Washington Editor

WASHINGTON - Shares of CombinatoRx Inc. plunged 17 percent Tuesday after FDA drug reviewers said Exalgo, a once-daily, extended-release formulation of hydromorphone, may pose a relatively higher risk for abuse and overdose than most other opioids.

Exalgo is being developed by Canadian drugmaker Neuromed Pharmaceuticals Inc., which in June entered an all-stock merger deal with CombinatoRx, expected to close in the fourth quarter. Dublin, Ireland-based Covidien plc, whose shares also dipped slightly Tuesday, acquired the U.S. rights to the drug in June. (See BioWorld Today, July 2, 2009.)

Shares of CombinatoRx (NASDAQ:CRXX) closed at $1.73, a loss of 36 cents, while Covidien's stock (NYSE:COV) fell 40 cents, to close at $40.85.

The FDA's Anesthetic Life Support Drugs and Drug Safety and Risk Management Advisory Committees will examine the new drug application (NDA) for Exalgo at a joint meeting Wednesday in Gaithersburg, Md.

The companies are seeking to sell Exalgo to treat moderate to severe pain in patients requiring an opioid analgesic over an extended period.

Knoll Pharmaceuticals, the initial NDA holder, submitted an application to the FDA in December 1999 for the drug, which previously was called Dilaudid CR, but received an approvable letter due to several deficiencies, including the need for an adequate and well-controlled Phase III trial showing efficacy as a treatment for moderate to severe pain.

Johnson & Johnson subsidiary ALZA Corp. later acquired the rights and again changed the drug's name to OROS Hydromorphone HCl. Neuromed obtained the drug from ALZA in April 2007, and later that year entered into a special protocol assessment with the FDA to further study the opioid, which the company renamed Exalgo.

Neuromed in May submitted a response to the FDA for the drug.

The only hydromorphone available as an oral formulation in the U.S. is immediate-release hydromorphone, which is sold by Stamford, Conn.-based Purdue Pharma LP as Dilaudid.

The FDA in September 2004 had approved Purdue Pharma's extended-release hydromorphone Palladone, but that drug was voluntarily removed from the market in July 2005 because of a high occurrence of "dose-dumping" - when opioids are crushed or dissolved, resulting in the active ingredient being rapidly released into the bloodstream, often causing a euphoric high.

The FDA concluded that in Palladone's case, however, the extended-release mechanism was likely being defeated in many instances unintentionally when users were taking it with alcohol, often resulting in lethal overdoses.

Intentional or not, regulators noted that the human bite force is great enough to crush Exalgo, which could result in the immediate release of the drug's active ingredient, causing an overdose.

Hydromorphone has a higher abuse potential than most other opiate drugs, and extended-release formulations, such as Exalgo, contain several times more opioid in a single dose than immediate-release formulations.

Abuse of Exalgo by an intravenous route, such as when the drug is dissolved in water or another solution and injected, could be deadly, the FDA noted.

"Overall, this product has a high abuse potential and has the same safety concerns observed by other similar extended-release highly potent opioid drug products that are abused and diverted," the agency's drug reviewers said in briefing documents released ahead of Wednesday's advisory meeting.

The FDA wants its advisers to provide recommendations about whether Exalgo's potential for abuse and overdose can be effectively managed.

Specifically, regulators are asking whether an interim risk evaluation and mitigation strategy (REMS) plan should be imposed on Exalgo, pending implementation of the agency's required opioid class REMS program, announced in February. (See BioWorld Today, Feb. 17, 2009, and June 1, 2009.)

The FDA noted that it required a similar interim REMS when it approved King Pharmaceutical Inc.'s long-acting opioid analgesic Embeda (morphine sulfate extended-release sequestered naltrexone hydrochloride) last month.

Regulators also want panelists to consider whether Exalgo's REMS should include a restricted distribution program similar to one imposed by the FDA for BioDelivery Sciences International's and Meda AB's Onsolis (fentanyl buccal soluble film), which requires each patient, prescriber, distributor and pharmacy to enroll in a registry. (See BioWorld Today, July 17, 2009.)

The FDA's panel Thursday will be taking a second look at Purdue Pharma's reformulation of the firm's oral controlled-release oxycodone product OxyContin, which the company designed to be abuse-deterrent.

The overall consensus of the panel at the May 5, 2008, meeting was that the available data were not adequate to evaluate whether the new OxyContin formulation would reduce abuse, misuse or diversion due to the poor quality of the studies performed by Purdue, and said additional testing was needed to support the company's claim of the drug's tamper resistance.

But in briefing documents posted Tuesday, the FDA's drug reviewers said the tamper-resistant properties of the reformulated OxyContin "are limited." However, they added, the tamper-resistant characteristics of the reformulated OxyContin "may provide an advantage" over the currently marketed version.