Ganymed Pharmaceuticals AG

After previous rejections, Astellas reached a milestone to celebrate over the weekend when its new stomach cancer treatment, Vyloy (zolbetuximab), received its first approval from the U.S. Food and Drug Administration (FDA). On Friday, the FDA officially approved Vyloy as a first-line treatment for ClDN18.2-positive adult patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2) negative gastric or gastroesophageal junction adenocarcinoma. This approval marks Vyloy as the first anti-ClDN18.2 (known as Claudin-18.2) drug approved in the United States, a transmembrane protein that has become a high-profile target in oncology. It has attracted the attention of several companies, including AstraZeneca, Leap Therapeutics, Legend and Moderna. The FDA approval specifically covers Vyloy in combination with fluoropyrimidine and platinum-containing chemotherapy agents. To ensure patient availability, the FDA has approved both Ventana Medical System and Roche's CLDN18.2-positive companion diagnostic test. In clinical studies, Vyloy has demonstrated significant efficacy. In the SPOTLIGHT study, which included 565 patients, the median progression-free survival (PFS) of patients in the Vyloy combined chemotherapy group was 10.6 months, which was significantly better than 8.7 months in the placebo combined chemotherapy group. At the same time, the median overall survival (OS) of patients in the Vyloy group was 18.2 months, which was also better than 15.5 months in the control group. Another GLOW study of 507 patients showed that Vyloy helped patients achieve a median PFS of 8.2 months, compared to 6.8 months in the placebo/chemotherapy group, and a median OS of 14.4 months and 12.2 months, respectively. It's worth noting that Vyloy's path to approval was not smooth. Despite being granted a priority review label by the FDA in July 2023, after receiving a full response letter in January, the FDA rejected the application for the drug due to unresolved deficiencies identified during pre-licensing inspections at third-party manufacturing facilities. However, Astellas responded quickly, announcing in late May that the FDA had accepted its resubmitted application. The approval of Vyloy is significant for Astellas. The company acquired its interest in Vyloy in 2016 when it acquired Ganymed Pharmaceuticals for $1.4 billion. Despite setbacks in the U.S. regulatory process, Vyloy has received several approvals overseas, including a successful listing in Japan. In addition, Vyloy has received regulatory approvals in Europe and the United Kingdom. While Astellas currently has a leading position in the anti-ClDN18.2 field, several other companies are also actively advancing clinical trials of related drug candidates. For example, Astrazeneca has invested tens of millions of dollars to acquire global rights to an antibody-drug conjugate that targets CLDN18.2. At the same time, while Merck has adjusted its business in this area, other companies such as Kellen are still showing positive research results and potential.

Astellas will have to clear up issues with a third-party manufacturer before it can get its gastric cancer candidate zolbetuximab across the FDA finish line. Two successful phase 3 trials put Astellas’ monoclonal antibody zolbetuximab on track to become the first approved therapy to treat one of the hottest targets in oncology—tumors that are claudin (CLDN) positive. But the Japanese company will have to clear up manufacturing issues first. The FDA has sent a complete response letter to Astellas, rejecting zolbetuximab because of unresolved deficiencies identified in a pre-license inspection of a third-party manufacturing facility, the company said. The U.S. regulator granted zolbetuximab priority review in July of last year and established a decision date of Jan. 12. The application is for locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are claudin (CLDN) 18.2 positive. The FDA raised no concerns about the clinical data for zolbetuximab and is not requesting a new study, Astellas said. The company added that the delay would have limited impact on financial results for the fiscal year ending on March 31 of this year. “We remain confident in zolbetuximab’s clinical profile and potential to fill a significant therapeutic gap,” Moitreyee Chatterjee-Kishore, Ph.D., Astellas’ chief of immuno-oncology development, said in a release. Astellas gained zolbetuximab in a $1.4 billion purchase of Ganymed Pharmaceuticals in 2016. In the SPOTLIGHT trial, zolbetuximab improved progression-free survival (PFS) in a genetically defined population of gastric and gastroesophageal junction cancer patients. Then in March of last year, Astellas revealed that in the GLOW trial, which combined zolbetuximab with a chemotherapy regimen, it improved PFS and overall survival. Other companies investigating treatments to combat CLDN 18.2 include AstraZeneca, Leap Therapeutics, BioNTech and Legend.

Astellas thinks it has the basis for regulatory submissions. Astellas Pharma’s zolbetuximab has gone two for two, chalking up a second phase 3 win to cement its status as the front-runner in the race to deliver a drug against one of the hottest targets in cancer today. In November, the Japanese drugmaker reported that the SPOTLIGHT phase 3 clinical trial had linked the anti-CLDN18.2 antibody to improved progression-free survival (PFS) in a genetically defined population of gastric and gastroesophageal junction cancer patients. The success put Astellas one study away from having the data to file for approval of zolbetuximab.  Now, Astellas has reported data from its second placebo-controlled study, GLOW. As happened in the earlier trial, GLOW found adding the investigational antibody to a chemotherapy regimen improved PFS, the primary endpoint, and overall survival (OS) in CLDN18.2-positive, HER2-negative cancer patients.  The two studies targeted the same populations and enrolled similar numbers of patients, 507 in GLOW versus 566 in SPOTLIGHT. The key difference was the choice of chemotherapy regimen. GLOW used the capecitabine-oxaliplatin combination CAPOX while SPOTLIGHT used the mFOLFOX6 cocktail of oxaliplatin, leucovorin and fluorouracil.  Both trials randomized patients to take zolbetuximab or placebo on top of the chemotherapy regimens. In GLOW, the median PFS and OS durations achieved by the zolbetuximab-chemotherapy combination were lower than in SPOTLIGHT. But with the placebo arm also performing better in SPOTLIGHT, the deltas between the treatment and control groups were similar. Median PFS in GLOW’s zolbetuximab group was 8.21 months, versus 6.8 months in the placebo cohort. The median PFS for zolbetuximab and the control in SPOTLIGHT were 10.61 months and 8.67 months, respectively. Similarly, the median OS for zolbetuximab and placebo in GLOW, 14.39 months and 12.16 months, were lower than the figures in SPOTLIGHT, 18.23 months and 15.54 months.  The safety and tolerability results from GLOW were consistent with previous studies, with the rates of nausea, vomiting and decreased appetite being the key differences between the treatment and control arms, and as such Astellas thinks it has the basis for regulatory submissions. Approval would enable Astellas to start recouping the 422 million euros ($452 million) it spent to acquire zolbetuximab in its 2016 takeover of Ganymed Pharmaceuticals, although it is also on the hook for more milestone payments.  Barring any regulatory snags, Astellas will become the first company to bring an anti-CLDN18.2 drug to market. It is unlikely to be the last. A long list of drug developers are tackling the target using a range of modalities, with AstraZeneca alone inking two deals in the past year for an antibody-drug conjugate and a bispecific antibody against CLDN18.2.