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CRL on Probuphine Raises Questions on Adcom Relevance

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By Marie Powers Staff Writer

Titan Pharmaceuticals Inc. expressed surprise and disappointment after receiving a complete response letter (CRL) late Tuesday from the FDA for investigational drug Probuphine, a subdermal implant designed for the maintenance treatment of opioid dependence in adults. The reaction may have been warranted, however. At first blush, the CRL appeared to have all the trappings of an ambush.

The South San Francisco-based company said the CRL requested additional clinical data demonstrating both the ability of Probuphine to show opioid blockade of relevant doses of agonists and the effect of Probuphine at higher doses than studied to approximate blood plasma levels associated with daily 12 mg to 16 mg sublingual doses of buprenorphine.

In addition, the CRL raised questions about physician training associated with Probuphine's insertion and removal and included recommendations regarding product labeling and the implementation of the drug's Risk Evaluation and Mitigation Strategy (REMS) – topics that were raised at the drug's Psychopharmacologic Drugs Advisory Committee (PDAC) meeting, despite a generally favorable review.

Sunil Bhonsle, Titan's president, said the company will meet with the FDA to discuss the scope of the CRL comments and obtain clarification before determining the path forward. In a statement, Marc Rubin, executive chairman, said Titan, and its partner, Braeburn Pharmaceuticals Sprl, "remains committed to making Probuphine available for patients that need it."

Despite the stiff upper lip, Titan's shares (NASDAQ:TTNP) swooned Wednesday morning, falling from Tuesday's closing price of $1.66 to a 52-week low of 32 cents. Later in the day, shares regained a bit, closing at 43 cents for a loss of 74 percent. More than 16 million shares changed hands.

Probuphine uses Titan's ProNeura technology to deliver six months of buprenorphine hydrochloride following a single treatment, using a maintenance formulation with less abuse potential than currently marketed Suboxone (buprenorphine/naloxone, Reckitt Benckiser Pharmaceuticals Inc.).

Probuphine's clinical development program was capped by a randomized, placebo- and active-controlled Phase III confirmatory study that enrolled 287 adults at 20 U.S. sites across three dosing arms: Probuphine (114 patients), Suboxone (119) and placebo implants (54). Findings confirmed the efficacy of Probuphine compared with placebo on the primary endpoint: percentages of urine samples tested negative for illicit opioid use over the 24-week treatment period. The urine samples supported results from patient self-reports of opioid use. (See BioWorld Today, June 11, 2011.)

Data from an open-label, six-month safety re-treatment study of patients with opioid dependence who previously completed six months of treatment in the trial showed the re-treatment was well tolerated. Patients reported decreased use of illicit opioids, good control of opioid withdrawal and cravings and high overall satisfaction with Probuphine.

Rubin said the diversion-resistant formulation "is consistent with the recently issued FDA guidance supporting diversion- and abuse-resistant products" and noted the NDA was granted priority review by the FDA. "We believe Probuphine has demonstrated both safety and efficacy in accordance with primary endpoints that were pre-agreed with the FDA," he added.

FDA Not Swayed by Positive Adcom Vote

In March, the PDAC voted 10-4, with one abstention, in favor of Probuphine's approval. By a margin of 12 in favor, one opposed and one abstention, the PDAC also determined that Titan adequately characterized the safety profile of Probuphine. (See BioWorld Today, March 22, 2013.)

Nevertheless, the FDA raised concerns during the adcom meeting about the surgical risks associated with implantation and removal of the device and about long-term use. Titan officials indicated the proposed REMS was crafted around the assumption that Probuphine would be subject to current restrictions placed on other forms of buprenorphine and scheduled as a CIII controlled substance that would be acquired and implanted only by Drug Addiction Treatment Act-waived physicians.

The REMS included a medication guide for each patient and treating physician as well as Elements to Assure Safe Use that included physician training for proper insertion and removal of the implant. Titan presented information at the adcom showing that, as part of the development process, the company modified the standard procedure for inserting and removing implants, leading to fewer adverse events. The physician training program incorporated nonsurgeons, such as psychiatrists, although the FDA criticized the fact that some prescribers would go through clinical training but not procedural.

The PDAC voted 5-2 in favor, with six abstentions, on the adequacy of Titan's REMS. Those who supported the application indicated that, on balance, the need for a marketed product with reduced abuse potential outweighed other concerns.

Burrill Institutional Research analyst Elemer Piros suggested following the adcom that Probuphine's PDUFA date might be extended by three months to tweak the REMS program. Based on the positive PDAC votes, he was generally bullish long term, maintaining a "market outperform" rating and raising Titan's target price from $4 to $5 per share.

A standard PDUFA extension certainly would have provided more predictability for Probuphine than the CRL, as Piros indicated on Wednesday, when he downgraded Titan to "market perform" and removed the price target in an investment opinion headlined, "The FDA is Unreasonable."

Piros criticized as "highly unusual" the FDA's request for clinical data on higher doses of Probuphine. Titan's Phase III trial "clearly demonstrated equivalence of Probuphine to the standard of care oral pill Suboxone," he wrote, with Probuphine six-month depot compared to 12 mg to 16 mg per day of Suboxone. "If the clinical performance of Probuphine is equivalent to the standard of care, why should we care about mechanistic studies characterizing receptor blockade?"

U.S. and Canadian rights to Probuphine are licensed to Braeburn, which is wholly owned by Apple Tree Partners IV LP. Titan received a nonrefundable $15.75 million up-front payment through the agreement, inked in December 2012, and is eligible for up to $50 million upon approval, up to $130 million upon achievement of sales milestones and up to $35 million in regulatory milestones. Through a spokesman, Braeburn officials declined comment on the CRL or next steps for Probuphine.

Titan reported 2012 operating expenses of $15.5 million, including research and development expenses of approximately $10.6 million. As of Dec. 31, 2012, Titan had cash and equivalents of about $18.1 million, which the company said would fund operations through June 2014. Titan will provide more detailed financial guidance after meeting with the FDA to discuss the scope of the CRL comments and determining the path forward for Probuphine, according to Bhonsle.