Opioid Market Snapshot: No Pain, No Gain For Abuse-Deterrence Claims

Abuse-deterrent opioids address a serious unmet need and help differentiate brands from the field of generics, but so far Purdue’s OxyContin remains the only opioid on the market with abuse-deterrent claims, even though FDA recently approved two new opioid analgesics.

Abuse deterrence is one way drug manufacturers can make opioid analgesics stand out in the highly genericized and crowded market for pain, but gaining FDA approval for abuse-deterrence claims and demonstrating the value of these products has proven challenging.

Prescription drug abuse is a public health threat that government officials are calling “epidemic,” presenting an opportunity for drug makers who can develop tamper-resistant technologies to thwart drug abuse – while protecting their opioid franchises at the same time.

Industry has been investing heavily to develop abuse-deterrent drugs and technology, but few products have reached the market. Even Pfizer Inc., with its deep pockets, hasn’t been able to get an abuse-deterrent product to market the way it planned after acquiring the pain specialist King Pharmaceuticals Inc. in 2011. Only one drug, Purdue Pharma LP’s reformulated OxyContin (oxycodone controlled release), includes abuse-deterrent claims in labeling. For years, OxyContin was the poster child of opioid drug abuse, but now there are signs the reformulated version has had an impact curbing abuse.

The challenges have been greater than some drug makers anticipated, with the biggest challenge being FDA’s cautious stance on abuse-deterrent opioids. Such products incorporate technologies that make the drug hard harder to crush, snort or dissolve for injection or block the euphoric high from taking the drugs not as directed through aversion techniques.

Given the risk of abuse and the serious consequences, including death, associated with it, there is good reason FDA has been reticent to approve abuse-deterrent labeling claims without clear evidence the drugs work as intended.

FDA offered some encouragement last year when it released a draft guidance on opioid drug development, outlining the types of studies drug makers should conduct if they hope to receive certain abuse-deterrent claims (Also see "FDA’s Opioid Guidance: Industry Celebrates Multi-Tiered Labeling Cake" - Pink Sheet, 14 Jan, 2013.). But there is still plenty to sort out, and FDA so far has approached such reviews on a case-by-case basis. FDA Commissioner Margaret Hamburg defended the agency’s policy of not requiring opioids to have abuse-deterrent properties during a Senate hearing on Capitol Hill March 13, decrying the “poor” quality of abuse-deterrent technology (Also see "Abuse-Deterrent Testimony: Hamburg Defends Opioid Policy On The Hill" - Pink Sheet, 14 Mar, 2014.).

Drug manufacturers aren’t walking away from the potential opportunity, however. Opioids are a mainstay of treatment for patients suffering from post-operative pain, cancer-induced pain and moderate to severe chronic pain. OxyContin generated sales of $2.77 billion in 2012, according to the market research group Frost & Sullivan, and privately held Purdue was able to successfully protect the brand against generic competition last year when FDA ruled not to allow generic oxycodone on the market in favor of the reformulated abuse-deterrent version (Also see "OxyContin’s Abuse-Deterrent Claims Strong, But Stronger Claims Possible" - Pink Sheet, 22 Apr, 2013.).

The case of OxyContin highlights just how valuable an abuse-deterrent formulation can be to protecting an opioid brand, but others have not been as successful. For example, FDA did allow generic versions of Endo International PLC’s Opana ER (oxymorphone) to stay on the market despite the availability of Endo’s reformulated crush-resistant Opana ER (Also see "FDA Crushes Endo’s Hopes, Allows Original Opana Generics To Remain On Market" - Pink Sheet, 10 May, 2013.).

The impact of that decision has weighed on Endo, which saw sales of Opana ER fall 24% to $227.9 million in 2013 as a result of the generic competition. Endo also lost its top-selling Lidoderm (lidocaine) pain patch to generic competition last year, resulting in a complete strategy shift for the specialty pharma, though it still says it remains committed to the space.

New Opioids, But Without Abuse-Deterrent Claims

More recently, FDA approved a new opioid product from Mallinckrodt PLC, Xartemis XR (oxycodone/acetaminophen), but did not approve abuse-deterrent claims in labeling, despite the company’s attempt to get them.

Following the March 11 approval, Xartemis XR will be the first extended-release oral combination of oxycodone and acetaminophen on the market, but it will compete with immediate-release versions of the combination available generically and known by the brand name Percocet and marketed by Endo. Xartemis XR is dosed twice daily while labeling for Percocet recommends dosing every four to six hours.

The Changing Opioid Landscape
Drug Manufacturer/Product	Development Stage	Abuse-Deterrent Status
Purdue OxyContin (oxycodone)	Marketed	Approved with abuse-deterrent claims
Endo Opana ER (oxymorphone)	Marketed	Abuse-deterrent properties but no claims in labeling
Mallinckrodt Xartemis XR (oxycodone/acetaminophen)	Marketed	Abuse-deterrent properties but no claims in labeling
Zogenix Zohydro ER (hydrocodone)	Marketed	No abuse-deterrent properties
Purdue Targiniq ER (oxycodone/ naloxone)	NDA filed	Requesting abuse-deterrent claims
Purdue hydrocodone ER	NDA planned in 2014	Requesting abuse-deterrent claims
Pfizer Remoxy (oxycodone)	Phase III (NDA planned in 2015)	Abuse-deterrent properties
Pfizer ALO-02 (extended-release oxycodone/naltrexone	Phase III (filing status N/A)	Abuse-deterrent aversion properties
Source: “The Pink Sheet” and company filings

Mallinckrodt had been hoping to promote the product’s abuse-deterrent properties as well, which would have been another advantage for the brand competing in a genericized market. The company submitted positive results from a human abuse liability study showing intact and crushed versions of the drug had statistically significantly lower measures of drug liking, drug high and good drug effects than comparable doses of Percocet when measured at the peak drug effect.

Without the abuse-deterrent claims, the case for Xartemis XR will be that much more challenging to make to physicians and payers.

Mallinckrodt Chief Scientific Officer Mario Saltarelli remained upbeat in an interview. “The real innovation here is that this will provide pain patients with their first opportunity to use this particular combination formulation in a twice-daily dosing, which means much longer period of drug availability,” he said. “We believe this provides a completely novel treatment option for physicians and that payers will recognize this.”

The review of Xartemis XR is one of the first times the agency has reviewed a new opioid for abuse-deterrent properties since the agency released its draft guidance last year.

“I think it is really important to understand the whole science of abuse deterrence is one that is being developed as we speak,” said Saltarelli. “We are all, both industry as well as FDA, trying to understand exactly how we can actually utilize data to be able to define abuse deterrence as we go forward.”

The company will continue to study the abuse-deterrence properties of Xartemis XR and collect post-marketing epidemiologic data, he added, with hopes to eventually add the claims to the product’s labeling.

“We do intend to be collecting post-marketing epidemiologic data to understand how our drug is working and whether or not there is any evidence that it is being abused at rate that is different than any other opioids that are out there,” Saltarelli added.

Should FDA Require Abuse Deterrence? Zohydro Sparks Debate

Another new opioid recently hit the market without any abuse-deterrent properties, a fact that could limit the drug’s market potential. The drug is Zohydro ER, a single-entity extended-release hydrocodone and the first drug to launch from Zogenix Inc.The controversial opioid analgesic was approved by FDA last year even though it does not contain any abuse-deterrent properties and an advisory committee voted overwhelmingly against its approval (Also see "FDA Clears Zohydro Single-Entity Hydrocodone Without Abuse Deterrence Properties" - Pink Sheet, 25 Oct, 2013.).

Zohydro was approved with a strict Risk Evaluation and Mitigation Strategy and its use is limited to patients for whom non-opioid analgesics or immediate-release opioids are ineffective or not tolerated. But the issue of the drug’s approval has sparked public debate about whether or not FDA should allow opioids without abuse-deterrent properties on the market at all.

Market Snapshots

This is the latest in a series of snapshots of key therapeutic areas at an intriguing point of regulatory and business development. Other snapshots include:

• (Also see "Market Snapshot: Gram-Negative Antibiotics Progress As Urgency Grows" - Pink Sheet, 3 Mar, 2014.)
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Public health authorities and members of Congress have called for FDA to reverse its decision on Zohydro ER because of concerns about the potential for abuse given that it is a higher dose of pure hydrocodone than what is currently on the market. The public pressure has created a public relations nightmare for Zogenix in the midst of its first commercial launch (Also see "Congress Presses FDA On Zohydro Approval As Product Launch Nears" - Pink Sheet, 13 Feb, 2014.). Zogenix is also in the middle of a congressional investigation into whether some pharma companies paid to attend private meetings with FDA that may have influenced approval decisions (Also see "Opioid “Pay To Play” Investigation Struggling In Congress" - Pink Sheet, 12 Mar, 2014.).

Zogenix just began shipping Zohydro in March and is positioning the drug as the first long-acting, single-agent hydrocodone product on the market (without the addition of acetaminophen). Combination products like Vicodin, which combines hydrocodone with acetaminophen, are available generically. Hydrocodone products are the most commonly prescribed opioid analgesic in the U.S., with nearly 143 million prescriptions for hydrocodone-containing products dispensed in 2012, according to the Drug Enforcement Agency. Last year, FDA recommended combination hydrocodone products be moved to DEA’s more restrictive Schedule II from Schedule III because of growing abuse (Also see "Hydrocodone Reclassification Could Benefit Long-Acting Opioids" - Pink Sheet, 24 Oct, 2013.).

Zogenix could find Zohydro pushed out of the market sooner than it expected, however, if Purdue successfully gets an abuse-deterrent version of the drug to market as it intends to do (Also see "Purdue In The Lead To Bring Abuse-Deterrent Hydrocodone To Market" - Pink Sheet, 12 Mar, 2014.). Purdue announced March 12 that it is planning to file an NDA for an abuse-deterrent extended-release hydrocodone product later in 2014, after announcing positive Phase III data. Purdue’s version of the product was developed using the same abuse-deterrent technology that is found in OxyContin.

Zogenix is developing its own abuse-deterrent formulations of Zohydro ER – two, in fact – but the earliest the company expects one could reach the market is in 2016. If an abuse-deterrent formulation should reach the market, FDA may indeed pull Zohydro from the market. There is no guarantee that is the direction FDA would take, but the agency has shown a willingness to favor abuse-deterrent drugs over those without such properties when data support their use.

For companies like Purdue it is important that FDA take a hardline approach to drugs that don’t contain abuse-deterrent properties to encourage further investment in the space.

Crossing The Data Threshold

Purdue had years of epidemiological data in hand when FDA finally agreed to allow abuse-deterrent claims in labeling for OxyContin. Some studies have suggested the reformulated oxycodone is abused less, like one published in the Journal of Pain in April 2013, which showed lower rates of abuse on eight outcome measures compared to historical data in a surveillance of 140,496 individuals in 357 U.S. treatment centers between June 1, 2009 and March 31, 2012.

“We believe it is important having a series of abuse-deterrent approaches with a variety of opioids so that doctors have choices that they can rotate among drugs if they need to,” said Purdue’s Senior VP-R&D Gary Stiles.

The reformulated OxyContin has been on the market since 2010 and the information was just added to labeling in 2013. The company hopes it will eventually have enough data in hand to convince FDA labeling for OxyContin can carry the fourth and strongest claim allowed under the opioid draft guidance, that a drug has demonstrated reduced abuse in the community.

“Because this is an emerging science, we were prudent in requesting labeling from FDA,” Purdue VP-Regulatory Affairs Todd Baumgartner said in an interview. “We waited until we had a solid two to three years of epidemiological data on OxyContin demonstrating that the concept of abuse deterrence has been proven in the real world.”

FDA has also admitted that the epidemiologic data submitted by Purdue were a big factor in its favorable decision on OxyContin last year. Purdue submitted in vitro, pharmacokinetic, clinical abuse potential and post-marketing data supporting a conclusion that the new formula posed less intranasal abuse, FDA said in a response denying Endo’s citizen petition to block generic versions of Opana ER. Endo did not provide a clinical abuse potential study to evaluate abusers’ ability to snort the reformulation or their preferences.

Like Mallinckrodt, Endo is continuing to collect epidemiological data on Opana ER with the intent of getting FDA to reverse its decision.

Purdue believes its methodical approach to developing abuse-deterrent drugs, beginning with in vitro lab testing and carrying all the way through to post-marketing studies, is the key to unlocking the opportunity for abuse-deterrent opioids. The company is moving to establish a full portfolio of abuse-deterrent opioid drugs.

More Products On The Way

In addition to OxyContin and the hydrocodone product, Purdue filed an NDA for an abuse-deterrent combination of oxycodone and naloxone last year (Also see "Purdue NDA For Oxycodone/Naloxone Combo Tests New FDA Policy" - Pink Sheet, 25 Nov, 2013.). The company is hoping to market it under the brand name Targiniq ER. When the drug is crushed, snorted or injected, naloxone, a mu opioid antagonist, works to block the euphoric effect of opioid abuse and can cause withdrawal symptoms.

“We believe it is important having a series of abuse-deterrent approaches with a variety of opioids so that doctors have choices that they can rotate among drugs if they need to,” said Purdue’s Senior VP-R&D Gary Stiles.

But others want in on the action, with one big name being Pfizer. The big pharma bought into the specialized pain field in 2011 with the $3.6 billion acquisition of King and expected to have a promising rival to OxyContin on the market in the near-term (Also see "Pfizer To Buy King Pharma For $3.6 Billion To Boost Pain Franchise" - Pink Sheet, 18 Oct, 2010.). But the development of King’s abuse-deterrent formulation of oxycodone, Remoxy ultimately was set back years after it was rejected by FDA in 2011 due to manufacturing issues (Also see "Remoxy's "Complete Response" Letter Has No Clear Culprit But Many Suspects" - Pink Sheet, 24 Jun, 2011.).

The product’s future has been uncertain, but in October, Pfizer announced that it has addressed the manufacturing issues and is moving ahead with two clinical trials testing a new formula (Also see "Pfizer’s Remoxy Clears Manufacturing Hurdle, Still Needs BE, Abuse-Potential Studies" - Pink Sheet, 22 Oct, 2013.). The company has initiated a bioequivalence study and an abuse liability study testing the new formula, with plans to resubmit an NDA for Remoxy in 2015. It is good news for Pfizer’s two partners on Remoxy, Pain Therapeutics Inc., which originally developed the product, and Durect Corp., which developed the abuse-deterrent technology.

If Remoxy reaches the market it would go head-to-head against OxyContin and could eat away at that drug’s market-leading market share. Pfizer declined to discuss the Remoxy market opportunity, but the company’s partner, Durect, which stands to receive a royalty on sales, said they see enormous commercial potential.

“I don’t think Pfizer wants to go forward with a product unless the market potential is very significant. It doesn’t move the needle at Pfizer if it is a couple-hundred-million-dollar product,” said Chief Financial Officer Matthew Hogan. “The remaining steps they have to do technically are not that onerous.”

Nonetheless, both drugs face the threat they will have to compete against abuse-deterrent generic versions, which are expected to enter the market in a limited basis in late 2014.

Purdue reached a patent infringement settlement with Allergan PLC in April 2013 that allows the generic drug maker to bring a defined quantity of a generic OxyContin to market effective as of Jan. 1, 2014 if it is able to secure FDA approval, or an authorized generic version in October. FDA has not yet laid out how its guidance on abuse-deterrent opioids applies to generics, but generic drug makers certainly want to get into the market (Also see "Generics Of Abuse-Deterrent Opioids Will Get FDA Guidance, Eventually" - Pink Sheet, 7 Oct, 2013.).

And other new drugs could threaten the opioid category’s hold on the pain market, namely new approaches to treating pain like nerve growth factor inhibitors and other mechanisms that reduce the potential for abuse or eliminate it altogether. Until those drugs materialize as commercial products, opioids are here to stay and abuse-deterrent options offer the best path forward for society and drug manufacturers.