Vicineum Receives FDA Priority Review for BCG-Unresponsive NMIBC; Licensed to Qilu Pharmaceutical for Greater China

February 17, 2021 /Bio ValleyBIOON/ -- Qilu Pharmaceutical’s partner, Sesen Bio, recently announced that the U.S. Food and Drug Administration (FDA) has accepted the Biologics License Application (BLA) for Vicineum (oportuzumab monatox, VB4-845) and granted it Priority Review. The drug is indicated for the treatment of high-risk, Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). In addition,FDAstated that there are no current plans to convene an advisory committeeMeetingTo discuss the BLA for Vicineum. Previously,FDAVicineum has been granted Fast Track Designation (FTD).

Priority review means that,FDAA review decision will be made within six months of accepting the BLA. For the Vicineum BLA, the expected Prescription Drug User Fee Act (PDUFA) target date is August 18, 2021. Sesen Bio plans to submit a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) in the next 1-2 months.

Sesen Bio previously projected that, upon successful commercialization, Vicineum would achieve global annual peak sales of $1–3 billion, with the U.S. market expected to contribute $400–900 million.

In late July 2020, Qilu Pharmaceutical entered into an exclusive licensing agreement with Sesen Bio, securing the exclusive rights to develop and commercialize Vicineum in the Greater China region (including Mainland China, Hong Kong, Macau, and Taiwan). Vicineum is being developed for the treatment of Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) as well as other types of cancer. The total value of this collaboration was USD 35 million. (For details on the collaboration and the Vicineum project, see:July 2020 Business Update Presentation）

Bladder cancer is the sixth most common cancer in the United States, with approximately 80% of patients beingDiagnosisfor NMIBC. For patients unresponsive to BCG, the recommended treatments are radical cystectomy (complete removal of the bladder) or Merck’s anti-PD-1 therapy Keytruda (pembrolizumab). Market research conducted by Sesen Bio indicates that when choosing between Vicineum and Keytruda, physicians select Vicineum in more than 80% of cases. If approved, Vicineum will represent a best-in-class therapeutic option.

Vicineum is a next-generation antibody-drug conjugate (ADC), a locally administered fusion protein that isTumorA humanized scFv immunotoxin targeting the epithelial cell adhesion molecule (EpCAM) antigen on the cell surface, composed of a recombinant humanized anti-EpCAM antibody scFv conjugated with Pseudomonas exotoxin A. Upon binding to EpCAM expressed by cancer cells, it is internalized into the cytoplasm, inducingApoptosis。

Vicineum is composed of a stable genetically engineered peptide chain to ensure that exotoxin A remains attached until it is internalized by cancer cells, thereby reducing the risk of toxicity to healthy tissues and improving safety. Preclinical studies have confirmed that EpCAM is overexpressed in NMIBC cells but is barely expressed in normal bladder cells. In both the United States and the European Union, Vicineum was granted orphan drug designation in 2005 and in August 2018 wasFDAGranted Fast Track designation for the treatment of BCG-unresponsive NMIBC.

Mechanism of Action of Vicineum (Click the image to view a larger version)

Bladder cancer is a common malignancy, with approximately 80% of cases classified as non-muscle-invasive bladder cancer (NMIBC), meaning the cancer cells are confined to the inner lining of the bladder or have grown into the bladder lumen but have not yet invaded the muscle layer or other tissues. NMIBC predominantly affects men and is associated with exposure to carcinogens. The recurrence rate after initial surgical resection is high, with over 60% of patients undergoing Bacillus Calmette-Guérin (BCG) immunotherapy. Although BCG is effective in many patients, issues with tolerance have been observed, and many patients experience disease recurrence. If BCG therapy fails or if long-term BCG treatment is required, radical cystectomy is the recommended therapeutic option.

In December 2019, Sesen Bio initiated the rolling submission of its Biologics License Application (BLA) for Vicinium to the U.S. FDA through the rolling review process. The FDA’s rolling review mechanism allows pharmaceutical companies to submit completed sections of their New Drug Application (NDA) or Biologics License Application (BLA) to theFDA, without having to wait until each section is complete before reviewing the entire NDA or BLA. In May 2020, Sesen Bio received positive scientific advice from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) regarding the EU regulatory pathway for Vicineum.

The efficacy of Vicinium in treating Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) has been demonstrated in the Phase III VISTA study (NCT02449239). In August 2019, Sesen Bio announced data for the primary and secondary endpoints of this study. Updated 12-month data further support the favorable benefit-risk profile of Vicinium in patients with high-risk BCG-unresponsive NMIBC, which also formed part of the company’s submission to the U.S.FDAThe basis for submitting the BLA.

Bladder Cancer (Image source: medscape.com)

VISTA is a single-arm, 24-month, open-label, multicenter Phase III study evaluating vicinium as a monotherapy administered via intravesical instillation for the treatment of patients with high-risk, BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC). The study enrolled a total of 133 patients with high-grade NMIBC, including carcinoma in situ (CIS) or papillary cancer (with or without CIS), who had previously received BCG therapy. Patients were stratified into three cohorts based on histology and the time to disease recurrence following adequate BCG therapy (defined as at least two induction courses, with the first course comprising at least five doses and the second course at least two doses): Cohort 1 included patients with refractory or recurrent CIS within 6 months of BCG therapy; Cohort 2 included patients with recurrent CIS occurring 6–11 months after BCG therapy; and Cohort 3 included patients with refractory or recurrent papillary cancer (without CIS) within 6 months of BCG therapy. In the study, patients received locally administered vicinium twice weekly for 6 weeks, followed by once weekly for 6 weeks, and then every other week for up to 2 years.

As of the data cutoff date of May 29, 2019, the primary and secondary endpoint data were updated as follows: (1) Complete response rate: At 3, 6, 9, and 12 months, the rates for Cohort 1 were 39%, 26%, 20%, and 17%, respectively, and for Cohort 2 were 57%, 57%, 43%, and 14%, respectively. The pooled analysis of Cohorts 1 and 2 showed rates of 40%, 28%, 21%, and 17% at 3, 6, 9, and 12 months, respectively. (2) Duration of response: The median duration for Cohort 1 was 273 days. In the pooled analysis of all patients with carcinoma in situ (CIS) from Cohorts 1 and 2, among those who achieved a complete response at 3 months, 52% maintained a complete response lasting ≥12 months after treatment initiation. (3) Time to disease recurrence: High-risk papillary non-muscle-invasive bladder cancer (NMIBC) is associated with higher rates of progression and recurrence; therefore, time to disease recurrence is a key secondary endpoint for patients with high-risk papillary NMIBC. The median time to disease recurrence for patients in Cohort 3 was 402 days. (4) Time to cystectomy:FDAThe guidelines indicate that the treatment goal for BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) is to avoid cystectomy; therefore, time to cystectomy is a key secondary endpoint. Results showed that, based on Kaplan-Meier analysis, an estimated >75% of patients remained cystectomy-free at 2.5 years, and 88% of responders remained cystectomy-free at 3 years. (5) Progression-free survival: Kaplan-Meier analysis indicated that 90% of patients had progression-free survival ≥2 years. (6) Event-free survival: Kaplan-Meier analysis showed that 29% of patients remained event-free at the 12-month time point. (7) Overall survival: Kaplan-Meier analysis demonstrated that 96% of patients had overall survival ≥2 years. (8) Safety: Vicinium continued to demonstrate good tolerability, with 95% of adverse events being Grade 1 or 2. The most common treatment-related adverse events were dysuria (14%), hematuria (13%), and urinary tract infection (12%), all of which are consistent with the characteristics of bladder cancer patients and catheter-based treatment, and were manageable and reversible. (Bioon.com)

Original Source: Sesen Bio AnnouncesFDA Acceptance and Priority Review of its Biologics License application for Vicineum™