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Facility Inspection a Sticking Point in Impax's Rytary CRL

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By Catherine Shaffer
Staff Writer

The FDA issued a complete response letter to Impax Pharmaceuticals, of Hayward, Calif., a division of Impax Laboratories Inc., for Rytary (IPX066), indicating that a re-inspection of the company's Hayward facility pursuant to a warning letter issued in May 2011 is necessary before the new drug application (NDA) may be approved.

The company had withdrawn the Hayward site from the NDA as an alternative site of commercial production, but the FDA requires resolution of the issues raised in the warning letter due to past involvement of the site in the development of the drug. Impax said it will work with the FDA on next steps for the application.

Impax reported receipt of the FDA warning letter in June 2011. The letter was issued following inspection of the manufacturing facility in Hayward between Dec. 13, 2010, and Jan. 21, 2011. The FDA cited deviations from current good manufacturing practice (cGMP) for finished pharmaceuticals related to sampling and testing of in-process materials and drug products, production record review, and the FDA's investigation of failure of certain batches to meet specifications.

As a result, Impax voluntarily recalled five lots of Fenofibrate capsules (200 mg) and took a number of corrective actions including a thorough review of its manufacturing systems and standards.

The warning letter pertained to the Hayward facility only, and not to any other manufacturing facility. The FDA additionally informed Impax that until remedial action was complete and the FDA confirmed compliance with cGMP, it may withhold approval of pending and new applications listing the Hayward facility as a manufacturing location.

It's clear now that simply promising not to manufacture the Rytary drug material at the compromised Hayward site will not satisfy the FDA, and that Impax will have to work through the re-inspection process before the drug can be approved.

Rytary, previously designated IPX066, is an investigational extended-release capsule formulation of carbidopa-levodopa for idiopathic Parkinson's disease.

Impax and partner GlaxoSmithKline plc reported positive top-line results from the ASCEND-PD Phase III trial of IPX066 compared to carbidopa-levodopa plus entacapone (CLE) in August 2011.

That study was a randomized, double-blind three-treatment, two-week crossover study, one of three Phase III studies that the companies carried out.

Subjects taking a stable dose of CLE transitioned to IPX066 over a six-week period, and then were randomized to IPX066 or CLE for two weeks, then crossed over to the other treatment for another two weeks after a one-week washout with IPX066.

Eighty-four subjects completed the study and were enrolled in a six-month open-label extension study.

The study met its primary endpoint of reducing "off time" during waking hours as measured by patient diary. Off time was defined as the portion of the day during which motor symptoms of Parkinson's return after medication has worn off.

Baseline off time for patients in the study was 5.9 hours, or 36.1 percent. Patients randomized to IPX066 had off time of 3.8 hours (24 percent) compared to 5.2 hours (32.5 percent) for CLE.

That added up to a 33.5 percent decrease in off time for the IPX066 group, compared to a 10 percent decrease for the CLE group.

The IPX066 group experienced somewhat more adverse events, with a rate of 20 percent, than the CLE group, which had an adverse event rate of 14 percent. Two serious treatment-emergent adverse events occurred in the IPX066 group, with none in the CLE group.

The Phase III ADVANCE-PD study compared IPX066 to carbidopa-levodopa in patients with advanced Parkinson's disease who had motor fluctuations. That randomized, double-blind, active-control, parallel-group study evaluated improvements in off time in 393 subjects.

The results showed a 37 percent improvement from baseline for the IPX066 group, and a 17 percent improvement from baseline for carbidopa-levodopa.

The rate of adverse events in the IPX066 group was 43 percent, compared to 40 percent for the carbidopa-levodopa group.

Lastly, the Phase III APEX-PD study assessed change from baseline in the sum of United Parkinson's Disease Rating Scale parts II and III, and met that endpoint as well as secondary endpoints, including clinician global impression of change and patient global impression of change, with no serious adverse events associated with IPX066.

Jefferies analyst Corey Davis wrote, "We've been skeptical on Rytary commercially but most expected approval here so it's a meaningful negative surprise." Davis noted that there is little clarity on what the FDA may require after a successful Hayward re-inspection, leaving the timing of potential Rytary approval ambiguous.

Jefferies lowered its price target for Impax stock to $18.

Cannacord Genuity's Randall Stanicky saw the event as an opportunity to buy on weakness. He lowered Cannacord's price target to $25, noting, "We struggled with whether or not to downgrade the stock, but aren't for two reasons." First, Cannacord expected the stock to open below $20, reflecting investor disappointment with the news, and second, analysts view a near-term warning letter close-out as the largest catalyst and believe the stock will rise closer to $25.

Impax's stock (NASDAQ:IPXL) lost $1.49, to close at $19.53 Tuesday.