Egalet's Bid For Arymo ER Intranasal Abuse-Deterrence Claim Blocked By MorphaBond Exclusivity

Morphine sulfate extended-release product’s approval with only one of three routes of abuse raises questions about how effectively US FDA’s policies are encouraging development of abuse-deterrent opioid formulations.

The US FDA's approval of Egalet Corp.'s Arymo ER (morphine sulfate extended-release) with deterrence claims for only one of three routes of abuse may raise concerns that the regulator's decision-making on marketing exclusivity and human abuse liability study endpoints could discourage development of abuse-deterrent opioid formulations.

On Jan. 9, FDA approved Arymo ER with a labeling claim for deterrence by the intravenous route of abuse. However, the agency did not approve Egalet's requested deterrence claims for the intranasal and oral routes of abuse, despite advisory committee endorsements of both.

Arymo ER becomes the eighth opioid formulation approved with abuse-deterrent labeling.

On the issue of intranasal abuse deterrence, FDA concluded that three-year Waxman/Hatch marketing exclusivity protecting another morphine sulfate extended-release product, Inspirion Delivery Sciences LLC's MorphaBond, prevents Egalet from getting the claim until October 2018.

In addition, Egalet said, the agency decided against awarding an oral abuse-deterrence claim because a human abuse liability study failed to demonstrate a statistically significant effect on a key secondary endpoint related to the desire to take drug again – an endpoint the agency has increasingly highlighted as important to its assessment of purported abuse-deterrent formulations.

A day after approving Arymo, the agency announced plans for an advisory committee review of safety and abuse issues involving another type of opioid, oxymorphone. (Also see "Endo’s Opana ER, Generic Oxymorphone Safety Get US FDA Panel Review" - Pink Sheet, 10 Jan, 2017.)

MorphaBond's Recent Exclusivity Award

The Arymo approval marks the eighth opioid formulation approved with abuse-deterrent labeling pursuant to an agency guidance document for such products, and the third extended-release morphine product. However, it also reflects the evolving regulatory decision-making in this space and the ongoing challenges that developers of such products face in trying to meet FDA's expectations.

Arymo employs Egalet's Guardian Technology, a polymer matrix tablet technology that uses a novel application of injection molding to manufacture pharmaceutical tablets. The resulting tablets are extremely hard and resistant to particle size reduction. In addition, the product is difficult to draw into a syringe because it becomes a viscous hydrogel on contact with liquid.

In August, an FDA advisory committee voted overwhelmingly for deterrence labeling for the intravenous, intranasal and oral routes of abuse. (Also see "FDA Panel Nod For Egalet Opioid's Deterrence Claims Made Easier By Tablet Hardness" - Pink Sheet, 4 Aug, 2016.)

Background materials for that meeting suggested the agency had the most skepticism about an oral claim. (Also see "Egalet's Arymo ER Opioid Has Questionable Oral Abuse-Deterrent Effect" - Pink Sheet, 2 Aug, 2016.) However, the advisory committee concluded that the hardness of Arymo tablets was enough to justify an oral claim despite questions about the clinical relevance of a human oral abuse liability study.

As has been the case with a number of new drug applications for abuse-deterrent opioid formulations, FDA missed the user fee goal date for Arymo; the approval came almost three months late (Also see "Keeping Track: FDA Rejects Mealtime Insulin, Antihistamine; Misses Goal For Another Opioid" - Pink Sheet, 14 Oct, 2016.).

The exclusivity issue related to the intranasal abuse claim seems to have been unwelcome news that Egalet learned late in the review process.

MorphaBond was approved in October 2015 with claims for abuse deterrence by the intranasal and intravenous routes. The product has not yet launched, although that may soon change.

In October 2016, Inspirion and Daiichi Sankyo Co. Ltd. announced an agreement for the Japanese pharma to commercialize MorphaBond in the US. Daiichi told the Pink Sheet that the MorphaBond launch is anticipated in 2017

In November 2016, FDA granted MorphaBond exclusivity for the intranasal route of abuse, with that marketing protection expiring three years after the product's approval, on Oct. 2, 2018.

A statement posted on FDA's website Jan. 9 said that as the agency reviews new drug applications it "works through various issues that may arise, including exclusivity."

"Due to MorphaBond’s marketing exclusivity, no other single-entity extended-release morphine product … can be approved for that use at this time." – FDA

MorphaBond "has marketing exclusivity for labeling describing the expected reduction of abuse of single-entity extended-release morphine by the intranasal route due to physicochemical properties," FDA said. "Due to MorphaBond’s marketing exclusivity, no other single-entity extended-release morphine product submitted in an abbreviated new drug application or 505(b)(2) application can be approved for that use at this time."

During an investor call to discuss the Arymo approval, Egalet CEO Robert Radie was asked whether the company was surprised by the exclusivity decision.

"We considered it but really couldn't have predicted it based on our assessment of previous exclusivity findings in this class," Radie said. He added that the company's evaluation was further complicated by the fact that the information about MorphaBond's exclusivity for the intranasal claim did not show up in FDA's Orange Book until Nov. 30.

‘Route Of Abuse’ Exclusivity Approach

Kurt Karst, a director at the law firm Hyman, Phelps and McNamara, said that with the MorphaBond exclusivity determination FDA seems to be articulating a "route of abuse exclusivity approach. It seems to be consistent with their overall exclusivity approach." Karst predicted there are likely to be more sponsors like Egalet that see their abuse-deterrence claims for new products blocked by late-announced FDA exclusivity decisions on approved opioid formulations.

Egalet expects that Arymo will receive the intranasal abuse-deterrence labeling after the MorphaBond claim's marketing protection expires in October 2018, Radie said.

MorphaBond's intravenous abuse-deterrence labeling claim did not prevent a similar claim for Arymo because such claims are supported only by in vitro studies. "In vitro studies may not form the basis for eligibility of three-year exclusivity – new clinical studies must be conducted for a drug to be considered eligible for three-year exclusivity," the agency told the Pink Sheet.

"Because the science of abuse deterrence is still evolving and the agency does not yet know which technologies will ultimately prove most effective in deterring opioid abuse, the agency believes that it is in the interest of public health to encourage development of multiple abuse-deterrent alternatives while continuing to promote and protect innovation," FDA said.

However, Radie believes the award of award of marketing exclusivity to MorphaBond was contrary to FDA's April 2015 final guidance on the evaluation and labeling of abuse-deterrent opioid formulations.

"We believe that sponsors should be rewarded for innovation and new clinical data, however we believe this particular finding is inconsistent with the whole concept of incremental improvement that is described in the guidance for this class of products," Radie said. "But we're all learning. Everybody who's in this space is learning, I think, on a regular basis."

Importance Of ‘Take Drug Again’ Endpoint

Those learnings in the abuse-deterrence formulation space would appear to extend to the design of human abuse liability studies to support labeling claims.

Arymo labeling includes favorable oral pharmacokinetic data and results from a human abuse potential study in which Arymo demonstrated a statistically significant reduction in peak effect on the Drug Liking Visual Analog Scale compared to crushed extended-release morphine, the study's primary endpoint.

However, there were no statistically significant differences in mean peak effect between Arymo and comparator on the measures of Take Drug Again and Overall Drug Liking.

In public discussions on abuse-deterrent opioid formulations, FDA review staff have increasingly stressed the importance of the Take Drug Again endpoint as a means for understanding the clinical relevance of other pharmacodynamic and pharmacokinetic parameters.

"Although the results of the oral human abuse potential study showed a difference in the Drug Liking endpoint, there was no statistically significant reduction in the response to Take Drug Again," Arymo ER labeling states. "Therefore, it cannot be concluded that Arymo ER has physical and chemical properties that are expected to reduce abuse via the oral route."

Radie said that with regard to the oral claim, "we'll evaluate … going forward whether or not it makes sense to do any additional work to strengthen that part of the label."

"The agency is quite dug in on the importance of this secondary endpoint of Take Drug Again." – Egalet CEO Radie

The exec was asked whether FDA's emphasis on the Take Drug Again endpoint would make the company rethink how it conducts human abuse liability studies for an abuse-deterrent formulation of extended-release oxycodone currently in Phase III.

"Yes, for sure," Radie replied. "I think that there's a lot of sponsors including Egalet that are trying to figure out what is the path forward to solve this oral abuse-deterrent claim because it is elusive."

"We felt as though we had followed the guidance," Radie said. "We did a maximum manipulation step for our oral study. But the agency is quite dug in on the importance of this secondary endpoint of Take Drug Again, and so we will absolutely evaluate that as we think about how to go forward to see such a claim for EG-002."

Will Fewer Claims Limit Commercial Prospects?

On the investor call, Radie was asked whether having only one labeled abuse-deterrence claim, for the intravenous route, might affect Egalet's ability to compete in the marketplace. In addition to MorphaBond, Pfizer Inc.'s Embeda (morphine sulfate/naltrexone extended-release) has deterrence labeling claims for the intranasal and oral routes of abuse.

"I don't think it changes our commercial strategy at all," Radie said, noting that 98% of the extended-release morphine market currently comprises non-abuse deterrent formulations.

"There's plenty of room for all of these products to help to convert those easily abusable products into non-abusable forms," he said. "I don't believe the market right now is so sophisticated that folks are looking at three claims versus two claims versus just looking at the big picture – recognizing that we have the IV claim, which is the most important for morphine, we have all of the data from our oral studies in the label and we know why the intranasal data is not going to be in there but is published."

Arymo is expected to launch in the first quarter.