Titan Pharmaceuticals, Inc. announced additional positive results from its phase III placebo- and active drug-controlled confirmatory clinical study of Probuphine, evaluating the safety and efficacy of its investigational drug in treating patients with opioid dependence. Probuphine was found to be well tolerated and Probuphine treatment resulted in a significant improvement in the global severity of opioid dependence (p = 0.0003) and overall patient improvement (p = 0.0002) versus placebo, as assessed by clinicians.

The additional data analyses also confirm Probuphine’s non-inferiority to the approved drug Suboxone. These findings build upon the clinically meaningful and statistically significant top line data announced by Titan in July 2011, which confirmed the efficacy of Probuphine compared to placebo for two primary endpoints (p < 0.0001 for both). Titan has been invited to present these findings during a plenary session on September 10 and in a poster presentation on September 8 at the 13th annual meeting of the International Society of Addiction Medicine (ISAM) in Oslo, Norway.

“As a clinician, I can say that the advent and introduction of buprenorphine has absolutely changed and improved the landscape of opioid dependence treatment. However, there are also real concerns and increasing worry about medication compliance and diversion within the current treatment setting,” said Walter Ling, MD, Professor of Psychiatry and Director, Integrated Substance Abuse Programmes at the David Geffen School of Medicine at UCLA and a lead investigator in the Probuphine phase III study. “Probuphine represents a new, different and potentially improved method of delivering buprenorphine to patients - one that could lessen or eliminate physicians’ concerns about medication compliance and diversion.”

Probuphine is an innovative, subcutaneous implant formulation that delivers a steady, round-the-clock dose of the marketed drug buprenorphine over six months following a single treatment. Probuphine, designed using Titan’s proprietary ProNeura technology, has been developed to reduce the risk of diversion and abuse while assuring compliance to treatment and potentially improved medical outcomes.

“In my opinion, Probuphine combines the right medication with the right delivery system. We all know that people with opioid addiction may have difficulty taking effective medications reliably,” said Dr Richard N Rosenthal, chairman of Psychiatry at St. Luke’s-Roosevelt Hospital Centre, a teaching hospital of Columbia University, and past president of the American Academy of Addiction Psychiatry. “These phase III trial results confirm that this medication strategy has specific promise in our national battle against opioid dependence, in that it is both efficacious and reduces the potential risk to patients from missed doses and to the public through intentional or unintentional diversion.”

The phase III clinical trial was a randomized, placebo and active-controlled, multi-centre study conducted at 20 sites in the US that treated 287 patients, aged 18 to 60 years across three dosing arms: Probuphine (114 patients), the approved and widely-used sublingual formulation of buprenorphine, Suboxone, (119 patients) and placebo implants (54 patients).

Patients were treated for up to 24 weeks and the Probuphine and placebo dosing arms were double-blinded, while the Suboxone arm was open-label. Highlights of the additional trial analyses announced include: Probuphine demonstrated a statistical and clinical superiority over placebo on the Cumulative Distribution Function of the percentages of urine samples negative for opioids over the trial’s weeks 1-16 (p < 0.0001) and weeks 17-24 (p = 0.0002) - this is consistent with the findings of Titan’s first Phase 3 trial of Probuphine, which was published in the Journal of the American Medical Association (JAMA) in October 2010.

Probuphine also demonstrated statistical and clinical superiority over placebo for the 24-week treatment period in the mean percentages of urine samples negative for illicit opioids (least square mean of 36% for Probuphine versus 14% for placebo, p < 0.0001). Probuphine treatment resulted in significant improvement in clinician-rated global severity of opioid dependence (p = 0.0003) and clinician-rated global improvement in opioid dependence (p = 0.0002) versus placebo at the end of the 24-week treatment period.

Consistent with the previously reported non-inferiority of Probuphine to Suboxone in the Cumulative Distribution Function of the percentages of urine samples negative for opioids over 24 weeks of treatment, additional data analyses confirm that there were no differences in the mean percentage of negative urine results (36% for Probuphine versus 35% for Suboxone).
There were also no treatment differences observed between Probuphine and Suboxone in clinician-rated global severity (p = 0.7831) and clinician-rated global improvement (p = 0.9881). Probuphine was well tolerated - the majority of adverse events were mild to moderate in severity and unrelated to the study treatment.

“We believe Probuphine represents an important step forward in the treatment of opioid dependence and are looking forward to sharing additional findings with the scientific and clinical community at the ISAM annual meeting next month and at future medical conferences and in peer-reviewed publications. We are also planning to review the program at a pre-NDA meeting with the FDA this fall,” said Katherine L Beebe, PhD, Principal Investigator for the study and executive vice president and chief development officer of Titan. “Another near-term priority is to establish a strategic commercialization partnership and, ultimately, to deliver a safe and effective treatment option for patients with opioid dependence.”

The World Health Organization estimates that between 4.6 and 5.2 million individuals in the US and Europe use illicit opioids such as heroin, and more than 2.0 million individuals in the US alone are addicted to prescription opioid medications. It is estimated that more than 1.0 million people in the US and Europe currently receive pharmacological treatment for opioid addiction.

Probuphine is designed to deliver six months of continuous round-the-clock, long-term therapeutic levels of the drug buprenorphine following a single subcutaneous treatment. Buprenorphine, an approved agent for the treatment of opioid addiction, is currently available mainly in the form of sublingual tablet and film formulations. The safety and effectiveness of treatment with Probuphine has been demonstrated in several late-stage and phase III studies conducted to date, including a 163-patient placebo-controlled study which demonstrated clinically meaningful and statistically significant treatment with Probuphine over a 24-week period and was published in the Journal of the American Medical Association (JAMA) and a confirmatory study of 287 patients that showed statistically significant efficacy versus placebo and non-inferiority with a currently marketed sublingual formulation of buprenorphine.

Probuphine was developed using ProNeura, Titan’s continuous drug delivery system that consists of a small, solid rod made from a mixture of ethylene-vinyl acetate (EVA) and a drug substance. The resulting product is a solid matrix that is placed subcutaneously, normally in the upper arm in a simple office procedure, and is removed in a similar manner at the end of the treatment period. The drug substance is released slowly, at continuous levels, through the process of diffusion. This results in a constant rate of release similar to intravenous administration.