Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

Developers of the narcotic painkillers cheer FDA’s about-face, which generics tried but failed to stop.

FDA’s new support for tightening the prescribing and dispensing of hydrocodone-containing drugs may have united the agency with advocates combating abuse of the narcotic painkillers—but has divided industry along branded-vs.-generic lines.

Generic drugmakers failed to dissuade FDA from supporting reclassification of hydrocodone combination products like Vicodin from Drug Enforcement Agency (DEA) Schedule III to Schedule II, the stricter standard now covering oxycodone products. Schedule II would halve the length of hydrocodone prescriptions to three months, and require that prescriptions be written by doctors, not nurse practitioners or physician assistants. However, four developers of branded hydrocodone products told GEN reclassification won’t likely reduce their sales or change their drug development programs.

Zogenix won the latest FDA approval for a hydrocodone product October 25, for Zohydro™ ER (hydrocodone bitartrate) extended-release (ER) capsules—the first since the agency retreated from years of resisting reclassification. The first ER, single-entity acetaminophen-free hydrocodone product, Zohydro ER is an opioid agonist indicated for managing pain severe enough to require daily, around-the-clock, long-term opioid treatment, where alternative treatment options are inadequate, using Alkermes’ Spheroidal Oral Drug Absorption System (SODAS®) drug delivery technology.

“As an extended-release opioid, we knew that Zohydro ER was always going to be classified as a DEA Schedule II drug. We support the FDA’s decision,” Zogenix spokeswoman Julie Normart told GEN on Tuesday. “There are several people who suffer from chronic pain who are using immediate-release hydrocodone chronically and Zohydro ER would represent a good alternative for them.”

Zogenix says the stricter classification would better reduce the potential for abusing the drug. The company and FDA agreed on final safety labeling and post-marketing requirements consistent with new rules adopted in September for all ER and long-acting opioid painkillers.

Zogenix didn’t design Zohydro ER with an abuse-deterrent formulation, as FDA required for OxyContin (oxycodone). In January, FDA issued draft guidance requiring abuse-resistant measures for all opioids, but the agency has yet to finalize it or demand all opioids be marketed with them. FDA has also stopped short of demanding abuse resistance in generic versions of oxymorphone product Opana ER (which like OxyContin was also reintroduced with abuse deterrence), as requested by its maker Endo Pharmaceuticals.

While abuse resistance wasn’t available when Elan began developing Zohydro in 2002, five years before Zogenix won U.S. rights, Normart said Zogenix was committed to creating an abuse-resistant version; “efforts are underway.” Normart acknowledged that reclassification of hydrocodone may reduce the overall size of its market, most of which consists of products made by generic drugmakers: “Supporting prescribers in the selection of the appropriate patient and use of the product is the primary focus, not the size of the market.”

Not All Are Happy with Reclassification

But the Generic Pharmaceutical Association (GPhA), which represents 30 drugmakers selling 85% of U.S.-marketed generics, plus makers of hydrocodone-containing analgesic and cough medicines, says reclassification would shrink the market and impose costs on industry that included:

  • Larger vaults and associated security systems to manufacturing, packaging, receipt, storage, and distribution of finished goods.
  • Larger in-store safes and associated security systems.
  • Incremental staff pharmacists to directly manage dispensing and accountability—from paperwork to pill counting—of a significantly higher volume of Schedule II products.

“Significant and costly changes to the facilities and processes for manufacturing, packaging, and distribution of hydrocodone-containing products are required throughout the supply chain to accommodate the volume of product that will now be regulated as a Schedule II product,” David Gaugh, R.Ph., GPhA’s svp for sciences and regulatory affairs, said in January, addressing FDA’s Drug Safety and Risk Management Advisory Committee.

A GPhA spokesperson at deadline had not answered GEN questions on those costs and its current views on reclassification.

GPhA recommended more studies to assess hydrocodone product abuse, a balance of demand- and supply-reducing measures, more education efforts with other stakeholders, and a process and timeline for implementation with wholesalers, retailers, and regulators that assures patients uninterrupted patient access to hydrocodone drugs, Gaugh said.

GPhA acknowledged hydrocodone drug abuse is rising, as FDA noted in reversing its earlier opposition to reclassification. CDC published data in February showing hydrocodone and other opioid analgesics were involved in about three of every four pharmaceutical overdose deaths (16,651 of 22,134). They accounted for about 60% of the 38,329 U.S. drug overdose deaths in 2010—the 11th consecutive annual increase.

DEA has final say over hydrocodone reclassification.

“This action will not change our ability to provide a superior treatment to both doctors and patients that should, ultimately, provide overall cost savings to the healthcare system,” Michael G. McCully of Charleston Laboratories told GEN.

Charleston said Tuesday it completed a Phase III clinical trial midway for its lead compound CL-108, designed to prevent opioid-induced nausea and vomiting. CL-108—developed on the expectation of reclassification—combines 7.5 mg of hydrocodone with 12.5 mg of IR promethazine and 325 mg of acetaminophen.

CL-108 met both efficacy endpoints of its Phase III study, Charleston said, by delivering significant effect on opioid-induced nausea and vomiting (OINV) compared to a commercial product, and significant relief of moderate to severe pain. “We hope to have additional data available on the study in the next 4–6 weeks, which will include several secondary outcome measures,” McCully said.

Abuse-Resistant Painkillers

KemPharm is pursuing a 505(b)(2) NDA for its lead drug candidate KP201 (benzhydrocodone hydrochloride and acetaminophen) for acute, moderate to moderately severe pain. 505(b)(2) NDAs include studies not conducted by or for an applicant, but require full safety and efficacy studies. On Friday, the company said it completed a successful end-of-Phase II meeting with FDA, and can submit a 505(b)(2) in the third quarter of 2014 without any additional efficacy, toxicology or safety data.

KemPharm’s data portfolio includes results of two recently completed pivotal studies. One showed KP201 effectively released and achieved steady-state plasma concentrations of hydrocodone, its active metabolite hydromorphone, and acetaminophen. The other showed bioequivalence; KP201 effectively released hydrocodone, hydromorphone, and acetaminophen into the bloodstream at amounts equivalent to Norco® (hydrocodone bitartrate and acetaminophen).

“We have a number of other bioequivalency studies that have to be concluded,” before KemPharm files an NDA for KP201, Travis C. Mickle, Ph.D., KemPharm’s president and CEO, told GEN.

The next clinical milestone, KemPharm says, is completion of oral and intranasal abuse liability studies in Q1 2014.

KP201 adds a ligand to hydrocodone, using a tech platform based on its Ligand Activated Therapy (LAT) technology, to create an IR drug the company says can reduce abuse potential and opioid-induced constipation—two key features KemPharm is adding as it develops other drugs. The company pipeline includes an ER hydrocodone (KP214) and an IR hydromorphone (KP511), both in preclinical phases.

Until something better comes along, hydrocodone should continue filling the niche within the pain drug segment between oxycodone and codeine.

“We see it as, if every product is now Schedule II, and there’s still this need for these types of products, then better versions like KP201 or abuse-deterrent products will do better in the marketplace. They now have equal footing with the cheaper generic,” Dr. Mickle said.

Dr. Mickle doesn’t see reclassification changing how physicians prescribe hydrocodone products, since most prescriptions are for acute pain.

OxyContin’s developer has an ongoing Phase III study to assess long-term safety of once-daily hydrocodone bitartrate tablets: “This formulation incorporates chemical and physical properties which are intended to make the tablets more difficult to manipulate for the purpose of intentional misuse and abuse by various routes of administration (e.g., snorting and intravenous (iv) injection),” Purdue Pharma spokesman James Heins told GEN.

Signature Therapeutics develops abuse-resistant opioid drugs through its Bio-MD™ platform, inserting abuse resistance into the molecule, changing its structure, then activating the same receptors as standard opioid drugs. While the company has placed priority on ER oxycodone (PF614), Signature’s pipeline includes an ER hydromorphone (PF329) that demonstrated safety, dose proportionality, and a clinically beneficial ER profile in two Phase I studies; and eight preclinical abuse-resistant opioids, three of them hydrocodone products—IR hydromorphone (PFR03321), IR hydrocodone (PF6129), and ER hydrocodone (PFR06176/177).

“We are definitely doing pre-IND work now on PF614. There are a couple of others that we may be able to have in Phase I next year. I think it’s a little bit too early to know for sure,” Wesley D. Sterman, M.D., Signature’s president and CEO, told GEN.

But not early to conclude that barring any new revelation, DEA will reclassify hydrocodone products. GPhA conceded as much by failing to comment on FDA’s action, and by pleading for flexible implementation. The only issue is how to ensure shorter prescriptions don’t lead to even more abuse—an issue FDA could address by finalizing its abuse-resistance guidance, applying it immediately to all new opioids, then over time for current products. The pain of losing lives to opioid abuse is the worst pain of all.

Previous articleJ&J, Two Subsidiaries, to Pay $2.2B in Civil, Criminal Penalties
Next articleGenetic Alliance & PhRMA Partner to Drive Patient-Focused Drug Development