FDA Recognizes Astellas’ Renewed Submission of Biologics License Application for Zolbetuximab and Establishes Revised Action Deadline

Today, Astellas announced that the U.S. Food and Drug Administration (FDA) has acknowledged the resubmission of the Biologics License Application (BLA) for zolbetuximab, a groundbreaking investigational monoclonal antibody targeting claudin (CLDN) 18.2. This resubmission is intended for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors test positive for CLDN18.2. If approved, zolbetuximab would mark the first CLDN18.2-targeted therapy approved for this patient demographic in the U.S. The FDA has set a new target action date of November 9, 2024, under the Prescription Drug User Fee Act (PDUFA).

In the United States, it’s estimated that 26,890 individuals will receive a gastric cancer diagnosis, with 10,880 succumbing to the disease in 2024. Due to symptom overlap with common stomach-related ailments, gastric cancer is frequently diagnosed at advanced or metastatic stages, resulting in a five-year relative survival rate of only 7% for patients at the metastatic stage.

Moitreyee Chatterjee-Kishore, Ph.D., M.B.A., Senior Vice President and Head of Immuno-Oncology Development at Astellas, expressed the company’s dedication to advancing targeted therapies for challenging cancers. She noted the significant unmet needs faced by those with advanced gastric or GEJ cancer and highlighted the FDA’s acknowledgment of the zolbetuximab BLA resubmission as a pivotal step toward offering a vital treatment option to eligible U.S. patients confronting this lethal disease.

The zolbetuximab BLA was resubmitted on May 9, 2024, following a complete response letter issued on January 4, 2024, due to third-party manufacturing deficiencies identified during a pre-license facility inspection. Notably, the FDA did not raise concerns regarding zolbetuximab’s clinical data, including efficacy or safety, and did not request additional clinical studies to support BLA approval.

The submission was based on results from the Phase 3 SPOTLIGHT and GLOW clinical trials. In these trials, approximately 38% of screened patients had CLDN18.2-positive tumors. CLDN18.2 positivity was defined as ≥75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining.

On March 26, 2024, Japan’s Ministry of Health, Labour and Welfare (MHLW) approved zolbetuximab, making it the first and only CLDN18.2-targeted treatment approved for patients with CLDN18.2-positive, unresectable, advanced, or recurrent gastric cancer. Astellas has also submitted applications for zolbetuximab to regulatory agencies globally, with ongoing reviews.

Astellas has already integrated the impact of the FDA’s acknowledgment of the BLA resubmission for zolbetuximab into its financial forecast for the current fiscal year ending March 31, 2025.

Zolbetuximab is a claudin 18.2-directed cytolytic antibody investigated in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors are CLDN18.2 positive. It targets and binds to CLDN18.2, a transmembrane protein, and in preclinical studies, depleted CLDN18.2-positive cells via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, regulatory approval in the U.S. or commercial availability is not guaranteed.

Gastric cancer, or stomach cancer, ranks as the fifth most commonly diagnosed cancer globally. In the U.S., an estimated 130,263 individuals live with gastric cancer, categorizing it as a rare disease. Symptoms vary and can include indigestion, nausea, and unexplained weight loss. Advanced stages of gastric cancer exhibit even more severe symptoms and have a dismal five-year relative survival rate.

SPOTLIGHT is a Phase 3 clinical trial assessing the efficacy and safety of zolbetuximab plus mFOLFOX6 compared to placebo plus mFOLFOX6 as a first-line treatment in patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors were CLDN18.2 positive. The study’s primary endpoint is progression-free survival (PFS), with secondary endpoints including overall survival (OS), objective response rate (ORR), and safety measures.

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