New bladder cancer drug fails first hurdle

Two Food and Drug Administration advisory panels voted 18-6 against use of Mycobacterium phlei cell wall-nucleic acid complex (MCNA), an intravesical drug being evaluated for the treatment of non–muscle-invasive bladder cancer at high risk of recurrence or progression in adults failing prior Bacillus Calmette-Guérin (BCG) immunotherapy.

At a meeting of the FDA’s Oncologic Drugs Advisory Committee (ODAC) and the Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC), several panel members expressed being conflicted in their vote, but said they ultimately felt MCNA did not show a clear risk:benefit advantage based on the data presented from a small, single pivotal trial that failed to meet its primary efficacy end point.

“I think it is an effective drug that would be a nice alternative to BCG, but I wasn’t convinced that there was enough of a difference in mechanism of action to accept a single-arm study that wasn’t overwhelmingly convincing that it was better than what is currently being done for these patients,” said Dr. David L. Bartlett, a CTGTAC member with the University of Pittsburgh Medical Center.

Also voting no was ODAC member Dr. Harold J. Burstein of the Dana-Farber Cancer Institute in Boston, who said the toxicity may be low with MCNA, but that he was unclear how to talk to patients about its benefits.

“What do you tell the patient that it does? I can’t answer that question,” he said. “It’s not clear that it spares the bladder. It’s not clear that it improves their longevity. Most of these patients we’ve been told aren’t going to be candidates for cystectomy for any number of reasons, so it doesn’t seem likely that it’s going to avoid or prevent a cystectomy in these patients.”

Although the data submitted for priority review by Telesta Therapeutics was less than stellar, CTGTAC and ODAC jointly considered the biologics license application because limited treatment options exist for patients with BCG-refractory non–muscle-invasive bladder cancer (NMIBC).

Current U.S. and European guidelines recommend cystectomy for high-risk NMIBC after BCG failure, but not all patients are candidates for or want to undergo bladder removal because of the associated high morbidity and poor quality of life. No new intravesical treatments for NMIBC have been approved since valrubicin (Valstar) in 1998 and it is indicated only for BCG-refractory carcinoma in situ (CIS).

MCNA is a suspension containing M. phlei cell wall fragments complexed with nucleic acid oligomers. It is thought to have a dual mechanism of action: direct anti-proliferative/cytotoxic action and indirect immune stimulant activity.

The clinical evidence for MCNA was based on the single-arm, phase III Study 301 in 129 patients with NMIBC at high risk of progression treated with six weekly instillations of MCNA during induction followed by maintenance therapy up to month 24. The disease-free survival (DFS) rate at 1 year was 23.7%, well short of the 40% target set for the primary endpoint.

Still, responses lasted a median of 34 months in the 28 responders and overall progression rates were similar to historical data in BCG-naive controls, according to Zvi Cohen, Ph.D., director of clinical research at Telesta. The rate of bladder removal at 1 year was almost three times lower among responders than among nonresponders (18% vs. 49.5%). In all, 55 (43%) patients went on to cystectomy.

The key safety concern for the panelists was whether treatment with MCNA would put patients at greater risk of muscle-invasive disease and metastasis by delaying cystectomy, the main treatment option for high-risk NMIBC following BCG failure. Notably, 15 (11.6%) patients in Study 301 developed metastatic bladder cancer, Dr. Cohen said.

In patients with CIS-containing disease, the complete response rate was 27% at 6 months and median duration of response was 15.1 months. Active CIS does not typically regress on its own, suggesting a treatment effect from MCNA.

In the subgroup with papillary tumors only, the DFS rate was 35.1% at 1 year, but it was unclear whether this was due to MCNA treatment or because these patients were required to undergo tumor resection within 56 days of their first dose.

The FDA took issue with statistical considerations in Study 301, including the definition of DFS duration, and conducted its own landmark analysis showing a DFS rate at 1 year of 20.9%. Higher DFS rates at 1 year were seen in papillary only vs. CIS-containing disease (27.8% vs. 18.8%) and in BCG-relapsing vs. BCG-refractory disease (36.4% vs. 17.8%), reported Dr. Kristin Baird, medical officer with the Office of Cellular, Tissue, and Gene Therapies (OCTGT) at the FDA’s Center for Biologics Evaluation and Research (CBER).

Common local drug-related adverse events occurring in at least 10% of patients in Study 301 were hematuria, dysuria, urinary tract infection, pollakiuria, and micturition urgency. Fatigue was the most common systemic adverse event.

Two drug-related serious adverse events occurred: moderate hematuria and severe urinary tract infection, Dr. Cohen said. Four deaths occurred during the study, but none were thought to be drug related.

The study did not enroll BCG-naive patients, so it is unclear whether MCNA may be altered by BCG or whether prior BCG is necessary to prime responses to MCNA. In vitro data using a prior formulation of the drug suggested benefit in BCG-naive patients, but it was noted that MCNA is eliminated more quickly than BCG and that de novo studies would be needed to sort out this issue.

One panelist pointed out the practical consideration that BCG shortages have been a frequent problem for patients, despite the drug’s being around for decades, and that there may be some pressure to use MCNA first-line if BCG is unavailable. Cost data were not provided for BCG.

Dr. Patrick C. Walsh, professor and director of Brady Urological Institute at Johns Hopkins Medical Institutions, Baltimore, agreed that the action of MCNA may be limited, but voted in favor of approval.

“My concern was delay in cystectomy and I’ve been convinced at this meeting that if you delayed cystectomy for 6 months and you gave this drug and it didn’t work, I don’t think the patient would be harmed,” he said.

CTGTAC chair Dr. Timothy P. Cripe of Ohio State University, Columbus, also voted in favor, noting that the risk:benefit ratio was favorable because there is clearly some benefit to the drug and very little risk.

“With immunotherapies on the rise, if this were approved, I’m sure there’d be a lot more trials and combinations that would augment its activity,” he added.

CTGTAC member Dr. Bruce J. Roth of Washington University, St. Louis, voted no because of the quality of the data, but suggested, as did others, that he would like MCNA to return before the FDA in other, better-designed trials.

The initial vote was 19 for and 6 against approval, but it was discovered that one vote was made via proxy, which is not allowed, and the official record was amended to 18 for and 6 against.

MCNA was granted priority review status in September and the Prescription Drug User Fee Act (PDUFA) date set was for Feb. 27, 2016. Following news of the negative vote, Telesta’s share price fell 50%.

Members of FDA advisory panels have been cleared of potential conflicts of interest by the FDA prior to the meeting.

[email protected]

Two Food and Drug Administration advisory panels voted 18-6 against use of Mycobacterium phlei cell wall-nucleic acid complex (MCNA), an intravesical drug being evaluated for the treatment of non–muscle-invasive bladder cancer at high risk of recurrence or progression in adults failing prior Bacillus Calmette-Guérin (BCG) immunotherapy.

At a meeting of the FDA’s Oncologic Drugs Advisory Committee (ODAC) and the Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC), several panel members expressed being conflicted in their vote, but said they ultimately felt MCNA did not show a clear risk:benefit advantage based on the data presented from a small, single pivotal trial that failed to meet its primary efficacy end point.

“I think it is an effective drug that would be a nice alternative to BCG, but I wasn’t convinced that there was enough of a difference in mechanism of action to accept a single-arm study that wasn’t overwhelmingly convincing that it was better than what is currently being done for these patients,” said Dr. David L. Bartlett, a CTGTAC member with the University of Pittsburgh Medical Center.

Also voting no was ODAC member Dr. Harold J. Burstein of the Dana-Farber Cancer Institute in Boston, who said the toxicity may be low with MCNA, but that he was unclear how to talk to patients about its benefits.

“What do you tell the patient that it does? I can’t answer that question,” he said. “It’s not clear that it spares the bladder. It’s not clear that it improves their longevity. Most of these patients we’ve been told aren’t going to be candidates for cystectomy for any number of reasons, so it doesn’t seem likely that it’s going to avoid or prevent a cystectomy in these patients.”

Although the data submitted for priority review by Telesta Therapeutics was less than stellar, CTGTAC and ODAC jointly considered the biologics license application because limited treatment options exist for patients with BCG-refractory non–muscle-invasive bladder cancer (NMIBC).

Current U.S. and European guidelines recommend cystectomy for high-risk NMIBC after BCG failure, but not all patients are candidates for or want to undergo bladder removal because of the associated high morbidity and poor quality of life. No new intravesical treatments for NMIBC have been approved since valrubicin (Valstar) in 1998 and it is indicated only for BCG-refractory carcinoma in situ (CIS).

MCNA is a suspension containing M. phlei cell wall fragments complexed with nucleic acid oligomers. It is thought to have a dual mechanism of action: direct anti-proliferative/cytotoxic action and indirect immune stimulant activity.

The clinical evidence for MCNA was based on the single-arm, phase III Study 301 in 129 patients with NMIBC at high risk of progression treated with six weekly instillations of MCNA during induction followed by maintenance therapy up to month 24. The disease-free survival (DFS) rate at 1 year was 23.7%, well short of the 40% target set for the primary endpoint.

Still, responses lasted a median of 34 months in the 28 responders and overall progression rates were similar to historical data in BCG-naive controls, according to Zvi Cohen, Ph.D., director of clinical research at Telesta. The rate of bladder removal at 1 year was almost three times lower among responders than among nonresponders (18% vs. 49.5%). In all, 55 (43%) patients went on to cystectomy.

The key safety concern for the panelists was whether treatment with MCNA would put patients at greater risk of muscle-invasive disease and metastasis by delaying cystectomy, the main treatment option for high-risk NMIBC following BCG failure. Notably, 15 (11.6%) patients in Study 301 developed metastatic bladder cancer, Dr. Cohen said.

In patients with CIS-containing disease, the complete response rate was 27% at 6 months and median duration of response was 15.1 months. Active CIS does not typically regress on its own, suggesting a treatment effect from MCNA.

In the subgroup with papillary tumors only, the DFS rate was 35.1% at 1 year, but it was unclear whether this was due to MCNA treatment or because these patients were required to undergo tumor resection within 56 days of their first dose.

The FDA took issue with statistical considerations in Study 301, including the definition of DFS duration, and conducted its own landmark analysis showing a DFS rate at 1 year of 20.9%. Higher DFS rates at 1 year were seen in papillary only vs. CIS-containing disease (27.8% vs. 18.8%) and in BCG-relapsing vs. BCG-refractory disease (36.4% vs. 17.8%), reported Dr. Kristin Baird, medical officer with the Office of Cellular, Tissue, and Gene Therapies (OCTGT) at the FDA’s Center for Biologics Evaluation and Research (CBER).

Common local drug-related adverse events occurring in at least 10% of patients in Study 301 were hematuria, dysuria, urinary tract infection, pollakiuria, and micturition urgency. Fatigue was the most common systemic adverse event.

Two drug-related serious adverse events occurred: moderate hematuria and severe urinary tract infection, Dr. Cohen said. Four deaths occurred during the study, but none were thought to be drug related.

The study did not enroll BCG-naive patients, so it is unclear whether MCNA may be altered by BCG or whether prior BCG is necessary to prime responses to MCNA. In vitro data using a prior formulation of the drug suggested benefit in BCG-naive patients, but it was noted that MCNA is eliminated more quickly than BCG and that de novo studies would be needed to sort out this issue.

One panelist pointed out the practical consideration that BCG shortages have been a frequent problem for patients, despite the drug’s being around for decades, and that there may be some pressure to use MCNA first-line if BCG is unavailable. Cost data were not provided for BCG.

Dr. Patrick C. Walsh, professor and director of Brady Urological Institute at Johns Hopkins Medical Institutions, Baltimore, agreed that the action of MCNA may be limited, but voted in favor of approval.

“My concern was delay in cystectomy and I’ve been convinced at this meeting that if you delayed cystectomy for 6 months and you gave this drug and it didn’t work, I don’t think the patient would be harmed,” he said.

CTGTAC chair Dr. Timothy P. Cripe of Ohio State University, Columbus, also voted in favor, noting that the risk:benefit ratio was favorable because there is clearly some benefit to the drug and very little risk.

“With immunotherapies on the rise, if this were approved, I’m sure there’d be a lot more trials and combinations that would augment its activity,” he added.

CTGTAC member Dr. Bruce J. Roth of Washington University, St. Louis, voted no because of the quality of the data, but suggested, as did others, that he would like MCNA to return before the FDA in other, better-designed trials.

The initial vote was 19 for and 6 against approval, but it was discovered that one vote was made via proxy, which is not allowed, and the official record was amended to 18 for and 6 against.

MCNA was granted priority review status in September and the Prescription Drug User Fee Act (PDUFA) date set was for Feb. 27, 2016. Following news of the negative vote, Telesta’s share price fell 50%.

Members of FDA advisory panels have been cleared of potential conflicts of interest by the FDA prior to the meeting.

[email protected]

Two Food and Drug Administration advisory panels voted 18-6 against use of Mycobacterium phlei cell wall-nucleic acid complex (MCNA), an intravesical drug being evaluated for the treatment of non–muscle-invasive bladder cancer at high risk of recurrence or progression in adults failing prior Bacillus Calmette-Guérin (BCG) immunotherapy.

At a meeting of the FDA’s Oncologic Drugs Advisory Committee (ODAC) and the Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC), several panel members expressed being conflicted in their vote, but said they ultimately felt MCNA did not show a clear risk:benefit advantage based on the data presented from a small, single pivotal trial that failed to meet its primary efficacy end point.

“I think it is an effective drug that would be a nice alternative to BCG, but I wasn’t convinced that there was enough of a difference in mechanism of action to accept a single-arm study that wasn’t overwhelmingly convincing that it was better than what is currently being done for these patients,” said Dr. David L. Bartlett, a CTGTAC member with the University of Pittsburgh Medical Center.

Also voting no was ODAC member Dr. Harold J. Burstein of the Dana-Farber Cancer Institute in Boston, who said the toxicity may be low with MCNA, but that he was unclear how to talk to patients about its benefits.

“What do you tell the patient that it does? I can’t answer that question,” he said. “It’s not clear that it spares the bladder. It’s not clear that it improves their longevity. Most of these patients we’ve been told aren’t going to be candidates for cystectomy for any number of reasons, so it doesn’t seem likely that it’s going to avoid or prevent a cystectomy in these patients.”

Although the data submitted for priority review by Telesta Therapeutics was less than stellar, CTGTAC and ODAC jointly considered the biologics license application because limited treatment options exist for patients with BCG-refractory non–muscle-invasive bladder cancer (NMIBC).

Current U.S. and European guidelines recommend cystectomy for high-risk NMIBC after BCG failure, but not all patients are candidates for or want to undergo bladder removal because of the associated high morbidity and poor quality of life. No new intravesical treatments for NMIBC have been approved since valrubicin (Valstar) in 1998 and it is indicated only for BCG-refractory carcinoma in situ (CIS).

MCNA is a suspension containing M. phlei cell wall fragments complexed with nucleic acid oligomers. It is thought to have a dual mechanism of action: direct anti-proliferative/cytotoxic action and indirect immune stimulant activity.

The clinical evidence for MCNA was based on the single-arm, phase III Study 301 in 129 patients with NMIBC at high risk of progression treated with six weekly instillations of MCNA during induction followed by maintenance therapy up to month 24. The disease-free survival (DFS) rate at 1 year was 23.7%, well short of the 40% target set for the primary endpoint.

Still, responses lasted a median of 34 months in the 28 responders and overall progression rates were similar to historical data in BCG-naive controls, according to Zvi Cohen, Ph.D., director of clinical research at Telesta. The rate of bladder removal at 1 year was almost three times lower among responders than among nonresponders (18% vs. 49.5%). In all, 55 (43%) patients went on to cystectomy.

The key safety concern for the panelists was whether treatment with MCNA would put patients at greater risk of muscle-invasive disease and metastasis by delaying cystectomy, the main treatment option for high-risk NMIBC following BCG failure. Notably, 15 (11.6%) patients in Study 301 developed metastatic bladder cancer, Dr. Cohen said.

In patients with CIS-containing disease, the complete response rate was 27% at 6 months and median duration of response was 15.1 months. Active CIS does not typically regress on its own, suggesting a treatment effect from MCNA.

In the subgroup with papillary tumors only, the DFS rate was 35.1% at 1 year, but it was unclear whether this was due to MCNA treatment or because these patients were required to undergo tumor resection within 56 days of their first dose.

The FDA took issue with statistical considerations in Study 301, including the definition of DFS duration, and conducted its own landmark analysis showing a DFS rate at 1 year of 20.9%. Higher DFS rates at 1 year were seen in papillary only vs. CIS-containing disease (27.8% vs. 18.8%) and in BCG-relapsing vs. BCG-refractory disease (36.4% vs. 17.8%), reported Dr. Kristin Baird, medical officer with the Office of Cellular, Tissue, and Gene Therapies (OCTGT) at the FDA’s Center for Biologics Evaluation and Research (CBER).

Common local drug-related adverse events occurring in at least 10% of patients in Study 301 were hematuria, dysuria, urinary tract infection, pollakiuria, and micturition urgency. Fatigue was the most common systemic adverse event.

Two drug-related serious adverse events occurred: moderate hematuria and severe urinary tract infection, Dr. Cohen said. Four deaths occurred during the study, but none were thought to be drug related.

The study did not enroll BCG-naive patients, so it is unclear whether MCNA may be altered by BCG or whether prior BCG is necessary to prime responses to MCNA. In vitro data using a prior formulation of the drug suggested benefit in BCG-naive patients, but it was noted that MCNA is eliminated more quickly than BCG and that de novo studies would be needed to sort out this issue.

One panelist pointed out the practical consideration that BCG shortages have been a frequent problem for patients, despite the drug’s being around for decades, and that there may be some pressure to use MCNA first-line if BCG is unavailable. Cost data were not provided for BCG.

Dr. Patrick C. Walsh, professor and director of Brady Urological Institute at Johns Hopkins Medical Institutions, Baltimore, agreed that the action of MCNA may be limited, but voted in favor of approval.

“My concern was delay in cystectomy and I’ve been convinced at this meeting that if you delayed cystectomy for 6 months and you gave this drug and it didn’t work, I don’t think the patient would be harmed,” he said.

CTGTAC chair Dr. Timothy P. Cripe of Ohio State University, Columbus, also voted in favor, noting that the risk:benefit ratio was favorable because there is clearly some benefit to the drug and very little risk.

“With immunotherapies on the rise, if this were approved, I’m sure there’d be a lot more trials and combinations that would augment its activity,” he added.

CTGTAC member Dr. Bruce J. Roth of Washington University, St. Louis, voted no because of the quality of the data, but suggested, as did others, that he would like MCNA to return before the FDA in other, better-designed trials.

The initial vote was 19 for and 6 against approval, but it was discovered that one vote was made via proxy, which is not allowed, and the official record was amended to 18 for and 6 against.

MCNA was granted priority review status in September and the Prescription Drug User Fee Act (PDUFA) date set was for Feb. 27, 2016. Following news of the negative vote, Telesta’s share price fell 50%.

Members of FDA advisory panels have been cleared of potential conflicts of interest by the FDA prior to the meeting.

[email protected]