Can KemPharm's Apadaz Meet FDA Opioid Abuse Deterrent Standards?

KemPharm Inc. is mum about what additional actions FDA is requesting to win abuse-deterrent labeling claims for its immediate-release opioid candidate Apadaz (benzhydrocodone/acetaminophen). But since the agency and its advisory panel both found KemPharm's data to be inadequate for an abuse deterrent claim, the company likely will have to conduct further studies.

FDA issued a "complete response" letter regarding its new drug application for Apadaz, and "included in the CRL is guidance that describes all specific deficiencies that the FDA has identified in the application," the company states in a June 13 release. But KemPharm declined to provide information as to what the deficiencies consist of and whether it will have to conduct additional studies to demonstrate abuse deterrence.

KemPharm announced on June 9, the user fee action date, that it filed an amendment to its NDA to provide the agency with additional information. The company said FDA had provided it with a draft label and the additional information it submitted could strengthen the draft, particularly the section relating to abuse-deterrent labeling. KemPharm said it is evaluating the points raised in the letter and will request an End of Review meeting with FDA "to determine the pathway forward for Apadaz."

A complete response letter was expected. At a May 5 meeting, FDA's Anesthetic and Analgesic Drug Products and Drug Safety and Risk Management advisory committee members voted for approval of Apadaz based on its bioequivalence to the reference drug, Allergan PLC's Norco (hydrocodone/acetaminophen). But they voted against approval of abuse deterrent labeling, saying the product offered very incremental steps in deterring abuse (Also see "KemPharm's Opioid Apadaz Will Likely Miss Out On Abuse Deterrence Claim" - Pink Sheet, 5 May, 2016.).

Apadaz consists of benzohydrocodone, a prodrug of hydrocodone, covalently bound to benzoic acid, and acetaminophen. KemPharm says the prodrug imparts abuse-deterrent properties at the molecular level. Benzohydrocodone is designed to remain inactive until it is metabolized into hydrocodone enzymes in the intestinal tract to deliver its pharmacologic effects and therefore crushing and grinding the drug has no impact on its release profile. The approach is different from other opioids formulated with abuse-deterrent technologies, such as physical-chemical barriers, opioid antagonists and aversive agents.

The company has sought to show the drug's ability to deter abuse by snorting and intravenous administration. It says the prodrug is inefficient or delayed for these routes of abuse and therefore does not create the same rewarding effects as other combination products.

KemPharm Cites FDA 'Confusion' About Tampering, Clinical Studies

FDA may be seeking additional data to assess 'drug liking' of Apadaz versus Narco.

During the panel meeting, an FDA reviewer said that in one clinical abuse potential study, insufflation of Norco and Apadaz produced similar maximum drug liking, high, or willingness to take the drug again, and the results were worse than placebo. He said there was a failure of the primary endpoint of maximum effect of drug liking and that subjects were willing, if given the opportunity, to insufflate either Norco or Apadaz.

Sharon Hertz, director of the Division of Anesthesia, Analgesia, and Addiction Products, told the committee that FDA would accept an incremental improvement in abuse deterrence but that there was a difference in interpretation of the Apadaz data between the agency and the sponsor. She stated that the agency weighs willingness to take a drug again in conjunction with other pharmacodynamic measures of drug liking and drug high and that it did not feel Apadaz met the criteria to show this correlation.

In an earnings call a week after the advisory committee meeting, KemPharm CEO Travis Mickle said "there was some confusion, both with the committee and the FDA, related to some of the data on tampering and clinical studies that were done."

"I think there's very reasonable approaches that you can take to help and recalibrate positions around what is a prodrug, how does it work … why isn't tampering relevant or irrelevant, and what is the relevance of the clinical data," Mickle added.

Cowen & Co. analyst Ken Cacciatore pressed for more specifics on the disagreement between KemPharm and FDA. Mickle said he could not go into details but added that there were differences of opinion on some endpoints as far as drug liking over time.

"Here it's just again about clarifications as opposed to a true disagreement between the agency and ourselves," Mickle said. "Many times those can be easily resolved."

Mickle noted that in one study in which super-therapeutic doses were used there was a safety indication with Apadaz that has prompted the company to plan a study looking at respiratory depression and respiratory drive and how it may be affected at the high-dose level. He said the study would be starting shortly.

'No Value' In Moving Ahead Without Abuse-Deterrent Claim

Getting the abuse deterrent label claim is imperative for the company. Asked if KemPharm would still launch the product without this label, Mickle replied that if the label is no different than Norco's "I can tell all the listeners very honestly I see no value in moving that product ahead."

However, he said "if there are potential studies and paths that we think are low risk and can be negotiated with the agency, then that could be certainly tempered, or differentiated at that point."

An analyst also asked Mickle if there were examples of when FDA went against an advisory committee's recommendation that could be comparable to the situation with Apadaz. Mickle cited the case of Zogenix Inc.'s (now Pernix Therapeutics Holdings Inc.'s) opioid Zohydro ER (hydrocodone extended release), which FDA approved despite its lack of abuse deterrent properties over the recommendation of its advisory panel.

"Here you kind of have a similar instance where the panel actually agreed that safety and efficacy were both met, but the abuse deterrent properties weren't what they had seen with other products," Mickle stated.

In fact, FDA's actions on Zohydro were even bolder than Mickle suggests. The initial application didn't include any abuse-deterrent technology, and FDA approved it over the objections of its advisory committee because the agency believed having an acetaminophen-free product offered an important safety option – and because it believed that use of abuse-deterrent technology available at the time would not have a profound impact (Also see "Zohydro Approval Haunts FDA Panelist At Vantrela Meeting" - Pink Sheet, 13 Jun, 2016.).

But FDA's approval of Zohydro was met with a barrage of criticism from members of Congress, state attorneys generals, and consumer groups who called on the agency to retract the approval (Also see "FDA’s Zohydro ER Headache Worsening: States, DOJ Question Approval" - Pink Sheet, 7 Apr, 2014.).

So now, the agency is unlikely to reject an advisory panel's views on an opioid product. In response to criticism for its handling of opioids – and in an effort to get Robert Califf confirmed as Commissioner – FDA issued an opioid action plan in February. One of the cornerstones of the plan is for FDA to obtain guidance from outside experts in the field of pain management and abuse.

FDA's plan also states that the agency will convene an expert advisory committee before approving any new drug application for an opioid that does not have abuse-deterrent properties (Also see "FDA's Opioid Action Plan Could Clear Califf Nomination Roadblock" - Pink Sheet, 4 Feb, 2016.).

The agency has approved six opioid products with abuse-deterrent label claims, all of which are long-acting/extended-release formulations. If approved, Apadaz would be the first immediate-release analgesic with the labeling claim.

According to KemPharm, in 2015, there were approximately 260 million opioid prescriptions, of which about 235 million were for immediate release opioids. Of the IR prescriptions, about 95 million were for hydrocodone/acetaminophen products.

Panels Back Abuse-Deterrent Claims For Two Other Opioids

The agency has been seeking advisory committee input on opioids with abuse deterrent features. Teva Pharmaceutical Industries Ltd.'s long-acting opioid Vantrela ER (hydrocodone extended-release) and Pfizer Inc.'s extended release opioid Troxyca (oxycodone/naltrexone) fared better than Apadaz as the Anesthetic and Analgesic Drug Products and Drug Safety and Risk Management advisory committees recommended approval of both products with abuse-deterrent labeling last week.

For Vantrela, the panels voted 14-3 in support of abuse-deterrent labeling claims for the oral and intranasal routes of abuse and 16-1 for claims related to the intravenous route, though they noted that the formulation represented an incremental improvement in the opioid product class (Also see "Teva's Vantrela Gets FDA Panel Nod For Three Abuse-Deterrent Claims" - Pink Sheet, 7 Jun, 2016.).

In its briefing document for the meeting, FDA had raised doubts about the ability of Vantrela to deter oral abuse based on in vitro data that showed a large amount of the active drug substance could be extracted under certain circumstances. The agency did not raise these concerns at the meeting.

The committees recommended a nasal abuse-deterrent claim for Troxyca by a vote of 11-4 and an intravenous abuse-deterrent claim by a vote of 9-6 but recommended against an oral abuse-deterrent claim by a vote of 9-6. However, some panelists voiced concern about approving the claims without post-market data (Also see "Opioids Need Post-Marketing Data To Inform Abuse-Deterrent Claims, FDA Panel Says" - Pink Sheet, 8 Jun, 2016.).

Vantrela's abuse-deterrent technology consists of three complementary formulation layers designed to release drug substance over a 12-hour period when administered orally as instructed and to retain its extended-release properties when manipulated. Troxyca' s technology releases naltrexone, a mu-opioid receptor that blocks the effects of oxycodone, if the capsule is physically or chemically manipulated.