UPDATE 2-FDA reviewers say Titan drug dose may be insufficient

Tue Mar 19, 2013 12:58pm EDT

* Review comes ahead of advisory committee meeting on Thursday

* Probuphine is experimental drug to treat opioid addiction

* Titan stock down 41 pct at $1.20 in over-the-counter trade

By Toni Clarke

March 19 (Reuters) - Titan Pharmaceuticals Inc's experimental drug to treat opioid addiction was less effective in a clinical trial than might have been expected, suggesting the proposed dose could be too low, reviewers for the U.S. Food and Drug Administration said in documents published on Tuesday.

The commentary was published on the FDA's website ahead of an advisory panel meeting to be held on Thursday and sent the company's stock down 41 percent to $1.20 in over-the counter trading at midday on Tuesday.

The reviewers said they would ask the advisory panel whether Titan should explore dosing further before the drug, Probuphine, is approved.

Probuphine is a long-acting version of buprenorphine, a drug sold by Britain's Reckitt-Benckiser Group Plc under the brand names Subutex and Suboxone.

Unlike Subutex and Suboxone, which are dissolved daily under the tongue, Titan's drug is implanted under the skin of the upper arm during a 10-15-minute office procedure and delivers a continuous supply of buprenorphine for six months.

Clinical data shows Probuphine to be more effective than placebo in curbing addiction, but the results were still not particularly robust, the reviewers said.

Only 8 percent of patients provided opioid-negative urine samples for at least 80 percent of tests, while roughly a quarter of Probuphine-treated patients were unable to provide four opioid-negative samples over the course of six months, the reviewers said.

"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 the medication for six months," the reviewers said. "It prompts speculation that the dose is simply not high enough."

Drug overdose death rates have more than tripled since 1990, according to federal data. In 2008, more than 36,000 people died from an overdose, mostly caused by opioid painkillers, which outpaced deaths from heroin and cocaine combined.

ADDITIONAL SAFETY CONCERN

While the safety of Probuphine appears largely in keeping with that of other buprenorphine products, it presents an additional safety concern, reviewers said. It must be implanted, potentially leading to surgery-related complications. They said the product is in some ways similar to Norplant, an implantable, progestin-releasing contraceptive which is no longer marketed in the United States.

Even though insertion and removal of Norplant was performed by trained healthcare providers, there were cases of implantation and removal-related complications, some with disabling consequences, the reviewers said. They will ask the advisory committee whether it believes the company has adequately addressed these concerns under its proposed risk mitigation plan and whether the drug's benefit is enough to outweigh the potential risks.

In December, Titan licensed the U.S. and Canadian rights to Probuphine to Braeburn Pharmaceuticals, a company owned by the venture capital firm Apple Tree Partners. Titan received an up-front payment of $15.75 million and will receive up to $50 million if Probuphine is approved.

Reviewers noted that the dose of buprenorphine delivered by four Probuphine implants is less than a third of the dose delivered buprenorphine tablets.

"Potentially, Probuphine could deliver just enough buprenorphine to allow patients to continue to use illicit opioids without experiencing withdrawal when they stop," the reviewers said.

RECKITT DOMINANCE

To date, the market for buprenorphine has been dominated by Reckitt, a consumer goods company whose products range from cleaning supplies to condoms. Subutex and Suboxone generated sales in 2012 of roughly $1.3 billion.

Suboxone and Subutex lost market exclusivity in 2009, and while generic competitors promptly introduced cheap copies of Subutex they were slow to develop alternatives to Suboxone. In the meantime, Reckitt persuaded many physicians to switch from Suboxone tablets to Suboxone Film, its newer, patent-protected wafer-like strip that patients dissolve under the tongue. At the end of 2012, according to Reckitt, Suboxone Film had captured 64 percent of the market.

Even as it switched patients to Suboxone Film, Reckitt aggressively fought to block generic competition to Suboxone tablets. In a move generic drug critics claimed was designed to thwart competition, Reckitt produced a report showing that children were eight times more likely to be accidentally exposed to Suboxone tablets than to Suboxone Film.

It petitioned the FDA to reject all generic versions of Suboxone tablets unless packaging safety standards were improved. The company said it could not ignore the danger posed by the tablets it had been selling for a decade, and in September said it would only sell Suboxone Film.

The FDA rejected Reckitt's petition, saying there was not enough evidence to support the need for stricter packaging rules. And it expressed skepticism over Reckitt's motives, saying the timing of its decision to stop marketing the tablet, "given its close alignment with the period in which generic competition for this product was expected to begin," could not be ignored.

Earlier this year the FDA approved generic versions of Suboxone tablets from Amneal Pharmaceuticals LLC and Actavis Inc .

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