On May 1, 2025 Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biotechnology company working to develop a new class of drugs based on targeted protein degradation, reported financial results for the first quarter ended March 31, 2025, and provided a corporate update (Press release, Arvinas, MAY 1, 2025, View Source [SID1234652423]).

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"The positive readout from our first Phase 3 trial, the first ever for a PROTAC, is a tremendous accomplishment and one which we are very proud of," said John Houston, Ph.D., Chairperson, Chief Executive Officer and President at Arvinas. "Our conviction is high that vepdegestrant can be highly competitive as a monotherapy treatment option for metastatic breast cancer in the second-line, ESR1 mutant setting. We are on track to submit a regulatory filing with health authorities, which we believe could result in the first ever approval of a PROTAC and an exciting opportunity to bring a novel treatment to patients with ESR1 mutant advanced metastatic breast cancer."

"Beyond the second-line monotherapy opportunity, we and our partners at Pfizer have removed plans for a Phase 3 first-line combination trial with atirmociclib, as well as the planned Phase 3 second-line combination trial with a CDK4/6 inhibitor, from our joint development plan," continued Dr. Houston. "This decision was made following a review of the totality of emerging information, including external data results, the evolving treatment landscape in metastatic breast cancer, and long-term capital allocation. We and Pfizer are working to evaluate future combination plans with the potential to maximize patient benefit and shareholder value."

1Q 2025 Business Highlights and Recent Developments

Vepdegestrant: Oral PROTAC ER degrader: As part of Arvinas global collaboration with Pfizer, the companies:

Reported positive topline data for VERITAC-2, the Phase 3 pivotal 2L+ trial of monotherapy vepdegestrant in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced or metastatic breast cancer, in the estrogen receptor 1-mutant population.
VERITAC-2 data accepted for oral presentation at the 2025 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (May 30 – June 3, 2025).
Announced that Pfizer will add a vepdegestrant/KAT6 cohort to its ongoing Phase 1 trial evaluating its investigational KAT6 inhibitor (PF-07248144) in combination with endocrine therapies following CDK4/6 inhibitor treatment.
Removed the first-line Phase 3 combination trial with Pfizer’s novel investigational CDK4 inhibitor, atirmociclib, from the agreed-upon joint development plan.
Removed the second-line Phase 3 combination trial with a CDK4/6 inhibitor from the agreed-upon joint development plan.
ARV-102: Oral PROTAC LRRK2 degrader

Presented single ascending dose (SAD) and multiple ascending dose (MAD) data from the ongoing Phase 1 clinical trial in healthy volunteers in an oral session at the Alzheimer’s Disease/Parkinson’s Disease (AD/PD) conference in Vienna, Austria demonstrating blood-brain barrier penetration, and central and peripheral LRRK2 degradation:
At a single oral dose of at least 60 mg, and once daily repeated oral doses of at least 20 mg, ARV-102 achieved greater than 50% LRRK2 reduction in the cerebral spinal fluid (CSF) and greater than 90% LRRK2 reduction in the peripheral blood mononuclear cells (PBMCs), indicating substantial central and peripheral LRRK2 protein degradation.
Inhibition of Rab10 phosphorylation in PBMCs and reduction of bis(monoacylglycerol)phosphate (BMP) in urine following single doses of ARV-102, signifying downstream LRRK2 pathway engagement.
Bioavailable and brain penetrant with dose dependent exposure in the CSF.
ARV-102 was generally safe and well tolerated with no serious adverse events reported after single or multiple doses.
ARV-393: Oral PROTAC BCL6 degrader

Continued recruiting patients in the first-in-human Phase 1 clinical trial in patients with non-Hodgkin lymphoma (NHL) (ClinicalTrials.gov Identifier: NCT06393738).
Presented new preclinical data of ARV-393 in combination with standard of care (SOC) biologic agents and small molecule inhibitors (SMI) in high-grade B-cell lymphoma (HGBCL) and aggressive diffuse large B-cell lymphoma (DLBCL) models at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting demonstrating that ARV-393 had broad and significant combinability with:
SOC chemotherapy:
ARV-393 in combination with R-CHOP, induced significantly greater tumor growth inhibition (TGI) compared with rituximab, CHOP, R-CHOP, or ARV-393 alone, with complete tumor regressions enabled by the combination.
SOC biologics:
Similarly, the combination of ARV-393 and SOC biologics targeting CD19 (tafasitamab), CD79b (polatuzumab vedotin), or CD20 (rituximab) resulted in tumor regressions and demonstrated significantly stronger TGI compared with either agent alone.
Investigational small molecule inhibitors targeting clinically validated oncogenic drivers of lymphoma:
Combination of ARV-393 with a BTK inhibitor (acalabrutinib), a BCL2 inhibitor (venetoclax), or an EZH2 inhibitor (tazemetostat) induced tumor regressions in the majority of mice.
Overall, current preclinical data suggest that ARV-393 has the potential to be an attractive combination partner for development of novel therapies for lymphoma, including chemo-free combination regimens and/or "all oral" treatment options.
ARV-806: Novel PROTAC KRAS G12D degrader

Filed an Investigational New Drug (IND) application and received a safe-to-proceed letter from the U.S. Food and Drug Administration.
Corporate updates:
As part of a Company-wide cost reduction effort:

Announced the removal of two Phase 3 trials from the vepdegestrant development plan
Announced a reduction in workforce of approximately one-third across the Company to streamline operations across the organization and enable the efficient progression of the Company’s portfolio. The reduction is planned to be completed in the second quarter of 2025.
Announced a reprioritization of the Company’s preclinical portfolio to focus on assets that have the greatest potential to deliver value for patients, physicians and shareholders.
Updated guidance for its cash runway into the second half of 2028.
"We continuously evaluate and refine our long-term strategy, and recent challenges in the capital markets have required us to expeditiously evaluate our business priorities and capital needs," continued Dr. Houston. "Although difficult, the workforce reduction is a prudent decision that we believe will right-size the Company for future success. I want to thank all the talented employees who were directly impacted by this decision. I’m proud of the progress we have made together, and want to acknowledge their contributions, and commitment, to discovering and developing new treatment options for patients with serious diseases."

Anticipated Upcoming Milestones and Expectations

Vepdegestrant: Oral PROTAC ER degrader
As part of Arvinas’ global collaboration with Pfizer, the companies plan to:

Present detailed results from the VERITAC-2 Phase 3 clinical trial in a late-breaker oral presentation at ASCO (Free ASCO Whitepaper) (2Q 2025).
VERITAC-2 abstract will be featured in the ASCO (Free ASCO Whitepaper) press program and has been selected to be included in the "2025 Best of ASCO (Free ASCO Whitepaper) Program."
Share data with global regulatory authorities to potentially support regulatory filings (2Q 2025) and submit new drug application to the U.S. Food and Drug Administration for potential approval (2H 2025).
Add a combination cohort of vepdegestrant plus Pfizer’s KAT6 inhibitor (PF-07248144) to Pfizer’s ongoing Phase 1 trial (NCT04606446).
The trial is currently evaluating Pfizer’s KAT6 inhibitor in combination with endocrine therapies following CDK4/6 inhibitor treatments; the trial is being operationalized and funded by Pfizer.
ARV-102: Oral PROTAC LRRK2 degrader

Present final data from the SAD/MAD cohorts of the Phase 1 clinical trial in healthy volunteers (2H 2025).
Continue enrollment and present initial data from the SAD cohort of the ongoing Phase 1 clinical trial in patients with Parkinson’s disease (2H 2025).
Initiate the MAD cohort of the Phase 1 clinical trial in patients with Parkinson’s disease (2H 2025).
ARV-393: Oral PROTAC BCL6 degrader

Present new preclinical data demonstrating single agent activity of ARV-393 in patient derived xenograft models of transformed Follicular Lymphoma and a patient-derived xenograft model of nTFHL-AI (angioimmunoblastic type of nodal T-follicular helper cell lymphoma), a rare and aggressive non-Hodgkin lymphoma with high unmet need and limited treatment options, at the European Hematology Association (EHA) (Free EHA Whitepaper) 2025 conference in Milan, Italy (June 12-15, 2025).
Share preclinical data in combination with an emerging SOC option in 2L DLBCL (2H 2025).
Share preliminary clinical data from the ongoing Phase 1 clinical trial in patients with NHL (NCT06393738) (2H 2025).
ARV-806: Novel PROTAC KRAS G12D degrader

Initiate a first-in-human Phase 1 trial in patients with solid tumors harboring KRAS G12D mutations (2H 2025).
Financial Guidance
Based on its current operating plan, Arvinas believes its cash, cash equivalents, and marketable securities as of March 31, 2025, is sufficient to fund planned operating expenses and capital expenditure requirements into the second half of 2028.

First Quarter Financial Results
Cash, Cash Equivalents, and Marketable Securities Position: As of March 31, 2025, cash, cash equivalents and marketable securities were $954.3 million as compared with cash, cash equivalents and marketable securities of $1,039.4 million as of December 31, 2024. The decrease in cash, cash equivalents and marketable securities of $85.1 million for the three months ended March 31, 2025 was primarily related to cash used in operations of $85.1 million, the purchase of lab equipment and leasehold improvements of $0.4 million and $0.1 million of long term debt repayments, partially offset by unrealized gains on marketable securities of $0.5 million.

Research and Development Expenses: Generally Accepted Accounting Principles (GAAP) Research and development (R&D) expenses were $90.8 million for the quarter ended March 31, 2025, as compared with $84.3 million for the quarter ended March 31, 2024. The increase in research and development expenses of $6.5 million for the quarter was primarily due to an increase in external expenses of $7.8 million, partially offset by a decrease in compensation and related personnel expenses of $1.4 million, which are not allocated by program. External expenses include (i) program-specific expenses, which increased by $10.0 million, primarily driven by increases in our ARV-102, vepdegestrant, ARV-393 and other programs of $5.2 million, $5.0 million, $1.4 million and $2.5 million, respectively, offset by decreases in our luxdegalutamide (ARV-766) and bavdegalutamide (ARV-110) programs of $3.6 million and $0.5 million, respectively, and (ii) our non-program specific expenses, which decreased by $2.2 million.

Non-GAAP R&D expenses were $79.3 million for the quarter ended March 31, 2025, as compared with $71.9 million for the quarter ended March 31, 2024, excluding $11.5 million and $12.4 million of non-cash stock-based compensation expense for the quarters ended March 31, 2025 and 2024, respectively. A reconciliation of GAAP to non-GAAP financial measures used in this press release can be found at the end of this press release.

General and Administrative Expenses: GAAP General and administrative (G&A) expenses were $26.6 million for the quarter ended March 31, 2025, as compared with $24.3 million for the quarter ended March 31, 2024. The increase in general and administrative expenses of $2.3 million for the quarter was primarily due an increase in professional fees of $2.4 million, inclusive of an increase in the amortization of costs to obtain a contract of $2.6 million related to changes in total Vepdegestrant (ARV-471) Collaboration Agreement program cost estimates resulting from the removal of two Phase 3 combination trials from the development plan and an increase in costs related to developing our commercial operations of $2.3 million, partially offset by a decrease in personnel and infrastructure related costs of $2.4 million.

Non-GAAP G&A expenses were $23.1 million for the quarter ended March 31, 2025, as compared with $18.0 million for the quarter ended March 31, 2024, excluding $3.5 million and $6.3 million of non-cash stock-based compensation expense for the quarters ended March 31, 2025 and 2024, respectively. A reconciliation of GAAP to non-GAAP financial measures used in this press release can be found at the end of this press release.

Revenue: Revenue was $188.8 million for the quarter ended March 31, 2025 as compared with $25.3 million for the quarter ended March 31, 2024. Revenue for the quarter is related to the Vepdegestrant (ARV-471) Collaboration Agreement with Pfizer and the collaboration and license agreement with Pfizer. The increase in revenue of $163.5 million was primarily due to an increase in revenue from the Vepdegestrant (ARV-471) Collaboration Agreement with Pfizer totaling $167.8 million related to changes in total program cost estimates resulting from the removal of the first-line Phase 3 combination trial with Pfizer’s novel investigational CDK4 inhibitor, atirmociclib, and the removal of the second-line Phase 3 combination trial with a CDK4/6 inhibitor from the development plan, offset by a decrease in revenue from the Pfizer Research Collaboration Agreement of $2.7 million due to changes in estimates of the performance period duration under the agreement resulting from updated research timelines and a decrease in revenue from the Bayer Collaboration Agreement of $1.6 million related to the termination of the Bayer Collaboration Agreement in August 2024.

Investor Call & Webcast Details
Arvinas will host a conference call and webcast today, May 1, 2025, at 8:00 a.m. ET to review its first quarter 2025 financial results and discuss recent corporate updates. Participants are invited to listen by going to the Events and Presentation section under the Investors page on the Arvinas website at www.arvinas.com. A replay of the webcast will be available on the Arvinas website following the completion of the event and will be archived for up to 30 days.

On May 1, 2025 Exact Sciences Corp. (Nasdaq: EXAS), a leading provider of cancer screening and diagnostic tests, reported that the Company generated revenue of $707 million for the first quarter ended March 31, 2025, compared to $638 million for the same period of 2024 (Press release, Exact Sciences, MAY 1, 2025, View Source [SID1234652439]).

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"Our strong first quarter results pave the way for 2025 to mark our most transformative year yet," said Kevin Conroy, chairman and CEO. "The Exact Sciences team just launched two innovative tests: Cologuard Plus, our next-generation colon cancer screening test, and Oncodetect, our molecular residual disease test. These additions expand our portfolio and move us closer to our goal of helping to eradicate cancer by preventing it, detecting it earlier, and guiding personalized treatment. With growing momentum in our commercial organization and improved profitability, we raised our full-year outlook and continue to build a foundation for sustained, long-term growth."

First-quarter 2025 financial results

For the three-month period ended March 31, 2025, as compared to the same period of 2024 (where applicable):

Total revenue was $707 million, an increase of 11% on a reported and core revenue basis
Screening revenue was $540 million, an increase of 14%
Precision Oncology revenue was $167 million, an increase of 2%, or 4% on a core revenue basis
Gross margin was 71%, and adjusted gross margin was 74%, an increase of nearly 50 basis points
Net loss was $101 million, or $0.54 per share, an improvement of $9 million and $0.06 per share, respectively
Adjusted EBITDA was $63 million, an increase of $24 million or 61%, and adjusted EBITDA margin was 9%, an increase of 280 basis points
Operating cash flow was $31 million and free cash flow was break-even, increases of $113 million and $120 million, respectively
Cash, cash equivalents, and marketable securities were $786 million at the end of the quarter
Screening primarily includes laboratory service revenue from Cologuard tests and PreventionGenetics. Precision Oncology includes laboratory service revenue from global Oncotype DX and therapy selection tests.

Platform and pipeline advancements

In the first quarter, Exact Sciences launched the Cologuard Plus test, the company’s next-generation colon cancer screening test. The Cologuard Plus test detects cancers and precancerous polyps with even greater sensitivity than the Cologuard test while reducing false positives by nearly 40 percent. This advancement enhances the Company’s screening capabilities and reinforces its commitment to delivering high-quality, non-invasive options for patients. The Company launched the Cologuard Plus test with Medicare coverage and secured HEDIS guideline inclusion in March 2025.

In April, Exact Sciences launched the Oncodetect test, its molecular residual disease and recurrence monitoring test. Oncodetect identifies residual disease up to two years earlier than imaging, the current standard of care. The Company expects to obtain Medicare reimbursement in colon cancer in the second quarter of 2025.

Exact Sciences is on track for the launch of CancerguardTM EX, a laboratory-developed multi-cancer screening test, in the second half of 2025. Additionally, Exact Sciences is on track to share results from the pivotal BLUE-C study supporting its colon cancer blood test in mid-summer of 2025. The Company will bring both tests to patients through its large commercial organization and unique ExactNexusTM technology platform.

2025 outlook

The Company has updated its full-year 2025 revenue and adjusted EBITDA guidance:

Prior guidance

May 1 update

Change at midpoint

Y/Y growth rate

Total revenue

$3.025 – $3.085 billion

$3.070 – $3.120 billion

$40.0 million

12%

Screening

$2.350 – $2.390 billion

$2.390 – $2.425 billion

$37.5 million

14%

Precision Oncology

$675 – $695 million

$680 – $695 million

$2.5 million

5%

Adjusted EBITDA

$410 – $440 million

$425 – $455 million

$15.0 million

36%

First-quarter 2025 conference call & webcast

Company management will host a conference call and webcast on Thursday, May 1, 2025, at 5 p.m. ET to discuss first-quarter 2025 results. The webcast will be available at exactsciences.com. Domestic callers should dial 888-330-2384 and international callers should dial +1-240-789-2701. The access code for both domestic and international callers is 4437608. A replay of the webcast will be available at exactsciences.com. The webcast, conference call, and replay are open to all interested parties.

Non-GAAP disclosure

In addition to the Company’s financial results determined in accordance with U.S. GAAP, the Company provides non-GAAP measures that it determines to be useful in evaluating its operating performance and liquidity. The Company presents the following non-GAAP measures:

Core revenue — Core revenue is calculated to adjust for recent acquisitions and divestitures and foreign currency exchange rate fluctuations. Revenue from recent acquisitions is adjusted for the 12 months following acquisition when the periods are not comparable. To exclude the impact of change in foreign currency exchange rates from the prior period under comparison, the Company converts the current period non-U.S. dollar denominated revenue using the prior year comparative period exchange rates.

Adjusted EBITDA and adjusted EBITDA margin — The Company defines adjusted EBITDA as net loss adjusted for interest expense, income tax expense or benefit, depreciation expense, amortization of acquired intangible assets, investment income or loss, and certain other items which include significant non-cash items and other charges or benefits resulting from transactions or events that are highly variable, significant in size, and that we do not believe are indicative of ongoing or future business operations. These items are discussed in more detail below in the tables captioned "U.S. GAAP to Non-GAAP Reconciliation". Adjusted EBITDA margin is calculated as adjusted EBITDA divided by total revenue.

Adjusted gross profit, adjusted research and development expenses, adjusted sales and marketing expenses, adjusted general and administrative expenses, adjusted loss from operations, adjusted net loss before tax, adjusted income tax expense (benefit), adjusted net loss, and adjusted earnings per share — The Company refers to various "adjusted" amounts or measures on an "adjusted" basis, which exclude the impact of amortization of intangible assets and certain charges or benefits resulting from transactions or events that are highly variable, significant in size, and that we do not believe are indicative of ongoing or future business operations. These items are described in more detail below in the tables captioned "U.S. GAAP to Non-GAAP Reconciliation". The Company also presents certain of these adjusted measures as a percentage of revenue including adjusted gross margin.

Free cash flow — The Company defines free cash flow as net cash used in or provided by operating activities, reduced by purchases of property, plant and equipment. Management uses free cash flow as a liquidity measure.

Management believes that presentation of non-GAAP financial measures provides supplemental information useful to investors in understanding our underlying operating results and trends. Non-GAAP financial information, when taken collectively, may be helpful to investors because it provides consistency and comparability of the Company’s operating results across reporting periods. Management uses this non-GAAP financial information to establish budgets, manage the Company’s business, and set incentive and compensation arrangements. Free cash flow provides useful information to management and investors since it measures our ability to generate cash from business operations. Non-GAAP financial information is presented for supplemental information purposes only, has limitations as an analytical tool and should not be considered in isolation or as a substitute for financial information presented in accordance with U.S. GAAP. For example, adjusted gross margin and adjusted gross profit exclude the amortization of acquired intangible assets although such measures include the revenue associated with the acquisitions. Additionally, adjusted EBITDA and other adjusted operating result metrics exclude a number of expense items that are included in net loss. As a result, positive adjusted EBITDA, adjusted operating income, or adjusted earnings per share may be achieved while a significant net loss persists. For more information on these non-GAAP financial measures, see the tables captioned "U.S. GAAP to Non-GAAP Reconciliation." The Company presents certain forward-looking statements about the Company’s future financial performance that include non-GAAP measures. These non-GAAP measures include adjustments like stock-based compensation, acquisition and integration costs including gains and losses on contingent consideration, and other significant charges or gains that are difficult to predict for future periods because the nature of the adjustments pertain to events that have not yet occurred. Additionally, management does not forecast many of the excluded items for internal use. Information reconciling forward-looking non-GAAP measures to U.S. GAAP measures is therefore not available without unreasonable effort and is not provided. The occurrence, timing, and amount of any of the items excluded from GAAP to calculate non-GAAP could significantly impact the Company’s GAAP results.

About the Cologuard and Cologuard Plus tests:

Developed in collaboration with Mayo Clinic, the Cologuard and Cologuard Plus tests are non-invasive colorectal cancer (CRC) screening options for the 110 million U.S. adults ages 45 or older who are at average risk for the disease.

The Cologuard test revolutionized CRC screening by detecting specific DNA markers and blood associated with cancer and precancer in stool, allowing patients to use the test at home without special preparation or time off. It is covered by Medicare and included in national screening guidelines from both the American Cancer Society (2018) and the U.S. Preventive Services Task Force (2021). Since its launch in 2014, the Cologuard test has been used to screen for CRC 19 million times.

Building on this success, the FDA-approved Cologuard Plus test raises the performance bar even further and features novel biomarkers, improved laboratory processes, and enhanced sample stability. The Cologuard Plus test is expected to reduce false positives by nearly 40%, to help minimize unnecessary follow-up colonoscopies. Both tests demonstrate Exact Sciences’ commitment to improving CRC screening access and outcomes. Exact Sciences launched the Cologuard Plus test with Medicare coverage and guideline inclusion in the first quarter of 2025.

About the Oncodetect test

Molecular residual disease refers to the presence of tumor-specific DNA in the body. These fragments of genetic information, known as circulating tumor DNA (ctDNA), are shed into the bloodstream by tumors, and their presence may indicate that cancer is present. Exact Sciences’ MRD offering leverages our in-house capabilities in whole exome sequencing to offer a tumor-informed MRD test for a personalized approach to detecting and monitoring residual cancer in patients with solid tumors. By identifying somatic genomic alterations in tumor DNA and detecting a subset in ctDNA from blood, the Oncodetect test enables the detection of ctDNA before, during, and after treatment. This critical information can guide therapy decisions and monitor for cancer recurrence.

About the Cancerguard test

The Cancerguard test, currently in development, is designed to detect multiple cancers in their earliest stages from a single blood draw. Building upon decades of research, Exact Sciences intends to harness the additive sensitivity of multiple biomarker classes to detect more cancers in earlier stages. The Cancerguard test will utilize a streamlined and standardized imaging-based diagnostic pathway, which may result in fewer follow-up procedures. The test is being developed to provide high specificity to help minimize false positives while detecting multiple cancers, including those with the biggest toll on human health. These features describe current development goals. The Cancerguard test has not been cleared or approved by the U.S. Food and Drug Administration or any other national regulatory authority. To learn more, visit View Source

About Exact Sciences’ Precision Oncology portfolio

Exact Sciences’ Precision Oncology portfolio delivers actionable genomic insights to inform prognosis and cancer treatment after a diagnosis. In breast cancer, the Oncotype DX Breast Recurrence Score test is the only test shown to predict the likelihood of chemotherapy benefit as well as recurrence in invasive breast cancer. The Oncotype DX test is recognized as the standard of care and is included in all major breast cancer treatment guidelines. The OncoExTra test applies comprehensive tumor profiling, utilizing whole exome and whole transcriptome sequencing, to aid in therapy selection for patients with advanced, metastatic, refractory, relapsed, or recurrent cancer. With an extensive panel of approximately 20,000 genes and 169 introns, the OncoExTra test is one of the most comprehensive genomic (DNA) and transcriptomic (RNA) panels available today. Exact Sciences enables patients to take a more active role in their cancer care and makes it easy for providers to order tests, interpret results, and personalize medicine, by applying real-world evidence and guideline recommendations. To learn more, visit precisiononcology.exactsciences.com.

About PreventionGenetics

Founded in 2004 and located in Marshfield, Wisconsin, PreventionGenetics is a CLIA and ISO 15189:2012 accredited laboratory. PreventionGenetics delivers clinical genetic testing of the highest quality at fair prices with exemplary service to people around the world. PreventionGenetics has 25 PhD geneticists on staff and provides tests for nearly all clinically relevant genes including the powerful and comprehensive germline whole genome sequencing test, PGnome and whole exome sequencing test, PGxome. PreventionGenetics was acquired by Exact Sciences in December 2021.

On May 1, 2025 Intima Bioscience, a clinical stage oncology company focused on curative intent in solid tumor cancers, reported data from a first-in-human study using CRISPR knockout of the intracellular immune checkpoint CISH in T cells administered to patients with metastatic colorectal cancer at the 2025 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Intima Bioscience, MAY 1, 2025, View Source [SID1234652462]).

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"Over the last decade, the fast-growing field of Immuno-Oncology has nearly entirely focused on neutralizing cell surface targets. Inhibiting promising intracellular checkpoint targets like CISH have dramatic anti-cancer potential, but have traditionally been thought to be undruggable," said Emil Lou, M.D., Ph.D., Principal Investigator of the clinical trial and Professor of Hematology and Oncology at the University of Minnesota. "This first-in-human study used CRISPR/Cas9 deletion of CISH as a model system to evaluate the viability of CISH checkpoint inhibition as a novel strategy for solid tumor immunotherapy."

In a featured oral presentation at the AACR (Free AACR Whitepaper) Meeting, Dr. Lou provided the first report of the effects of administering neoantigen reactive TILs with knockout of CISH, a gene which encodes cytokine-inducible SH2-containing protein, in patients with metastatic colorectal cancer. The study’s results were contemporaneously published in The Lancet Oncology. This dataset consisted of 12 patients who had received multiple lines of therapy, including standard-of-care chemotherapy and biologic agents.

"This is the first clinical trial to test genetic disruption of CISH as a harbinger of a new class of immune checkpoints that have pan cancer activity and are not limited by any given tumor’s surface PD-L1 expression. Multiple genomic screens have converged on nominating these intracellular immune checkpoints as highly promising therapeutic targets to advance immunotherapy beyond the current limits of the PD1/PD-L1 paradigm," said Christopher A. Klebanoff, M.D., a senior advisor to the study and immunotherapy expert at Memorial Sloan Kettering Cancer Center (MSK), Associate Attending, Laboratory Head, and Member, Immuno-Oncology Program (IOP).

Key points from this proof-of-concept clinical trial:

The most common severe adverse events included expected hematological events attributable to the preparative lymphodepleting chemotherapy regimen or expected effects of IL-2 (12 patients [100%]). No episodes of high-grade cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome were observed. No serious adverse events or patient deaths resulted from targeting the CISH checkpoint.
A patient with young adult/early onset Stage IV colorectal cancer resistant to multiple lines of chemotherapy and immunotherapy was treated on this trial and developed a clinical complete response which is ongoing after more than two years.
Detailed molecular and genetic analysis of this patient demonstrated ongoing persistence of CISH inhibited T cells synchronous with the ongoing complete response to this treatment.
As a testament to the end stage nature of the treated patient population, the median progression-free survival on this trial was 57 days, and median overall survival was 129 days.
A companion scientific paper entitled "CISH, a novel intracellular immune checkpoint, in comparison and combination to existing and emerging cancer immune checkpoints" comprehensively evaluates the intrinsic single agent and combination anti-cancer activity of CISH relative to other prevailing immune checkpoints. This preprint has been submitted for peer review.

Dr. Lou added: "In metastatic colorectal cancer, where treatment options are limited and survival outcomes are uniformly fatal, CISH represents a promising new target that may overcome the limitations of current immunotherapies. We believe these data, including an exceptional complete response attributed to CISH knockout, resoundingly support the potential role of CISH checkpoint inhibition in addressing this significant unmet need and underline the possibility of small molecule drugging of CISH to democratize access to patients beyond this proof-of-concept cell therapy clinical trial."

NB: The National Cancer Institute of the NIH formally defines an exceptional response as a complete response in which less than 10% of patients respond overall.

About CISH
The cytokine-inducible SH2-containing protein CISH is an intracellular cancer immune checkpoint that functions as a negative modulator of T-cell receptor (TCR) signaling and cancer neoantigen recognition. CISH negatively regulates antigen-specific cytokine release and T cell expansion via its capacity to bind PLC-γ1, a proximal mediator of TCR complex signaling. Inhibition of CISH in T cells is believed to help overcome immune evasion regardless of tumor type or PD-L1 expression.

On May 1, 2025 Ascendis Pharma A/S (Nasdaq: ASND) reported financial results for the first quarter ended March 31, 2025, and provided a business update (Press release, Ascendis Pharma, MAY 1, 2025, View Source [SID1234652424]).

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"The strong global launch of YORVIPATH positions 2025 to be an inflection point for Ascendis with growing revenue and a path to cashflow breakeven in the near term," said Jan Mikkelsen, Ascendis Pharma’s President and Chief Executive Officer. "We look forward to potential approvals of our third product, TransCon CNP, as a monotherapy in children with achondroplasia, and we believe the upcoming topline COACH combination trial data may demonstrate improved outcomes, including growth, compared to TransCon CNP alone. With our diversified pipeline, robust supply chain, and strong global commercial capabilities we are well-positioned to deliver on our commitment to provide patients with highly differentiated medicines."

Select Highlights & Anticipated 2025 Milestones

TransCon PTH:
(palopegteriparatide, marketed as YORVIPATH)
YORVIPATH revenue for the first quarter of 2025 totaled €44.7 million.
Continued strong start to U.S. YORVIPATH launch, with more than 1,750 prescriptions as of March 31, 2025, and more than 1,000 unique prescribing health care providers.
On track for commercial launch in at least five additional Europe Direct countries in 2025.
International Markets exclusive distribution agreements covering 75+ countries.
TransCon hGH:
(lonapegsomatropin, marketed as SKYTROFA)
SKYTROFA revenue for the first quarter of 2025 totaled €51.3 million.
Prescription Drug User Fee Act (PDUFA) goal date of July 27, 2025, for Food & Drug Administration (FDA) review of supplemental Biologics License Application (BLA) for the treatment of adults with growth hormone deficiency.
During the third quarter of 2025, plan to submit an Investigational New Drug (IND) application or similar for a basket trial evaluating TransCon hGH in additional indications.
TransCon CNP
(navepegritide)
Submitted New Drug Application (NDA) to the FDA for the treatment of children with achondroplasia in the first quarter of 2025; expect to submit Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) during the third quarter of 2025.
During the fourth quarter of 2025, plan to submit an IND or similar to investigate TransCon CNP alone or in combination with TransCon hGH for the treatment of hypochondroplasia.
TransCon CNP + TransCon hGH Combination Therapy
(navepegritide plus lonapegsomatropin, marketed as SKYTROFA)
Topline Week 26 data from COACH, the combination TransCon CNP and TransCon hGH trial of children with achondroplasia (ages 2-11 years) expected in the second quarter of 2025.
Oncology Programs
Clinical development of TransCon IL-2 β/γ continues, including ongoing investigation of clinical activity in platinum-resistant ovarian cancer.
Financial Update
As of March 31, 2025, Ascendis Pharma had cash and cash equivalents totaling €518 million which includes the completion of previously announced share repurchase program and the net settlement of certain Restricted Stock Units for €29 million, compared to €560 million as of December 31, 2024.
On March 21, 2025, VISEN Pharmaceuticals ("VISEN") closed its initial public offering on the Hong Kong Stock Exchange and began trading under the stock code 2561.HK. Ascendis Pharma holds 41,136,364 shares in VISEN. As of March 31, 2025, the total market value of our equity position in VISEN was approximately €260 million.
First Quarter 2025 Financial Results
Total revenue for the first quarter of 2025 was €101.0 million, compared to €95.9 million during the same period in 2024. The year-over-year increase in revenue was primarily attributable to an increase in product revenue which reflected a contribution of €44.7 million from YORVIPATH, following its commercial launch. Non-product revenue decreased to €4.9 million in the first quarter of 2025, compared to €29.4 million for the same period for 2024.

Total Revenue
(In EUR’000s) Three Months Ended
March 31,
2025 2024
Revenue
Commercial products 96,028 66,499
Rendering of services and clinical supply 3,524 4,625
Licenses 1,402 24,770
Total revenue 100,954 95,894

Commercial Product Revenue
(In EUR’000s) Three Months Ended
March 31,
2025 2024
Revenue from commercial products
SKYTROFA 51,340 65,005
YORVIPATH 44,688 1,494
Total revenue from commercial products 96,028 66,499

Research and development costs for the first quarter of 2025 were €86.6 million, compared to €70.7 million during the same period in 2024. The first quarter of 2024 was positively impacted by a reversal of prior period write-downs of pre-launch inventories related to TransCon PTH. The first quarter of 2025 was negatively impacted by an impairment charge related to property, plant and equipment due to change in activities at one of our sites in the U.S.

Selling, general, and administrative expenses for the first quarter of 2025 were €101.0 million, compared to €66.8 million during the same period in 2024. The increase was primarily due to the impact from commercial expansion including global launch activities for YORVIPATH, as well as an impairment charge related to property, plant and equipment due to change in activities at one of our sites in the U.S.

Total operating expenses for the first quarter of 2025 were €187.6 million compared to €137.5 million during the same period in 2024.

Net finance expenses for the first quarter of 2025 was €15.9 million compared to €73.6 million during the same period in 2024. The decrease was primarily driven by non-cash items.

For the first quarter of 2025, Ascendis Pharma reported a net loss of €94.6 million, or €1.58 per share (basic and diluted) compared to a net loss of €131.0 million, or €2.30 per share (basic and diluted) for the same period in 2024.

As of March 31, 2025, Ascendis Pharma had cash and cash equivalents totaling €518 million compared to €560 million as of December 31, 2024. As of March 31, 2025, Ascendis Pharma had 60,970,565 ordinary shares outstanding, including 597,055 ordinary shares represented by ADSs held by the company.

Conference Call and Webcast Information
Ascendis Pharma will host a conference call and webcast today at 4:30 pm Eastern Time (ET) to discuss its first quarter 2025 financial results.

Those who would like to participate may access the live webcast here, or register in advance for the teleconference here. The link to the live webcast will also be available on the Investors & News section of the Ascendis Pharma website at View Source A replay of the webcast will be available in this section of the Ascendis Pharma website shortly after the conclusion of the event for 30 days.

On May 1, 2025 Blue Earth Therapeutics reported further progress in development of its radiohybrid, lutetium-labelled, PSMA targeted, investigational radioligand therapy, with enrolment of the first two patients in a Phase 2 clinical trial (Press release, Blue Earth Therapeutics, MAY 1, 2025, View Source [SID1234652463]). The primary measure of efficacy in the study will be the proportion of patients achieving a ≥50% reduction in PSA levels, as well as assessing radiographic progression-free survival and patient safety (NCT05413850).

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The study is testing multiple dosing regimens that focus on delivering higher radiation doses when tumor burden is usually highest, at the beginning of treatment. This approach contrasts to pivotal studies of earlier radioligand therapies where the same dose was administered in every cycle2 regardless of tumor burden. The study design aligns with the US FDA Project Optimus initiative where the goal is that drug developers optimize dosing early in a product’s development to deliver the best possible benefit risk profile.

Loading doses will be delivered by either a) giving a higher dose in the first two treatment cycles, or b) shortening the time between administration of the first three doses to three weeks from the usual six weeks. The study is also designed to test the clinical benefit of administration of high total doses of administered radioactivity, up to 60GBq. The Phase 1 data confirmed a high ratio of uptake in tumor tissues vs. uptake in healthy tissues such as kidneys and salivary glands1.

David Gauden DPhil, CEO of Blue Earth Therapeutics said, "This is an important step forward in the development of Lutetium (177Lu) rhPSMA-10.1 injection and builds on the strong data seen in the Phase 1 clinical trial. Commencement of treatment of patients at full intended therapeutic dosing levels provides a great opportunity to assess the benefit this therapy can bring to patients. With up to 20 sites enrolling patients, we expect to see first results from the study early next year. We are grateful to the physicians and patients of Biogenix Molecular in Florida, who have just recruited the first patients for the study."

About metastatic prostate cancer
In 2025 it is estimated that there will be 50,055 new cases of metastatic prostate cancer in the United States (de novo diagnoses plus recurrence from earlier stage diagnoses).3 Five-year survival for newly diagnosed metastatic prostate cancer is low, 36.6%.4 While death rates from prostate cancer have declined over the past three decades4, there is still considerable room to improve patient outcomes.

About Radiohybrid Prostate–Specific Membrane Antigen (rhPSMA)
rhPSMA compounds are referred to as radiohybrid ("rh"), as each molecule possesses four distinct domains. The first consists of a Prostate–Specific Membrane Antigen–targeted receptor ligand. It is attached to two labelling moieties which may be radiolabelled with diagnostic isotopes such as 18F or 68Ga for PET imaging, or with therapeutic isotopes such as 177Lu or 225Ac for radioligand therapy, all of which are joined together by a modifiable linker which can be used to modulate important pharmacokinetic characteristics. Radiohybrid PSMA offers the potential for targeted treatment for men with prostate cancer and originated at the Technical University of Munich, Germany. Blue Earth Diagnostics acquired exclusive worldwide rights to rhPSMA diagnostic imaging technology from Scintomics GmbH in 2018, and therapeutic rights in 2020, and has sublicensed the therapeutic application to its sister company Blue Earth Therapeutics.