On April 2, 2024 Jazz Pharmaceuticals plc (Nasdaq: JAZZ) reported that the company has completed the rolling submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) seeking accelerated approval for the HER2-targeted bispecific antibody zanidatamab as a treatment for previously-treated, unresectable, locally advanced, or metastatic HER2-positive biliary tract cancer (BTC) (Press release, Jazz Pharmaceuticals, APR 2, 2024, View Source [SID1234641719]). If approved, zanidatamab would be the first HER2-targeted treatment specifically approved for BTC in the U.S.

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"This important milestone brings us one step closer to delivering zanidatamab, a targeted treatment option, to patients living with HER2-positive BTC, a type of cancer that is associated with a five-year overall survival rate of less than 5%," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development of Jazz Pharmaceuticals. "Zanidatamab is a biparatopic HER2-targeted bispecific antibody that simultaneously binds two non-overlapping epitopes of HER2 resulting in multiple mechanisms of action. Second-line (2L) BTC represents the first of multiple indications we are evaluating and we are excited about zanidatamab’s potential as a new option for multiple HER2-expressing cancers, with ongoing Phase 3 trials in 1L BTC, 1L gastroesophageal adenocarcinoma (GEA), and previously treated breast cancer."

The BLA includes data from the Phase 2b HERIZON-BTC-01 trial of zanidatamab in previously treated HER2-positive BTC. The primary endpoint was confirmed objective response rate (cORR) by independent central review (ICR) in Cohort 1. Data as of Oct. 10, 2022, from the 80 HER2-positive BTC patients enrolled in Cohort 1 of the trial demonstrated a cORR of 41.3% [95% confidence interval (CI): 30.4, 52.8] with a Kaplan Meier (KM) estimated median duration of response (DOR) of 12.9 months [95% CI: 6.0-not estimable] by ICR. Historical response rates for 2L standard-of-care chemotherapy in patients with BTC are reported to be 5 to 15%1,2. The KM estimated median progression-free survival (PFS) was 5.5 months [95% CI: 3.7, 7.2] with a range of 0.3 to 18.5 months.

Zanidatamab demonstrated a manageable and tolerable safety profile, with only two patients (2.3%) in HERIZON-BTC-01 experiencing adverse events (AEs) leading to treatment discontinuation. There were no Grade 4 AEs, and no deaths were considered treatment-related. The most common AEs were diarrhea and infusion-related reactions, which were predominately low-grade, reversible and manageable prophylactically with routine supportive care.

These data were featured as an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2023, published in The Lancet Oncology, and included in the 2023 Best of ASCO (Free ASCO Whitepaper) program. Quality-of-life data from this trial were also presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023 and at the 2024 ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium.

The HERIZON-BTC-302 Phase 3 trial (NCT06282575) of zanidatamab in 1L advanced or metastatic HER2-positive BTC was recently initiated and is open for enrollment. The global, open-label, randomized trial will evaluate the efficacy and safety of zanidatamab in combination with standard-of-care therapy against standard-of-care therapy alone. The primary objective of the study is to compare the efficacy of zanidatamab and chemotherapy (cisplatin plus gemcitabine) with or without the addition of a programmed death protein 1/ligand 1 (PD-1/L-1) inhibitor versus chemotherapy with or without a PD-1/L1 inhibitor in patients. HERIZON-BTC-302 is proposed as the confirmatory trial for zanidatamab in BTC.

About Zanidatamab
Zanidatamab is an investigational bispecific antibody that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding. This unique design and increased binding results in multiple mechanisms of action, including dual HER2 signal blockade, removal of HER2 protein from the cell surface, and immune-mediated cytotoxicity leading to encouraging antitumor activity in patients. Zanidatamab is being developed in multiple clinical trials as a targeted treatment option for patients with solid tumors that express HER2. Zanidatamab is being developed by Jazz and BeiGene, Ltd. (BeiGene) under license agreements from Zymeworks, which first developed the molecule.

The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for zanidatamab development in patients with previously treated HER2 gene-amplified biliary tract cancers (BTC), and two Fast Track designations for zanidatamab: one as a single agent for refractory BTC and one in combination with standard of care chemotherapy for 1L gastroesophageal adenocarcinoma (GEA). Additionally, zanidatamab has received Orphan Drug designations from FDA for the treatment of BTC and GEA, as well as Orphan Drug designation from the European Medicines Agency for the treatment of BTC and gastric cancer. Zanidatamab was also granted Breakthrough Therapy designation from the Center for Drug Evaluation (CDE) in China.

About Biliary Tract Cancer
Biliary tract cancer (BTC), including gallbladder cancer and intrahepatic and extrahepatic cholangiocarcinoma, account for <1% of all adult cancers and are often associated with a poor prognosis3,4. The human epidermal growth factor receptor 2 (HER2) is a well-validated target for antitumor therapy in other cancers. Across the U.S., Europe, and Japan, approximately 12,000 people are diagnosed with BTC annually5,6,7,8 and most patients (> 65%) are diagnosed with tumors that cannot be removed surgically.

On April 2, 2024 Freenome, a biotechnology company pioneering an early cancer detection platform, reported topline results from PREEMPT CRC, a prospective, registrational clinical study to validate its blood-based test for the early detection of colorectal cancer (CRC) among average-risk adults (Press release, Freenome, APR 2, 2024, View Source [SID1234641718]).

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In a prespecified analysis, the Freenome blood test for CRC screening demonstrated 79.2% sensitivity in detecting colorectal cancer (Stage I: 57.1%, Stage II: 100%, Stage III: 82.4%, Stage IV: 100%) with 91.5% specificity for non-advanced colorectal neoplasia. The test also showed 12.5% sensitivity in detecting advanced adenomas (AA), with a sensitivity of 29% for AAs with high-grade dysplasia, also referred to as Stage 0. All endpoints were powered at 96% or greater.

When specificity was adjusted to the Centers for Medicare and Medicaid Services (CMS) National Coverage Determination (NCD) cut-off of 90%, there was a corresponding increase in the sensitivity for AA (14.8%) while maintaining CRC sensitivity. With the addition of proteins, an improved sensitivity for both AA (16.4%) and CRC (80.5%) at the 90% cut-off was observed. Additional study findings will be presented at a future scientific meeting.

"These results advance our early cancer detection programs toward mainstream clinical use, and we are grateful to the participants, partners and communities who helped accomplish this study," said Lance Baldo, M.D., chief medical officer at Freenome. "PREEMPT CRC was designed and executed with high scientific rigor and generated valuable data and insights that enable near- and long-term test improvements. These clinical performance metrics set a standard from which Freenome will continue to innovate, including the evaluation of prespecified test versioning."

PREEMPT CRC was a prospective, registrational study designed to validate the Freenome blood test for CRC screening. Conducted at more than 200 sites, the study enrolled 48,995 asymptomatic, average-risk adults between the ages of 45 and 85 scheduled to undergo a screening colonoscopy. The results were based on data from the 27,010 eligible participants who enrolled consecutively in the study after a predetermined cut-off date. The retained samples from these participants, along with samples from over 16,000 additional participants not utilized in the present analysis, remain available to support future test improvements.

The study leveraged a hybrid model involving virtual and traditional recruitment methods to reach underserved communities and ensure a representative population that includes people from all 48 states in the continental U.S. In addition, real-world data (RWD) collection through tokenization was integrated into the trial to complement the molecular data with longitudinal clinical outcomes that can be applied to CRC and other early cancer detection applications as part of the company’s platform and test versioning roadmap.

"While physicians have screening tools available for colorectal cancer, the associated inconvenience and discomfort of these methods deter many from getting recommended screenings," said Aasma Shaukat, M.D., M.P.H., professor of medicine at the NYU Grossman School of Medicine and a principal investigator for the PREEMPT CRC study. "By providing a more convenient option, Freenome’s blood test for the early detection of CRC has the potential to boost screening adherence rates and improve accessibility for people in all communities."

"In the PREEMPT CRC study, we brought communities together to confront a common enemy – cancer," said Mike Nolan, chief executive officer at Freenome. "We built Freenome to be able to integrate many analytes and computational methods into one test to implement a ‘staircase’ of increasing performance for the benefit of patient care. The performance of this initial version establishes a strong foundation and we expect to broaden it to other cancers. Our platform uniquely enables our team to efficiently iterate as we consistently push to achieve what is possible for patients."

About PREEMPT CRC
PREEMPT CRC (NCT04369053) was a prospective, registrational clinical study to validate Freenome’s blood test for the early detection of colorectal cancer (CRC) among average-risk adults. Initiated in 2020, the study was conducted at more than 200 sites and enrolled 48,995 asymptomatic, average-risk participants between the ages of 45 and 85 scheduled to undergo a screening colonoscopy. Freenome and the U.S. Food and Drug Administration agreed upon a predetermined cut-off date for the period most affected by the COVID-19 pandemic. Of the 48,995 participants enrolled, 27,010 were evaluated.

The study leveraged a novel hybrid model involving virtual and traditional recruitment methods to reach underserved communities and ensure a representative population. The decentralized recruitment strategy underscores Freenome’s commitment to promoting equity and diversity in clinical studies, ensuring its tests are designed for everyone.

Freenome’s partners in PREEMPT CRC included the Colorectal Cancer Alliance, Dia de la Mujer Latina, the Intercultural Center for Health Research and Wellness, and historically Black colleges and universities (HBCUs), including Morehouse School of Medicine. Freenome also worked with CVS Health Clinical Trial Services to help drive study enrollment through coordinated communication efforts targeting patients with already scheduled colonoscopies.

About Colorectal Cancer
Though colorectal cancer (CRC) is curable if detected early, sub-optimal screening rates mean CRC is often detected too late for successful treatment, making it the second cause of cancer deaths in the U.S.2 Nearly twice as many people under the age of 55 are diagnosed with CRC than a decade ago, and more people are dying from the disease each year.3 In response, the U.S. Preventive Services Task Force lowered the screening guidelines for average-risk adults from 50 to 45 years old.4

Following screening guidelines can improve detection rates, and catching CRC early can lead to better outcomes.4 Despite the effectiveness of screenings in reducing CRC mortality, only 59% of U.S. adults adhere to screening guidelines.5 Recent data show that providing a blood test as a screening option to individuals who previously declined a colonoscopy or stool test increased screening rates.

On April 2, 2024 EpicentRx, Inc, a clinical-stage biotechnology drug and device company with two therapeutic platforms that address cancer and inflammatory diseases of unmet clinical need, reported that an abstract on its lead therapy, AdAPT-001, will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting to be held in San Diego, CA from April 5-10, 2024 (Press release, EpicentRx, APR 2, 2024, View Source;trap-program-in-checkpoint-inhibitor-resistant-patients-at-the-2024-aacr-meeting-302105991.html [SID1234641717]).

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AdAPT-001 constitutes a novel strategy to deliver a transforming growth factor-beta (TGF-β) trap to tumors. Importantly, data from a Phase 1/2 clinical trial demonstrate that administration of AdAPT-001 successfully converted immunologically cold tumors, such as sarcomas and triple negative breast cancer, into immunologically hot tumors. Furthermore, AdAPT-001 administration also demonstrates reversion of established resistance to checkpoint inhibitors.

"We’re excited to share groundbreaking clinical data with our lead therapy, AdAPT-001, against several treatment- and checkpoint inhibitor resistant solid tumors," said Tony R. Reid, MD, PhD, CEO of EpicentRx. "We’re also thrilled to be working with top-notch investigators like Dr. Anthony P. Conley from the MD Anderson Cancer Center and Dr. Lucy B. Kennedy from the Cleveland Clinic."

"Immune checkpoint inhibitors are largely ineffective against sarcomas. TGF-β is a soluble protein that suppresses immune responses," said treating study investigator and sarcoma oncologist, Dr. Conley from the MD Anderson Cancer Center. "Based on the several unprecedented responses that I have seen with AdAPT-001, which expresses a TGF-β trap, this TGF-β blockade from AdAPT-001 synergizes with PD-1/PD-L1 inhibition in checkpoint-resistant sarcoma."

Poster Presentation:
Title: Improved clinical outcomes in patients that received treatment beyond tumor progression with AdAPT-001 +/- a checkpoint inhibitor
Presenters: Dr. Anthony P. Conley of MD Anderson Cancer Center and Drs Tony Reid (CEO) and Chris Larson (VP) of EpicentRx.
Date and Time: Tuesday, April 9, 2024, 1:30 PM – 5:00 PM PDT
Location: Poster Section 48
Poster Number: 23

About AdAPT-001
AdAPT-001 is an investigational immunotherapy with a TGF-β receptor-immunoglobulin Fc fusion trap, designed to neutralize isoforms 1 and 3 of the profibrotic, proangiogenic, prohypoxic, and immunosuppressive cytokine, TGF-β, and to sensitize resistant tumors to checkpoint blockade.

In the ongoing Phase 1/2 BETA PRIME trial, AdAPT-001 was administered as single-agent and in combination with checkpoint inhibitors to patients with treatment-refractory tumors.

Importantly, AdAPT-001 plus checkpoint inhibitors improved toxicity and AE profile over what is typically observed with checkpoint inhibitors. No dose limiting toxicities, AdAPT-001 related serious adverse events, or dose reductions have been observed to date.

On April 2, 2024 Convergent Therapeutics Inc., a clinical stage biotechnology company focused on developing next generation radiopharmaceutical therapies for the treatment of prostate cancer and other cancers, reported that the U.S. Food and Drug Administration ("FDA") has cleared the investigational new drug ("IND") application for CONV01-α, its lead candidate for the treatment of patients with advanced prostate cancer (Press release, Convergent Therapeutics, APR 2, 2024, View Source;a-best-in-class-radioantibody-targeting-prostate-specific-membrane-antigen-302106271.html [SID1234641716]).

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"Receiving clearance of our IND is a significant milestone for Convergent Therapeutics," said Convergent’s Co-founder and CEO, Philip Kantoff, MD. "While we have already treated well over 100 prostate cancer patients in the context of investigator INDs, this new IND will allow us to rapidly advance CONV01-α into Phase 3 studies and expand the scope of clinical development of CONV01-α as a monotherapy and in combination with other cancer therapies."

In a multi-dose, dose escalation study conducted in advanced prostate cancer patients, CONV01-α demonstrated a prostate-specific antigen decline of 50% (PSA50) in 67% of patients and a PSA decline of 90% (PSA90) in 27% of patients and was well tolerated.1 Ongoing studies suggest CONV01-α may be highly effective when used alone or in combination with other cancer therapies.

"Importantly, patients also showed minimal side effects in Phase 1/2 trials. CONV01-α’s ideal biodistribution delivers potent alpha particles while avoiding immediate and significant salivary gland toxicity as well as the potential delayed renal toxicity," said Neil Bander, MD, Convergent’s Co-founder and CSO. "CONV01-α’s design increases delivery of tumor-killing radiation to malignant cells while greatly reducing both off-tumor effects and the amount of radiation delivered per dose, thereby improving both treatment efficacy and safety."

About CONV01-α

CONV01-α, Convergent’s alpha emitting radioantibody, combines the precision and pharmacokinetics of antibodies with the tumor-killing potential of alpha emitting radionuclides. Specifically, CONV01-α uses a humanized monoclonal antibody targeted at prostate-specific membrane antigen (PSMA) which is highly overexpressed in prostate cancer cells. Since PSMA is a validated target, several therapeutics are directed at this antigen and CONV01-α is differentiated by its use of both an antibody and alpha emitter. CONV01-α is linked to a powerful radionuclide called 225Ac, which releases alpha particles which kill cancer cells through DNA double strand breaks. Unlike other radioactive sources, alpha particles deliver high-energy radiation over very short distances, thereby minimizing radiation exposure to healthy neighboring cells and tissues. Pairing highly selective antibodies with such a powerful yet precise payload offers the ideal combination to treat many types of cancers.

On April 2, 2024 Marengo Therapeutics, Inc, a clinical-stage biotech company pioneering a new way to activate T cells that target the Vβ chain of the T cell receptor (TCR) and select the right T cell subsets against cancer, reported that Ipsen (Euronext: IPN; ADR: IPSEY) has nominated the first clinical drug candidate (DC) of two from its multi-year strategic partnership in oncology (Press release, Marengo Therapeutics, APR 2, 2024, View Source [SID1234641715]).

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This clinical candidate reflects a productive collaboration since the strategic partnership was signed in August 2022. Marengo and Ipsen plan to advance the program through IND-enabling studies and into clinical development. This nomination represents the first of two selective T cell activation repertoire (STAR) T cell bi-functional activator programs that Marengo and Ipsen will advance as part of the collaboration.

"The DC nomination is a testament to our close partnership with Ipsen and to the expertise and dedication of Marengo’s R&D team," said Zhen Su, M.D., MBA, Chief Executive Officer of Marengo. "It underscores the potential of our STAR TCR Vb T cell activator platform to deliver a range of first-in-class precision T cell bispecific antibodies for the treatment of refractory solid tumors. We look forward to the next phase of the collaboration as we work to advance treatment options for patients living with cancer."

Under the terms of the agreement, Marengo will receive a milestone payment for this pre-defined pre-clinical milestone. Marengo is leading the research and preclinical development efforts while Ipsen will assume responsibilities for regulatory submissions, clinical development and commercialization.