Washington Editor

CombinatoRx Inc.'s shares jumped 33.3 percent Tuesday after the company and its U.S. commercialization partner Covidien plc said the FDA had approved Exalgo, a once-daily, extended-release formulation of hydromorphone, for moderate to severe pain in opioid-tolerant patients requiring continuous, around-the-clock opioid analgesia for an extended period of time.

The approval triggered a $40 million milestone payment from Covidien to CombinatoRx under a deal struck last summer.

"These were events where they were happy to find their checkbook," CombinatoRx Chief Financial Officer Justin Renz told BioWorld Today.

Investors Tuesday drove shares of Cambridge, Mass.-based CombinatoRx (NASDAQ:CRXX) up 37 cents, to close at $1.48. Dublin, Ireland-based Covidien's shares (NYSE:COV) also got a slight bump, gaining 76 cents, to close at $50.29.

The approval makes Exalgo the only oral extended-release hydromorphone product available in the U.S., noted Herbert Neuman, chief medical officer for Covidien's pharmaceuticals division.

Stamford, Conn.-based Purdue Pharma LP's extended-release hydromorphone product Palladone was voluntarily removed from the market in July 2005 less than a year after approval because of a high occurrence of unintentional "dose-dumping" - when opioids are accidentally or intentionally crushed or dissolved, resulting in the active ingredient being rapidly released into the bloodstream, often causing a euphoric high. The only other oral hydromorphone available in the U.S. is an immediate-release version, which is sold by Purdue Pharma as Dilaudid.

Exalgo is an "important addition to the armamentarium" for patients with moderate to sever pain not responding to current opioid therapy, Neuman insisted. Its oral osmotic delivery system, known as OROS Push-Pull, is designed to release the hydromorphone at a consistent rate throughout the day, which minimizes the occurrences of breakthrough pain often experienced by chronic opioid users, he explained.

Only prescribers registered with the Drug Enforcement Administration can prescribe Exalgo, a Schedule II controlled substance.

Exalgo was approved with a risk evaluation and mitigation strategy (REMS) program, which includes a patient-friendly medication guide, an education program and elements to assure safe use, Neuman told BioWorld Today.

Exalgo's REMS also includes "safe-use tools" for prescribers, patients and pharmacists to ensure the "right patients" get the drug and at the appropriate dosages, he said.

Neuman noted, however, that Exalgo's REMS is less restrictive than the one Covidien initially had recommended to the FDA, which currently is working on developing a classwide opioid REMS.

Covidien spokesman John Gillespie emphasized that Exalgo's REMS is not considered a temporary or interim program. But when the classwide REMS is issued, Neuman said his company would be "willing and eager" to alter its program, if necessary, "to suit the best practices."

CombinatoRx's Renz noted that the FDA in November had extended its review time of Exalgo by three months after the companies had provided the agency with supplemental information, which the agency determined to be a major amendment to the new drug application (NDA). The "primary focus" of that extension, he said, was REMS-related. "We both felt that it was fair for us to have the three-month extension rather than go any other route," Renz said.

An FDA advisory panel last fall had recommended that Exalgo have a phased marketing rollout, possibly starting with the lowest dosage strengths and targeting specific medical specialties and patient types, such as those with cancer, rather than putting all strengths on the market at once. (See BioWorld Today, Sept. 24, 2009.)

But the FDA approved Exalgo in three strengths: 8 mg, 12 mg and 16 mg, CombinatoRx CEO Mark Corrigan told BioWorld Today. He insisted that Exalgo's approved labeling "gives relatively explicit guidelines with regard to how physicians should dose it," with conversion tables for other existing opioid-based therapies.

The physician pool expected to prescribe Exalgo are "very familiar with opioids," Corrigan maintained.

The drug, which is sold as Jurnista by Johnson & Johnson in several European countries, had a long path to U.S. approval. Knoll Pharmaceuticals, the initial NDA holder, submitted an application in December 1999 for the drug, which then 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.

J&J subsidiary ALZA Corp. later acquired the rights and again changed the drug's name to OROS Hydromorphone HCl. Neuromed Pharmaceuticals Inc., which merged last year with CombinatoRx in an all-stock transaction, obtained the medication in April 2007 from ALZA, and later that year, entered into a special protocol assessment with the FDA to further study the opioid, which the company renamed Exalgo. (See BioWorld Today, July 2, 2009.)

Neuromed in May submitted its revised application to the FDA. "This approval is an excellent testament to the teamwork and all you could ever hope in terms of synergy of a merger, where the administrative capabilities of the former CombinatoRx married the outstanding clinical development capabilities of the former Neuromed," Renz said. "We put together a very complicated merger structure that CombinatoRx was driving, while the former Neuromed team was driving hard on the Exalgo approval process," he added.

Effective with Exalgo's approval, about 38.6 million additional shares of CombinatoRx common stock are outstanding under the merger deal, resulting in the firm having total common shares outstanding of 88.6 million.

In addition to the $40 million payment from Covidien, CombinatoRx is eligible to receive tiered royalties on Exalgo net sales, Corrigan said.

With the expected new pot of funds, "there's going to be an enhanced focus of the organization into the central nervous system space," he said, adding that his company also will be focusing investment on some of its lead clinical assets and "maintaining what is already a very strong discovery research platform.

"We are in that rarefied air of a biotechnology company with important assets and the funding to actually pursue those options with a time frame in which we can really make the investments that will generate shareholder value," Corrigan said.

Published  March 3, 2010