The world’s first! Astellas Claudin18.2 monoclonal antibody approved in Japan

On March 26, Astellas announced that its Claudin18.2 antibody Zolbetuximab (Vyloy) was approved for marketing in Japan, and the approved indication is advanced gastric cancer. This approval marks Zolbetuximab becoming the first and only CLDN18.2 targeted therapy approved by regulatory agencies in the world.

Two studies support

The approval of Zolbetuximab was based on the results of two phase III clinical studies, SPOTLIGHT and GLOW.

2.GLOW study: Phase III clinical study of zolbetuximab combined with CAPOX

SPOTLIGHT study: Phase III clinical study of zolbetuximab combined with mFOLFOX6 (Spotlight study)

The GLOW and SPOTLIGHT studies are key components of Astellas’ gastric cancer drug development program, which addresses the treatment needs of patients with locally advanced unresectable or metastatic gastric cancer or gastroesophageal junction adenocarcinoma and is developing drugs including zolbetuximab. Targeted treatment options.

The GLOW study evaluated Zolbetuximab + CAPOX (a combination chemotherapy regimen including capecitabine and oxaliplatin) compared with placebo + CAPOX. The SPOTLIGHT study evaluated Zolbetuximab + mFOLFOX6 (a combination chemotherapy regimen including oxaliplatin, leucovorin, and fluorouracil) compared with placebo + mFOLFOX6. Both trials met the primary endpoint of progression-free survival (PFS), as well as the key secondary endpoint of overall survival (OS).

The most common adverse events (TEAEs) in ≥20% of patients treated with Zolbetuximab in combination with mFOLFOX6 or CAPOX were nausea, vomiting, decreased appetite, neutropenia, and weight loss. In clinical trials, adverse reactions were managed with antiemetics, dose interruptions, and infusion rate modifications.

In SPOTLIGHT and GLOW, approximately 38% of screened patients were positive for CLDN18.2. CLDN18.2 positivity is defined as ≥75% of tumor cells showing moderate to strong membranous CLDN18 staining and should be confirmed by a pathologist or laboratory with sufficient experience in the use of approved in vitro diagnostic agents or medical devices. Astellas collaborated with Roche Diagnostics to develop the newly approved VENTANA® CLDN18 (43-14A) RxDx Assay, an IHC companion diagnostic test, to identify patients who may be eligible for VYLOY treatment.

Moitreyee Chatterjee-Kishore, Ph.D., head of immuno-oncology development at Astellas, said in a company press release that Zolbetuximab marks the dawn of a new era in gastric cancer treatment. Stomach cancer is the third most lethal cancer in Japan, according to Astellas.

Zolbetuximab’s road to approval in Japan was relatively smooth, but its journey overseas was full of thorns.

Has been rejected by FDA

The Claudin18.2 target became famous at the 2016 ASCO conference, and the R&D enthusiasm of global pharmaceutical companies was quickly ignited. Zolbetuximab, which was in the Phase II clinical stage at the time, was spotted by Astellis, which had a keen sense of smell, and spent US$1.4 billion to acquire Ganymed and acquire Zolbetuximab.

After Astellas took over, the research and development of Zolbetuximab progressed smoothly. In November and December 2022, Astellas successively announced the experimental data of two key phase III clinical trials of Zolbetuximab, SPOTLIGHT and GLOW, and the results showed that it is combined with standard chemotherapy. Use of CLDN18.2 can prolong the survival of patients with advanced gastric cancer or gastroesophageal junction cancer, and the clinical data are encouraging.

Based on excellent data, the FDA granted priority approval in July 2023 to zolbetuximab for the first-line treatment of patients with unresectable, locally advanced or metastatic, HER2-negative, gastric or gastroesophageal junction (GEJ) disease, with a target action date of 2024 January 12th.

But what awaited Astellas was indeed a rejection notice from the FDA.

On January 9, 2024, Astellas received a complete response letter from the FDA regarding the approval of zolbetuximab, temporarily refusing to approve marketing.

In the CRL letter, the FDA pointed out unresolved deficiencies at zolbetuximab’s third-party manufacturing facility and stated that it would not be able to approve the drug before the original PDUFA date. Among them, the FDA did not raise any questions about the clinical data of zolbetuximab, but it also did not require Astellas to conduct additional clinical trials.

Astellas stated that these production defects will not cause any hidden dangers to safety and effectiveness data, and the company is communicating closely with the FDA and third-party manufacturers to resolve the production defects as soon as possible.

Although it was temporarily defeated by the FDA, Astellas has submitted marketing applications for Zolbetuximab in China and Europe, and this time it was approved for marketing in Japan, becoming the first in the world.

summary

The Claudin18.2 target has great potential, and many companies around the world have developed multiple technical routes around Claudin18.2. Domestically, Innovent, as the leader, has launched a comprehensive strategy for Claudin18.2. All four of Innovent’s Claudin18.2 targeted drugs have entered clinical trials, covering monoclonal antibodies, dual antibodies, ADCs and CAR-T. In addition, Keji Biotechnology, CSPC Pharmaceutical Group, Qilu Pharmaceutical, and Lixin Pharmaceutical all have at least two (or more) Claudin18.2 targeted drugs with technical routes. Multinational giants such as AstraZeneca and Merck have also introduced Claudin18.2 potential pipelines from China. We look forward to more Claudin18.2-targeted drugs being released in the future to benefit patients around the world.