On March 19, 2024 AstraZeneca reported that it has entered into a definitive agreement to acquire Fusion Pharmaceuticals Inc., a clinical-stage biopharmaceutical company developing next-generation radioconjugates (RCs) (Press release, AstraZeneca, MAR 19, 2024, View Source [SID1234641248]). The acquisition marks a major step forward in AstraZeneca delivering on its ambition to transform cancer treatment and outcomes for patients by replacing traditional regimens like chemotherapy and radiotherapy with more targeted treatments.

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RCs have emerged as a promising modality in cancer treatment over recent years. These medicines deliver a radioactive isotope directly to cancer cells through precise targeting using molecules such as antibodies, peptides or small molecules. This approach has many potential advantages compared to traditional radiotherapy including minimising damage to healthy cells and enabling access to tumours not reachable through external beam radiation.

This acquisition complements AstraZeneca’s leading oncology portfolio with the addition of the Fusion pipeline of RCs, including their most advanced programme, FPI-2265, a potential new treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). FPI-2265 targets prostate-specific membrane antigen (PSMA), a protein that is highly expressed in mCRPC, and is currently in a Phase II trial.

The acquisition brings new expertise and pioneering R&D, manufacturing and supply chain capabilities in actinium-based RCs to AstraZeneca. It also strengthens the Company’s presence in and commitment to Canada.

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Between thirty and fifty per cent of patients with cancer today receive radiotherapy at some point during treatment, and the acquisition of Fusion furthers our ambition to transform this aspect of care with next-generation radioconjugates. Together with Fusion, we have an opportunity to accelerate the development of FPI-2265 as a potential new treatment for prostate cancer, and to harness their innovative actinium-based platform to develop radioconjugates as foundational regimens."

John Valliant, Chief Executive Officer, Fusion, said: "This acquisition combines Fusion’s expertise and capabilities in radioconjugates, including our industry-leading radiopharmaceutical R&D, pipeline, manufacturing and actinium-225 supply chain, with AstraZeneca’s leadership in small molecules and biologics engineering to develop novel radioconjugates. Expanding on our existing collaboration with AstraZeneca where we have advanced FPI-2068, an EGFR-cMET targeted radioconjugate into Phase I clinical trials, gives us a unique opportunity to accelerate the development of next-generation radioconjugates with the aim of transforming patient outcomes."

Fusion will become a wholly owned subsidiary of AstraZeneca, with operations continuing in Canada and the US.

Financial considerations
Under the terms of the definitive agreement, AstraZeneca, through a subsidiary, will acquire all of Fusion’s outstanding shares pursuant to a plan of arrangement for a price of $21.00 per share in cash at closing plus a non-transferable contingent value right of $3.00 per share in cash payable upon the achievement of a specified regulatory milestone. The upfront cash portion of the consideration represents a transaction value of approximately $2bn, a 97% premium to Fusion’s closing market price of $10.64 on 18th March 2024 and an 85% premium to the 30-day volume-weighted average price (VWAP) of $11.37 before this announcement. Combined, the upfront and maximum potential contingent value payments represent, if achieved, a transaction value of approximately $2.4bn, a 126% premium to Fusion’s closing market price on 18th March 2024 and a 111% premium to the 30-day VWAP. As part of the transaction, AstraZeneca will acquire the cash, cash equivalents and short term investments on Fusion’s balance sheet, which totalled $234m as of 31st December 2023.

The transaction is expected to close in the second quarter of 2024, subject to customary closing conditions, including the approval of Fusion shareholders and regulatory clearances.

Notes

Radioconjugates in oncology
RCs combine the precise targeting of antibodies, small molecules or peptides with potent medical radioisotopes to deliver radiation directly to cancer cells. By seeking out cancer cells, RCs provide a more precise mechanism of cancer cell killing compared with traditional radiation therapy, with the goal of improving efficacy while minimising toxicity on healthy cells. RCs are administered via systemic delivery, which enables their use in tumour types not accessible to external beam radiation and the targeting of cancer cells that have spread from the main tumour to other sites in the body.

About FPI-2265
FPI-2265 is an actinium-225 based PSMA-targeting RC for mCRPC, currently in a Phase II trial.

Actinium-225 emits alpha particles and holds the promise of being a next-generation radioisotope in cancer treatment. By delivering a greater radiation dose over a shorter distance, alpha particles such as actinium-225 have the potential for more potent cancer cell killing, and targeted delivery, thereby minimising damage to surrounding healthy tissue.

On March 18, 2024 Natera, Inc. (NASDAQ: NTRA), a global leader in cell-free DNA testing, reported a collaboration with the Fédération Francophone de Cancérologie Digestive and CHU Dijon Bourgogne on the CIRCULATE-PRODIGE-70 study, a randomized, multicenter, prospective phase III clinical trial in France investigating molecular residual disease (MRD)-guided adjuvant treatment in stage II colorectal cancer (CRC) patients (Press release, Natera, MAR 18, 2024, View Source [SID1234641247]).

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The study’s main objective is to determine the benefit of adjuvant chemotherapy (ACT) in stage II CRC patients with detectable circulating tumor DNA (ctDNA) post-surgery. Patients who are Signatera MRD-positive will be randomized to receive ACT (FOLFOX 6m) or pursue observation (no chemotherapy). Patients who are Signatera MRD-negative will be treated according to the standard of care (observation). Approximately 1,600 patients will be tested with Signatera, and a successful study result is expected to pave the way for the adoption and reimbursement of Signatera in France. The initial readout is expected in 2025.

CIRCULATE-France is complementary to the CIRCULATE-Japan and CIRCULATE-US trials. While the Japanese and U.S. trials evaluate the benefit of MRD-guided treatment in stage III and high-risk stage II CRC patients, the French trial is focused on stage II CRC.

"With more than 44,000 people in France affected by CRC, there is a significant need for more accurate tools to identify those who will benefit from adjuvant systemic therapy and those who can be treated with surgery alone," said Julien Taieb, MD, PhD, head of the gastroenterology and gastrointestinal oncology department at the Université Paris-Cité and principal investigator of the study. "We believe this randomized study could establish a new standard of MRD-guided care in stage II colorectal cancer, potentially improving treatment decisions for thousands of patients."

Natera has joined the study in progress. A separate methylation-based tumor-naive ctDNA assay, developed in-house by UMR-1138 Centre de Recherche des Cordeliers, was used to screen the first 800 patients for eligibility. The principal investigators elected to add Signatera, Natera’s personalized and tumor-informed MRD test, to enhance MRD detection.

"We are pleased to have been selected to support this pivotal trial, which underscores the value of personalized MRD testing across various clinical settings in colorectal cancer," said Adham Jurdi, MD, senior medical director of oncology at Natera. "We are encouraged by the early momentum of this study and look forward to partnering with the Fédération Francophone de Cancérologie Digestive to improve survival and outcomes for colorectal cancer patients in France."

About Signatera

Signatera is a personalized, tumor-informed, molecular residual disease test for patients previously diagnosed with cancer. Custom-built for each individual, Signatera uses circulating tumor DNA to detect and quantify cancer left in the body, identify recurrence earlier than standard of care tools, and help optimize treatment decisions. The test is available for clinical and research use and is covered by Medicare for patients with colorectal cancer, breast cancer, ovarian cancer and muscle invasive bladder cancer, as well as for immunotherapy monitoring of any solid tumor. Signatera has been clinically validated across multiple cancer types and indications, with published evidence in more than 50 peer-reviewed papers.

On March 18, 2024 Eureka Therapeutics, Inc., a clinical-stage biotechnology company developing novel T-cell therapies to treat cancer, reported the advancement of its ARYA-3 clinical trial to Phase II (NCT04864054) (Press release, Eureka Therapeutics, MAR 18, 2024, View Source [SID1234641246]). This milestone represents one of the first engineered T-cell programs targeting solid tumors to reach Phase II.

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The ARYA-3 trial is evaluating Eureka’s investigational ARTEMIS ECT204 T-cell therapy in adult patients with GPC3-positive advanced hepatocellular carcinoma (HCC), the predominant type of liver cancer. Glypican 3 (GPC3) is a promising target for HCC therapies and is found in more than 70% of HCC cells. The GPC3 protein is also expressed in other solid tumors, including ovarian and lung cancer.

The ARYA-3 trial has successfully completed Phase I and is now enrolling patients in Phase II. During this phase, the treatment’s efficacy and safety are evaluated in a larger patient population, offering crucial insights into its potential therapeutic benefits.

"We are excited by the favorable safety profile and promising early efficacy signals in Phase I of our ARYA-3 study. Moving to Phase II marks a significant milestone in our mission to advance cutting-edge therapies for cancer treatment," said Dr. Cheng Liu, President and CEO of Eureka Therapeutics. "We remain committed to building a pipeline of next-generation T-cell therapy for solid tumors."

ARYA-3 is an Open-Label, Dose Escalation, Multi-Center Phase I/II Clinical Trial of ECT204 T-Cell Therapy. In this study, a patient’s T cells are collected and genetically modified to express Eureka’s proprietary anti-GPC3 ARTEMIS T cell receptors (AbTCR). These modified T cells are then reintroduced into the patient to specifically seek out and destroy GPC3-expressing cancer cells. Eureka has previously demonstrated that its proprietary ARTEMIS T-cell receptor platform has several advantages over conventional chimeric antigen receptors (CARs), including better tumor infiltration, safety, and T cell persistence. The clinical trial is actively enrolling patients at both City of Hope and Kansas University Medical Center.

Patients, caregivers and health care professionals interested in Eureka’s clinical trials and technology can find more information by visiting eurekaconnectme.com.

On March 18, 2024 GRAIL, LLC, a healthcare company whose mission is to detect cancer early when it can be cured, reported that participants from Japan, via a collaboration with AstraZeneca (LSE/STO/Nasdaq:AZN), will have their samples tested using GRAIL’s novel risk classification test on its Methylation Platform (Press release, Grail, MAR 18, 2024, View Source [SID1234641245]). This assay has been validated for recurrence risk classification in newly diagnosed Stage I lung adenocarcinoma.

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GRAIL’s Methylation Platform enables tissue-free, blood-based cancer detection that can be customized for a suite of precision applications across hematological and solid tumors, including risk stratification, molecular subtyping, and molecular response. This study with AstraZeneca aims to demonstrate the test’s capability to deliver results within 10 days without the need for tumor tissue, supporting use in future global pharmaceutical clinical trials.

"The development of this risk classification test as part of GRAIL’s clinical oncology portfolio is a significant milestone in our ongoing commitment to support patient care with novel, non-invasive tests for early detection and beyond," said Jeffrey Venstrom, MD, Chief Medical Officer at GRAIL. "GRAIL’s tissue-free, blood-only methodology is designed to aid in clinical trial selection with potential for customizable diagnostic approaches that can enable precision oncology."

In 2022, GRAIL announced a broad strategic collaboration with AstraZeneca to develop and commercialize companion diagnostic (CDx) assays for use with AstraZeneca’s therapies.

In December 2023, GRAIL announced the analytical and clinical validation of a novel prognostic test in Stage I lung adenocarcinoma.

On March 18, 2024 Fennec Pharmaceuticals Inc. (NASDAQ: FENC; TSX: FRX), a commercial stage specialty pharmaceutical company, and Norgine, a leading European specialist pharmaceutical company, reported an exclusive licensing agreement under which Norgine will commercialize PEDMARQSI in Europe, Australia and New Zealand (Press release, Fennec Pharmaceuticals, MAR 18, 2024, View Source [SID1234641244]). PEDMARQSI is the first and only approved therapy in the EU and U.K. for the prevention of ototoxicity (hearing loss) induced by cisplatin chemotherapy in patients 1 month to < 18 years of age with localized, non-metastatic solid tumors.

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Under the terms of the licensing agreement, Fennec will receive €40 million in upfront consideration and up to €210 million in additional commercial and regulatory milestone payments and double-digit tiered royalties on net sales of PEDMARQSI in the licensed territories up to the mid-twenties. Norgine will be responsible for all commercialization activities in the licensed territories and will hold all marketing authorizations in the licensed territories.

It is estimated that more than 5,000 pediatric patients annually are eligible for platinum-based chemotherapy in Europe. PEDMARQSI was granted EU marketing authorization by the European Commission in June 2023, and received UK approval from the MHRA in October 2023. Approvals were based on safety and efficacy data from two open-label, randomized Phase 3 trials, SIOPEL 6 (pivotal) and Clinical Oncology Group [COG] Protocol ACCL0431. The studies compared PEDMARQSI plus cisplatin-based regimens to cisplatin-based regimens alone for the reduction of cisplatin-induced hearing loss in pediatric patients. PEDMARQSI holds eight years plus two years of data and market protection in Europe based on its Pediatric Use Marketing Authorization. Approval in Switzerland, Australia and New Zealand will also be pursued.

The first study (SIOPEL-6) involved 114 children with hepatoblastoma (a cancer of the liver), with an average age of about 19 months. The results showed that 35% (20 out of 57) of children who received Pedmarqsi 6 hours after each dose of cisplatin developed hearing loss compared with 67% (35 out of 52) of children who only received cisplatin. The second study involved 125 children aged 1 month to 18 years with different types of cancer, including hepatoblastoma, neuroblastoma (a cancer of immature nerve cells) and tumours of the central nervous system. The study found that hearing loss was experienced by 29% (14 out of 49) of children who received Pedmarqsi after each cisplatin dose compared with 56% (31 out of 55) of those who received only cisplatin.

"We are delighted to partner with Norgine, who shares our belief in the potential of PEDMARQSI to mitigate the risk of permanent and irreversible hearing loss that can occur in pediatric patients treated with cisplatin. Further, this partnership is an important step in achieving our mission of expanding PEDMARQSI to patients across the globe who are at risk of suffering from cisplatin-induced ototoxicity," said Rosty Raykov, Chief Executive Officer of Fennec Pharmaceuticals. "From a deal perspective, the terms provided us many important benefits, including an upfront payment further solidifying our balance sheet, attractive economic terms providing meaningful participation in the ex-US success of PEDMARQSI and an experienced partner to successfully launch PEDMARQSI in the licensed territory."

Chris Bath, Chief Executive Officer of Norgine, said "We are thrilled to announce our partnership with Fennec, to bring this vital medicine to pediatric patients who are being treated with cisplatin, across Europe and ANZ. We look forward to working with the Fennec team and launching PEDMARQSI in our territories in the coming months, establishing it as the standard of care in this critical patient population with high unmet need. This important milestone for our company builds on our 30 year track record of creating partnerships of enduring value and further underscores Norgine’s position as the specialty pharma partner of choice across Europe and ANZ."

Moelis & Company LLC acted as financial advisor, and LaBarge Weinstein LLP acted as legal advisor to Fennec. Arnold & Porter acted as legal advisor to Norgine.