Braeburn's Buprenorphine Candidate Faces Safety Gauntlet At US FDA Panel
Executive Summary
Unlike its potential competitor Indivior, Braeburn didn't submit a proposed REMS for its subcutaneous opioid abuse treatment, but if approved, both buprenorphine candidates will probably end up with similar risk management restrictions.
Braeburn Pharmaceuticals Inc.'s subcutaneous buprenorphine formulation appears to be in good shape heading into a US FDA advisory panel, although the opioid use disorder (OUD) treatment will likely be subject to similar discussions regarding a Risk Evaluation and Mitigation Strategy (REMS) that Indivior PLCwill face the day before for its own OUD candidate.
FDA's Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee will convene in a joint session Nov. 1 to weigh in on Braeburn's CAM 2038 (buprenorphine injectable), one day after the same panel will discuss Indivior's subcutaneous RBP-6000 (buprenorphine injectable). (Also see "Buprenorphine Injectable Opioid Abuse Treatment: Will REMS Prevent Misuse?" - Pink Sheet, 29 Oct, 2017.)
Unlike Indivior, however, Braeburn did not initially propose a REMS to FDA. The drugmaker instead proposed to voluntarily restrict distribution of the product to healthcare settings for administration only by healthcare providers.
FDA, however, will likely require a REMS for Braeburn's treatment, citing product-specific concerns with CAM 2038 such as the prefilled syringes.
The agency also cited concerns with Braeburn's pivotal trial. The company tested dosages in the Phase III pivotal trial that were lower than those shown to provide a blocking plasma level in the Phase II blockade study.
Although there were no major safety signals, FDA additionally question whether the safety findings would be generalizable to a large population of OUD patients, with small numbers of patients receiving the highest and lowest doses.
Braeburn is specifically seeking approval for CAM 2038 in weekly doses of 8, 16, 24 and 32 mg, and monthly formulations of 64, 96, 128 and 160 mg. FDA says a primary focus of the discussion will be on the dose and formulation-specific safety findings.
Several opioid-dependence treatments on the US market are approved in sublingual formulations, which have been increasingly identified in the illicit drug market, and are known to be abused and misused, FDA says. The agency also noted that sublingual formulations have been implicated in many cases of accidental poisonings in children.
A depot injection "would be difficult to divert or abuse, and would be less likely to be accidentally ingested by children," FDA's Division of Anesthesia, Analgesia and Addiction Products said in briefing documents published Oct. 30 in advance of the meeting.
"In addition, if a depot or implantable product provided a sufficient plasma level of buprenorphine to block the effects of exogenous opioids, the nature of the product would enforce compliance so that patients could not periodically discontinue use in order to allow the blocking effect to dissipate, so that they could in order to experience the effects of their opioids of choice."
If approved, CAM2038 would be the first FDA-backed once-weekly and once-monthly injectable buprenorphine product indicated for OUD.
A Similar REMS
Braeburn initially suggested that since CAM 2038 is an injectable designed to be administered only by healthcare professionals, there should no need for additional training or risk management interventions. FDA, however, asserted that all buprenorphine products indicated for the medication-assistant treatment (MAT) of opioid dependence are approved with a REMS, and that CAM 2038's risk profile differs from that of other buprenorphine products.
FDA specifically pointed to the product's prefilled syringes, which the agency says are "ready to inject and also easier to inject than other formulations." The agency also noted that 50% of subjects in the clinical studies reported history of intravenous drug abuse, and that results of intravenous injection of CAM 2038 were not studied by Braeburn. Adverse events that may result from intravenous injection include embolus and rapid dissolution, resulting in high levels of opioid, FDA says.
The agency laid out a possible REMS for Braeburn's product that resembles that proposed by Indivior for its own subcutaneous buprenorphine candidate. According to the briefing documents, FDA is considering a REMS that limits dispensing of Braeburn's product to certain settings DATA 2000 (Drug Addiction Treatment Act of 2000)-waived prescriber or are Drug Enforcement Administration (DEA) registrants to prevent dispensing directly to the patient for home use, which is consistent with Indivior's proposed REMS.
The agency is additionally considering requiring healthcare settings that include both inpatient and outpatient services and integrated healthcare systems, such as Kaiser Permanente and the Department of Defense to become certified to dispense the treatment if they wish to use it. FDA is also considering this aspect part of a REMS for Indivior's product.
"Although the Applicant endorses a program by which only qualified [healthcare providers] will be administering CAM 2038, there is a risk of accidental exposure of this drug injected intravenously from its intended subcutaneous delivery, should it be obtained outside of a controlled environment,"
"In addition, because buprenorphine is a partial agonist of the μ-opioid receptor, the temptation might exist to for misuse or abuse within the intended-to-treat population of OUD patients."
FDA is asking its advisory panel to weigh in on the proposal.
Are Lower Doses Efficacious?
A second concern of FDA is that the drugmaker tested dosages of CAM 2038 in its Phase III pivotal trial for which it did not evaluate their ability to be an effective blockade to the hydromorphone challenge.
The Phase II blockade study showed that the 32 mg weekly dose "definitively" provided a blockade of exogenous opioids after the first dose, and that the 24 mg and 32 mg weekly doses provided blockade after the second dose. There is no confirmatory support, however, for the weekly doses below 24 mg or for monthly doses that provide lower plasma exposures.
Therefore, it is unclear whether the 8 mg and 16 mg weekly formulations are able to block the effects of exogenous opioids, FDA says.
The agency will ask the advisory panel whether the efficacy data "are sufficient to conclude that the drug is effective for the intended use at all the doses proposed for marketing."
In the Phase III trial, CAM 2038 achieved its primary endpoint of responder rate that was non-inferior versus the Subutex (buprenorphine) comparator. The responder rate included no evidence of illicit opioid use in urine samples obtained at weeks 10, 11, 12 and 13. Braeburn's product also demonstrated superiority for the secondary endpoint of Cumulative Distribution Function (CDF) of the percentage of urine toxicology negative for illicit opioids as confirmed by self-reporting.
CAM 2038 did not, however, achieve superiority for responder rate compared with Subutex.
Generalizing Long-Term Safety
FDA is additionally questioning whether the product's long-term safety profile can be generalized to the larger OUD population, noting that there were particularly small number of patients evaluated in the highest and lowest doses of the drug.
"Therefore, a primary focus of this discussion will be on the dose and formulation-specific safety findings (e.g., injection site reactions) unique to this buprenorphine subcutaneous depot delivery system," the briefing documents state.
There were no serious adverse events related to injection site injury, and the pattern of serious adverse events was consistent known safety profile of buprenorphine, FDA says.
The division, however, noted that it has not yet reviewed a product of this nature before, and questioned whether the site of a syringe "can elicit cravings in patients in recovery" who have a history of intravenous drug abuse.
Enhancing Treatments' Reputation, Access
The advisory committee meeting comes on the heels of FDA Commissioner Scott Gottlieb testifying before the House Energy and Commerce Committee Oct. 25 that the agency would seek to "break the stigma" associated with opioid addiction recovery medications by "taking a more active role in speaking out about the proper use of these drugs." (Also see " Addiction Recovery Medications' 'Stigma' Needs To Be Eliminated, Gottlieb Says" - Pink Sheet, 25 Oct, 2017.)
Accessing medication-assisted treatment has also been difficult for patients in the US. Gottlieb has also called for expanded labelling indications for such treatments to improve coverage, and former Rep. Patrick Kennedy, who serves as a member of the President's Commission on Combating Drug Addiction and the Opioid Crisis, criticized the Centers for Medicare and Medicaid Services (CMS) for its reimbursement policy of these treatments. (Also see "US FDA May Change Opioid Labeling To Limit Dispensing By Indication" - Pink Sheet, 14 Sep, 2017.)