Urogen Pharma Ltd. overcame a decidedly mixed U.S. FDA advisory panel meeting to nail down approval of Zusduri (mitomycin, formerly known as UGN-102) for recurrent low-grade, intermediate-risk, non-muscle invasive bladder cancer (LG-IR-NMIBC).

Shares of the Princeton, N.J.-based firm (NASDAQ:URGN) closed June 12 at $11.08, up $3.78, or 51%, on the news, which follows the Oncologic Drugs Advisory Committee’s (ODAC) narrowly negative, 4-5 vote May 21 on the intravesical solution’s benefit/risk profile. The hydrogel-based formulation is delivered directly into the bladder during an outpatient procedure using a urinary catheter to enable the treatment of tumors by nonsurgical means.

The approval is based on positive results from the phase III Envision trial that showed Zusduri provided 78% complete response (CR) for patients at three months. Of those subjects, 79% remained event-free 12 months later. The most common (≥10%) adverse reactions, including laboratory abnormalities, were increased creatinine, increased potassium, dysuria, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, increased eosinophils, decreased lymphocytes, urinary tract infection, decreased neutrophils and hematuria. Serious reactions occurred in 12% of patients given Zusduri: urinary retention (0.8%) and urethral stenosis (0.4%).

The existing standard of care for LG-IR-NMIBC is a surgical procedure typically performed under general anesthesia called transurethral resection of bladder tumor (TURBT). Due to high recurrence rates of the disease, repeated TURBTs may be necessary. Urogen plans to make Zusduri available in the U.S. on or around July 1.

As a postmarketing commitment, Urogen has agreed with the FDA to complete the ongoing Envision study and provide the agency with annual updates on duration of response for all patients with ongoing complete responses. Such check-ins will continue until all subjects turn up a recurrence of LG-IR-NMIBC, progression, death, loss to follow-up, or the reaching of 63 months after the first instillation as planned in the protocol – whichever occurs first.

After the ODAC meeting, opinions varied on the FDA’s most likely decision. Some were optimistic since the panel’s urology specialists as well as the patient representative all voted yes at the meeting and said that the drug would be an important alternative to a continuing cycle of surgery for patients with recurrent disease. Mark Ball, a research doctor at the National Cancer Institute’s Urologic Oncology Branch, conceded that a fully enrolled randomized trial, instead of single-arm Envision, would have made a stronger case for Zusduri, but said the results were still encouraging. The toxicity of the drug was not alarming, he said, especially when compared with the problems with untreated cancer or repeated TURBTs.

Urogen slated a conference call for the morning of June 13 to discuss the green light. Meanwhile, D. Boral analyst Jason Kolbert deemed the FDA move “surprising” and said in a dispatch to investors that Zusduri’s approval “validates the agency’s willingness to exercise flexibility in high-unmet-need indications, despite divided advisory input.” 

Shares of Urogen had declined sharply in the wake of the ODAC vote, falling 64% in May and 33% year-to-date. “With this regulatory overhang now cleared, investor attention is likely to shift toward commercial execution, postmarketing commitments, and clarity on the launch timeline,” he said.

Kolbert, in an earlier report, echoed Ball in offering a probable explanation for the uncertain ODAC balloting. “While the complete response rate at three months was robust [in Envision], the absence of a randomized control group made it difficult for some committee members to fully assess whether the observed effects were attributable to the treatment or influenced by natural disease fluctuation or selection bias.” Such a choice of design, he said, although “not uncommon in certain settings with high unmet needs, often leads to more subjective interpretations of efficacy, especially among more conservative reviewers.” 

Urogen’s Jelmyto, also a form of mitomycin, was approved for low-grade upper tract urothelial cancer in April 2020.

Another high-profile player in NMIBC is sasanlimab from New York-based Pfizer Inc. At the meeting of the American Urological Association in Las Vegas at the start of May, Pfizer unveiled numbers from the pivotal phase III study with sasanlimab, an anti-PD-1 monoclonal antibody used with standard-of-care Bacillus Calmette Guerin (BCG) as induction therapy, with or without maintenance, in patients with BCG-naïve, high-risk disease. The trial met its primary endpoint of event-free survival (EFS) by investigator assessment, turning up a clinically meaningful and statistically significant improvement with sasanlimab in combination with BCG (induction and maintenance) as compared to BCG alone (induction and maintenance; HR 0.68; 95%, CI 0.49-0.94; 2-sided p=0.019), with the median EFS not yet reached. The findings show a 32% reduction in risk of disease-related events, including high-grade disease recurrence or progression with the sasanlimab-paired regimen as compared with BCG alone.