Japan's MHLW Grants Priority Review to First-in-Class ADC Padcev (enfortumab vedotin) for PD-(L)1 Inhibitor-Refractory Bladder Cancer Patients

May 15, 2021 /BioonBIOON/ -- Astellas recently announced that Japan's Ministry of Health, Labour and Welfare (MHLW) has accepted the New Drug Application (NDA) and granted priority review for the targeted anticancer drug Padcev (enfortumab vedotin), which is indicated for the treatment of patients with locally advanced or metastatic urothelial cancer (UC, the most common type of bladder cancer) whose disease has progressed following prior anticancer therapy. In the new drug approval process, the MHLW grants priority review to marketing approval applications based on the clinical efficacy of the drug and the severity of the targeted disease.

If approved,Padcev will become Japan's first antibody-drug conjugate (ADC) for the treatment of urothelial carcinoma (UC).. UC accounts for approximately 90% of bladder cancer cases. Locally advanced or metastatic UC is an aggressive disease characterized by low survival rates and high medical costs.

Senior Vice President, Astellas &TumorAndrew Krivoshik, M.D., Head of the Therapeutic Area, stated: “The decision by Japan's Ministry of Health, Labour and Welfare to grant priority review to enfortumab vedotin reflects the urgent need in Japan for new treatments for advanced urothelial carcinoma, which is estimated to cause 9,500 deaths annually.”

Bladder Cancer - (Image Source - medscape.com)

Urothelial carcinoma (UC) is the most common type of bladder cancer, accounting for approximately 90% of bladder cancer cases. Padcev is a first-in-class antibody-drug conjugate (ADC) that targets a cell surface protein highly expressed in bladder cancer. The drug consists of enfortumab, a human IgG1 monoclonal antibody targeting Nectin-4, conjugated to the cytotoxic payload MMAE (monomethyl auristatin E, a microtubule-disrupting agent). Nectin-4 is a cell adhesion molecule expressed in multiple solid tumors, including urothelial carcinoma (UC).TumorTherapeutic targets with moderate to high expression. In this drug, the ADC linker technology originates from Seattle.`Genetics`Company (Seagen), target identification will be completed by Astellas.

In December 2019, Padcev received U.S.FDAAccelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC, the most common type of bladder cancer), specifically: patients who have previously received a PD-1/L1 inhibitor and a platinum-containing chemotherapy regimen in the neoadjuvant, adjuvant, or locally advanced/metastatic disease setting.

It is worth noting that,Padcev is the world's first ADC approved for the treatment of UC, and the first drug approved for patients with locally advanced or metastatic UC who have previously received platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.In the United States, the drug was approved through the FDA's Priority Review program. Previously,FDABreakthrough Therapy designation has been granted to Padcev for the treatment of the aforementioned patients with UC.

In Japan, the NDA for Padcev was based on the results of two global clinical trials (EV-301 and EV-201), both of which included sites in Japan,Clinical Trial• The Phase 3 EV-301 confirmatory trial was conducted in adult patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based chemotherapy and a PD-1/L1 inhibitor, comparing Padcev with chemotherapy. Results showed that at a median follow-up of 11.1 months,Compared with the chemotherapy group, the Padcev group demonstrated significantly prolonged overall survival.（Median OS: 12.88 months vs. 8.97 months; HR=0.70; p=0.001）、Significantly prolonged progression-free survival(median PFS: 5.55 months vs 3.71 months; HR=0.62; p<0.001).

The Phase 2 EV-201 trial evaluated the efficacy and safety of Padcev in patients with locally advanced or metastatic urothelial carcinoma (UC) who had previously received PD-1/PD-L1 inhibitors, including those who had also received platinum-based chemotherapy (Cohort 1) and those who were platinum-naïve and cisplatin-ineligible (Cohort 2). Results from Cohort 1 showed that Padcev treatment rapidly shrank most patients’Tumor，the objective response rate (ORR) was 44% (55/125, 95% CI: 35.1-53.2), the complete response rate (CR) was 12% (15/125), and the median duration of response (DOR) was 7.6 months (range: 0.95-11.3+). Results from Cohort 2 showed that among patients treated with Padcev, the confirmed objective response rate (ORR) was 52%, with a complete response rate (CR) of 20%; the median duration of response (mDOR) was 10.9 months, and the median progression-free survival (mPFS) and median overall survival (mOS) were 5.8 months and 14.7 months, respectively.

In February this year, Astellas and SeattleGeneticsthe company to the United StatesFDATwo supplemental Biologics License Applications (sBLAs) were submitted. The first, based on the Phase 3 EV-301 trial, aims to convert Padcev from accelerated approval to full approval. The second, based on Cohort 2 of the pivotal EV-201 trial, aims to expand the current drug label to include patients with locally advanced or metastatic urothelial cancer (UC) who have previously received a PD-1/L1 inhibitor and are ineligible for cisplatin therapy.

FDAwill be in real-timeTumorThese two applications will be reviewed under the Real-Time Oncology Review (RTOR) pilot program. The RTOR program aims to explore a more efficient review process to ensure earlier patient access to safe and effective therapies. Among them, the sBLA seeking regular approval for Padcev is based on data from the global Phase 3 EV-301 confirmatory trial. The second sBLA is based on results from Cohort 2 of the pivotal Phase 2 EV-201 trial. The EV-301 trial met its primary endpoint of improved overall survival (OS) and confirmed the objective response data from the EV-201 trial. (Bioon.com)

Source: Japan's Ministry of Health, Labour and Welfare Grants Priority Review for Enfortumab Vedotin New Drugapplication