On May 9, 2023 -Boundless Bio, a clinical stage, next-generation precision oncology company developing innovative therapeutics directed against extrachromosomal DNA (ecDNA) for patients with oncogene amplified cancer, reported that the first patient has been dosed with BBI-355 in a first-in-human, Phase 1/2 clinical trial for patients with locally advanced or metastatic solid tumors with oncogene amplifications (NCT05827614) (Press release, Boundless Bio, MAY 9, 2023, View Source [SID1234631316]). ecDNA is a key driver of high copy number amplification in cancer, and Boundless Bio has validated several drug targets that are essential for ecDNA function in cancer cells. As the company reported at the AACR (Free AACR Whitepaper) Annual Meeting 20221 and the AACR (Free AACR Whitepaper) Annual Meeting 20232, a critical vulnerability of tumor cells that rely upon oncogene amplification on ecDNA to grow and survive is that they exhibit very high levels of DNA replication stress. Hence ecDNA bearing cancer cells are hyper-reliant for survival on checkpoint kinase 1 (CHK1), cells’ master regulator of replication stress, and are hypersensitive to inactivation of CHK1. BBI-355 is an orally available, potent, and selective small molecule inhibitor of CHK1 and represents the first ecDNA-directed therapy (ecDTx) developed for cancer patients that harbor oncogene amplification on ecDNA.

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"We are excited to announce dosing of the first patient in our first-in-human clinical study of BBI-355," said Klaus Wagner, M.D., Ph.D., Chief Medical Officer at Boundless Bio. "Preclinically, single agent BBI-355 demonstrates potent anti-cancer activity in ecDNA-enabled oncogene amplified tumor models and robust, synergistic efficacy in combination with select cancer therapies. There is a large unmet medical need for cancer patients with oncogene amplification, and we look forward to working with some of the top U.S. cancer centers to bring new and promising treatment options to these patients."

"Memorial Sloan Kettering Cancer Center (MSKCC) is excited to participate in the POTENTIATE study and advance our understanding of ecDNA-driven cancer," said Alexander Drilon, M.D., Chief of Early Drug Development Service at MSKCC and Weill Cornell Medical Center. "There is a significant need to develop new therapies for patients with cancers enabled by oncogene amplification as there are very few options for these patients."

"Initiation of the first the clinical study of our first ecDTx marks a significant milestone for Boundless Bio," said Zachary Hornby, President and Chief Executive Officer at Boundless Bio. "We’re delighted to work with the participating investigators in the POTENTIATE study, and we are eager to determine whether BBI-355 could represent new hope for patients with oncogene amplified tumors."

References

1Chowdhry et al. Replication stress and the inability to repair damaged DNA, the potential "Achilles’ heel" of ecDNA+ tumor cells [abstract]. Cancer Res 2022;82(12_Suppl): Abstract nr 1520.
2Chowdhry et al. Tumors driven by oncogene amplified extrachromosomal DNA (ecDNA) demonstrate enhanced sensitivity to cell cycle checkpoint kinase 1 (CHK1) inhibition [abstract]. Cancer Res 2023;83(7_Suppl): Abstract nr 1626.

POTENTIATE Study Background

BBI-355 is being evaluated in a first-in-human Phase 1/2 clinical trial ("POTENTIATE": Precision Oncology Trial Evaluating Novel Therapeutic Interrupting Amplifications Tied to ecDNA) in patients with locally advanced or metastatic solid tumors with oncogene amplifications, whose disease has progressed despite all standard therapies or for whom no further standard or clinically acceptable therapy exists. The open-label, non-randomized, 3-part study involves: (Part 1) BBI-355 single agent dose escalation and expansion in cancer patients with oncogene amplification, (Part 2) dose escalation of BBI-355 in combination with select therapies in cancer patients with specific oncogene amplifications, and (Part 3) dose expansion of BBI-355 in combination with select therapies in cancer patients with specific oncogene amplification on ecDNA. BBI-355 is administered orally every other day. In Part 3 of the study, an ecDNA diagnostic clinical trial assay (CTA) called ECHO (ecDNA Harboring Oncogenes) will be implemented to determine the presence of oncogenes amplified on ecDNA in patient tumor samples. ECHO is a proprietary bioinformatic diagnostic algorithm designed by Boundless Bio and developed in collaboration with SOPHiA GENETICS to detect oncogenes amplified on ecDNA from tumor biopsy samples using routine clinical NGS assays.

About BBI-355

BBI-355 is a potentially best-in-class checkpoint kinase 1 (CHK1) inhibitor and the first ecDNA-directed therapy (ecDTx) being investigated to treat patients with oncogene amplified cancer. CHK1 is a master regulator of DNA replication stress (RS), which frequently arises from oncogene amplification on ecDNA. Inhibition of CHK1 by BBI-355 is synthetic lethal in cancer cells with oncogene amplification on ecDNA due to their heightened RS. CHK1 was identified and validated as an ecDNA essential target via Boundless Bio’s proprietary Spyglass research platform, leading Boundless Bio to develop BBI-355, an orally available, potent, and selective CHK1 inhibitor.

About Extrachromosomal DNA (ecDNA)

ecDNA are circular units of nuclear DNA that are physically distinct from chromosomes and are found only within cancer cells. ecDNA encode full length genes, including oncogenes and regulatory regions, are highly transcriptionally active, and lack centromeres. ecDNA replicate and express within cancer cells and, due to their lack of centromeres, can be asymmetrically passed to daughter cells during cell division, leading to focal gene amplification and gene copy number heterogeneity in cancer. By leveraging the plasticity afforded by ecDNA, cancer cells can rapidly increase or decrease copy number of select genes located on ecDNA to enable survival under selective pressures, including targeted therapy, chemotherapy, or radiation, thereby making ecDNA one of cancer’s primary mechanisms of growth and treatment resistance. ecDNA are a key driver of the most aggressive and difficult-to-treat cancers, specifically those characterized by high copy number amplification of oncogenes.

On May 9, 2023 Affini-T Therapeutics, Inc., a precision immunotherapy company unlocking the power of T cells against oncogenic driver mutations, reported that preclinical data for its oncogenic driver program targeting KRAS G12D, AFNT–212, will be presented at the American Society of Gene and Cell Therapy (ASGCT) (Free ASGCT Whitepaper) 26th Annual Meeting in Los Angeles, California (Press release, Affini-T Therapeutics, MAY 9, 2023, View Source [SID1234631315]).

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"Our mission is to address the significant unmet needs of patients with hard-to-treat solid tumors by advancing precision immunotherapies that target oncogenic driver mutations," said Loïc Vincent, Ph.D., Chief Scientific Officer, Affini-T Therapeutics. "We believe gene editing is an important tool in the development of cell therapies as it allows for precise and targeted modifications within cells, aimed to improve safety and activity of these therapies. We look forward to presenting encouraging preclinical data for our gene-edited KRAS G12D-targeting TCR-T cell therapy, AFNT-212, at ASGCT (Free ASGCT Whitepaper) this year."

Poster presentation details are as follows:

Abstract: #1691, May 19, 12:00-2:00 pm PT: Novel CRISPR-Associated Gene Editing Systems Enable Efficient and Specific TRAC/TRBC Knockout Triggering Robust Expression and Sensitivity of a T Cell Receptor Specific for Mutant KRAS G12D – Presenting Author: Ankit Gupta, Ph.D., Director of Gene Editing, Affini-T Therapeutics

On May 9, 2023 Pfizer and Thermo Fisher Scientific Inc. (NYSE: TMO) reported that they have entered into a collaboration agreement to help increase local access to next-generation sequencing (NGS)-based testing for lung and breast cancer patients in more than 30 countries across Latin America, Africa, the Middle East and Asia where advanced genomic testing has previously been limited or unavailable (Press release, Thermo Fisher Scientific, MAY 9, 2023, View Source [SID1234631314]). Access to local NGS testing can help to provide faster analysis of associated genes, empowering healthcare providers to select the right therapy for that individual patient.

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Cancer is a leading cause of death globally, accounting for nearly 10 million deaths in 2020, or around one in six deaths. Breast and lung cancer are the leading types of cancer diagnosed and are responsible for almost 4.5 million deaths worldwide. By 2040, the global burden for cancer is expected to grow to 27.5 million new cancer cases and 16.3 million cancer deaths.3 Under the agreement, Thermo Fisher will identify local labs that will be using the company’s NGS technology and ensure they have the necessary infrastructure, trained staff, and quality control measures to meet industry standards for NGS testing services for breast and lung cancer. Pfizer will explore ways to enable affordable patient access for NGS testing for these types of cancer and work to raise healthcare provider awareness regarding the benefits of advanced testing. The two companies will continue to evaluate opportunities to expand geographically and to expand testing for other types of cancer.

"Anyone facing a cancer diagnosis should have access to cutting-edge testing that can match them with an appropriate, optimized treatment plan and better inform their care. Today, we aim to bring rapid NGS testing to an increased number of decentralized labs, closer to where patients are treated," said Gianluca Pettiti, executive vice president at Thermo Fisher Scientific. "We are moving one step closer to delivering precision insights to underserved patients so they can receive a more tailored path for their care no matter where they are in the world."

"The more we understand the complex science behind cancer, the better we can treat it. Our experience has taught us that cancer cannot always be treated with a broad brush and often requires an individualized approach based on precise disease characteristics," said Nick Lagunowich, Pfizer Global President of Emerging Markets. "In many parts of the world, access to next-generation sequencing may be limited or unaffordable for cancer patients. This program aims to improve their treatment journey and help increase their chances for improved outcomes."

Single gene testing has historically been used to match patients with appropriate targeted therapies. However, this can be a time intensive process if sequential tests are needed and there may not be enough tissue to run every test – which may require additional biopsy procedures. As more targeted therapies are available that can be matched through a broader set of genomic markers, next-generation sequencing is quickly replacing sequential, single biomarker tests. By screening a single tumor tissue or blood sample for multiple biomarkers simultaneously, NGS can provide clinical teams with rapid and actionable genomic insights to help inform precision oncology treatment decisions for eligible patients.

A retrospective observational real-world data study looked at newly diagnosed stage IV non-small cell lung cancer patients, and found outcomes such as apparent survival and time to next treatment were significantly compromised if actionable mutations were identified after systemic treatment was initiated (e.g. chemotherapy and immunotherapy). However, when treatment was initiated based on molecular results, patients experienced better outcomes compared to patients who were treated prior to receiving molecular results, supporting the need for rapid molecular testing to inform better treatment decisions.

On May 9, 2023 BostonGene reported that as part of its ongoing commitment to improving the diagnosis and personalized treatment recommendations for cancer patients, it will participate in and present at PEGS Boston Summit on May 15 – 19, 2023, at the Hynes Convention Center (Press release, BostonGene, MAY 9, 2023, View Source [SID1234631313]). The event is the leading biologics event covering all aspects of biologic drug development with in-depth presentations on protein and antibody engineering, immunotherapy, oncology, expression, analytics, immunogenicity, and more. BostonGene will also exhibit at booth #228.

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BostonGene session details can be found below:

Comprehensive genomic and immune profiling of tumor tissue and peripheral blood to predict immunotherapy response and identify mechanisms of immune escape

Monday, May 15 | 2:50 PM ET
Speaker: Michael Goldberg, PhD, Director of Immunology, BostonGene
The session will address how BostonGene’s innovative AI and ML-based solutions can precisely predict immunotherapy responses, resistance, and immune-related adverse events. The presentation will underscore how our comprehensive genomic and immune profiling platform will assist in providing patients with the most effective treatments and mechanistic stratification that will propel bringing novel agents and combinations into the clinic and ultimately accelerate the next phase of drug discovery.

To learn more, or to schedule a meeting with BostonGene during PEGS Boston 2023, please contact Maria Proia at [email protected].

On May 9, 2023 Guardant Health, Inc. (Nasdaq: GH), a leading precision oncology company focused on helping conquer cancer globally through use of its proprietary tests, vast data sets and advanced analytics, reported financial results for the quarter ended March 31, 2023 (Press release, Guardant Health, MAY 9, 2023, View Source [SID1234631312]).

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First Quarter 2023 Financial Highlights

Revenue of $128.7 million for the first quarter of 2023, an increase of 34% over the first quarter of 2022
Reported 39,100 tests to clinical customers and 6,150 tests to biopharmaceutical customers in the first quarter of 2023, representing an increase of 45% and 21%, respectively, over the first quarter of 2022
Recent Operating Highlights

Delivered record clinical volumes driven by the FDA approval of Guardant360 CDx for ESR1 mutations in metastatic breast cancer and expanded commercial coverage to more than 300 million lives
Received Medicare coverage for Guardant Response, the first blood-only liquid biopsy for I-O monitoring for all solid tumors

Filed premarket approval (PMA) application for Shield blood-based CRC screening, and FDA review process underway
Presented additional data from ECLIPSE trial at Digestive Disease Week (DDW)
Strengthened leadership team with the appointment of Ines Dahne-Steuber as Chief Operating Officer to drive further operating efficiency and scale, and the promotion of Darya Chudova to Chief Technology Officer to continue innovation of our market-leading technology platform
"We are off to a very strong start with robust clinical volume growth fueled by continued expansion in lung cancer and a step change in breast cancer volumes following our recent FDA approval of Guardant360 CDx in metastatic breast cancer," said Helmy Eltoukhy, co-founder and co-CEO. "With the recent coverage of Guardant Response, we now have full Medicare coverage across our Therapy Selection and MRD product portfolios. This coverage will help drive continued volume growth as we approach breakeven in our Therapy Selection core business and execute on our strategy to be the worldwide leader in precision oncology."

"Each quarter we are making more progress on our goal of developing a new patient-preferred market category in CRC screening. Shield is the first mover in this category that achieved 83% overall CRC sensitivity at 90% specificity in range with other guideline-recommended non-invasive CRC screening tests. Based on this study readout, our team has recently submitted the PMA, and the FDA review is currently underway," said AmirAli Talasaz, co-founder and co-CEO. "Today at DDW, the study investigators presented additional insights for the ECLIPSE trial. Sensitivity of our test at stage I-III was 81% where cure rates are highest, and 72% in detecting localized disease that would most likely be cured through surgical procedures. Based on our ECLIPSE results, we believe that as a longitudinal screening test, taken every three years, Shield will detect nearly all CRCs at a curable stage and will save many lives."

First Quarter 2023 Financial Results

Revenue was $128.7 million for the three months ended March 31, 2023, a 34% increase from $96.1 million for the three months ended March 31, 2022. Precision oncology revenue grew 35%, driven predominantly by an increase in clinical testing volume and biopharma sample volume, which grew 45% and 21%, respectively, over the prior year period. Development services and other revenue increased by 28%, primarily due to revenues earned from our partnership agreements during the three months ended March 31, 2022.

Gross profit, or total revenue less cost of precision oncology testing and cost of development services and other, was $75.6 million for the first quarter of 2023, an increase of $11.5 million from $64.1 million for the corresponding prior year period. Gross margin, or gross profit divided by total revenue, was 59%, as compared to 67% for the corresponding prior year period. Precision oncology gross margin was 60% in the first quarter of 2023, as compared to 64% in the prior year period. The reduction is due to the change in mix between clinical and biopharma revenue, as well as the year over year change in blended clinical ASP due to the increased proportion of volume coming from Reveal, TissueNext and Response. Development services and other gross margin was 48% in the first quarter of 2023, as compared to 89% in the prior year period. The change is due to a one-time cost incurred in the first quarter of 2023 related to one of our partnership agreements and to the inclusion of the cost of processing Shield LDT samples as part of our screening market development activities.

Operating expenses were $209.7 million for the first quarter of 2023, as compared to $187.5 million for the corresponding prior year period, an increase of 12%. Non-GAAP operating expenses were $188.3 million for the first quarter of 2023, as compared to $158.7 million for the corresponding prior year period.

Net loss was $133.5 million for the first quarter of 2023, as compared to $123.2 million for the corresponding prior year period. Net loss per share was $1.30 for the first quarter of 2023, as compared to $1.21 for the corresponding prior year period. Non-GAAP net loss was $108.5 million for the first quarter of 2023, as compared to $93.2 million for the corresponding prior year period. Non-GAAP net loss per share was $1.06 for the first quarter of 2023, as compared to $0.91 for the corresponding prior year period.

Adjusted EBITDA loss was $101.0 million for the first quarter of 2023, as compared to a $86.6 million loss for the corresponding prior year period.

Free cash outflow for the first quarter of 2023 was $82.0 million. Cash, cash equivalents and marketable debt securities were $937.0 million as of March 31, 2023.

2023 Guidance

Guardant Health expects full year 2023 revenue to be in the range of $535 million to $545 million, representing growth of 19% to 21% compared to full year 2022. This compares to its previous guidance range of $525 million to $540 million. Guardant Health continues to expect full year 2023 operating expenses to be below full year 2022, driven by efficiency measures and continued leverage of its existing infrastructure, and free cash outflow to be approximately $350 million in 2023.

Webcast Information

Guardant Health will host a conference call to discuss the first quarter and full year 2023 financial results after market close on Tuesday, May 9, 2023 at 1:30 pm Pacific Time / 4:30 pm Eastern Time. A webcast of the conference call can be accessed at View Source The webcast will be archived and available for replay for at least 90 days after the event.

Non-GAAP Measures

Guardant Health has presented in this release certain financial information in accordance with U.S. Generally Accepted Accounting Principles (GAAP) and also on a non-GAAP basis, including non-GAAP cost of precision oncology testing, non-GAAP cost of development services and other, non-GAAP research and development expense, non-GAAP sales and marketing expense, non-GAAP general and administrative expense, non-GAAP loss from operations, non-GAAP net loss, non-GAAP net loss per share, basic and diluted, Adjusted EBITDA, and free cash flow.

We define our non-GAAP measures as the applicable GAAP measure adjusted for the impacts of stock-based compensation and related employer payroll tax payments, changes in estimated fair value of noncontrolling interest liability, contingent consideration, acquisition related expenses, amortization of intangible assets, fair value adjustments on marketable equity securities, impairment of non-marketable securities and other assets, and other non-recurring items.

Adjusted EBITDA is defined as net loss adjusted for interest income; interest expense; other income (expense), net; provision for (benefit from) income taxes; depreciation and amortization expense; stock-based compensation expense and related employer payroll tax payments; changes in estimated fair value of noncontrolling interest liability; adjustments relating to contingent consideration; and, if applicable in a reporting period, acquisition-related expenses, and other non-recurring items. Free cash flow is defined as net cash used in operating activities in the period less purchases of property and equipment in the period.

We believe that the exclusion of certain income and expenses in calculating these non-GAAP financial measures can provide a useful measure for investors when comparing our period-to-period core operating results, and when comparing those same results to that published by our peers. We exclude certain other items because we believe that these income (expenses) do not reflect expected future operating expenses. Additionally, certain items are inconsistent in amounts and frequency, making it difficult to perform a meaningful evaluation of our current or past operating performance. We use these non-GAAP financial measures to evaluate ongoing operations, for internal planning and forecasting purposes, and to manage our business.

These non-GAAP financial measures are not intended to be considered in isolation from, as substitute for, or as superior to, the corresponding financial measures prepared in accordance with GAAP. There are limitations inherent in non-GAAP financial measures because they exclude charges and credits that are required to be included in a GAAP presentation, and do not present the full measure of our recorded costs against its revenue. In addition, our definition of the non-GAAP financial measures may differ from non-GAAP measures used by other companies.