Nancy A. Melville

December 21, 2017

SAN DIEGO, California ― An injectable, subcutaneous form of buprenorphine (CAM2038, Braeburn Pharmaceuticals) demonstrated noninferiority to sublingual buprenorphine tablets for opioid use disorder (OUD) in new research findings.

Results of a randomized phase 3 efficacy and safety trial show that the drug, which can be administered weekly or monthly, may be a second injectable option for improving adherence and reducing misuse of the drug.

"The advantage of this is you get a nice sustained blood level of buprenorphine over the duration of its intended exposure, either weekly or monthly. This potentially eliminates the need for the transmucosal buprenorphine, which a lot of practitioners are always concerned about in terms of diversion potential," said coauthor Michelle Lofwall, MD, of the University of Kentucky in Lexington.

The results were presented here at the American Academy of Addiction Psychiatry (AAAP) 28th Annual Meeting.

Low Adherence Rates

Buprenorphine, an opioid partial agonist, is valued for its ability to reduce illicit opioid use by reducing craving and opioid withdrawal symptoms without the euphoria of opioids. However, adherence rates among patients using the drug are relatively low ― about 50% ― prompting efforts to develop alternative, longer-lasting formulations.

A depot version of buprenorphine, Probuphine (Braeburn), which was approved by the FDA in 2016, is implanted beneath the skin. It provides delivery of buprenorphine for up to 6 months, but weekly or monthly subcutaneous formulations provide greater flexibility in both timing and dosing.

In addition, more frequent dosing regimens make it more likely that patients will adhere to the regular counseling sessions that are required as a condition of buprenorphine treatment. By contrast, the 6-month implant can increase the risk of patients skipping counseling.

The phase 3 double-blind, double-dummy study included 428 treatment-seeking adults with moderate to severe OUD. Participants were randomly allocated to receive either weekly subcutaneous buprenorphine injections for 12 weeks followed by monthly injections for another 12 weeks (n = 213), or daily sublingual tablets of buprenorphine/naloxone for 24 weeks (n = 215).

The study met its primary endpoints of noninferiority to oral buprenorphine with naloxone in terms of the mean proportion of opioid-negative urine samples throughout the study (oral, 28.4%; vs injectable, 35.1%; 95% confidence interval [C], -0.1% to 13.6% for proportional differences; P < .001) and responder rates (oral, 14.4%; vs injectable, 17.8%; 95% CI, -3.5% to 10.4% for proportional differences; P < .001).

Patients were considered to have responded to treatment if they showed no evidence of illicit opioid use.

In addition, the injectable formulation was shown to be superior to the oral formulation in a subanalysis of the measure of the percentage of illicit opioid-negative urine samples with self-report of no illicit opioid use during weeks 5 to 24 of the study (P = .001).

For both groups, the reduction in symptoms of opioid withdrawal and craving and in retention rates was relative high, at about 70%.

There were five overdoses, one intentional and four unintentional, in the oral formulation group and none in the injectable buprenorphine group.

The safety profile of the injectable drug was similar to that of the oral formulation, with the exception of some mild to moderate injection-site adverse events.

Dr Lofwall noted a case that underscores the need for longer-lasting formulations.

"One of the overdoses was in the context of someone being jailed who was not given access to their study medication, so when they left jail, they were in withdrawal and used heroin to treat the withdrawal. I think it's a very resounding example and seems an important rationale for how an injectable product could help us in the field," she said.

Under Review

The US Food and Drug Administration (FDA) is currently conducting a priority review of a new drug application for CAM2038. A decision is expected in January.

If approved, the drug would enter the market alongside Sublocade (Indivior Pharmaceuticals), which, as reported by Medscape Medical News, was approved by the FDA in November as the first once-monthly injectable buprenorphine for moderate to severe opioid use disorder.

Unlike Sublocade, which requires refrigeration, CAM2038 can be stored at room temperature. The product is delivered through a technology called FluidCrystal. It is ready for use in prefilled syringes with safety devices in doses of 8 mg to 32 mg for once-weekly administration and 64 mg to 160 mg for once-monthly injections.

The medication has very low viscosity, so a small, less painful needle can be used.

"The syringe has a very small needle and could be injected in various areas, including the arms, legs, or belly," Dr Lofwall said.

The flexibility of dosing should greatly expand the number of patients who could benefit from buprenorphine treatment, Dr Lofwall told Medscape Medical News.

"This will hopefully be something that is available to all patients, because there are multiple doses and weekly and monthly formulations. So patients who are new to treatment as well as already in treatment would be candidates, as opposed to [the 6-month implant] Probuphine, which is only for patients on a stable dose of 8 mg or less of Suboxone equivalent and doing well," she said.

Addresses Patients' Needs

Elie Aoun, MD, who moderated the session, agreed that the weekly and monthly dosing of CAM2038 could be particularly useful in addressing patients' needs.

"The weekly dosing could be beneficial, for instance, for patients you have concerns about and want to see every week, while the monthly could be good for those with more significant compliance issues," he told Medscape Medical News.

"Even if they are missing appointments, [the clinician] can at least know the patient is still getting the medication," said Dr Aoun, a forensic psychiatry fellow at Columbia University School of Medicine, New York City.

However, he said he had some concerns about longer-term implants.

"We work with a very high-risk population, and giving a medication that may stay in their system for several months at a time is concerning because you need to have regular access to the patient in order to identify signs of stress and risk factors for relapse, such as life events," Dr Aoun said.

His personal preference is to start patients on oral buprenorphine.

"If I'm starting a patient on buprenorphine, I would want my patients to be on the oral medication at least for a while to ensure that they are doing well, are not allergic, and are coming back to my office to allow for the building of a therapeutic rapport with the patient before starting them on an injectable medication. Even if it's not required, I think it would be a good idea," he said.

The Substance Abuse and Mental Health Services Administration estimates that in 2016, approximately 11.6 million adults misused opioids in the United States but that only a small fraction ― 1.1 million ― received medication-assisted therapy (MAT),

The three drugs approved for MAT for opioid addiction ― buprenorphine, methadone, and naltrexone ― have all been shown to be safe and effective. The need for these drugs was recently underscored in the final report of the President's Commission on Combating Drug Addiction and the Opioid Crisis, issued in November.

The study received funding from Braeburn Pharmaceuticals. Dr Lofwall has consulted for Braeburn and Indivior. Dr Aoun has disclosed no relevant financial relationships.

American Academy of Addiction Psychiatry (AAAP) 28th Annual Meeting. Abstract B5, presented December 9, 2017.

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