Endo Pharmaceuticals Inc.'s Belbuca (buprenorphine buccal film) will join a crowded market of extended-release/long-acting opioids with its expected first quarter 2016 launch, but its formulation differences might help it stand out.

On Oct. 23, FDA approved Belbuca, a transmucosal form of the partial mu-opiate receptor agonist buprenorphine, for management of pain severe enough to require daily, around-the clock, long-term opioid treatment and for which alternative treatment options are inadequate.

While there are buccal formulations of immediate-release opioids for breakthrough pain, Belbuca is the only buccal formulation for chronic pain in the extended-release/long-acting (ER/LA) opioid product category, Endo said.

It is the second long-acting form of buprenorphine approved for chronic pain management. Purdue Pharma LP's Butrans (buprenorphine transdermal system) was approved in June 2010 and is labeled for the same indication.

FDA has previously approved transmucosal versions of immediate-release buprenorphine, in combination with naloxone, for maintenance treatment of opioid dependence. These include Indivior PLC's sublingual film Suboxone and BioDelivery Sciences International Inc.'s buccal film Bunavail.

Multiple Dosing Options

Belbuca is expected to launch in the first quarter of 2016 in seven dosage strengths. The multiple dosing options, which range from 75 mcg to 900 mcg every 12 hours, will enable physicians to individualize titration and treatment based on the optimally effective and tolerable dose for each patient, Endo said in a press release.

"Belbuca provides a unique approach for chronic pain management, combining the proven efficacy and established safety of buprenorphine with a novel buccal film delivery system that adds convenience and flexibility," Carolinas Pain Institute Director Richard Rauck said in the same release.

The company has not yet announced the product's wholesale acquisition price. "Endo is working with insurance carriers to ensure that appropriate patients will have access to Belbuca. In addition, we will be offering a copay card to help patients with access," a spokeswoman said.

The company said the 505(b)(2) NDA referenced two Indivior products: injectable Buprenex, covering the molecule buprenorphine, and Subutex, a sublingual tablet formulation for oral administration.

Labeling reflects results from two 12-week, double-blind, randomized, placebo-controlled Phase III trials in opioid-experienced and opioid-naïve patients with moderate-to-severe chronic low back pain. A third trial in patients with low back pain did not show a statistically significant pain reduction with Belbuca compared to placebo, according to labeling.

As with Butrans, Belbuca will be part of the Risk Evaluation and Mitigation Strategy for the ER/LA opioid product class. The shared system REMS was first approved in July 2012 Also see "Opioid Prescriber Knowledge Assessment Due Year After Patient Assessment" - Pink Sheet, 16 July, 2012.. It currently encompasses more than 50 branded and generic products, none of which are buccal formulations.

Belbuca is subject to the same five post-marketing study requirements that FDA imposed across the class in September 2013 Also see "Opioid Post-marketing Studies: Can Sponsors Work Well Together Again?" - Pink Sheet, 16 September, 2013.. Endo is part of the consortium of sponsors conducting these studies, which will satisfy the Belbuca post-marketing requirements.

The agency also is requiring Endo to conduct a multiple ascending-dose clinical trial in adults to determine the maximum tolerated dose of Belbuca without co-administration of naltrexone; this study will inform dosing for a thorough QT trial, which is also required.

In addition, the company must conduct a pharmacokinetic and safety study in patients ages 7-16 years old.

New Formulation, But Not Abuse Deterrent

While Belbuca represents a new formulation, it does not contain the abuse-deterrent properties that FDA has been encouraging opioid product sponsors to develop in light of growing concerns around abuse, misuse and diversion ([A#14150401006]).

The approval, however, is in keeping with FDA's regulatory approach of allowing new formulations to reach market even if they do not contain abuse-deterrent properties.

Although more than two dozen manufacturers have discussed abuse-deterrent product development with the agency, to date there are only five approved opioids with such labeling claims: Purdue Pharma LP’s OxyContin (oxycodone), Targiniq ER (oxycodone/naloxone) and Hysingla ER (hydrocodone), Pfizer Inc.’s Embeda (morphine sulfate/naltrexone hydrochloride) and Inspirion Delivery Technologies' MorphaBond (morphine sulfate). All are ER/LA products.

[Editor's note: This story was updated Oct. 27 to reflect FDA's early-October approval of MorphaBond as the fifth product with abuse-deterrent labeling claims.]

During a September advisory committee review of opioid products with purported abuse-deterrent properties, FDA's external experts recommended approval of Collegium Pharmaceutical Inc.'s Xtampza ER (oxycodone extended-release) but not Purdue's Avridi (oxycodone immediate-release) ([A#00150921012]).

Endo has said it plans to file supplemental data supporting abuse-deterrent claims for its Opana ER (oxymorphone extended-release tablets) in early 2016 ([A#14150810001]).

With regard to Belbuca, Endo noted that buprenorphine is a Schedule III controlled substance, meaning that it has been defined as having lower abuse potential than Schedule II drugs, a category that includes most opioid analgesics.

Approval Triggers Milestone Payment

Belbuca incorporates BioDelivery Sciences' BioErodible MucoAdhesive (BEMA) technology, which the company said allows for high bioavailability of buprenorphine in the bloodstream.

BioDelivery Sciences said the Belbuca approval triggered a $50m milestone payment from Endo pursuant to a 2012 worldwide license and development agreement. [See Deal] Commercial launch may trigger additional milestone payments from Endo if future sales milestones are met, BioDelivery Sciences said, adding that it also may be entitled to receive tiered royalties on net sales that start in the mid-teens.

"Based on current operations and forecasts, BDSI estimates that the $50m milestone payment from Endo, when combined with current cash on hand, provides BDSI with sufficient capital to operate its business to approximately the middle of 2017," said the company.

The company's BEMA drug delivery technology also is incorporated in the buprenorphine/naloxone combination product Bunavail, as well as Onsolis (fentanyl buccal soluble film), a treatment for breakthrough cancer pain.

Onsolis, an immediate-release product, was first approved in 2009 but has had a difficult commercial road and is not currently on the U.S. market.

The drug was formerly partnered with Meda AB, but BioDelivery Sciences reacquired the NDA and North American marketing rights in January 2015. The company recently received FDA approval for a new formulation to address appearance-related changes but said it would not reintroduce the product in the US before 2016 and is exploring partnering opportunities ([A#00150817006]).

Endo's Belbuca Is First Buccal Film In Extended-Release Opioid Class

More from United States

More from North America