New Drug Application Expected to Be Resubmitted in Second Half of 2015
Princeton, New Jersey — June 8, 2015 — Braeburn Pharmaceuticals, an Apple Tree Partners company, today reported positive topline results from the Phase 3 double-blind, double-dummy clinical study of Probuphine®, the investigational subdermal implant containing buprenorphine HCl for the long-term maintenance treatment of opioid addiction. The study met the pre-specified primary endpoint of non-inferiority, as well as all secondary efficacy endpoints, which were established in consultation with the U.S. Food and Drug Administration (FDA) prior to initiating the study. Braeburn has exclusive commercialization rights to Probuphine in the United States and Canada under a license from Titan Pharmaceuticals, Inc. (OTCQB: TTNP).
The subjects in this Phase 3 study were clinically-stable patients receiving maintenance treatment with a daily sublingual dose of buprenorphine/naloxone of 8mg or less for at least three months prior to entering the trial. The study enrolled 177 subjects who were randomized to receive either the Probuphine implants or sublingual tablets, for a treatment period of six months. Subjects in one group received four Probuphine implants plus daily placebo sublingual tablets. A second group received four placebo implants plus daily sublingual buprenorphine/naloxone tablets (£8mg/day).
The primary objective of the study was to show non-inferiority between the two treatment groups and the primary efficacy analysis was a non-inferiority comparison of the proportion of treatment responders in each group. A responder was defined as having at least four out of six months free of illicit opiates based on urine testing and subject self-report. Analyses were carried out according to the pre-planned Statistical Analysis Plan. Response rates were 96.4% for the Probuphine arm and 87.6% for the sublingual buprenorphine/naloxone arm. The two-sided 95% confidence interval (0.009, 0.167) of the treatment difference (Probuphine - sublingual - buprenorphine/naloxone) was well within the pre-defined successful margin for non-inferiority. The safety and tolerability profiles for each treatment group were also comparable. The implantation procedures were well tolerated and comparable to observations from earlier studies with Probuphine.
"This study marks the first time that a well-controlled opioid treatment study has been conducted in stable patients," said Richard N. Rosenthal, M.D., Professor of Psychiatry and Medical Director of Addiction Psychiatry at the Icahn School of Medicine at Mount Sinai. "The data from this trial are encouraging and underscore the benefit of longer term medical treatments for patients with opioid addiction. I am confident that the implant, if approved by FDA, will be at least as effective as a sublingual formulation and have the added benefits of reducing problems related to compliance, misuse and abuse."
"Today's results bring us one critical step closer to our goal of making long-acting buprenorphine products available to patients," said Behshad Sheldon, President and CEO of Braeburn. "We are grateful to the FDA for providing guidance on the study design and to our investigators for helping execute it. We hope these results pave the way for Probuphine, if approved by FDA, to become a uniquely effective option in addiction treatment, enabling patients to manage their treatment more conveniently and giving doctors confidence that medicine is delivered as intended, without worrying about it getting into the wrong hands or unintentionally harming children."
This clinical study was designed in consultation with the FDA to address a key question in the Complete Response Letter (CRL) issued in April 2013 regarding the clinical benefit of Probuphine. Titan and Braeburn intend to resubmit the New Drug Application (NDA) forProbuphine to the FDA in the second half of this year. The NDA is still considered to be under priority review by the FDA based onProbuphine's potential for decreased abuse, diversion, overdose, and pediatric exposure risk.
Highlights of the trial include:
· There were 177 subjects randomized in the study and 173 subjects were included in the Intent to Treat (ITT) population; 89 in the sublingual buprenorphine/naloxone arm and 84 in the Probuphine arm.
· There were 78 (87.6%) responders in the sublingual buprenorphine/naloxone arm and 81 (96.4%) responders in theProbuphine arm.
· The number of subjects with no evidence of illicit opioid use for all six months based on urine testing was higher in theProbuphine arm (88%) than the sublingual buprenorphine/naloxone arm (72%) (p=0.008).
- A sequential superiority analysis, which was conducted to further evaluate the observed numerical difference between the proportion of responders on the two treatment arms, indicates a statistically significant difference in favor of Probuphine over the sublingual buprenorphine/naloxone treatment arms, (p< 0.05).
- Symptoms of opioid withdrawal and cravings across the six month study were comparable in both treatment arms.
- The overall safety profile was comparable between treatment groups, and the implant insertion and removal procedures were generally well tolerated. A total of 23% of Probuphine treated subjects and 13.5% of subjects in the sublingual buprenorphine/naloxone group had an implant site adverse event, the majority of which were assessed by the clinical investigators as "mild" in severity.
"Abstinence from illicit opioid use is an important measure of successful treatment in this patient population, and the data from this study clearly support the use of Probuphine for maintenance treatment," said Frank Vocci, Ph.D., President, Friends Research Institute, Inc. and Co-Lead Investigator of Braeburn's Phase 3 Probuphine clinical study.
"The development of medications like Probuphine is critical to addressing the tremendous unmet need for new and effective addiction treatment options," said Frank E. Young, M.D., Ph.D., Executive Vice President, Regulatory and Medical Affairs, Braeburn Pharmaceuticals. "Braeburn strongly believes in the potential of Probuphine to offer people living with opioid addiction a unique approach to achieving sustained, long-term recovery. We remain committed to working with the FDA toward the goal of adding Probuphine to the short list of proven medication-assisted treatment (MAT) options."
If approved by the FDA, Probuphine would be the first marketed product to provide maintenance treatment of opioid addiction continuously for six months following a single procedure. Probuphine was developed using Titan's proprietary platform technology, ProNeura™, a non-biodegradable drug delivery implant designed to provide continuous, long- term steady state levels of medication in the blood. It is administered in a short subdermal insertion procedure in a physician's office, and removed similarly at the end of the treatment period.
About the Phase 3 Probuphine Clinical Trial
The study population included 177 clinically stable patients who were receiving maintenance treatment with an FDA-approved sublingual formulation of buprenorphine/naloxone at a daily dose of 8 mg or less. Patients were randomized in a double-blind, double-dummy design to receive either (a) four Probuphine implants and placebo sublingual tablets or (b) to continue with daily sublingual buprenorphine/naloxone therapy and receive four placebo implants. Patient selection criteria restricted the trial to individuals who were previously stabilized on sublingual buprenorphine treatment at doses of 8mg or less, for a period of at least three months.
The efficacy and safety of Probuphine was previously studied in several clinical trials, including two successful, controlled Phase 3 studies in a total of 450 subjects over 24 weeks of treatment (results were published in the Journal of the American Medical Association and Addiction). The double-dummy design and patient selection criteria in this current trial distinguish it from the two earlier Phase 3 studies. In this trial, subjects were receiving buprenorphine treatment at daily doses of 8mg or less for a period of at least three months and considered to be stable patients by their physician, whereas in the first two trials enrolled subjects were de-novo patients who had not received any medication assisted therapy in the prior three months and were inducted at doses of 12-16mg and then treated with Probuphine. The current trial was designed consistent with FDA guidance and based on the results of the first two trials.
About Opioid Addiction
According to recent estimates, there are 2.2 million people with opioid dependence in the U.S. Approximately 20 percent of this population is addicted to illicit opioids, such as heroin, and the other 80 percent to prescription opioids, such as oxycodone, hydrocodone, methadone, hydromorphone and codeine. Before the year 2000, medication-assisted therapies for opioid dependence were available in the U.S. only from a limited number of approved facilities. The Drug Addiction Treatment Act of 2000 (DATA 2000) allowed medical office-based treatment of opioid dependence and greatly expanded patient access to medication-assisted treatments. Sales of buprenorphine drug products for the treatment of opioid addiction in 2014 were approximately $1.75 billion in the United States.
Probuphine is an investigational subdermal implant designed to deliver buprenorphine continuously for six months following a single treatment, and to promote patient compliance and retention. Buprenorphine, which is the active ingredient in multiple FDA-approved drug products for the treatment of opioid dependence, is currently available in tablet and film formulations that require self-administration by patients on a daily basis.
Probuphine was developed using ProNeura™, Titan Pharmaceutical's continuous drug delivery system that consists of a small, solid implant made from a mixture of ethylene-vinyl acetate (EVA) and a drug substance. The resulting construct is a solid matrix that is placed subdermally, normally in the upper arm in an outpatient office procedure, and removed in a similar manner at the end of the treatment period.
The efficacy and safety of Probuphine has previously been studied in several clinical trials, including a 163-patient, placebo-controlled study over a 24-week period (published in the Journal of the American Medical Association (JAMA)), and a follow on study of 287 patients (published in the journal Addiction).
About Braeburn Pharmaceuticals
Braeburn Pharmaceuticals, an Apple Tree Partners company, is a late-stage specialty pharmaceutical company focused on novel, long-acting implantable and injectable therapies for serious neurological and psychiatric disorders, including addiction, pain, and schizophrenia. Long-acting therapeutic treatment options can be essential to improving patient outcomes and facilitating recovery in these conditions, which are often complicated by stigma and present significant public health challenges. Braeburn's investigational product pipeline includes: Probuphine®, a six-month buprenorphine implant for treatment of opioid addiction; CAM2038, weekly and monthly subcutaneous injection depot formulations of buprenorphine for treatment of opioid addiction and pain; a risperidone six-month implant for treatment of schizophrenia; and a novel molecule, ATI-9242, for treatment of schizophrenia. For more information on Braeburn, visit: www.braeburnpharmaceuticals.