Braeburn Pharmaceuticals Announces Probuphine Data Published in the Journal of the American Medical Association

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Study Results Find FDA-approved Six-month Buprenorphine Implant to be Non-inferior to Continued Sublingual Buprenorphine for Maintenance Treatment of Opioid Use Disorder

Braeburn Pharmaceuticals announces that the results of the first comparative trial to evaluate efficacy and safety of a six-month buprenorphine implant relative to sublingual buprenorphine in patients with opioid use disorder were published online today in the Journal of the American Medical Association. The study found that participants who were clinically stable on sublingual buprenorphine maintained stability when transferred to the six-month buprenorphine implant, and that they were more likely to sustain abstinence from illicit opioids throughout the six months than participants who remained on sublingual buprenorphine.

"This study demonstrates the efficacy of the six-month buprenorphine implant, an innovative approach to treating stable patients with opioid use disorder. In the Probuphine implant and sublingual buprenorphine groups, 81/84 (96.4%) and 78/89 (87.6%) of participants, respectively, were responders," said lead author, Richard N. Rosenthal, MD, Center for Addictive Disorders, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, N.Y. "While the trial was designed to assess non-inferiority, the buprenorphine implant was shown to be superior to sublingual buprenorphine based on the responder rate, with a p value of 0.03."

"We are proud that the results of this rigorously-conducted study have been published in such a prestigious medical journal," said Behshad Sheldon, President and CEO of Braeburn Pharmaceuticals. "Opioid use disorder is an underserved chronic disease and we are pleased to have added to the clinical evidence base for the use of medication in the treatment of this deadly disease."

The study showed that Probuphine was non-inferior to sublingual buprenorphine on the primary endpoint of at least 4 of 6 months with no illicit opioid use by drug testing and self-report among opioid-dependent adults previously stabilized on sublingual buprenorphine. Additionally, relative to participants using sublingual buprenorphine, participants maintained on Probuphine were more likely to sustain abstinence from illicit opioids. At 6 months 85.7% of the Probuphine implant group remained abstinent each month relative to 71.9% of the sublingual buprenorphine group (p=0.03).  Non-implant- and implant-related adverse events (AEs) occurred in 48.3% and 23% of the buprenorphine implant group and 52.8% and 13.5% of participants in the sublingual buprenorphine group, respectively.

"This is the first time a population of patients who are stable on buprenorphine have been studied for six months in a double-blind, double-dummy trial, which represents the most rigorous type of clinical studies. It is critical to continue to generate this type of evidence in opioid use disorder," said Frank Vocci, President of Friends Research Institute in Baltimore.

Study Design

This randomized, double-blind, double-dummy, active-controlled, 26-week, multicenter study in clinically stable adults receiving 8 mg or less sublingual buprenorphine evaluated the safety and efficacy of 4 Probuphine implants compared with daily sublingual buprenorphine in 177 patients. The study was conducted at 21 United States office-based buprenorphine outpatient treatment sites. Eligible participants had a primary diagnosis of Opioid Use Disorder; were aged 18 to 65 years; received sublingual buprenorphine as an outpatient at a stable dose of 8 mg or less and showed no evidence of opioid withdrawal or illicit opioid-positive urine samples for at least 90 days prior to study entry.

Study Results

Primary Outcomes
In the buprenorphine implant and sublingual buprenorphine groups, 81/84 (96.4%) and 78/89 (87.6%) of participants, respectively, were responders. The difference was 8.8% (1-sided 97.5% CI, 0.009 to ∞; p <0.001 for non-inferiority; p = 0.03 for superiority) on the primary outcome measure vs sublingual buprenorphine. In a sensitivity analysis for all randomized participants, with all missing urine samples imputed as positive and no illicit opioid use for all 6 months, 70/87 (80.5%) participants receiving buprenorphine implants and 60/90 (66.7%) receiving sublingual buprenorphine were abstinent, resulting in a proportion difference of 13.8% (2-sided 95% CI, −0.266 to −0.010; p = 0.038). Additional sensitivity analyses all demonstrated non-inferiority and were consistent with primary efficacy results. Including an analysis by the FDA, that was based on imputation methods and treatment of supplemental use, they determined that Probuphine satisfied the non-inferiority in an evaluation of the proportion of patients with no evidence of illicit opioid use throughout the 6 month period. Probuphine n=55 (63%) versus sublingual n=57 (64%).

Secondary Outcomes
Relative to sublingual buprenorphine, a larger proportion of participants receiving buprenorphine implants demonstrated no evidence of illicit opioid use throughout 6 months of treatment. At 6 months, cumulative abstinence was 72/84 (85.7%) for buprenorphine implants vs 64/89 (71.9%) for sublingual buprenorphine (hazard ratio [HR] 13.8, 95% CI 0.018–0.258, p = 0.03). This difference became statistically significant starting at month 3 and was sustained throughout month 6. Time to first evidence of illicit opioid use was also significantly longer for buprenorphine implants relative to sublingual buprenorphine (HR 0.49, 95% CI 0.25–0.97, p = 0.04).

Safety

Serious AEs (SAEs) occurred in 5 participants; 3 in the sublingual buprenorphine group (biliary colic, chronic cholecystitis, bronchitis) and 2 in the buprenorphine implant group (convulsions, worsening bipolar I disorder). One buprenorphine implant participant discontinued due to an AE (muscle spasms).

Medication-related and implant-related AEs were consistent with the known safety profile of buprenorphine and the previously published implantation procedure.  Buprenorphine implants were associated with higher incidences of local site AEs vs sublingual buprenorphine. There were no cases of migration of implants beyond the local insertion site.

About Probuphine 

Probuphine is the only six-month treatment for opioid dependence that delivers buprenorphine continuously using Titan Pharmaceuticals' (NASDAQ: TTNP) ProNeura™ technology. Probuphine is placed under the skin of the upper arm during an outpatient office procedure and is removed in a similar manner. Probuphine is not distributed by pharmacies; qualified healthcare providers can register for Probuphine training at www.probuphineREMS.com or by calling 1-866-397-8939. Probuphine is available in all 50 U.S. States; people interested in finding a provider in their area can visit www.probuphinerems.com/probuphine-locator.

Probuphine Indication and Important Safety Information

PROBUPHINE is indicated for the maintenance treatment of opioid dependence in patients who have achieved and sustained prolonged clinical stability on low-to-moderate doses of a transmucosal buprenorphine-containing product (i.e., doses of no more than 8 mg per day of Subutex or Suboxone sublingual tablet or generic equivalent).

PROBUPHINE should be used as part of a complete treatment program to include counseling and psychosocial support.

PROBUPHINE is not appropriate for new entrants to treatment and patients who have not achieved and sustained prolonged clinical stability, while being maintained on buprenorphine 8 mg per day or less of a Subutex or Suboxone sublingual tablet or generic equivalent.

WARNING: IMPLANT MIGRATION, PROTRUSION, EXPULSION and NERVE DAMAGE ASSOCIATED WITH INSERTION and REMOVAL 
Risk Associated with Insertion and Removal 
Insertion and removal of PROBUPHINE are associated with the risk of implant migration, protrusion, expulsion resulting from the procedure. Rare but serious complications including nerve damage and migration resulting in embolism and death may result from improper insertion of drug implants inserted in the upper arm. Additional complications may include local migration, protrusion and expulsion. Incomplete insertions or infections may lead to protrusion or expulsion. Because of the risks associated with insertion and removal, PROBUPHINE is available only through a restricted program called the PROBUPHINE REMS Program. All Healthcare Providers must successfully complete a live training program on the insertion and removal procedures and become certified, prior to performing insertions or prescribing PROBUPHINE implants. Patients must be monitored to ensure that PROBUPHINE is removed by a healthcare provider certified to perform insertions.

Please see additional Important Safety Information in the Package Insert that can be found at probuphine.com or by following this link http://probuphinerems.com/wp-content/uploads/2016/02/final-approved-pi.pdf.

About Opioid Use Disorder and Buprenorphine 

Opioid use disorder is a chronic brain disease and one of the fastest growing public health epidemics in America. In the U.S., 2.5 million people struggle with opioid addiction and, according to the Centers for Disease Control, 78 people die each day from the disease. There is a growing body of evidence that opioid addiction is not a choice or a moral failing, but the result of genetic predisposition combined with environmental factors. Nonetheless, individuals struggling with this disease continue to be stigmatized. Research has also shown that opioid use disorder is best treated with a combination of medication and psychosocial support. The majority of individuals with opioid addiction cannot sustain recovery without long-term outpatient medical treatment.

Buprenorphine is a partial opioid agonist, which may help individuals to stop opioid use without experiencing withdrawal symptoms. Before FDA approval of Probuphine, buprenorphine was only available in oral form which must be taken daily.

About Braeburn Pharmaceuticals

Braeburn Pharmaceuticals, an Apple Tree Partners company, is a pharmaceutical company focused on long-acting therapeutic treatment options that are essential to improving patient outcomes and facilitating recovery in neurological and psychiatric disorders, which are often complicated by stigma and present significant public health challenges. Braeburn's commercial product, Probuphine® (buprenorphine) implant was approved by the FDA in May 2016. Braeburn's investigational product pipeline consists of long-acting implantable and injectable therapies for serious neurological and psychiatric disorders, including opioid addiction, pain, and schizophrenia. Braeburn's pipeline products are at various stages of clinical development and include CAM2038, weekly and monthly subcutaneous injection depot formulations of buprenorphine, being investigated in opioid addiction and pain; a risperidone six-month implant being investigated in schizophrenia; and a novel molecule, ATI-9242, being investigated for treatment of schizophrenia. More information on Braeburn can be found at www.braeburnpharmaceuticals.com.