’s evidentiary standard of efficacy when evaluating the results of a clinical trial generally relies on a p-value of less than or equal to 0.05.

Despite the advancements in precision medicine and targeted therapies for these other forms of driver oncogene alterations, as well as immunotherapies for patients whose cancers lack driver oncogenes, both targeted therapies and immunotherapies have proven largely ineffective in oncogene-amplified cancers.

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Examples of Commercial Targeted Therapies Not Approved for Oncogene Amplifications

Targeted agents that have shown efficacy in patients whose cancers are driven by other oncogene alterations, including point mutations, gene fusions, or skipping deletions, have generally failed to demonstrate robust efficacy in patients whose tumors are driven by oncogene amplification. The lack of approved therapies targeting oncogene amplified tumors exists despite extensive clinical testing of targeted agents in oncogene amplified cancer populations. Clinical studies have shown limited success in treating patients with EGFR, FGFR, and CDK4 amplified solid tumors with matching molecular targeted therapies. For example, approved and clinical-stage CDK4/6 inhibitors showed only a collective 2% overall response rate (ORR) in CDK4 amplified tumors, and FGFR inhibitors showed only a collective 13% ORR in patients with FGFR amplified tumors. This unfortunate trend has been observed across several classes of targeted agents when tested in oncogene-amplified tumors. In fact, despite continuous advancement of the precision oncology field, of the more than 200 FDA approved targeted therapies to date, only HER2 inhibitors have ever been approved for oncogene amplified or overexpressed cancer populations.

FGFR Inhibitors Demonstrated Less Clinical Benefit in Patients with FGFR Amplifications Than in Patients with Other FGFR Alterations (Mutations, Fusions)

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The presence of oncogene amplification is also associated with a lack of response when patients are treated with immunotherapies, for instance immune checkpoint inhibitors such as pembrolizumab. Furthermore, immune checkpoint inhibitors have been associated with rapid clinical worsening, known as hyper-progression, in patients with oncogene amplified tumors. There is growing evidence that oncogene amplifications could be one of the mechanisms that cancers use to escape immune surveillance or alter the tumor immune environment to avoid being eliminated by the immune system.

Role of extrachromosomal DNA in Oncogene Amplified Cancers

Chromosomal instability and tumor variability, or heterogeneity, account for many failures of targeted therapies in patients with cancer. Oncogene amplification is a consequence of chromosomal instability, arising through either numerical and/or structural alterations in chromosomes including the formation of ecDNA. It has long been recognized that oncogenes can be amplified not only on chromosomes but also on ecDNA. However, the frequency, importance, and specific role of ecDNA in cancer biology has not been well understood until recently. We believe the emerging science of ecDNA, first elucidated by our scientific founders and now the core focus of our Company, brings a new understanding of oncogene amplifications in cancer.

ecDNA are cancer-specific, circular fragments of genomic DNA that often encode full-length genes and regulatory regions such as promoters. ecDNA are physically separate from chromosomes, but still reside in the nucleus, and have unique properties that make them a common cellular mechanism for oncogene amplification. ecDNA often range in size from 2-5 megabase pairs in length and are visible through various forms of microscopy, as seen in the figure below. They have been observed in cancer cells by pathologists for more than 60 years, but until recently their function was unclear.

Microscopy Images of Chromosomes and ecDNA

Some of the most common driver oncogenes, such as EGFR, MYC, KRAS, FGFR, etc., are found to be amplified on ecDNA and can confer a selective fitness advantage to cancer cells. Oncogenes amplified on ecDNA have several features that distinguish them from amplifications located on chromosomes, including:

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Overexpression– Genes on ecDNA behave differently from genes on chromosomes because ecDNA are not properly regulated at the epigenetic level. ecDNA have a circular structure that is less tightly compacted compared to chromosomes, allowing easier access to their DNA. The easier access of the DNA to the cellular transcriptional machinery results in highly transcriptionally active genes that are often more actively expressed than genes located on chromosomes.

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Heterogeneity – ecDNA lack centromeres, a critical regulatory component of chromosomal segregation in cell division. Thus, in contrast to chromosomes, ecDNA can segregate unequally during cell division. This property supports a non-Mendelian inheritance pattern for ecDNA, enabling extreme gene copy number changes in relatively few cell divisions and extensive copy number heterogeneity, thereby driving rapid adaptability and tumor evolution.

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These features distinguish oncogene amplification on ecDNA from other forms of oncogenic alterations and uniquely enable amplification dependent tumors to rapidly adapt and evade therapeutics such as targeted therapies.

Circular Shape of ecDNA Enhances Transcriptional Activity, Leading to High Oncogene Expression

ecDNA Are Inherited via a Non-Mendelian Pattern, Leading to Genomic Heterogeneity

Until recently, the presence of ecDNA in cancer was thought to be a rare event, approximately 1.4% of cancers, and of unclear significance. In 2014, it was demonstrated that ecDNA-enabled gene amplifications are a primary driver of oncogenesis and play a critical role in driving tumor heterogeneity and enabling resistance to targeted therapies. In 2017, it was further demonstrated that ecDNA-enabled gene amplifications were observed in many human cancer types but almost never found in normal cells. More recent publications have shown ecDNA-enabled gene amplifications to be present in 14 to 17% of cancer patients, suggesting an incident population of approximately 750,000 new patients each year in the major addressable markets of the United States, European Union, and Japan, of which approximately 200,000 new patients are in the United States each year. More than half of all cancer cases with high-copy number gene amplification (copy number value >8) have been observed to be in association with ecDNA.

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Incident Population of Cancer Patients with ecDNA in the United States, European Union, and Japan is Estimated to be 750,000 Each Year

As seen in the figure below, many of the most aggressive tumor types contain the highest prevalence of ecDNA, including approximately 60% of glioblastomas and approximately 50% of liposarcomas. In fact, based on an analysis of several data sets including The Cancer Genome Atlas (TCGA), Pan-Cancer Analysis of Whole Genomes (PCAWG), and Genomics England (GEL), ecDNA was observed in more than 25% of cases from many different tumor types including: glioblastoma, liposarcoma, esophageal/upper gastrointestinal cancer, ovarian cancer, bladder cancer, lung squamous cancer, head and neck cancer, breast cancer, and gastric cancer.

ecDNA Occur Broadly Across Tumor Types but Not in Normal Healthy Tissue

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Unfortunately, as seen in the figure below, patients whose cancers harbor oncogene amplifications experience significantly shorter survival than cancer patients whose tumors are driven by other molecular alterations, such as mutations or fusions. Due to ecDNA’s unique properties in cancer cells, patients with ecDNA-enabled oncogene amplification experience even worse survival. These data strongly indicate that patients with oncogene amplified cancers, including those with ecDNA, are in dire need of a new therapeutic paradigm.

Patients with Oncogene Amplification on ecDNA Have Worse Survival

Role of ecDNA in Cancer’s Resistance to Therapy

The remarkable genomic plasticity of ecDNA-enabled tumors enables cancers to resist therapies by rapidly adapting their oncogene levels, or by switching their oncogenic drivers all together.

ecDNA’s role in enabling resistance to molecular targeted therapies has become better understood through recent preclinical studies. For instance, as seen in the figure below, preclinical studies in a gastric cancer cell line containing FGFR2 amplified on ecDNA demonstrated that cellular resistance to the pan-FGFR inhibitor infigratinib could be driven by oncogene dependency switching from FGFR2 amplification on ecDNA to a new, rapid amplification of EGFR on ecDNA. Strikingly, this dependency was reversed back to FGFR2 amplification on ecDNA under EGFR inhibitory pressure via erlotinib. In each case, the initial cell population was sensitive to the respective targeted therapy, resulting in short lived anti-proliferative effects lasting several weeks. Regrowth and resistance to the targeted therapies occurred coincident with switching of the oncogenes amplified on ecDNA.

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Dynamic Changes in Average Oncogene Copy Number on ecDNA in Gastric Cancer Cells in Response to Sequential Targeted Therapeutic Pressure

Similarly, mutant oncogenes, such as BRAFV600E, KRASG12C, etc., can be amplified on ecDNA as a resistance mechanism to corresponding targeted therapies, such as BRAF or KRAS inhibitors. For example, a mutant BRAFV600E melanoma cell line developed ecDNA-enabled amplification of BRAFV600E after exposure to dual BRAF/MEK inhibition. This phenomenon has also been documented in clinical cases of melanoma patients treated with an approved BRAF/MEK inhibitor regimen. Relatedly, amplification of KRASG12C on ecDNA has been reported as a clinical resistance mechanism to the KRASG12C inhibitor adagrasib and to the KRASG12C inhibitor sotorasib in combination with EGFR inhibitors; this ecDNA enabled amplification was observed in vitro and in vivo to confer resistance to both of these clinically validated KRASG12C inhibitors.

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Treatment of Colorectal Cancer Cells with KRASG12C Inhibitors Generated Resistance via Amplification of KRASG12C on ecDNA

In other models, evasion of therapeutic response to the EGFR inhibitor erlotinib was facilitated by rapid loss of the population of EGFRvIII amplifications on ecDNA in patient-derived glioblastoma cells, contemporaneous with occurrence of a new cell population containing MDM2 amplificationon ecDNA; this observed effect was consistent with an equivalent lack of response to EGFR inhibitors in EGFR amplified cancer patients.

ecDNA can also facilitate resistance to therapeutic classes outside of targeted therapies. ecDNA-enabled resistance to chemotherapy was first demonstrated in a mouse cancer cell line whereby methotrexate treatment led to high amplification of DHFR on ecDNA, which was lost upon removal of methotrexate. Similar instances of DHFR ecDNA amplification have been recapitulated in multiple human cancer cell lines. Furthermore, amplification of drug efflux pump genes on ecDNA, including the family of ABC transporters, has been observed to facilitate resistance to various chemotherapies and other modalities.

Collectively, these data highlight the striking genomic plasticity and precipitous rise and fall of ecDNA-enabled gene amplification that both drives oncogenesis and enables cancer cells to adapt to various therapeutic pressures, leading to rapid resistance. The rapid adaptability afforded by ecDNA-enabled genomic plasticity, including oncogene switching, helps account for the failure of targeted therapies against oncogene amplification-driven tumors, as well as amplification-driven resistance, resulting in a futile, clinical ‘whack-a-mole’ phenomenon. We believe a new and differentiated strategy is needed to interfere with the underlying ecDNA biology that engenders tumor adaptability, heterogeneity, and therapeutic resistance.

Our Approach to Treating ecDNA-Enabled Cancer

We aspire to improve clinical outcomes for patients with oncogene amplified cancer by identifying targets essential for the formation and function of ecDNA in cancer cells, then designing and developing drugs to inhibit those targets. As described above, ecDNA contribute to oncogenesis by facilitating high copy number gene amplification and expression and to therapeutic resistance by providing rapid genomic plasticity. While cancer cells can use ecDNA for certain advantages, their reliance on ecDNA can also expose

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them to potential vulnerabilities. We use our proprietary Spyglass platform to interrogate ecDNA biology in cancer with the goal of identifying these vulnerabilities in the form of cellular targets that are essential for oncogene amplified tumor cell survival.

We explore the ecDNA lifecycle to identify nodes of synthetic lethality in cancers reliant on amplification biology. In contrast to current precision medicine approaches that focus on targeting proteins that result directly from mutations or fusions of oncogenes such as, EGFR, BRAF, ALK, our precision medicine approach centers on disrupting ecDNA functionality in the cancer cells of patients who are genomically selected based on the presence of ecDNA-enabled oncogene amplification in their tumors. Instead of targeting the specific protein products of the oncogenes encoded by ecDNA, our novel small molecule ecDTx are designed to inhibit cellular machinery proteins that enable ecDNA to function properly, such as those critical for ecDNA formation, expression, replication, repair, and segregation.

We are developing our ecDTx to be administered as single agents and in combination with other therapies. The rationale for a combination approach is based on the observation described above that applying targeted therapy, or other therapeutic pressure, to oncogene amplified cancer cells causes them to respond and adapt via increased reliance on ecDNA. We believe this increased reliance on ecDNA for survival makes the cancer cells more susceptible to our ecDTx. We liken this phenomenon to a cellular vice grip concept as the targeted therapy pushes the surviving cancer cell population to higher reliance on ecDNA, and the ecDTx kills the cancer cells that most rely on ecDNA to survive. Our therapeutic approach is based on the concept of synthetic lethality and uses a strategy to interfere with cancer’s ability to employ amplification biology to grow, adapt, and survive.

While targeting ecDNA biology is a novel approach to cancer treatment, our ecDTx drug discovery and development process is rooted in traditional small molecule drug discovery methodology.

Spyglass Platform

We have built our proprietary Spyglass platform to identify specific, druggable targets essential to ecDNA formation and function in cancer cells. To our knowledge, Spyglass is the only platform for identifying ecDNA-enabled vulnerabilities in cancer. We preclinically validate each drug target through our purpose-built validation funnel consisting of multiple oncogene-amplified cancer models. The targets that we identify and preclinically validate represent synthetic lethalities for oncogene amplified tumors.

Spyglass Platform

Spyglass consists of the following elements:

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Model Systems– A heavily curated library of oncogene amplified cancer model systems, including ecDNA-enabled models, and control models. This library consists of approximately 2,000 well characterized cancer models (in vitro and in vivo), of which approximately 300 are in-house, including:

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a panel of ecDNA-enabled models, representing multiple different tumor types, such as colorectal, gastric cancer, and sarcoma and multiple different oncodriver amplifications such as EGFR, FGFR2, CDK4, KRAS, and MYC;

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a panel of matched control lines of various other states of gene amplification ranging from no amplification to chromosomal forms of amplification;

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the ecDNA-enabled models consist of both “driver oncogene amplified systems” where ecDNA is a primary driver of oncogenesis and “treatment induced resistance systems” where ecDNA becomes the dominant resistance mechanism under therapeutic pressure, such as targeted therapy or chemotherapy; and

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in vivo models, including cell derived (CDX) and patient derived (PDX) tumor xenografts.

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Analytical Tools – A suite of custom-built analytical tools designed to detect, quantify, characterize, monitor, and perturb ecDNA, including:

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imaging tools for visual detection and monitoring of ecDNA;

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off-the-shelf sequencing tools coupled to our proprietary analytical methods to detect, quantify, and characterize ecDNA; and

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whole genome and custom built CRISPR libraries and shRNA to analyze the biology of oncogene and resistance gene amplified cancer cells.

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Bioinformatics Data – Large databases to understand amplification biology, including:

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preclinical databases to support target identification, target validation, biological pathway mapping, model library expansion, biomarker discovery, and preliminary indication finding; and

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clinical databases of cancer patient genomic data and clinical outcome data to validate preclinical findings and help us identify tumor indications representing the largest opportunity and highest unmet need for our novel ecDTx.

Analytical Tools for Model Characterization

WES – whole exome sequencing; SNV – single nucleotide variant; CNV – copy number variation; MSI – microsatellite instability; Indel – insertion and deletion; ECHO – propriety ecDNA diagnostic; ECS – ecDNA solution; RUO – research use only; LP: low-pass; WGS – whole genome sequencing; AA – amplicon architect; SV – structural variation; mFISH – metaphase fluorescence in situ hybridization; iFISH – interphase fluorescence in situ hybridization

Target Identification and Validation

Through Spyglass, we have developed a sophisticated understanding of amplification biology, including ecDNA biology, and key cellular mechanisms that facilitate tumor growth and development of resistance to therapeutic treatments. This understanding has given us new insight on how to disrupt amplification biology and cancer cell growth. Through multiple screening methods, we have identified several potential targets that differ not only by class, but also in the role the target plays in the formation and function of ecDNA in cancer cells.

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To complement our target identification approach, we have established a robust target validation funnel through which all our candidate targets must pass before we declare them as targets suitable for initiation of drug discovery efforts. This target validation funnel consists of:

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differential single agent sensitivity in multi cell line panels of matched ecDNA positive (ecDNA+) and ecDNA negative (ecDNA-) cancer cell lines;

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genetic, such as CRISPR, or pharmacologic inhibition of candidate targets in ecDNA-enabled cancer cells in vitro and/or in vivo;

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phenotypic assessment of ecDNA function in ecDNA-enabled cancer cells in vitro and/or in vivo;

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phenotypic assessment of ecDNA location and distribution in cancer cells;

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synthetic lethality assessment, in combination with various therapeutic classes, in inducible ecDNA assays in vitro and/or in vivo; and

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in vivo assessments performed in multiple CDX and PDX xenograft models representing various cancer types, such as gastric cancer, sarcoma, colorectal cancer, and various oncodriver amplifications, such as EGFR, FGFR2, CDK4, and MYC.

Target Identification and Validation Process

The targets that our platform has identified as suitable for drug discovery efforts consist of targets that are either novel, previously clinically validated but lacking approved drugs, or have approved pharmaceutical agents but nonselective to the target. There appears to be a wide range of potential targets whose inhibition impact distinct aspects of the ecDNA life cycle, including enzymatic machinery responsible for segregation, replication, transcription, and repair. Each category of targets may have differentiated benefits in terms of optimal treatment setting, efficacy, tolerability, therapeutic index, and single agent versus combination approach. In addition to targets against which we have initiated drug discovery efforts, we also have multiple additional candidate targets for which we are currently pursuing preclinical target validation efforts. We believe that our ability to identify and pursue ecDNA-essential targets represents a unique capability and a sustainable engine for novel target identification, drug discovery, and value creation.

Our Pipeline of ecDNA-Directed Therapeutic Candidates

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We are pioneering a new and differentiated approach to precision medicine focused on developing ecDTx. Our ecDTx are novel, small molecules that target specific biological pathways believed to be essential to ecDNA function in cancer cells. Through Spyglass, we are able to better understand the lifecycle of ecDNA, including ecDNA formation, segregation, maintenance, replication, transcription, and degradation. We have identified several vulnerability nodes of ecDNA biology for therapeutic intervention and are developing novel drug candidates to intercept these nodes. Our drug discovery efforts span multiple ecDNA synthetic lethal targets, including:

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CHK1: a DNA replication checkpoint kinase target that manages the cellular response to RS arising from oncogene amplification on ecDNA; and

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Kinesin: a target essential for ecDNA segregation and inheritance during cell division.

Our diversified ecDTx pipeline currently consists of two small molecule programs against both a novel and a known cancer target. In addition, our Spyglass platform continues to yield new candidate targets for potential future drug discovery efforts.

Our Pipeline and Platform

Our Lead ecDTx: BBI-355 CHK1 Inhibitor

Our lead ecDTx, BBI-355, is a novel, oral, selective small molecule CHK1 inhibitor being studied in the ongoing first-in-human Phase 1/2 POTENTIATE clinical trial in patients with oncogene amplified cancers agnostic to tumor type. In preclinical models, BBI-355 showed inhibition of CHK1 in a host of tumor cell lines. CHK1 is a master regulator of cells’ response to RS. RS is elevated in oncogene amplified cancer cells, including those with ecDNA, and, because of this, represents a key vulnerability of those cells. BBI-355 is designed to exploit this elevated RS in oncogene amplified cancer cells by disrupting proper CHK1 function in regulating RS and thereby facilitating catastrophic RS to preferentially kill cancer cells relative to healthy cells. We expect to have preliminary clinical proof of concept safety and antitumor activity data of BBI-355 from the POTENTIATE trial in the second half of 2025.

CHK1 Synthetic Lethality in Oncogene Amplified Cancer

With every mammalian cell division, chromosomes comprised of billions of nucleotides must be precisely copied in coordination with the cell cycle to avoid dysregulated DNA replication or RS, which can lead to DNA damage, mis-segregation of genetic material, and, if unregulated, cell death. RS is characterized by uncoupling of the replicative helicase and DNA polymerase, slowdown of DNA synthesis, and/or replication fork stalling. These result in long stretches of fragile single stranded DNA (ssDNA) that is protected temporarily by binding to phosphorylated RPA protein (pRPA) to allow time for the rest of the cellular RS response to resolve any DNA damage. Low level RS is tolerated by cancer cells through an increased reliance on specific cellular machinery responsible for RS mitigation. In contrast, excessive RS can result in extensive DNA damage and cell death through replication and/or cell division catastrophe. Results from multiple in vitro studies suggest that cancer cells with gene amplifications on ecDNA exhibited elevated intrinsic levels of RS and were hypersensitive to further increases in RS, thus providing the rationale to leverage this liability as a therapeutic strategy to treat oncogene amplified cancers.

Circular ecDNA creates abnormally high accessibility of the DNA encoded on the circle, and those DNA remain accessible throughout the cell cycle. Open, accessible DNA is available to the cellular machinery for DNA replication and for RNA transcription.

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In healthy cells, these two processes are tightly coordinated so that cells do not replicate and transcribe the same regions of DNA at the same time. When transcription and replication do occur at the same time and place, transcription-replication collisions occur, resulting in stalled replication forks and RS. Consequently, tumor cells that have ecDNA also have colliding transcription and replication and are therefore under a great deal of RS, as detected by high pRPA levels. This elevated RS creates a unique, druggable, cancer-specific vulnerability.

ecDNA- enabled Cancer Cells Demonstrate Elevated Intrinsic Levels of RS

We are seeking to exploit this synthetic lethal relationship to identify druggable targets essential for survival of cells harboring ecDNA. To this end, as seen in the figure below, we conducted a CRISPR kinome screen in cancer cells resistant to the cancer drug methotrexate via amplification of the gene DHFR on ecDNA. In this ecDNA model system, genetic inactivation of the kinase CHK1 (encoded by CHEK1) resulted in enhanced cytotoxicity in ecDNA-enabled cells as compared to ecDNA negative cells, providing evidence of CHK1 as a potential drug target for ecDNA-enabled tumors.

CRISPR Kinome Screen Identified CHK1 (CHEK1) Inhibition as a Top Synthetic Lethality Hit in ecDNA-enabled Methotrexate Resistant (MTX-R) Cancer Cells

CHK1 is cells’ master regulator of the RS response. CHK1 protects stalled DNA forks, manages DNA replication origin firing, temporarily arrests the cell cycle to allow time for DNA repair, and orchestrates repair through homologous recombination. As such, as seen in the figure below, CHK1 serves an essential role in managing RS, making it a potential therapeutic target for cancer therapy in tumors with high RS, such as those with ecDNA-enabled oncogene amplifications.

CHK1 is the Cellular Master Regulator of the Response to ecDNA-Induced RS

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In our research, both genetic inactivation and pharmacological inhibition of CHK1 using structurally distinct inhibitors resulted in enhanced cytotoxicity to ecDNA-enabled cells compared to cells lacking ecDNA. This synthetic lethal relationship was observed across multiple preclinical models spanning different cancer indications and oncogene amplifications, such as EGFR, FGFR2, CDK4, MYC, and MET. CHK1 inhibition, both as a single agent and in combination with targeted therapy, resulted in tumor growth inhibition and tumor regressions, which correlated with reduced levels of ecDNA-based gene amplification and protein expression in ecDNA-enabled xenograft models.

Historical Challenges with CHK1 Inhibitor Development

CHK1 has been considered a cancer target for many years, and several biopharmaceutical companies have attempted to develop CHK1 inhibitors for cancer. In the past, a major challenge to developing CHK1 inhibitors to treat cancer was difficulty in accurately identifying tumors with high RS or other vulnerabilities that would respond well to this therapeutic approach. Despite strong preclinical data and preliminary evidence of clinical activity for CHK1 inhibition, to date, no development programs have advanced to registration, which we believe is due to lack of adequate predictive biomarker(s) and optimal clinical development strategies. In addition, a range of other challenges have stalled the clinical advancement of prior CHK1 inhibitors. These challenges included suboptimal drug properties, potential compound scaffold-specific safety liabilities, such as potential cardiotoxicities and drug-drug interactions, as well as weak potency or selectivity.

Our Differentiated Approach

Through extensive preclinical studies in oncogene amplified cancer models, we determined what we consider the optimal CHK1 inhibitor profile for targeting oncogene amplified tumors and designed our lead ecDTx, BBI-355, accordingly. We believe that with the optimized biochemical profile of BBI-355, alongside our differentiated precision oncology development strategy, coupled with our approach to identify patients with oncogene amplifications, including those on ecDNA using our ecDNA diagnostic, we can overcome the challenges encountered with prior CHK1 inhibitors. BBI-355 showed picomolar biochemical inhibition of CHK1, low nanomolar activity in a host of tumor cell lines, and substantial antitumor activity in multiple ecDNA-enabled xenograft models representing several tumor types and various driver oncogene amplifications. We are developing BBI-355 for the treatment of oncogene amplified solid tumors, including those with amplifications on ecDNA as detected by our proprietary ecDNA diagnostic.

Properties of BBI-355 observed in preclinical studies are shown below. BBI-355 is a novel, oral, selective small molecule inhibitor of CHK1, and we believe has a predicted low risk of drug-drug interaction and cardiovascular liabilities based on in vitro CYP and hERG/cardiomyocyte study results, respectively.

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Preclinical Properties of BBI-355 CHK1 Inhibitor

BBI-355 In Vitro Preclinical Data

BBI-355 was first characterized extensively in vitro. As seen in the figure below, the kinase selectivity of BBI-355 was evaluated in a broad screen, displaying minimal off-target activity and with high selectivity across the kinome.

Kinase Selectivity of BBI-355

As seen in the figure below, BBI-355 demonstrated broad cytotoxicity against a host of tumor cell lines, with IC50 ranges from approximately 5 nM – 200 nM. Consistent with the enhanced reliance that ecDNA-enabled oncogene amplified cancer cells have on CHK1 due to their intrinsic elevated RS, we have observed increased sensitivity in ecDNA-enabled cancer cell lines over ecDNA negative cancer cell lines. This observation was exemplified using a near isogenic matched cell line pair of colorectal cancer cell lines (COLO320 ecDNA-enabled (+) versus COLO320 ecDNA (-)), wherein BBI-355 was approximately 10-fold more cytotoxic in

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ecDNA-enabled cells. Importantly, the potency of cytotoxicity in the ecDNA-enabled cancer cells paralleled the IC50 for cellular biomarkers of RS, including pRPA, pCHK1, and gH2AX.

BBI-355 Demonstrated Increased In Vitro Activity in ecDNA+ Versus ecDNA- Cancer Cells

BBI-355 Preferentially Increased RS in ecDNA+ Oncogene Amplified Cancer Cells

BBI-355 Single Agent In Vivo Preclinical Data

As seen in the figure below, the antitumor activity of BBI-355 was further exemplified in vivo in multiple ecDNA-enabled xenograft models representing several tumor types and various driver oncogene amplifications. Orally administered BBI-355 demonstrated single agent activity, including regressions in several cases, in an ecDNA-enabled CDK4 amplified osteosarcoma CDX model, ecDNA-enabled EGFR & MET amplified NSCLC PDX model, ecDNA-enabled MYCN amplified neuroblastoma CDX model, and ecDNA-enabled FGFR2 amplified gastric cancer PDX model.

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BBI-355 Demonstrated Single Agent In Vivo Activity Across Multiple ecDNA+ Oncogene Amplified Models

BBI-355 Combination In Vivo Preclinical Data

Cancers that harbor amplified oncogenes, such as EGFR,FGFR, or CDK4, typically do not respond well to single agent targeted therapies. We believe this is because ecDNA can facilitate rapid genomic plasticity, leading to resistance to selective therapeutic pressure. We believe this ecDNA-enabled resistance to targeted therapies can be overcome by combining our ecDTx, such as BBI-355, with targeted agents to interrupt the potential for ecDNA to facilitate resistance. We believe that this ecDTx and targeted therapy combination strategy may be effective across multiple different oncogene cargos encoded on the ecDNA and may lead to higher response rates, deeper regressions, and longer duration of responses as compared to single agent targeted therapies.

Preclinically, we have observed that applying targeted therapy pressure to tumors with ecDNA-enabled oncogene amplification induced tumor cells to evade such pressure via ecDNA-based resistance mechanisms, further increasing RS and reliance on CHK1. Accordingly, and consistent with the vice grip analogy described above, BBI-355 demonstrated combination activity when administered alongside targeted therapies in ecDNA-enabled oncogene amplified xenograft models that are generally resistant to treatment with targeted therapies alone.

As an example, in the figure below, oral administration of BBI-355 led to tumor regressions when dosed in combination with the FGFR inhibitor infigratinib in an ecDNA-enabled FGFR2 amplified gastric cancer CDX model. In this model, treatment with single agent infigratinib led to rapid resistance via ecDNA-enabled amplification of FGFR2. Combining BBI-355 with infigratinib inhibited this resistance and induced tumor regressions. Pharmacodynamic (PD) analysis demonstrated that BBI-355 inhibited the expected increase in FGFR2 copy number that would otherwise be caused by single agent infigratinib to confer resistance to infigratinib.

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BBI-355 In Vivo Antitumor Activity in Combination with Infigratinib in an ecDNA-enabled FGFR2 Amplified Gastric Cancer CDX Model

The oncogene cargo-agnostic nature of this combination approach is reflected in a second ecDNA-enabled EGFR amplified patient-derived gastric cancer xenograft model. In this model, monotherapy treatment with the EGFR inhibitor erlotinib resulted in limited antitumor activity, as seen in the figure below. However, combination with orally administered BBI-355 resulted in statistically significant greater and longer tumor growth inhibition, including regressions in some cases.

BBI-355 In Vivo Antitumor Activity in Combination with Erlotinib in an ecDNA-enabled EGFR Amplified Gastric Cancer PDX Model

As seen in the figure below, oral administration of BBI-355 similarly led to tumor regressions when dosed in combination with the CDK4/6 inhibitor palbociclib in an ecDNA-enabled CDK4 amplified osteosarcoma CDX model. In this model, treatment with single agent palbociclib led to rapid resistance. Combining BBI-355 with palbociclib inhibited this resistance and induced tumor regressions.

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BBI-355 In Vivo Antitumor Activity in Combination with Palbociclib in an ecDNA-enabled CDK4 Amplified Osteosarcoma CDX Model

BBI-355 Clinical Development Plan

Through a comprehensive analysis of the prevalence of ecDNA-enabled gene amplifications alongside clinical outcomes associated with the use of targeted therapies, we have identified specific high unmet need patient populations with oncogene amplified cancers. For our initial targeted indications for clinical development, we are prioritizing cancers with wildtype EGFR amplifications, FGFR1-4 amplifications, or CDK4/6 amplifications.

In May 2023, we enrolled the first patient in our ongoing Phase 1/2 clinical trial of BBI-355 in patients with oncogene amplified cancers. The title of the trial (NCT05827614) is: “An Open-Label, Multicenter, First-in-Human, Dose-Escalation and Dose-Expansion, Phase 1/2 Study of BBI-355 and BBI-355 in Combination with Select Targeted Therapies in Subjects with Locally Advanced or Metastatic Solid Tumors with Oncogene Amplifications.” We also call the trial POTENTIATE, for Precision Oncology Trial Evaluating Novel Therapeutic Interrupting Amplifications Tied to ecDNA. We expect to have preliminary proof of concept safety and antitumor activity data of BBI-355 from the POTENTIATE clinical trial in the second half of 2025.

The design of the trial is an open-label, non-randomized, three-part, Phase 1/2 clinical trial to evaluate the safety and tolerability, human PK, PD biomarkers and preliminary antitumor activity, as well as identify the maximum tolerated dose (MTD) and RP2D of BBI-355 administered as a single agent or in combination with select targeted therapies. In the trial, BBI-355 is administered orally every other day (Q2D) or on less frequent dosing schedules to patients with locally advanced or metastatic non-resectable solid tumors harboring oncogene amplifications whose disease has progressed despite all standard therapies or for whom no further standard or clinically acceptable therapy exists. The trial has three parts: Part 1 is a dose escalation of BBI-355 as a single agent and will include a single agent dose expansion cohort at the RP2D in patients with platinum-resistant high-grade serous ovarian cancer or endometrial cancer. Parts 2 and 3 of this trial will be conducted in 3 separate modules, each module testing the combination of BBI-355 with one of the selected targeted therapies, EGFR inhibitor (module 1), pan-FGFR inhibitor (module 2), or CDK4/6 inhibitor (module 3), in patients with cancers harboring amplification of EGFR, FGFR1-4, or CDK4/6, respectively. Notably, patients will be excluded from enrollment in any part of the trial if they harbor other pathogenic driver oncogene alterations, for example EGFR, FGFR3, KRAS, BRAF mutations or ALK, NTRK, FGFR2, RET, ROS1 fusions.

In Part 1 of the trial, patients with amplification of driver oncogenes, as determined by standard NGS testing, are eligible for enrollment. The goal of Part 1 is to evaluate the safety, tolerability, PK and PD of single agent BBI-355, to determine the RP2D and MTD of BBI-355, and to evaluate preliminary single agent antitumor activity in patients with oncogene amplifications. Single agent BBI-355 will be further tested in a dose expansion cohort at the RP2D in platinum-resistant high-grade serous ovarian cancer or endometrial cancer patients with oncogene amplifications.

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In Part 2 of the trial, patients with amplification of driver oncogenes of interest, EGFR, FGFR1-4, or CDK4/CDK6, as determined by standard NGS testing, will be enrolled in the corresponding module. The goal of Part 2 is to evaluate safety, tolerability, PK, and PD, as well as the RP2D and MTD, and to evaluate preliminary antitumor activity of BBI-355 in combination with the respective targeted therapy inhibitor studied in each module, that is the EGFR inhibitor erlotinib (module 1), pan-FGFR inhibitor futibatinib (module 2), or CDK4/CDK6 inhibitor abemaciclib (module 3).

In Part 3 of the trial, patients with amplification of oncogenes of interest, EGFR, FGFR1-4, or CDK4/CDK6, including those enabled by ecDNA as determined by testing with our ecDNA diagnostic clinical trial assay (see “Our Precision Medicine Approach” below), will be enrolled. The goal of Part 3 is to further evaluate combination antitumor activity at the combination RP2D.

We have entered into clinical trial collaboration and supply agreements with each of Taiho Oncology and Eli Lilly providing for no-cost supply of futibatinib and abemaciclib, respectively, for use in the applicable modules of Parts 2 and 3 of this trial. These agreements also provide for the sharing of certain clinical trial data but have no financial obligations and terminate upon conclusion of the trial.

It is anticipated that approximately 250 to 350 patients will be enrolled in total in this trial. Should any cohort of the trial demonstrate compelling signs of clinical antitumor activity, along with acceptable safety and tolerability, we would seek to engage with the FDA and other global regulatory bodies to discuss potential registrational paths, including the designs of any additional clinical trials we may need to conduct to support potential registrations for BBI-355. We may also consider expanding this trial with additional matched targeted agent and oncogene amplification cohorts based on our ongoing research and the dynamic clinical therapeutic landscape.

Design of BBI-355 Phase 1/2 POTENTIATE Clinical Trial

High-Grade Serous Ovarian Carcinoma (HGSOC)

Bayesian Optimal Interval (BOIN)

Preliminary Results from Part 1 of the POTENTIATE trial

Preliminary data from the ongoing POTENTIATE trial as of the dates noted below have been obtained from 22 subjects enrolled across six dosing cohorts in Part 1 of the trial. Subjects have been treated or are ongoing on an oral Q2D dosing regimen in escalating dose cohorts of 20 mg (N=3), 40 mg (N=4), 60 mg (N=3), and 80 mg (N=4), and on an oral 2 days on and 5 days off weekly dosing regimen (2ON/5OFF) at 80 mg (N=5) and 120 mg (N=3).

Phase 1 Preliminary PK, PD, and Antitumor Activity Data

Preliminary PK data analysis as of February 21, 2024, revealed good oral bioavailability of BBI-355 across the dosing range, including a dose proportional increase of Cmax and AUC values, with some inter-subject variability. The average half-life of BBI-355 was approximately 40 hours, and average drug accumulation was approximately 2 to 3-fold from day 1 to steady state. Average PK exposures at the 40 mg, 60 mg, and 80 mg Q2D doses achieved or exceeded the minimum PK concentration required for tumor regression in certain rodent cancer xenograft models.

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BBI-355 Preliminary Multi-Dose Fitted Human PK Data

A clinical PD assay measuring pCHK1 by immunohistochemistry (IHC) showed CHK1 target engagement in skin punch biopsies across the dosing range as well as in tumor tissue of one patient who consented to serial tumor biopsy.

BBI-355 Preliminary Human PD Data (pCHK1 in serial biopsy)

As for preliminary clinical antitumor activity as of February 21, 2024, stable disease (per RECIST 1.1 criteria) was observed in five of eighteen RECIST evaluable subjects, including regression of target lesions by approximately 20% in a patient with metastatic breast cancer harboring oncogene amplifications who had been a subject in the POTENTIATE trial for approximately six months and is continuing in the trial.

Phase 1 Safety and Tolerability Data

Preliminary clinical safety data as of the data cut-off date of March 4, 2024, showed that, BBI-355 was generally well-tolerated at the first three dose levels (20 mg, 40 mg, 60 mg) administered Q2D, without any dose-limiting toxicities (DLTs) or drug-related serious adverse events (SAEs). At the 80 mg Q2D dose level, DLTs, specifically Grade 4 platelet count decrease and neutrophil count decrease, occurred in two of four subjects, and this dose level was determined to exceed the target toxicity rate. Therefore, 60 mg was determined to be the MTD with this dosing regimen.

BBI-355 was also evaluated on a 2ON/5OFF dosing regimen. Preliminary clinical safety data in this dosing regimen, showed that, as of the data cut-off date of March 4, 2024, BBI-355 was generally well tolerated at the first dose level (80mg), with one DLT, specifically, administration of less than 70% of the intended dose in the DLT evaluation period due to an adverse event of Grade 4 neutrophil count decrease, in one out of five subjects at this dose level. At the 120 mg 2ON/5OFF dose level, DLTs occurred in two of three subjects, specifically one subject experienced a Grade 4 platelet count decrease and a second subject experienced an administration of less than 70% of the intended dose in the DLT evaluation period following Grade 4 neutrophil count decrease, and therefore this dose level was determined to exceed the target toxicity rate or MTD.

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We may consider evaluating other dose levels or dosing schedules to further inform the single agent RP2D and dosing schedule before proceeding to Part 1 dose expansion in platinum-resistant high-grade serous ovarian cancer or endometrial cancer. We anticipate that in the enrolled subjects continuing in the trial as well as those we may enroll in potential future dose escalation cohorts, we may observe toxicities that are novel or on-target class effects for CHK1 inhibitors, which may also constitute DLTs and/or drug-related SAEs.

The following safety information is as of the data cut-off date of March 4, 2024. The most common reported drug-related adverse events (i.e., number of subjects with a specific adverse event) and across all dosing cohorts were neutrophil count decrease or neutropenia (N=4), fatigue (N=4), nausea (N=4), platelet count decrease (N=3), lymphocyte count decrease (N=3), white blood cell count decrease (N=3), diarrhea (N=3), vomiting (N=2), urinary frequency (N=2), headache (N=2), anorexia or loss of appetite (N=2), and dry skin (N=2). Two subjects experienced drug-related SAEs; a Grade 4 platelet count decrease and Grade 4 neutrophil count decrease in one subject, while the other subject experienced Grade 3 anemia leading to hospitalization. All observed hematologic toxicities were asymptomatic, are considered an on-target class effect for CHK1 inhibitors, and have been reported for several other clinical stage CHK1/2 inhibitors.

Based on the totality of the clinical safety, PK, PD, and antitumor activity observed, the POTENTIATE trial advanced into Part 2 of the study. We expect to have preliminary clinical proof of concept safety and antitumor activity data of BBI-355 in the second half of 2025.

Addressable Patient Populations for BBI-355

We estimate that BBI-355, if approved for the combination indications we are targeting in the POTENTIATE trial, could address an initial potential U.S. patient population of approximately 30,000 new patients per year with EGFR, FGFR1-4,or CDK4/6, on ecDNA across a broad range of tumor types. Beyond the United States, we estimate that BBI-355, if approved for such indications, could address approximately 40,000 such patients in the European Union and over 10,000 such patients in Japan, representing a total potential addressable patient population of 80,000 new patients annually in the United States, European Union, and Japan. Our goal is to achieve a tumor agnostic label for BBI-355 in combination with targeted therapies (e.g., an EGFR inhibitor, a pan-FGFR inhibitor, and a CDK4/6 inhibitor) for patients with EGFR, FGFR1-4, or CDK4/6 amplifications. Guided by our ecDNA diagnostic test, we are evaluating basket trial cohorts of each of these indications and treatment settings.

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EGFR Amplified Tumor Types – Using U.S. SEER incidence data by tumor type and adjusting for ecDNA prevalence, we estimate a potential patient population of approximately 5,000 new patients annually in the United States alone for EGFR amplifications. This estimate includes patients with esophageal and gastric cancer, head and neck squamous cell carcinoma, non-small cell lung cancer (NSCLC) squamous cell carcinoma, and other tumor types that exhibit EGFR driver oncogene amplifications on ecDNA, with the potential to expand to glioblastoma, which has high ecDNA prevalence.

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FGFR1-4 Amplified Tumor Types – The potential FGFR1-4 amplified patient population, including early and late stage metastatic, represents up to approximately 18,000 new patients annually in the United States alone. This population includes patients with breast cancer, NSCLC squamous cell carcinoma, esophageal and gastric cancer, bladder cancer, and other tumor types that exhibit FGFR1-4 driver oncogene amplifications on ecDNA.

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CDK4/6 Amplified Tumor Types – The potential CDK4/6 amplified patient population, including early and late stage metastatic, represents approximately 6,000 new patients annually in the United States alone. This population includes patients with liposarcoma, NSCLC squamous cell carcinoma, esophageal and gastric cancer, and other tumor types that exhibit CDK4/6 driver oncogene amplifications on ecDNA, with the potential to expand to glioblastoma.

We also estimate that BBI-355, if approved for the monotherapy indications we are targeting in the POTENTIATE trial, could address a total potential patient population of approximately 65,000 new patients per year with high-grade serous ovarian cancer or endometrial cancer, each with oncogene amplification, in the United States, European Union, and Japan.

In addition to the gene amplified cancer types described above, we are currently conducting preclinical studies of BBI-355 in MDM2 amplified cancers, MET amplified cancers, AR amplified metastatic castration-resistant prostate cancer (mCRPC), and BRAFV600E metastatic colorectal cancers (mCRC). In the future, we intend to pursue additional gene amplified tumor settings as well. Clinical success in one or more of these indications could expand the potential addressable patient population for BBI-355.

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Initial Indications for BBI-355 May Represent a Total Addressable Population of 145,000 New Patients in the United States, the European Union, and Japan Each Year

Central Nervous System (CNS) Penetrant CHK1 Inhibitor Program: BBI-098

In addition to BBI-355, we have also identified a second CHK1 inhibitor candidate with a differentiated profile from BBI-355. This novel ecDTx compound, BBI-098, is orally available, selective, has shown picomolar biochemical inhibition of CHK1, and has demonstrated CNS penetrance in preclinical models. We have nominated BBI-098 as a development candidate and have completed non-Good Laboratory Practice (non-GLP) dose range finding toxicology studies. We are currently conducting in vivo studies in multiple glioblastoma pharmacology models. If those studies are successful and we are able to demonstrate clinical activity of CHK1 inhibition in ecDNA-bearing cancers with our BBI-355 ecDTx, then we may advance BBI-098 into GLP toxicology studies and formulation development to pursue ecDNA-bearing oncology CNS indications such as glioblastoma or brain metastases. Properties of BBI-098 observed in preclinical studies are shown below.

Preclinical Properties of BBI-098 CNS Penetrant CHK1 Inhibitor

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Our Kinesin Program

Our next ecDTx program is directed against a novel member of a class of druggable proteins, the kinesins. This ecDTx target has no approved drugs and, to our knowledge, no other publicly disclosed drug discovery efforts. This kinesin is involved with ecDNA segregation during cellular division and targeting it leverages the fact that ecDNA, unlike chromosomes, lack centromeres.

The cell has evolved numerous redundant mechanisms governing the interactions of chromosomes with the mitotic spindle, the highly coordinated network of factors that separates chromosomes equally into daughter cells during cell division. The primary and essential attachment point for chromosomes to the mitotic spindle is via the centromere, although additional non-essential factors can assist in shepherding chromosomes independently of the centromere. Whereas these centromere-independent segregation factors are non-essentialto chromosome segregation, they may be required for ecDNA due to ecDNA’s lack of centromeres. Consistent with this hypothesis, when certain proteins are genetically deactivated, it can result in abnormal ecDNA segregation during cell division. As shown below, in certain cancer cell lines genetic deactivation of certain proteins can lead to aggregation and eventual loss of ecDNA that is statistically significant. This defect in the segregation process during cell division is directly correlated with significant cytotoxicity in certain ecDNA-enabled tumor cells while demonstrating minimal impact on non-cancerous cells, where such targets may be non-essential.

Genetic Inhibition of Novel Kinesin Target Was Associated with (1) Abnormal ecDNA Segregation, (2) Depleted ecDNA Levels, and (3) Cytotoxicity in Tumor Cells

Through Spyglass, we identified a novel kinesin essential for ecDNA segregation during cellular division. We preclinically validated this target in vitro by demonstrating that genetic inactivation was associated with statistically significant differential sensitivity (and reduction of ecDNA levels) in multiple ecDNA tumor cell lines compared to non-ecDNA-bearing tumor cell lines. We also preclinically validated this target in vivo in multiple tumor models by demonstrating that treatment with our selective degraders led to statistically significant tumor growth inhibition and reduction in oncogene copy number in concert with the degradation of the kinesin target. The therapeutic potential of targeting this kinesin may extend beyond ecDNA-driven cancers, given that tumor cells with other forms of chromosomal instability (CIN) have also demonstrated sensitivity to inactivation of this kinesin in cellular cytotoxicity assays. We have generated orally available nanomolar degraders against this target and are currently advancing our Kinesin program through lead optimization and expect to select a development candidate by mid-2025 and submit an IND in the first half of 2026.

Ongoing Discovery Efforts for Future Programs

In addition to our programs described above, we continue to leverage Spyglass to identify and preclinically validate additional targets. These candidate targets span multiple, diverse nodes, including those leveraging ecDNA, in oncogene amplified cancers. We have preclinically validated multiple additional targets and have initiated ecDTx drug discovery efforts to identify inhibitors against such targets. We expect to continue to identify and preclinically validate additional ecDNA targets and, more broadly, targets associated with oncogene and resistance gene amplification, using our Spyglass platform in the future.

Our Precision Medicine Approach – ecDNA Diagnostic Test

Precision medicine aims to identify and treat patients with specific biomarkers to maximize the likelihood of therapeutic benefit while minimizing side effects. We developed an ecDNA diagnostic test, internally called ECHO, to detect ecDNA in patient tumor specimens and identify patients most likely to benefit from our ecDTx. Our ecDNA diagnostic is a proprietary software algorithm designed to detect the presence of ecDNA by analyzing genomic data in the form of raw data output format files, such as FASTQ or binary sequence alignment map files, generated from routine clinical NGS assays that are commonly used by commercial reference

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laboratories and academic laboratories to profile patient tumor samples. Our ecDNA diagnostic is currently being used as a clinical trial assay to determine ecDNA status of patients enrolled in the BBI-355 POTENTIATE trial. To our knowledge, this is the first and only ecDNA diagnostic in clinical use. As data from our clinical studies mature, we intend to discuss with the FDA whether the ecDNA diagnostic will be appropriate or required to enable commercialization of certain of our ecDTx, if approved.

Competition

The biotechnology and pharmaceutical industries are characterized by rapid evolution of technologies and understanding of disease etiology, intense development and commercial competition, and a strong emphasis on intellectual property. We believe that our approach, strategy, scientific capabilities, know-how, and experience, particularly in the fields of ecDNA and precision oncology, provide us with competitive advantages. Nonetheless, we expect substantial competition from multiple sources, including major biopharmaceutical, specialty pharmaceutical, and existing or emerging biotechnology companies, academic research institutions, governmental agencies, and public and private research institutions worldwide. Many of our competitors, either alone or through collaborations, have or will have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals, and marketing approved products than we do. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These companies may be or may become interested in developing ecDNA-directed therapeutic candidates and may rapidly develop programs that compete with ours by studying ecDNA at scale in the context of oncogene amplified cancer. Even if they do not advance programs with the same mechanism(s) of action as ours, these companies could develop products or product candidates that are competitive with ours or that have a superior product profile and may do so at a rapid pace. These competitors also compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites and patient enrollment in clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs. As a result, our competitors may discover, develop, license, or commercialize products before or more successfully than we do.

We face competition from segments of the pharmaceutical, biotechnology, and other related markets that pursue the development of precision oncology therapies for patients with genetically defined cancers. In addition, we may face competition from companies developing product candidates that are based on synthetic lethality in cancer.

Furthermore, we also face competition more broadly across the oncology market for cost-effective and reimbursable cancer treatments. The most common methods of treating patients with cancer are surgery, radiation, and drug therapy, including chemotherapy, hormone therapy, biologic therapy, such as monoclonal and bispecific antibodies, antibody-drug conjugates, radiopharmaceuticals, immunotherapy, cell-based therapy, and targeted therapy, or a combination of any such methods. There are a variety of available drug therapies marketed for cancer. In many cases, these drugs are administered in combination to enhance efficacy. While our ecDTx, if any are approved, may compete with these existing drugs and other therapies, to the extent they are ultimately used in combination with or as an adjunct to these therapies, our ecDTx may not be competitive with them. Some of these drugs are branded and subject to patent protection, and others are available on a generic basis. Insurers and other third-party payors may also encourage the use of generic products or specific branded products. As a result, obtaining market acceptance of, and gaining significant share of the market for, any of our ecDTx that we successfully introduce to the market may pose challenges. In addition, many companies are developing new oncology therapeutics, and we cannot predict what the standard of care will be as our product candidates progress through clinical development.

For BBI-355, Acrivon Therapeutics, Esperas Pharma, Sumitomo Pharma, and PharmaEngine have CHK1 inhibitors in clinical development. BenevolentAI, Fosun Pharma, and Impact Therapeutics have publicly disclosed preclinical-stage CHK1 inhibitors.

For our pipeline of ecDTx programs, potential competition includes established companies as well as emerging biotechnology companies that launch programs against any of the targets we are pursuing. However, we are not aware of any companies with ecDNA-directed therapeutic programs in clinical development and a patient selection strategy for ecDNA-enabled oncogene amplification. We are currently aware of one early-stage private company that is focused on research in ecDNA, Econic Biosciences.

We could see a reduction or elimination in our potential commercial opportunity if our competitors develop and commercialize drugs that are safer, more effective, have fewer or less severe side effects, are more convenient to administer, are less expensive, or have more favorable commercial labeling than our ecDTx, regardless of whether they target ecDNA as a mechanism of action. Our competitors also may obtain FDA or other regulatory approval for their drugs more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market. The key competitive factors affecting the success of all our ecDTx, if approved, are likely to be their efficacy, safety, route of administration, convenience, price, level of generic competition, and availability of reimbursement from government and other third-party payors.

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Intellectual Property

We strive to protect the intellectual property and proprietary technology that we consider important to our business through a variety of methods. We seek to obtain domestic and international patent protection and endeavor to promptly file patent applications for new commercially valuable inventions as they arise to expand our intellectual property portfolio. We also rely on proprietary know-how and trade secrets to protect certain innovations that may be important to our business and to benefit from their confidential status.

As of March 27, 2025, our intellectual property portfolio included 25 patent families solely owned by us, which include 3 pending US provisional applications, 14 pending US non-provisional patent applications, 4 issued US patents, pending applications in Australia, Brazil, Canada, China, Eurasia, Europe, India, Israel, Japan, Korea, Mexico, Singapore, South Africa and Taiwan, as well as 7 pending applications filed pursuant to the Patent Cooperation Treaty (PCT).

We continually assess and refine our intellectual property strategy as we discover and validate new ecDNA targets, develop new ecDTx product candidates, and make improvements to our Spyglass platform and our ecDNA diagnostic test. To that end, we are prepared to file additional patent applications as appropriate to support our intellectual property strategy, or where we seek to adapt to competition or seize business opportunities.

We cannot be sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications we may own or license in the future, nor can we be sure that any patents we may own or license in the future will be useful in protecting our technology. Please see “Risk Factors—Risks Related to Our Intellectual Property” for additional information on the risks associated with our intellectual property strategy and portfolio.

Intellectual Property Relating to Our CHK1 Program

With regard to our CHK1 program including our BBI-355 and BBI-098 product candidates, as of March 27, 2025, we owned 10 patent families, including 3 pending US non-provisional patent applications, 2 issued US patents, pending applications in Australia, Brazil, Canada, China, Eurasia, Europe, India, Israel, Japan, Korea, Mexico, Singapore, South Africa and Taiwan, as well as 5 pending applications filed pursuant to the Patent Cooperation Treaty (PCT). These patent rights relate to compositions of matter, as well as methods of treating diseases using CHK1 inhibitors. We expect these patents and patents issued from these applications, if any, to expire in 2041-2045 without accounting for any patent term adjustment or extension that may be available.

Intellectual Property Relating to Our Precision Medicine Program

With regard to our precision medicine program, we have developed a proprietary ecDNA diagnostic to detect ecDNA based on the data outputs from NGS tests routinely used to profile patient tumor samples. As of March 27, 2025, we owned 1 patent family related to methods of detecting ecDNA signatures in cancers that is currently pending in the US, China, Europe, and Japan. Additionally, we own 1 pending US non-provisional patent application related to our ecDNA diagnostic. We expect patents issued from these applications, if any, to expire in 2041-2044 without accounting for any patent term adjustment or extension that may be available. We also protect the intellectual property related to ecDNA detection as a trade secret.

Scope and Duration of Intellectual Property Protection

The term of individual patents depends upon the laws of the countries in which they are obtained. In most countries in which we file, the patent term is 20 years from the earliest date of filing of a non-provisional patent application. However, the actual protection afforded by a patent varies on a product-by-product basis, from country-to-country, and depends upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory-related extensions, the availability of legal remedies in a particular country, and the validity and enforceability of the patent. Under certain circumstances, the term of US patents may be adjusted for delays encountered during prosecution that are caused by the USPTO. Additionally, the term of a patent as it specifically relates to an FDA regulated product may be extended. For example, for drugs that are regulated by the FDA under the Hatch-Waxman Act, the FDA is permitted to extend the exclusivity term that covers such drug for up to five years beyond the normal expiration date of the patent, depending on the timing of the issuance of the patent, the IND filing, the NDA filing and the approval date, and provided that the term of the patent does not extend beyond 14 years from the NDA approval date. In the future, if and when our product candidates receive FDA approval, we expect to apply for patent term extensions on patents covering those product candidates. We intend to seek patent term extensions to any of our issued patents in jurisdictions where these are available; however, there is no guarantee that the applicable authorities, including the USPTO and FDA, will agree with our assessment of whether such extensions should be granted, and even if granted, the length of such extensions.

The patent positions of companies like ours are generally uncertain and involve complex legal and factual questions. No consistent policy regarding the scope of claims allowable in patents in the field of oncology therapy has emerged in the US. The patent situation

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outside of the US is even more uncertain. Changes in the patent laws and rules, either by legislation, judicial decisions, or regulatory interpretation in the US and other countries may diminish our ability to protect our inventions and enforce our intellectual property rights, and more generally could affect the value of our intellectual property. In particular, our ability to stop third parties from making, using, selling, offering to sell, importing, or otherwise commercializing any of our patented inventions, either directly or indirectly, will depend in part on our success in obtaining, defending, and enforcing patent claims that cover our technology, inventions, and improvements. We cannot be sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications filed by us in the future, nor can we be sure that any of our patents that may be granted to us in the future will be commercially useful in protecting our product candidates and the methods used to manufacture them.

The area of patent and other intellectual property rights in the biopharmaceutical industry is an evolving one with many risks and uncertainties, and third parties may have blocking patents that could be used to prevent us from commercializing our product candidates and practicing our proprietary technology. Our patents that may issue in the future may be challenged, narrowed, circumvented, or invalidated, which could limit our ability to stop competitors from marketing related product candidates. In addition, our competitors may independently develop similar technologies, and the rights granted under any issued patents may not provide us with protection or competitive advantages against competitors with similar technology. For these and other reasons, we may have competition for our product candidates. Moreover, because of the extensive time required for development, testing, and regulatory review of a potential product, it is possible that before any product candidate can be commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby reducing any protection afforded by the patent. For this and other risks related to our proprietary technology, inventions, improvements, and product candidates, please see the section titled “Risk Factors—Risks Related to Our Intellectual Property.”

We also rely on trade secret protection for our confidential and proprietary information. Although we take steps to protect our confidential and proprietary information as trade secrets, including through contractual means with our employees, consultants, outside scientific collaborators, sponsored researchers, and other advisors, third parties may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to our trade secrets or disclose our technology. Thus, we may not be able to meaningfully protect our technology as trade secrets. It is our policy to require our employees, consultants, outside scientific collaborators, sponsored researchers, and other advisors to execute confidentiality agreements under the commencement of employment or consulting relationships with us. These agreements provide that all confidential information concerning our business or financial affairs developed or made known to the individual during the individual’s relationship with us is to be kept confidential and not disclosed to third parties except in specific circumstances. In the case of employees, the agreements provide that all inventions conceived by the individual, and which are related to our current or planned business or research and development or made during normal working hours, on our premises or using our equipment or proprietary information, are our exclusive property. In many cases our agreements with consultants, outside scientific collaborators, sponsored researchers, and other advisors require them to assign or grant us licenses to inventions they invent as a result of the work or services they render under such agreements or grant us an option to negotiate a license to use such inventions. Despite these efforts, we cannot provide any assurances that all such agreements have been duly executed, and any of these parties may breach the agreements and disclose our proprietary information, and we may not be able to obtain adequate remedies for such breaches.

We also seek to preserve the integrity and confidentiality of our proprietary technology and processes by maintaining physical security of our premises and physical and electronic security of our information technology systems. Although we have confidence in these individuals, organizations, and systems, agreements or security measures may be breached, and we may not have adequate remedies for any breach. To the extent that our employees, contractors, consultants, collaborators, and advisors use intellectual property owned by others in their work for us, disputes may arise as to the rights in relation to the resulting know-how or inventions.

We seek trademark protection in the United States and in certain other jurisdictions where available and when we deem appropriate. We currently have registrations for our “Boundless Bio” mark in the United States as well as in certain foreign jurisdictions, including the European Union. We have registrations for our “UNBOUND BY CONVENTION, BOUND TO SAVE LIVES” mark in the United States. We have also filed a trademark application in the United States for registration of our “ECHO” mark, and we have registrations for our “ECHO” mark in certain foreign jurisdictions, including the European Union. For more information, please see the section titled “Risk Factors—Risks Related to Our Intellectual Property.”

Manufacturing

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 ecDTx for preclinical and clinical testing, as well as for commercial manufacture if any of our ecDTx obtain marketing approval. We work with our current manufacturers to ensure that we will be able to scale up our manufacturing capabilities to support our clinical plans. We also plan to continue to evaluate additional manufacturers to build redundancies into our supply chain. In addition, we rely on third parties to package, label, store, and distribute our ecDTx, and we intend to rely on third parties for our commercial products if marketing approval is obtained. We believe that this strategy allows us to maintain

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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 design and development of our ecDTx.

Commercialization

We intend to retain significant development and commercial rights to our ecDTx and, if marketing approval is obtained, to commercialize our ecDTx on our own, or potentially with a partner, in the United States and other regions. We currently have no sales, marketing, or commercial product distribution capabilities. We intend to build the necessary infrastructure and capabilities over time for the United States, and potentially other regions, following further advancement of our ecDTx. Clinical data, the size of the addressable patient population, the size of the commercial infrastructure, and manufacturing needs may all influence or alter our commercialization plans.

Government Regulation

Government authorities in the United States, at the federal, state and local level, and other countries extensively regulate, among other things, the research, development, testing, manufacture, quality control, import, export, safety, effectiveness, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, marketing and post-approval activities of drug and biological product candidates, such as those we are developing.

U.S. Drug Development Process

In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act (FDCA) and its implementing regulations. Drugs are also subject to other federal, state, and local statutes and regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, and local statutes and regulations require the expenditure of substantial time and financial resources. The process required by the FDA before a new drug may be marketed in the United States generally involves the following:

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completion of nonclinical or preclinical laboratory tests, animal studies and formulation studies, with certain studies conducted in accordance with Good Laboratory Practice (GLP) regulations, and other applicable regulations;

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submission to the FDA of an Investigational New Drug Application (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 site before each trial may be initiated;

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performance of adequate and well-controlled human clinical trials in accordance with Good Clinical Practice regulations (GCPs) to evaluate the safety and efficacy of the product candidate for its intended use;

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

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a determination by the FDA within 60 days of its receipt of an NDA to file the application for review;

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satisfactory completion of an FDA advisory committee review, if applicable;

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satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug is produced to assess compliance with current Good Manufacturing Practice requirements (cGMPs) to assure that the facilities, methods, and controls are adequate to preserve the drug’s identity, strength, quality, and purity;

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satisfactory completion of potential inspection of selected clinical investigation sites to assess compliance with GCPs; and

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FDA review and approval of the NDA to permit commercial marketing of the product for particular indications for use in the United States.

Once a product candidate is identified for development, it enters the preclinical testing stage. Preclinical tests include laboratory evaluations of product chemistry, toxicity, and formulation, as well as animal studies. An IND sponsor must submit, among other things, the results of the preclinical tests, together with manufacturing information and analytical data, to the FDA as part of an IND. An IND is a request for allowance from the FDA to administer an investigational drug product to humans. An IND will also include a protocol detailing, among other things, the objectives of the clinical trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated, if the trial includes an efficacy evaluation. Some preclinical testing may continue even after the IND is submitted. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, places the clinical trial on a clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. Clinical holds also may be imposed by the FDA at any time before or during clinical trials due to safety concerns about ongoing or proposed clinical trials or non-compliance with specific FDA requirements, and in such case, the trials may not begin or

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continue until the FDA notifies the sponsor that the hold has been lifted. FDA may also place a trial on a partial clinical hold. A partial clinical hold is a delay or suspension of only part of the clinical work requested or ongoing under the IND. No more than 30 days after imposition of a clinical hold or partial clinical hold, the FDA will provide the sponsor a written explanation of the basis for the hold. Following issuance of a clinical hold or partial clinical hold, an investigation (or full investigation in the case of a partial clinical hold) may only begin or resume after the FDA has notified the sponsor that the investigation may proceed.

All clinical trials must be conducted under the supervision of one or more qualified investigators in accordance with GCPs, which include, among other things, the requirement that all research subjects provide their informed consent in writing for their participation in any clinical trial. Clinical trials must be conducted under protocols detailing, among other things, the objectives of the trial, dosing procedures, subject selection and exclusion criteria and the safety and effectiveness criteria to be evaluated. Each protocol must be submitted to the FDA as part of the IND, and a separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments. While the IND is active, progress reports summarizing the results of the clinical trials and nonclinical studies performed since the last progress report, among other information, must be submitted at least annually to the FDA, and written IND safety reports must be submitted to the FDA and investigators for serious and unexpected suspected adverse events, findings from other studies suggesting a significant risk to humans exposed to the same or similar drugs, findings from animal or in vitro testing suggesting a significant risk to humans, and any clinically important increased incidence of a serious suspected adverse reaction compared to that listed in the protocol or investigator brochure. The sponsor must report to the FDA any suspected adverse reaction that is both serious and unexpected within fifteen days after the sponsor’s initial receipt of the information. The sponsor must also report to the FDA any unexpected fatal or life-threatening suspected adverse reaction within seven calendar days after the sponsor’s initial receipt of the information.

Furthermore, an independent IRB at each institution participating in the clinical trial must review and approve each protocol before a clinical trial commences at that institution and must also approve the information regarding the trial and the consent form that must be provided to each trial subject or his or her legal representative, monitor the trial until completed and otherwise comply with IRB regulations. The FDA or the sponsor may suspend 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. In addition, some clinical trials are overseen by an independent group of qualified experts organized by the sponsor, known as a data safety monitoring board or committee. Depending on its charter, this group may determine whether a trial may move forward at designated check points based on access to certain data from the trial. There are also requirements governing the registration of certain clinical trials and reporting of ongoing clinical studies and clinical trial results to public registries, including clinicaltrials.gov.

Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:

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Phase 1: The product candidate is initially introduced into healthy human subjects or patients with the target disease or condition, and tested for safety, dosage tolerance, absorption, metabolism, distribution and excretion and, if possible, to gain an early indication of its effectiveness, identify any adverse effects, and determine maximal dosage.

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Phase 2: The product candidate is administered to a limited patient population with a specified disease or condition to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product candidate for specific targeted diseases and to determine dosage tolerance and appropriate dosage.

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Phase 3: The product candidate is administered to an expanded patient population to further evaluate dosage, to provide substantial evidence of efficacy, purity, and potency, and to further test for safety, generally at multiple geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall risk-benefit ratio of the product candidate and provide an adequate basis for product labeling.

Post-approval trials, sometimes referred to as Phase 4 studies, may be conducted after initial 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.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug and finalize a process for manufacturing the product in commercial quantities in accordance with cGMPs. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, the manufacturer must develop methods for testing the identity, strength, quality and purity of the final drug. In addition, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

U.S. Review and Approval Process

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The results of product development, preclinical and other non-clinical studies, and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and other relevant information are submitted to the FDA as part of an NDA requesting approval to market the product. The submission of an NDA is subject to the payment of substantial user fees; a waiver of such fees may be obtained under certain limited circumstances.

In addition, the Pediatric Research Equity Act (PREA), requires a sponsor to conduct pediatric clinical trials for most drugs, for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration. Under PREA, original NDAs and supplements must contain a pediatric assessment unless the sponsor has received a deferral or waiver. The required assessment must evaluate the safety and effectiveness, or safety, purity, and potency of the product for the claimed indications in all relevant pediatric subpopulations and support dosing and administration for each pediatric subpopulation for which the product is deemed safe and effective, or safe, pure, and potent. The sponsor may request or the FDA may grant a deferral of pediatric clinical trials for some or all of the pediatric subpopulations. A deferral may be granted for several reasons, including a finding that the drug is ready for approval for use in adults before pediatric clinical trials are complete or that additional safety or effectiveness data needs to be collected before the pediatric clinical trials begin. The FDA must send a non-compliance letter to any sponsor that fails to submit the required assessment, keep a deferral current, or fails to submit a request for approval of a pediatric formulation.

Once an NDA has been submitted, the FDA conducts a preliminary review of the application within the first 60 days after submission, before accepting it for filing, to determine whether it is sufficiently complete to permit substantive review. The FDA may request additional information rather than accept an NDA for filing. In this event, the NDA must be resubmitted with the additional information. The resubmitted application also is subject to review before the FDA accepts it for filing. Once filed, the FDA reviews an NDA to determine, among other things, whether a product is safe and effective for its intended use and whether its manufacturing is cGMP-compliant to assure and preserve the product’s identity, strength, quality, and purity. Under the Prescription Drug User Fee Act (PDUFA) guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of an NDA for a new molecular entity to complete a standard review and act on the submission. This review typically takes twelve months from the date the NDA is submitted to FDA because the FDA has approximately two months to make a “filing” decision after the application is submitted.

The FDA may refer an application for a novel drug to an advisory committee. An advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates, and provides recommendations as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

Before approving an NDA, the FDA will typically inspect the facility or facilities where the product is manufactured to assure compliance with cGMPs. Additionally, before approving an NDA, the FDA may inspect one or more clinical trial sites to assure compliance with GCPs. After the FDA evaluates an NDA and conducts any required inspections of manufacturing facilities where the investigational product and/or its drug substance will be produced, the FDA may issue an approval letter or a Complete Response Letter (CRL). An approval letter authorizes commercial marketing of the drug with prescribing information for specific indications. A CRL indicates that the review cycle for the application is complete, and the application will not be approved in its present form. A CRL usually describes the specific deficiencies in the NDA identified by the FDA and may require additional clinical data, including additional clinical trials or other significant and time-consuming requirements related to clinical trials, nonclinical studies, or manufacturing. If a CRL is issued, the sponsor must 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 resubmitted NDA does not satisfy the criteria for approval.

If a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product. In addition, the FDA may require that contraindications, warnings or precautions be included in the product’s labeling; require that post-approval studies be conducted to further assess the drug’s safety or effectiveness; require testing and surveillance programs to monitor the safety of the commercialized product; or impose other conditions, including distribution restrictions or other risk management mechanisms, including a risk evaluation and mitigation strategy (REMS) to assure safe use of the product. If the FDA concludes a REMS is needed, the sponsor of the NDA must submit a proposed REMS, which could include medication guides, physician communication plans or elements to assure safe use, such as restricted distribution methods, patient registries, and other risk minimization tools. The FDA will not approve the NDA without an approved REMS, if required. Any of these limitations on approval or marketing could restrict the commercial promotion, distribution, prescription or dispensing of products.

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Orphan Drug Designation

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug intended to treat a rare disease or condition, which is a disease or condition that affects fewer than 200,000 individuals in the United States or, if it affects more than 200,000 individuals in the United States, there is no reasonable expectation that the cost of developing and making a drug product available in the United States for this type of disease or condition will be recovered from sales of the product. Orphan designation must be requested before submitting an NDA. After the FDA grants orphan designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Orphan 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 product exclusivity, which means that the FDA may not approve any other applications to market the same drug for the same disease or condition for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity or inability to manufacture the product in sufficient quantities. The designation of such drug also entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages, and user-fee waivers. However, competitors, may receive approval of different products for the disease or condition for which the orphan product has exclusivity or obtain approval for the same product but for a different disease or condition for which the orphan product has exclusivity. Orphan exclusivity also could block the approval of a competing product for seven years if a competitor obtains approval of the “same drug,” as defined by the FDA, or if the active moiety of the product candidate is determined to be contained within the competitor’s product for the same disease or condition. In addition, if an orphan designated product receives marketing approval for a disease or condition broader than what is designated, it may not be entitled to orphan exclusivity.

Expedited Development and Review Programs

The FDA has a number of programs intended to expedite the development or review of a marketing application for an investigational drug. For example, the fast track designation program is intended to expedite or facilitate the process for developing and reviewing product candidates that meet certain criteria. Specifically, investigational drugs are eligible for fast track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition. The sponsor of a fast track product candidate has opportunities for more frequent interactions with the applicable FDA review team during product development and, once an NDA is submitted, the application may be eligible for priority review. With regard to a fast track product candidate, the FDA may consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

A product candidate intended to treat a serious or life-threatening disease or condition may also be eligible for breakthrough therapy designation to expedite its development and review. A product candidate can receive breakthrough therapy designation if preliminary clinical evidence indicates that the product candidate, alone or in combination with one or more other drugs or biologics, may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. The designation includes all of the fast track program features, as well as more intensive FDA interaction and guidance beginning as early as Phase 1 and an organizational commitment to expedite the development and review of the product candidate, including involvement of senior managers.

An NDA may also be eligible for priority review if the product candidate is designed to treat a serious condition and, if approved, would provide a significant improvement in safety or efficacy compared to available therapies. The FDA will attempt to direct additional resources to the evaluation of an NDA designated for priority review in an effort to facilitate the review. The FDA endeavors to review applications with priority review designations within six months of the filing date as compared to ten months for review of new molecular entity NDAs under its current PDUFA review goals.

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In addition, depending on the design of the applicable clinical trials, a product candidate may be eligible for accelerated approval. Specifically, drugs intended to treat serious or life-threatening diseases or conditions may be eligible for accelerated approval upon a determination that the product candidate has 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, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. As a condition of approval, the FDA generally requires that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled confirmatory clinical trials and may require that such confirmatory trials be underway prior to granting accelerated approval. Drugs receiving accelerated approval may be subject to expedited withdrawal procedures if the sponsor fails to conduct the required confirmatory trials in a timely manner or if such trials fail to verify the predicted clinical benefit. In addition, the FDA currently requires as a condition of accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

Fast track designation, breakthrough therapy designation, priority review, and accelerated approval do not change the standards for approval but may expedite the development or approval process. Even if a product candidate 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 for FDA review or approval will not be shortened.

Post-Approval Requirements

Any drug manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to record-keeping, reporting of adverse experiences, periodic reporting, product sampling and distribution, and advertising and promotion of the product. After approval, most changes to the approved product, such as adding new indications, or additional labeling claims, are subject to further FDA review and approval. There also are continuing, annual program fees for any marketed products.

Drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP requirements, which impose certain procedural and documentation requirements upon NDA holders and their third-party manufacturers. Changes to the manufacturing process are strictly regulated, and, depending on the significance of the change, may require prior FDA approval before being implemented. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain compliance with cGMPs and other aspects of regulatory compliance.

The FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information; imposition of requirements for post-market studies or clinical studies to assess new safety risks; or imposition of distribution restrictions or other restrictions under a REMS program. Other potential consequences include, among other things:

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restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market, or product recalls;

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fines, warning letters, or untitled letters;

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clinical holds on ongoing or planned clinical studies;

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refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of approvals;

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product seizure or detention, or refusal to permit the import or export of products;

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consent decrees, corporate integrity agreements, debarment, or exclusion from federal healthcare programs;

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mandated modification of promotional materials and labeling and the issuance of corrective information;

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the issuance of safety alerts, Dear Healthcare Provider letters, press releases, and other communications containing warnings or other safety information about the product; or

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injunctions or the imposition of civil or criminal penalties.

In addition, the FDA closely regulates the marketing, labeling, advertising, and promotion of drug products. A sponsor can only make those claims relating to safety and efficacy that are approved by the FDA and in accordance with the provisions of the approved label. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses. Failure to

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comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising, and potential civil and criminal penalties. Physicians may prescribe legally-available products for uses that are not described in the product’s labeling and that differ from those tested by us and approved by the FDA. Such off-label uses are common across medical specialties. Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances. The FDA does not regulate the behavior of physicians in their choice of treatments. The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products.

Marketing Exclusivity

Market exclusivity provisions under the FDCA can delay the submission or the approval of certain marketing applications. The FDCA provides a five-year period of non-patent data exclusivity within the United States to the first applicant to obtain approval of an NDA for a new chemical entity. A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period, the FDA may not accept for review an abbreviated new drug application (ANDA), or an NDA submitted under Section 505(b)(2) (505(b)(2) NDA) submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original innovative drug or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval. However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed with the FDA by the innovator NDA holder.

The FDCA alternatively provides three years of non-patent exclusivity for an NDA or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example new indications, dosages or strengths of an existing drug. This three-year exclusivity covers only the modification for which the drug received approval based on the new clinical investigations and does not prohibit the FDA from approving ANDAs or 505(b)(2) NDAs for drugs containing the active agent for the original indication or condition of use. Five-year and three-year exclusivity will not delay the submission or approval of a full NDA. However, an applicant submitting a full NDA would be required to conduct, or obtain a right of reference to, all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

Pediatric exclusivity is another type of marketing exclusivity available in the United States. Pediatric exclusivity provides for an additional six months of marketing exclusivity attached to an existing period of regulatory exclusivity or available patent term if a sponsor conducts clinical trials in children in response to a “written request” from the FDA. The issuance of a written request does not require the sponsor to undertake the described clinical trials, and the FDA’s grant of pediatric exclusivity does not require the FDA to approve labeling containing information on pediatric use based on the studies conducted.

FDA Regulation of Companion Diagnostics

We believe that certain of our ecDTx may require an in vitro diagnostic to identify appropriate patient populations for investigation and/or use of our ecDTx. These diagnostics, often referred to as companion diagnostics, are regulated as medical devices. In the United States, the FDCA and its implementing regulations, and other federal and state statutes and regulations govern, among other things, medical device design and development, preclinical and clinical testing, premarket clearance or approval, registration and listing, manufacturing, labeling, storage, advertising and promotion, sales and distribution, export and import, and post-market surveillance. Unless an exemption applies, diagnostic tests require marketing clearance or approval from the FDA prior to commercial distribution. The two primary types of FDA marketing authorization applicable to a medical device are premarket notification, also called 510(k) clearance, and premarket approval (PMA). Most companion diagnostics for oncology product candidates, such as those we are developing, utilize the PMA pathway.

If use of a companion diagnostic is deemed essential to the safe and effective use of a drug product, then the FDA generally will require approval or clearance of the diagnostic contemporaneously with the approval of the therapeutic product. In August 2014, the FDA issued a final guidance document addressing the development and approval process for “In Vitro Companion Diagnostic Devices.” According to the guidance, for novel product candidates, a companion diagnostic device and its corresponding drug candidate should be approved or cleared contemporaneously by FDA for the use indicated in the therapeutic product labeling. The guidance also explains that a companion diagnostic device used to make treatment decisions in clinical trials of a drug generally will be considered an investigational device, unless it is employed for an intended use for which the device is already approved or cleared. If used to make critical treatment decisions, such as patient selection, the diagnostic device may be considered a significant risk device under the FDA’s Investigational Device Exemption (IDE) regulations. In which case, the sponsor of the diagnostic device will be required to submit and obtain approval of an IDE application and subsequently comply with the IDE regulations. However, according to the guidance, if a diagnostic device and a drug are to be studied together to support their respective approvals, both products can be studied in the same investigational study, if the study meets both the requirements of applicable IDE regulations and the IND regulations. The guidance provides that, depending on the details of the study plan and degree of risk posed to subjects, a sponsor may seek to submit an IND alone, or both an IND and an IDE.

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The FDA has generally required companion diagnostics intended to select the patients who will respond to cancer treatment to obtain approval of a PMA for that diagnostic simultaneously with approval of the therapeutic. The PMA process, including the gathering of clinical and preclinical data and the submission to and review by the FDA, can take several years or longer. It involves a rigorous premarket review during which the applicant must prepare and provide the FDA with reasonable assurance of the device’s safety and effectiveness and information about the device and its components regarding, among other things, device design, manufacturing, and labeling. In addition, PMAs for certain devices must generally include the results from extensive preclinical and adequate and well-controlled clinical trials to establish the safety and effectiveness of the device for each indication for which FDA approval is sought. In particular, for a diagnostic, the applicant must demonstrate that the diagnostic produces reproducible results when the same sample is tested multiple times by multiple users at multiple laboratories. As part of the PMA review, the FDA will typically inspect the manufacturer’s facilities for compliance with the Quality System Regulation (QSR), which currently imposes elaborate testing, control, documentation, and other quality assurance requirements.

If the FDA’s evaluation of the PMA application is favorable, the FDA may issue an approvable letter requiring the applicant’s agreement to specific conditions, such as changes in labeling, or specific additional information, such as submission of final labeling, to secure final approval of the PMA. If the FDA’s evaluation of the PMA or manufacturing facilities is not favorable, the FDA will deny approval of the PMA or issue a not approvable letter. A not approvable letter will outline the deficiencies in the application and, where practical, will identify what is necessary to make the PMA approvable. The FDA may also determine that additional clinical trials are necessary, in which case the PMA approval may be delayed for several months or years while the trials are conducted and then the data submitted in an amendment to the PMA. If and when the FDA concludes that the applicable criteria have been met, the FDA will issue a PMA for the approved indications, which can be more limited than those originally sought by the applicant. The PMA can include post-approval conditions that the FDA believes necessary to ensure the safety and effectiveness of the device, including, among other things, restrictions on labeling, promotion, sale, and distribution. Once granted, PMA approval may be withdrawn by the FDA if compliance with post approval requirements, conditions of approval or other regulatory standards are not maintained, or problems are identified following initial marketing.

After a device is commercialized, it remains subject to significant regulatory requirements. Medical devices may be marketed only for the uses and indications for which they are cleared or approved. Device manufacturers must also establish registration and device listings with the FDA. A medical device manufacturer’s manufacturing processes and those of its suppliers are required to comply with the applicable portions of the QSR, which currently cover the methods and documentation of the design, testing, production, processes, controls, quality assurance, labeling, packaging, and shipping of medical devices. Domestic facility records and manufacturing processes are subject to periodic unscheduled inspections by the FDA. The FDA also may inspect foreign facilities that export products to the United States.

Other Healthcare Laws

Pharmaceutical companies are subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states and foreign jurisdictions in which they conduct their business. Such laws include, without limitation, U.S. federal and state anti-kickback, fraud and abuse, false claims, pricing reporting, and physician payment transparency laws and regulations regarding drug pricing and payments or other transfers of value made to physicians and other licensed healthcare professionals as well as similar foreign laws in the jurisdictions outside the United States. Violation of any of such laws or any other governmental regulations that apply may result in significant penalties, including, without limitation, administrative civil and criminal penalties, damages, disgorgement fines, additional reporting requirements and oversight obligations, contractual damages, the curtailment or restructuring of operations, exclusion from participation in governmental healthcare programs and/ or imprisonment.

Coverage and Reimbursement

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