FDA Accepts Astellas' Resubmission for Zolbetuximab, Sets New Action Date

Astellas Pharma Inc. has announced that the U.S. Food and Drug Administration (FDA) has acknowledged the resubmission of their Biologics License Application (BLA) for zolbetuximab. This investigational monoclonal antibody targets claudin (CLDN) 18.2 and is intended for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma, given their tumors are CLDN18.2 positive. If approved, zolbetuximab would become the first CLDN18.2-targeted therapy for this patient group in the U.S. The FDA has set a target action date under the Prescription Drug User Fee Act (PDUFA) for November 9, 2024.

In the U.S., gastric cancer is a severe health issue, with approximately 26,890 new diagnoses and 10,880 deaths estimated for 2024. Due to the overlap of early-stage gastric cancer symptoms with more common gastrointestinal conditions, the disease is frequently diagnosed at an advanced or metastatic stage. The five-year relative survival rate for these patients is a mere 7%.

According to Moitreyee Chatterjee-Kishore, Ph.D., M.B.A., Senior Vice President and Head of Immuno-Oncology Development at Astellas, the company is dedicated to developing new treatments for challenging cancers. The FDA’s acknowledgment of the BLA resubmission for zolbetuximab is a significant step toward providing a new treatment option for patients in the U.S. battling advanced gastric or GEJ cancer.

The BLA for zolbetuximab was resubmitted following a complete response letter from the FDA in January 2024, which cited third-party manufacturing issues identified during a pre-license inspection. Importantly, the FDA did not raise concerns regarding zolbetuximab's clinical data, including its safety and efficacy, and no additional clinical studies were requested to support the BLA.

The resubmission is supported by data from two Phase 3 clinical trials, SPOTLIGHT and GLOW. The SPOTLIGHT trial compared zolbetuximab plus the mFOLFOX6 chemotherapy regimen to a placebo plus mFOLFOX6, while the GLOW trial compared zolbetuximab plus the CAPOX chemotherapy regimen to a placebo plus CAPOX. In both studies, approximately 38% of patients screened had CLDN18.2 positive tumors.

The Ministry of Health, Labour and Welfare (MHLW) in Japan approved zolbetuximab in March 2024, making it the first CLDN18.2-targeted treatment for advanced or recurrent gastric cancer in the country. Regulatory applications for zolbetuximab are also under review in other regions worldwide.

Zolbetuximab is an investigational claudin 18.2-directed cytolytic antibody designed to be used in combination with fluoropyrimidine and platinum-containing chemotherapy. It targets and binds to CLDN18.2, a transmembrane protein, and has shown effectiveness in pre-clinical studies through mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, regulatory approval in the U.S. is still pending, and there is no assurance that zolbetuximab will become commercially available for its intended uses.

Gastric cancer, also known as stomach cancer, is the fifth most commonly diagnosed cancer globally. In the U.S., around 130,263 people are living with the disease. Symptoms include indigestion, abdominal discomfort, nausea, vomiting, and more severe signs like unexplained weight loss and blood in the stool. Risk factors include older age, male gender, family history, H. pylori infection, smoking, and gastroesophageal reflux disease (GERD). Advanced gastric cancer often has a poor prognosis, especially when diagnosed at a metastatic stage.

Astellas is also progressing with other investigational treatments targeting CLDN18.2, including ASP2138, a bispecific monoclonal antibody currently in Phase 1/1b trials, and an expanded Phase 2 trial of zolbetuximab for metastatic pancreatic adenocarcinoma.

Astellas is committed to addressing unmet medical needs through innovative therapies and is actively working on overcoming the challenges posed by advanced gastric and GEJ cancers.