Titan Pharmaceuticals Announces Positive Results from Phase III Clinical Trial of Probuphine for the Treatment of Opioid Addiction

Titan Pharmaceuticals, Inc. (AMEX:TTP) today announced positive, statistically significant results from its randomized, double-blind, placebo controlled, multi-center Phase III clinical trial of Probuphine®. Probuphine is Titan’s novel, subcutaneous implant formulation designed using its ProNeura technology to deliver six months of buprenorphine. Buprenorphine is currently marketed as a sublingual formulation for the treatment of opioid addiction.

Probuphine showed a clinically and statistically significant difference over placebo in illicit opioid use over 16 weeks as measured by urine testing performed three times per week (p=0.0361) – this was the primary endpoint acceptable to the U.S. Food and Drug Administration (FDA). Additionally, Probuphine achieved statistical significance in the Phase III trial’s key secondary endpoint, the difference in illicit opioid use from weeks 17-24 (p=0.0004). Moreover, Probuphine treatment showed a statistically significant difference in illicit opioid use versus placebo over the full six-month (weeks 1-24) period (p=0.0117).

“We are extremely pleased by these positive results and the potential of Probuphine to be an important advance in the treatment of opioid addiction,” said Marc Rubin, M.D., President and CEO of Titan. “Even as buprenorphine, with estimated sales of half a billion dollars in worldwide sales, is fast becoming the gold standard for opioid addiction treatment, there are growing concerns about compliance with and abuse of the currently available treatment options and a critical need for safe, effective treatment options. These data show that our proprietary subcutaneous implant can safely deliver Probuphine over six months. We look forward to completing this development program and forging strategic alliances to commercialize Probuphine worldwide.”

Additional secondary efficacy analyses, including the mean percentage of urines negative for illicit opioids over treatment weeks 1-16, 17-24, and the complete six-month period also statistically favored Probuphine over placebo. Another important indicator of treatment effectiveness, patient retention, was approximately 66 percent for Probuphine compared to 31 percent for placebo. Probuphine was also well tolerated throughout the six-month trial.

“These data are very promising and I believe that the success of Probuphine should have a very significant impact on our ability to effectively treat opioid addiction,” said Walter Ling, M.D., Professor of Psychiatry and Director of the Integrated Substance Abuse Programs at the David Geffen School of Medicine at UCLA, and a principal investigator in this trial. “As a clinician, I am concerned by the growing problem of opioid addiction, especially prescription opioid abuse, and the challenge of effectively treating our patients with a safe, abuse-resistant and diversion-resistant treatment. These data could translate into a dramatic change in our treatment possibilities.”

Worldwide, it is estimated that there are 6 million opioid addicts. Approximately one-half of this potential patient population is addicted to illicit opioids, such as heroin, and the other half to prescription drugs, such as oxycontin, methadone, and codeine. Until recently, the only approved medication assisted therapies for opioid addiction had been available at only a limited number of authorized facilities in the U.S. As of 2000, U.S. physicians can be certified to prescribe less restricted opioid addiction medications in an office setting, which has greatly expanded patient access to opioid addiction pharmaceutical therapies. Despite these advances, this remains a highly underserved market with only about 750,000 people globally receiving medicinal treatment for opioid addiction.
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source: Business Wire

Mixed progress for bupe

As city includes hard-core addicts, more drop out

Baltimore has doubled the number of people using the medication buprenorphine to shake off heroin addiction but has struggled to keep them in treatment.

As the Baltimore Buprenorphine Initiative has accepted more hard-core drug addicts dealing with complications such as mental illness, more drop out. At the start of the initiative in October 2006, officials had picked mostly highly motivated participants.

The retention rate dropped to 52 percent for the year that ended June 30 compared with 65 percent in fiscal year 2007. That is prompting city health officials to question which patients do best on buprenorphine, sold as Suboxone and widely known as "bupe."

"Who is the right candidate for bupe?" asked Dr. Joshua M. Sharfstein, Baltimore's health commissioner. "It's just really hard to tell." He said officials will examine that issue closely.

The initiative, which cost about $2 million last year, is "continuing to gain momentum," he said. "More clinics are participating. More patients are being treated. More doctors are interested in seeing patients."

The novel program introduces addicts to Suboxone in city-backed clinics that stabilize patients before transferring them into the care of private doctors who have become qualified to prescribe the drug.

The city has streamlined its process of securing health insurance for the mostly low-income participants and added clinics and doctors to expand access.

But the 771 patients who entered the program over the past year are taking longer than the first year's 388 patients to make the transfer because they still abuse drugs other than heroin, such as cocaine.

Some studies have shown that methadone is better for longtime heroin addicts while Suboxone is best for people who are newly addicted or who are hooked on pain pills like OxyContin. Sharfstein hopes that pairing public and private resources will render buprenorphine an effective new weapon to battle heroin addiction.

In 2006, more than 10,000 city residents were admitted to facilities for heroin addiction treatment. Each year more 200 die from overdoses of heroin and other narcotics.

Valarie Clark abused heroin for nearly 20 years. After enrolling in the city initiative nearly two years ago, she has experienced her longest stretch without using heroin.

But her struggles demonstrate the challenge of getting even the best patients - Clark was held up as model before the City Council last summer - to stick with treatment.

Last month, after a dispute in her recovery house, Clark moved out and stopped taking Suboxone, without consulting her doctor or therapist at Total Health Care, the city's largest participating clinic.

She fell into a depression that left her with a choice: heroin or bupe.

"I would have used," said Clark, 52.

But she chose the bupe, starting again with the pills left over from her earlier prescription. "The depression went away and I'm continuing my therapy," she said. "I'm back in the [recovery] house."

A recent report showed that fewer addicts stuck with Suboxone treatment after 90 days than in the first year. The city's goal was to retain 67 percent at least that long. In the period from October 2006 to June 2007, the initiative succeeded in keeping 65 percent that long. But that dropped to just over half in the 12 months ending June 30.

"The retention rate has fallen," Sharfstein said.

One major reason is that the initiative has broadened its reach to take in people who are new to treatment, who suffer from other psychological problems or addictions and who engage in high-risk activities like prostitution.

It also took longer for patients to get off all drugs so they could be transferred out of city-backed clinics into the care of private doctors. Many patients stop using heroin but continue to abuse cocaine, leaving them ineligible to transfer. The city had wanted to transfer patients to the medical system after 90 days. In the first year, it took an average of 155 days. For the year that ended June 30, it took 163 days.

In addition, the initiative's pace of training doctors has lagged. Sharfstein had wanted 100 doctors to receive the federal waiver required to prescribe the pills. So far, 82 have received the clearance after completing an eight-hour training course.

The initiative also made a special effort to recruit more psychiatrists to deal with patients suffering both addiction and other mental illnesses.

"I would characterize this as good progress," Sharfstein said in an e-mail. "While we have not had 100 new waivered doctors yet, I am confident we will get there."

Suboxone's expense remains an issue. Methadone for heroin addiction costs about $8,000 per person over two years, the city reported last year. Suboxone treatment costs nearly twice that and has gotten more expensive.

Wendy Merrick, who directs addiction care at Total Health Care in West Baltimore, said the price per bottle of 30 pills has increased from $107.15 to $111.70.

To help cut costs, the Baltimore Substance Abuse Systems Inc., which manages most of the budgets for nearly all of the participating addiction treatment centers in Baltimore, has started buying in bulk, said Marla Oros, a consultant with BSAS.

The city's first report on its initiative in July 2007 made little mention of efforts to prevent misuse and illegal sales of buprenorphine. In December, The Sun published a three-part series that showed that abuse of Suboxone was on the rise across the nation as its availability increased. The drug was rolled out in 2003 after the federal government allowed doctors to prescribe it from their offices, unlike methadone, which is dispensed from highly regulated clinics.

The latest report devotes an entire section to efforts that the city has taken to minimize misuse of the drug: counting pills, testing urine and monitoring patients when they first start taking the pills. But the report states that "there is no evidence of a significant public health threat from buprenorphine diversion in Baltimore at this time."

A survey of 30 Baltimore physicians conducted by a consultant with the drug's manufacturer, Reckitt Benckiser Pharmaceuticals Inc., found that 67 percent were "aware of buying and selling of Suboxone, a percentage higher than the national average," the report states.

Clark, who was profiled in the series and has returned to treatment at Total Health Care, said she has seen the street demand for Suboxone increase.

"I was just at Lexington Market getting lunch and, wow, it's amazing," said Clark, who first tried Suboxone on the street. "It's almost like people are asking for Suboxone more than other things. The bupes. They ask for bupes."
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doug.donovan@baltsun.com

Copyright © 2008, The Baltimore Sun

Misuse of 'bupe' is found to be on rise

In a report to federal regulators, the manufacturer of buprenorphine has provided the starkest evidence to date that misuse of the drug is growing in parts of the country where it is most widely prescribed as an addiction treatment.

Reckitt Benckiser Pharmaceuticals Inc. outlines problems such as a rise in the number of children sickened by accidentally ingesting the pills; an increase, in some areas, of people taking the drug to get high; and commonplace street sales in some cities for as little as $2 per tablet.

The U.S. Food and Drug Administration received the report Jan. 8. A spokesman for the agency said it is under review but declined to comment further. If federal officials conclude that abuse of the drug has become a problem, they can seek further controls over its distribution.

The report linked misuse and illicit sales to the federally sanctioned practice of allowing doctors to prescribe large quantities of the drug for patients to take at home. "It was the patients in treatment for opioid abuse - no doubt selling or trading their own supply of buprenorphine - who were seen as major contributors to the street supply," the report stated.

Federal officials didn't anticipate such abuses when they spent $26 million to develop the drug and help Reckitt Benckiser bring it to market. Congress considered buprenorphine, sold mainly in the U.S. as Suboxone, the centerpiece of its plan to broaden access to addiction treatment.

The latest report closely parallels the findings of a series published in December in The Sun, which revealed that while buprenorphine has been shown to be highly effective as an addiction treatment, its misuse is increasing. The newspaper also identified patterns of illegal sales as well as several deaths caused by taking the drug in combination with other substances.

Many specialists in addiction medicine believe that in the five years the drug has been on the market, its benefits have outweighed any problems. That's also the view of Baltimore's health commissioner, Dr. Joshua M. Sharfstein, who has asked the General Assembly for $5 million to expand buprenorphine treatment for heroin addicts.

Reckitt Benckiser submits the reports as part of a "post marketing surveillance" system as a condition of the FDA's 2002 approval of the drug. The surveillance, conducted by a consultant hired by the company, is intended to alert U.S. regulators to any abuse. A copy of the document was obtained by The Sun.

The report, covering the period from July through September 2007, is based largely on questionnaires to patients seeking drug treatment and to doctors and workers at drug clinics, including three in Baltimore. The consultant also conducts "street-level" interviews, analyzes poisoning and injury data, and reviews postings on Internet sites frequented by drug abusers.

The surveillance revealed:

• There was a substantial increase in the numbers of patients entering drug treatment who were aware of abuse and illegal sales of buprenorphine - on par with methadone for the first time. They described street sales in a number of places, including Chicago's West Side, where the drug was "easy to purchase" for $2 to $5 per tablet. Most addicts reported using it on the street to avoid withdrawal sickness.

• At poison control centers across the nation, more than a quarter of 1,876 buprenorphine exposures involved children under 6 years of age from Jan. 1, 2006, to Sept. 30, 2007, the company said. The rate of buprenorphine exposures in children was higher than the rates for methadone and oxycodone, which are far more commonly prescribed, the report said. The children who ingested buprenorphine, whose names and locations were not stated, all recovered.

The levels have been mirrored in Maryland, according to the Maryland Poison Center at the University of Maryland School of Pharmacy. Over the past three years, 35 children were exposed to buprenorphine, amounting to 28 percent of the total of 121 exposures. By comparison, 27 children were exposed to methadone, or 9 percent of the 293 cases for that medication, and 75 were exposed to oxycodone, or 14 percent of the 501 exposures to that medication.

• A major source of illegal Suboxone, according to 17 percent of doctors surveyed, was "lax or inappropriate" prescribing of the drug by their peers. More than half the doctors questioned in New England, where Suboxone is most widely available as an addiction treatment, said they believed it was just as easy to buy illegally as methadone and other widely abused narcotics. Drug abusers who were interviewed generally agreed.

• Interviews with drug treatment clients in Lynn, Mass., suggested that growing numbers of drug abusers might be turning to Suboxone to get high. In past reports, company officials have said 90 percent of people abusing Suboxone buy it on the street to ward off symptoms of narcotics withdrawal. But a third of the drug abusers questioned in Massachusetts said they used the drug to get high.

In Vermont, a researcher reported that 14 percent of prescription opioid abusers reported that buprenorphine was their "primary opioid of abuse."

"There is evidence that there is experimental use and illegal diversion of buprenorphine, especially the most frequently prescribed product - Suboxone," the report said.

Harriet Ullman, a spokeswoman for Richmond, Va.-based Reckitt Benckiser, said that no one at the company was available to comment and referred questions to the company's consultant, Dr. Charles R. Schuster, managing member of CRS Associates LLC. Schuster said in an interview that "a small percentage" of drug abusers have been experimenting with the drug. He said the company is working to help train doctors how to reduce abuse of the drug.

Dr. Sidney H. Schnoll, a Connecticut physician and a member of an eight-member advisory group established to review the quarterly surveillance reports, conceded that the company faces "issues" with abuse of the drug.

But he said that all drugs have risks. "You have to balance the benefits with the risks," Schnoll said. "Right now [the balance is] in favor of this drug."

Suboxone, which is dissolved under the tongue, relieves addicts' cravings for narcotics and the sickness that comes on when they stop using them abruptly. Some patients say the pills free them from the need to obtain street drugs, allowing them to focus on seeking jobs or taking other steps to turn their lives around.

Unlike methadone, which is distributed by clinics that often require patients to show up every day to receive their doses, Suboxone is designed to be taken unsupervised. Take-home policies in the United States, where doctors are permitted to prescribe a month's supply with up to five refills, are more lenient than those in many other countries.

Baltimore health officials said they hope to avoid some of the illegal diversion by starting addicts in clinic settings and stabilizing them before referring them to private doctors. These clinics are also providing extensive counseling services, which many private doctors are unable or unwilling to provide across the country.

Sharfstein and state health officials recently told Maryland lawmakers they were taking steps to minimize misuse as they expand treatment with the drug.

City officials conceded that "bupe" can be purchased illegally on Baltimore streets, just like heroin and other narcotics. Schuster said that the company has plans to step up surveillance in Baltimore by conducting more "street" interviews but that details were still being worked out.

source: The Baltimore Sun