Braeburn Announces Publication of a Post Hoc Analysis of Data from Patients Using Fentanyl Treated with BRIXADI in a Phase 3 Efficacy and Safety Study

PLYMOUTH MEETING, Pa., June 25, 2024 /PRNewswire/ -- Braeburn Inc. announces the publication of a post hoc analysis in the Journal of the American Medical Association (JAMA) Network Open. The analysis evaluated data in patients with evidence of fentanyl use from the Phase 3 Clinical Efficacy and Safety trial comparing BRIXADI (buprenorphine) extended-release injection for subcutaneous use (CIII) to daily sublingual buprenorphine/naloxone (SL BPN/NX) in patients with moderate to severe opioid use disorder (OUD).

"Fentanyl is a primary driver of the continued growth of the opioid epidemic. The findings support prior observational studies that buprenorphine is effective against fentanyl, and is consistent with evidence from the BRIXADI Phase 3 Study," said Edward V. Nunes, M.D., Professor of Psychiatry, Columbia University Irving Medical Center Department of Psychiatry. "Further research is needed to assess the efficacy of medications for OUD in the current landscape."

The Phase 3, 24-week, randomized, double-blind, double-dummy active-controlled, multicenter, study was conducted at 35 US outpatient clinical centers. The post hoc analysis included a subgroup of 123 participants (BRIXADI, n=64; SL BPN/NX, n=59) who had evidence of baseline fentanyl use. The Phase 3 trial was designed to include participants characteristic of the patient population with moderate to severe OUD. 

Key highlights of the Post Hoc Analysis: 

• Assessments in this analysis included urine toxicology for illicit opioid use including fentanyl, Clinical Opiate Withdrawal Scale (COWS), Subjective Opiate Withdrawal Scale (SOWS), Visual Analog Scale (VAS), and adverse events (AEs).
• In the fentanyl-positive subgroup, the mean percentage of urine samples negative for fentanyl during the study was 74.6% for the BRIXADI arm versus 61.9% for SL BPN/NX. 
• In the fentanyl-positive subgroup, the mean percentage of urine samples negative for opioids was 28.5% for the BRIXADI arm versus 18.8% for SL BPN/NX. Similarly, in the fentanyl-negative subgroup, the mean percentage of urine samples negative for opioids was 36.7% for BRIXADI versus 30.6% in the SL BPN/NX arm. 
• No substantial variance was observed in rates of study completion between fentanyl-positive and fentanyl-negative subgroups (60.2% and 56.7%, respectively). 
• With the exception of injection-site AEs such as swelling, inflammation, and induration, the observed AEs from this analysis were consistent with the known safety profile of BPN. Three nonfatal heroin overdoses were reported overall: one in the fentanyl-negative subgroup and two in the fentanyl-positive subgroup, all occurred in patients receiving SL BPN/NX. 
• Limitations of the post hoc analysis include that patients were primarily using heroin mixed with fentanyl. The analysis was not prespecified and the parent trial was not designed to assess the differences in treatment response between the subgroups. Differences in outcomes could be related to overall disease severity rather than fentanyl use.

"This is the first study that evaluated data from patients testing positive for fentanyl at baseline in a phase 3 trial comparing the safety and effectiveness of long-acting buprenorphine to SL BPN/NX for the treatment of OUD," remarked Natalie R. Budilovsky-Kelley, PharmD, Senior Director, Medical Affairs at Braeburn. "These findings provide additional information regarding treatment of patients with OUD who are using fentanyl."¹

The full publication "Extended-Release Injection vs Sublingual Buprenorphine for Opioid Use Disorder with Fentanyl Use" is available online at JAMA Network Open today.

"We are grateful to partner with researchers that share our unwavering commitment to those impacted by OUD to address this urgent public health crisis," remarked Joshua M. Cohen, MD, MPH, FAHS, Chief Medical Officer at Braeburn. "Braeburn remains committed to furthering the scientific understanding of the treatment of OUD."

About the Phase 3 Trial
The data were collected during a 24-week, randomized, double-blind trial (NCT02651584) conducted from December 2015 to November 2016 across 35 outpatient sites in the United States. Patients were randomized to daily SL placebo alongside BRIXADI weekly (first 12 weeks; Phase 1) and BRIXADI monthly (last 12 weeks; Phase 2); or to daily SL BPN/NX (24 weeks) with matched weekly and monthly subcutaneous placebo injections (SL-BPN/NX group). Of the 428 patients included in the study, more than 28% had evidence of fentanyl use at baseline.

About BRIXADI®
INDICATIONS AND USAGE
BRIXADI is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine. 

BRIXADI should be used as part of a complete treatment plan that includes counseling and psychosocial support. 

IMPORTANT SAFETY INFORMATION 

BRIXADI (buprenorphine) extended-release injection (weekly, 50 mg/mL buprenorphine) and BRIXADI (monthly, 356 mg/mL buprenorphine) are different formulations. Doses of BRIXADI (weekly) cannot be combined to yield an equivalent monthly dose. 

BRIXADI is contraindicated in patients with hypersensitivity (e.g. anaphylactic shock) to buprenorphine or any other ingredients in the solution for injection.

WARNINGS AND PRECAUTIONS
Addiction, Abuse, and Misuse: BRIXADI contains buprenorphine, a Schedule III controlled substance that can be abused in a manner similar to other opioids. Buprenorphine is sought by people with opioid use disorder and is subject to criminal diversion. Monitor all patients for progression of opioid dependence and addictive behaviors. 

Respiratory and CNS Depression: Buprenorphine has been associated with life-threatening respiratory depression and death. Use BRIXADI with caution in patients with compromised respiratory function. Due to its extended-release characteristics, if BRIXADI is discontinued as a result of compromised respiratory function, monitor patients for ongoing buprenorphine effects for approximately 1 month for BRIXADI (weekly) and for approximately 4 months for BRIXADI (monthly). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose: Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with BRIXADI. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone, and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered. 

Concomitant Use of Benzodiazepines or other CNS Depressants: Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increase the risk of adverse reactions including respiratory depression, overdose and death. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient's buprenorphine treatment and coordinate care to minimize the risk associated with concomitant use. Inform patients and caregivers that potentially fatal additive effects may occur if BRIXADI is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider.

Neonatal Opioid Withdrawal Syndrome, Pregnancy, and Lactation: Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare providers should observe newborns for signs of NOWS and manage accordingly. Advise pregnant women receiving opioid addiction treatment with BRIXADI of the risk of neonatal opioid withdrawal syndrome. Warn patients that buprenorphine passes into breast milk. Advise the nursing mother taking buprenorphine to monitor the infant for increased drowsiness and breathing difficulties. 

Adrenal Insufficiency: If adrenal insufficiency is diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. 

Risk of Opioid Withdrawal with Abrupt Discontinuation: Patients who elect to discontinue BRIXADI treatment should be monitored for withdrawal signs and symptoms with consideration given to the product's extended-release characteristics. 

Risk of Hepatitis, Hepatic Events, and Use in Patients with Impaired Hepatic Function: Liver function tests should be performed on all patients prior to initiation, during treatment, and if a hepatic event is suspected. Because buprenorphine levels cannot be rapidly decreased, patients with pre–existing moderate to severe hepatic impairment are not candidates for treatment with BRIXADI. Patients who develop moderate to severe hepatic impairment while being treated with BRIXADI should be monitored for signs and symptoms of toxicity or overdose of buprenorphine and may require a dose adjustment.

Hypersensitivity Reactions: Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported in patients receiving buprenorphine-containing products. The most common signs and symptoms include rashes, hives, and pruritus. The BRIXADI needle cap is synthetically derived from natural rubber latex which may cause allergic reactions in latex-sensitive individuals. 

Precipitation of Opioid Withdrawal in Patients Dependent on Full Opioid Agonists: BRIXADI injection may precipitate opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists such as heroin, morphine, or methadone before the effects of the full opioid agonist have subsided. In patients who are new entrants to treatment, to avoid precipitating an opioid withdrawal syndrome, administer a 4 mg test dose of transmucosal buprenorphine when objective signs of mild to moderate withdrawal appear and monitor for precipitated withdrawal before injecting BRIXADI. 

Risks Associated with Treatment of Emergent Acute Pain:  While on BRIXADI, situations may arise where patients need acute pain management, or may require anesthesia. Treat patients receiving BRIXADI with non-opioid analgesic whenever possible. Patients requiring opioid therapy for analgesia may be treated with a high-affinity full opioid analgesic under the supervision of a healthcare provider, with particular attention to respiratory function. Higher doses may be required for analgesic effect. Therefore, a higher potential for toxicity exists with opioid administration. Advise patients of the importance of instructing their family members, in the event of emergency, to inform the treating healthcare provider or emergency room staff that the patient is being treated with BRIXADI. 

Use in Opioid Naïve Patients: There have been reported deaths of opioid naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet. BRIXADI is not appropriate for use in opioid naïve patients.

Patients at Risk for Arrhythmia: Thorough QT studies with buprenorphine products have demonstrated QT prolongation ≤ 15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT-prolonging agents is not known. 

Impairment of Ability to Drive and Operate Machinery: BRIXADI may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. Caution patients about driving or operating hazardous machinery until they are reasonably certain that BRIXADI does not adversely affect their ability to engage in such activities.

Orthostatic Hypotension: Buprenorphine may produce orthostatic hypotension in ambulatory patients.

Elevation of Cerebrospinal Fluid Pressure: Buprenorphine may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. 

Elevation of Intracholedochal Pressure: Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.

Effects in Acute Abdominal Conditions: Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Unintentional Pediatric Exposure: Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it.

ADVERSE REACTIONS
Adverse reactions commonly associated with BRIXADI administration (in ≥5% of patients) were injection site pain, headache, constipation, nausea, injection site erythema, injection site pruritus, insomnia, and urinary tract infection.

To report SUSPECTED ADVERSE REACTIONS, contact Braeburn at 1-833-274-9234 or FDA at 1-800-FDA1088 or www.fda.gov/medwatch. 

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING, and MEDICATION GUIDE. 

About Braeburn
Braeburn is dedicated to delivering solutions for people living with the serious consequences of opioid use disorder. At Braeburn, we challenge the status quo and champion transformation of the management of opioid use disorder (OUD) by partnering with the community to create a world where every person with OUD gets the best possible care and opportunity to reach their full potential. Visit https://braeburnrx.com to learn more. Connect with Braeburn on LinkedIn at https://linkedin.com/company/Braeburn.

1. Lofwall MR, Walsh SL, Nunes EV, et al. Weekly and Monthly Subcutaneous Buprenorphine Depot Formulations vs Daily Sublingual Buprenorphine With Naloxone for Treatment of Opioid Use Disorder: A Randomized Clinical Trial. JAMA Intern Med. 2018;178(6):764–773. doi:10.1001/jamainternmed.2018.1052. 

For additional information, please contact: 
Sabrina Romano: [email protected]

SOURCE Braeburn