Regulatory Discussions Continue Regarding BLA for Vicineum in BCG-Unresponsive NMIBC

Nov 2, 2021

Sesen Bio met with the FDA to discuss questions related to the Chemistry, Manufacturing, and Controls that were raised in the complete response letter previously issued by the regulatory agency regarding the biologics license application for Vicineum as a potential treatment for patients with Bacillus Calmette-Guérin–unresponsive non–muscle invasive bladder cancer.

Sesen Bio met with the FDA to discuss questions related to the Chemistry, Manufacturing, and Controls (CMC) that were raised in the complete response letter (CRL) previously issued by the regulatory agency regarding the biologics license application (BLA) for Vicineum (oportuzumab monatox-qqrs) as a potential treatment for patients with Bacillus Calmette-Guérin (BCG)–unresponsive non–muscle invasive bladder cancer (NIMBC).1

In August 2021, the FDA issued the CRL after they determined that the application could not be approved as it was, and they issued recommendations specific to clinical/statistical findings and analyses and product quality. They also cited CMC issues during a pre-approval inspection.2

During the CMC Type A Meeting, both parties reviewed issues associated with CMC to be further discussed during the review of the application for the product upon potential resubmission. Sesen Bio, the manufacturer of Vicineum, shared that they have a “clear understanding” of the additional data needed to resubmit the BLA.

In the discussion, the FDA also confirmed that the Vicineum manufactured using the proposed commercial process is similar to the product that has been evaluated in prior trials. The agency also confirmed that the company can use the product manufactured during process validation for any future trials that are needed to address issues raised in the letter, and that these trials could proceed as the CMC issues are being addressed.

“We are pleased by the collaborative dialogue with the FDA during our CMC Type A Meeting,” Thomas Cannell, MD, president and chief executive officer of Sesen Bio, stated in a press release. “Our team looks forward to continued progress as we prepare for the Clinical Type A Meeting, and we remain committed to working diligently to fulfill our mission of saving and improving the lives of patients by bringing new treatment options to market.”

Vicineum is a recombinant fusion protein that was developed to target epithelial cell adhesion molecule–specific antigens on the surface of cancer cells to deliver Pseudomonas Exotoxin A, a potent inhibitor of protein synthesis.

The product is being investigated in patients with NMIBC who had received prior standard-of-care BCG as part of the open-label, multicenter, single-arm, phase 3 VISTA trial (NCT024492339).3

VISTA enrolled patients with disease that was either refractory or relapsed following treatment with BCG. To be eligible for enrollment, patients needed to have a Karnofsky performance status of 60 or higher and acceptable organ function.4 Those who were pregnant or breastfeeding, had evidence of urethral tract transitional cell carcinoma within the 2 years prior to treatment, had hydronephrosis, received any intravesicular or other chemotherapy treatment within 2 weeks or an investigational agent 4 weeks before to the initial dose of the study drug, were excluded.

The primary efficacy end points of the trial were complete response (CR) rate and duration of response (DOR) for patients in cohort 1. Key secondary end points included time to disease recurrence for patients in cohort 3, as well as time to cystectomy, progression-free survival, event-free survival, and overall survival (OS) for patients across the cohorts examined.

In 89 patients with carcinoma in situ, with or without papillary disease that was refractory or recurred less than 11 months after their last course of BCG, Vicineum induced a CR rate of 40% (95% CI, 33%-51%) at 3 months. At 6 months, 9 months, and 12 months, the CR rates achieved with the agent were 28% (95% CI, 19%-39%), 21% (95% CI, 13%-31%), and 17% (95% CI, 10%-26%), respectively.

Cohort 1 was comprised of patients who had carcinoma in situ with or without papillary disease that was refractory or recurred within 6 months of their last course of BCG (n = 82). In these patients, Vicineum induced CR rates of 39%, 26%, 20%, and 17% at 3 months, 6 months, 9 months, and 12 months, respectively.

Patients with carcinoma in situ with or without papillary disease that was refractory or recurred after 6 months, but less than or equal to 11 months, following their last course of BCG comprised cohort 2. At 3 months, the CR rate achieved with Vicineum was 57%; at 6 months, 9 months, and 12 months, these rates were 57%, 43%, and 14%, respectively.

A median DOR of 273 days (95% CI, 122–not applicable [NA]) per the Kaplan-Meier method was observed in those who comprised cohort 1. Moreover, an ad-hoc analysis of pooled data for 93 patients in either cohort 1 or 2 indicated that of those who responded to Vicineum at 3 months, 52% achieved a CR that persisted for 12 months or longer after treatment initiation.

Moreover, patients with high-risk papillary disease experienced higher rates of progressive disease and recurrence. The median time to recurrence in 40 patients who were included in cohort 3 was 402 days (95% CI, 170–NA).

Of all the patients who received treatment with Vicineum (n = 133), more than 75% were estimated to continue to be free of cystectomy at 2.5 years. Data from an ad-hoc analysis that looked at responders vs non-responders showed that 88% of responders were estimated to remain cystectomy free at 3 years. Additionally, 90% of all patients who received Vicineum are estimated to be free of disease progression at 2 years or longer, and 29% were estimated to remain event free at 1 year. Ninety-six percent of patients were estimated to experience an OS of 2 years or longer.

Most adverse effects (AE) reported by patients across the cohorts were low grade. The most common AEs experienced with Vicineum included dysuria (14%), hematuria (13%), and urinary tract infection (12%). Toxicities were noted to be both manageable and reversible.

Only 4 patients discontinued treatment with the product because of AEs. Moreover, 14% of patients experienced serious AEs (SAEs), irrespective of treatment attribution. Four SAEs were reported in 3 patients, and those included grade 3 acute kidney injury, grade 2 pyrexia, grade 4 cholestatic hepatitis, and grade 5 renal failure.

Sesen Bio shared that they are preparing for a separate Type A Meeting to discuss recommendations pertaining to additional clinical/statistical findings and analyses the agency raised in the letter. The company expects this meeting to be held later in 2021. They plan to leverage information from the CMC Type A Meeting and the Clinical Type A Meeting to “synchronize the regulatory reviews of Vicineum.”


  1. Sesen Bio announces productive CMC Type A Meeting with the FDA. News release. Sesen Bio. November 1, 2021. Accessed November 2, 2021.
  2. Sesen Bio receives complete response letter from FDA for Vicineum (oportuzumab monatox-qqrs). News release. Sesen Bio. August 13, 2021. Accessed November 2, 2021.
  3. Sesen Bio reports positive, preliminary data update from phase 3 VISTA trial for high-risk non-muscle invasive bladder cancer. News release. Sensen Bio. August 8, 2019. Accessed November 2, 2021.
  4. Vicinium treatment for subjects with non-muscle invasive bladder cancer previously treated with BCG. Updated October 14, 2020. Accessed November 2, 2021.
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