Citing insufficient data, a too-small study and a patient population that was not clearly defined, an FDA advisory panel recommended the FDA reject the biologics license application (BLA) for Telesta Therapeutics Inc.'s bladder cancer drug, MCNA.

The joint meeting of the FDA's Cellular, Tissue and Gene Therapies and Oncology Drugs advisory committees voted 6-18 (the original 6-19 vote was adjusted due to a voting irregularity) against the use of MCNA in high-risk non-muscle invasive bladder cancer (NMIBC) patients who have failed prior BCG therapy. But for many committee members, the decision was not cut and dry.

Describing herself as "fairly conflicted," Leisha Emens, the associate director of oncology at Johns Hopkins University School of Medicine, said she believes MCNA has a role, "but I have a lot of trouble putting my hands around exactly what that role is based on the data."

Use of a single-arm study for NMIBC was accepted during a 2013 FDA/American Urological Association workshop as a design that could provide sufficient evidence of benefit, provided the results were robust. A majority of adcom members, however, indicated the results from the 129-patient phase III study supporting the BLA were less than persuasive.

Study 301 measured disease-free survival (DFS) at one year, and showed that about 24 percent of treated patients were disease-free at one year. While that fell short of the primary endpoint, the FDA was willing to accept the application, even granting priority review, based on promising data from a subset of patients in the study.

Among patients who were disease-free, MCNA response was durable, lasting nearly three years, according to Cortellis Clinical Trials Intelligence.

Telesta said the results also indicated that patients treated with MCNA were not at a greater risk of disease progression, bladder removal or death. In fact, investigators argued that patients were able to potentially preserve their bladders for longer. A total of 55 of 129 patients in the study underwent bladder removal during the trial period, with a median time to bladder removal of 263 days from the first instillation of MCNA vs. 173.5 days for patients in whom MCNA failed.

But in the absence of a control arm, several panelists noted that it was impossible to know whether those outcomes in fact signified a clear improvement. There was also the issue that, like BCG, or Bacillus Calmette-Guerin, the precise mechanism of action of MCNA is not known. It's not even clear, others pointed out, whether MCNA works differently enough from BCG to warrant approval – or whether it relies on BCG to prime the immune system or might prove handy in a first-line setting.

Derived from the cell wall fractionation of a nonpathogenic bacteria, MCNA (Mycobacterium phlei cell wall-nucleic acid complex) is believed to work via a dual action of immune stimulation and direct anticancer effects, and preclinical studies have shown that it had effects on proliferation, cell cycle arrest and apoptosis. As a sterile suspension for intravesical administration, the product was developed to follow the same dosing paradigm of BCG therapy.

Nearly all panelists agreed that MCNA appeared safe and well tolerated, which for some offered a sufficient reason to provide an alternative treatment in NMIBC, a disease that has not seen a new therapy approved in nearly three decades. The most widely used drug, BCG, has its problems. As a live, attenuated strain of M. bovis, it cannot be administered immediately postop and it's been plagued by drug shortage issues in recent years. Meanwhile, a substantial percentage of patients – estimates put the figure at roughly 40 percent – relapse on or are refractory to BCG. For those patients, often the only option is cystectomy, or bladder removal which, as Monica Smith, of the Bladder Cancer Advocacy Network, noted during the public hearing part of the meeting is a "major life change for patients."

Her comments were echoed by panel member Thomas Griffith, microbiology associate professor and department of urology member at the University of Minnesota, one of the six yes votes. "I think a lot of the deficiencies raised were clearly there, but I felt the weaknesses were outweighed by a number of strengths," particularly the fact that there are few options. "We need something that is not so much of a radical procedure" for patients.

A few panelists said they would vote in favor of MCNA if the label indicated use only for those patients who were not eligible or who refused cystectomy. For Michael Menefee, assistant professor in the division of hematology and oncology at the Mayo Clinic, however, even that modification would elicit a no vote. "I think the problem lies in that the study was not well designed to answer the question . . . with the confidence we would like to have," he said.

NMIBC, referring to bladder cancer that has not penetrated beyond the first layer of the bladder to the detrusor muscle, accounts for about three-fourths of all bladder cancer cases. Of those, roughly half are considered high-grade. The space has seen few changes in treatment, though some chemo combinations are used off-label. Other candidates are advancing, perhaps most notably, Spectrum Pharmaceuticals Inc.'s apaziquone, which has launched a special protocol assessment-designed pivotal program in NMIBC patients immediately following transurethral resection of bladder tumors. (See BioWorld Today, Oct. 27, 2015.)

The FDA, which is not bound by the adcom's vote but generally follows its advice, is set to make a decision on MCNA by the Feb. 27 PDUFA date.

Should the FDA break with the adcom, Telesta is gearing up for commercial launch. The Montreal-based firm ended the third quarter with $40.2 million in cash, which included the receipt of a $10 million up-front license fee from ex-U.S. MCNA partner Ipsen SA, of Paris. Ipsen licensed rights to develop and commercialize the product in the rest of the world, excepting Canada, South Africa, Mexico, South Korea and Japan, in exchange for up to $137 million in up-front and milestone payments, plus tiered, double-digit royalties on net sales of MCNA in the licensed territories.

Trading of Telesta's shares (TSX.TST), which fell 50 percent, or C40 cents (US30 cents), were halted midday Wednesday.