European Medicines Agency Accepts Astellas' Marketing Authorization Application for Zolbetuximab

TOKYO, July 13, 2023 /PRNewswire/ -- Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, "Astellas") today announced the European Medicines Agency (EMA) has accepted for regulatory review the company's marketing authorization application (MAA) for zolbetuximab, a first-in-class investigational Claudin 18.2 (CLDN18.2)-targeted monoclonal antibody, for first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2-positive. If approved, zolbetuximab would be the first CLDN18.2-targeted therapy available in Europe for these patients.

Gastric cancer accounted for 3.1% of all new cancer cases in Europe in 2020, with around 136,000 new cases diagnosed.¹ The average five-year survival rate for patients with gastric cancer in Europe is 26% across all stages.²

"Patients with gastric cancer in Europe face extremely low five-year survival rates regardless of their disease stage, and innovative therapies that extend survival are needed," said Moitreyee Chatterjee-Kishore, PhD, MBA, Senior Vice President and Head of Immuno-Oncology Development, Astellas. "The EMA's acceptance of the zolbetuximab MAA continues a cascade of regulatory milestones for Astellas that are aimed at bringing a new option to patients with advanced gastric and GEJ cancer."

The MAA is based on results from the Phase 3 SPOTLIGHT and GLOW clinical trials. The SPOTLIGHT study evaluated zolbetuximab plus mFOLFOX6 (a combination regimen that includes oxaliplatin, leucovorin and fluorouracil) compared to placebo plus mFOLFOX6. The GLOW study evaluated zolbetuximab plus CAPOX (a combination chemotherapy regimen that includes capecitabine and oxaliplatin) compared to placebo plus CAPOX.

In both SPOTLIGHT and GLOW, approximately 38% of patients screened for the trials had tumors that were CLDN18.2-positive (≥75% of tumor cells with moderate-to-strong membranous CLDN18 staining intensity), as determined by a validated immunohistochemistry assay.^3,4 

The anticipated recommendation by the Committee for Medicinal Products for Human Use (CHMP) of the EMA regarding the MAA and subsequent European Commission (EC) decision are expected in calendar year 2024.

Astellas has already reflected the impact from this acceptance in its financial forecast of the current fiscal year ending March 31, 2024.

About Locally Advanced Unresectable or Metastatic Gastric and Gastroesophageal Junction Cancer 
Gastric cancer, also commonly known as stomach cancer, is the fifth most commonly diagnosed cancer worldwide.⁵ Gastric cancer accounted for 3.1% of all new cancer cases in Europe in 2020, with around 136,000 new cases diagnosed.¹ The average five-year survival rate for patients with gastric cancer in Europe is 26% across all stages.² Signs and symptoms can include indigestion or heartburn, pain or discomfort in the abdomen, nausea and vomiting, diarrhea or constipation, bloating of the stomach after meals, loss of appetite, and sensation of food getting stuck in the throat while eating.⁶ Signs of more advanced gastric cancer can include unexplained weight loss, weakness and fatigue and vomiting blood or having blood in the stool.⁷ Risk factors associated with gastric cancer can include older age, male gender, family history, H. pylori infection, smoking and gastroesophageal reflux disease (GERD).^6,8 Because early-stage gastric cancer symptoms frequently overlap with more common stomach-related conditions, gastric cancer is often diagnosed in the advanced or metastatic stage, or once it has spread from the tumor's origin to other body tissues or organs.⁶ The five-year relative survival rate for patients at the metastatic stage is 6.6%.⁹ Gastroesophageal junction (GEJ) adenocarcinoma is a cancer that starts at the area where the esophagus joins the stomach.¹⁰

About Zolbetuximab 
Zolbetuximab is an investigational, first-in-class chimeric IgG1 monoclonal antibody (mAb) that targets and binds to Claudin 18.2 (CLDN18.2), a transmembrane protein. Zolbetuximab acts by binding to CLDN18.2 on the cancer cell surface of gastric epithelial cells. In pre-clinical studies, this binding interaction then induces cancer cell death by activating two distinct immune system pathways — antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).¹¹ Zolbetuximab has not been approved by any regulatory bodies for the treatment of patients with gastric and GEJ cancers, and there is no guarantee the agent will receive regulatory approval or become commercially available for the uses being investigated.

INVESTIGATIONAL STUDIES

About SPOTLIGHT Phase 3 Clinical Trial
SPOTLIGHT is a Phase 3, global, multi-center, double-blind, randomized study, assessing the efficacy and safety of zolbetuximab (IMAB362) plus mFOLFOX6 (a combination regimen that includes oxaliplatin, leucovorin and fluorouracil) 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 enrolled 565 patients at 215 study locations in the U.S., Canada, United Kingdom, Australia, Europe, South America and Asia. The primary endpoint is progression-free survival (PFS) in participants treated with the combination of zolbetuximab plus mFOLFOX6 compared to those treated with placebo plus mFOLFOX6. Secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response (DOR), safety and tolerability and quality-of-life parameters.

Data from the SPOTLIGHT clinical trial were presented during the 2023 American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium in an oral presentation on January 19 and were subsequently published in The Lancet on April 14.³ 

For more information, please visit clinicaltrials.gov under Identifier NCT03504397.

About GLOW Phase 3 Clinical Trial
GLOW is a Phase 3, global, multi-center, double-blind, randomized study, assessing the efficacy and safety of zolbetuximab (IMAB362) plus CAPOX (a combination chemotherapy regimen that includes capecitabine and oxaliplatin) compared to placebo plus CAPOX 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 enrolled 507 patients at 166 study locations in the U.S., Canada, United Kingdom, Europe, South America and Asia. The primary endpoint is PFS in participants treated with the combination of zolbetuximab plus CAPOX compared to those treated with placebo plus CAPOX. Secondary endpoints include OS, ORR, DOR, safety and tolerability and quality-of-life parameters.

Data from the GLOW study were initially presented at the March 2023 American Society of Clinical Oncology (ASCO) Plenary Series with an updated oral presentation at the 2023 ASCO Annual Meeting on June 3.⁴ 

For more information, please visit clinicaltrials.gov under Identifier NCT03653507.

Investigational Pipeline in CLDN18.2
An expanded Phase 2 trial in metastatic pancreatic adenocarcinoma is in progress. The trial is a randomized, multi-center, open-label study, evaluating the safety and efficacy of investigational zolbetuximab in combination with gemcitabine plus nab-paclitaxel as a first-line treatment in patients with metastatic pancreatic adenocarcinoma with CLDN18.2-positive tumors (defined as ≥75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining based on a validated immunohistochemistry assay). For more information, please visit clinicaltrials.gov under Identifier NCT03816163.

In addition to zolbetuximab, ASP2138 is under development in our Primary Focus Immuno-Oncology. ASP2138 is a bispecific monoclonal antibody that binds to CD3 and CLDN18.2, and it is currently in a Phase 1 trial for people with gastric, GEJ or pancreatic adenocarcinoma. The safety and efficacy of the agent under investigation have not been established for the uses being considered. For more information, please visit clinicaltrials.gov under Identifier NCT05365581.

There is no guarantee that the agent will receive regulatory approval and become commercially available for the uses being investigated.

About Astellas
Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+^® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into VALUE for patients. For more information, please visit our website at https://www.astellas.com/eu.

Cautionary Notes
In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties.

Information about pharmaceutical products (including products currently in development) which is included in this press release is not intended to constitute an advertisement or medical advice.

References
¹ World Health Organization. Cancer Today. Available at: https://gco.iarc.fr/today/. Last accessed June 28, 2023.
² Rawla P and Barsouk A. Epidemiology of gastric cancer: global trends, risk factors and prevention. Przeglad gastroenterologiczny 2019;14(1):26-38.
³ Shitara K, et al. Zolbetuximab plus mFOLFOX6 in patients with claudin-18 isoform 2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastrooesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomized, double-blind, phase 3 trial. The Lancet. Published online April 14, 2023; S0140-6736(23)00620-7.
⁴ Xu RH, Shitara K, Ajani JA, et al. Updates on Abstract 405736: Zolbetuximab + CAPOX in 1L claudin-18.2+ (CLDN18.2+)/HER2− locally advanced (LA) or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary phase 3 results from GLOW. Presented at: 2023 ASCO Annual Meeting. Abstract 405736.
⁵ Sung H, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49.
⁶ American Cancer Society. Signs and symptoms of stomach cancer (01-22-2021). Available at https://www.cancer.org/cancer/stomach-cancer/detection-diagnosis-staging/signs-symptoms.html. Last accessed June 28, 2023.
⁷ National Cancer Institute. Gastric cancer treatment (PDQ®): patient version (08-24-2021). Available at https://www.cancer.gov/types/stomach/patient/stomach-treatment-pdq. Last accessed June 28, 2023.
⁸ American Cancer Society. Esophageal cancer risk factors (06-09-2020). Available at https://www.cancer.org/cancer/esophagus-cancer/causes-risks-prevention/risk-factors.html. Last accessed June 28, 2023.
⁹ National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: stomach cancer. Available at https://seer.cancer.gov/statfacts/html/stomach.html. Last accessed June 28, 2023.
¹⁰ American Cancer Society. About esophagus cancer (03-20-2020). Available at https://www.cancer.org/content/dam/CRC/PDF/Public/8614.00.pdf. Last accessed June 28, 2023.
¹¹ Sahin U, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol. 2021;32(5):609-19.

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