|Buprenorphine (orange) binds to the mu opioid receptors in the brain to block opioids from attaching to them. Titan hopes to commercialize the implant to deliver the drug, which is currently available in sublingual tablet and oral formulations.--Courtesy of Titan Pharmaceuticals|
Titan Pharmaceuticals ($TTNP) announced that it has resubmitted its application for FDA approval of its subdermal implant for the delivery of buprenorphine/naloxone as a maintenance treatment for opioid addiction. The move follows a surprise rejection in 2013.
The Probuphine drug delivery system is being developed with Braeburn Pharmaceuticals, which will be in charge of commercialization in the U.S. and Canada if FDA approval occurs.
"We are extremely pleased by the Braeburn and Titan teams' expeditious preparation of this NDA following the positive results of the final Phase III trial," said Titan Executive Vice President Kate Glassman Beebe in a statement. "We expect a six-month review cycle, and if approved, Probuphine would be the first marketed product to provide maintenance treatment of opioid addiction continuously for six months following a single procedure. Probuphine has the potential to increase patient compliance and decrease the risk of diversion, and could become an essential tool in the treatment of opioid addiction."
In June, Braeburn said the implant passed the test of noninferiority to sublingually administered buprenorphine/naloxone in its Phase III trial. More than 96% of the 84 patients in the Probuphine arm responded to therapy, meaning they spent at least four out of 6 months free of illicit opiates, compared with 87.6% among the 89 patients in the control group, who received sublingual pills.
The trial was double-blind and double-dummy, meaning patients on the Probuphine buprenorphine/naloxone-delivering implant received daily placebo sublingual pills, and those taking sublingual buprenorphine pills received four placebo implants.
A Titan spokeswoman previously explained changes to the second, now-completed trial, writing in an email: "The current trial was designed to address the FDA's main concern that the Probuphine dose used in the earlier studies was too low for the kind of patients who were being tested, and the clinical benefit would be greater in a different patient population. Specifically, the patients in the earlier studies were new to medication treatment, and required a 12-16 mg/day dose of sublingual buprenorphine to achieve clinical control over withdrawal symptoms and opioid cravings. The patients in the current study are considered clinically stable by their treating physician and have received a maintenance dose of less than or equal to 8 mg/day of sublingual buprenorphine for at least 3 months prior to randomization."
The candidate uses Titan's ProNeura drug delivery system. "The continuous drug delivery system consists of a small, solid rod made from a mixture of ethylene-vinyl acetate and a drug substance," Titan explains on its website. It is typically placed subdermally in the upper arm and delivers buprenorphine for 6 months. Titan also says that the delivery system has shown promise as a treatment for Parkinson's disease in nonclinical studies.
In 2013, the FDA also expressed concern about "human factors testing of the training associated with Probuphine's insertion and removal." Braeburn says 23% of Probuphine patients had an implant site adverse event; that's higher than 13.5% of those in the control group.
The implant delivers buprenorphine, which is currently available in sublingual tablet and oral formulations--a market with 2012 annual sales of about $1.5 billion in the U.S.
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