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Novel targeted immunotoxin: Vicinium launches rolling submission

Release date: 2020-01-06 Views: 0

Source: Biovalley  

Sesen Bio is a late-stage clinical biopharmaceutical company focused on developing targeted fusion protein therapies for the treatment of cancer. Recently, the company announced that it has started rolling submission of Vicinium (oportuzumab monatox) biological product approval application (BLA), which is a next-generation antibody drug conjugate (ADC), to the US Food and Drug Administration (FDA). For the treatment of non-muscle invasive bladder cancer (NMIBC) that does not respond to BCG. In 2018, the FDA granted Vicinium Fast-Track Designation.

Rolling review allows pharmaceutical companies to submit completed parts of their new drug application (NDA) or biological product approval application (BLA) to the FDA without having to wait for each part to be completed before reviewing the entire NDA or BLA.

Currently, Sesen Bio has submitted completed non-clinical and clinical modules and partially completed chemical, manufacturing and control (CMC) modules. After finalizing the CMC module, the company expects to complete the BLA submission in 2020. If the FDA accepts the BLA, the company plans to apply for priority review.

Dr. Thomas Cannell, President and Chief Executive Officer of Sesen Bio, said: "At present, there are still significant unmet medical needs in the treatment of NMIBC, and the continuing shortage of BCG has compounded this situation. The launch of the Vicinium BLA rolling submission marks the Sesen Bio A huge achievement for the company is also an important step forward for us in helping to save and restore the lives of cancer patients. "

Bladder cancer is the sixth most common cancer in the United States. About 80% are NMIBC. Cancer cells are located in the bladder or have grown into the bladder cavity, but have not spread to muscles or other tissues. NMIBC mainly affects men and is related to carcinogen exposure. The recurrence rate of patients after initial surgical resection is high, and more than 60% of patients will receive BCG immunotherapy. Although BCG is effective in many patients, tolerability problems have been observed, and many patients experience recurrence of the disease. If BCG is ineffective or the patient needs to receive BCG for a long time, the recommended treatment option is to completely remove the bladder.

Vicinium, a fusion protein for local administration, is a lead candidate by Sesen Bio and is being developed for the treatment of high-risk NMIBC. vicinium is a humanized scFv immunotoxin that targets the epithelial cell adhesion molecule (EpCAM) antigen on the surface of tumor cells. It is a combination of recombinant humanized anti-EpCAM antibody scFv and Pseudomonas exotoxin A. Once EpCAM expressed in combination with cancer cells is internalized into the cytoplasm and induces apoptosis. Vicinium consists 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 over-expressed in NMIBC cells, while rarely or not expressed in normal bladder cells. In the United States and the European Union, vicinium was granted orphan drug status in 2005 and Fast Track status by the FDA in August 2018 for the treatment of NMIBC that does not respond to BCG immunotherapy.

Vicinium mechanism of action

In August of this year, Sesen Bio released updated primary and secondary endpoint data for VISTA (NCT02449239), a Phase III clinical study of Vicinium for bladder cancer. The updated 12-month data further supports the powerful benefit risks of Vicinium in the treatment of high-risk, BCG-nonresponsive, non-muscle-invasive bladder cancer (NMIBC) patients, and these data are also the basis for the company's submission of BLA to the US FDA.

VISTA is a single-arm, 24-month, open-label, multicenter, phase III study that is assessing vicinium as a monotherapy for the treatment of high-risk NMIBC patients with non-response to BCG immunotherapy through intravesical administration. A total of 133 patients with high-grade NMIBC carcinoma in situ (CIS) or papillary carcinoma (with or without CIS) were included in the study. These patients had received BCG. In the study, patients entered three cohorts based on histology and adequate BCG treatment (at least 2 courses of BCG, at least 5 doses in the first course, and at least 2 doses in the second course) (Cohort 1: BCG treatment 6 Refractory or relapsed CIS within 1 month; Cohort 2: Relapsed CIS within 6-11 months of BCG treatment; Cohort 3: Refractory or relapsed papillary cancer within 6 months of BCG treatment [no CIS]. In the study, patients received topical administration of vicinium twice a week for 6 weeks, followed by a weekly treatment for 6 weeks, and then every other week for 2 years.

As of the data cut-off on May 29, 2019, the primary and secondary endpoint data are updated as follows:

(1) Complete remission rate: Cohort 1 and cohort 2 are 39%, 26%, 20%, 17% and 57%, 57%, 43 at 3 months, 6 months, 9 months, and 12 months. %, 14%; Cohort 1 and Cohort 2 show 40%, 28%, 21%, and 17% at the time points of 3 months, 6 months, 9 months, and 12 months.

(2) Duration of remission: The median time of cohort 1 was 273 days; a summary analysis of all CIS patients in cohort 1 and cohort 2 showed that 52% of patients who achieved complete remission at the 3-month time point were initiating treatment The duration of complete remission was ≥12 months.

(3) Disease recurrence time: High-risk papilloma NMIBC is associated with higher progression and recurrence rate, so the disease recurrence time is a key secondary endpoint for patients with high-risk papilloma NMIBC. The median disease recurrence time of cohort 3 patients was 402 days. .

(4) Cystectomy time: The FDA guidelines state that the goal of BCG non-responding NMIBC treatment is to avoid cystectomy, so cystectomy time is a key secondary endpoint. The results show that Kaplan-Meier analysis is used to estimate that> 75% of patients The bladder remained unresected for 2.5 years, and 88% of the respondents remained unresected for 3 years.

(5) Progression-free survival: Using Kaplan-Meier analysis, 90% of patients have progression-free survival ≥ 2 years. (6) Event-free survival: Using Kaplan-Meier analysis, 29% of patients maintained event-free survival at 12 months.

(7) Overall survival time: According to Kaplan-Meier analysis, 96% of patients had a total survival time of ≥ 2 years.

(8) Safety: vicinium continues to show good tolerance, 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 infections (12%), all of which are consistent with the characteristics of bladder cancer patients and the use of catheters for treatment, and are controllable and reversible of.

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