Intellipharmaceutics International Inc.'s Rexista (oxycodone extended-release) may serve as an early test case for potentially stricter scrutiny from the US FDA – under the leadership of Commissioner Scott Gottlieb – of new abuse-deterrent formulations when the long-acting opioid goes before an advisory committee in late July.
However, even if FDA determines Rexista should be approved with abuse-deterrent labeling, market availability and labeling claims could be delayed for months if not years by patent and exclusivity issues.
FDA's Anesthetic and Analgesic Drug Products committee and Drug Safety and Risk Management panel will jointly convene July 26 to review Intellipharmaceutics' opioid for the management of moderate-to-severe pain when a continuous around-the-clock analgesic is needed for an extended period of time, according to a notice scheduled to publish in the July 3 Federal Register.
Rexista is based on Intellipharmaceutics' proprietary delivery system and is intended as an abuse- and alcohol-deterrent, controlled-release formulation of oxycodone.
The committee will consider the product's overall risk/benefit profile and whether the sponsor has demonstrated abuse-deterrent properties to support labeling language pursuant to a FDA's April 2015 guidance on abuse-deterrent opioids.
Rexista is based on Intellipharmaceutics' proprietary nPODDDS delivery system and is intended as an abuse- and alcohol-deterrent, controlled-release, oral formulation of oxycodone, the company said.
The 505(b)(2) NDA submitted in November includes pharmacokinetic studies intended to demonstrate bioequivalence to Purdue Pharma LP's OxyContin (oxycodone extended-release) and data to support deterrence labeling for the oral, intranasal and intravenous routes of abuse. The user fee goal date is Sept. 25.
Priority Agenda Item For New FDA Head
Rexista is the first opioid to come up for advisory committee review since Gottlieb took the agency's helm in mid-May and began announcing pieces of a still-emerging agenda to address opioid misuse and abuse.
During his confirmation hearings, Gottlieb promised to set the agency on a more activist course to counter the opioid epidemic, including enhanced scrutiny of the abuse liability for new drugs, new nomenclature around abuse-deterrent opioid formulations, and a bigger push for development of non-opioid pain treatments. (Also see "Opioid Policy At US FDA: Gottlieb Seeks More Activist Role To Combat Abuse" - Pink Sheet, 6 Apr, 2017.)
In one of his first actions at the agency, Gottlieb announced the formation of an Opioid Policy Steering Committee and tasked the group with determining whether FDA has the proper policy framework for premarket evaluation of new opioids. (Also see "Opioid Policy At US FDA To Become 'More Forceful,' Gottlieb Says" - Pink Sheet, 23 May, 2017.)
In early June, FDA announced it has requested the market withdrawal of Endo Pharmaceuticals Inc.'s Opana ER (oxymorphone extended-release) due to its intravenous abuse potential. The product's current formulation was aimed at deterring intranasal and intravenous abuse, but FDA repeatedly denied Endo's request for abuse-deterrent labeling. (Also see "Opana ER Should Come Off The US Market, FDA Tells Endo" - Pink Sheet, 8 Jun, 2017.)
FDA's conclusion that Opana ER had a negative risk/benefit profile was in concurrence with the majority of members of the anesthetic/analgesic and drug safety/risk management panels at a March meeting. However, most of the committee members favored stricter labeling and risk management strategies over market withdrawal. (Also see "Opana ER Looking At REMS – Or Worse – After US FDA Panel Weighs Intravenous Abuse Risk" - Pink Sheet, 14 Mar, 2017.)
The Opana review shined a light on the vexing issue of how best to assess the real-world impact of opioid formulations intended to deter abuse. The agency will host a two-day public workshop on this issue in mid-July, two weeks before the Rexista review. (Also see "Postmarketing Studies On Abuse-Deterrent Opioids Could Get New Look" - Pink Sheet, 14 Jun, 2017.)
'Early Warning' Of Abuse
FDA has approved 10 opioids with abuse-deterrent labeling pursuant to the guidance. Whether the agency begins taking a more skeptical view of the evidentiary support for approval of such products under Gottlieb remains to be seen, but the unique aspects of the Rexista formulation are sure to be the focus of close scrutiny by FDA reviewers and advisory committee members alike.
Intellipharmaceutics' formulation is intended to present a significant barrier to tampering when subjected to various forms of physical and chemical manipulation and is designed to prevent dose dumping when inadvertently co-administered with alcohol.
"In addition, when crushed or pulverized and hydrated, the proposed extended-release formulation is designed to coagulate instantaneously and entrap the drug in a viscous hydrogel, which is intended to prevent syringing, injecting and snorting," the company said. "Our Rexista formulation is difficult to abuse through the application of heat or an open flame, making it difficult to inhale the active ingredient from burning."
The formulation contains a blue dye that is emitted once the tablet is tampered with or crushed, which may act as a deterrent to abusers.
In addition, the formulation contains a blue dye that is emitted once the tablet is tampered with or crushed, which may act as a deterrent to a user who attempts to abuse it orally or via the intranasal route. "If approved, Rexista may be the only abuse-deterrent oxycodone product with properties that may provide early warning of drug abuse if the product is manipulated or abused," the company said.
Deterrence labeling claims for the oral, intranasal and intravenous routes of abuse would set Rexista apart from the two other currently approved, long-acting, single-ingredient oxycodone formulations with abuse-deterrent labeling.
Both Purdue's OxyContin and Collegium Pharmaceutical Inc.'s Xtampza ER are labeled for deterrence by the intranasal and intravenous routes of abuse. Collegium has submitted an sNDA for enhanced labeling on deterrence by crushing the formulation; FDA's goal date for the application is estimated to be in August. (Also see "User Fee Goal Dates" - Pink Sheet, 7 Feb, 2017.)
Exclusivity A Potential Obstacle To Deterrence Labeling …
It's possible that FDA could conclude an intranasal abuse deterrence claim for Rexista is temporarily blocked by Xtampza.
In January, FDA determined that an intranasal abuse-deterrence claim for Egalet Corp.'s Arymo(morphine sulfate extended-release) was blocked by three-year Waxman-Hatch exclusivity protecting Inspirion Delivery Sciences LLC's MorphaBond, another morphine product approved with intranasal abuse deterrence labeling. (Also see "Egalet's Bid For Arymo ER Intranasal Abuse-Deterrence Claim Blocked By MorphaBond Exclusivity" - Pink Sheet, 10 Jan, 2017.)
MorphaBond's intravenous claim is not protected by Waxman-Hatch exclusivity because it was not supported by new clinical studies but, rather in vitro data. Consequently, Arymo was approved with an intravenous deterrence claim.
Nevertheless, FDA's adoption of a route-of abuse approach to exclusivity has raised public health concerns that even the agency seems to acknowledge. In March, Egalet announced FDA would allow the company to distribute promotional materials and communications to healthcare professionals about Arymo ER's intranasal abuse-deterrence properties despite the absence of a labeling claim. (Also see "Off-Label Opioid Promotion: US FDA ‘Does Not Object’ To Intranasal Deterrence Data, Egalet Says" - Pink Sheet, 30 Mar, 2017.)
It's possible that FDA could determine the intranasal deterrence claim for Xtampza, which was approved in April 2016, qualifies for three years of exclusivity protection, which could prevent a similar claim for Rexista prior to April 2019.
… While OxyContin Patents Could Block Product Approval
OxyContin added labeling claims for intranasal and intravenous abuse deterrence in April 2013, so any exclusivity that might have attached to those claims would have long expired. However, Purdue's patents on the opioid could block full approval of Rexista until August 2019.
The 30-month stay of approval resulting from the OxyContin patent litigation runs until August 2019.
In April, Purdue sued Intellipharmaceutics for infringement of six OxyContin patents. The litigation has resulted in a 30-month stay of FDA final approval for Rexista that runs until Aug. 24, 2019 "unless the stay is earlier terminated by a final declaration of the courts that the patents are invalid, or are not infringed, or the matter is otherwise settled among the parties," Intellipharmaceutics said.
Patent litigation between Purdue and Collegium also delayed final approval of Xtampza by several months, although Collegium succeeded in getting three OxyContin patents declared invalid by a federal court.