FDA staff review raises big questions about fate of Titan's Probuphine

Titan Pharmaceuticals ($TTNP) looks like it's headed into choppy waters as it braces for an upcoming advisory committee review of its lead drug for opioid addiction. In an FDA review handed out to outside advisers in advance of their panel discussion and vote Thursday, staffers critiqued the efficacy data provided, the dose used in the pivotal study as well as its design, and the purported benefits and unanswered questions about the risks it presents to patients and their families.

Titan had trumpeted Phase III data purporting to show that Probuphine, an implant that releases buprenorphine over a period of 6 months, was better than a placebo at preventing addicts from using illicit opioids. Investigators also said it was noninferior to the approved therapy. But staffers picked apart that argument in the review.

"Even after allowing four months for engagement in treatment, only three Probuphine-treated patients were fully abstinent from opioids," said the staff. "Approximately 8% provided negative samples for at least 80% of tests." 

"At the other end of the spectrum, about a quarter of Probuphine-treated patients were unable to provide even as few as 4 opioid-negative urine samples over the course of six months," the FDA staffers continued. "While the placebo group had even more discouraging results, supporting the conclusion that Probuphine does have an effect on drug use, overall, the response was not what one might hope for, given that the product ensures compliance with medication for six months. It prompts speculation that the dose is simply not high enough. … Potentially, Probuphine could deliver just enough buprenorphine to allow patients to continue to use illicit opioids without experiencing withdrawal when they stop."

Even if addicts get Probuphine, the staff notes, many will still need buprenorphine to manage their addiction, leaving the drug accessible to children--a threat the new therapy was supposed to avoid. A total of "40%-62% of Probuphine-treated patients required supplemental buprenorphine, and 11-12% required supplemental buprenorphine even after receiving a fifth implant."

There were problems with inserting the implants but the trial was too small to fully assess the risks, the FDA went on. And there were unanswered questions to consider about how long treatment would continue or what happens to patients after they stop treatment. And what happens to the addicts if they drop out of the program and never get the implants removed?

It's not unusual for a staff review to focus on unanswered questions or worries about efficacy and safety. Panelists are supposed to put developers through some tough questioning, to make sure the therapy lives up to expectations. But a barrage of criticisms like this may prove difficult to withstand, leaving Titan on shaky ground. 

- here's the staff review (PDF)