Is a fourth complete response letter (CRL) in the works for embattled pain drug Remoxy ER?

Wall Street seemed to think so, sending shares of developer Pain Therapeutics Inc. (NASDAQ:PTIE) down 71.5 percent to close Wednesday at $2.44, the day after a joint meeting of the FDA's Anesthetic and Analgesic Drug Products Advisory Committee and Drug Safety and Risk Management Advisory Committee voted 14-3, recommending against approval of the abuse-deterrent, extended-release, oral formulation of opioid drug oxycodone.

The NDA, seeking approval of Remoxy ER for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate, has a PDUFA date of Aug. 7. While recommendations of advisory committees are not binding, the agency generally follows their advice, which could be bad news for a product that has already encountered a number of regulatory roadblocks due in part to the FDA's evolving guidance for abuse-deterrent opioids.

Its first CRL came in 2008, with the agency stating that additional nonclinical data were needed. A 2011 CRL raised concerns related to chemistry, manufacturing and controls, including inconsistent release performance of certain drug lots during in vitro testing. By the time the agency reviewed Remoxy ER a third time, in 2016, the opioid crisis headlines had made the agency reluctant to grant approval to any opioid product without sufficient data to prove abuse deterrence. In 2017, the agency released guidance for abuse-deterrent opioid products. (See BioWorld Today, June 27, 2011, and Sept. 27, 2016.)

For its part, Pain has maintained its studies were "extensive," including lab, pharmacokinetic and human abuse potential studies, including an abuse potential study via the intranasal route and a nonclinical abuse trial using household solvents. And, in December, the Austin, Texas-based firm reported a positive meeting with the FDA. A resubmission under the 505(b)(2) pathway followed in February. (See BioWorld Today, March 22, 2017.)

A gel capsule formulated using Durect Corp.'s technology, Remoxy ER is described as having a "thick, sticky, high viscosity, hydrophobic gel formation" designed to prevent users from cutting, grating or dividing into smaller pieces. It also is designed to resist "syringe-ability, injection and rapid extraction in ingestible solvents." Pain's latest application seeks marketing approval with a deterrence label against injection, snorting and inhalation/smoking routes of abuse.

In its briefing documents ahead of the advisory meeting, FDA reviewers listed 10 currently approved long-acting opioid analgesics labeled with abuse-deterrent properties: Oxycontin (oxycodone extended-release tablets, Purdue Pharma LP), Targiniq (oxycodone and naloxone extended-release tablets, Purdue Pharma LP), Embeda (morphine sulfate and naltrexone extended-release capsules, Pfizer Inc.), Hysingla ER (hydrocodone extended-release tablets, Purdue Pharma LP), Morphabond (morphine sulfate extended-release tablets, Daiichi Sankyo Co. Ltd.), Xtampza ER (oxycodone extended-release capsules, Collegium Pharmaceuticals Inc.), Troxyca ER (oxycodone and naltrexone extended-release capsules, Pfizer Inc.), Arymo ER (morphine sulfate extended-release tablets, Egalet Corp.) and Vantrela ER (hydrocodone extended-release tablets, Teva Pharmaceutical Co. Ltd.). One immediate-release product is available, Roxybond (oxycodone HCl immediate-release tablets, Inspirion Delivery Sciences LLC).

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